FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dimyan, MA Cohen, LG AF Dimyan, Michael A. Cohen, Leonardo G. TI Contribution of Transcranial Magnetic Stimulation to the Understanding of Functional Recovery Mechanisms After Stroke SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Review DE stroke; TMS; tDCS; motor cortex; rehabilitation ID HUMAN MOTOR CORTEX; INDUCED MOVEMENT THERAPY; HUMAN CEREBRAL-CORTEX; TIME FOLLOWING STROKE; UNAFFECTED HEMISPHERE; INTERHEMISPHERIC INHIBITION; CORTICOSPINAL EXCITABILITY; SOMATOSENSORY STIMULATION; CORTICAL EXCITABILITY; NEUROTROPHIC FACTOR AB Motor impairments are a major cause of morbidity and disability after stroke. This article reviews evidence obtained using transcranial magnetic stimulation (TMS) that provides new insight into mechanisms of impaired motor control and disability. They briefly discuss the use of TMS in the diagnosis, prognosis, and therapy of poststroke motor disability. Particular emphasis is placed on TMS as a tool to explore mechanisms of neuroplasticity during spontaneous and treatment-induced recovery of motor function to develop more rational and clinically useful interventions for stroke rehabilitation. C1 [Dimyan, Michael A.; Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Dimyan, MA (reprint author), 10 Ctr Dr MSC1428,Bldg 10,Rm 7D50, Bethesda, MD 20892 USA. EM michaeladimyan@gmail.com RI Dimyan, Michael/B-1715-2012; OI Dimyan, Michael/0000-0002-9715-9741 FU NINDS Intramural Competitive Postdoctoral Fellowship; NINDS Intramural Research Program, NIH FX Michael A. Dimyan is supported by an NINDS Intramural Competitive Postdoctoral Fellowship. This work was supported by the NINDS Intramural Research Program, NIH. NR 159 TC 51 Z9 54 U1 0 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD FEB PY 2010 VL 24 IS 2 BP 125 EP 135 DI 10.1177/1545968309345270 PG 11 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 549BJ UT WOS:000274015500002 PM 19767591 ER PT J AU Macbeth, AH Luine, VN AF Macbeth, Abbe H. Luine, Victoria N. TI Changes in anxiety and cognition due to reproductive experience: A review of data from rodent and human mothers SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Pregnancy; Cognition; Anxiety; Memory; Postpartum; Neurochemistry ID PITUITARY-ADRENAL AXIS; DENDRITIC SPINE DENSITY; EARLY POSTPARTUM PERIOD; VIRGIN FEMALE RATS; CORTICOTROPIN-RELEASING HORMONE; HIPPOCAMPAL CELL-PROLIFERATION; OBSESSIVE-COMPULSIVE DISORDER; AFFECTS SPATIAL REFERENCE; NEUROTROPHIC FACTOR BDNF; AGE-RELATED-CHANGES AB Rodent research suggests that pregnancy, motherhood and attendant offspring care affect changes in neural function and behaviors that are not directly maternal in nature, but involve cognition, affect, and responses to stress. Thus, female rats having had one pregnancy and bout of rearing (primiparous), or multiple pregnancies and bouts of rearing (multiparous), generally show greater resilience to stress, decreased anxiety, and better memory abilities than female rats that have never experienced motherhood (virgin or nulliparous). Moreover, some studies show that these neural changes remain long after the last pregnancy, persisting even into old age. In the current review, we will begin by discussing these behavioral and neural changes in rodents and provide some information concerning their possible mechanisms. Then we will review data from studies examining anxiety and cognition in postpartum human mothers. While this data is less conclusive than that from non-human animals, it appears that reproductive experience may confer some beneficial changes to human mothers in terms of lowering the anxiety/stress response and enhancing certain aspects of memory. Published by Elsevier Ltd. C1 [Macbeth, Abbe H.] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. [Luine, Victoria N.] CUNY, Hunter Coll, Dept Psychol, New York, NY 10065 USA. RP Macbeth, AH (reprint author), NIMH, Sect Neural Gene Express, NIH, DHHS, 9000 Rockville Pike,Bldg 49 5A51, Bethesda, MD 20892 USA. EM macbetha@mail.nih.gov NR 191 TC 59 Z9 59 U1 2 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD FEB PY 2010 VL 34 IS 3 BP 452 EP 467 DI 10.1016/j.neubiorev.2009.08.011 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 557NC UT WOS:000274675000010 PM 19761791 ER PT J AU Collins, CC Epstein, DH Parzynski, CS Zimmerman, D Moolchan, ET Heishman, SJ AF Collins, Charles C. Epstein, David H. Parzynski, Craig S. Zimmerman, Debra Moolchan, Eric T. Heishman, Stephen J. TI Puffing behavior during the smoking of a single cigarette in tobacco-dependent adolescents SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID NICOTINE CIGARETTES; TOPOGRAPHY; SMOKERS; EXPOSURE AB Introduction: Adult and adolescent smokers regulate their nicotine and smoke intake by smoking low-yield cigarettes more intensely than high-yield cigarettes. One likely mechanism of nicotine regulation is altered puffing topography, which has been demonstrated in adult smokers. The purpose of this study was to examine the pattern of puffing behavior during the smoking of a single cigarette in adolescents. Methods: Tobacco-dependent adolescents (n = 89) were enrolled in a treatment trial testing the efficacy of nicotine replacement therapy. About 1 week before their quit date, participants smoked ad libitum one of their usual brand of cigarettes during a laboratory session. Smoking topography measures included puff volume, puff duration, puff velocity, and interpuff interval. Results: Controlling for sex, race, and number of puffs, puff volume and puff duration decreased 12.8% and 24.5%, respectively, from the first 3 to the last 3 puffs. Puff velocity and interpuff interval increased 14.8% and 13.5%, respectively. Puff volume was positively correlated with puff duration and puff velocity, whereas puff duration and puff velocity were negatively correlated. However, none of the topography measures were correlated with smoking history variables. Discussion: These results suggest that adolescent smokers, like adults, are able to regulate smoke and nicotine intake on a puff-by-puff basis, therefore indicating that this aspect of smoking control is acquired early in the tobacco-dependence process. C1 [Collins, Charles C.; Parzynski, Craig S.; Moolchan, Eric T.; Heishman, Stephen J.] NIDA, Nicotine Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Epstein, David H.] NIDA, Treatment Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zimmerman, Debra] NIDA, Off Clin Director, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Heishman, SJ (reprint author), NIDA, Nicotine Psychopharmacol Sect, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM heishman@nih.gov FU National Institutes of Health; National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. NR 20 TC 19 Z9 19 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2010 VL 12 IS 2 BP 164 EP 167 DI 10.1093/ntr/ntp176 PG 4 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 553CQ UT WOS:000274342900011 PM 19969556 ER PT J AU Landon, MB Spong, CY Thom, E Carpenter, MW Ramin, SM Casey, B Wapner, RJ Varner, MW Rouse, DJ Thorp, JM Sciscione, A Catalano, P Harper, M Saade, G Lain, KY Sorokin, Y Peaceman, AM Tolosa, JE Anderson, GB AF Landon, Mark B. Spong, Catherine Y. Thom, Elizabeth Carpenter, Marshall W. Ramin, Susan M. Casey, Brian Wapner, Ronald J. Varner, Michael W. Rouse, Dwight J. Thorp, John M., Jr. Sciscione, Anthony Catalano, Patrick Harper, Margaret Saade, George Lain, Kristine Y. Sorokin, Yoram Peaceman, Alan M. Tolosa, Jorge E. Anderson, Garland B. CA Eunice Kennedy Shriver Natl Inst C TI A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Landon, Mark B.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Brown Univ, Dept Obstet, Providence, RI 02912 USA. Brown Univ, Dept Gynecol, Providence, RI 02912 USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Landon, MB (reprint author), Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD FEB PY 2010 VL 65 IS 2 BP 69 EP 70 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 552SZ UT WOS:000274315100001 ER PT J AU Mahabadi, V Amory, JK Swerdloff, RS Bremner, WJ Page, ST Sitruk-Ware, R Christensen, PD Kumar, N Tsong, YY Blithe, D Wang, C AF Mahabadi, Vahid Amory, John K. Swerdloff, Ronald S. Bremner, William J. Page, Stephanie T. Sitruk-Ware, Regine Christensen, Peter D. Kumar, Narender Tsong, Yun-Yen Blithe, Diana Wang, Christina TI Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Mahabadi, Vahid] Harbor UCLA Med Ctr, Div Endocrinol, Dept Med, Torrance, CA 90509 USA. Los Angeles Biomed Res Inst, Torrance, CA USA. Univ Washington, Dept Med, Seattle, WA USA. Populat Council, Ctr Biomed Res, New York, NY 10021 USA. NICHHD, Contracept & Reprod Hlth Branch, NIH, Bethesda, MD 20892 USA. RP Mahabadi, V (reprint author), Harbor UCLA Med Ctr, Div Endocrinol, Dept Med, Torrance, CA 90509 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD FEB PY 2010 VL 65 IS 2 BP 105 EP 106 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 552SZ UT WOS:000274315100020 ER PT J AU Harper, M Thom, E Klebanoff, MA Thorp, J Sorokin, Y Varner, MW Wapner, RJ Caritis, SN Iams, JD Carpenter, MW Peaceman, AM Mercer, BM Sciscione, A Rouse, DJ Ramin, SM Anderson, GD AF Harper, Margaret Thom, Elizabeth Klebanoff, Mark A. Thorp, John, Jr. Sorokin, Yoram Varner, Michael W. Wapner, Ronald J. Caritis, Steve N. Iams, Jay D. Carpenter, Marshall W. Peaceman, Alan M. Mercer, Brian M. Sciscione, Anthony Rouse, Dwight J. Ramin, Susan M. Anderson, Garland D. CA Eunice Kennedy Shriver Natl Inst C TI Omega-3 Fatty Acid Supplementation to Prevent Recurrent Preterm Birth A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med ID FISH-OIL SUPPLEMENTATION; HIGH-RISK PREGNANCIES; N-3 FATTY-ACIDS; CLINICAL-TRIALS; GROWTH MEASURES; DELIVERY; WOMEN; METAANALYSIS; PARTURITION; DURATION AB OBJECTIVE: To assess whether the addition of an omega-3 long-chain polyunsaturated fatty acid supplement would reduce preterm birth in women with at least one prior spontaneous preterm birth receiving 17 alpha-hydroxyprogesterone caproate. METHODS: We conducted a randomized, double-masked, placebo-controlled trial in 13 centers. Women with a history of prior spontaneous singleton preterm birth and a current singleton gestation were assigned to either a daily omega-3 supplement (1,200 eicosapentaenoic acid and 800 mg clocosahexaenoic acid) or matching placebo from 16-22 through 36 weeks of gestation. All participants received weekly intramuscular 17 alpha-hydroxyprogesterone caproate (250 mg). The primary study outcome was delivery before 37 weeks of gestation. A sample size of 800 was necessary to have 80% power to detect a 30% reduction in the primary outcome from 30%, assuming a type I error two-sided of 5%. RESULTS: A total of 852 women were included, and none was lost to follow up. Delivery before 37 weeks of gestation occurred in 37.8% (164/434) of women in the omega-3 group and 41.6% (174/418) in the placebo group (relative risk 0.91, 95% confidence interval 0.77-1.07). CONCLUSION: Omega-3 long-chain polyunsaturated fatty acid supplementation offered no benefit in reducing preterm birth among women receiving 17 alpha-hydroxyprogesterone caproate who have a history of preterm delivery. C1 Wake Forest Univ Hlth Sci, Dept Obstet, Winston Salem, NC 27157 USA. Wake Forest Univ Hlth Sci, Dept Gynecol, Winston Salem, NC 27157 USA. Univ N Carolina, Chapel Hill, NC USA. Wayne State Univ, Detroit, MI USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Columbia Univ, New York, NY USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Northwestern Univ, Chicago, IL 60611 USA. Case Western Reserve Univ, Metrohlth Med Ctr, Cleveland, OH USA. Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. Univ Alabama, Birmingham, AL USA. Univ Texas Houston, Houston, TX USA. Univ Texas Galveston, Med Branch, Galveston, TX 77550 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Harper, M (reprint author), Wake Forest Univ Hlth Sci, Dept OB GYN, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM harper.margaret@gmail.com RI Varner, Michael/K-9890-2013 OI Peaceman, Alan/0000-0002-4515-4850; caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [M01 RR000080, MO1-RR-000080]; NICHD NIH HHS [U10 HD027860, HD21410, HD27860, HD27869, HD27915, HD27917, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, U01 HD019897, U01 HD036801, U10 HD021410, U10 HD027869, U10 HD027915, U10 HD027917, U10 HD034136, U10 HD034208, U10 HD036801, U10 HD040485, U10 HD040500, U10 HD040512, U10 HD040544, U10 HD040545, U10 HD040560, UG1 HD027869, UG1 HD027915, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 36 TC 49 Z9 50 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 234 EP 242 PN 1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500005 PM 20093894 ER PT J AU Castle, PE Fetterman, B Poitras, N Lorey, T Shaber, R Kinney, W AF Castle, Philip E. Fetterman, Barbara Poitras, Nancy Lorey, Thomas Shaber, Ruth Kinney, Walter TI Relationship of Atypical Glandular Cell Cytology, Age, and Human Papillomavirus Detection to Cervical and Endometrial Cancer Risks SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID 2001 BETHESDA SYSTEM; UNDETERMINED SIGNIFICANCE; CLINICAL-SIGNIFICANCE; MANAGEMENT; UTILITY; ADENOCARCINOMA; CLASSIFICATION; WOMEN AB OBJECTIVE: To quantify the age-specific and reproductive organ-specific cancer risk after an atypical glandular cell (AGC) cytologic interpretation in large clinic-based sample in which routine high-risk human papillomavirus (HPV) testing is conducted. METHODS: To estimate the absolute risk of cervical precancer, cervical cancer, and endometrial cancer in women with AGC cytology, we conducted a cross-sectional study of women with AGC cytology (n=1,422) in a large health maintenance organization that introduced high-risk HPV DNA testing into cervical cancer screening in 2003. Risks and binomial exact 95% confidence intervals (Cis) of cervical intraepithelial neoplasia grade 2 or more severe (CIN 2 or worse) and endometrial cancer were calculated. RESULTS: A total of 238 women with AGC cytology (16.7%, 95% CI 14.8-18.8%) were diagnosed with CIN 2 or worse, endometrial cancer, or other cancers. Among women aged 50 years or older, 420 high-risk HPV-negative women were at a 10.5% (95% CI 7.7-13.8%) risk of endometrial cancer, and 77 high-risk HPV-positive women were at a 10.4% (95% CI 4.6-19.4%) risk of cervical cancer and 0% (95% CI 0.0-4.7%) risk of endometrial cancer. CONCLUSION: High-risk HPV testing may distinguish between risk of endometrial cancer and cervical cancer in women with AGC cervical cytology, particularly in women aged 50 years or older. (Obstet Gynecol 2010;115:243-8) C1 [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Kaiser Permanente No Calif, Reg Lab, Berkeley, CA USA. Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU National Institutes of Health, National Cancer Institute; Women's Health Research Institute at Kaiser Permanente Northern California FX Dr. Castle was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. This work was supported by the Women's Health Research Institute at Kaiser Permanente Northern California. NR 17 TC 35 Z9 40 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 243 EP 248 PN 1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500006 PM 20093895 ER PT J AU Kiely, M El-Mohandes, AAE El-Khorazaty, MN Gantz, MG AF Kiely, Michele El-Mohandes, Ayman A. E. El-Khorazaty, M. Nabil Gantz, Marie G. TI An Integrated Intervention to Reduce Intimate Partner Violence in Pregnancy A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID LOW-BIRTH-WEIGHT; AFRICAN-AMERICAN WOMEN; UNITED-STATES; HISPANIC COUPLES; PRETERM BIRTH; PRENATAL-CARE; SUBSTANCE USE; COMMUNITY VIOLENCE; DOMESTIC VIOLENCE; SMOKING AB OBJECTIVE: To estimate the efficacy of a psycho-behavioral intervention in reducing intimate partner violence recurrence during pregnancy and postpartum and in improving birth outcomes in African-American women. METHODS: We conducted a randomized controlled trial for which 1,044 women were recruited. Women were randomly assigned to receive either intervention (n=521) or usual care (n=523). Individually tailored counseling sessions were adapted from evidence-based interventions for intimate partner violence and other risks. Logistic regression was used to model intimate partner violence victimization recurrence and to predict minor, severe, physical, and sexual intimate partner violence. RESULTS: Women randomly assigned to the intervention group were less likely to have recurrent episodes of intimate partner violence victimization (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.29-0.80). Women with minor intimate partner violence were significantly less likely to experience further episodes during pregnancy (OR 0.48, 95% CI 0.26-0.86, OR 0.53, 95% CI 0.28-0.99) and postpartum (OR 0.56, 95% CI 0.34-0.93). Numbers needed to treat were 17, 12, and 22, respectively, as compared with the usual care group. Women with severe intimate partner violence showed significantly reduced episodes postpartum (OR 0.39, 95% CI 0.18-0.82); the number needed to treat was 27. Women who experienced physical intimate partner violence showed significant reduction at the first follow-up (OR 0.49,95% CI 0.27-0.91) and postpartum (OR 0.47,95% CI 0.27-0.82); the numbers needed to treat were 18 and 20 respectively. Women in the intervention group had significantly fewer very preterm neonates (1.5% intervention group, 6.6% usual care group; P=.03) and an increased mean gestational age (38.2+/-3.3 intervention group, 36.9+/-5.9 usual care group; P=.016). CONCLUSION: A relatively brief intervention during pregnancy had discernible effects on intimate partner violence and pregnancy outcomes. Screening for intimate partner violence as well as other psychosocial and behavioral risks and incorporating similar interventions in prenatal care is strongly recommended. C1 [Kiely, Michele] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. Univ Nebraska Med Ctr, Coll Publ Hlth, Omaha, NE USA. RTI Int, Rockville, MD USA. RP Kiely, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd, Rockville, MD 20852 USA. EM kielym@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, 5U18HD036104]; National Center oil Minority Health and Health Disparities FX Supported by grants 3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, 5U18HD036104, Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center oil Minority Health and Health Disparities. NR 52 TC 97 Z9 99 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 273 EP 283 PN 1 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500010 PM 20093899 ER PT J AU Brubaker, L Rickey, L Xu, Y Markland, A Lemack, G Ghetti, C Kahn, MA Nagaraju, P Norton, P Chang, TD Stoddard, A AF Brubaker, Linda Rickey, Leslie Xu, Yan Markland, Alayne Lemack, Gary Ghetti, Chiara Kahn, Margie A. Nagaraju, Pradeep Norton, Peggy Chang, T. Debuene Stoddard, Anne CA Urinary Incontinence Treatment Net TI Symptoms of Combined Prolapse and Urinary Incontinence in Large Surgical Cohorts SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PELVIC ORGAN PROLAPSE; QUALITY-OF-LIFE; UROGENITAL DISTRESS INVENTORY; STRESS-INCONTINENCE; IMPACT QUESTIONNAIRE; FLOOR DISORDERS; WOMEN; PREVALENCE; SEVERITY; STANDARDIZATION AB OBJECTIVE: To estimate whether prolapse severity is a major contributor to urinary incontinence severity, as measured by validated incontinence questionnaires. METHODS: We analyzed data from two large female stress urinary incontinence (SUI) surgical cohorts: the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr) study (N=655) and the subsequent Trial of Mid-Urethral Slings (TOMUS) study (N=597). All participants completed a standardized baseline assessment including validated measures of symptom severity, quality of life, objective measures of urine loss (Urogenital Distress Inventory [UDI], Medical, Epidemiologic, and Social Aspects of Aging questionnaire, Incontinence Impact Questionnaire, and pad test), as well as the Pelvic Organ Prolapse Quantification assessment. Groups were compared using the) chi(2); test (categorical measures) or the one-way analysis of variance (continuous measures). Statistical significance was defined as P<.05. RESULTS: The SISTEr and TOMUS samples were similar for many variables including age (52 and 53 years, respectively), nulliparity (9% and 12%), prior urinary incontinence (UI) surgery (14% and 13%), and prior hysterectomy (31% and 28%), but other differences necessitated separate analysis of the two cohorts. There was not a statistically significant difference in UDI scores according to prolapse stage in either study population. Patients with prior surgery for pelvic organ prolapse and SUI had more incontinence symptoms and were more bothered by their UI regardless of prolapse stage. CONCLUSION: Prolapse stage is not strongly or consistently associated with incontinence severity in women who select surgical treatment of SUI. Prior pelvic organ prolapse and UI surgery is associated with worse UI severity and bother. C1 Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Loyola Univ, Stritch Sch Med, Dept Urol, Chicago, IL 60611 USA. Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Birmingham VA Med Ctr, Birmingham, AL USA. Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. Kaiser Permanente, San Diego, CA USA. William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. NIDDK, NIH, Bethesda, MD USA. RP Brubaker, L (reprint author), Loyola Univ Chicago, Stritch Sch Med, 2160 S 1st Ave,Bldg 103, Maywood, IL 60153 USA. EM LBrubaker@lumc.edu FU Pfizer (New York, AT); Allergan (Irvine, CA) FX Dr. Brubaker has received research funding from Pfizer (New York, AT) and Allergan (Irvine, CA) and. has been a research consultant for Pfizer. Dr. Lemak has been a clinical trial participant for Allergan, a consultant and lecturer for Astellas (Deerfield, IL) and Pfizer, and a lecturer for Novartis (Basel, Switzerland). Dr. Ghetti served as a co-investigator for the Bridges study with the University of California, San Francisco, which was partially funded by Pfizer. The other authors did not report any potential conflicts of interest. NR 24 TC 4 Z9 5 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 310 EP 316 PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500015 PM 20093904 ER PT J AU Incerti, M Vink, J Roberson, R Wood, L Abebe, D Spong, CY AF Incerti, Maddalena Vink, Joy Roberson, Robin Wood, Lorraine Abebe, Daniel Spong, Catherine Y. TI Reversal of Alcohol-Induced Learning Deficits in the Young Adult in a Model of Fetal Alcohol Syndrome SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; METHYL-D-ASPARTATE; DEPENDENT NEUROTROPHIC FACTOR; PRENATAL ETHANOL EXPOSURE; NEUROPROTECTIVE PEPTIDE; MOUSE MODEL; RAT HIPPOCAMPUS; NMDA RECEPTORS; PREVENTION; GROWTH AB OBJECTIVE: To evaluate whether treatment with neuroprotective peptides to young adult mice prenatally exposed to alcohol reverses alcohol-induced learning deficits in a mouse model of fetal alcohol syndrome, whether the mechanism involves the N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid type A (GABA,) receptors, and whether it is related to glial cells. METHODS: C57B16/J mice were treated with alcohol (0.03 ml/g) or placebo on gestational day 8. On day 40, male mice exposed to alcohol in utero were treated daily for 10 days with D-NAPVSIPQ and D-SALLRSIPA (n=20) or placebo (n=13); and control offspring were treated with placebo (n=46), with the treatment blinded. Learning evaluation began after 3 days using the Morris water-maze and the T-maze. The hippocampus, cortex, and cerebellum were isolated. Expression of NR2A, NR2B, GABA(A)beta 3, GABA(A)alpha 5, vasoactive intestinal peptide (VIP), activity-dependent neuroprotective protein, and glial fibrillary acidic protein was measured using calibrator-normalized relative real-time polymerase chain reaction. Statistical analysis included analysis of variance and Fisher's protected least significant difference. RESULTS: Treatment with D-NAPVSIPQ and D-SALLRSIPA reversed the alcohol-induced learning deficit in both learning tests as well as the NR2A and NR2B down-regulation in the hippocampus and the up-regulation of NR2A in the cortex and NR2B in the cortex and cerebellum (all P<.05). No significant differences were found in GABA(a) expression. Moreover, the peptides changed activity-dependent neuroprotective protein expression in the cortex (P=.016) but not the down-regulation of VIP (P=.883), probably because the peptides are downstream from VIP. CONCLUSION: Alcohol-induced learning deficit was reversed and expression of NR2A and NR2B was restored in the hippocampus and cortex of young adult mice treated with D-NAPVSIPQ and D-SALLRSIPA. Given the role of NMDA receptors in learning, this may explain in part the mechanism of prevention of alcohol-induced learning deficits by D-NAPVSIPQ and D-SALLRSIPA. (Obstet Gynecol 2010;115:350-6) C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD USA. Columbia Univ, Med Ctr, Div Maternal Fetal Med, New York, NY USA. RP Incerti, M (reprint author), NICHHD, Unit Perinatal & Dev Neurobiol, NIH, Bldg 9,Room 1W125,9 Mem Dr, Bethesda, MD 20892 USA. EM maddalena.incerti@gmail.com FU Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health FX Supported by the Division of Intramural Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health. NR 31 TC 15 Z9 15 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2010 VL 115 IS 2 BP 350 EP 356 PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 547FS UT WOS:000273872500021 PM 20093910 ER PT J AU Vlaanderen, J Moore, LE Smith, MT Lan, Q Zhang, L Skibola, CF Rothman, N Vermeulen, R AF Vlaanderen, J. Moore, L. E. Smith, M. T. Lan, Q. Zhang, L. Skibola, C. F. Rothman, N. Vermeulen, R. TI Application of OMICS technologies in occupational and environmental health research; current status and projections SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Review ID COMPARATIVE GENOMIC HYBRIDIZATION; SINGLE NUCLEOTIDE POLYMORPHISMS; BENZENE-EXPOSED WORKERS; EXCISION-REPAIR GENES; DNA METHYLATION; SYSTEMS BIOLOGY; BREAST-CANCER; HUMAN-DISEASE; LUNG-CANCER; MOLECULAR EPIDEMIOLOGY AB OMICS technologies are relatively new biomarker discovery tools that can be applied to study large sets of biological molecules. Their application in human observational studies (HOS) has become feasible in recent years due to a spectacular increase in the sensitivity, resolution and throughput of OMICS-based assays. Although, the number of OMICS techniques is ever expanding, the five most developed OMICS technologies are genotyping, transcriptomics, epigenomics, proteomics and metabolomics. These techniques have been applied in HOS to various extents. However, their application in occupational environmental health (OEH) research has been limited. Here, we will discuss the opportunities these new techniques provide for OEH research. In addition we will address difficulties and limitations to the interpretation of the data that is generated by OMICS technologies. To illustrate the current status of the application of OMICS in OEH research, we will provide examples of studies that used OMICS technologies to investigate human health effects of two well-known toxicants, benzene and arsenic. C1 [Vlaanderen, J.] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3508 TD Utrecht, Netherlands. [Moore, L. E.; Lan, Q.; Rothman, N.] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Smith, M. T.; Zhang, L.; Skibola, C. F.] Univ Calif Berkeley, Div Environm Hlth Sci, Berkeley, CA 94720 USA. RP Vlaanderen, J (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, POB 80178, NL-3508 TD Utrecht, Netherlands. EM j.j.vlaanderen@uu.nl RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU NIH [P42ES004705, R01 ES006721, R01 CA122663, U54 ES016115] FX European Union 6th Framework Program " ECNIS" (FOOD-CT-2005-513943). MTS, LZ and CFS were supported by NIH grants P42ES004705, R01 ES006721, R01 CA122663, and U54 ES016115. NR 98 TC 45 Z9 48 U1 1 U2 17 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD FEB PY 2010 VL 67 IS 2 BP 136 EP 143 DI 10.1136/oem.2008.042788 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 552NM UT WOS:000274298800014 PM 19933307 ER PT J AU Guo, L Mei, N Liao, W Chan, PC Fu, PP AF Guo, Lei Mei, Nan Liao, Wayne Chan, Po-Chuen Fu, Peter P. TI Ginkgo Biloba Extract Induces Gene Expression Changes in Xenobiotics Metabolism and the Myc-Centered Network SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID HERBAL DIETARY-SUPPLEMENTS; HUMAN CYTOCHROMES P450; ST-JOHNS-WORT; C-MYC; BOTANICAL SUPPLEMENTATION; PYRROLIZIDINE ALKALOIDS; DRUG INTERACTIONS; ORAL TREATMENT; KAVA EXTRACT; PHASE-I AB The use of herbal dietary supplements in the United States is rapidly growing, and it is crucial that the quality and safety of these preparations be ensured. To date, it is still a challenge to determine the mechanisms of toxicity induced by mixtures containing many chemical components, such as herbal dietary supplements. We previously proposed that analyses of the gene expression profiles using microarrays in the livers of rodents treated with herbal dietary supplements is a potentially practical approach for understanding the mechanism of toxicity. In this study, we utilized microarrays to analyze gene expression changes in the livers of male B6C3F1 mice administered Ginkgo biloba leaf extract (GBE) by gavage for 2 years, and to determine pathways and mechanisms associated with GBE treatments. Analysis of 31,802 genes revealed that there were 129, 289, and 2,011 genes significantly changed in the 200, 600, and 2,000 mg/kg treatment groups, respectively, when compared with control animals. Drug metabolizing genes were significantly altered in response to GBE treatments. Pathway and network analyses were applied to investigate the gene relationships, functional clustering, and mechanisms involved in GBE exposure. These analyses indicate alteration in the expression of genes coding for drug metabolizing enzymes, the NRF2-mediated oxidative stress response pathway, and the Myc gene-centered network named "cell cycle, cellular movement, and cancer" were found. These results indicate that Ginkgo biloba-related drug metabolizing enzymes may cause herb-drug interactions and contribute to hepatotoxicity. In addition, the outcomes of pathway and network analysis may be used to elucidate the toxic mechanisms of Ginkgo biloba. C1 [Guo, Lei] US FDA, Natl Ctr Toxicol Res, Div Syst Toxicol, Jefferson, AR 72079 USA. [Mei, Nan] US FDA, Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, Jefferson, AR 72079 USA. [Liao, Wayne] PhalanxBio Inc, Palo Alto, CA USA. [Chan, Po-Chuen] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Guo, L (reprint author), US FDA, Natl Ctr Toxicol Res, Div Syst Toxicol, Jefferson, AR 72079 USA. EM lei.guo@fda.hhs.gov; peter.fu@fda.hhs.gov RI Guo, Lei/E-9232-2011; mei, nan/E-8915-2011 OI mei, nan/0000-0002-3501-9014 FU NIH, National Institute of Environmental Health Sciences FX We thank Drs. Tucker A. Patterson and James C. Fuscoe for their critical review of this manuscript. This article is not an official guidance or policy statement of the National Toxicology Program (NTP) or U.S. Food and Drug Administration (FDA). No official support or endorsement by the FDA or NTP is intended or should be inferred. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 58 TC 22 Z9 22 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD FEB PY 2010 VL 14 IS 1 BP 75 EP 90 DI 10.1089/omi.2009.0115 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 554GO UT WOS:000274423700004 PM 20141330 ER PT J AU Shabason, JE Tofilon, PJ Camphausen, K AF Shabason, Jacob E. Tofilon, Philip J. Camphausen, Kevin TI HDAC Inhibitors in Cancer Care SO ONCOLOGY-NEW YORK LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; T-CELL LYMPHOMA; PHASE-II TRIAL; INCREASING THERAPEUTIC GAIN; VALPROIC ACID; GAMMA-H2AX FOCI; IN-VITRO; GLIOBLASTOMA-MULTIFORME; EPIGENETIC THERAPY AB The epigenetic control of gene expression has been shown to play an important role in cancer initiation, progression, and resistance. Thus, agents that modify the epigenetic environment of tumors will likely be an important addition to the anticancer arsenal. Specifically, there is much interest in modulating histone acetylation using a new class of drugs, histone deacetylase (HDAC) inhibitors. Preclinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging preclinical data, numerous HDAC inhibitors are being investigated in clinical trials either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy, or radiation therapy. In fact, vorinostat and depsipeptide, two actively studied HDAC inhibitors, were recently approved for the treatment of refractory cutaneous T-cell lymphoma. Although the use of HDAC inhibitors has generated great enthusiasm, a significant amount of work still needs to be done in order to understand their mechanisms of action, as well as to determine the appropriate patient characteristics and subsets of cancer for which HDAC inhibitors hold the most potential for effective treatment. C1 [Shabason, Jacob E.; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Shabason, Jacob E.] NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. [Tofilon, Philip J.] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr 3B42, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 37 TC 23 Z9 27 U1 0 U2 5 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD FEB PY 2010 VL 24 IS 2 BP 180 EP 185 PG 6 WC Oncology SC Oncology GA 800BB UT WOS:000293330900008 PM 20361469 ER PT J AU Sack, U Walther, W Shoemaker, RH Fichtner, I Schlag, PM Stein, U AF Sack, U. Walther, W. Shoemaker, R. H. Fichtner, I. Schlag, P. M. Stein, U. TI Niclosamide, a newly identified inhibitor that restricts S100A4-induced metastasis formation in colon cancer SO ONKOLOGIE LA English DT Meeting Abstract C1 [Sack, U.; Walther, W.; Fichtner, I.; Stein, U.] Max Delbruck Ctr Mol Med, Berlin, Germany. [Walther, W.; Stein, U.] Expt & Clin Res Ctr, Berlin, Germany. [Shoemaker, R. H.] NCI, Frederick, MD 21701 USA. [Schlag, P. M.] Charite Comprehens Canc Ctr, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD FEB PY 2010 VL 33 SU 2 BP 74 EP 74 PG 1 GA 558LY UT WOS:000274745200202 ER PT J AU Montgomery, MP Kamel, F Pericak-Vance, MA Haines, JL Postel, EA Agarwal, A Richards, M Scott, WK Schmidt, S AF Montgomery, Martha P. Kamel, Freya Pericak-Vance, Margaret A. Haines, Jonathan L. Postel, Eric A. Agarwal, Anita Richards, Marie Scott, William K. Schmidt, Silke TI Overall Diet Quality and Age-Related Macular Degeneration SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE AHEI alternate healthy eating index; AMD age-related macular degeneration; HEI healthy eating index ID MAJOR CHRONIC DISEASE; HEALTHY EATING INDEX; GUIDELINES-FOR-AMERICANS; FISH INTAKE; MEDITERRANEAN DIET; PRIMARY PREVENTION; RISK; MACULOPATHY; ADHERENCE; FAT AB Purpose: To examine overall diet quality in relation to advanced age-related macular degeneration (AMD). Methods: This case-control study identified 437 advanced AMD patients and 259 unrelated controls using stereoscopic color fundus photographs. Participants were predominantly non-Hispanic White men and women from North Carolina and Tennessee. A 97-item Block food frequency questionnaire was used to gather diet information, and overall diet quality was measured using the Healthy Eating Index (HEI) and Alternate Healthy Eating Index (AHEI). Results: Participants in the highest quartile of diet quality had significantly reduced odds of AMD according to the AHEI score (0.54, 95% confidence interval 0.30-0.99) and non-significantly reduced odds of AMD according to the HEI (0.75, 0.41-1.38). Odds of AMD were also 51% lower in the highest quartile of fish intake compared to the lowest quartile (odds ratio = 0.49, 0.26-0.90). Conclusions: We found that advanced AMD was significantly related to overall diet quality. The AHEI score may be a useful instrument for assessing AMD risk due to diet, and it could potentially be improved by incorporating more specific information regarding micronutrient intake. C1 [Schmidt, Silke] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA. [Montgomery, Martha P.; Kamel, Freya; Scott, William K.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Inst Human Genom, Miami, FL 33136 USA. [Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Postel, Eric A.] Duke Univ, Ctr Eye, Durham, NC 27710 USA. [Postel, Eric A.] Duke Univ, Dept Ophthalmol, Med Ctr, Durham, NC 27710 USA. [Agarwal, Anita] Vanderbilt Univ, Med Ctr, Vanderbilt Eye Ctr, Nashville, TN USA. [Richards, Marie] WESTAT Corp, Durham, NC USA. RP Schmidt, S (reprint author), Duke Univ, Med Ctr, Ctr Human Genet, Box 3445, Durham, NC 27710 USA. EM silke.schmidt@duke.edu RI Haines, Jonathan/C-3374-2012; OI Kamel, Freya/0000-0001-5052-6615 FU National Eye Institute, National Institutes of Health (NIH) [EY12118]; National Institute of Environmental Health Sciences; General Clinical Research Center [RR 00095] FX William K. Scott and Silke Schmidt are co-senior authors. This study was supported by grant EY12118 from the National Eye Institute, National Institutes of Health (NIH) and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. It was also supported in part by a General Clinical Research Center award (RR 00095) to Vanderbilt University. We express our appreciation to all the participants and their relatives who generously participated in the study We thank Kristen Hutchins, Dr. Monica de la Paz, Jennifer Caldwell, Ruth Domurath, Maureen Shaw, and Jason Galloway for participant ascertainment and data management. Drs. Scott and Schmidt had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 43 TC 16 Z9 16 U1 4 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0928-6586 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD FEB PY 2010 VL 17 IS 1 BP 58 EP 65 DI 10.3109/09286580903450353 PG 8 WC Ophthalmology SC Ophthalmology GA 569IX UT WOS:000275590900008 PM 20100101 ER PT J AU Clemons, TE Gillies, MC Chew, EY Bird, AC Peto, T Figueroa, MJ Harrington, MW AF Clemons, Traci E. Gillies, Marc C. Chew, Emily Y. Bird, Alan C. Peto, Tunde Figueroa, Maria J. Harrington, Molly W. CA MacTel Res Grp TI Baseline Characteristics of Participants in the Natural History Study of Macular Telangiectasia (MacTel) MacTel Project Report No. 2 SO OPHTHALMIC EPIDEMIOLOGY LA English DT Article DE Idiopathic; Macular; Natural history; Telangiectasia; Visual acuity ID JUXTAFOVEOLAR RETINAL TELANGIECTASIS AB Purpose: To describe the baseline characteristics of a large international cohort of patients with macular telangiectasia type 2 (MacTel Type 2) in anticipation of a longitudinal natural history study to evaluate structural and functional changes, identify potential risk factors and related outcomes. Methods: Images including fundus photographs, fluorescein angiograms, optical coherence tomography and fundus autofluorescence were collected. A grading system for MacTel type 2 was developed by the central reading center to evaluate lesion characteristics. Relationships between lesion characteristics and visual acuity were evaluated. Results: A total of 310 participants have been enrolled in the study. The mean time since diagnosis was 3 years (range 0 to 25 years). The mean age at the baseline examination was 61 9 years. The mean visual acuity in the better eye was approximately 20/32 Snellen equivalents and approximately 20/50 in the worse eye. The visual acuity in the better eye of half of the participants was 20/32 or better. We found some relationships between visual acuity and lesions characteristic of MacTel Type 2. Conclusions: This is the first large-scale study of patients with MacTel Type 2. More than half of the patients had 20/32 or better vision in their better eye, which is a sign that decreased function in these participants may not be reflected in central visual acuity. These findings highlight the limitation of using visual acuity measurements as a measure of function and as an outcome measure in potential clinical trials in patients with MacTel Type 2. C1 [Clemons, Traci E.; Figueroa, Maria J.; Harrington, Molly W.] EMMES Corp, Rockville, MD 20850 USA. [Gillies, Marc C.] Save Sight Inst, Sydney, NSW, Australia. [Chew, Emily Y.] NEI, Bethesda, MD 20892 USA. [Bird, Alan C.; Peto, Tunde] Moorfields Eye Hosp, London, England. RP Clemons, TE (reprint author), EMMES Corp, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM tclemons@emmes.com RI gillies, mark/B-3242-2012; Sahel, Jose-Alain/F-3172-2017 FU Lowy Medical Research Institute, LTD. FX This study was supported by the Lowy Medical Research Institute, LTD. The investigations were performed according to the guidelines of the Declaration of Helsinki and Institutional Review Board approval was obtained. NR 17 TC 43 Z9 44 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0928-6586 J9 OPHTHAL EPIDEMIOL JI Ophthalmic Epidemiol. PD FEB PY 2010 VL 17 IS 1 BP 66 EP 73 DI 10.3109/09286580903450361 PG 8 WC Ophthalmology SC Ophthalmology GA 569IX UT WOS:000275590900009 PM 20100102 ER PT J AU Pujari, SS Kempen, JH Newcomb, CW Gangaputra, S Daniel, E Suhler, EB Thorne, JE Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Foster, CS AF Pujari, Siddharth S. Kempen, John H. Newcomb, Craig W. Gangaputra, Sapna Daniel, Ebenezer Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Foster, C. Stephen TI Cyclophosphamide for Ocular Inflammatory Diseases SO OPHTHALMOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; KOYANAGI-HARADA-SYNDROME; WEGENERS-GRANULOMATOSIS; INTRAVENOUS CYCLOPHOSPHAMIDE; RHEUMATOID-ARTHRITIS; IMMUNOSUPPRESSIVE THERAPY; PULSE CYCLOPHOSPHAMIDE; FOLLOW-UP; DRUGS; MANAGEMENT AB Purpose: To evaluate the outcomes of cyclophosphamide therapy for noninfectious ocular inflammation. Design: Retrospective cohort study. Participants: Two hundred fifteen patients with noninfectious ocular inflammation observed from initiation of cyclophosphamide. Methods: Patients initiating cyclophosphamide, without other immunosuppressive drugs (other than corticosteroids), were identified at 4 centers. Dose of cyclophosphamide, response to therapy, corticosteroid-sparing effects, frequency of discontinuation, and reasons for discontinuation were obtained by medical record review of every visit. Main Outcome Measures: Control of inflammation, corticosteroid-sparing effects, and discontinuation of therapy. Results: The 215 patients (381 involved eyes) meeting eligibility criteria carried diagnoses of uveitis (20.4%), scleritis (22.3%), ocular mucous membrane pemphigoid (45.6%), or other forms of ocular inflammation (11.6%). Overall, approximately 49.2% (95% confidence interval [CI], 41.7%-57.2%) gained sustained control of inflammation (for at least 28 days) within 6 months, and 76% (95% CI, 68.3%-83.7%) gained sustained control of inflammation within 12 months. Corticosteroid-sparing success (sustained control of inflammation while tapering prednisone to 10 mg or less among those not meeting success criteria initially) was gained by 30.0% and 61.2% by 6 and 12 months, respectively. Disease remission leading to discontinuation of cyclophosphamide occurred at the rate of 0.32/person-year (95% CI, 0.24-0.41), and the estimated proportion with remission at or before 2 years was 63.1% (95% CI, 51.5%-74.8%). Cyclophosphamide was discontinued by 33.5% of patients within 1 year because of side effects, usually of a reversible nature. Conclusions: The data suggest that cyclophosphamide is effective for most patients for controlling inflammation and allowing tapering of systemic corticosteroids to 10 mg prednisone or less, although 1 year of therapy may be needed to achieve these goals. Unlike with most other immunosuppressive drugs, disease remission was induced by treatment in most patients who were able to tolerate therapy. To titrate therapy properly and to minimize the risk of serious potential side effects, a systematic program of laboratory monitoring is required. Judicious use of cyclophosphamide seems to be beneficial for severe ocular inflammation cases where the potentially vision-saving benefits outweigh the substantial potential side effects of therapy, or when indicated for associated systemic inflammatory diseases. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 356-365 (C) 2010 by the American Academy of Ophthalmology. C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Pujari, Siddharth S.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Dept Epidemiol, Philadelphia, PA 19104 USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Gangaputra, Sapna; Daniel, Ebenezer; Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute, Bethesda, Maryland [EY014943]; Research to Prevent Blindness, Inc., New York; Paul and Evanina Mackall Foundation, New York; National Eye Institute; Veterans' Administration, Washington, DC FX Supported primarily by the National Eye Institute, Bethesda, Maryland (grant no.: EY014943 [JHK]). Additional support was provided by Research to Prevent Blindness, Inc., New York, New York, and the Paul and Evanina Mackall Foundation, New York, NY. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Dr Levy- Clarke previously was supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. Dr Suhler also received support from the Veterans' Administration, Washington, DC. None of the sponsors had any role in the design and conduct of the report; collection, management, analysis, and interpretation of the data; nor in the preparation, review, and approval of this manuscript. NR 65 TC 51 Z9 52 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2010 VL 117 IS 2 BP 356 EP 365 DI 10.1016/j.ophtha.2009.06.060 PG 10 WC Ophthalmology SC Ophthalmology GA 555RB UT WOS:000274530300024 PM 19969366 ER PT J AU Zaidi, AA Ying, GS Daniel, E Gangaputra, S Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Kempen, JH AF Zaidi, Ali A. Ying, Gui-Shuang Daniel, Ebenezer Gangaputra, Sapna Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Kempen, John H. CA Systemic Immunosuppressive Therapy TI Hypopyon in Patients with Uveitis SO OPHTHALMOLOGY LA English DT Article ID BEHCETS-DISEASE AB Purpose: To evaluate the risk of and risk factors for hypopyon among patients with uveitis and to evaluate the risk of visual changes and complications after hypopyon. Design: Retrospective cohort study. Participants: Patients with uveitis at 4 academic ocular inflammation subspecialty practices. Methods: Data were ascertained by standardized chart review. Main Outcome Measures: Prevalence and incidence of hypopyon, risk factors for hypopyon, and incidence of visual acuity changes and ocular complications after hypopyon. Results: Among 4911 patients with uveitis, 41 (8.3/1000) cases of hypopyon were identified at the time of cohort entry. Of these, 2885 initially free of hypopyon were followed over 9451 person-years, during which 81 patients (2.8%) developed hypopyon (8.57/1000 person-years). Risk factors for incident hypopyon included Behcet's disease (adjusted relative risk [RR] = 5.30; 95% confidence interval [CI], 2.76-10.2), spondyloarthropathy (adjusted RR = 2.86; 95% CI, 1.48-5.52), and human leukocyte antigen (HLA)-B27 positivity (adjusted RR = 2.04; 95% CI, 1.17-3.56). Patients with both a spondyloarthropathy and HLA-B27 had a higher risk than either factor alone (crude RR = 4.39; 95% CI, 2.26-8.51). Diagnosis of intermediate uveitis (+/- anterior uveitis) was associated with a lower risk of hypopyon (with respect to anterior uveitis only, adjusted RR = 0.35; 95% CI, 0.15-0.85). Hypopyon incidence tended to be lower among patients with sarcoidosis (crude RR = 0.22; 95% CI, 0.06-0.90; adjusted RR = -0.28; 95% CI, 0.07-1.15). Post-hypopyon eyes and eyes not developing hypopyon had a similar incidence of band keratopathy, posterior synechiae, ocular hypertension, hypotony, macular edema, epiretinal membrane, cataract surgery, or glaucoma surgery. Post-hypopyon eyes were more likely than eyes not developing hypopyon to gain 3 lines of vision (crude RR = 1.54; 95% CI, 1.05-2.24) and were less likely to develop 20/200 or worse visual acuity (crude RR = 0.41; 95% CI, 0.17-0.99); otherwise, visual outcomes were similar in these groups. Conclusions: Hypopyon is an uncommon occurrence in patients with uveitis. Risk factors included Behcet's disease, HLA-B27 positivity, and spondyloarthropathy. Intermediate uveitis cases (+/- anterior uveitis) had a lower risk of hypopyon. On average, post-hypopyon eyes were no more likely than other eyes with uveitis to develop structural ocular complications or lose visual acuity. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2010; 117: 366-372 (C) 2010 by the American Academy of Ophthalmology. C1 [Zaidi, Ali A.; Ying, Gui-Shuang; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Zaidi, Ali A.; Ying, Gui-Shuang; Daniel, Ebenezer; Kempen, John H.] Univ Penn, Ocular Inflammat Serv, Philadelphia, PA 19104 USA. [Ying, Gui-Shuang; Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat, Philadelphia, PA 19104 USA. [Ying, Gui-Shuang; Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Epidemiol, Philadelphia, PA 19104 USA. [Daniel, Ebenezer; Gangaputra, Sapna; Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute [EY014943]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; Prevent Blindness James S. Adams Special Scholar Award; National Eye Institute FX Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Dr. Suhler also received support from the Veteran's Affairs Administration. Dr. Levy-Clarke was previously supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. NR 12 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2010 VL 117 IS 2 BP 366 EP 372 DI 10.1016/j.ophtha.2009.07.025 PG 7 WC Ophthalmology SC Ophthalmology GA 555RB UT WOS:000274530300025 PM 20006905 ER PT J AU Cyert, L Ying, GS Dobson, V Quinn, G Maguire, M Kulp, MT Ciner, E Schmidt, PP Moore, B Maguire, MG Orel-Bixler, D Peskin, E Redford, M Schultz, J AF Cyert, Lynn Ying, Gui-Shuang Dobson, Velma Quinn, Graham Maguire, Maureen Kulp, Marjean Taylor Ciner, Elise Schmidt, Paulette P. Moore, Bruce Maguire, Maureen G. Orel-Bixler, Deborah Peskin, Ellen Redford, Maryann Schultz, Janet CA Vision Preschoolers VIP Study Grp TI Effect of Age Using Lea Symbols or HOTV for Preschool Vision Screening SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE visual acuity; HOTV letter optotypes; Lea Symbols; preschool vision screening; children's vision ID AMBLYOPIA TREATMENT; CHILDREN AB Purpose. To compare the effectiveness of the Lea Symbols and the HOTV distance visual acuity tests, presented monocularly in linear, crowded formats at 3 m, as vision screening tests to identify 3- to 5-year-old children in need of eye care. Methods. Subjects were 1,142 3- to 5-year-old Head Start children who completed a comprehensive eye examination, used to determine if the child had one or more targeted conditions: amblyopia, strabismus, significant refractive error, or unexplained reduced visual acuity. Each child was tested on both tests by masked examiners, with test order determined randomly. The optotype sizes administered were age-based according to the child's age at school entry on September 1. Children of age 3 were tested with 10/100, 10/32, 10/25, and 10/20 optotypes whereas those who were 4 were tested with 10/100, 10/25, 10/20, and 10/16 optotypes. Results. Most children (>95%) completed both tests, with no statistically significant differences. Pass/fail cut-offs were set to yield specificities as close as possible to 90%. The largest sensitivity differences observed were in the 3-year-old group (mean age, 45.3 months), where the sensitivity for detection of 2 1 targeted conditions was 61% for the Lea Symbols and was 46% for the HOTV letters (difference 15%, 95% confidence interval: -0.01 to 0.30) and the sensitivity for detection of group I conditions was 83% for the Lea Symbols and 57% for the HOTV letters (difference 26%, 95% confidence interval: -0.01 to 0.49). However, neither these differences nor any of the other age group sensitivity differences were statistically significant. For the 3-year-old children, the pass/fail criterion was one line larger for the HOTV letters than for the Lea Symbols. Conclusions. Most children completed both tests. Although the 3-year-old children achieved better acuity scores with the Lea Symbols test, there were no statistically significant differences in sensitivity between tests for any age group. (Optom Vis Sci 2010;87:87-95) C1 [Cyert, Lynn; Ying, Gui-Shuang; Maguire, Maureen G.; Peskin, Ellen] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Ciner, Elise] Penn Coll Optometry, Philadelphia, PA 19141 USA. [Cyert, Lynn] NE State Univ, Oklahoma Coll Optometry, Tahlequah, OK 74464 USA. [Dobson, Velma] Univ Arizona, Dept Ophthalmol, Tucson, AZ USA. [Kulp, Marjean Taylor; Schmidt, Paulette P.] Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. [Moore, Bruce] New England Coll Optometry, Boston, MA USA. [Orel-Bixler, Deborah] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. [Quinn, Graham] Childrens Hosp Philadelphia, Div Pediat Ophthalmol, Philadelphia, PA 19104 USA. [Redford, Maryann] NEI, Bethesda, MD 20892 USA. [Schultz, Janet] Reginald S Lourie Early Head Start Program, Rockville, MD USA. [Vision Preschoolers VIP Study Grp] NE State Univ, Coll Optometry, Tahlequah, OK 74464 USA. RP Cyert, L (reprint author), NE State Univ, Oklahoma Coll Optometry, 1001 N Grand Ave, Tahlequah, OK 74464 USA. EM cyert@nsuok.edu FU VIP Study Group Executive Committee; National Eye Institute, National Institutes of Health, Department of Health and Human Services [EY12644, EY12545, EY12550, EY12534, EY12647, EY12648, EY12547]; Research to Prevent Blindness; Morris Funds at the Ohio State University College of Optometry [525044]; [R21EY018908] FX This work was supported by the institution of each VIP Study Group Executive Committee member and by grants from the National Eye Institute, National Institutes of Health, Department of Health and Human Services: EY12644 (PS); EY12545 (EC); EY12550 (LC); EY12534 (BM); EY12647 (DOB); EY12648 (PS, MTK); and EY12547 (MM).; GSY received support from R21EY018908. Further support was provided by an unrestricted gift to the University of Pennsylvania from Research to Prevent Blindness and a gift from the Paul and Evanina Bell Mackall Foundation Trust to MM; and the Morris Funds at the Ohio State University College of Optometry to PS (525044). NR 17 TC 9 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD FEB PY 2010 VL 87 IS 2 BP 87 EP 95 PG 9 WC Ophthalmology SC Ophthalmology GA 552IW UT WOS:000274284100003 ER PT J AU Schmidt, P Baumritter, A Ciner, E Cyert, L Dobson, V Haas, B Kulp, MT Maguire, M Moore, B Orel-Bixler, D Peskin, E Quinn, G Redford, M Schultz, J Ying, GS Qualley, P Howard, D Suzuki, LM Fisher, S Fong, D Frane, S Hsiao-Threlkeld, C Koseoglu, S Moy, AM Shapiro, S Verdon, L Watson, T McDonnell, S Paez, E Sloan, D Smith, E Soto, L Prinz, R Edelstein, J Moe, B Bolden, J Umana, S Silbert, A Quinn, N Bordeau, H Carlson, N Croteau, A Flynn, M Kran, B Ramsey, J Suckow, M Weissberg, E Chery, M Diaz, M Gonzalez, L Braverman, E Johnson, R Henderson, C Bonila, M Doherty, C Peace-Pierre, C Saxbe, A Tabb, V Biddle, M Hudson, J Ackerman, M Anderson, S Earley, M Edwards, K Evans, N Gebhart, H Henry, J Hertle, R Hutchinson, J Jenkins, L Toole, A Johnson, K Shoemaker, R Atkinson, R Hochstedler, F James, T Jones, T Kellum, J Martin, D Dunagan, C Cline, J Rund, S Duson, A Parke, L Boas, M Burgess, S Copenhaven, P Francis, E Gallaway, M Menacker, S Schwartz, J Scombordi-Raghu, B Swiatocha, J Zikoski, E Kennedy, L Little, R Moss, G Rorie, L Stokes, S Figueroa, J Nesmith, E Gold, G Carter, A Harvey, D Hall, S Hildebrand, L Lapsley, M Quenzer, C Rosenbach, L Cheatham, L Chambless, A Beats, C Carter, J Coy, D Long, J Rice, S Dreadfulwater, S McCully, C Wyers, R Blake, R Boswell, J Brown, A Fisher, J Larrison, J Brightwell-Arnold, M Holmes, C James, A Khvatov, A O'Brien, L Whearry, C AF Schmidt, Paulette Baumritter, Agnieshka Ciner, Elise Cyert, Lynn Dobson, Velma Haas, Beth Kulp, Marjean Taylor Maguire, Maureen Moore, Bruce Orel-Bixler, Deborah Peskin, Ellen Quinn, Graham Redford, Maryann Schultz, Janet Ying, Gui-Shuang Qualley, Pamela Howard, Dru Suzuki, Lempi Miller Fisher, Sarah Fong, Darlene Frane, Sara Hsiao-Threlkeld, Cindy Koseoglu, Selim Moy, A. Mika Shapiro, Sharyn Verdon, Lisa Watson, Tonya McDonnell, Sean Paez, Erika Sloan, Darlene Smith, Evelyn Soto, Leticia Prinz, Robert Edelstein, Joan Moe, Beatrice Bolden, Joanne Umana, Sandra Silbert, Amy Quinn, Nicole Bordeau, Heather Carlson, Nancy Croteau, Amy Flynn, Micki Kran, Barry Ramsey, Jean Suckow, Melissa Weissberg, Erik Chery, Marthedala Diaz, Maria Gonzalez, Leticia Braverman, Edward Johnson, Rosalyn Henderson, Charlene Bonila, Maria Doherty, Cathy Peace-Pierre, Cynthia Saxbe, Ann Tabb, Vadra Biddle, Molly Hudson, Jason Ackerman, Melanie Anderson, Sandra Earley, Michael Edwards, Kristyne Evans, Nancy Gebhart, Heather Henry, Jay Hertle, Richard Hutchinson, Jeffrey Jenkins, LeVelle Toole, Andrew Johnson, Keith Shoemaker, Richard Atkinson, Rita Hochstedler, Fran James, Tonya Jones, Tasha Kellum, June Martin, Denise Dunagan, Christina Cline, Joy Rund, Sue Duson, Angela Parke, Lydia Boas, Mark Burgess, Shannon Copenhaven, Penelope Francis, Ellie Gallaway, Michael Menacker, Sheryl Schwartz, Janet Scombordi-Raghu, Brandy Swiatocha, Janet Zikoski, Edward Kennedy, Leslie Little, Rosemary Moss, Geneva Rorie, Latricia Stokes, Shirley Figueroa, Jose Nesmith, Eric Gold, Gwen Carter, Ashanti Harvey, David Hall, Sandra Hildebrand, Lisa Lapsley, Margaret Quenzer, Cecilia Rosenbach, Lynn Cheatham, Linda Chambless, Anna Beats, Colby Carter, Jerry Coy, Debbie Long, Jeffrey Rice, Shelly Dreadfulwater, Shelly McCully, Cindy Wyers, Rod Blake, Ramona Boswell, Jamey Brown, Anna Fisher, Jeff Larrison, Jody Brightwell-Arnold, Mary Holmes, Christine James, Andrew Khvatov, Aleksandr O'Brien, Lori Whearry, Claressa CA Vision Preschoolers VIP Study Grp TI Impact of Confidence Number on Accuracy of the SureSight Vision Screener SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE confidence number; SureSight Vision Screener; screening accuracy; pre-school vision screening ID WELCH-ALLYN-SURESIGHT; CYCLOPLEGIC AUTOREFRACTION; AMBLYOPIA TREATMENT; PRESCHOOLERS; CHILDREN; TESTS AB Purpose. To assess the relation between the confidence number provided by the Welch Allyn SureSight Vision Screener and screening accuracy, and to determine whether repeated testing to achieve a higher confidence number improves screening accuracy in pre-school children. Methods. Lay and nurse screeners screened 1452 children enrolled in the Vision in Preschoolers (VIP) Phase II Study. All children also Underwent a comprehensive eye examination. By using statistical comparison of proportions, we examined sensitivity and specificity for detecting any Ocular condition targeted for detection in the VIP study and conditions grouped by severity and by type (amblyopia, strabismus, significant refractive error, and unexplained decreased visual acuity) among children who had confidence numbers <= 4 (retest necessary), 5 (retest if possible), >= 6 (acceptable). Among the 687 (47.3%)) children who had repeated testing by either lay or nurse screeners because of a low confidence number (<6) for one or both eyes in the initial testing, the same analyses were also conducted to compare results between the initial reading and repeated test reading with the highest confidence number in the same child. These analyses were based on the failure criteria associated with 90% specificity for detecting any VIP condition in VIP Phase II. Results. A lower confidence number category were associated with higher sensitivity (0.71, 0.65, and 0.59 for <= 4, 5, and >= 6, respectively, p = 0.04) but no statistical difference in specificity (0.85, 0.85, and 0.91, p = 0.07) of detecting any VIP-targeted condition. Children with any VIP-targeted condition were as likely to be detected using the initial confidence number reading as using the higher confidence number reading from repeated testing. Conclusions. A higher confidence number obtained during screening with the SureSight Vision Screener is not associated with better screening accuracy. Repeated testing to reach the manufacturer's recommended minimum value is not helpful in pre-school vision screening. (Optom Vis Sci 2010;87:96-103) C1 [Orel-Bixler, Deborah; Qualley, Pamela; Howard, Dru; Suzuki, Lempi Miller; Fisher, Sarah; Fong, Darlene; Frane, Sara; Hsiao-Threlkeld, Cindy; Koseoglu, Selim; Moy, A. Mika; Shapiro, Sharyn; Verdon, Lisa; Watson, Tonya; McDonnell, Sean; Paez, Erika; Sloan, Darlene; Smith, Evelyn; Soto, Leticia; Prinz, Robert; Edelstein, Joan; Moe, Beatrice] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA. [Moore, Bruce; Bolden, Joanne; Umana, Sandra; Silbert, Amy; Quinn, Nicole; Bordeau, Heather; Carlson, Nancy; Croteau, Amy; Flynn, Micki; Kran, Barry; Ramsey, Jean; Suckow, Melissa; Weissberg, Erik; Chery, Marthedala; Diaz, Maria; Gonzalez, Leticia; Braverman, Edward; Johnson, Rosalyn; Henderson, Charlene; Bonila, Maria; Doherty, Cathy; Peace-Pierre, Cynthia; Saxbe, Ann; Tabb, Vadra] New England Coll Optometry, Boston, MA USA. [Schmidt, Paulette; Kulp, Marjean Taylor; Biddle, Molly; Hudson, Jason; Ackerman, Melanie; Anderson, Sandra; Earley, Michael; Edwards, Kristyne; Evans, Nancy; Gebhart, Heather; Henry, Jay; Hertle, Richard; Hutchinson, Jeffrey; Jenkins, LeVelle; Toole, Andrew; Johnson, Keith; Shoemaker, Richard; Atkinson, Rita; Hochstedler, Fran; James, Tonya; Jones, Tasha; Kellum, June; Martin, Denise; Dunagan, Christina; Cline, Joy; Rund, Sue] Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. [Ciner, Elise; Quinn, Graham; Duson, Angela; Parke, Lydia; Boas, Mark; Burgess, Shannon; Copenhaven, Penelope; Francis, Ellie; Gallaway, Michael; Menacker, Sheryl; Schwartz, Janet; Scombordi-Raghu, Brandy; Swiatocha, Janet; Zikoski, Edward; Kennedy, Leslie; Little, Rosemary; Moss, Geneva; Rorie, Latricia; Stokes, Shirley; Figueroa, Jose; Nesmith, Eric; Gold, Gwen; Carter, Ashanti; Harvey, David; Hall, Sandra; Hildebrand, Lisa; Lapsley, Margaret; Quenzer, Cecilia; Rosenbach, Lynn] Penn Coll Optometry, Philadelphia, PA 19141 USA. [Cyert, Lynn; Cheatham, Linda; Chambless, Anna; Beats, Colby; Carter, Jerry; Coy, Debbie; Long, Jeffrey; Rice, Shelly; Dreadfulwater, Shelly; McCully, Cindy; Wyers, Rod; Blake, Ramona; Boswell, Jamey; Brown, Anna; Fisher, Jeff; Larrison, Jody] NE State Univ, Coll Optometry, Tahlequah, OK USA. [Baumritter, Agnieshka; Maguire, Maureen; Peskin, Ellen; Ying, Gui-Shuang; Brightwell-Arnold, Mary; Holmes, Christine; James, Andrew; Khvatov, Aleksandr; O'Brien, Lori; Whearry, Claressa] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Redford, Maryann] NEI, Bethesda, MD 20892 USA. RP Ying, GS (reprint author), Univ Penn, Scheie Eye Inst, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM gsying@mail.med.upenn.edu RI Toole, Andrew/I-2450-2016 FU National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda [U10EY12534, U10EY12545, U10EY12547, U10EY12550, U10EY12644, U10EY12647, U10EY12648, R21EY018908] FX This work was supported by grants from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD: U10EY12534; U10EY12545; U10EY12547; U10EY12550; U10EY12644; U10EY12647; U10EY12648; and R21EY018908. NR 19 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD FEB PY 2010 VL 87 IS 2 BP 96 EP 103 PG 8 WC Ophthalmology SC Ophthalmology GA 552IW UT WOS:000274284100004 ER PT J AU Thompson, BW Miller, ST Rogers, ZR Rees, RC Ware, RE Waclawiw, MA Iyer, RV Casella, JF Luchtman-Jones, L Rana, S Thornburg, CD Kalpatthi, RV Barredo, JC Brown, RC Sarnaik, S Howard, TH Luck, L Wang, WC AF Thompson, Bruce W. Miller, Scott T. Rogers, Zora R. Rees, Renee C. Ware, Russell E. Waclawiw, Myron A. Iyer, Rathi V. Casella, James F. Luchtman-Jones, Lori Rana, Sohail Thornburg, Courtney D. Kalpatthi, Ram V. Barredo, Julio C. Brown, R. Clark Sarnaik, Sharada Howard, Thomas H. Luck, Lori Wang, Winfred C. TI The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG): Challenges of Study Design SO PEDIATRIC BLOOD & CANCER LA English DT Article DE clinical trial; hydroxyurea; infants; sickle cell ID SICKLE-CELL-DISEASE; HEMOGLOBIN-F PRODUCTION; FETAL HEMOGLOBIN; RISK-FACTORS; CHILDREN; ANEMIA; THERAPY; NEPHROPATHY; ENDOTHELIUM; ERYTHROCYTE AB Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might Support widespread use of the drug at all early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating Young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially Vulnerable subjects were allayed by inclusion of a research Subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of all unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400). Pediatr Blood Cancer 2010;54:250-255. (C) 2009 Wiley-Liss, Inc. C1 [Thompson, Bruce W.; Rees, Renee C.] Clin Trials & Surveys Corp, Baltimore, MD 21117 USA. [Miller, Scott T.] Suny Downstate Med Ctr, Kings Cty Hosp Ctr, Brooklyn, NY 11203 USA. [Rogers, Zora R.] UT SW Med Ctr, Dallas, TX USA. [Ware, Russell E.; Wang, Winfred C.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Waclawiw, Myron A.] NHLBI, Bethesda, MD 20892 USA. [Iyer, Rathi V.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Casella, James F.] Johns Hopkins Univ, Baltimore, MD USA. [Luchtman-Jones, Lori] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Rana, Sohail] Howard Univ, Washington, DC 20059 USA. [Thornburg, Courtney D.] Duke Univ, Med Ctr, Durham, NC USA. [Kalpatthi, Ram V.] Med Univ S Carolina, Charleston, SC 29425 USA. [Barredo, Julio C.] Univ Miami, Miami, FL USA. [Brown, R. Clark] Emory Univ, Atlanta, GA 30322 USA. [Sarnaik, Sharada] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Howard, Thomas H.] Univ Alabama, Birmingham, AL USA. [Luck, Lori] Drexel Univ, Philadelphia, PA 19104 USA. RP Thompson, BW (reprint author), Clin Trials & Surveys Corp, 10065 Red Run Blvd,Suite 250, Baltimore, MD 21117 USA. EM bthompson@c-tasc.com FU National Heart, Lung, and Blood Institute/National Institutes of Health [N01-HB-07150, N01-HB-07160]; Best Pharmaceuticals for Children Act; National Institute of Child Health and Human Development FX We acknowledge the efforts of the BABY HUG subjects and their families, the contributions of all who participated in BABY HUG (http://www.c-tasc.com/cms/StudySites/babyhug.htm) and the support of the National Heart, Lung, and Blood Institute/National Institutes of Health Contracts N01-HB-07150 to N01-HB-07160, with partial support of the Best Pharmaceuticals for Children Act and the National Institute of Child Health and Human Development. NR 44 TC 29 Z9 29 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2010 VL 54 IS 2 BP 250 EP 255 DI 10.1002/pbc.22269 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 538TK UT WOS:000273206700014 PM 19731330 ER PT J AU Smith, MA Morton, CL Kolb, EA Gorlick, R Keir, ST Carol, H Lock, R Kang, MH Reynolds, CP Maris, JM Watkins, AE Houghton, PJ AF Smith, Malcolm A. Morton, Christopher L. Kolb, E. Anders Gorlick, Richard Keir, Stephen T. Carol, Hernan Lock, Richard Kang, Min H. Reynolds, C. Patrick Maris, John M. Watkins, Amy E. Houghton, Peter J. TI Initial Testing (Stage 1) of Mapatumumab (HGS-ETR1) by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; mapatumumab; preclinical testing ID APOPTOSIS-INDUCING LIGAND; HUMAN MONOCLONAL-ANTIBODY; TRAIL-INDUCED APOPTOSIS; EWINGS-SARCOMA FAMILY; CELL-LINES; IN-VIVO; RESISTANCE; DEATH; NEUROBLASTOMA; MODELS AB Mapatumumab (HGS-ETR1) is a fully human IgG1 agonistic monoclonal antibody that exclusively targets and activates tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). It was tested in vitro at concentrations from 0.01 to 100 mu g/ml and in vivo at a close of 10 mg/kg administered intra-peritoneally using a twice-weekly schedule. Mapatumumab demonstrated limited activity against the 23 cell lines of the PPTP in vitro panel with no lines achieving 50% growth inhibition. Mapatumumab induced significant differences in event-free survival distribution compared to controls in 9 of 37 evaluable solid tumor xenografts tested, but in none of the 8 ALL xenografts. Pediatr Blood Cancer 2010;54:307-310. (C) 2009 Wiley-Liss, Inc. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, EPN, Bethesda, MD 20892 USA. [Morton, Christopher L.; Watkins, Amy E.; Houghton, Peter J.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Kang, Min H.; Reynolds, C. Patrick] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med & Abramson, Family Canc Res Inst, Philadelphia, PA 19104 USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, EPN, Room 7025, Bethesda, MD 20892 USA. EM smithm@ctep.nic.nih.gov RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [N01-CM-42216, CA21765, CA108786] FX This work was supported by N01-CM-42216, CA21765, and CA108786 from the National Cancer Institute, and mapatumumab was provided by Human Genome Sciences. In addition to the authors, the manuscript represents work contributed by the following: Sherry Ansher, Joshua Courtright, Edward Favours, Henry S. Friedman, Debbie Payne-Turner, Charles Stopford, Chandra Tucker, Jianrong Wu, Joe Zeidner, Ellen Zhang, and Jian Zhang. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. NR 23 TC 11 Z9 11 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2010 VL 54 IS 2 BP 307 EP 310 DI 10.1002/pbc.22188 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 538TK UT WOS:000273206700024 PM 19856388 ER PT J AU Wayne, AS Baird, K Egeler, RM AF Wayne, Alan S. Baird, Kristin Egeler, R. Maarten TI Hematopoietic Stem Cell Transplantation for Leukemia SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Leukemia; Hematopoietic stem cell transplantation; HSCT; Pediatric ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; PEDIATRIC-ONCOLOGY-GROUP; CHILDRENS-CANCER-GROUP; JUVENILE MYELOMONOCYTIC LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; HLA-IDENTICAL SIBLINGS; TOTAL-BODY IRRADIATION AB Leukemia represents the most common pediatric malignancy, accounting for approximately 30% of all cancers in children less than 20 years of age. Most children diagnosed with leukemia are cured without hematopoietic stem cell transplantation (HSCT), but for some high-risk subgroups, allogeneic HSCT plays an important role in their therapeutic approach. The characteristics of these high-risk subgroups and the role of HSCT in childhood leukemias are discussed. C1 [Wayne, Alan S.; Baird, Kristin] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Egeler, R. Maarten] Leiden Univ, Med Ctr, Dept Pediat Immunol Hematol Oncol Bone Marrow Tra, NL-2300 RC Leiden, Netherlands. RP Wayne, AS (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-3750,9000 Rockville Pike,MSC 1104, Bethesda, MD 20892 USA. EM waynea@mail.nih.gov FU Intramural NIH HHS [ZIC BC010596-06, Z99 CA999999, ZIC SC010353-10] NR 169 TC 15 Z9 17 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2010 VL 57 IS 1 BP 1 EP + DI 10.1016/j.pcl.2009.11.005 PG 26 WC Pediatrics SC Pediatrics GA 588AW UT WOS:000277039300002 PM 20307709 ER PT J AU Coppes, MJ Fry, TJ Mackall, CL AF Coppes, Max J. Fry, Terry J. Mackall, Crystal L. TI Hematopoietic Stem Cell Transplantation Preface SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Editorial Material ID BONE-MARROW TRANSPLANTATION C1 [Coppes, Max J.; Fry, Terry J.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat Immunol, Washington, DC 20010 USA. [Coppes, Max J.] Georgetown Univ, Washington, DC USA. [Mackall, Crystal L.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Coppes, MJ (reprint author), Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat Immunol, 4 W Wing,111 Michigan Ave NW, Washington, DC 20010 USA. EM MCoppes@cnmc.org; tfry@cnmc.org; cm35c@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2010 VL 57 IS 1 BP XVII EP XIX DI 10.1016/j.pcl.2010.01.021 PG 3 WC Pediatrics SC Pediatrics GA 588AW UT WOS:000277039300001 ER PT J AU Ahmed, N Heslop, HE Mackall, CL AF Ahmed, Nabil Heslop, Helen E. Mackall, Crystal L. TI T-cell-based Therapies for Malignancy and Infection in Childhood SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Hematopoietic stem cell transplantation; Pediatrics; Adoptive immunotherapy; Tumor vaccines; Tumor antigens; Lymphopenia; Immune reconstitution; Chimeric antigen receptor ID CHRONIC MYELOGENOUS LEUKEMIA; DONOR LYMPHOCYTE INFUSIONS; CHRONIC MYELOID-LEUKEMIA; ADOPTIVE TRANSFER; CANCER-IMMUNOTHERAPY; TUMOR-ANTIGEN; NEUROBLASTOMA-CELLS; VIRAL-INFECTIONS; HODGKINS-DISEASE; GENE-EXPRESSION AB One major advance in T-cell-based immunotherapy in the last 20 years has been the molecular definition of numerous viral and tumor antigens. Adoptive T-cell transfer has shown definite clinical benefit in the prophylaxis and treatment of viral infections that develop in pediatric patients after allogeneic transplant and in posttransplant lymphoproliferative disease associated with Epstein-Barr virus. Developing adoptive T-cell therapies for other malignancies presents additional challenges. This article describes the recent advances in T-cell-based therapies for malignancy and infection in childhood and strategies to enhance the effector functions of T cells and optimize the cellular product, including gene modification and modulation of the host environment. C1 [Ahmed, Nabil] Baylor Coll Med, Ctr Cell & Gene Therapy, Dept Pediat, Houston, TX 77030 USA. [Heslop, Helen E.] Baylor Coll Med, Ctr Cell & Gene Therapy, Dept Pediat & Med, Houston, TX 77030 USA. [Heslop, Helen E.] Methodist Hosp, Houston, TX 77030 USA. [Mackall, Crystal L.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ahmed, N (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, Dept Pediat, 1102 Bates St,Suite 1770,MC3-3320, Houston, TX 77030 USA. EM nahmed@bcm.edu FU Dana Foundation; V-Foundation for Cancer Research; American Brain Tumor Association; Doris Duke Distinguished Clinical Scientist Award; NIH/NCI [P01 CA94237] FX N.A. is supported by grants from the Dana Foundation, the V-Foundation for Cancer Research and the American Brain Tumor Association. H.E.H. is the recipient of a Doris Duke Distinguished Clinical Scientist Award and the NIH/NCI P01 CA94237 and SPORE-in Lymphoma. This work was supported, in part, by the Intramural Research Program of the National Cancer Institute (C.L.M.). NR 72 TC 5 Z9 5 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 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2010 VL 57 IS 1 BP 83 EP 96 DI 10.1016/j.pcl.2009.11.002 PG 14 WC Pediatrics SC Pediatrics GA 588AW UT WOS:000277039300006 PM 20307713 ER PT J AU Baird, K Cooke, K Schultz, KR AF Baird, Kristin Cooke, Kenneth Schultz, Kirk R. TI Chronic Graft-Versus-Host Disease (GVHD) in Children SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Chronic graft-versus-host disease; GVHD; Children; Hematopoeitic stem cell transplant ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; UMBILICAL-CORD-BLOOD; MINOR HISTOCOMPATIBILITY ANTIGENS; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; NONINFECTIOUS PULMONARY COMPLICATIONS; SOLUBLE INTERLEUKIN-2-RECEPTOR LEVELS; OBLITERANS ORGANIZING PNEUMONIA AB Five-year survival rates for childhood cancer now exceed 80% and with the significant progress made by the transplant community in developing less toxic conditioning regimens and in the treatment of posttransplant complications, allo-hematopoietic stem cell transplantation (HSCT) contributes significantly to that population of long-term survivors. In this context, the acute and long-term toxicities of chronic graft-versus-host disease (cGVHD) have an ever-increasing effect on organ function, quality of life, and survival; patients and families who initially felt great relief to be cured from the primary disease, now face the challenge of a chronic debilitating illness for which preventative and treatment strategies are suboptimal. Hence, the development of novel strategies that reduce and/or control cGVHD, preserve graft-versus-tumor effects, facilitate engraftment and immune reconstitution, and enhance survival after allo-HSCT represents one of the most significant challenges facing physician-scientists and patients. C1 [Baird, Kristin] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cooke, Kenneth] Case Western Reserve Univ, Sch Med, Pediat Blood & Marrow Transplantat Program, Cleveland, OH USA. [Cooke, Kenneth] Case Western Reserve Univ, Sch Med, Multidisciplinary Initiat Graft Vs Host Dis, Cleveland, OH USA. [Cooke, Kenneth] Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. [Schultz, Kirk R.] BC Childrens Hosp, Childhood Canc Res Program, Vancouver, BC V6H 3V4, Canada. [Schultz, Kirk R.] Child & Family Res Inst, Vancouver, BC, Canada. RP Baird, K (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-3750,9000 Rockville Pike,MSC 1104, Bethesda, MD 20892 USA. EM kbaird@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 190 TC 30 Z9 31 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2010 VL 57 IS 1 BP 297 EP + DI 10.1016/j.pcl.2009.11.003 PG 27 WC Pediatrics SC Pediatrics GA 588AW UT WOS:000277039300015 PM 20307722 ER PT J AU Henderson, WA Hadigan, CM AF Henderson, Wendy A. Hadigan, Colleen M. TI Liver Histology Damage in Children With Chronic Hepatitis C Reply SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID INFECTION C1 [Henderson, Wendy A.; Hadigan, Colleen M.] NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Henderson, WA (reprint author), NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. OI Henderson, Wendy/0000-0003-3924-7118 NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD FEB PY 2010 VL 29 IS 2 BP 190 EP 190 PG 1 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 549EV UT WOS:000274029600030 ER PT J AU Gerson, AC Wentz, A Abraham, AG Mendley, SR Hooper, SR Butler, RW Gipson, DS Lande, MB Shinnar, S Moxey-Mims, MM Warady, BA Furth, SL AF Gerson, Arlene C. Wentz, Alicia Abraham, Allison G. Mendley, Susan R. Hooper, Stephen R. Butler, Robert W. Gipson, Debbie S. Lande, Marc B. Shinnar, Shlomo Moxey-Mims, Marva M. Warady, Bradley A. Furth, Susan L. TI Health-Related Quality of Life of Children With Mild to Moderate Chronic Kidney Disease SO PEDIATRICS LA English DT Article DE HRQoL; kidney disease; QoL; short stature ID GENERIC CORE SCALES; STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; GROWTH-HORMONE TREATMENT; SOCIOECONOMIC-STATUS; FACTORIAL INVARIANCE; PEDIATRIC-PATIENTS; CHRONIC ILLNESS; SELF-REPORT; ADOLESCENTS AB OBJECTIVE: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) with healthy children; to evaluate the association between CKD severity and HRQoL; and to identity demographic, socioeconomic, and health-status variables that are associated with impairment in HRQoL in children with mild to moderate CKD. METHODS: This was a cross-sectional assessment of HRQoL in children who were aged 2 to 16 and had mild to moderate CKD using the Pediatric Inventory of Quality of Life Core Scales (PedsQL). Overall HRQoL and PedsQL domain means for parents and youth were compared with previously published norms by using independent sample ttests. Study participants were categorized by kidney disease stage (measured by iohexol-based glomerular filtration rate [iGFR]), and group differences in HRQoL were evaluated by using analysis of variance and Cuzick trend tests. The association between hypothesized predictors of HRQoL and PedsQL scores was evaluated with linear and logistic regression analyses. RESULTS: The study sample comprised 402 participants (mean age: 11 years, 60% male, 70% white, median iGFR: 42.5 mL/min per 1.73 m(2), median CKD duration: 7 years). Youth with CKD had significantly lower physical, school, emotional, and social domain scores than healthy youth. iGFR was not associated with HRQoL. Longer disease duration and older age were associated with higher PedsQL scores in the domains of physical, emotional, and social functioning. Older age was associated with lower school domain scores. Maternal education >= 16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning. Short stature was associated with lower scores in the physical functioning domain. CONCLUSIONS: Children with mild to moderate CKD, in comparison with healthy children, reported poorer overall HRQoL and poorer physical, school, emotional, and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended. Pediatrics 2010; 125:e349-e357 C1 [Gerson, Arlene C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Nephrol, Baltimore, MD 21287 USA. [Furth, Susan L.] Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Wentz, Alicia; Abraham, Allison G.; Furth, Susan L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mendley, Susan R.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Hooper, Stephen R.; Gipson, Debbie S.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. [Butler, Robert W.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR USA. [Lande, Marc B.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Shinnar, Shlomo] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Moxey-Mims, Marva M.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Warady, Bradley A.] Childrens Mercy Hosp, Dept Pediat, Kansas City, KS USA. RP Gerson, AC (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Nephrol, 200 N Wolfe St,3060, Baltimore, MD 21287 USA. EM agerson@jhmi.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurologic Disorders and Stroke; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute [UO1-DK-66143, UO1-DK-66174, UO1-DK-66116] FX Data in this article were collected by the CKiD with clinical coordinating centers (principal investigators) at Children's Mercy Hospital and the University of Missouri-Kansas City (Bradley Warady, MD) and Johns Hopkins School of Medicine (Susan Furth, MD, PhD) and data coordinating center (principal investigator) at the Johns Hopkins Bloomberg School of Public Health (Alvaro Munoz, PhD). The CKiD is funded by the National Institute of Diabetes and Digestive and Kidney Diseases with additional funding from the National Institute of Neurologic Disorders and Stroke; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the National Heart, Lung, and Blood Institute (UO1-DK-66143, UO1-DK-66174, and UO1-DK-66116). The CKID Web site is located at www.statepi.jhsph.edu/ckid. NR 47 TC 57 Z9 59 U1 2 U2 13 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 FEB PY 2010 VL 125 IS 2 BP E349 EP E357 DI 10.1542/peds.2009-0085 PG 9 WC Pediatrics SC Pediatrics GA 573VH UT WOS:000275942900050 PM 20083528 ER PT J AU Williams, PL Marino, M Malee, K Brogly, S Hughes, MD Mofenson, LM AF Williams, Paige L. Marino, Miguel Malee, Kathleen Brogly, Susan Hughes, Michael D. Mofenson, Lynne M. CA PACTG 219C Team TI Neurodevelopment and In Utero Antiretroviral Exposure of HIV-Exposed Uninfected Infants SO PEDIATRICS LA English DT Article DE Bayley scales; mental development; motor development; maternal health; antiretroviral treatment; low birth weight ID HUMAN-IMMUNODEFICIENCY-VIRUS; PERSISTENT MITOCHONDRIAL DYSFUNCTION; TRANSCRIPTASE INHIBITOR EXPOSURE; TO-CHILD TRANSMISSION; INFECTED WOMEN; HIV-1-INFECTED MOTHERS; PERINATAL TRANSMISSION; CLINICAL-TRIALS; PREGNANT-WOMEN; UNITED-STATES AB OBJECTIVE: Antiretroviral (ARV) drugs are routinely provided to HIV-infected pregnant women to prevent HIV mother-to-child transmission. Although ARV use has significantly reduced mother-to-child transmission to <2% in the United States, it remains crucial to monitor uninfected infants and children for adverse consequences of in utero ARV exposure. METHODS: We studied neurodevelopmental function in HIV-exposed uninfected children who were enrolled in Pediatric AIDS Clinical Trials Group 219/219C, a multisite, prospective, cohort study. Mental and motor functioning were assessed with the Bayley Scales of Infant Development (BSID), first and second editions. ARV exposure information was collected during pregnancy or within the first years of life. Linear regression methods were used to evaluate the association of in utero ARV exposure on Mental Developmental Index and Psychomotor Developmental Index at 2 years of age, controlling for demographic factors (age, gender, and race/ethnicity) and potential confounders: test version, primary language, primary caregiver, caregiver education level, low birth weight, geographic and urban/rural location, birth year, and maternal illicit drug use. RESULTS: Among 1840 infants who were born between 1993 and 2006, 1694 (92%) were exposed to ARV in utero and 146 (8%) were not exposed. After controlling for confounders, children who were exposed in utero to any ARV did not have lower Mental Developmental Index and Psychomotor Developmental Index scores than unexposed children. Among low birth weight infants, significantly higher BSID scores were observed for prenatally ARV-exposed than unexposed children. Maternal illicit drug use was reported for 17% of mothers but was not associated with BSID scores. CONCLUSIONS: Mental and motor functioning scores were not lower for infants with in utero ARV exposure compared with no exposure. Although these results are reassuring, continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important. Pediatrics 2010; 125: e250-e260 C1 [Williams, Paige L.; Marino, Miguel; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Williams, Paige L.; Brogly, Susan; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Malee, Kathleen] Childrens Mem Hosp, Chicago, IL 60614 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver NICHHD, Rockville, MD USA. RP Williams, PL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave,Bldg 1,415, Boston, MA 02115 USA. EM paige@sdac.harvard.edu OI Mofenson, Lynne/0000-0002-2818-9808; Bonagura, Vincent/0000-0002-0681-2099 FU NCI NIH HHS [T32 CA009337]; NIAID NIH HHS [1 U01 AI068616, 5 U01 AI41110, U01 AI041110, U01 AI068616, U01 AI068632, U01 AI068632-03]; NICHD NIH HHS [HHSN267200800001C]; NIDDK NIH HHS [HHSN267200800001G] NR 44 TC 31 Z9 35 U1 1 U2 6 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 FEB PY 2010 VL 125 IS 2 BP E250 EP E260 DI 10.1542/peds.2009-1112 PG 11 WC Pediatrics SC Pediatrics GA 573VH UT WOS:000275942900038 PM 20083530 ER PT J AU Giraud, AS Dumesny, C Whitley, JC Parker, LM Jennings, I Kemp, B Moody, TW Sancho, V Jensen, RT Shulkes, A AF Giraud, A. S. Dumesny, C. Whitley, J. C. Parker, L. M. Jennings, I. Kemp, B. Moody, T. W. Sancho, V. Jensen, R. T. Shulkes, A. TI Isolation, identification and biological activity of gastrin-releasing peptide 1-46 (oGRP(1-46)), the primary GRP gene-derived peptide product of the pregnant ovine endometrium SO PEPTIDES LA English DT Article DE Ovine; Gastrin-releasing peptide; Pregnancy; Endometrium ID MAMMALIAN BOMBESIN RECEPTORS; C-TERMINAL FRAGMENTS; HIGH-AFFINITY; UTERUS; EXPRESSION; CANCER; PROLIFERATION; LOCALIZATION; PHARMACOLOGY; PRECURSOR AB We have previously demonstrated that pregnant ovine endometrium expresses the gastrin-releasing peptide (GRP) gene at a high level following conceptus implantation. Here we report the isolation, characterization and biological activity of ovine GRP1-46, the primary product of this gene in the pregnant endometrium. Full thickness 125-140-day pregnant sheep uterus (term is 145 day) was homogenized in 80% acetonitrile/2% trifluoroacetic acid (1:7 ACN/TFA), concentrated on reverse-phase C18 cartridges and chromatographed successively on gel filtration (Sephadex G-50) and reverse-phase HPLC (C18 mu Bondapak). Purification was monitored by RIA. Purified GRP peptide was analysed by mass spectrometry giving a major mass ion at 4963 which corresponds exactly to GRP1-46. Other mass ions from pro-GRP did not contain a biologically active N-terminus or antigenic determinant. Proteolytic cleavage of pro-GRP to give rise to GRP(1-46) would require preferential cleavage at the Glu-Glu bond by a Glu-C2-like enzyme, rather than the trypsin-like and C-terminal amidation enzymes (PAM) that produce GRP(18-27) and GRP(1-27) in other tissues. GRP(1-46) was synthesized and receptor binding and biological activity tested on a range of rodent and human cell lines that express GRP-related receptors GRPR, NMBR and BRS3. GRP1-46 bound GRPR and NMBR with low affinity, and mobilized inositol phosphate in cell lines expressing the GRPR and NMBR, but not BRS-3. This study describes a new processed product of the GRP gene, GRP-46, which is highly expressed in the pregnant sheep endometrium and which acts as a weak agonist at the GRPR and NMBR. (C) 2009 Elsevier Inc. All rights reserved. C1 [Giraud, A. S.; Parker, L. M.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Dumesny, C.; Shulkes, A.] Univ Melbourne, Dept Surg, Heidelberg, Vic, Australia. [Kemp, B.] St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia. [Moody, T. W.; Sancho, V.; Jensen, R. T.] NIDDK, Gastrointestinal Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Whitley, J. C.] Univ Melbourne, Dept Vet Sci, Parkville, Vic 3052, Australia. [Jennings, I.] Monash Univ, Dept Med Chem, Fac Pharm & Pharmaceut Sci, Parkville, Vic, Australia. RP Giraud, AS (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. EM andrew.giraud@mcri.edu.au RI Kemp, Bruce/L-2633-2014 OI Kemp, Bruce/0000-0001-6735-5082 FU National Health and Medical Research Council of Australia; NIDDK, NIH FX We thank the late Professor John Walsh and the late Ms Helen Wong (Department of Medicine, UCLA, Los Angeles, CA) for donating antisera 8684. This work was supported by projects grants from the National Health and Medical Research Council of Australia and intramural funds of NIDDK, NIH. NR 28 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2010 VL 31 IS 2 BP 284 EP 290 DI 10.1016/j.peptides.2009.11.013 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 560BQ UT WOS:000274877200014 PM 19944725 ER PT J AU Sinha, GP Sabri, F Dimitriadis, EK Iwasa, KH AF Sinha, Ghanshyam P. Sabri, Firouzeh Dimitriadis, Emilios K. Iwasa, Kuni H. TI Organization of membrane motor in outer hair cells: an atomic force microscopic study SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Outer hair cells; Atomic force microscopy; Prestin; Cytosolic plasma membrane; Hair Cell; Microscopy; Mechanoelectrical transduction; Immunocytochemistry ID PLASMA-MEMBRANE; PROTEIN PRESTIN; GUINEA-PIG; COCHLEAR AMPLIFICATION; CORTICAL CYTOSKELETON; MOTILITY; CHARGE; ELECTROMOTILITY; CAPACITANCE; GENERATION AB Using atomic force microscopy, we imaged the cytosolic surface of the lateral plasma membrane of outer hair cells from guinea pigs' inner ear. We used a "cell-free" preparation, in which a patch of plasma membrane was firmly attached to a substrate and the cytoplasmic face was exposed. The membrane patches contained densely packed particles whose diameter, after correcting for the geometry of the probing tip, was similar to 10 nm. The particles were predominantly aligned unidirectionally with spacing of similar to 36 nm. The density of the particle was similar to 850 mu m(-2), which could be an underestimate presumably due to the method of sample preparation. Antibody-labeled specimens showed particles more elevated than unlabeled preparation indicative of primary and secondary antibody complexes. The corrected diameters of these particles labeled with anti-actin were similar to 12 nm while that with antiprestin were similar to 8 nm. The alignment pattern in antiprestin-labeled specimens resembled that of the unlabeled preparation. Specimens labeled with actin antibodies did not show such alignment. We interpret that the particles observed in the unlabeled membranes correspond to the 10-nm particles reported by electron microscopy and that these particles contain prestin, a member of the SLC26 family, which is essential for electromotility. C1 [Sinha, Ghanshyam P.; Sabri, Firouzeh; Iwasa, Kuni H.] Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, Rockville, MD 20850 USA. [Dimitriadis, Emilios K.] Natl Inst Biomed Imaging Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Iwasa, KH (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, 5 Res Court, Rockville, MD 20850 USA. EM iwasa@nih.gov OI Iwasa, Kuni/0000-0002-9397-7704 FU NIDCD, NIH FX We thank Dr. Bechara Kachar for kindly providing us with prestin antibodies. We also thank Drs. Ronald Petralia and Paul Gallant for useful comments. This work is supported by the intramural research program of NIDCD, NIH. NR 58 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2010 VL 459 IS 3 BP 427 EP 439 DI 10.1007/s00424-009-0742-3 PG 13 WC Physiology SC Physiology GA 556JM UT WOS:000274586900008 PM 19809831 ER PT J AU Jones, JD Hall, FS Uhl, GR Riley, AL AF Jones, Jermaine D. Hall, F. Scott Uhl, George R. Riley, Anthony L. TI Dopamine, norepinephrine and serotonin transporter gene deletions differentially alter cocaine-induced taste aversion SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Taste aversion; DAT; NET; SERT; Knockout; Monoamine ID CONDITIONED PLACE PREFERENCE; RECEPTOR KNOCKOUT MICE; MONOAMINE TRANSPORTERS; BEHAVIORAL-RESPONSES; DEFICIENT MICE; PANIC ATTACKS; MUTANT MICE; D1 RECEPTOR; OUT MICE; LACKING AB Although cocaine is primarily known for its powerful hedonic effects, there is evidence that its affective experience has a notable aversive component that is less well understood. A variety of pharmacological and molecular approaches have implicated enhanced monoamine (MA) neurotransmission in the aversive effects of cocaine. Although numerous studies have yielded data supportive of the role of the monoamines (indirectly and directly), the specific system suggested to be involved differs across studies and paradigms (Freeman et al., 2005b; Grupp, 1997; Roberts and Fibiger, 1997). Monoamine transporter knockout mice have been useful in the study of many different aspects of cocaine effects relevant to human drug use and addiction, yet an assessment of the effects of deletion of the genes for the dopamine, norepinephrine and serotonin transporters (DAT, NET, and SERT, respectively) on cocaine's aversive properties has yet to be performed (Uhl et al., 2002). In the current investigation, the strength of cocaine-induced aversions was compared among three groups of transgenic mice with deletions of the genes responsible for the production of one of the monoamine transporters. When compared to their respective WT controls, dopamine transporter deletion slightly attenuated cocaine-induced aversion while deletion of SERT or NET resulted in a more significant delay in the onset and strength of cocaine-induced taste aversions. The data lead us to conclude that the action of cocaine to inhibit NET contributes most substantially to its aversive effects, with some involvement of SERT and minimal contribution of DAT. (C) 2009 Elsevier Inc. All rights reserved. C1 [Jones, Jermaine D.; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Hall, F. Scott; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD USA. RP Jones, JD (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Subst Use Res Ctr, 1051 Riverside Dr, New York, NY 10032 USA. EM JermaineDJones@gmail.com RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Mellon Foundation; National Institute on Drug Abuse FX This research was supported by a grant from the Mellon Foundation (ALR), and also, in part, by the Intramural Research Program of the National Institute on Drug Abuse (FSH, GRU). Requests for reprints should be sent to Jermaine Jones, Substance Use Research Center, New York State Psychiatric Institute, 1051 Riverside Dr. New York, NY 10032. NR 70 TC 14 Z9 14 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD FEB PY 2010 VL 94 IS 4 BP 580 EP 587 DI 10.1016/j.pbb.2009.11.014 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 561CV UT WOS:000274954000012 PM 19969013 ER PT J AU Damiano, DL Arnold, AS Steele, KM Delp, SL AF Damiano, Diane L. Arnold, Allison S. Steele, Katherine M. Delp, Scott L. TI Can Strength Training Predictably Improve Gait Kinematics? A Pilot Study on the Effects of Hip and Knee Extensor Strengthening on Lower-Extremity Alignment in Cerebral Palsy SO PHYSICAL THERAPY LA English DT Article ID LIMB STANCE PHASE; DYNAMIC SIMULATIONS; CROUCH GAIT; CHILDREN; EXERCISE; MOVEMENT; ROTATION; MUSCLES; WALKING AB Background. Computer simulations have demonstrated that excessive hip and knee flexion during gait, as frequently seen in ambulatory children with cerebral palsy (CP), call reduce the ability of muscles to provide antigravity support and increase the tendency of hip muscles to internally rotate the thigh. These findings Suggest that therapies for improving upright posture during gait also may reduce excessive internal rotation. Objective. The goal of this study was to determine whether strength training call diminish the degree of crouched, internally rotated gait ill children with Spastic diplegic CP. Design. This was a pilot prospective clinical trial. Methods. Eight children with CP participated in an 8-week progressive resistance exercise program, with 3-dimensional gait analysis and isokinetic testing performed before and after the program. Secondary measures included passive range of motion, the Ashworth Scale, and the PedsQL CP Module. To identify factors that may have influenced Outcome, individual and Subgroup data were examined for patterns of change within and across variables. Results. Strength (force-generating capacity) increased significantly in the left hip extensors, with smaller, nonsignificant mean increases in the other 3 extensor muscle groups, yet kinematic and functional outcomes were inconsistent. The first reported subject-specific computer simulations of crouch gait were created for one child who showed substantial benefit to examine the factors that may have contributed to this outcome. Limitations. The sample was small, with wide variability in outcomes Conclusions. Strength training may improve walking function and alignment in some patients for whom weakness is a major contributor to their gait deficits. However, in other patients, it may produce no change or even undesired outcomes. Given the variability of outcomes in this and other strengthening studies in CP, analytical approaches to determine the Sources of variability are needed to better identify those individuals Who are most likely to benefit from strengthening. C1 [Damiano, Diane L.] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Arnold, Allison S.] Harvard Univ, Concord Field Stn, Bedford, MA USA. [Steele, Katherine M.] Stanford Univ, Dept Mech Engn, Sch Engn, Stanford, CA 94305 USA. [Delp, Scott L.] Stanford Univ, Sch Engn & Med, Stanford, CA 94305 USA. RP Damiano, DL (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bldg 10,Room 1-1469, Bethesda, MD 20892 USA. EM damianod@cc.nih.gov RI Damiano, Diane/B-3338-2010; Van Mulders, Benjamin/P-1241-2014 OI Damiano, Diane/0000-0002-2770-5356; FU United Cerebral Palsy Research & Education Foundation; intramural program at the National Institutes of Health FX The authors acknowledge the United Cerebral Palsy Research & Education Foundation for funding this project. This research also was supported, in part, by the intramural program at the National Institutes of Health. The authors thank Julie Anderson for her assistance in all aspects of the study and Tom Nuzum and Dave Reddy for conducting the training sessions for all participants. NR 26 TC 45 Z9 48 U1 2 U2 24 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD FEB PY 2010 VL 90 IS 2 BP 269 EP 279 DI 10.2522/ptj.20090062 PG 11 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 550LT UT WOS:000274130000016 PM 20022999 ER PT J AU Tchapyjnikov, D Li, YD Pisitkun, T Hoffert, JD Yu, MJ Knepper, MA AF Tchapyjnikov, Dmitry Li, Yuedan Pisitkun, Trairak Hoffert, Jason D. Yu, Ming-Jiun Knepper, Mark A. TI Proteomic profiling of nuclei from native renal inner medullary collecting duct cells using LC-MS/MS SO PHYSIOLOGICAL GENOMICS LA English DT Article DE vasopressin; transcription; aquaporin ID RAT-KIDNEY; WATER CHANNEL; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATION; PROTEIN IDENTIFICATIONS; INTRACELLULAR CA2+; MASS-SPECTROMETRY; AQP2 EXPRESSION; VASOPRESSIN; PHOSPHORYLATION AB Tchapyjnikov D, Li Y, Pisitkun T, Hoffert JD, Yu M-J, Knepper MA. Proteomic profiling of nuclei from native renal inner medullary collecting duct cells using LC-MS/MS. Physiol Genomics 40: 167-183, 2010. First published December 8, 2009; doi:10.1152/physiolgenomics.00148.2009.-Vasopressin is a peptide hormone that regulates renal water excretion in part through its actions on the collecting duct. The regulation occurs in part via control of transcription of genes coding for the water channels aquaporin-2 (Aqp2) and aquaporin-3 (Aqp3). To identify transcription factors expressed in collecting duct cells, we have carried out LC-MS/MS-based proteomic profiling of nuclei isolated from native rat inner medullary collecting ducts (IMCDs). To maximize the number of proteins identified, we matched spectra to rat amino acid sequences using three different search algorithms (SEQUEST, InsPecT, and OMSSA). All searches were coupled to target-decoy methodology to limit false-discovery identifications to 2% of the total for single-peptide identifications. In addition, we developed a computational tool (ProMatch) to identify and eliminate ambiguous identifications. With this approach, we identified > 3,500 proteins, including 154 proteins classified as "transcription factor" proteins (Panther Classification System). Among these, are members of CREB, ETS, RXR, NFAT, HOX, GATA, EBOX, EGR, MYT1, KLF, and CP2 families, which were found to have evolutionarily conserved putative binding sites in the 5'-flanking region or first intron of the Aqp2 gene, as well as members of EBOX, NR2, GRE, MAZ, KLF, and SP1 families corresponding to conserved sites in the 5'-flanking region of the Aqp3 gene. In addition, several novel phosphorylation sites in nuclear proteins were identified using the neutral loss-scanning LC-MS(3) technique. The newly identified proteins have been incorporated into the IMCD Proteome Database (http://dir.nhlbi.nih.gov/papers/lkem/imcd/). C1 [Tchapyjnikov, Dmitry; Li, Yuedan; Pisitkun, Trairak; Hoffert, Jason D.; Yu, Ming-Jiun; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 NR 54 TC 30 Z9 30 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD FEB PY 2010 VL 40 IS 3 BP 167 EP 183 DI 10.1152/physiolgenomics.00148.2009 PG 17 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 552JV UT WOS:000274287000006 PM 19996160 ER PT J AU Coelho, SG Hearing, VJ AF Coelho, Sergio G. Hearing, Vincent J. TI UVA tanning is involved in the increased incidence of skin cancers in fair-skinned young women SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanoma; young women; UVA; sunlamps; tanning ID MELANOCORTIN 1 RECEPTOR; INDUCED DNA-DAMAGE; CUTANEOUS MELANOMA; VITAMIN-D; ULTRAVIOLET-RADIATION; MALIGNANT-MELANOMA; UNITED-STATES; PIGMENTATION; RISK; ADOLESCENTS AB Melanomas are the most prevalent cancers in 25-29 yr old females and compose roughly 12% of cancers in 20-40 yr old women; under the age of 40, women have a higher incidence of melanomas than do men. Within the past few decades, the alarming trend to use commercial sunlamps for cosmetic pigmentation is of particular concern, especially since 71% of those patrons are women with 50% of patrons under the age of 29. A major problem may be the use of UVA-rich sunlamps which produce a visible tan but afford little to no protection from subsequent UV exposure. We hypothesize that the additional exposure of adolescents to unnaturally large amounts of UVA from artificial UV sources is implicated in the increasing incidence of malignant melanomas disproportionately in young women. C1 [Coelho, Sergio G.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM hearingv@nih.gov FU National Cancer Institute at NIH FX This research was supported in part by the Intramural Research Program of the National Cancer Institute at NIH. NR 58 TC 48 Z9 49 U1 1 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2010 VL 23 IS 1 BP 57 EP 63 DI 10.1111/j.1755-148X.2009.00656.x PG 7 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 543UW UT WOS:000273605300010 PM 19968819 ER PT J AU Amarnath, S Costanzo, CM Mariotti, J Ullman, JL Telford, WG Kapoor, V Riley, JL Levine, BL June, CH Fong, T Warner, NL Fowler, DH AF Amarnath, Shoba Costanzo, Carliann M. Mariotti, Jacopo Ullman, Jessica L. Telford, William G. Kapoor, Veena Riley, James L. Levine, Bruce L. June, Carl H. Fong, Timothy Warner, Noel L. Fowler, Daniel H. TI Regulatory T Cells and Human Myeloid Dendritic Cells Promote Tolerance via Programmed Death Ligand-1 SO PLOS BIOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; TGF-BETA; MEDIATED SUPPRESSION; CLINICAL-APPLICATION; SELF-TOLERANCE; CUTTING EDGE; EX-VIVO; EXPRESSION; FOXP3; PD-1 AB Immunotherapy using regulatory T cells (Treg) has been proposed, yet cellular and molecular mechanisms of human Tregs remain incompletely characterized. Here, we demonstrate that human Tregs promote the generation of myeloid dendritic cells (DC) with reduced capacity to stimulate effector T cell responses. In a model of xenogeneic graft-versus-host disease (GVHD), allogeneic human DC conditioned with Tregs suppressed human T cell activation and completely abrogated posttransplant lethality. Tregs induced programmed death ligand-1 (PD-L1) expression on Treg-conditioned DC; subsequently, Treg-conditioned DC induced PD-L1 expression in vivo on effector T cells. PD-L1 blockade reversed Treg-conditioned DC function in vitro and in vivo, thereby demonstrating that human Tregs can promote immune suppression via DC modulation through PD-L1 up-regulation. This identification of a human Treg downstream cellular effector ( DC) and molecular mechanism (PD-L1) will facilitate the rational design of clinical trials to modulate alloreactivity. C1 [Amarnath, Shoba; Costanzo, Carliann M.; Mariotti, Jacopo; Ullman, Jessica L.; Telford, William G.; Kapoor, Veena; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Riley, James L.; Levine, Bruce L.; June, Carl H.] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Fong, Timothy; Warner, Noel L.] BD BioSci, San Jose, CA USA. RP Amarnath, S (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. EM samarnath@mail.nih.gov RI Levine, Bruce/D-1688-2009; OI Riley, James/0000-0002-1057-576X FU Center for Cancer Research; National Cancer Institute; Intramural Research Program; Juvenile Diabetes Research Foundation FX This work was supported by the Center for Cancer Research, National Cancer Institute, Intramural Research Program, and in part by the Juvenile Diabetes Research Foundation Collaborative Center for Cell Therapy. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 56 TC 42 Z9 48 U1 0 U2 5 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 FEB PY 2010 VL 8 IS 2 AR e1000302 DI 10.1371/journal.pbio.1000302 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 564ZM UT WOS:000275257300006 PM 20126379 ER PT J AU Richards, S Gibbs, RA Gerardo, NM Moran, N Nakabachi, A Stern, D Tagu, D Wilson, ACC Muzny, D Kovar, C Cree, A Chacko, J Chandrabose, MN Dao, MD Dinh, HH Gabisi, RA Hines, S Hume, J Jhangian, SN Joshi, V Lewis, LR Liu, YS Lopez, J Morgan, MB Nguyen, NB Okwuonu, GO Ruiz, SJ Santibanez, J Wright, RA Fowler, GR Hitchens, ME Lozado, RJ Moen, C Steffen, D Warren, JT Zhang, JK Nazareth, LV Chavez, D Davis, C Lee, SL Patel, BM Pu, LL Bell, SN Johnson, AJ Vattathil, S Williams, RL Shigenobu, S Dang, PM Morioka, M Fukatsu, T Kudo, T Miyagishima, SY Jiang, HY Worley, KC Legeai, F Gauthier, JP Collin, O Zhang, L Chen, HC Ermolaeva, O Hlavina, W Kapustin, Y Kiryutin, B Kitts, P Maglott, D Murphy, T Pruitt, K Sapojnikov, V Souvorov, A Thibaud-Nissen, F Camara, F Guigo, R Stanke, M Solovyev, V Kosarev, P Gilbert, D Gabaldon, T Huerta-Cepas, J Marcet-Houben, M Pignatelli, M Moya, A Rispe, C Ollivier, M Quesneville, H Permal, E Llorens, C Futami, R Hedges, D Robertson, HM Alioto, T Mariotti, M Nikoh, N McCutcheon, JP Burke, G Kamins, A Latorre, A Kudo, T Moran, NA Ashton, P Calevro, F Charles, H Colella, S Douglas, A Jander, G Jones, DH Febvay, G Kamphuis, LG Kushlan, PF Macdonald, S Ramsey, J Schwartz, J Seah, S Thomas, G Vellozo, A Cass, B Degnan, P Hurwitz, B Leonardo, T Koga, R Altincicek, B Anselme, C Atamian, H Barribeau, SM de Vos, M Duncan, EJ Evans, J Ghanim, M Heddi, A Kaloshian, I Vincent-Monegat, C Parker, BJ Perez-Brocal, V Rahbe, Y Spragg, CJ Tamames, J Tamarit, D Tamborindeguy, C Vilcinskas, A Bickel, RD Brisson, JA Butts, T Chang, CC Christiaens, O Davis, GK Duncan, E Ferrier, D Iga, M Janssen, R Lu, HL McGregor, A Miura, T Smagghe, G Smith, J van der Zee, M Velarde, R Wilson, M Dearden, P Edwards, OR Gordon, K Hilgarth, RS Rider, SD Robertson, HM Srinivasan, D Walsh, TK Ishikawa, A Jaubert-Possamai, S Fenton, B Huang, WT Jones, DH Rizk, G Lavenier, D Nicolas, J Smadja, C Robertson, HM Zhou, JJ Vieira, FG He, XL Liu, RH Rozas, J Field, LM Ashton, PD Campbell, P Carolan, JC Douglas, AE Fitzroy, CIJ Reardon, KT Reeck, GR Singh, K Wilkinson, TL Huybrechts, J Abdel-latief, M Robichon, A Veenstra, JA Hauser, F Cazzamali, G Schneider, M Williamson, M Stafflinger, E Hansen, KK Grimmelikhuijzen, CJP Price, DRG Caillaud, M van Fleet, E Ren, QH Gatehouse, JA Brault, V Monsion, B Diaz, J Hunnicutt, L Ju, HJ Pechuan, X Aguilar, J Cortes, T Ortiz-Rivas, B Martinez-Torres, D Dombrovsky, A Dale, RP Davies, TGE Williamson, MS Jones, A Sattelle, D Williamson, S Wolstenholme, A Vellozo, A Cottret, L Febvay, G Calevro, F Sagot, MF Heckel, DG Hunter, W AF Richards, Stephen Gibbs, Richard A. Gerardo, Nicole M. Moran, Nancy Nakabachi, Atsushi Stern, David Tagu, Denis Wilson, Alex C. C. Muzny, Donna Kovar, Christie Cree, Andy Chacko, Joseph Chandrabose, Mimi N. Dao, Marvin Diep Dinh, Huyen H. Gabisi, Ramatu Ayiesha Hines, Sandra Hume, Jennifer Jhangian, Shalini N. Joshi, Vandita Lewis, Lora R. Liu, Yih-shin Lopez, John Morgan, Margaret B. Nguyen, Ngoc Bich Okwuonu, Geoffrey O. Ruiz, San Juana Santibanez, Jireh Wright, Rita A. Fowler, Gerald R. Hitchens, Matthew E. Lozado, Ryan J. Moen, Charles Steffen, David Warren, James T. Zhang, Jingkun Nazareth, Lynne V. Chavez, Dean Davis, Clay Lee, Sandra L. Patel, Bella Mayurkumar Pu, Ling-Ling Bell, Stephanie N. Johnson, Angela Jolivet Vattathil, Selina Williams, Rex L., Jr. Shigenobu, Shuji Dang, Phat M. Morioka, Mizue Fukatsu, Takema Kudo, Toshiaki Miyagishima, Shin-ya Jiang, Huaiyang Worley, Kim C. Legeai, Fabrice Gauthier, Jean-Pierre Collin, Olivier Zhang, Lan Chen, Hsiu-Chuan Ermolaeva, Olga Hlavina, Wratko Kapustin, Yuri Kiryutin, Boris Kitts, Paul Maglott, Donna Murphy, Terence Pruitt, Kim Sapojnikov, Victor Souvorov, Alexandre Thibaud-Nissen, Francoise Camara, Francisco Guigo, Roderic Stanke, Mario Solovyev, Victor Kosarev, Peter Gilbert, Don Gabaldon, Toni Huerta-Cepas, Jaime Marcet-Houben, Marina Pignatelli, Miguel Moya, Andres Rispe, Claude Ollivier, Morgane Quesneville, Hadi Permal, Emmanuelle Llorens, Carlos Futami, Ricardo Hedges, Dale Robertson, Hugh M. Alioto, Tyler Mariotti, Marco Nikoh, Naruo McCutcheon, John P. Burke, Gaelen Kamins, Alexandra Latorre, Amparo Kudo, Toshiaki Moran, Nancy A. Ashton, Peter Calevro, Federica Charles, Hubert Colella, Stefano Douglas, Angela Jander, Georg Jones, Derek H. Febvay, Gerard Kamphuis, Lars G. Kushlan, Philip F. Macdonald, Sandy Ramsey, John Schwartz, Julia Seah, Stuart Thomas, Gavin Vellozo, Augusto Cass, Bodil Degnan, Patrick Hurwitz, Bonnie Leonardo, Teresa Koga, Ryuichi Altincicek, Boran Anselme, Caroline Atamian, Hagop Barribeau, Seth M. de Vos, Martin Duncan, Elizabeth J. Evans, Jay Ghanim, Murad Heddi, Abdelaziz Kaloshian, Isgouhi Vincent-Monegat, Carole Parker, Ben J. Perez-Brocal, Vicente Rahbe, Yvan Spragg, Chelsea J. Tamames, Javier Tamarit, Daniel Tamborindeguy, Cecilia Vilcinskas, Andreas Bickel, Ryan D. Brisson, Jennifer A. Butts, Thomas Chang, Chun-che Christiaens, Olivier Davis, Gregory K. Duncan, Elizabeth Ferrier, David Iga, Masatoshi Janssen, Ralf Lu, Hsiao-Ling McGregor, Alistair Miura, Toru Smagghe, Guy Smith, James van der Zee, Maurijn Velarde, Rodrigo Wilson, Megan Dearden, Peter Edwards, Owain R. Gordon, Karl Hilgarth, Roland S. Rider, Stanley Dean, Jr. Robertson, Hugh M. Srinivasan, Dayalan Walsh, Thomas K. Ishikawa, Asano Jaubert-Possamai, Stephanie Fenton, Brian Huang, Wenting Jones, Derek H. Rizk, Guillaume Lavenier, Dominique Nicolas, Jacques Smadja, Carole Robertson, Hugh M. Zhou, Jing-Jiang Vieira, Filipe G. He, Xiao-Li Liu, Renhu Rozas, Julio Field, Linda M. Ashton, Peter D. Campbell, Peter Carolan, James C. Douglas, Angela E. Fitzroy, Carol I. J. Reardon, Karen T. Reeck, Gerald R. Singh, Karam Wilkinson, Thomas L. Huybrechts, Jurgen Abdel-latief, Mohatmed Robichon, Alain Veenstra, Jan A. Hauser, Frank Cazzamali, Giuseppe Schneider, Martina Williamson, Michael Stafflinger, Elisabeth Hansen, Karina K. Grimmelikhuijzen, Cornelis J. P. Price, Daniel R. G. Caillaud, Marina van Fleet, Eric Ren, Qinghu Gatehouse, John A. Brault, Veronique Monsion, Baptiste Diaz, Jason Hunnicutt, Laura Ju, Ho-Jong Pechuan, Ximo Aguilar, Jose Cortes, Teresa Ortiz-Rivas, Benjamin Martinez-Torres, David Dombrovsky, Aviv Dale, Richard P. Davies, T. G. Emyr Williamson, Martin S. Jones, Andrew Sattelle, David Williamson, Sally Wolstenholme, Adrian Vellozo, Augusto Cottret, Ludovic Febvay, Gerard Calevro, Federica Sagot, Marie France Heckel, David G. Hunter, Wayne CA Int Aphid Genomics Consortium TI Genome Sequence of the Pea Aphid Acyrthosiphon pisum SO PLOS BIOLOGY LA English DT Article ID DROSOPHILA CIRCADIAN CLOCK; DNA-SEQUENCES; REPETITIVE ELEMENTS; SYMBIOTIC BACTERIA; PHEROMONE-BINDING; GENE-EXPRESSION; CPG METHYLATION; TANDEM REPEATS; APIS-MELLIFERA; SOCIAL INSECT AB Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems. C1 [Richards, Stephen; Gibbs, Richard A.; Muzny, Donna; Kovar, Christie; Cree, Andy; Chacko, Joseph; Chandrabose, Mimi N.; Dao, Marvin Diep; Dinh, Huyen H.; Gabisi, Ramatu Ayiesha; Hines, Sandra; Hume, Jennifer; Jhangian, Shalini N.; Joshi, Vandita; Lewis, Lora R.; Liu, Yih-shin; Lopez, John; Morgan, Margaret B.; Nguyen, Ngoc Bich; Okwuonu, Geoffrey O.; Ruiz, San Juana; Santibanez, Jireh; Wright, Rita A.; Fowler, Gerald R.; Hitchens, Matthew E.; Lozado, Ryan J.; Moen, Charles; Steffen, David; Warren, James T.; Zhang, Jingkun; Nazareth, Lynne V.; Chavez, Dean; Davis, Clay; Lee, Sandra L.; Patel, Bella Mayurkumar; Pu, Ling-Ling; Bell, Stephanie N.; Johnson, Angela Jolivet; Vattathil, Selina; Williams, Rex L., Jr.; Jiang, Huaiyang; Worley, Kim C.; Zhang, Lan] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Gerardo, Nicole M.; Kamins, Alexandra; Barribeau, Seth M.; Parker, Ben J.; Spragg, Chelsea J.] Emory Univ, O Wayne Rollins Res Ctr, Dept Biol, Atlanta, GA 30322 USA. [Moran, Nancy; Burke, Gaelen; Moran, Nancy A.; Cass, Bodil; Degnan, Patrick; Hurwitz, Bonnie] Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ USA. [Nakabachi, Atsushi; Miyagishima, Shin-ya] RIKEN, Adv Sci Inst, Wako, Saitama 3510198, Japan. [Stern, David; Shigenobu, Shuji; Leonardo, Teresa; Srinivasan, Dayalan] Princeton Univ, Howard Hughes Med Inst, Princeton, NJ 08544 USA. [Stern, David; Shigenobu, Shuji; Leonardo, Teresa; Srinivasan, Dayalan] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Tagu, Denis; Legeai, Fabrice; Gauthier, Jean-Pierre; Rispe, Claude; Ollivier, Morgane; Jaubert-Possamai, Stephanie] INRA, UMR BiO3P, Domaine De La Motte, Le Rheu, France. [Wilson, Alex C. C.; Jones, Derek H.; Kushlan, Philip F.; Schwartz, Julia; Huang, Wenting; Jones, Derek H.] Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. [Shigenobu, Shuji] JST, PRESTO, Saitama 3320012, Japan. [Shigenobu, Shuji] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Okazaki, Aichi, Japan. [Dang, Phat M.; Souvorov, Alexandre] ARS, USDA, Natl Peanut Res Lab, Dawson, GA USA. [Morioka, Mizue] Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Tokyo, Japan. [Fukatsu, Takema; Koga, Ryuichi] Natl Inst Adv Ind Sci & Technol, Tsukuba, Ibaraki, Japan. [Kudo, Toshiaki; Kudo, Toshiaki] Discovery Res Inst, Saitama, Japan. [Collin, Olivier] EPI Symbiose, CNRS, IRISA, Rennes, France. [Chen, Hsiu-Chuan; Ermolaeva, Olga; Hlavina, Wratko; Kapustin, Yuri; Kiryutin, Boris; Kitts, Paul; Maglott, Donna; Murphy, Terence; Pruitt, Kim; Sapojnikov, Victor; Thibaud-Nissen, Francoise] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Camara, Francisco; Guigo, Roderic] Univ Pompeu Fabra, Ctr Regulacio Genom, Barcelona, Spain. [Guigo, Roderic] Univ Pompeu Fabra, Res Grp Biomed Informat, Barcelona, Spain. [Stanke, Mario] Inst Mikrobiol & Genet, Abt Bioinformat, Gottingen, Germany. [Solovyev, Victor] Univ London, Dept Comp Sci, Surrey, England. [Kosarev, Peter] Softberry Inc, Mt Kisco, NY 10549 USA. [Gilbert, Don] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Guigo, Roderic; Gabaldon, Toni; Huerta-Cepas, Jaime; Marcet-Houben, Marina; Alioto, Tyler; Mariotti, Marco] CRG, Bioinformat & Genom Programme, Barcelona, Spain. [Pignatelli, Miguel; Moya, Andres; Llorens, Carlos; Latorre, Amparo; Perez-Brocal, Vicente; Tamames, Javier; Tamarit, Daniel; Pechuan, Ximo; Aguilar, Jose; Cortes, Teresa; Ortiz-Rivas, Benjamin; Martinez-Torres, David] Univ Valencia, Inst Cavanilles Biodivers & Biol Evolut, Valencia, Spain. [Pignatelli, Miguel; Moya, Andres; Latorre, Amparo; Tamames, Javier] CIBEResp, Valencia, Spain. [Pignatelli, Miguel; Moya, Andres; Latorre, Amparo; Tamames, Javier] Conselleria Sanidad Generalitat Valenciana, CSISP, Valencia, Spain. [Quesneville, Hadi; Permal, Emmanuelle] Ctr Rech Versailles, INRA, Unite Rech Genom Info UR INRA 1164, Versailles, France. [Hedges, Dale] Miami Inst Human Genom, Miami, FL USA. [Robertson, Hugh M.; Robertson, Hugh M.; Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Nikoh, Naruo] Open Univ, Div Nat Sci, Chiba, Japan. [McCutcheon, John P.] Univ Arizona, Ctr Insect Sci, Tucson, AZ 85721 USA. [Ashton, Peter; Macdonald, Sandy; Thomas, Gavin; Ashton, Peter D.] Univ York, Dept Biol, York, N Yorkshire, England. [Calevro, Federica; Charles, Hubert; Colella, Stefano; Febvay, Gerard; Vellozo, Augusto; Anselme, Caroline; Heddi, Abdelaziz; Vincent-Monegat, Carole; Perez-Brocal, Vicente; Rahbe, Yvan; Vellozo, Augusto; Febvay, Gerard; Calevro, Federica] Univ Lyon, INSA Lyon, INRA, IFR41,UMR203,Biol Fonct Insects & Interact BF2I, Villeurbanne, France. [Douglas, Angela; Douglas, Angela E.] Cornell Univ, Dept Entomol, Ithaca, NY 14853 USA. [Jander, Georg; Ramsey, John; de Vos, Martin] Boyce Thompson Inst Plant Res, Ithaca, NY USA. [Kamphuis, Lars G.; Edwards, Owain R.; Walsh, Thomas K.] CSIRO Entomol, CELS, Floreat Pk, Australia. [Kamphuis, Lars G.; Seah, Stuart; Singh, Karam] CSIRO Plant Ind, CELS, Floreat Pk, Australia. [Vellozo, Augusto; Vellozo, Augusto; Cottret, Ludovic; Sagot, Marie France] Univ Lyon, CNRS, UMR5558, Lab Biometrie & Biol Evolut, Villeurbanne, France. [Altincicek, Boran; Vilcinskas, Andreas] Univ Giessen, Inst Phytopathol & Appl Zool, Interdisciplinary Res Ctr, Giessen, Germany. [Anselme, Caroline; Robichon, Alain] Univ Nice, CNRS 6243, INRA 1301, UMR Interact Biot & Sante Vegetale, Sophia Antipolis, France. [Atamian, Hagop; Kaloshian, Isgouhi] Univ Calif, Grad Program Genet Genom & Bioinformat, Riverside, CA USA. [Atamian, Hagop; Kaloshian, Isgouhi] Univ Calif, Dept Nematol, Riverside, CA 92507 USA. [Duncan, Elizabeth J.; Duncan, Elizabeth; Smith, James; Wilson, Megan; Dearden, Peter] Univ Otago, Lab Evolut & Dev, Dunedin, New Zealand. [Duncan, Elizabeth J.; Duncan, Elizabeth; Smith, James; Wilson, Megan; Dearden, Peter] Univ Otago, Dept Biochem, Natl Res Ctr Growth & Dev, Dunedin, New Zealand. [Evans, Jay] USDA ARS, Bee Res Lab, Beltsville, MD 20705 USA. [Ghanim, Murad] Volcani Ctr, Dept Entomol, Bet Dagan, Israel. [Tamborindeguy, Cecilia] Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA. [Bickel, Ryan D.; Brisson, Jennifer A.] Univ So Calif, Los Angeles, CA USA. [Butts, Thomas] Univ Oxford, Dept Zool, Oxford, England. [Chang, Chun-che; Lu, Hsiao-Ling] Natl Taiwan Univ, Coll Bioresources & Agr, Inst Biotechnol, Dept Entomol,Lab Genet & Dev, Taipei, Taiwan. [Christiaens, Olivier; Iga, Masatoshi; Smagghe, Guy] Univ Ghent, Dept Crop Protect, Lab Agrozool, Ghent, Belgium. [Davis, Gregory K.] Bryn Mawr Coll, Dept Biol, Bryn Mawr, PA 19010 USA. [Ferrier, David] Univ St Andrews, Scottish Oceans Inst, St Andrews, Fife, Scotland. [Janssen, Ralf] Uppsala Univ, Dept Earth Sci, Uppsala, Sweden. [McGregor, Alistair] Univ Vet Med Vienna, Inst Populat Genet, Vienna, Austria. [Miura, Toru; Ishikawa, Asano] Hokkaido Univ, Grad Sch Environm Sci, Sapporo, Hokkaido, Japan. [van der Zee, Maurijn] Leiden Univ, Inst Biol, Leiden, Netherlands. [Velarde, Rodrigo] Wake Forest Univ, Dept Biol, Winston Salem, NC 27109 USA. [Gordon, Karl; Campbell, Peter] Black Mt Labs, CSIRO Entomol, Acton, Australia. [Hilgarth, Roland S.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Rider, Stanley Dean, Jr.] Texas A&M Univ, Dept Pathobiol, College Stn, TX 77843 USA. [Fenton, Brian] SCRI, Dundee, Scotland. [Fenton, Brian] Scottish Crop Res Inst, Dundee, Scotland. [Legeai, Fabrice; Rizk, Guillaume; Nicolas, Jacques] EPI Symbiose, INRIA, IRISA, Rennes, France. Univ Rennes 1, EPI Symbiose, IRISA, Rennes, France. [Lavenier, Dominique] EPI Symbiose, INRIA, ENS Cachan, Rennes, France. [Smadja, Carole] Univ Sheffield, Dept Anim & Plant Sci, Sheffield, S Yorkshire, England. [Zhou, Jing-Jiang; He, Xiao-Li; Liu, Renhu; Field, Linda M.; Davies, T. G. Emyr; Williamson, Martin S.] Rothamsted Res, Dept Biol Chem, Harpenden, Herts, England. [Vieira, Filipe G.; Rozas, Julio] Univ Barcelona, Dept Genet, Barcelona, Spain. [Carolan, James C.; Fitzroy, Carol I. J.; Reardon, Karen T.; Wilkinson, Thomas L.] Univ Coll Dublin, UCD Sch Biol & Environm Sci, Dublin, Ireland. [Edwards, Owain R.; Reeck, Gerald R.] Cooperat Res Ctr Natl Plant Biosecur, Canberra, ACT, Australia. [Reeck, Gerald R.] Kansas State Univ, Dept Biochem, Manhattan, KS 66506 USA. [Huybrechts, Jurgen] Res Grp Funct Genom & Proteom, Louvain, Belgium. [Abdel-latief, Mohatmed] Free Univ Berlin, Inst Angew Zool, Berlin, Germany. [Veenstra, Jan A.] Univ Bordeaux, CNRS, Talence, France. [Hauser, Frank; Cazzamali, Giuseppe; Schneider, Martina; Williamson, Michael; Stafflinger, Elisabeth; Hansen, Karina K.; Grimmelikhuijzen, Cornelis J. P.] Univ Copenhagen, Dept Biol, Ctr Funct & Comparat Insect Genom, Copenhagen, Denmark. [Price, Daniel R. G.; Gatehouse, John A.] Univ Durham, Sch Biol & Biomed Sci, Durham, England. [Caillaud, Marina; van Fleet, Eric; Diaz, Jason] Ithaca Coll, Dept Biol, Ithaca, NY 14850 USA. [Ren, Qinghu] J Craig Venter Inst, Rockville, MD 20850 USA. [Brault, Veronique; Monsion, Baptiste] INRA UMR SVQV, Equipe Virol Vect, Colmar, France. [Hunnicutt, Laura] N Carolina State Univ, Genom Sci Program, Raleigh, NC 27695 USA. [Ju, Ho-Jong] Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY 14853 USA. [Dombrovsky, Aviv] Volcani Ctr, Dept Virol, Bet Dagan, Israel. [Dale, Richard P.] Syngenta, Jealotts Hill Res Ctr, Bracknell, Berks, England. [Jones, Andrew; Sattelle, David] Univ Oxford, Dept Phisol Anat & Genet, MRC, Funct Genom Unit, Oxford, England. [Williamson, Sally; Wolstenholme, Adrian] Univ Bath, Dept Biol & Biochem, Bath, Avon, England. [Heckel, David G.] Max Planck Inst Chem Ecol, Jena, Germany. [Hunter, Wayne] ARS, USDA, US Hort Res Lab, Ft Pierce, FL USA. RP Richards, S (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. EM stephenr@bcm.tmc.edu RI Rozas, Julio/A-1733-2009; Dearden, Peter/B-7607-2008; Veenstra, Jan/B-4610-2008; Vellozo, Augusto/B-1344-2008; Thomas, Gavin/E-5753-2011; Colella, Stefano/A-7040-2008; Gabaldon, Toni/A-7336-2008; Campbell, Peter/B-7232-2008; Edwards, Owain/B-9707-2008; CHARLES, Hubert/B-9392-2011; Shigenobu, Shuji/B-6239-2011; Davies, Thomas /D-6091-2011; Altincicek, Boran/C-1191-2009; Vincent-Monegat, Carole/G-7287-2011; Gordon, Karl/A-1976-2008; Latorre, Amparo/E-4997-2015; Hauser, Frank/M-2952-2014; Camara Ferreira, Francisco/G-9841-2015; Marcet-Houben, Marina/H-2170-2015; Pechuan, Joaquin/H-7327-2015; Guigo, Roderic/D-1303-2010; Garrett Vieira, Filipe/B-9464-2015; Singh, Karam/C-3235-2012; Alioto, Tyler/K-7267-2015; Smadja, Carole/A-1562-2013; Heckel, David/K-2138-2013; Perez Brocal, Vicente/K-3627-2014; Davies, Thomas/C-2795-2017; Walsh, Thomas/C-1263-2009; Nakabachi, Atsushi/H-1661-2011; Moran, Nancy/G-1591-2010; Kamphuis, Lars/B-5360-2011; UMR IGEPP, INRA/A-4054-2011; Burke, Gaelen/A-4304-2013; FEBVAY, Gerard/B-2215-2008; Ferrier, David/D-7595-2013; Rahbe, Yvan/B-9389-2009; Tamborindeguy, Cecilia/A-6110-2012; Huerta-Cepas, Jaime/H-5093-2013; Cortes, Teresa/D-1690-2014; Evans, Jay/C-8408-2012; Moya, Andres/A-8190-2008 OI Aguilar-Rodriguez, Jose/0000-0001-7622-5482; Solovyev, Victor/0000-0001-8885-493X; Rozas, Julio/0000-0002-6839-9148; Dearden, Peter/0000-0001-7790-9675; Vellozo, Augusto/0000-0001-9653-2017; Thomas, Gavin/0000-0002-9763-1313; Colella, Stefano/0000-0003-3139-6055; Gabaldon, Toni/0000-0003-0019-1735; Shigenobu, Shuji/0000-0003-4640-2323; Altincicek, Boran/0000-0003-2019-452X; Duncan, Elizabeth/0000-0002-1841-504X; Gatehouse, John/0000-0002-7192-568X; Chang, Chun-che/0000-0002-3586-1607; Ashton, Peter/0000-0002-7446-5009; Wilson, Megan/0000-0003-3425-5071; Grimmelikhuijzen, Cornelis/0000-0001-6486-2046; Tagu, Denis/0000-0002-6320-8648; Veenstra, Jan/0000-0002-2783-0018; Gordon, Karl/0000-0002-4371-0454; Martinez-Torres, David/0000-0002-1689-5529; Latorre, Amparo/0000-0002-9146-7284; Macdonald, Sandy/0000-0002-4112-0987; Monsion, Baptiste/0000-0002-5174-4742; Hauser, Frank/0000-0001-5563-2345; Camara Ferreira, Francisco/0000-0002-1971-5466; Marcet-Houben, Marina/0000-0003-4838-187X; Pechuan, Joaquin/0000-0001-8938-7931; Guigo, Roderic/0000-0002-5738-4477; Garrett Vieira, Filipe/0000-0002-8464-7770; Singh, Karam/0000-0002-2777-7448; Alioto, Tyler/0000-0002-2960-5420; Heckel, David/0000-0001-8991-2150; Perez Brocal, Vicente/0000-0002-1927-9676; Davies, Thomas/0000-0002-9452-2947; Walsh, Thomas/0000-0001-8425-0135; FEBVAY, Gerard/0000-0002-0654-2340; Ferrier, David/0000-0003-3247-6233; Rahbe, Yvan/0000-0002-0074-4443; Cortes, Teresa/0000-0002-5746-3300; Evans, Jay/0000-0002-0036-4651; Moya, Andres/0000-0002-2867-1119 FU National Human Genome Research Institute [5-U54-HG003273]; French National Institute for Agricultural Research (INRA); French National Institute for Research in Computer Science and Control (INRIA); American Genetic Association Special Event Award; NRI, US Department of Agriculture Cooperative State Research, Education, and Extension [2007-04628]; NIH, National Library of Medicine FX Work at the Baylor Medical College Human Genome Sequencing Center was funded by grant 5-U54-HG003273 from the National Human Genome Research Institute. AphidBase is supported with funding from the French National Institute for Agricultural Research (INRA) and the French National Institute for Research in Computer Science and Control (INRIA). Pea Aphid Genome Annotation Workshop I was supported by an American Genetic Association Special Event Award and an NRI, US Department of Agriculture Cooperative State Research, Education, and Extension Service 2007-04628 award to ACCW. FgenesH models were donated by Softberry, Inc. This research was additionally supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 130 TC 461 Z9 464 U1 20 U2 273 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 FEB PY 2010 VL 8 IS 2 AR e1000313 DI 10.1371/journal.pbio.1000313 PG 24 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 564ZM UT WOS:000275257300009 ER PT J AU Shaman, J Pitzer, VE Viboud, C Grenfell, BT Lipsitch, M AF Shaman, Jeffrey Pitzer, Virginia E. Viboud, Cecile Grenfell, Bryan T. Lipsitch, Marc TI Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States SO PLOS BIOLOGY LA English DT Article ID PANDEMIC INFLUENZA; VIRUS; TRANSMISSION; IMPACT; HEMAGGLUTININ; STRATEGIES; MORTALITY; SURVIVAL; EPIDEMIC; CLOSURE AB Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent reanalysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here, we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions. C1 [Shaman, Jeffrey] Oregon State Univ, Coll Ocean & Atmospher Sci, Corvallis, OR 97331 USA. [Pitzer, Virginia E.; Viboud, Cecile; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pitzer, Virginia E.] Penn State Univ, Ctr Infect Dis Dynam, State Coll, PA USA. [Pitzer, Virginia E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. [Lipsitch, Marc] Harvard Univ, Harvard Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Harvard Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Shaman, J (reprint author), Oregon State Univ, Coll Ocean & Atmospher Sci, Corvallis, OR 97331 USA. EM jshaman@coas.oregonstate.edu OI Pitzer, Virginia/0000-0003-1015-2289; Lipsitch, Marc/0000-0003-1504-9213 FU US National Institutes of Health (NIH) [5U01GM076497, 1U54GM088588, R01GM083983-01]; Bill and Melinda Gates Foundation; RAPIDD program of the Science and Technology Directorate; US Department of Homeland Security; Fogarty International Center, NIH FX This work was supported, in part, by the US National Institutes of Health (NIH) Models of Infectious Disease Agent Study program through cooperative agreements 5U01GM076497 ( ML) and 1U54GM088588 ( ML and JS). VEP and BG were supported by NIH grant R01GM083983-01, the Bill and Melinda Gates Foundation, the RAPIDD program of the Science and Technology Directorate, US Department of Homeland Security, and the Fogarty International Center, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 168 Z9 173 U1 1 U2 22 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 FEB PY 2010 VL 8 IS 2 AR e1000316 DI 10.1371/journal.pbio.1000316 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 564ZM UT WOS:000275257300005 PM 20186267 ER PT J AU Zhang, Y Malone, JH Powell, SK Periwal, V Spana, E MacAlpine, DM Oliver, B AF Zhang, Yu Malone, John H. Powell, Sara K. Periwal, Vipul Spana, Eric MacAlpine, David M. Oliver, Brian TI Expression in Aneuploid Drosophila S2 Cells SO PLOS BIOLOGY LA English DT Article ID DOSAGE COMPENSATION COMPLEX; GENE-EXPRESSION; X-CHROMOSOME; ANALYSIS REVEALS; GENOME; MELANOGASTER; TRANSCRIPTION; PROTEINS; SEQUENCE; MODEL AB Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype (, two X chromosomes and four sets of autosomes, or 2X; 4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system "anticipates'' the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal-independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components. C1 [Zhang, Yu; Malone, John H.; Oliver, Brian] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Powell, Sara K.; MacAlpine, David M.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. [Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. [Spana, Eric] Duke Univ, Dept Biol, Durham, NC USA. RP Zhang, Y (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM oliver@helix.nih.gov RI Periwal, Vipul/I-1728-2012 FU The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Human Genome Research Institute (NHGRI) [HG004279]; Whitehead Foundation FX This work was supported by the The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Intramural Research Program, National Human Genome Research Institute (NHGRI) extramural grant HG004279, and a Whitehead Foundation Scholar Award. The funders had no role in study design, data collection and analysis or preparation of the manuscript. NR 49 TC 33 Z9 33 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1545-7885 J9 PLOS BIOL JI PLoS. Biol. PD FEB PY 2010 VL 8 IS 2 AR e1000320 DI 10.1371/journal.pbio.1000320 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 564ZM UT WOS:000275257300010 PM 20186269 ER PT J AU Deo, RC Hunter, L Lewis, GD Pare, G Vasan, RS Chasman, D Wang, TJ Gerszten, RE Roth, FP AF Deo, Rahul C. Hunter, Luke Lewis, Gregory D. Pare, Guillaume Vasan, Ramachandran S. Chasman, Daniel Wang, Thomas J. Gerszten, Robert E. Roth, Frederick P. TI Interpreting Metabolomic Profiles using Unbiased Pathway Models SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CITRIN DEFICIENCY; PROSTATE-CANCER; BREAST-CANCER; HUMAN-DISEASE; NETWORK; INSULIN; ASSOCIATION; CLASSIFICATION; PREDICTION; SIGNATURES AB Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for "active modules''-regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities. C1 [Deo, Rahul C.; Hunter, Luke; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Deo, Rahul C.; Lewis, Gregory D.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Lewis, Gregory D.; Gerszten, Robert E.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Pare, Guillaume; Chasman, Daniel] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. [Pare, Guillaume; Chasman, Daniel] Harvard Univ, Brigham & Womens Hosp, Sch Med, Donald W Reynolds Ctr Cardiovasc Res, Boston, MA 02115 USA. [Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Deo, RC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM fritz_roth@hms.harvard.edu RI Roth, Frederick/H-6308-2011; OI Ramachandran, Vasan/0000-0001-7357-5970; Roth, Frederick/0000-0002-6628-649X FU NIH [T32 HL007208, HL096738, DK081572-02, HL081341, HG004233, HG0017115, NS035611, HG003224]; AHA; Leducq Foundation; Canadian Institute for Advanced Research FX RCD was supported by NIH grant T32 HL007208; REG was supported by NIH Grants HL096738, DK081572-02, the AHA Established Investigator Award and the Leducq Foundation; and FPR was supported by NIH grants HL081341, HG004233, HG0017115, NS035611, HG003224 and by the Canadian Institute for Advanced Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 32 Z9 32 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2010 VL 6 IS 2 AR e1000692 DI 10.1371/journal.pcbi.1000692 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 565AI UT WOS:000275260000012 PM 20195502 ER PT J AU Kim, S Aladjem, MI McFadden, GB Kohn, KW AF Kim, Sohyoung Aladjem, Mirit I. McFadden, Geoffrey B. Kohn, Kurt W. TI Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID P53-MDM2 FEEDBACK LOOP; MOLECULAR INTERACTION MAPS; IN-VIVO; BIOREGULATORY NETWORKS; SWITCH; ACTIVATION; APOPTOSIS; SYSTEMS; MODEL; PHOSPHORYLATION AB Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53: MdmX and Mdm2: MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation. C1 [Kim, Sohyoung; Aladjem, Mirit I.; Kohn, Kurt W.] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [McFadden, Geoffrey B.] Natl Inst Stand & Technol, Informat Technol Lab, Math & Computat Sci Div, Gaithersburg, MD USA. RP Kim, S (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov; kohnk@dc37a.nci.nih.gov RI Aladjem, Mirit/G-2169-2010; McFadden, Geoffrey/A-7920-2008; OI Aladjem, Mirit/0000-0002-1875-3110; McFadden, Geoffrey/0000-0001-6723-2103; Kim, Sohyoung/0000-0002-6140-7918 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD FEB PY 2010 VL 6 IS 2 AR e1000665 DI 10.1371/journal.pcbi.1000665 PG 18 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 565AI UT WOS:000275260000029 PM 20174603 ER PT J AU Krief, S Escalante, AA Pacheco, MA Mugisha, L Andre, C Halbwax, M Fischer, A Krief, JM Kasenene, JM Crandfield, M Cornejo, OE Chavatte, JM Lin, C Letourneur, F Gruner, AC McCutchan, TF Renia, L Snounou, G AF Krief, Sabrina Escalante, Ananias A. Pacheco, M. Andreina Mugisha, Lawrence Andre, Claudine Halbwax, Michel Fischer, Anne Krief, Jean-Michel Kasenene, John M. Crandfield, Mike Cornejo, Omar E. Chavatte, Jean-Marc Lin, Clara Letourneur, Franck Gruener, Anne Charlotte McCutchan, Thomas F. Renia, Laurent Snounou, Georges TI On the Diversity of Malaria Parasites in African Apes and the Origin of Plasmodium falciparum from Bonobos SO PLOS PATHOGENS LA English DT Article ID EVOLUTIONARY ORIGIN; GENE-SEQUENCES; CYTOCHROME-B; VIVAX; HUMANS; SUBSTITUTION; POPULATIONS; CHIMPANZEES; INFECTIONS; CONFIDENCE AB The origin of Plasmodium falciparum, the etiological agent of the most dangerous forms of human malaria, remains controversial. Although investigations of homologous parasites in African Apes are crucial to resolve this issue, studies have been restricted to a chimpanzee parasite related to P. falciparum, P. reichenowi, for which a single isolate was available until very recently. Using PCR amplification, we detected Plasmodium parasites in blood samples from 18 of 91 individuals of the genus Pan, including six chimpanzees (three Pan troglodytes troglodytes, three Pan t. schweinfurthii) and twelve bonobos (Pan paniscus). We obtained sequences of the parasites' mitochondrial genomes and/or from two nuclear genes from 14 samples. In addition to P. reichenowi, three other hitherto unknown lineages were found in the chimpanzees. One is related to P. vivax and two to P. falciparum that are likely to belong to distinct species. In the bonobos we found P. falciparum parasites whose mitochondrial genomes indicated that they were distinct from those present in humans, and another parasite lineage related to P. malariae. Phylogenetic analyses based on this diverse set of Plasmodium parasites in African Apes shed new light on the evolutionary history of P. falciparum. The data suggested that P. falciparum did not originate from P. reichenowi of chimpanzees (Pan troglodytes), but rather evolved in bonobos (Pan paniscus), from which it subsequently colonized humans by a host-switch. Finally, our data and that of others indicated that chimpanzees and bonobos maintain malaria parasites, to which humans are susceptible, a factor of some relevance to the renewed efforts to eradicate malaria. C1 [Krief, Sabrina] Museum Natl Hist Nat, UMR 7206, USM 104, F-75231 Paris, France. [Escalante, Ananias A.; Pacheco, M. Andreina] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. [Mugisha, Lawrence] CSWCT, Entebbe, Uganda. [Andre, Claudine] Petites Chutes de la Lukaya, Lola Ya Bonobo Bonobo Sanctuary, Kinshasa, Zaire. [Halbwax, Michel; Fischer, Anne] Max Planck Inst Evolutionary Anthropol, Leipzig, Germany. [Krief, Jean-Michel] Projet Conservat Grands Singes, Paris, France. [Kasenene, John M.] Makerere Univ, Dept Bot, Kampala, Uganda. [Kasenene, John M.] Makerere Univ, Biol Field Stn, Ft Portal, Uganda. [Crandfield, Mike] Maryland Zoo Baltimore, Res & Conservat Program, Baltimore, MD USA. [Cornejo, Omar E.] Emory Univ, Program Populat Biol Ecol & Evolut, Atlanta, GA 30322 USA. [Chavatte, Jean-Marc; Snounou, Georges] Museum Natl Hist Nat, USM0307, F-75231 Paris, France. [Lin, Clara; Gruener, Anne Charlotte; Renia, Laurent; Snounou, Georges] ASTAR, Singapore Immunol Network, Lab Malaria Immunobiol, Singapore, Singapore. [Letourneur, Franck; Gruener, Anne Charlotte; Renia, Laurent] Univ Paris 05, CNRS, Inst Cochin, UMR 8104, Paris, France. [Letourneur, Franck; Gruener, Anne Charlotte; Renia, Laurent] INSERM, U567, Paris, France. [McCutchan, Thomas F.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Snounou, Georges] INSERM, UMR S 945, Paris, France. [Snounou, Georges] Univ Paris 06, Fac Med Pitie Salpetriere, Paris, France. [Snounou, Georges] Natl Univ Singapore, Dept Microbiol, Singapore 117548, Singapore. RP Krief, S (reprint author), Museum Natl Hist Nat, UMR 7206, USM 104, F-75231 Paris, France. EM Ananias.Escalante@asu.edu; georges.snounou@upmc.fr RI Renia, Laurent/E-2117-2011; Gruner, Anne Charlotte/C-1841-2012; Snounou, Georges/F-3352-2011; OI Renia, Laurent/0000-0003-0349-1557; Snounou, Georges/0000-0002-6133-6398; Chavatte, Jean-Marc/0000-0002-0003-541X FU Museum National d'Histoire Naturelle (Paris, France); Fyssen Foundation; US National Institutes of Health [GM080586]; INSERM; Agency for Science, Technology and Research (A*STAR), Singapore FX This study was financially supported by the Museum National d'Histoire Naturelle (Paris, France), the Fyssen Foundation and a Leakey grant to SK. AAE was supported by an R01 grant (GM080586) from the US National Institutes of Health. The US NIH intramural program supported TFM. LR, ACG, CL and GS were supported by INSERM and the Agency for Science, Technology and Research (A*STAR), Singapore. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 101 Z9 105 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2010 VL 6 IS 2 AR e1000765 DI 10.1371/journal.ppat.1000765 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 565LZ UT WOS:000275295900017 PM 20169187 ER PT J AU Mazurov, D Ilinskaya, A Heidecker, G Lloyd, P Derse, D AF Mazurov, Dmitriy Ilinskaya, Anna Heidecker, Gisela Lloyd, Patricia Derse, David TI Quantitative Comparison of HTLV-1 and HIV-1 Cell-to-Cell Infection with New Replication Dependent Vectors SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPSTEIN-BARR-VIRUS; LEUKEMIA-VIRUS; VIROLOGICAL-SYNAPSE; LYMPHOTROPIC-VIRUS; MEDIATED TRANSMISSION; INDICATOR GENE; TAX PROTEIN; GAG PROTEIN; DC-SIGN AB We have developed an efficient method to quantify cell-to-cell infection with single-cycle, replication dependent reporter vectors. This system was used to examine the mechanisms of infection with HTLV-1 and HIV-1 vectors in lymphocyte cell lines. Effector cells transfected with reporter vector, packaging vector, and Env expression plasmid produced virus-like particles that transduced reporter gene activity into cocultured target cells with zero background. Reporter gene expression was detected exclusively in target cells and required an Env-expression plasmid and a viral packaging vector, which provided essential structural and enzymatic proteins for virus replication. Cell-cell fusion did not contribute to infection, as reporter protein was rarely detected in syncytia. Coculture of transfected Jurkat T cells and target Raji/CD4 B cells enhanced HIV-1 infection two fold and HTLV-1 infection ten thousand fold in comparison with cell-free infection of Raji/CD4 cells. Agents that interfere with actin and tubulin polymerization strongly inhibited HTLV-1 and modestly decreased HIV-1 cell-to-cell infection, an indication that cytoskeletal remodeling was more important for HTLV-1 transmission. Time course studies showed that HTLV-1 transmission occurred very rapidly after cell mixing, whereas slower kinetics of HIV-1 coculture infection implies a different mechanism of infectious transmission. HTLV-1 Tax was demonstrated to play an important role in altering cell-cell interactions that enhance virus infection and replication. Interestingly, superantigen-induced synapses between Jurkat cells and Raji/CD4 cells did not enhance infection for either HTLV-1 or HIV-1. In general, the dependence on cell-to-cell infection was determined by the virus, the effector and target cell types, and by the nature of the cell-cell interaction. C1 [Mazurov, Dmitriy] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NCI, SAIC Frederick, Frederick, MD 21701 USA. RP Mazurov, D (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM dvmazurov@yandex.ru FU National Institutes of Health; National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This work was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute, Center for Cancer Research (DM, AI, GH and DD), and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400 (PL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 72 Z9 73 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2010 VL 6 IS 2 AR e1000788 DI 10.1371/journal.ppat.1000788 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 565LZ UT WOS:000275295900038 PM 20195464 ER PT J AU Singh, S Alam, MM Pal-Bhowmick, I Brzostowski, JA Chitnis, CE AF Singh, Shailja Alam, M. Mahmood Pal-Bhowmick, Ipsita Brzostowski, Joseph A. Chitnis, Chetan E. TI Distinct External Signals Trigger Sequential Release of Apical Organelles during Erythrocyte Invasion by Malaria Parasites SO PLOS PATHOGENS LA English DT Article ID PLASMODIUM-FALCIPARUM MEROZOITES; RED-BLOOD-CELLS; TOXOPLASMA-GONDII; MICRONEME DISCHARGE; INTRACELLULAR CA2+; BINDING ANTIGEN; HOST-CELLS; SECRETION; PROTEINS; IDENTIFICATION AB The invasion of erythrocytes by Plasmodium merozoites requires specific interactions between host receptors and parasite ligands. Parasite proteins that bind erythrocyte receptors during invasion are localized in apical organelles called micronemes and rhoptries. The regulated secretion of microneme and rhoptry proteins to the merozoite surface to enable receptor binding is a critical step in the invasion process. The sequence of these secretion events and the external signals that trigger release are not known. We have used time-lapse video microscopy to study changes in intracellular calcium levels in Plasmodium falciparum merozoites during erythrocyte invasion. In addition, we have developed flow cytometry based methods to measure relative levels of cytosolic calcium and study surface expression of apical organelle proteins in P. falciparum merozoites in response to different external signals. We demonstrate that exposure of P. falciparum merozoites to low potassium ion concentrations as found in blood plasma leads to a rise in cytosolic calcium levels through a phospholipase C mediated pathway. Rise in cytosolic calcium triggers secretion of microneme proteins such as the 175 kD erythrocyte binding antigen (EBA175) and apical membrane antigen-1 (AMA-1) to the merozoite surface. Subsequently, interaction of EBA175 with glycophorin A (glyA), its receptor on erythrocytes, restores basal cytosolic calcium levels and triggers release of rhoptry proteins. Our results identify for the first time the external signals responsible for the sequential release of microneme and rhoptry proteins during erythrocyte invasion and provide a starting point for the dissection of signal transduction pathways involved in regulated exocytosis of these key apical organelles. Signaling pathway components involved in apical organelle discharge may serve as novel targets for drug development since inhibition of microneme and rhoptry secretion can block invasion and limit blood-stage parasite growth. C1 [Singh, Shailja; Alam, M. Mahmood; Chitnis, Chetan E.] Int Ctr Genet Engn & Biotechnol, Malaria Grp, New Delhi, India. [Pal-Bhowmick, Ipsita] NIAID, LMVR, NIH, Rockville, MD USA. [Brzostowski, Joseph A.] NIAID, Lab Immunogenet Imaging Facil, NIH, Rockville, MD USA. RP Singh, S (reprint author), Int Ctr Genet Engn & Biotechnol, Malaria Grp, New Delhi, India. EM cchitnis@icgeb.res.in OI Alam, Mohammad Mahmood/0000-0003-2148-4887 FU ICGEB, New Delhi; European Commission FX This work was supported in part by core funds from ICGEB, New Delhi, and in part by MalSig project funded by European Commission under FP7. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 120 Z9 120 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2010 VL 6 IS 2 AR e1000746 DI 10.1371/journal.ppat.1000746 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 565LZ UT WOS:000275295900002 PM 20140184 ER PT J AU Vadyvaloo, V Jarrett, C Sturdevant, DE Sebbane, F Hinnebusch, BJ AF Vadyvaloo, Viveka Jarrett, Clayton Sturdevant, Daniel E. Sebbane, Florent Hinnebusch, B. Joseph TI Transit through the Flea Vector Induces a Pretransmission Innate Immunity Resistance Phenotype in Yersinia pestis SO PLOS PATHOGENS LA English DT Article ID ESCHERICHIA-COLI; GENE-EXPRESSION; BIOFILM FORMATION; PSEUDOMONAS-AERUGINOSA; PASTEURELLA-PESTIS; BUBONIC PLAGUE; ANTIMICROBIAL PEPTIDES; CAENORHABDITIS-ELEGANS; FRANCISELLA-TULARENSIS; BORNE PLAGUE AB Yersinia pestis, the agent of plague, is transmitted to mammals by infected fleas. Y. pestis exhibits a distinct life stage in the flea, where it grows in the form of a cohesive biofilm that promotes transmission. After transmission, the temperature shift to 37 degrees C induces many known virulence factors of Y. pestis that confer resistance to innate immunity. These factors are not produced in the low-temperature environment of the flea, however, suggesting that Y. pestis is vulnerable to the initial encounter with innate immune cells at the flea bite site. In this study, we used whole-genome microarrays to compare the Y. pestis in vivo transcriptome in infective fleas to in vitro transcriptomes in temperature-matched biofilm and planktonic cultures, and to the previously characterized in vivo gene expression profile in the rat bubo. In addition to genes involved in metabolic adaptation to the flea gut and biofilm formation, several genes with known or predicted roles in resistance to innate immunity and pathogenicity in the mammal were upregulated in the flea. Y. pestis from infected fleas were more resistant to phagocytosis by macrophages than in vitro-grown bacteria, in part attributable to a cluster of insecticidal-like toxin genes that were highly expressed only in the flea. Our results suggest that transit through the flea vector induces a phenotype that enhances survival and dissemination of Y. pestis after transmission to the mammalian host. C1 [Vadyvaloo, Viveka; Jarrett, Clayton; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sturdevant, Daniel E.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. [Sebbane, Florent] Inst Pasteur, Inst Natl Sante & Rech Med, U801, F-59019 Lille, France. [Sebbane, Florent] Univ Lille Nord France, Lille, France. RP Vadyvaloo, V (reprint author), Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. EM jhinnebusch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was supported by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 50 Z9 50 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD FEB PY 2010 VL 6 IS 2 AR e1000783 DI 10.1371/journal.ppat.1000783 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 565LZ UT WOS:000275295900033 PM 20195507 ER PT J AU Higgins, JP Higgins, SE Wolfenden, AD Henderson, SN Torres-Rodriguez, A Vicente, JL Hargis, BM Tellez, G AF Higgins, J. P. Higgins, S. E. Wolfenden, A. D. Henderson, S. N. Torres-Rodriguez, A. Vicente, J. L. Hargis, B. M. Tellez, G. TI Effect of lactic acid bacteria probiotic culture treatment timing on Salmonella Enteritidis in neonatal broilers SO POULTRY SCIENCE LA English DT Article DE Salmonella; probiotic; Lactobacillus; poultry ID INTESTINAL EPITHELIAL-CELLS; NF-KAPPA-B; COMPETITIVE-EXCLUSION; INNATE IMMUNITY; CECAL TONSILS; CHICKENS; INFECTION; COLONIZATION; TYPHIMURIUM; PERFORMANCE AB In the present study, a series of experiments were conducted to evaluate the ability of a combination of 3 ATCC lactobacilli (LAB3) or a commercially available probiotic culture (PROB) to reduce Salmonella enterica serovar Enteritidis (Salmonella Enteritidis) in broiler chicks. Additionally, we varied the timing of PROB administration in relationship to Salmonella challenge and determined the influence on recovery of enteric Salmonella. In experiments 1 to 3, chicks were randomly assigned to treatment groups and were then challenged via oral gavage with Salmonella Enteritidis. Chicks were treated 1 h after Salmonella Enteritidis challenge with LAB3 or PROB. Twenty-four hours posttreatment, cecal tonsils were collected for recovery of enteric Salmonella. In experiments 4 to 7, day-of-hatch chicks were randomly assigned to treatment groups and were then treated with PROB via oral gavage and placed into pens. Chicks were challenged with Salmonella Enteritidis 24 h after treatment via oral gavage. At 24 h after Salmonella Enteritidis challenge, cecal tonsils were collected and recovery of enteric Salmonella was determined. In experiments 8 to 10, 1-d-old chicks were randomly assigned to treatment groups and were then challenged via oral gavage with Salmonella Enteritidis and placed into pens. Chicks were treated 24 h after challenge with PROB via oral gavage. Twenty-four hours post PROB treatment, cecal tonsils were collected and enriched as described above. It was found that PROB significantly reduced cecal Salmonella Enteritidis recovery 24 h after treatment as compared with controls or LAB3-treated chicks in experiments 1 to 3 (P < 0.05). Administration of PROB 24 h before Salmonella Enteritidis challenge significantly reduced recovery of Salmonella Enteritidis in 2 out of 4 experiments and no reduction in cecal Salmonella Enteritidis was observed when chicks were challenged with Salmonella Enteritidis and treated 24 h later with PROB. These data demonstrate that PROB more effectively reduced Salmonella Enteritidis than LAB3, and the timing of PROB treatment affects Salmonella Enteritidis-associated reductions. C1 [Wolfenden, A. D.; Henderson, S. N.; Torres-Rodriguez, A.; Vicente, J. L.; Hargis, B. M.; Tellez, G.] Univ Arkansas, Dept Poultry Sci, Fayetteville, AR 72701 USA. [Higgins, J. P.] NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. [Higgins, S. E.] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20904 USA. RP Tellez, G (reprint author), Univ Arkansas, Dept Poultry Sci, Fayetteville, AR 72701 USA. EM gtellez@uark.edu NR 37 TC 33 Z9 35 U1 2 U2 6 PU POULTRY SCIENCE ASSOC INC PI SAVOY PA 1111 N DUNLAP AVE, SAVOY, IL 61874-9604 USA SN 0032-5791 J9 POULTRY SCI JI Poult. Sci. PD FEB 1 PY 2010 VL 89 IS 2 BP 243 EP 247 DI 10.3382/ps.2009-00436 PG 5 WC Agriculture, Dairy & Animal Science SC Agriculture GA 544GA UT WOS:000273640500007 PM 20075275 ER PT J AU Kempner, ES Whittaker, JW Miller, JH AF Kempner, Ellis S. Whittaker, James W. Miller, Jay H. TI Radiation inactivation of galactose oxidase, a monomeric enzyme with a stable free radical SO PROTEIN SCIENCE LA English DT Article DE galactose oxidase; radiation; target sizes; enzymatic activity; surviving monomers ID SMOOTH-MUSCLE; TARGET SIZE; NITRATE REDUCTASE; ASSIMILATORY NADH; FRAGMENTATION; CATALYSIS AB To determine the radiation sensitivity of galactose oxidase, a 68 kDa monomeric enzyme containing a mononuclear copper ion coordinated with an unusually stable cysteinyl-tyrosine (Cys-Tyr) protein free radical. Both active enzyme and reversibly rendered inactive enzyme were irradiated in the frozen state with high-energy electrons. Surviving polypeptides and surviving enzyme activity were analyzed by radiation target theory giving the radiation sensitive mass for each property. In both active and inactive forms, protein monomer integrity was lost with a single radiation interaction anywhere in the polypeptide, but enzymatic activity was more resistant, yielding target sizes considerably smaller than that of the monomer. These results suggest that the structure of galactose oxidase must make its catalytic activity unusually robust, permitting the enzymatic properties to survive in molecules following cleavage of the polymer chain. Radiation target size for loss of monomers yielded the mass of monomers indicating a polypeptide chain cleavage after a radiation interaction anywhere in the monomer. Loss of enzymatic activity yielded a much smaller mass indicating a robust structure in which catalytic activity could be expressed in cleaved polypeptides. C1 [Kempner, Ellis S.; Miller, Jay H.] NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. [Whittaker, James W.] Oregon Hlth & Sci Univ, Sch Med, Dept Sci & Engn, Beaverton, OR 97006 USA. RP Kempner, ES (reprint author), NIAMSD, Phys Biol Lab, NIH, Bethesda, MD 20892 USA. EM eskempner@yahoo.com FU Intramural NIH HHS; NIGMS NIH HHS [GM046749] NR 31 TC 2 Z9 4 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2010 VL 19 IS 2 BP 236 EP 241 DI 10.1002/pro.302 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 551WW UT WOS:000274245100005 PM 19998406 ER PT J AU Shen, Y Bryan, PN He, YN Orban, J Baker, D Bax, A AF Shen, Yang Bryan, Philip N. He, Yanan Orban, John Baker, David Bax, Ad TI De novo structure generation using chemical shifts for proteins with high-sequence identity but different folds SO PROTEIN SCIENCE LA English DT Article DE NMR; chemical shift; structure prediction; CS-Rosetta ID IMMUNOGLOBULIN-BINDING DOMAIN; NUCLEAR-MAGNETIC-RESONANCE; STRUCTURE PREDICTION; SECONDARY STRUCTURE; C-13 NMR; CONFORMATION; RECOGNITION; HOMOLOGY; GENOMICS; DATABASE AB Proteins with high-sequence identity but very different folds present a special challenge to sequence-based protein structure prediction methods. In particular, a 56-residue three-helical bundle protein (GA(95)) and an alpha/beta-fold protein (GB(95)), which share 95% sequence identity, were targets in the CASP-8 structure prediction contest. With only 12 out of 300 submitted server-CASP8 models for GA(95) exhibiting the correct fold, this protein proved particularly challenging despite its small size. Here, we demonstrate that the information contained in NMR chemical shifts can readily be exploited by the CS-Rosetta structure prediction program and yields adequate convergence, even when input chemical shifts are limited to just amide (1)H(N) and (15)N or (1)H(N) and (1)H(alpha) values. C1 [Shen, Yang; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Bryan, Philip N.; He, Yanan; Orban, John] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Baker, David] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Baker, David] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 126, Bethesda, MD 20892 USA. EM bax@nih.gov RI Shen, Yang/C-3064-2008; Baker, David/K-8941-2012 OI Shen, Yang/0000-0003-1408-8034; Baker, David/0000-0001-7896-6217 FU NIH [GM62154]; W. M. Keck Foundation; NIH (NIGMS); Howard Hughes Medical Institutes FX Grant sponsor: NIH; Grant number: GM62154; Grant sponsors: NIH (Intramural Research Program of the NIDDK and Intramural AIDS- Targeted Antiviral Program of the Office of the Director); W. M. Keck Foundation; NIH (NIGMS); Howard Hughes Medical Institutes. NR 36 TC 32 Z9 32 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2010 VL 19 IS 2 BP 349 EP 356 DI 10.1002/pro.303 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 551WW UT WOS:000274245100016 PM 19998407 ER PT J AU Lake, CR AF Lake, C. Ray TI THIS ISSUE: Schizophrenia and Bipolar Disorder: No Dichotomy, A Continuum, or One Disease? SO PSYCHIATRIC ANNALS LA English DT Editorial Material ID MANIC-DEPRESSIVE ILLNESS; PSYCHOSES; SYMPTOMS C1 [Lake, C. Ray] Univ Kansas, Sch Med, Kansas City, MO 64110 USA. [Lake, C. Ray] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Lake, C. Ray] Uniformed Serv Univ Hlth Sci, Sch Med, Bethesda, MD 20814 USA. RP Lake, CR (reprint author), Univ Kansas, Sch Med, Kansas City, MO 64110 USA. NR 13 TC 1 Z9 1 U1 0 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD FEB PY 2010 VL 40 IS 2 BP 72 EP + DI 10.3928/00485718-20100127-02 PG 4 WC Psychiatry SC Psychiatry GA 555FW UT WOS:000274494900002 ER PT J AU Elmer, GI Pieper, JO Hamilton, LR Wise, RA AF Elmer, Greg I. Pieper, Jeanne O. Hamilton, Lindsey R. Wise, Roy A. TI Qualitative differences between C57BL/6J and DBA/2J mice in morphine potentiation of brain stimulation reward and intravenous self-administration SO PSYCHOPHARMACOLOGY LA English DT Article DE Intravenous; Self-administration; Recombinant inbred strain; QTL; Opioid; Addiction; Intracranial self-stimulation; Amphetamine ID INBRED MOUSE STRAINS; NUCLEUS-ACCUMBENS; DOPAMINE NEURONS; PLACE PREFERENCE; GENETIC-DIFFERENCES; INDUCED ANALGESIA; OPIOID RECEPTORS; CONGENIC STRAINS; DEFICIENT MICE; RATS AB The C57BL/6J (C57) and DBA/2J (DBA) mice are the most common genotypes used to identify chromosomal regions and neurochemical mechanisms of interest in opioid addiction. Unfortunately, outside of the oral two-bottle choice procedure, limited and sometimes controversial evidence is available for determining their relative sensitivity to the rewarding effects of morphine. The purpose of this study was to utilize classically accepted models of drug abuse liability to determine relative susceptibility to the rewarding effects of morphine. The ability of morphine or amphetamine to potentiate lateral hypothalamic brain stimulation and intravenous morphine self-administration (across three doses in a fixed ratio schedule and at the highest dose in progressive ratio schedules) was investigated in both genotypes. In both measures, C57 and DBA mice differed dramatically in their response to morphine. Morphine potentiated rewarding stimulation in the C57 mice but antagonized it in the DBA mice. Consistent with these findings, intravenous morphine did not serve as a positive reinforcer in DBA mice under conditions that were effective in the C57 mice using a fixed ratio schedule and failed to sustain levels of responding sufficient to maintain a constant rate of drug intake under a progressive ratio schedule. In contrast, amphetamine potentiated the rewarding effects of brain stimulation similarly in the two genotypes. These findings provide strong evidence that morphine is rewarding in the C57 genotype and not in the DBA genotype. Understanding their relative susceptibility is important given the prominence of these genotypes in candidate gene identification and gene mapping. C1 [Elmer, Greg I.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21228 USA. [Pieper, Jeanne O.; Hamilton, Lindsey R.; Wise, Roy A.] NIDA, Intramural Res Program, Behav Neurosci Sect, Baltimore, MD 21224 USA. RP Elmer, GI (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Maple & Locust Sts, Baltimore, MD 21228 USA. EM gelmer@mprc.umaryland.edu RI Wise, Roy/A-6465-2012 FU NIDA [NIDA/MPRC NS001, HHSN271200599091C, DA19813] FX This work was supported by the Intramural Research Program/NIDA, NIDA/MPRC NS001, HHSN271200599091C and in part by NIDA grant DA19813. NR 77 TC 20 Z9 21 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2010 VL 208 IS 2 BP 309 EP 321 DI 10.1007/s00213-009-1732-z PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 537FA UT WOS:000273097300014 PM 20013116 ER PT J AU Thomsen, M Wess, J Fulton, BS Fink-Jensen, A Caine, SB AF Thomsen, Morgane Wess, Juergen Fulton, Brian S. Fink-Jensen, Anders Caine, S. Barak TI Modulation of prepulse inhibition through both M-1 and M-4 muscarinic receptors in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE Prepulse inhibition; Muscarinic; Acetylcholine receptor; Antipsychotic; Knockout mice; M-1; M-4 ID ANTIPSYCHOTIC-LIKE ACTIVITY; PITUITARY-ADRENAL RESPONSES; ACOUSTIC STARTLE RESPONSE; ACETYLCHOLINE-RECEPTOR; KNOCKOUT MICE; N-DESMETHYLCLOZAPINE; AGONIST XANOMELINE; WORKING-MEMORY; SCHIZOPHRENIA; RATS AB Muscarinic cholinergic M-1 and M-4 receptors may participate in schizophrenia's etiology and have been proposed as targets for antipsychotic medications. Here, we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M-1 receptors (M-1-/-), M-4 receptors (M-4-/-), or both (M-1-/-M-4-/-). We measured prepulse inhibition (PPI) of startle without drugs and after treatment with scopolamine (0.32-1.8 mg/kg), xanomeline (3.2 mg/kg), oxotremorine (0.032-0.1 mg/kg), clozapine (1.0-5.6 mg/kg), or haloperidol (0.32-3.2 mg/kg). In female (but not male) mice, combined deletion of both M-1 and M-4 receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M-4-/- mice, but not in female M-1-/-M-4-/- or female M-1-/- mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M-1-/- mice, but not in M-4-/- mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation. Deletion of both M-1 and M-4 receptors can disrupt PPI, suggesting that (at least partially redundant) M-1 and M-4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M-1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M-4 receptor stimulation, while stimulation of non-M-1/M-4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M-1/M-4 receptors in mediating antipsychotic-like effects of clozapine. C1 [Thomsen, Morgane; Fulton, Brian S.; Caine, S. Barak] Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Fink-Jensen, Anders] Rigshosp Univ Hosp, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. [Fink-Jensen, Anders] Univ Copenhagen, Dept Pharmacol, DK-2100 Copenhagen, Denmark. RP Thomsen, M (reprint author), Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM mthomsen@mclean.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Disorders; NARSAD Young Investigator Award; Eleanor and Miles Shore/Harvard Medical School Fellowship FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Disorders (J.W). M. T. was supported in part by a NARSAD Young Investigator Award and an Eleanor and Miles Shore/Harvard Medical School Fellowship during this work. All procedures were carried out in accordance with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003). We thank Joon Y. Boon and Kate Woodard for technical assistance. NR 89 TC 23 Z9 23 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2010 VL 208 IS 3 BP 401 EP 416 DI 10.1007/s00213-009-1740-z PG 16 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 544BV UT WOS:000273627400006 PM 20013114 ER PT J AU Cippitelli, A Damadzic, R Hansson, AC Singley, E Sommer, WH Eskay, R Thorsell, A Heilig, M AF Cippitelli, Andrea Damadzic, Ruslan Hansson, Anita C. Singley, Erick Sommer, Wolfgang H. Eskay, Robert Thorsell, Annika Heilig, Markus TI Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking SO PSYCHOPHARMACOLOGY LA English DT Article DE Yohimbine; Reinstatement; Alcohol seeking; c-fos; NPY; Relapse ID CORTICOTROPIN-RELEASING-FACTOR; PITUITARY-ADRENAL AXIS; CENTRAL NUCLEUS; ETHANOL INTAKE; WISTAR RATS; C-FOS; NORADRENERGIC FUNCTION; ANTAGONIST ANTALARMIN; INDUCED INCREASES; ANXIOGENIC DRUGS AB Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine. NPY [5.0 or 10.0 mu g/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment. The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively. These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction. C1 [Cippitelli, Andrea; Damadzic, Ruslan; Hansson, Anita C.; Singley, Erick; Sommer, Wolfgang H.; Eskay, Robert; Thorsell, Annika; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,1-5330, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Sommer, Wolfgang/0000-0002-5903-6521; Thorsell, Annika/0000-0003-3535-3845 NR 53 TC 46 Z9 46 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2010 VL 208 IS 3 BP 417 EP 426 DI 10.1007/s00213-009-1741-y PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 544BV UT WOS:000273627400007 PM 20012021 ER PT J AU Bhatti, P Doody, MM Rajaraman, P Alexander, BH Yeager, M Hutchinson, A Burdette, L Thomas, G Hunter, DJ Simon, SL Weinstock, RM Rosenstein, M Stovall, M Preston, DL Linet, MS Hoover, RN Chanock, SJ Sigurdson, AJ AF Bhatti, Parveen Doody, Michele M. Rajaraman, Preetha Alexander, Bruce H. Yeager, Meredith Hutchinson, Amy Burdette, Laurie Thomas, Gilles Hunter, David J. Simon, Steven L. Weinstock, Robert M. Rosenstein, Marvin Stovall, Marilyn Preston, Dale L. Linet, Martha S. Hoover, Robert N. Chanock, Stephen J. Sigurdson, Alice J. TI Novel Breast Cancer Risk Alleles and Interaction with Ionizing Radiation among US Radiologic Technologists SO RADIATION RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; COMMON VARIANTS; EXPOSURE; POLYMORPHISMS; APOPTOSIS; EXPRESSION; GENES; LOCI AB As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible subpopulations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not rind significant variation in the radiation-related breast cancer risk for the variant in RAD51LI (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980 and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (P(interaction) = 0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete understanding of the way(s) in which these variants may increase breast cancer risk remains elusive, this approach may yield clues for further investigation. (C) 2010 by Radiation Research Society C1 [Bhatti, Parveen; Yeager, Meredith] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Bhatti, Parveen; Doody, Michele M.; Rajaraman, Preetha; Hunter, David J.; Simon, Steven L.; Linet, Martha S.; Hoover, Robert N.; Chanock, Stephen J.; Sigurdson, Alice J.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. [Yeager, Meredith; Hutchinson, Amy; Burdette, Laurie; Thomas, Gilles; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Weinstock, Robert M.; Rosenstein, Marvin] Res Triangle Inst, Bethesda, MD USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. [Preston, Dale L.] HiroSoft Int Corp, Seattle, WA USA. RP Bhatti, P (reprint author), Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. EM pbhatti@fhcrc.org FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We are grateful to the radiologic technologists who participated in the USRT Study, Jerry Reid of the American Registry of Radiologic Technologists for continued support of this study, Diane Kampa and Allison Iwan of the University of Minnesota for study coordination and data collection, and Laura Bowen of Information Management Systems for data management. This project has been funded in part by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, and by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 30 TC 17 Z9 18 U1 1 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2010 VL 173 IS 2 BP 214 EP 224 DI 10.1667/RR1985.1 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 552EH UT WOS:000274270200011 PM 20095854 ER PT J AU Stenholm, S Maggio, M Lauretani, F Bandinelli, S Ceda, GP Di Iorio, A Giallauria, F Guralnik, JM Ferrucci, L AF Stenholm, Sari Maggio, Marcello Lauretani, Fulvio Bandinelli, Stefania Ceda, Gian Paolo Di Iorio, Angelo Giallauria, Francesco Guralnik, Jack M. Ferrucci, Luigi TI Anabolic and Catabolic Biomarkers As Predictors of Muscle Strength Decline: The InCHIANTI Study SO REJUVENATION RESEARCH LA English DT Article ID C-REACTIVE PROTEIN; PHYSICAL PERFORMANCE; BODY-COMPOSITION; OLDER WOMEN; MEN; INTERLEUKIN-6; AGE; TESTOSTERONE; INFLAMMATION; EXERCISE AB Background: Poor muscle strength is a major public health concern in older persons, predisposing to functional limitations, increased fall risk, and higher mortality. Understanding risk factors for muscle strength decline may offer opportunities for prevention and treatment. One of the possible causes of muscle strength decline is imbalance between catabolic and anabolic signaling. This study aims to examine whether high levels of multiple catabolic and low levels of multiple anabolic biomarkers predict accelerated decline of muscle strength. Methods: In a representative sample of 716 men and women aged >= 65 years in the InCHIANTI study we measured C-reactive protein, interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha receptor 1 as well as dehydroepiandrosterone sulfate (DHEA-S), insulin-like growth factor-1, and bioavailable testosterone. Biomarker values were divided into tertiles and the numbers of catabolic/anabolic biomarkers in the highest/lowest tertile were calculated. Hand-grip strength was measured at baseline and 3- and 6-year follow up. Results: In adjusted linear mixed models, higher concentration of IL-6 (p = 0.02) and IL-1RA (p=0.04) as well as lower levels of DHEA-S (p = 0.01) predicted muscle strength decline. After combining all inflammatory markers, the rate of decline in grip strength was progressively greater with the increasing number of dysregulated catabolic biomarkers (p = 0.01). No effect on accelerated muscle strength decline was seen according to number of dysregulated anabolic hormones. Conclusions: Having multiple elevated catabolic biomarkers is a better predictor of muscle strength decline than a single biomarker alone, suggesting that a catabolic dysregulation is at the core of the mechanism leading to muscle strength decline with aging. C1 [Stenholm, Sari; Giallauria, Francesco; Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Stenholm, Sari] Natl Inst Hlth & Welf, Funct Capac Unit, Turku, Finland. [Maggio, Marcello; Ceda, Gian Paolo] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, I-43100 Parma, Italy. [Lauretani, Fulvio] Univ Hosp Parma, Geriatr Rehabil Dept, Geriatr Unit, Parma, Italy. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Di Iorio, Angelo] Univ G DAnnunzio Chieti, Dept Med & Sci Aging, Lab Clin Epidemiol, Chieti, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Stenholm, S (reprint author), Harbor Hosp, NIA, Clin Res Branch, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM stenholmsm@mail.nih.gov RI Stenholm, Sari/G-6940-2011; Giallauria, Francesco/B-5681-2013; Lauretani, Fulvio/K-5115-2016; OI Giallauria, Francesco/0000-0003-4119-9397; Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging, National Institutes of Health, Baltimore, Maryland [263 MD 9164, 263 MD 821336, N01-AG-5-0002]; Finnish Academy [125494 SS] FX The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U. S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-up 2 study (2004-2006) was financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore, Maryland. This work was also supported by grant from the Finnish Academy (no. 125494 SS). The authors have no financial or personal conflicts of interest. None of the sponsoring institutions interfered with the design, methods, subject recruitment, data collections, analysis and preparation of paper. NR 37 TC 29 Z9 29 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD FEB PY 2010 VL 13 IS 1 BP 3 EP 11 DI 10.1089/rej.2009.0891 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 569EK UT WOS:000275578900002 PM 20230273 ER PT J AU Brooks, SC Schmicker, RH Rea, TD Aufderheide, TP Davis, DP Morrison, LJ Sahni, R Sears, GK Griffiths, DE Sopko, G Emerson, SS Dorian, P AF Brooks, Steven C. Schmicker, Robert H. Rea, Thomas D. Aufderheide, Tom P. Davis, Daniel P. Morrison, Laurie J. Sahni, Ritu Sears, Gena K. Griffiths, Denise E. Sopko, George Emerson, Scott S. Dorian, Paul CA ROC Investigators TI Out-of-hospital cardiac arrest frequency and survival: Evidence for temporal variability SO RESUSCITATION LA English DT Article DE Out-of-hospital cardiac arrest; Circadian rhythm; Temporal variation ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; ACUTE MYOCARDIAL-INFARCTION; CIRCADIAN VARIATION; VENTRICULAR TACHYARRHYTHMIAS; DEATH; POPULATION; ONSET; IMPLEMENTATION; METAANALYSIS; DISEASE AB Aim: Some cardiac phenomena demonstrate temporal variability. We evaluated temporal variability in out-of-hospital cardiac arrest (OHCA) frequency and outcome. Methods: Prospective cohort Study (the Resuscitation Outcomes Consortium) of all OHCA of presumed cardiac cause who were treated by emergency medical services within 9 US and Canadian sites between 12/1/2005 and 02/28/2007. In each site, Emergency Medical System records were collected and analyzed. Outcomes were individually verified by trained data abstractors. Results: There were 9667 included patients. Median age was 68 (IQR 24) years, 66.7% were male and 8.3% survived to hospital discharge. The frequency of cardiac arrest varied significantly across time blocks (p < 0.001). Compared to the 0001-0600 hourly time block, the odds ratios and 95% CIs for the Occurrence of OHCA were 2.02 (1.90, 2.15) in the 0601-1200 block, 2.01 (1.89, 2.15) in the 1201-1800 block, and 1.73 (1.62, 1.85) in the 1801-2400 block. The frequency of all OHCA varied significantly by day of week (p = 0.03) and month of year (p < 0.001) with the highest frequencies on Saturday and during December. Survival to hospital discharge was lowest when the OHCA occurred during the 0001-0600 time block (7.3%) and highest during the 1201-1800 time block (9.6%). Survival was highest for OHCAs occurring on Mondays (10.0%) and lowest for those on Wednesdays (6.8%) (p = 0.02). Conclusion:There is temporal variability in OHCA frequency and Outcome. Underlying patient, EMS system and environmental factors need to be explored to offer further insight into these observed patterns. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Brooks, Steven C.; Morrison, Laurie J.] Univ Toronto, St Michaels Hosp, Keenan Res Ctr,Dept Med, Li Ka Shing Knowledge Inst,Div Emergency Med, Toronto, ON M5B 1M8, Canada. [Brooks, Steven C.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Emergency Serv, Div Emergency Med,Dept Med, Toronto, ON M5B 1M8, Canada. [Schmicker, Robert H.; Sears, Gena K.; Emerson, Scott S.] Univ Washington, Clin Trials Ctr, Seattle, WA 98195 USA. [Rea, Thomas D.] Univ Washington, Div Gen Med, Seattle, WA 98195 USA. [Aufderheide, Tom P.] Med Coll Wisconsin, Dept Emergency Med, Milwaukee, WI 53226 USA. [Davis, Daniel P.] Univ Calif San Diego, Dept Emergency Med, San Diego, CA 92103 USA. [Sahni, Ritu; Griffiths, Denise E.] Oregon Hlth & Sci Univ, Ctr Policy & Res Emergency Med, Portland, OR 97201 USA. [Sopko, George] NHLBI, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Dorian, Paul] Univ Toronto, Dept Med, Div Cardiol, Toronto, ON M5B 1M8, Canada. RP Brooks, SC (reprint author), Univ Toronto, St Michaels Hosp, Keenan Res Ctr,Dept Med, Li Ka Shing Knowledge Inst,Div Emergency Med, 30 Bond St, Toronto, ON M5B 1M8, Canada. EM brooksst@smh.toronto.on.ca RI morrison, laurie/A-6325-2012; OI morrison, laurie/0000-0001-8369-9774; Brooks, Steven/0000-0002-4592-4974 FU National Heart, Lung and Blood Institute, National Institute of Neurological Disorders and Stroke [5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077885, HL077863]; Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defence Research and Development Canada; National American Heart Association; Heart and Stroke Foundation of Canada FX The Resuscitation Outcome Consortium (ROC) is supported by a series of cooperative agreements to 10 regional clinical centers and one data Coordinating Center (5U01 HL077863, HL077881, HL077871 HL077872, HL077866, HL077908, HL077867, HL077885, HL077885, HL077863) from the National Heart, Lung and Blood Institute in partnership with the National Institute of Neurological Disorders and Stroke, The Canadian Institutes of Health Research (CIHR)-Institute of Circulatory and Respiratory Health, Defence Research and Development Canada, The National American Heart Association, and the Heart and Stroke Foundation of Canada. NR 24 TC 35 Z9 39 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD FEB PY 2010 VL 81 IS 2 BP 175 EP 181 DI 10.1016/j.resuscitation.2009.10.021 PG 7 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA 561MU UT WOS:000274982500006 PM 19942338 ER PT J AU Abram, ME Sarafianos, SG Parniak, MA AF Abram, Michael E. Sarafianos, Stefan G. Parniak, Michael A. TI The mutation T477A in HIV-1 reverse transcriptase (RT) restores normal proteolytic processing of RT in virus with Gag-Pol mutated in the p51-RNH cleavage site SO RETROVIROLOGY LA English DT Article ID RNASE-H DOMAIN; LINKER INSERTION MUTAGENESIS; RIBONUCLEASE-H; MONOCLONAL-ANTIBODIES; ANGSTROM RESOLUTION; POLYMERASE-ACTIVITY; STRUCTURAL BASIS; VIRAL PROTEASE; TYPE-1; INHIBITION AB Background: The p51 subunit of the HIV-1 reverse transcriptase (RT) p66/p51 heterodimer arises from proteolytic cleavage of the RT p66 subunit C-terminal ribonuclease H (RNH) domain during virus maturation. Our previous work showed that mutations in the RT p51 down arrow RNH cleavage site resulted in virus with defects in proteolytic processing of RT and significantly attenuated infectivity. In some cases, virus fitness was restored after repeated passage of mutant viruses, due to reversion of the mutated sequences to wild-type. However, in one case, the recovered virus retained the mutated p51 down arrow RNH cleavage site but also developed an additional mutation, T477A, distal to the cleavage site. In this study we have characterized in detail the impact of the T477A mutation on intravirion processing of RT. Results: While the T477A mutation arose during serial passage only with the F440V mutant background, introduction of this substitution into a variety of RT p51 down arrow RNH cleavage site lethal mutant backgrounds was able to restore substantial infectivity and normal RT processing to these mutants. T477A had no phenotypic effect on wildtype HIV-1. We also evaluated the impact of T477A on the kinetics of intravirion Gag-Pol polyprotein processing of p51 down arrow RNH cleavage site mutants using the protease inhibitor ritonavir. Early processing intermediates accumulated in p51 down arrow RNH cleavage site mutant viruses, whereas introduction of T477A promoted the completion of processing and formation of the fully processed RT p66/p51 heterodimer. Conclusions: This work highlights the extraordinary plasticity of HIV-1 in adapting to seemingly lethal mutations that prevent RT heterodimer formation during virion polyprotein maturation. The ability of T477A to restore RT heterodimer formation and thus intravirion stability of the enzyme may arise from increased conformation flexibility in the RT p51 down arrow RNH cleavage site region, due to loss of a hydrogen bond associated with the normal threonine residue, thereby enabling proteolytic cleavage near the normal RT p51 down arrow RNH cleavage site. C1 [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. [Abram, Michael E.] NCI, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. [Sarafianos, Stefan G.] Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA. RP Parniak, MA (reprint author), Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. EM map167@pitt.edu OI Sarafianos, Stefan G/0000-0002-5840-154X FU NIH [AI073975, AI077424, AI079801, AI074389, AI076119] FX Research in the Parniak laboratory is supported in part by NIH grants AI073975, AI077424 and AI079801. Research in the Sarafianos laboratory is supported in part by NIH grants AI074389 and AI076119. NR 43 TC 6 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 1 PY 2010 VL 7 AR 6 DI 10.1186/1742-4690-7-6 PG 9 WC Virology SC Virology GA 562XH UT WOS:000275088600001 PM 20122159 ER PT J AU Aagaard, P Suetta, C Caserotti, P Magnusson, SP Kjaer, M AF Aagaard, P. Suetta, C. Caserotti, P. Magnusson, S. P. Kjaer, M. TI Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure SO SCANDINAVIAN JOURNAL OF MEDICINE & SCIENCE IN SPORTS LA English DT Review DE motor neurons; CNS; muscle power; RFD; strength training ID HUMAN SKELETAL-MUSCLE; GROWTH-FACTOR-I; MOTOR UNIT DISCHARGE; FORCE PRODUCTION CHARACTERISTICS; TIBIALIS-ANTERIOR MUSCLE; AGE-RELATED DIFFERENCES; WHOLE VASTUS LATERALIS; DIFFERENT FIBER TYPES; MYOSIN HEAVY-CHAIN; SOLEUS H-REFLEX AB Aging is characterized by loss of spinal motor neurons (MNs) due to apoptosis, reduced insulin-like growth factor I signaling, elevated amounts of circulating cytokines, and increased cell oxidative stress. The age-related loss of spinal MNs is paralleled by a reduction in muscle fiber number and size (sarcopenia), resulting in impaired mechanical muscle performance that in turn leads to a reduced functional capacity during everyday tasks. Concurrently, maximum muscle strength, power, and rate of force development are decreased with aging, even in highly trained master athletes. The impairment in muscle mechanical function is accompanied and partly caused by an age-related loss in neuromuscular function that comprise changes in maximal MN firing frequency, agonist muscle activation, antagonist muscle coactivation, force steadiness, and spinal inhibitory circuitry. Strength training appears to elicit effective countermeasures in elderly individuals even at a very old age (>80 years) by evoking muscle hypertrophy along with substantial changes in neuromuscular function, respectively. Notably, the training-induced changes in muscle mass and nervous system function leads to an improved functional capacity during activities of daily living. C1 [Aagaard, P.] Univ So Denmark, Inst Sports Sci & Clin Biomech, DK-5230 Odense, Denmark. [Suetta, C.; Magnusson, S. P.; Kjaer, M.] Bispebjerg Hosp, Inst Sports Med Copenhagen, DK-2400 Copenhagen, Denmark. [Magnusson, S. P.] Univ Copenhagen, Bispebjerg Hosp, Fac Hlth Sci, Dept Phys Therapy,Ctr Healthy Aging, Copenhagen, Denmark. [Caserotti, P.] NIH, Bethesda, MD 20892 USA. RP Aagaard, P (reprint author), Univ So Denmark, Inst Sports Sci & Clin Biomech, Campusvej 55, DK-5230 Odense, Denmark. EM paagaard@health.sdu.dk NR 137 TC 176 Z9 183 U1 9 U2 63 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0905-7188 J9 SCAND J MED SCI SPOR JI Scand. J. Med. Sci. Sports PD FEB PY 2010 VL 20 IS 1 BP 49 EP 64 DI 10.1111/j.1600-0838.2009.01084.x PG 16 WC Sport Sciences SC Sport Sciences GA 546PT UT WOS:000273823400007 PM 20487503 ER PT J AU Storms, G Elvevag, B AF Storms, Gert Elvevag, Brita TI Thinking about semantic concepts in schizophrenia: The more familiar the less deviation SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID MEMORY C1 [Elvevag, Brita] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Storms, Gert] Univ Leuven, Dept Psychol, Louvain, Belgium. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,3C104,MSC 1379, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU Intramural NIH HHS [NIH0010394655]; PHS HHS [NIH0010394655] NR 10 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB PY 2010 VL 116 IS 2-3 BP 295 EP 296 DI 10.1016/j.schres.2009.11.013 PG 2 WC Psychiatry SC Psychiatry GA 561AB UT WOS:000274946000028 PM 20022730 ER PT J AU Pons-Estel, GJ Alarcon, GS Scofield, L Reinlib, L Cooper, GS AF Pons-Estel, Guillermo J. Alarcon, Graciela S. Scofield, Lacie Reinlib, Leslie Cooper, Glinda S. TI Understanding the Epidemiology and Progression of Systemic Lupus Erythematosus SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE systemic lupus erythematosus; epidemiology; mortality; disease activity; quality of life; ethnicity; socioeconomic status ID 3 ETHNIC-GROUPS; QUALITY-OF-LIFE; MULTIETHNIC US COHORT; DISEASE-ACTIVITY; SOCIAL SUPPORT; CLINICAL-MANIFESTATIONS; HIGH PREVALENCE; LUMINA COHORT; RISK-FACTORS; IMMUNOLOGICAL FEATURES AB Objectives: This review examines the burden and patterns of disease in systemic lupus erythematosus (SLE) and the influence and interactions of gender, ethnicity, age, and psychosocial attributes with respect to disease progression, focusing on issues relevant to clinical practice and research. Methods: PubMed literature search complemented by review of bibliographies listed in identified articles. Results: An increased risk among reproductive age women is clearly seen in African Americans in the United States. However, in other populations, a different pattern is generally seen, with the highest age-specific incidence rates occurring in women after age 40 years. The disease is 2 to 4 times more frequent, and more severe, among nonwhite populations around the world and tends to be more severe in men and in pediatric and late-onset lupus. SLE patients now experience a higher than 90% survival rate at 5 years. The less favorable survival experience of ethnic minorities is possibly related to socioeconomic status rather than to ethnicity per se, and adequate social support has been shown to be a protective factor, in general, in SLE patients. Discordance between physician and patient ratings of disease activity may affect quality of care. Conclusions: Our understanding of ways to improve outcomes in SLE patients could benefit from patient-oriented research focusing on many dimensions of disease burden. Promising research initiatives include the inclusion of community-based patients in longitudinal studies, use of self-assessment tools for rating disease damage and activity, and a focus on self-perceived disease activity and treatment compliance. Published by Elsevier Inc. Semin Arthritis Rheum 39:257-268 C1 [Cooper, Glinda S.] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. [Pons-Estel, Guillermo J.; Alarcon, Graciela S.] Univ Alabama, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Scofield, Lacie] US Dept Hlth & Human Serv, Off Womens Hlth, Washington, DC USA. [Scofield, Lacie; Reinlib, Leslie; Cooper, Glinda S.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Cooper, GS (reprint author), US EPA, Natl Ctr Environm Assessment, Off Res & Dev, 8601-P,1200 Penn Ave NW, Washington, DC 20460 USA. EM cooper.glinda@epa.gov OI Pons-Estel, Guillermo/0000-0002-0647-929X FU U.S. Department of Health and Human Services' Office of Women's Health; The National Institute of Environmental Health Sciences; Lupus Foundation of America FX This article is based on presentations and discussions that took place during the workshop on "Lupus and the Environment: Disease Development, Progression and Flare," which was held in Washington, DC, September, 2005. The concept for this focused workshop was produced by the Federal Interagency Working Group on Women's Health and the Environment and support was provided by the U.S. Department of Health and Human Services' Office of Women's Health, The National Institute of Environmental Health Sciences, and the Lupus Foundation of America. The views expressed are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA, the National Institute of Environmental Health Sciences, or the Office of Women's Health of the Department of Health and Human Services. NR 132 TC 200 Z9 213 U1 3 U2 21 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD FEB PY 2010 VL 39 IS 4 BP 257 EP 268 DI 10.1016/j.semarthrit.2008.10.007 PG 12 WC Rheumatology SC Rheumatology GA 620KB UT WOS:000279497400004 PM 19136143 ER PT J AU Fugmann, SD AF Fugmann, Sebastian D. TI The origins of the Rag genes-From transposition to V(D)J recombination SO SEMINARS IN IMMUNOLOGY LA English DT Review DE RAG1; RAG2; Transposase; Evolution; Adaptive immunity ID IMMUNE-SYSTEM; BINDING DOMAIN; ACTIVE-SITE; SEA-URCHIN; IN-VIVO; SEQUENCE; DNA; IDENTIFICATION; PROTEINS; PHD AB The recombination activating genes 1 and 2 (Rag1 and Rag2) encode the key enzyme that is required for the generation of the highly diversified antigen receptor repertoire central to adaptive immunity. The longstanding model proposed that this gene pair was acquired by horizontal gene transfer to explain its abrupt appearance in the vertebrate lineage. The analyses of the enormous amount of sequence data created by many genome sequencing projects now provide the basis for a more refined model as to how this unique gene pair evolved from a selfish DNA transposon into a sophisticated DNA recombinase essential for immunity. Published by Elsevier Ltd. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Fugmann, SD (reprint author), NIA, Cellular & Mol Biol Lab, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM fugmanns@mail.nih.gov FU National Institute on Aging/National Institutes of Health FX I want to thank Jonathan Rast, Martin Flajnik and all members of my lab for stimulating discussions, and Shu Yuan Yang for helpful comments and suggestions on this manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging/National Institutes of Health. NR 49 TC 36 Z9 37 U1 4 U2 18 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD FEB PY 2010 VL 22 IS 1 BP 10 EP 16 DI 10.1016/j.smim.2009.11.004 PG 7 WC Immunology SC Immunology GA 563VM UT WOS:000275163300003 PM 20004590 ER PT J AU Marquardt, JU Thorgeirsson, SS AF Marquardt, Jens U. Thorgeirsson, Snorri S. TI Stem Cells in Hepatocarcinogenesis: Evidence from Genomic Data SO SEMINARS IN LIVER DISEASE LA English DT Review DE Hepatocellular carcinoma; stem/ progenitor cells; oval cells; comparative functional genomics; cancer stem cells; hepatocarcinogenesis ID HUMAN HEPATOCELLULAR-CARCINOMA; HEPATIC PROGENITOR CELLS; LIVER EPITHELIAL-CELLS; SIDE POPULATION CELLS; OVAL CELLS; RAT-LIVER; GENE-EXPRESSION; STEM/PROGENITOR CELLS; TUMOR HETEROGENEITY; FUNCTIONAL GENOMICS AB Increasing evidence suggests that many, perhaps all solid tumors contain a subset of cells that possess functional properties similar to the normal tissue stem cells, including self-renewal, unlimited proliferative capacity, and pluripotency. The hierarchical cancer model that places a cancer stem cell (CSC) population at the apex of tumor formation is based on this notion. The cancer stem cell hypothesis posits that CSCs are responsible not only for tumor initiation, but also generation of metastasis and local recurrence after therapy. Current definitions of the CSC are based only on functional properties regardless of potential cellular origin. Histopathology investigations of chronic liver diseases and experimental studies support the existence of CSCs in liver cancer. In particular, recent advances in microarray technologies utilizing integrative comparative genomic analysis of human hepatocellular carcinoma specimens, cancer cell lines, and transgenic models establish the molecular similarities between CSC and normal tissue stem cells and highlight the importance of CSC for the prognosis of liver cancer patients. The results have also uncovered the key "stemness'' and oncogenic pathways frequently disrupted during hepatocarcinogenesis providing the basis for identifying novel therapeutic targets against CSC. C1 [Marquardt, Jens U.; Thorgeirsson, Snorri S.] NCI, LEC, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, LEC, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov FU Intramural NIH HHS [ZIA BC011031-02] NR 86 TC 26 Z9 31 U1 0 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD FEB PY 2010 VL 30 IS 1 BP 26 EP 34 DI 10.1055/s-0030-1247130 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 557JJ UT WOS:000274665100004 PM 20175031 ER PT J AU Klebanoff, MA Nansel, TR Brotman, RM Zhang, J Yu, KF Schwebke, JR Andrews, WW AF Klebanoff, Mark A. Nansel, Tonja R. Brotman, Rebecca M. Zhang, Jun Yu, Kai-Fun Schwebke, Jane R. Andrews, William W. TI Personal Hygienic Behaviors and Bacterial Vaginosis SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID INTRAVAGINAL PRACTICES; AFRICAN WOMEN; VAGINAL FLORA; RISK; ASSOCIATION; SYMPTOMS AB Background: Vaginal douching is consistently associated with bacterial vaginosis (BV), but whether it is a cause or result of BV remains unknown. The association between BV and other feminine hygienic behaviors is less studied; if BV symptoms caused behavior change then all hygiene behaviors might be more common among women with BV, Lack of association between nondouching hygiene behavior and BV Would argue against reverse causation. Methods: In the Longitudinal Study of Vaginal Flora 3620 women had 13,517 visits where BV (Nugent score) was assessed. Associations between hygienic behavior and BV were assessed by Poisson regression. Results: After adjusting for demographic and sexual behavior factors, neither type of underwear (nylon vs. cotton prevalence ratio (PR) 1.05, 95% CI: 0.97-1.13), menstrual protection (tampons vs. pads; PR: 1.04, 95% CI: 0.95-1.12; pads and tampons vs. pads 1.00, 95% CI: 0.92-1.07), use of pads or panty liners when not menstruating (PR: 0.99, 95% Cl: 0.95-1.05), nor weekly or greater use of hygiene spray (PR: 1.01, 95% CI: 0.94-1.09), powder (PR: 1.02, 95% CI: 0.96-1.07) or towlettes (PR: 1.03, 95% CI: 0.94-1.13) were strongly associated with BV. PR for daily versus less than daily bathing and showering were 1.06 (95% CI: 1.02-1.12) and 1.04 (95% CI: 1.00-1.09). Douching remained associated with BV (PR for weekly or greater vs. never 1.17, 95% CI: 1.09-1.26) and was not substantially impacted by adjustment for other hygienic behavior. Conclusions: Douching, but not other feminine hygiene behaviors, is significantly associated with BV, providing additional evidence that douching may be causally associated with BV and is not simply a response to BV symptoms. C1 [Klebanoff, Mark A.; Nansel, Tonja R.; Zhang, Jun; Yu, Kai-Fun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Brotman, Rebecca M.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Schwebke, Jane R.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Andrews, William W.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, 6100 Bldg Room 7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov RI Brotman, Rebecca/H-5442-2011; OI Brotman, Rebecca/0000-0001-8762-6214; Nansel, Tonja/0000-0002-8298-7595 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; [N01-HD-8-3293] FX Supported by contract N01-HD-8-3293, and Intramural funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 24 TC 21 Z9 24 U1 0 U2 6 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 FEB PY 2010 VL 37 IS 2 BP 94 EP 99 DI 10.1097/OLQ.0b013e3181bc063c PG 6 WC Infectious Diseases SC Infectious Diseases GA 549RG UT WOS:000274070900006 PM 19823112 ER PT J AU Sharara-Chami, RI Joachim, M Pacak, K Majzoub, JA AF Sharara-Chami, Rana I. Joachim, Maria Pacak, Karel Majzoub, Joseph A. TI GLUCOCORTICOID TREATMENT-EFFECT ON ADRENAL MEDULLARY CATECHOLAMINE PRODUCTION SO SHOCK LA English DT Article DE PNMT; epinephrine; glucocorticoid; restraint stress; mouse; adrenal ID PHENYLETHANOLAMINE-N-METHYLTRANSFERASE; MESSENGER-RNA; CORTICOSTERONE; STRESS; ENZYME; MICE AB Glucocorticoid and epinephrine are important stress hormones secreted from the adrenal gland during critical illness. Adrenal glucocorticoid stimulates phenylethanolamine N-methyltransferase (PNMT) to convert norepinephrine to epinephrine in the adrenal medulla. Glucocorticoid is sometimes used in catecholamine-resistant septic shock in critically ill patients. By suppressing adrenal glucocorticoid production, glucocorticoid therapy might also reduce the secretion of epinephrine during stress. To investigate this, we used a mouse model subjected to glucocorticoid therapy under basal conditions (experiment 1) and during stress (experiment 2). In experiment 1, pellets containing 0% to 8% dexamethasone were implanted subcutaneously in mice for 4 weeks. In experiment 2, animals received 14 days of intraperitoneal injections of normal saline, low- or high-dose dexamethasone, followed by 2 h of restraint. We found that in experiment 1, adrenal corticosterone did not differ with dexamethasone treatment. Phenylethanolamine N-methyltransferase messenger RNA levels and adrenal catecholamines were highest in the 8% dexamethasone group. Compared with experiment 1, restrained control mice in experiment 2 had high adrenal corticosterone, which decreased with dexamethasone. Phenylethanolamine N-methyltransferase messenger RNA content doubled with restraint but decreased with dexamethasone treatment. As in experiment 1, adrenal catecholamine content increased significantly with dexamethasone treatment. We conclude that without stress, when adrenocorticotropic hormone is low, high doses of exogenous dexamethasone stimulate PNMT and catecholamine synthesis, likely independently of adrenal corticosterone concentration. After stress, adrenocorticotropic hormone levels are elevated, and exogenous dexamethasone suppresses endogenous corticosterone and PNMT production. Nonetheless, catecholamines increase, possibly due to direct neural stimulation, which may override the hormonal regulation of epinephrine synthesis during stress. C1 [Sharara-Chami, Rana I.] Harvard Univ, Sch Med, Div Crit Care Med, Dept Anesthesiol,Childrens Hosp Boston, Boston, MA 02115 USA. [Joachim, Maria; Majzoub, Joseph A.] Harvard Univ, Sch Med, Div Endocrinol, Dept Med,Childrens Hosp Boston, Boston, MA USA. [Pacak, Karel] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Sharara-Chami, RI (reprint author), Harvard Univ, Sch Med, Div Crit Care Med, Dept Anesthesiol,Childrens Hosp Boston, Boston, MA 02115 USA. EM rana.chamii@childrens.harvard.edu FU Timothy Murphy Fund FX The authors thank Masato Asai, MD, PhD, for the helpful discussions regarding quantitative reverse transcriptase polyinerase chain reaction and the generation of the cDNA plasnuds and Edwin Lai for the catecholainine measurements. This work was funded in part by the Timothy Murphy Fund. NR 20 TC 4 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD FEB PY 2010 VL 33 IS 2 BP 213 EP 217 DI 10.1097/SHK.0b013e3181af0633 PG 5 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 545QT UT WOS:000273752200014 PM 19503019 ER PT J AU Debette, S Bis, JC Fornage, M Schmidt, H Ikram, MA Sigurdsson, S Heiss, G Struchalin, M Smith, AV van der Lugt, A DeCarli, C Lumley, T Knopman, DS Enzinger, C Eiriksdottir, G Koudstaal, PJ DeStefano, AL Psaty, BM Dufouil, C Catellier, DJ Fazekas, F Aspelund, T Aulchenko, YS Beiser, A Rotter, JI Tzourio, C Shibata, DK Tscherner, M Harris, TB Rivadeneira, F Atwood, LD Rice, K Gottesman, RF van Buchem, MA Uitterlinden, AG Kelly-Hayes, M Cushman, M Zhu, YC Boerwinkle, E Gudnason, V Hofman, A Romero, JR Lopez, O van Duijn, CM Au, R Heckbert, SR Wolf, PA Mosley, TH Seshadri, S Breteler, MMB Schmidt, R Launer, LJ Longstreth, WT AF Debette, Stephanie Bis, Joshua C. Fornage, Myriam Schmidt, Helena Ikram, M. Arfan Sigurdsson, Sigurdur Heiss, Gerardo Struchalin, Maksim Smith, Albert V. van der Lugt, Aad DeCarli, Charles Lumley, Thomas Knopman, David S. Enzinger, Christian Eiriksdottir, Gudny Koudstaal, Peter J. DeStefano, Anita L. Psaty, Bruce M. Dufouil, Carole Catellier, Diane J. Fazekas, Franz Aspelund, Thor Aulchenko, Yurii S. Beiser, Alexa Rotter, Jerome I. Tzourio, Christophe Shibata, Dean K. Tscherner, Maria Harris, Tamara B. Rivadeneira, Fernando Atwood, Larry D. Rice, Kenneth Gottesman, Rebecca F. van Buchem, Mark A. Uitterlinden, Andre G. Kelly-Hayes, Margaret Cushman, Mary Zhu, Yicheng Boerwinkle, Eric Gudnason, Vilmundur Hofman, Albert Romero, Jose R. Lopez, Oscar van Duijn, Cornelia M. Au, Rhoda Heckbert, Susan R. Wolf, Philip A. Mosley, Thomas H. Seshadri, Sudha Breteler, Monique M. B. Schmidt, Reinhold Launer, Lenore J. Longstreth, W. T., Jr. TI Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium SO STROKE LA English DT Article DE brain infarction; cohort study; genome-wide association study; meta-analysis ID AUSTRIAN STROKE PREVENTION; ATHEROSCLEROSIS RISK; NEURITE OUTGROWTH; DISEASE; DESIGN; FLRT3; COMMUNITIES; FRAMINGHAM; PROTEINS; LESIONS AB Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >= 1 MRI infarct). Results-The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P = 4.64 x 10(-7)). Highly suggestive associations (P < 1.0 x 10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2) > 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions-This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. (Stroke. 2010; 41: 210-217.) C1 [Longstreth, W. T., Jr.] Univ Washington, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. [Sigurdsson, Sigurdur; Smith, Albert V.; Eiriksdottir, Gudny; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Catellier, Diane J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Shibata, Dean K.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98104 USA. [Gottesman, Rebecca F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS 39216 USA. [Schmidt, Helena; Enzinger, Christian; Fazekas, Franz] Med Univ Graz, Dept Neurol, Graz, Austria. [Schmidt, Reinhold] Med Univ Graz, Dept Neurogeriatr, Graz, Austria. [Enzinger, Christian; Schmidt, Reinhold] Med Univ Graz, Dept Neuroradiol, Graz, Austria. [Schmidt, Helena; Tscherner, Maria] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [Struchalin, Maksim] Erasmus MC Univ Med Ctr, Dept Epidemiol & Biostat, Dept Forens Mol Biol, Rotterdam, Netherlands. [Bis, Joshua C.; Psaty, Bruce M.; Longstreth, W. T., Jr.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Lumley, Thomas; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98104 USA. [Psaty, Bruce M.; Heckbert, Susan R.; Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Cushman, Mary] Univ Vermont, Dept Pathol & Med, Burlington, VT USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Lopez, Oscar] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Lopez, Oscar] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. [Debette, Stephanie; DeStefano, Anita L.; Beiser, Alexa; Atwood, Larry D.; Kelly-Hayes, Margaret; Romero, Jose R.; Au, Rhoda; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [DeStefano, Anita L.; Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Ikram, M. Arfan; Aulchenko, Yurii S.; Hofman, Albert; van Duijn, Cornelia M.; Breteler, Monique M. B.] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Koudstaal, Peter J.] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Ikram, M. Arfan; van der Lugt, Aad] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC Univ Med Ctr, Dept Clin Chem, Rotterdam, Netherlands. [DeCarli, Charles; Tzourio, Christophe; Zhu, Yicheng] INSERM, U708, Paris, France. [DeCarli, Charles; Tzourio, Christophe; Zhu, Yicheng] Univ Paris 06, Paris, France. [Zhu, Yicheng] Hop Lariboisiere, Serv Neurol, F-75475 Paris, France. [Zhu, Yicheng] Beijing Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China. RP Longstreth, WT (reprint author), Univ Washington, Harborview Med Ctr, Dept Neurol, Box 359775,325 9th Ave, Seattle, WA 98104 USA. EM wl@u.washington.edu RI DeCarli, Charles/B-5541-2009; Tzourio, christophe/B-4015-2009; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Dufouil, Carole/J-4968-2012; Rice, Kenneth/A-4150-2013; Aulchenko, Yurii/M-8270-2013; Breteler, Monique /J-5058-2014; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; OI Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Beiser, Alexa/0000-0001-8551-7778; Tzourio, christophe/0000-0002-6517-2984; Aspelund, Thor/0000-0002-7998-5433; Rice, Kenneth/0000-0001-5779-4495; Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Ikram, Mohammad Arfan/0000-0003-0372-8585 FU NIA [N01-AG-12100]; NEI; NIDCD; NHLBI; NIA Intramural Research Program, Hjartavernd; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL093029, N01-HC-85079, N01-HC- 85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research; Austrian Science Fond (FWF) [P20545-P05, P13180]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [M01RR00425]; Cedars-Sinai General Clinical Research Center Genotyping core; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [AG08122, AG16495, AG033193]; Netherlands Organization of Scientific Research Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [01493- 015; RIDE2]; Netherlands Genomics Initiative (NGI)/ Netherlands Organization for Scientific Research [050-060810]; NWO [918-46-615, 948-00-010]; Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands; Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN); Institut de la Longevite; Conseils Regionaux of Aquitaine and Bourgogne; Fondation de France; Ministry of Research-INSERM FX Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA contract N01-AG-12100 with contributions from NEI, NIDCD, and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; The Atherosclerosis Risk in Communities Study: The research is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, and grants R01HL087641 and R01HL093029; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; The Austrian Stroke Prevention Study: The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS.; Cardiovascular Health Study: The research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, and N01-HC-45133, and grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www. chs-nhlbi. org/pi. htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; Framingham Heart Study: From the Boston University School of Medicine and the Framingham Heart Study. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract number N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract number N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (AG08122, AG16495, and AG033193).; Rotterdam Study: The generation and management of genomewide association study genotype data for the Rotterdam Study is supported by the Netherlands Organization of Scientific Research Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (01493- 015; RIDE2), the Netherlands Genomics Initiative (NGI)/ Netherlands Organization for Scientific Research (project no. 050-060810), and NWO grants (918-46-615, 948-00-010). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands, Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.; 3C-Dijon Study: The Three-City (3C) Study is conducted under a partnership agreement between the Institut National de la Sante et de la Recherche Medicale (INSERM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Me dicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN), Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme "Cohortes et collections de donnees biologiques." NR 28 TC 50 Z9 51 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP 210 EP 217 DI 10.1161/STROKEAHA.109.569194 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600005 PM 20044523 ER PT J AU Sojkova, J Najjar, SS Beason-Held, LL Metter, EJ Davatzikos, C Kraut, MA Zonderman, AB Resnick, SM AF Sojkova, Jitka Najjar, Samer S. Beason-Held, Lori L. Metter, E. Jeffrey Davatzikos, Christos Kraut, Michael A. Zonderman, Alan B. Resnick, Susan M. TI Intima-Media Thickness and Regional Cerebral Blood Flow in Older Adults SO STROKE LA English DT Article DE aging; brain; carotid artery; common carotid artery; positron emission tomography; regional blood flow ID SPONTANEOUSLY HYPERTENSIVE-RATS; NITRIC-OXIDE SYNTHASE; ANGIOTENSIN-II; CAROTID ATHEROSCLEROSIS; BRAIN MICROVESSELS; ESTROGEN; COGNITION; RISK; SEX; PROGRESSION AB Background and Purpose-The relationship between the thickness of the carotid intima (IMT) and brain function remains unclear in those without clinical manifestations of cerebrovascular disease. Understanding the neural correlates of this vascular measure is important in view of emerging evidence linking poorer cognitive performance with increased IMT in individuals without clinical cerebrovascular disease. Methods-Seventy-three participants in the Baltimore Longitudinal Study of Aging (70.9 years; SD, 7.3) were evaluated with carotid artery ultrasound and resting [(15)O]H(2)O positron emission tomography. Results-After adjusting for age, gender, and gray and white matter volumes in the regions where IMT is related to regional cerebral blood flow (rCBF), we found that higher IMT was associated with lower rCBF in lingual, inferior occipital, and superior temporal regions. Higher IMT was also associated with higher rCBF in medial frontal gyrus, putamen, and hippocampal-uncal regions (P = 0.001). Whereas women had lower IMT (P = 0.01) and mean arterial pressure (P = 0.05) than men, they showed more robust associations between IMT and rCBF. The relationship between IMT and rCBF was only minimally affected by additional adjustment for mean arterial pressure. Conclusions-IMT is related to patterns of resting rCBF in older adults without clinical manifestations of cerebrovascular disease, suggesting that there are regional differences in CBF that are associated with subclinical vascular disease. (Stroke. 2010; 41: 273-279.) C1 [Resnick, Susan M.] NIA, Lab Personal & Cognit, NIH, Biomed Res Ctr,IRP, Baltimore, MD 21224 USA. [Sojkova, Jitka; Kraut, Michael A.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD USA. [Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. RP Resnick, SM (reprint author), NIA, Lab Personal & Cognit, NIH, Biomed Res Ctr,IRP, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM resnicks@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the NIH; National Institute on Aging; [N01-AG-3-2124] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and N01-AG-3-2124. NR 35 TC 17 Z9 18 U1 1 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 FEB PY 2010 VL 41 IS 2 BP 273 EP 279 DI 10.1161/STROKEAHA.109.566810 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600015 PM 20044526 ER PT J AU Wendell, CR Zonderman, AB Metter, EJ Najjar, SS Waldstein, SR AF Wendell, Carrington Rice Zonderman, Alan B. Metter, E. Jeffrey Najjar, Samer S. Waldstein, Shari R. TI Subclinical Cerebrovascular Disease and Cognitive Decline Response to Letter by Hadjiev and Mineva SO STROKE LA English DT Letter ID INTIMA-MEDIA THICKNESS; ATHEROSCLEROSIS; ASSOCIATION; MIDLIFE C1 [Wendell, Carrington Rice; Waldstein, Shari R.] Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. [Wendell, Carrington Rice; Zonderman, Alan B.; Metter, E. Jeffrey; Najjar, Samer S.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Waldstein, Shari R.] Univ Maryland, Sch Med, Div Gerontol, Dept Med, Baltimore, MD 21201 USA. [Waldstein, Shari R.] Baltimore VA Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD USA. RP Wendell, CR (reprint author), Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. NR 7 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2010 VL 41 IS 2 BP E113 EP E113 DI 10.1161/STROKEAHA.109.571257 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 548HR UT WOS:000273951600054 ER PT J AU Itoh, T Abe, K Hong, JS Inoue, O Pike, VW Innis, RB Fujita, M AF Itoh, Tetsuji Abe, Kohji Hong, Jinsoo Inoue, Osamu Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Effects of cAMP-Dependent Protein Kinase Activator and Inhibitor on In Vivo Rolipram Binding to Phosphodiesterase 4 in Conscious Rats SO SYNAPSE LA English DT Article DE small animal PET; dibutyryl-cAMP; Rp-adenosine-3 ',5 '-cyclic monophosphorothioate ID POSITRON-EMISSION-TOMOGRAPHY; BRAIN; PET; MONKEY; IV AB Rolipram is a selective inhibitor of phosphodiesterase-4 (PDE4), and positron emission tomography (PET) using [(11)C]rolipram can monitor the in vivo activity of this enzyme that is part of the cAMP second messenger cascade. cAMP-dependent protein kinase (PKA.) phosphorylates PDE4 and increases both enzyme activity and affinity for rolipram. In the present PET study, we examined effects of PKA modulators in conscious rats on the binding of [(11)C](R)-rolipram in comparison to the much less active enantiomer [(11)C](S)-rolipram. Unilateral injection of a PKA activator (dibutyryl-cAMP) and a PKA inhibitor (Rp-adenosine-3',5'-cyclic monophosphorothioate) into the striatum significantly increased and decreased, respectively, the binding of [(11)C](R)-rolipram. These effects were not caused by changes in blood flow or delivery of radioligand to brain, since these agents had no effect on the binding of [(11)C](S)-rolipram binding. These results support the value of measuring in vivo [(11)C](R)-rolipram binding in brain to assess responses to physiological or pharmacological challenges to the cAMP second messenger system. Synapse 64:172-176, 2010. Published (C) 2009 Wiley-Liss, Inc.(dagger) C1 [Itoh, Tetsuji; Abe, Kohji; Hong, Jinsoo; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Itoh, Tetsuji; Abe, Kohji] Shionogi & Co Ltd, Dev Res Labs, Osaka 5610825, Japan. [Abe, Kohji; Inoue, Osamu] Osaka Univ, Grad Sch Med, Div Hlth Sci, Osaka 5650871, Japan. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 31,Room B2B37,31 Ctr Dr,MSC 2035, Bethesda, MD 20892 USA. EM FujitaM@intra.nimh.nih.gov FU NIMH [Z01-NIH-002795-07, Z01-MH-002793-07] FX Contract grant sponsor: Intramural Program of NIMH; Contract grant numbers: Z01-NIH-002795-07, Z01-MH-002793-07 NR 14 TC 6 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2010 VL 64 IS 2 BP 172 EP 176 DI 10.1002/syn.20728 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 538PD UT WOS:000273195500010 PM 19852069 ER PT J AU Willerson, JT AF Willerson, James T. TI Texas Heart Institute Medal and the Ray C. Fish Award for Scientific Achievement in Cardiovascular Diseases SO TEXAS HEART INSTITUTE JOURNAL LA English DT Editorial Material C1 [Willerson, James T.] NHLBI, Specialized Ctr Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 0730-2347 J9 TEX HEART I J JI Tex. Heart Inst. J. PD FEB PY 2010 VL 37 IS 1 BP 1 EP 1 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 555ZH UT WOS:000274555100001 PM 20200620 ER PT J AU Brunet, BR Barnes, AJ Choo, RE Mura, P Jones, HE Huestis, MA AF Brunet, Bertrand R. Barnes, Allan J. Choo, Robin E. Mura, Patrick Jones, Hendree E. Huestis, Marilyn A. TI Monitoring Pregnant Women's Illicit Opiate and Cocaine Use With Sweat Testing SO THERAPEUTIC DRUG MONITORING LA English DT Article DE sweat patch; heroin; opiates; cocaine; sweat ID ABUSE-TREATMENT PATIENTS; HEROIN-MAINTENANCE PROGRAM; SUBSTANCE-ABUSE; GAS-CHROMATOGRAPHY; MASS-SPECTROMETRY; ORAL FLUID; DRUG-USE; METABOLITES; METHADONE; URINE AB Dependence on illicit drugs during pregnancy is a major public health concern as there may be associated adverse maternal, fetal, and neonatal consequences. Sweat patches (n = 389) were collected from 39 pregnant volunteers who provided written informed consent for this Institutional Review Board-approved protocol and wore patches, replaced approximately weekly, from study entry until delivery. Patches were analyzed for opiates (heroin, 6-acetylmorphine, 6-acetylcodeine, morphine and codeine) and cocaine (cocaine, benzoylecgonine, eegonine methyl ester, anhydroecgonine methyl ester) by solid phase extraction and gas chromatography mass spectrometry. Seventy-one percent (276) of collected sweat patches were >= 5 ng per patch (limit of quantification) for one or more analytes. Cocaine was present in 254 (65.3%) patches in concentrations ranging from 5.2 to 11,835 ng per patch with 154 of these high enough to satisfy the proposed Substance Abuse and Mental Health Services Administration guidelines for a confirmatory drug test (25 ng per patch). Interestingly, 6-acetylmorphine was the most prominent opiate analyte documented in 134 patches (34.4%) with 11.3% exceeding the proposed opiate Substance Abuse and Mental Health Services Administration cut-off (25 ng per patch). Heroin was identified in fewer patches (77), but in a similar concentration range (5.3-345.4 ng per patch). Polydrug use was evident by the presence of both cocaine and opiate metabolites in 136 (35.0%) patches. Sweat testing is an effective method for monitoring abstinence or illicit drug use relapse in this high-risk population of pregnant opiate- and/or cocaine-dependent women. C1 [Brunet, Bertrand R.] Univ Poitiers, INSERM, UMR 927, Fac Med & Pharm, Poitiers, France. [Barnes, Allan J.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Bethesda, MD USA. [Choo, Robin E.] Univ Pittsburgh, Dept Nat Sci, Titusville, PA USA. [Mura, Patrick] Ctr Hosp & Univ, Lab Toxicol & Pharmacocinet, Poitiers, France. [Jones, Hendree E.] Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, Baltimore, MD USA. RP Huestis, MA (reprint author), Biomed Res Ctr, 251 Bayview Blvd,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institutes of Health; National Institute on Drug Abuse Intramural Research Program; National Institute on Drug Abuse [DA12403] FX Supported by the National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, and National Institute on Drug Abuse extramural research grant DA12403 (Pl: HE Jones). We thank all those who helped in the course of this study, including CAP research staff for collection of specimens. NR 34 TC 13 Z9 14 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD FEB PY 2010 VL 32 IS 1 BP 40 EP 49 PG 10 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 549RP UT WOS:000274072000006 PM 19927046 ER PT J AU Caggiari, L De Zorzi, M Rehermann, B De Re, V AF Caggiari, L. De Zorzi, M. Rehermann, B. De Re, V. TI Identification of a new Patr-B*01 variant, Patr-B*0102, by sequence-based typing in a chimpanzee (Pan troglodytes) SO TISSUE ANTIGENS LA English DT Article DE Pan troglodytes; Patr-B; polymerase chain reaction-sequencing based typing ID CLASS-I AB Description of a new non-human primate major histocompatibility complex (MHC)-B (Patr-B) allele. C1 [Caggiari, L.; De Zorzi, M.; De Re, V.] Natl Canc Inst, IRCCS, Ctr Riferimento Oncol, DOMERT,Farmacol Sperimentale & Clin, I-33081 Aviano, Italy. [Rehermann, B.] NIDDKD, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP De Re, V (reprint author), Natl Canc Inst, IRCCS, Ctr Riferimento Oncol, DOMERT,Farmacol Sperimentale & Clin, Via Franco Gallini 2, I-33081 Aviano, Italy. EM vdere@cro.it NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD FEB PY 2010 VL 75 IS 2 BP 187 EP 188 PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 542FK UT WOS:000273478200017 ER PT J AU Huang, GTJ Yamaza, T Shea, LD Djouad, F Kuhn, NZ Tuan, RS Shi, S AF Huang, George T. -J. Yamaza, Takayoshi Shea, Lonnie D. Djouad, Farida Kuhn, Nastaran Z. Tuan, Rocky S. Shi, Songtao TI Stem/Progenitor Cell-Mediated De Novo Regeneration of Dental Pulp with Newly Deposited Continuous Layer of Dentin in an In Vivo Model SO TISSUE ENGINEERING PART A LA English DT Article ID GROWTH-FACTOR DELIVERY; MESENCHYMAL PROGENITOR CELLS; STEM-CELLS; APICAL PAPILLA; TISSUE; VITRO; TRANSPLANTATION; SCAFFOLDS; TEETH; MATRICES AB The ultimate goal of this study is to regenerate lost dental pulp and dentin via stem/progenitor cell-based approaches and tissue engineering technologies. In this study, we tested the possibility of regenerating vascularized human dental pulp in emptied root canal space and producing new dentin on existing dentinal walls using a stem/progenitor cell-mediated approach with a human root fragment and an immunocompromised mouse model. Stem/progenitor cells from apical papilla and dental pulp stem cells were isolated, characterized, seeded onto synthetic scaffolds consisting of poly-D, L-lactide/glycolide, inserted into the tooth fragments, and transplanted into mice. Our results showed that the root canal space was filled entirely by a pulp-like tissue with well-established vascularity. In addition, a continuous layer of dentin-like tissue was deposited onto the canal dentinal wall. This dentin-like structure appeared to be produced by a layer of newly formed odontoblast-like cells expressing dentin sialophosphoprotein, bone sialoprotein, alkaline phosphatase, and CD105. The cells in regenerated pulp-like tissue reacted positively to anti-human mitochondria antibodies, indicating their human origin. This study provides the first evidence showing that pulp-like tissue can be regenerated de novo in emptied root canal space by stem cells from apical papilla and dental pulp stem cells that give rise to odontoblast-like cells producing dentin-like tissue on existing dentinal walls. C1 [Huang, George T. -J.] Columbia Univ, Coll Dent Med, Div Endodont, Sect Oral & Diagnost Sci, New York, NY USA. [Huang, George T. -J.] Univ Maryland, Sch Dent, Coll Dent Surg, Dept Endodont Prosthodont & Operat Dent, Baltimore, MD 21201 USA. [Huang, George T. -J.; Djouad, Farida; Kuhn, Nastaran Z.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Yamaza, Takayoshi; Shi, Songtao] Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90089 USA. [Shea, Lonnie D.] Northwestern Univ, McCormick Sch Engn, Dept Chem & Biol Engn, Evanston, IL USA. RP Huang, GTJ (reprint author), Boston Univ, Henry M Goldman Sch Dent Med, Dept Endodont, 100 E Newton St, Boston, MA 02118 USA. EM gtjhuang@bu.edu RI Shea, Lonnie/B-7615-2009; OI Djouad, Farida/0000-0001-8248-6822 FU National Institutes of Health (NIH) [R01 DE019156-01, RO1 DE17449]; NIAMS/NIH [Z01 AR41131]; American Association of Endodontists Foundation FX This work was supported in part by grants from the National Institutes of Health (NIH) R01 DE019156-01 (G.T.-J.H.), RO1 DE17449 ( S. S.), by the NIAMS/NIH Intramural Research Program Z01 AR41131 ( R. S. T), and by an Endodontic Research Grant from American Association of Endodontists Foundation (G.T.-J.H.). We wish to thank Dr. Matthew Daniels (NIH/NHLBI, Electron Microscopy Core) for the assistance of SEM analysis, Dr. Larry Fisher (NIH/NIDCR) for providing antibodies, Dr. Wesley M. Jackson (NIH/NIAMS) for providing the RNA from cultured human myoblasts, and Dr. Yi Liu (USC) for the assistance of neurogenic studies. NR 27 TC 173 Z9 194 U1 7 U2 24 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD FEB PY 2010 VL 16 IS 2 BP 605 EP 615 DI 10.1089/ten.tea.2009.0518 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 552XT UT WOS:000274329000025 PM 19737072 ER PT J AU Scott, L Eskes, C Hoffmann, S Adriaens, E Alepee, N Bufo, M Clothier, R Facchini, D Faller, C Guest, R Harbell, J Hartung, T Kamp, H Le Varlet, B Meloni, M McNamee, P Osborne, R Pape, W Pfannenbecker, U Prinsen, M Seaman, C Spielmann, H Stokes, W Trouba, K Van den Berghe, C Van Goethem, F Vassallo, M Vinardell, P Zuang, V AF Scott, Laurie Eskes, Chantra Hoffmann, Sebastian Adriaens, Els Alepee, Nathalie Bufo, Monica Clothier, Richard Facchini, Davide Faller, Claudine Guest, Robert Harbell, John Hartung, Thomas Kamp, Hennicke Le Varlet, Beatrice Meloni, Marisa McNamee, Pauline Osborne, Rosemarie Pape, Wolfgang Pfannenbecker, Uwe Prinsen, Menk Seaman, Christopher Spielmann, Horst Stokes, William Trouba, Kevin Van den Berghe, Christine Van Goethem, Freddy Vassallo, Marco Vinardell, Pilar Zuang, Valerie TI A proposed eye irritation testing strategy to reduce and replace in vivo studies using Bottom-Up and Top-Down approaches SO TOXICOLOGY IN VITRO LA English DT Review DE Ocular irritation; In vitro tests; Alternatives ID HET-CAM TEST; RABBIT EYE; VITRO ALTERNATIVES; OCULAR SAFETY; CTFA EVALUATION; CORNEAL INJURY; PHASE-II; VALIDATION; PROGRAM; RECOMMENDATIONS AB In spite of over 20 years of effort, no single in vitro assay has been developed and validated as a full regulatory replacement for the Draize Eye Irritation test. However, companies have been using in vitro methods to screen new formulations and in some cases as their primary assessment of eye irritation potential for many years. The present report shows the outcome of an Expert Meeting convened by the European Centre for the Validation of Alternative Methods in February 2005 to identify test strategies for eye irritation. In this workshop test developers/users were requested to nominate methods to be considered as a basis for the identification of such testing strategies. Assays were evaluated and categorized based on their proposed applicability domains (e.g., categories of irritation severity, modes of action, chemical class, physicochemical compatibility). The analyses were based on the data developed from current practice and published studies, the ability to predict depth of injury (within the applicable range of severity), modes of action that could be addressed and compatibility with different physiochemical forms. The difficulty in predicting the middle category of irritancy (e.g. R36, GHS Categories 2A and 2B) was recognized. The testing scheme proposes using a Bottom-Up (begin with using test methods that can accurately identify non-irritants) or Top-Down (begin with using test methods that can accurately identify severe irritants) progression of in vitro tests (based on expected irritancy). irrespective of the starting point, the approach would identify non-irritants and severe irritants, leaving all others to the (mild/moderate) irritant GHS 2/R36 categories. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Eskes, Chantra; Hoffmann, Sebastian; Zuang, Valerie] European Commiss Joint Res Ctr, ECVAM, Ispra, Italy. [Scott, Laurie] Procter & Gamble Co, Brussels, Belgium. [Adriaens, Els] Univ Ghent, B-9000 Ghent, Belgium. [Alepee, Nathalie; Van den Berghe, Christine] LOreal, Aulnay Sous Bois, France. [Bufo, Monica; Vassallo, Marco] Res Pharma Srl, Trezzo Sull Adda, Italy. [Clothier, Richard] Univ Nottingham, FRAME, Sch Biomed Sci, Nottingham NG7 2RD, England. [Facchini, Davide; Hartung, Thomas] INT E GRA, Trezzo Sull Adda, Italy. [Faller, Claudine] Cosmital SA, Maryl, Switzerland. [Guest, Robert] Harlan Labs Ltd, Derby, England. [Kamp, Hennicke] BASF AG, Ludwigshafen, Germany. [Le Varlet, Beatrice] LVMH Parfums & Cosmet R&D, St Jean De Braye, France. [Meloni, Marisa] Vitroscreen SRL, Milan, Italy. [McNamee, Pauline] Procter & Gamble Co, Surrey, England. [Osborne, Rosemarie; Trouba, Kevin] Procter & Gamble Co, Cincinnati, OH 45202 USA. [Pape, Wolfgang; Pfannenbecker, Uwe] Beiersdorf AG, Hamburg, Germany. [Prinsen, Menk] TNO, Aj Zeist, Netherlands. [Spielmann, Horst] BfR ZEBET, Berlin, Germany. [Stokes, William] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Interagency Ctr Evaluat Alternat Toxicol Methods, Res Triangle Pk, NC USA. [Van Goethem, Freddy] Johnson & Johnson Pharmaceut R&D, Beerse, Belgium. [Vinardell, Pilar] Univ Barcelona, Barcelona, Spain. RP Zuang, V (reprint author), EC Joint Res Ctr, Ispra Site,Via E Fermi,2749,TP 580, I-21027 Ispra, VA, Italy. EM valerie.zuang@jrc.it OI Vinardell, Maria Plar/0000-0003-4533-5114 NR 41 TC 80 Z9 81 U1 1 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD FEB PY 2010 VL 24 IS 1 BP 1 EP 9 DI 10.1016/j.tiv.2009.05.019 PG 9 WC Toxicology SC Toxicology GA 548AA UT WOS:000273930000001 PM 19490935 ER PT J AU Urschitz, J Stoytchev, I Owens, J Dee, JA Yamashiro, H Morozumi, K Pelczar, P Kawasumi, M Kaminski, JM Coates, CJ Kommineni, VJM Moisyadi, S AF Urschitz, Johann Stoytchev, Ilko Owens, Jesse Dee, James A. Yamashiro, Hideaki Morozumi, Kazuto Pelczar, Pawel Kawasumi, Miyuri Kaminski, Joseph M. Coates, Craig J. Kommineni, Vally J. M. Moisyadi, Stefan TI Transgenesis with Transposase Enzymes SO TRANSGENIC RESEARCH LA English DT Meeting Abstract ID PIGGYBAC C1 [Urschitz, Johann; Stoytchev, Ilko; Owens, Jesse; Dee, James A.; Yamashiro, Hideaki; Morozumi, Kazuto; Kawasumi, Miyuri; Moisyadi, Stefan] Univ Hawaii, John A Burns Sch Med, Dept Anat Biochem & Physiol, Honolulu, HI 96822 USA. [Morozumi, Kazuto] Kiba Koen Clin, Etoh Ku, Tokyo, Japan. [Pelczar, Pawel] Univ Zurich, Inst Lab Anim Serv, CH-8091 Zurich, Switzerland. [Kawasumi, Miyuri] Keio Univ, Ctr Integrated Med Res 8N5, Shinjuku Ku, Tokyo 1608582, Japan. [Kaminski, Joseph M.] NIH, Bethesda, MD 20817 USA. [Coates, Craig J.; Kommineni, Vally J. M.] Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA. [Pelczar, Pawel; Coates, Craig J.; Moisyadi, Stefan] Manoa Biosci, Honolulu, HI 96822 USA. [Kaminski, Joseph M.; Moisyadi, Stefan] Med Coll Georgia, Augusta, GA 30912 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD FEB PY 2010 VL 19 IS 1 BP 132 EP 132 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 540KO UT WOS:000273330300016 ER PT J AU Pan, YP Tsai, CJ Ma, BY Nussinov, R AF Pan, Yongping Tsai, Chung-Jung Ma, Buyong Nussinov, Ruth TI Mechanisms of transcription factor selectivity SO TRENDS IN GENETICS LA English DT Review ID TUMOR-SUPPRESSOR P53; DNA-BINDING SPECIFICITY; RESPONSE-ELEMENTS; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; ENERGY LANDSCAPES; ALLOSTERIC MODULATORS; INFORMATION-THEORY; FOLDING FUNNELS; SMALL MOLECULES AB The initiation of transcription is regulated by transcription factors (TFs) binding to DNA response elements (REs). How do TFs recognize specific binding sites among the many similar ones available in the genome? Recent research has illustrated that even a single nucleotide substitution can alter the selective binding of TFs to coregulators, that prior binding events can lead to selective DNA binding, and that selectivity is influenced by the availability of binding sites in the genome. Here, we combine structural insights with recent genomics screens to address the problem of TF-DNA interaction specificity. The emerging picture of selective binding site sequence recognition and TF activation involves three major factors: the cellular network, protein and DNA as dynamic conformational ensembles and the tight packing of multiple TFs and coregulators on stretches of regulatory DNA. The classification of TF recognition mechanisms based on these factors impacts our understanding of how transcription initiation is regulated. C1 [Pan, Yongping; Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute and National Institute of Health [HHSN261.200800001E] FX Thanks to Dr Tom Schneider and the referees for the careful reading of the manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute and National Institute of Health under contract number HHSN261.200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 92 TC 79 Z9 80 U1 4 U2 28 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2010 VL 26 IS 2 BP 75 EP 83 DI 10.1016/j.tig.2009.12.003 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 561OM UT WOS:000274987400006 PM 20074831 ER PT J AU Motley, WW Talbot, K Fischbeck, KH AF Motley, William W. Talbot, Kevin Fischbeck, Kenneth H. TI GARS axonopathy: not every neuron's cup of tRNA SO TRENDS IN NEUROSCIENCES LA English DT Review ID MARIE-TOOTH-DISEASE; SPINAL MUSCULAR-ATROPHY; DIFFERENTIATION-ASSOCIATED PROTEIN-1; SYNTHETASE MUTATIONS; CHROMOSOME 7P; MOUSE MODEL; NEUROPATHY; GENE; MUTANT; DROSOPHILA AB Charcot-Marie-Tooth disease type 2D, a hereditary axonal neuropathy, is caused by mutations in glycyl-tRNA synthetase (GARS). The mutations are distributed throughout the protein in multiple functional domains. In biochemical and cell culture experiments, some mutant forms of GARS have been indistinguishable from wild-type protein, suggesting that these in vitro tests might not adequately assess the aberrant activity responsible for axonal degeneration. Recently, mouse and fly models have offered new insights into the disease mechanism. There are still gaps in our understanding of how mutations in a ubiquitously expressed component of the translation machinery result in axonal neuropathy. Here, we review recent reports, weigh the evidence for and against possible mechanisms and suggest areas of focus for future work. C1 [Motley, William W.; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Motley, William W.; Talbot, Kevin] Univ Oxford, MRC Funct Genom Unit, Oxford OX3 9DU, England. [Talbot, Kevin] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov RI Talbot, Kevin /F-7361-2011 FU NINDS; Marshall Commission FX The authors would like to thank Anthony Antonellis, Isabella Palazzolo, Deborah Kwon, Michael Mooney, Katherine Gribble and Barrington Burnett for helpful comments on the manuscript. We are grateful for support from the NINDS intramural program and the Marshall Commission (to W.W.M). NR 38 TC 34 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD FEB PY 2010 VL 33 IS 2 BP 59 EP 66 DI 10.1016/j.tins.2009.11.001 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 562WI UT WOS:000275085600001 PM 20152552 ER PT J AU Chaiworapongsa, T Romero, R Kusanovic, JP Mittal, P Kim, SK Gotsch, F Than, NG Mazaki-Tovi, S Vaisbuch, E Erez, O Yeo, L Hassan, SS Sorokin, Y AF Chaiworapongsa, T. Romero, R. Kusanovic, J. P. Mittal, P. Kim, S. K. Gotsch, F. Than, N. G. Mazaki-Tovi, S. Vaisbuch, E. Erez, O. Yeo, L. Hassan, S. S. Sorokin, Y. TI Plasma soluble endoglin concentration in pre-eclampsia is associated with an increased impedance to flow in the maternal and fetal circulations SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article; Proceedings Paper CT 18th World Congress on Ultrasound in Obstetrics and Gynecology CY AUG 24-28, 2008 CL Chicago, IL DE angiogenesis; pre-eclampsia; soluble endoglin; umbilical artery Doppler velocimetry; uterine artery Doppler velocimetry ID ENDOTHELIAL GROWTH-FACTOR; UTERINE ARTERY DOPPLER; FACTOR RECEPTOR-1 CONCENTRATION; BED SPIRAL ARTERIES; PLACENTAL BED; EARLY-ONSET; HYPERTENSIVE DISORDERS; PULSATILITY INDEX; NORMAL-PREGNANCY; RESTRICTION AB Objectives To examine the relationship between abnormalities in uterine (UtA) and/or umbilical artery (UA) Doppler velocimetry and maternal plasma concentrations of soluble endoglin (sEng) in patients with pre-eclampsia (PE). Methods A cross-sectional study was conducted in 135 normal pregnant women and 69 patients with PE. Patients with PE were subclassified into four groups: those who bad Doppler abnormalities in both the UtA and UA, patients who had Doppler abnormalities in the UtA alone, those who had Doppler abnormalities in the UA alone, and patients without Doppler abnormalities in either vessel. Plasma concentrations of sEng were determined by enzyme-linked immunosorbent assay. Results Among patients with PE, those with abnormal UtA and UA Doppler velocimetry bad the highest median plasma concentration of sEng compared with any other group (P < 0.001, Kruskal-Wallis test). Women with PE with normal Doppler velocimetry in both vessels bad the lowest median plasma concentration of sEng. There was a significant relationship between plasma concentrations of sEng and mean UtA resistance index (,Spearman Rho = 0.5, P < 0.001) as well as UA pulsatility index (Spearman Rho = 0.4, P = 0.002). Multiple regression analysis suggested that Doppler abnormalities in the UtA and UA as well as gestational age at blood sampling contributed to plasma sEng concentrations (P < 0.00.1.). Conclusions Abnormalities of impedance to blood flow in the UtA and UA are associated with an excess of sEng in the circulation of mothers with PE. These findings suggest that the 'antiangiogenic state' in PE is partially reflected in abnormalities of Doppler velocimetry. Copyright (C) 2010 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Chaiworapongsa, T.; Romero, R.; Kusanovic, J. P.; Mittal, P.; Kim, S. K.; Gotsch, F.; Than, N. G.; Mazaki-Tovi, S.; Vaisbuch, E.; Erez, O.; Yeo, L.; Hassan, S. S.; Sorokin, Y.] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS, Detroit, MI 48201 USA. [Chaiworapongsa, T.; Romero, R.; Kusanovic, J. P.; Mittal, P.; Mazaki-Tovi, S.; Vaisbuch, E.; Erez, O.; Yeo, L.; Hassan, S. S.; Sorokin, Y.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [ZIA HD002400-18, Z01 HD002400-17] NR 51 TC 19 Z9 19 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2010 VL 35 IS 2 BP 155 EP 162 DI 10.1002/uog.7491 PG 8 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 560ZN UT WOS:000274944500005 PM 20101637 ER PT J AU Lee, W Balasubramaniam, M Yeo, L Hassan, SS Gotsch, F Kusanovic, JP Goncalves, LF Romero, R AF Lee, W. Balasubramaniam, M. Yeo, L. Hassan, S. S. Gotsch, F. Kusanovic, J. P. Goncalves, L. F. Romero, R. TI Iliac crest angle: a novel sonographic parameter for the prediction of Down syndrome risk during the second trimester of pregnancy SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 3D ultrasonography; Down syndrome; iliac angle; iliac crest angle; iliac length; prenatal diagnosis ID MENSTRUAL AGE; 2ND-TRIMESTER FETUSES; FETAL; MARKER; 1ST-TRIMESTER; ULTRASOUND; TRISOMY-21; LENGTH; CIRCUMFERENCE; REEVALUATION AB Objectives To validate a new sonographic technique for the display and measurement of fetal iliac crest angle (ICA), and to determine the relative contribution of standardized fetal pelvic measurements for estimating risk of Down syndrome during the second trimester of pregnancy. Methods Three-dimensional ultrasonography of the fetal pelvis was performed during a second-trimester scan for genetic amniocentesis. A coronal view of the 'virtual pelvis' was obtained by applying a maximum intensity projection algorithm to visualize both iliac wings. Two different ICAs were measured from a coronal projection of the fetal pelvis (ICA-coronal 1 and ICA-coronal 2); the latter approach relied on using ischial tuberosities as reference landmarks. Next, a coronal projection of the fetal pelvis was rotated to demonstrate a rendered view of the axial fetal pelvis. Axial inner (ICA-inner), middle (ICA-middle) and outer (ICA-outer) ICAs were measured. The maximum anterior iliac distance measurement was defined as the widest separation between the most anterior points of the rendered iliac crests. The reproducibility of each ICA method was analyzed using Bland-Altman statistics. Simple and multiple logistic regression analysis determined the relative contribution of each parameter as a prenatal predictor of Down syndrome. Results Ninety-four normal fetuses and 19 fetuses with Down syndrome were examined. The ICA-middle and ICA-coronal 2 parameters were the most reproducible angle measurements. The mean +/- SD ICA-middle measurement for fetuses with Down syndrome was significantly greater than that for normal subjects (94.5 +/- 9.8 degrees vs. 83.1 +/- 6.5 degrees; P < 0.001). The mean +/- SD ICA-coronal 2 angle measurement for fetuses with Down syndrome was slightly greater than that for normal subjects (57.9 +/- 5.5 degrees vs. 51.9 +/- 7.1 degrees; P =0.0014). A multiple logistic regression model including ICA-middle and ICA-coronal 2 provided a predictive ability of 88.1% based on the area under the receiver-operating characteristics curve. This combination bad a sensitivity of 94.4% for a false-positive rate of 5% in the detection of Down syndrome. Conclusions Standardized iliac crest measurements of the fetal pelvis can be used to identify some fetuses at risk for trisomy 21 during the second trimester of pregnancy. Copyright (C) 2009 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Lee, W.] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. [Balasubramaniam, M.] William Beaumont Hosp, Div Biostat, Res Inst, Royal Oak, MI 48073 USA. [Lee, W.; Yeo, L.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Hutzel Hosp, Detroit, MI 48201 USA. [Romero, R.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Lee, W.; Yeo, L.; Hassan, S. S.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lee, W.; Yeo, L.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu FU Intramural Research Program of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development; National Institutes of Health, Department of Health and Human Services FX We wish to acknowledge the invaluable technical assistance of Melissa Powell, RDMS and Beverley McNie, BS, CCRP. This research was supported (in part) by the Intramural Research Program of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 32 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2010 VL 35 IS 2 BP 163 EP 171 DI 10.1002/uog.7477 PG 9 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 560ZN UT WOS:000274944500006 PM 20014361 ER PT J AU Palapattu, GS Singer, EA Messing, EM AF Palapattu, Ganesh S. Singer, Eric A. Messing, Edward M. TI Controversies Surrounding Lymph Node Dissection for Prostate Cancer SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Lymph node dissection; Lymph node; Prostate cancer; Lymphadenectomy; Radical prostatectomy; Review ID EXTENDED PELVIC LYMPHADENECTOMY; RADICAL RETROPUBIC PROSTATECTOMY; DISEASE PROGRESSION; PATHOLOGICAL STAGE; BLADDER-CANCER; PARTIN TABLES; ANTIGEN ERA; METASTASES; MEN; MANAGEMENT AB Despite the high frequency with which radical prostatectomy is used to treat prostate cancer, uncertainty exists regarding the merits of a simultaneous pelvic lymph node dissection. Unresolved issues include identifying the optimal candidate and selecting the appropriate surgical template, among others. In this article, the authors discuss the pros and cons of performing a pelvic lymph node dissection and the staging/diagnostic and therapeutic implications of this procedure. The lack of robust randomized clinical trials in the literature necessitates a careful analysis of retrospective and case series data. C1 [Palapattu, Ganesh S.] Methodist Hosp, Dept Urol, Houston, TX 77030 USA. [Singer, Eric A.] USN Hosp, NCI, Urol Oncol Branch, Bethesda, MD 20814 USA. [Messing, Edward M.] Univ Rochester, Med Ctr, Dept Urol, Rochester, NY 14642 USA. RP Palapattu, GS (reprint author), Methodist Hosp, Dept Urol, 6560 Fannin,Suite 2100, Houston, TX 77030 USA. EM gpalapattu@tmhs.org FU Clinical Fellowship Training Program [Z01 BC 011023]; NIH, National Cancer Institute, Center for Cancer Research FX Funding support to acknowledge: Z01 BC 011023 Clinical Fellowship Training Program.; This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 72 TC 6 Z9 7 U1 1 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 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD FEB PY 2010 VL 37 IS 1 BP 57 EP + DI 10.1016/j.ucl.2009.11.002 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 617CN UT WOS:000279258500008 PM 20152520 ER PT J AU Hinnebusch, BJ AF Hinnebusch, B. Joseph TI THE EVOLUTION OF STABLE FLEA-BORNE TRANSMISSION CYCLES OF YERSINIA PESTIS SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Meeting Abstract C1 [Hinnebusch, B. Joseph] NIH, Lab Zoonot Pathogens, Rocky Mt Labs, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD FEB PY 2010 VL 10 IS 1 SI SI BP 96 EP 96 PG 1 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 555PS UT WOS:000274526200022 ER PT J AU Chen, WZ Zhu, ZY Liao, HX Quinnan, GV Broder, CC Haynes, BF Dimitrov, DS AF Chen, Weizao Zhu, Zhongyu Liao, Huaxin Quinnan, Gerald V., Jr. Broder, Christopher C. Haynes, Barton F. Dimitrov, Dimiter S. TI Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins SO VIRUSES-BASEL LA English DT Article DE HIV-1; human; monoclonal antibody; IgM; gp120; immunogen ID IMMUNODEFICIENCY-VIRUS TYPE-1; PEROXIDASE-SPECIFIC AUTOANTIBODIES; ELICIT NEUTRALIZING ANTIBODIES; N-LINKED GLYCANS; HUMAN-IMMUNOGLOBULINS; RHESUS MACAQUES; LIGHT-CHAINS; IN-VIVO; GP120; IMMUNOGENICITY AB Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for their elicitation. All known broadly neutralizing mAbs (bnmAbs) are immunoglobulin (Ig) Gs (IgGs) and highly somatically hypermutated which could impede their elicitation. Ig Ms (IgMs) are on average significantly less divergent from germline antibodies and are relevant for the development of vaccine immunogens but are underexplored compared to IgGs. Here we describe the identification and characterization of several human IgM-derived mAbs against HIV-1 which were selected from a large phage-displayed naive human antibody library constructed from blood, lymph nodes and spleens of 59 healthy donors. These antibodies bound with high affinity to recombinant envelope glycoproteins (gp140s, Envs) of HIV-1 isolates from different clades. They enhanced or did not neutralize infection by some of the HIV-1 primary isolates using CCR5 as a coreceptor but neutralized all CXCR4 isolates tested although weakly. One of these antibodies with relatively low degree of somatic hypermutation was more extensively characterized. It bound to a highly conserved region partially overlapping with the coreceptor binding site and close to but not overlapping with the CD4 binding site. These results suggest the existence of conserved structures that could direct the immune response to non-neutralizing or even enhancing antibodies which may represent a strategy used by the virus to escape neutralizing immune responses. Further studies will show whether such a strategy plays a role in HIV infection of humans, how important that role could be, and what the mechanisms of infection enhancement are. The newly identified mAbs could be used as reagents to further characterize conserved non-neutralizing, weakly neutralizing or enhancing epitopes and modify or remove them from candidate vaccine immunogens. C1 [Chen, Weizao; Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Zhu, Zhongyu] NCI, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Liao, Huaxin; Haynes, Barton F.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Quinnan, Gerald V., Jr.; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Chen, WZ (reprint author), NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, NIH [N01-CO-12400]; Gates Foundation; NIH [AI078412] FX We thank Xiaodong Xiao in our group for helpful discussion. This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400, by the Gates Foundation (D.S.D.), and by the NIH grant AI078412 (G.V.Q. and C.C.B.). NR 53 TC 11 Z9 12 U1 2 U2 3 PU MDPI AG PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD FEB PY 2010 VL 2 IS 2 BP 547 EP 565 DI 10.3390/v2020547 PG 19 WC Virology SC Virology GA 632HN UT WOS:000280413400009 PM 21755021 ER PT J AU Petzold, A Altintas, A Laura, C Bartos, A Achim, F Blankenstein, MA Luc, H Castellazzi, M Cepok, S Comabella, M Constantinescu, CS Deisenhammer, F Deniz, G Gaye, M Espino, M Fainardi, E Franciotta, D Freedman, MS Giedraitis, V Gilhus, NE Giovannoni, G Glabinski, A Grieb, P Hartung, HP Hemmer, B Herukka, SK Hintzen, R Ingelsson, M Jackson, S Jacobsen, S Jafari, N Jalosinski, M Jarius, S Kapaki, E Bernd, CV Koel-Simmelink, MJA Kornhuber, J Kuhle, J Kurzepa, J Lalive, PH Lannfelt, L Lehmensiek, V Lewczuk, P Livrea, P Marnetto, F Martino, D Menge, T Norgren, N Papuc, E Paraskevas, GP Pirttila, T Rajda, C Rejdak, K Ricny, J Ripova, D Rosengren, L Ruggieri, M Schraen, S Shaw, G Sindic, C Siva, A Stigbrand, T Stonebridge, I Topcular, B Trojano, M Tumani, H Twaalfhoven, HAM Vecsei, L Van Pesch, V Vanderstichele, H Vedeler, C Verbeek, MM Villar, LM Weissert, R Wildemann, B Yang, C Yao, K Teunissen, CE AF Petzold, Axel Altintas, Ayse Andreoni, Laura Bartos, Ales Berthele, Achim Blankenstein, Marinus A. Buee, Luc Castellazzi, Massimiliano Cepok, Sabine Comabella, Manuel Constantinescu, Cris S. Deisenhammer, Florian Deniz, Gunnur Erten, Gaye Espino, Mercedes Fainardi, Enrico Franciotta, Diego Freedman, Mark S. Giedraitis, Vilmantas Gilhus, Nils Erik Giovannoni, Gavin Glabinski, Andrzej Grieb, Pawel Hartung, Hans-Peter Hemmer, Bernhard Herukka, Sanna-Kaisa Hintzen, Rogier Ingelsson, Martin Jackson, Samuel Jacobsen, Steve Jafari, Naghmeh Jalosinski, Marcin Jarius, Sven Kapaki, Elisabeth Kieseier, Bernd C. Koel-Simmelink, Marleen J. A. Kornhuber, Johannes Kuhle, Jens Kurzepa, Jacek Lalive, Patrice H. Lannfelt, Lars Lehmensiek, Vera Lewczuk, Piotr Livrea, Paolo Marnetto, Fabiana Martino, Davide Menge, Til Norgren, Niklas Papuc, Eva Paraskevas, George P. Pirttila, Tuula Rajda, Cecilia Rejdak, Konrad Ricny, Jan Ripova, Daniela Rosengren, Lars Ruggieri, Maddalena Schraen, Susanna Shaw, Gerry Sindic, Christian Siva, Aksel Stigbrand, Torgny Stonebridge, Iva Topcular, Baris Trojano, Maria Tumani, Hayrettin Twaalfhoven, Harry A. M. Vecsei, Laszlo Van Pesch, Vincent Vanderstichele, Hugo Vedeler, Christian Verbeek, Marcel M. Maria Villar, Luisa Weissert, Robert Wildemann, Brigitte Yang, Cui Yao, Karen Teunissen, Charlotte E. TI Neurofilament ELISA validation SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Neurofilament; NfL; NF-L; NEFL; Biomarker; Validation ID NEUROCHEMICAL DEMENTIA DIAGNOSTICS; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; MULTIPLE-SCLEROSIS; MARKERS; CSF; DEGENERATION; SUBUNIT; PROTEIN; ASSAYS AB Background: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. Methods: The UmanDiagnostics NF-light (R) enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68 kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories' accuracy and preparation of standards were documented and used for the statistical analyses. Results: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R = 0.60, p < 0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R = 0.98, p < 0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss' multi-rater kappa and Gwet's AC1 statistics. Conclusion: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online. (C) 2009 Elsevier B.V. All rights reserved. C1 [Petzold, Axel] UCL Inst Neurol, Dept Neuroinflammat, London WC1N 3BG, England. [Altintas, Ayse; Siva, Aksel] Istanbul Univ, Cerrahpasa Med Fac, Dept Neurol, Istanbul, Turkey. [Andreoni, Laura; Franciotta, Diego] Neurol Inst C Mondino, IRCCS, Lab Neuroimmunol, I-27100 Pavia, Italy. [Bartos, Ales; Ricny, Jan; Ripova, Daniela] Prague Psychiat Ctr, AD Ctr, Prague, Czech Republic. [Bartos, Ales] Charles Univ Prague, Univ Hosp Kralovske Vinohrady, Fac Med 3, Dept Neurol, Prague, Czech Republic. [Berthele, Achim; Cepok, Sabine; Hemmer, Bernhard] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany. [Blankenstein, Marinus A.; Twaalfhoven, Harry A. M.] Vrije Univ Amsterdam Med Ctr, Dept Clin Chem, Amsterdam, Netherlands. [Buee, Luc; Schraen, Susanna] Univ Lille 2, INSERM, Fac Med,JPArc Alzheimer & Tauopathies, Pole Rech Inst Med Predict & Rech Therapeut,U837,, F-59045 Lille, France. [Castellazzi, Massimiliano] Univ Ferrara, Lab Neurochim, Sez Clin Neurol, Dipartimento Discipline Med Chirurg Comunicaz & C, I-44100 Ferrara, Italy. [Comabella, Manuel] Hosp Univ Vall Hebron, Dept Neurol, Ctr Esclerosi Multiple Catalunya, Unitat Neuroimmunol Clin, Barcelona, Spain. [Constantinescu, Cris S.] Univ Nottingham, Sch Med, Div Clin Neurol, Nottingham, England. [Deisenhammer, Florian] Innsbruck Med Univ, Dept Clin Neurol, A-6020 Innsbruck, Austria. [Deniz, Gunnur; Erten, Gaye] Istanbul Univ, Inst Expt Med, Dept Immunol, Istanbul, Turkey. [Espino, Mercedes; Maria Villar, Luisa] Hosp Ramon & Cajal, Dept Immunol, E-28034 Madrid, Spain. [Fainardi, Enrico] Azienda Osped Univ, Neuroradiol Unit, Ferrara, Italy. [Freedman, Mark S.; Stonebridge, Iva] Ottawa Hosp Gen Campus, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Gilhus, Nils Erik; Vedeler, Christian] Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. [Gilhus, Nils Erik] Haukeland Hosp, Dept Neurol, N-5021 Bergen, Norway. [Giovannoni, Gavin; Jackson, Samuel] Queen Mary Univ London, Blizard Inst Cell Mol Sci, Barts & London Sch Med & Dent, London, England. [Glabinski, Andrzej; Jalosinski, Marcin] Med Univ Lodz, Kopermik Hosp, Dept Propedeut Neurol, Lodz, Poland. [Grieb, Pawel] Polish Acad Sci, Med Res Ctr, PL-02106 Pawinskiego, Poland. [Hartung, Hans-Peter; Kieseier, Bernd C.; Menge, Til] Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. [Herukka, Sanna-Kaisa; Pirttila, Tuula] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland. [Herukka, Sanna-Kaisa; Pirttila, Tuula] Kuopio Univ Hosp, Kuopio 70211, Finland. [Hintzen, Rogier; Jafari, Naghmeh] Erasmus MC, MS Ctr ErasMS, Dept Neurol, Rotterdam, Netherlands. [Giedraitis, Vilmantas; Ingelsson, Martin; Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth Geriatr, Rudbeck Lab, S-75185 Uppsala, Sweden. [Jacobsen, Steve; Yao, Karen] NINDS, NIH, Viral Immunol Sect, Bethesda, MD USA. [Jarius, Sven; Wildemann, Brigitte] Univ Heidelberg, Dept Neurol, Div Mol Neuroimmunol, D-6900 Heidelberg, Germany. [Kapaki, Elisabeth; Paraskevas, George P.] Athens Natl Univ, Eginit Hosp, Dept Neurol, Athens 11528, Greece. [Koel-Simmelink, Marleen J. A.; Teunissen, Charlotte E.] Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, NeuroUnit Biomarkers Inflammat & Neurodegenerat, Amsterdam, Netherlands. [Kornhuber, Johannes; Lewczuk, Piotr] Univ Klinikum Erlangen, Dept Psychiat & Psychotherapy, Erlangen, Germany. [Kuhle, Jens] Univ Basel, Univ Hosp, CH-4003 Basel, Switzerland. [Kurzepa, Jacek; Papuc, Eva; Rejdak, Konrad] Med Univ Lublin, Dept Neurol, PL-20954 Lublin, Poland. [Lalive, Patrice H.] Univ Hosp Geneva, Dept Neurosci, Div Neurol, Neuroimmunol Lab, Geneva, Switzerland. [Lalive, Patrice H.] Fac Med, Geneva, Switzerland. [Lalive, Patrice H.] Univ Hosp Geneva, Dept Genet, Geneva, Switzerland. [Lalive, Patrice H.] Univ Hosp Geneva, Lab Med, Lab Med Serv, Geneva, Switzerland. [Lehmensiek, Vera; Tumani, Hayrettin] Univ Ulm, Dept Neurol, D-89081 Ulm, Germany. [Livrea, Paolo; Martino, Davide; Ruggieri, Maddalena; Trojano, Maria] Univ Bari, Dept Neurol & Psychiat Sci, I-70100 Bari, Italy. [Marnetto, Fabiana] Multiple Sclerosis Ctr ASO San Luigi Gonzaga Orba, Turin, Italy. [Norgren, Niklas] Umea Biotech Incubator, UmanDiagnostics, SE-90736 Umea, Sweden. [Rajda, Cecilia; Vecsei, Laszlo] Univ Szeged, Dept Neurol, H-6725 Szeged, Hungary. [Rosengren, Lars] Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Clin Neurosci, Dept Neurol, SE-41345 Gothenburg, Sweden. [Shaw, Gerry; Yang, Cui] McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA. [Sindic, Christian; Van Pesch, Vincent] NCHM, Neurochem Unit, Brussels, Belgium. [Stigbrand, Torgny] Umea Univ, Dept Immunol, SE-90187 Umea, Sweden. [Topcular, Baris] Bakirkoy Prof Dr Mazhar Osman Teaching & Res Hosp, Istanbul, Turkey. [Vanderstichele, Hugo] RPR Gent, Innogenet NV, BTW BE 0427 550 660, B-9052 Ghent, Belgium. [Vedeler, Christian] Haukeland Hosp, Dept Neurol, N-5021 Bergen, Norway. [Verbeek, Marcel M.] Radboud Univ Nijmegen, Med Ctr, Donders Ctr Brain Cognit & Behav, Dept Neurol,Lab Pediat & Neurol,Alzheimer Ctr Nij, NL-6525 ED Nijmegen, Netherlands. [Weissert, Robert] Univ Geneva, Dept Neurosci, Div Neurol, Geneva, Switzerland. RP Petzold, A (reprint author), UCL Inst Neurol, Dept Neuroinflammat, Queen Sq, London WC1N 3BG, England. EM a.petzold@ion.uci.ac.uk; altintas13@gmail.com; laura.andreoni@mondino.it; bartos@pcp.lf3.cuni.cz; berthele@lrz.tu-muenchen.de; MA.Blankenstein@vumc.nl; luc.buee@inserm.fr; massimiliano.castellazzi@unife.it; cepok@lrz.tu-muenchen.de; mcomabel@ir.vhebron.net; Cris.Constantinescu@nottingham.ac.uk; florian.deisenhammer@i-med.ac.at; gdeniz@istanbul.edu.tr; gerten@istanbul.edu.tr; mespino.hrc@salud.madrid.org; e.fainardi@ospfe.it; diego.franciotta@mondino.it; MFREEDMAN@ottawahospital.on.ca; Vilmantas.Giedraitis@pubcare.uu.se; nils.gilhus@helse-bergen.no; g.giovannoni@qmul.ac.uk; aglabinski@gmail.com; pgrieb@cmdik.pan.pl; Hans-Peter.Hartung@uni-duesseldorf.de; hemmer@lrz.tu-muenchen.de; Sanna-Kaisa.Herukka@uku.fi; rhintzen@xs4all.nl; martin.ingelsson@pubcare.uu.se; s.j.jackson@qmul.ac.uk; jacobsons@ninds.nih.gov; n.jafari@erasmusmc.nl; marcin.jalosinski@gmail.com; Svenjarius@med.uni-heidelberg.de; ekapaki@med.uoa.gr; Bernd.Kieseier@uni-duesseldorf.de; MJA.Koel-Simmelink@vumc.nl; Johannes.Kornhuber@uk-erlangen.de; jkuhle@uhbs.ch; kurzepa@onet.pl; Patrice.Lalive@hcuge.ch; lars.lannfelt@pubcare.uu.se; vera.lehmensiek@uni-ulm.de; Piotr.Lewczuk@uk-erlangen.de; plivrea@neurol.uniba.it; fabiana.marnetto@unito.it; davidemartino@virgilio.it; menge@uni-duesseldorf.de; niklas.norgren@umandiagnostics.se; ewapap@yahoo.pl; geoprskvs44@gmail.com; tuula.pirttila@uku.fi; cecil@nepsy.szote.u-szeged.hu; krejdak@yahoo.com; ricny@pcp.lf3.cuni.cz; ripova@pcp.lf3.cuni.cz; Lars.Rosengren@neuro.gu.se; mruggieri@neurol.uniba.it; susanna.schraen@inserm.fr; shaw@mbi.ufl.edu; sindic@nchm.ucl.ac.be; asiva@tnn.net; torgny.stigbrand@climi.umu.se; istonebridge@ohri.ca; btopcular@gmail.com; mtrojano@neurol.uniba.it; hayrettin.tumani@uni-ulm.de; HAM.Twaalfhoven@vumc.nl; vecsei@nepsy.szote.u-szeged.hu; Vincent.Vanpesch@uclouvain.be; hugovdr@innogenetics.be; christian.vedeler@helse-bergen.no; M.Verbeek@cukz.umcn.nl; lvillar.hrc@salud.madrid.org; robert.weissert@hcuge.ch; Brigitte.Wildemann@med.uni-heidelberg.de; yangcui@ufl.edu; YaoK@ninds.nih.gov; c.teunissen@vumc.nl RI Verbeek, Marcel/D-1971-2010; Weissert, Robert/B-2585-2009; Kornhuber, Johannes/B-9613-2014; BUEE, Luc/B-3126-2010; Castellazzi, Massimiliano/K-5083-2016; Vecsei, Laszlo/B-2066-2010; Siva, Aksel/A-7727-2017 OI Constantinescu, Cris/0000-0003-2066-7585; Petzold, Axel/0000-0002-0344-9749; Blankenstein, Marinus/0000-0003-1186-0770; Bartos, Ales/0000-0002-8020-8252; Weissert, Robert/0000-0002-1295-1271; Kornhuber, Johannes/0000-0002-8096-3987; Villar, Luisa M/0000-0002-9067-3668; Livrea, Paolo/0000-0001-7410-3860; Rosengren, Lars/0000-0003-0505-8896; BUEE, Luc/0000-0002-6261-4230; Castellazzi, Massimiliano/0000-0001-6555-6075; Vecsei, Laszlo/0000-0001-8037-3672; NR 23 TC 28 Z9 28 U1 3 U2 15 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 JAN 31 PY 2010 VL 352 IS 1-2 BP 23 EP 31 DI 10.1016/j.jim.2009.09.014 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 550BO UT WOS:000274102000003 PM 19857497 ER PT J AU Ben-Tal, A Smith, JC AF Ben-Tal, Alona Smith, Jeffrey C. TI Control of breathing: Two types of delays studied in an integrated model of the respiratory system SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Brainstem; Respiration; Apnea; Hypercapnia; Hypoxia; Feedback regulation ID CONGESTIVE-HEART-FAILURE; GAS-EXCHANGE; MAMMALS; RHYTHM; SLEEP; HYPERCAPNIA; NETWORK AB We use a recently developed mathematical model that integrates a reduced representation of the brainstem respiratory neural controller together with peripheral gas exchange and transport to study numerically the dynamic response of the respiratory system to several physiological stimuli. We compare between the system responses with two major sources of delay: circulatory transport vs. neural feedback dynamics, and we show that the dynamics of the neural feedback processes dictates the dynamic response to hypoxia and hypercapnia. The source of the circulatory delay (blood velocity vs. distance from the lungs to chemoreceptors) was found to be important. Our model predicts that periodic breathing is associated with the ventilatory "afterdischarge" (slow recovery of ventilation) after a brief perturbation of CO(2). We also predict that there could be two possible mechanisms for the appearance of periodic breathing and that circulatory delay is not a necessary condition for this to occur in certain cases. (C) 2009 Elsevier B.V. All rights reserved. C1 [Ben-Tal, Alona] Massey Univ, Inst Informat & Math Sci, Auckland, New Zealand. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Ben-Tal, A (reprint author), Massey Univ, Inst Informat & Math Sci, Private Bag 102-904, Auckland, New Zealand. EM a.ben-tal@massey.ac.nz FU Government; NIH; NINDS FX This research was supported by the Marsden Fund Council from Government funding, administered by the Royal Society of New Zealand and the Intramural Research Program of NIH, NINDS. NR 33 TC 13 Z9 13 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD JAN 31 PY 2010 VL 170 IS 1 BP 103 EP 112 DI 10.1016/j.resp.2009.10.008 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 561NA UT WOS:000274983100015 PM 19853063 ER PT J AU Petroski, MD AF Petroski, Matthew D. TI Mechanism-Based Neddylation Inhibitor SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID PROTEIN-ACTIVATION; UBIQUITIN; E1; ENZYMES; LIGASES; CANCER; SYSTEM C1 Burnham Inst Med Res, Signal Transduct Program, NCI Canc Ctr, La Jolla, CA 92037 USA. RP Petroski, MD (reprint author), Burnham Inst Med Res, Signal Transduct Program, NCI Canc Ctr, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM petroski@burnham.org NR 10 TC 6 Z9 8 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD JAN 29 PY 2010 VL 17 IS 1 BP 6 EP 8 DI 10.1016/j.chembiol.2010.01.002 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562YP UT WOS:000275092300004 PM 20142034 ER PT J AU Zhu, JF Paul, WE AF Zhu, Jinfang Paul, William E. TI CD4(+) T Cell Plasticity-Th2 Cells Join the Crowd SO IMMUNITY LA English DT Editorial Material ID LINEAGE; DIFFERENTIATION C1 [Zhu, Jinfang; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov; wpaul@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU Intramural NIH HHS [Z99 AI999999] NR 8 TC 21 Z9 22 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 29 PY 2010 VL 32 IS 1 BP 11 EP 13 DI 10.1016/j.immuni.2010.01.001 PG 3 WC Immunology SC Immunology GA 550HW UT WOS:000274119900007 PM 20152167 ER PT J AU Hegazy, AN Peine, M Helmstetter, C Panse, I Frohlich, A Bergthaler, A Flatz, L Pinschewer, DD Radbruch, A Lohning, M AF Hegazy, Ahmed N. Peine, Michael Helmstetter, Caroline Panse, Isabel Froehlich, Anja Bergthaler, Andreas Flatz, Lukas Pinschewer, Daniel D. Radbruch, Andreas Loehning, Max TI Interferons Direct Th2 Cell Reprogramming to Generate a Stable GATA-3(+)T-bet(+) Cell Subset with Combined Th2 and Th1 Cell Functions SO IMMUNITY LA English DT Article ID CD4(+) T-CELLS; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; TRANSCRIPTION FACTOR GATA-3; VIRAL-INFECTION; LINEAGE COMMITMENT; HELPER LYMPHOCYTES; FATE DETERMINATION; STAT4 ACTIVATION; T(H)1 CELLS; IFN-ALPHA AB Current T cell differentiation models invoke separate T helper 2 (Th2) and Th1 cell lineages governed by the lineage-specifying transcription factors GATA-3 and T-bet. However, knowledge on the plasticity of Th2 cell lineage commitment is limited. Here we show that infection with Th1 cell-promoting lymphocytic choriomeningitis virus (LCMV) reprogrammed otherwise stably committed GATA-3(+) Th2 cells to adopt a GATA-3(+)T-bet(+) and interleukin-4(+)interferon-gamma(+) "Th2+1" phenotype that was maintained in vivo for months. Th2 cell reprogramming required T cell receptor stimulation, concerted type I and type 11 interferon and interleukin-12 signals, and T-bet. LCMV-triggered T-bet induction in adoptively transferred virus-specific Th2 cells was crucial to prevent viral persistence and fatal immunopathology. Thus, functional reprogramming of unfavorably differentiated Th2 cells may facilitate the establishment of protective immune responses. Stable coexpression of GATA-3 and T-bet provides a molecular concept for the long-term coexistence of Th2 and Th1 cell lineage characteristics in single memory T cells. C1 [Hegazy, Ahmed N.; Peine, Michael; Helmstetter, Caroline; Panse, Isabel; Froehlich, Anja; Loehning, Max] Charite, Dept Rheumatol & Clin Immunol, D-10117 Berlin, Germany. [Hegazy, Ahmed N.; Peine, Michael; Helmstetter, Caroline; Panse, Isabel; Froehlich, Anja; Radbruch, Andreas; Loehning, Max] German Rheumatism Res Ctr DRFZ, Leibniz Inst, D-10117 Berlin, Germany. [Bergthaler, Andreas] Inst Syst Biol, Seattle, WA 98103 USA. [Flatz, Lukas] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Pinschewer, Daniel D.] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva 4, Switzerland. RP Lohning, M (reprint author), Charite, Dept Rheumatol & Clin Immunol, D-10117 Berlin, Germany. EM loehning@drfz.de OI Bergthaler, Andreas/0000-0003-0597-1976 FU German Research Foundation [SFB650, SFB618, GRK1121]; German Federal Ministry of Education and Research (FORSYS); Volkswagen Foundation; Swiss National Science Foundation; International Max Planck Research School for Infectious Diseases and Immunology FX We are grateful to R.M. Zinkernagel and H. Hengartner for advice and long-term support and to A. Hamann, T. Hofer, K.M. Murphy, W.E. Paul, and J. Zhu for helpful discussions. We thank S. Ebel, T. Geske, H. Hecker-Kia, and H. Schliemann for expert technical assistance. This work was supported by the German Research Foundation (SFB650 and SFB618), the German Federal Ministry of Education and Research (FORSYS), the Volkswagen Foundation, and the Swiss National Science Foundation. A.N.H. is a fellow of GRK1121 of the German Research Foundation. M.P. and C.H. are fellows of the International Max Planck Research School for Infectious Diseases and Immunology. M.L. is a Lichtenberg fellow funded by the Volkswagen Foundation. NR 51 TC 164 Z9 168 U1 2 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JAN 29 PY 2010 VL 32 IS 1 BP 116 EP 128 DI 10.1016/j.immuni.2009.12.004 PG 13 WC Immunology SC Immunology GA 550HW UT WOS:000274119900016 PM 20079668 ER PT J AU Whittaker, GC Orr, SJ Quigley, L Hughes, L Francischetti, IMB Zhang, WG McVicar, DW AF Whittaker, Gillian C. Orr, Selinda J. Quigley, Laura Hughes, Laurel Francischetti, Ivo M. B. Zhang, Weigou McVicar, Daniel W. TI The Linker for Activation of B Cells (LAB)/Non-T Cell Activation Linker (NTAL) Regulates Triggering Receptor Expressed on Myeloid Cells (TREM)-2 Signaling and Macrophage Inflammatory Responses Independently of the Linker for Activation of T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE KINASE; NEGATIVE REGULATION; CUTTING EDGE; AMPLIFIES INFLAMMATION; CYTOKINE PRODUCTION; TRANSDUCTION; DAP12; LAT; TREM-2; MONOCYTES AB Triggering receptor expressed on myeloid cells-2 (TREM-2) is rapidly emerging as a key regulator of the innate immune response via its regulation of macrophage inflammatory responses. Here we demonstrate that proximal TREM-2 signaling parallels other DAP12-based receptor systems in its use of Syk and Src-family kinases. However, we find that the linker for activation of T cells (LAT) is severely reduced as monocytes differentiate into macrophages and that TREM-2 exclusively uses the linker for activation of B cells (LAB encoded by the gene Lat2(-/-)) to mediate downstream signaling. LAB is required for TREM-2-mediated activation of Erk1/2 and dampens proximal TREM-2 signals through a novel LAT-independent mechanism resulting in macrophages with proinflammatory properties. Thus, Lat2(-/-) macrophages have increased TREM-2-induced proximal phosphorylation, and lipopolysaccharide stimulation of these cells leads to increased interleukin-10 (IL-10) and decreased IL-12p40 production relative to wild type cells. Together these data identify LAB as a critical, LAT-independent regulator of TREM-2 signaling and macrophage development capable of controlling subsequent inflammatory responses. C1 [Whittaker, Gillian C.; Orr, Selinda J.; Quigley, Laura; Hughes, Laurel; McVicar, Daniel W.] NCI Frederick, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Francischetti, Ivo M. B.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [Zhang, Weigou] Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. RP McVicar, DW (reprint author), NCI Frederick, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 560,Rms 31-46, Frederick, MD 21702 USA. EM mcvicard@mail.nih.gov RI McVicar, Daniel/G-1970-2015; OI Orr, Selinda/0000-0001-8539-7825 FU National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health (Intramural Research Programs, NCI, Center for Cancer Research, and NIAID). NR 41 TC 15 Z9 15 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 JAN 29 PY 2010 VL 285 IS 5 AR 2976 DI 10.1074/jbc.M109.038398 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 546RR UT WOS:000273829000012 PM 19948717 ER PT J AU Zhang, YQ Yin, LY Anderson, J Ma, HY Gonzalez, FJ Willson, TM Edwards, PA AF Zhang, Yanqiao Yin, Liya Anderson, Jody Ma, Huiyan Gonzalez, Frank J. Willson, Timothy M. Edwards, Peter A. TI Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REVERSE CHOLESTEROL TRANSPORT; HIGH-DENSITY-LIPOPROTEIN; ORPHAN NUCLEAR RECEPTOR; N-TERMINAL KINASE; BILE-ACIDS; SR-BI; IN-VIVO; ESSENTIAL REGULATOR; LIPID HOMEOSTASIS; GENE-EXPRESSION AB Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4 alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4 alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease. C1 [Zhang, Yanqiao] Northeastern Ohio Univ Coll Med & Pharm, Dept Integrat Med Sci, Rootstown, OH 44272 USA. [Anderson, Jody; Edwards, Peter A.] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. [Edwards, Peter A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Edwards, Peter A.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Willson, Timothy M.] GlaxoSmithKline Inc, Discovery Med Chem, Res Triangle Pk, NC 27709 USA. RP Zhang, YQ (reprint author), Northeastern Ohio Univ Coll Med & Pharm, Dept Integrat Med Sci, 4209 State Route 44, Rootstown, OH 44272 USA. EM yzhang@neoucom.edu OI Anderson, James/0000-0003-2765-7996 FU National Institutes of Health [HL30568, HL68445]; American Heart Association Beginning [0565173Y]; Scientist Development [0830255N]; Laubisch Fund FX This work was supported, in part, by National Institutes of Health Grants HL30568 and HL68445 (to P. A. E.). This work was also supported by American Heart Association Beginning Grant-in-aid 0565173Y (to Y. Z.), Scientist Development Grant 0830255N (to Y. Z.), and a grant from the Laubisch Fund (to Y. Z.). NR 51 TC 43 Z9 44 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 29 PY 2010 VL 285 IS 5 AR 3035 DI 10.1074/jbc.M109.083899 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 546RR UT WOS:000273829000019 PM 19996107 ER PT J AU Dayhoff, JE Shoemaker, BA Bryant, SH Panchenko, AR AF Dayhoff, Judith E. Shoemaker, Benjamin A. Bryant, Stephen H. Panchenko, Anna R. TI Evolution of Protein Binding Modes in Homooligomers SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE homooligomer; protein interaction; protein binding mode; evolutionary conservation; homooligomer symmetry ID INTERACTION NETWORKS; QUATERNARY STRUCTURE; INTERFACES; CONTACTS; SYMMETRY; SEQUENCE; DIMERIZATION; AGGREGATION; ASSEMBLIES; INTEROLOGS AB The evolution of protein interactions cannot be deciphered without a detailed analysis of interaction interfaces and binding modes. We performed a large-scale study of protein homooligomers in terms of their symmetry, interface sizes, and conservation of binding modes. We also focused specifically on the evolution of protein binding modes from nine families of homooligomers and mapped 60 different binding modes and oligomerization states onto the phylogenetic trees of these families. We observed a significant tendency for the same binding modes to be clustered together and conserved within clades on phylogenetic trees; this trend is especially pronounced for close homologs with 70% sequence identity or higher. Some binding modes are conserved among very distant homologs, pointing to their ancient evolutionary origin, while others are very spec c for a certain phylogenetic group. Moreover, we found that the most ancient binding modes have a tendency to involve symmetrical (isologous) homodimer binding arrangements with larger interfaces, while recently evolved binding modes more often exhibit asymmetrical arrangements and smaller interfaces. (C) 2009 Published by Elsevier Ltd. C1 [Shoemaker, Benjamin A.; Bryant, Stephen H.; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Dayhoff, Judith E.] Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM panch@ncbi.nlm.nih.gov FU National Library of Medicine; Oak Ridge Institute for Science and Education FX The authors thank Chris Lanczycki for help with the CDtree software. The work was supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health/Department of Health and Human Services. J.E.D. also thanks the Oak Ridge Institute for Science and Education for the visiting fellowship. NR 59 TC 37 Z9 37 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 29 PY 2010 VL 395 IS 4 BP 860 EP 870 DI 10.1016/j.jmb.2009.10.052 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 555ZP UT WOS:000274556000014 PM 19879880 ER PT J AU Ziolkowska, NE Michejda, CJ Bujacz, GD AF Ziolkowska, Natasza E. Michejda, Christopher J. Bujacz, Grzegorz D. TI Structure of HIV-1 nonnucleoside reverse transcriptase inhibitors derivatives of N-benzyl-benzimidazole with different substituents in position 4 SO JOURNAL OF MOLECULAR STRUCTURE LA English DT Article DE AIDS; HIV-1; Reverse transcriptase inhibitor; Drug design; Crystal structure ID HUMAN-IMMUNODEFICIENCY-VIRUS; BIOLOGICAL-ACTIVITY; POTENT; BINDING; 1H,3H-THIAZOLO<3,4-A>BENZIMIDAZOLES; REPLICATION; DELAVIRDINE; MUTATIONS; INFECTION; COMPLEX AB The constant development of new drugs against HIV-1 is necessary due to global expansion of AIDS and HIV-1 drug resistance. Nonnucleoside reverse transcriptase inhibitors of HIV-1 (NNRTIs) are potentially effective and nontoxic drugs in AIDS therapy. The crystal structures of six nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) derivatives of N-benzyl-benzimidazole are reported here. The investigated compounds belong to the group of so called "butterfly like" inhibitors with characteristic two pi-electron moieties with an angled orientation. The structural data show the influence of the substituents of the benzimidazole ring on the geometry of the molecule and correlation between the structure of the inhibitor and its biological activity. (c) 2009 Elsevier B.V. All rights reserved. C1 [Ziolkowska, Natasza E.; Bujacz, Grzegorz D.] Tech Univ Lodz, Inst Tech Biochem, PL-90924 Lodz, Poland. [Michejda, Christopher J.] NCI, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. RP Bujacz, GD (reprint author), Tech Univ Lodz, Inst Tech Biochem, Ul Stefanowskiego 4-10, PL-90924 Lodz, Poland. EM gdbujacz@p.lodz.pl FU Polish Committee for Scientific Research, KBN [4P05F03114] FX This work was supported by the Polish Committee for Scientific Research, KBN, Grant No. 4P05F03114. Authors are grateful to Wieslaw Majzner for his assistance in collecting data on CAD4 diffractometer and Jerry N. Alexandratos for editorial suggestions. NR 31 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-2860 J9 J MOL STRUCT JI J. Mol. Struct. PD JAN 29 PY 2010 VL 963 IS 2-3 BP 188 EP 193 DI 10.1016/j.molstruc.2009.10.034 PG 6 WC Chemistry, Physical SC Chemistry GA 559YH UT WOS:000274867800015 ER PT J AU Monsurro, V Beghelli, S Wang, R Barbi, S Coin, S Di Pasquale, G Bersani, S Castellucci, M Sorio, C Eleuteri, S Worschech, A Chiorini, JA Pederzoli, P Alter, H Marincola, FM Scarpa, A AF Monsurro, Vladia Beghelli, Stefania Wang, Richard Barbi, Stefano Coin, Silvia Di Pasquale, Giovanni Bersani, Samantha Castellucci, Monica Sorio, Claudio Eleuteri, Stefano Worschech, Andrea Chiorini, Jay A. Pederzoli, Paolo Alter, Harvey Marincola, Francesco M. Scarpa, Aldo TI Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID IN-VIVO; AFRICAN-AMERICAN; VACCINIA VIRUS; BREAST-CANCER; INTERFERON; EXPRESSION; CELLS; TUMORS; LYMPHOCYTES; METASTASES AB Background: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested. Methods: We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines. Results: The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6. Conclusion: Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials. C1 [Wang, Richard; Worschech, Andrea; Alter, Harvey; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. [Wang, Richard; Worschech, Andrea; Alter, Harvey; Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. [Monsurro, Vladia; Beghelli, Stefania; Barbi, Stefano; Coin, Silvia; Bersani, Samantha; Castellucci, Monica; Sorio, Claudio; Eleuteri, Stefano; Scarpa, Aldo] Univ Verona, Sch Med, Dept Pathol, I-37100 Verona, Italy. [Beghelli, Stefania; Scarpa, Aldo] Verona Hosp Concern, ARC NET Ctr Appl Res Canc, Verona, Italy. [Di Pasquale, Giovanni; Chiorini, Jay A.] Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. [Pederzoli, Paolo] Univ Verona, Sch Med, Dept Surg, I-37100 Verona, Italy. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. EM FMarincola@mail.cc.nih.gov; aldo.scarpa@univr.it RI Worschech, Andrea/I-3919-2012; scarpa, aldo/K-6832-2016; OI Worschech, Andrea/0000-0002-4303-8653; scarpa, aldo/0000-0003-1678-739X; Sorio, Claudio/0000-0003-2739-4014 FU Associazione Italiana Ricerca Cancro (AIRC), Milan, Italy; Fondazione CariPaRo, Padova, Italy; Banco Popolare di Verona; Ministero della Salute, Rome, Italy; Ministero della Salute [RF-EMR-2006-361866]; Fondazione Cariverona, Verona, Italy; Fondazione Giorgio Zanotto, Verona, Italy; Fondazione Monte dei Paschi di Siena; European Community [PL018771] FX We thank Prof. M. Colombatti, Dr. D. Ramarli, Dr. G. Innamorati for providing Adenoviral and Lentiviral vectors and Prof G. Tridente for continuous support. Dr E. Bersan, Dr C. Chiamulera, Dr V. Lisi, Dr M. Krampera for assisting imaging collection. Ad5-Luc was a gift of Dr. Zheng Changyu (NIH/NIDCR), Ad5 wt was a gift of Dr. Beverly Handelman(NIH/NIDCR) This work was supported by: Associazione Italiana Ricerca Cancro (AIRC), Milan, Italy (AS); Fondazione CariPaRo, Padova, Italy (AS); Banco Popolare di Verona (VM); Ministero della Salute, Rome, Italy; Ministero della Salute - RF-EMR-2006-361866 (PP); Fondazione Cariverona, Verona, Italy (PP); Fondazione Giorgio Zanotto, Verona, Italy (PP); Fondazione Monte dei Paschi di Siena (AS); European Community FP VI Program Grant PL018771 (MolDiagPaca) (AS). NR 51 TC 18 Z9 19 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 29 PY 2010 VL 8 AR 10 DI 10.1186/1479-5876-8-10 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 574AE UT WOS:000275960000001 PM 20113473 ER PT J AU Kimmel, AR AF Kimmel, Alan R. TI An Orphan Nuclear Receptor Finds a Home SO MOLECULAR CELL LA English DT Editorial Material AB In this issue of Molecular Cell, Lee et al. (2010) show that the retinoic acid receptor-related orphan receptor alpha (ROR alpha) can suppress the Wnt/beta-catenin signaling pathway in a Wnt5a- and PKC-dependent manner that does not alter beta-catenin stabilization or the recruitment of beta-catenin to Wnt target promoters. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kimmel, AR (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov FU Intramural NIH HHS NR 8 TC 3 Z9 4 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 29 PY 2010 VL 37 IS 2 BP 155 EP 157 DI 10.1016/j.molcel.2010.01.008 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 550LY UT WOS:000274130600003 PM 20122397 ER PT J AU Tan, YHC Krishnaswamy, S Nandi, S Kanteti, R Vora, S Onel, K Hasina, R Lo, FY El-Hashani, E Cervantes, G Robinson, M Kales, SC Lipkowitz, S Karrison, T Sattler, M Vokes, EE Wang, YC Salgia, R AF Tan, Yi-Hung Carol Krishnaswamy, Soundararajan Nandi, Suvobroto Kanteti, Rajani Vora, Sapana Onel, Kenan Hasina, Rifat Lo, Fang-Yi El-Hashani, Essam Cervantes, Gustavo Robinson, Matthew Kales, Stephen C. Lipkowitz, Stanley Karrison, Theodore Sattler, Martin Vokes, Everett E. Wang, Yi-Ching Salgia, Ravi TI CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; ACQUIRED UNIPARENTAL DISOMY; C-CBL; UBIQUITIN LIGASE; BINDING-SITE; OF-FUNCTION; PROTEIN; DOMAIN; AMPLIFICATION; PHOSPHORYLATION AB Background: Non-small cell lung cancer (NSCLC) is a heterogeneous group of disorders with a number of genetic and proteomic alterations. c-CBL is an E3 ubiquitin ligase and adaptor molecule important in normal homeostasis and cancer. We determined the genetic variations of c-CBL, relationship to receptor tyrosine kinases (EGFR and MET), and functionality in NSCLC. Methods and Findings: Using archival formalin-fixed paraffin embedded (FFPE) extracted genomic DNA, we show that c-CBL mutations occur in somatic fashion for lung cancers. c-CBL mutations were not mutually exclusive of MET or EGFR mutations; however they were independent of p53 and KRAS mutations. In normal/tumor pairwise analysis, there was significant loss of heterozygosity (LOH) for the c-CBL locus (22%, n = 8/37) and none of these samples revealed any mutation in the remaining copy of c-CBL. The c-CBL LOH also positively correlated with EGFR and MET mutations observed in the same samples. Using select c-CBL somatic mutations such as S80N/H94Y, Q249E and W802* (obtained from Caucasian, Taiwanese and African-American samples, respectively) transfected in NSCLC cell lines, there was increased cell viability and cell motility. Conclusions: Taking the overall mutation rate of c-CBL to be a combination as somatic missense mutation and LOH, it is clear that c-CBL is highly mutated in lung cancers and may play an essential role in lung tumorigenesis and metastasis. C1 [Tan, Yi-Hung Carol; Lo, Fang-Yi] Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan. [Krishnaswamy, Soundararajan; Nandi, Suvobroto; Kanteti, Rajani; Hasina, Rifat; El-Hashani, Essam; Cervantes, Gustavo; Robinson, Matthew; Vokes, Everett E.; Salgia, Ravi] Univ Chicago, Pritzker Sch Med, Med Ctr, Canc Res Ctr,Dept Med, Chicago, IL 60637 USA. [Vora, Sapana; Onel, Kenan] Univ Chicago, Pritzker Sch Med, Med Ctr, Canc Res Ctr,Dept Pediat, Chicago, IL 60637 USA. [Kales, Stephen C.; Lipkowitz, Stanley] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Karrison, Theodore] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Sattler, Martin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sattler, Martin] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Yi-Ching] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, Tainan 70101, Taiwan. RP Tan, YHC (reprint author), Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan. EM rsalgia@medicine.bsd.uchicago.edu FU National Institutes of Health (NIH)/National Cancer Institute (NCI) [5RO1CA125541-03, 3RO1CA125541-03S109, 5RO1CA129501-02, 3RO1CA129501-02S109, 1R21CA140003-01]; MARF; V-Foundation; National Science Council, Taiwan [NSC96-2628-B-006-048-MY3] FX Funding: Supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) Grants: 5RO1CA125541-03, 3RO1CA125541-03S109, 5RO1CA129501-02, 3RO1CA129501-02S109, 1R21CA140003-01, MARF, V-Foundation, Cancer Research Foundation and American Respiratory Health Association of America (RS) and grant NSC96-2628-B-006-048-MY3 from the National Science Council, Taiwan. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funding agenices had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 50 Z9 51 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 29 PY 2010 VL 5 IS 1 AR e8972 DI 10.1371/journal.pone.0008972 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 550PA UT WOS:000274139100020 PM 20126411 ER PT J AU Lidstrom, J Li, Q Hoover, DR Kafulafula, G Mofenson, LM Fowler, MG Thigpen, MC Kumwenda, N Taha, TE Eshleman, SH AF Lidstrom, Jessica Li, Qing Hoover, Donald R. Kafulafula, George Mofenson, Lynne M. Fowler, Mary G. Thigpen, Michael C. Kumwenda, Newton Taha, Taha E. Eshleman, Susan H. TI Addition of extended zidovudine to extended nevirapine prophylaxis reduces nevirapine resistance in infants who were HIV-infected in utero SO AIDS LA English DT Article DE HIV-1; infants; Malawi; nevirapine; resistance ID SINGLE-DOSE NEVIRAPINE; IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; UGANDAN INFANTS; TRANSMISSION; AGE AB Background: In the Post-Exposure Prophylaxis of infants (PEPI)-Malawi trial, most women received single-dose nevirapine (NVP) at delivery, and infants in the extended study arms received single-dose NVP along with 1 week of daily zidovudine (ZDV), followed by either extended daily NVP or extended daily NVP and ZDV up to 14 weeks of age. Although extended NVP prophylaxis reduces the risk of postnatal HIV transmission, it may increase the risk of NVP resistance among infants who are HIV-infected despite prophylaxis. Methods: We analyzed 88 infants in the PEPI-Malawi trial who were HIV-infected in utero and who received prophylaxis for a median of 6 weeks prior to HIV diagnosis. HIV genotyping was performed using the ViroSeq HIV Genotyping System. Results: At 14 weeks of age, the proportion of infants with NVP resistance was lower in the extended NVP and ZDV arm than in the extended NVP arm (28/45, 62.2% vs. 37/43, 86.0%; P = 0.015). None of the infants had ZDV resistance. Addition of extended ZDV to extended NVP was associated with reduced risk of NVP resistance at 14 weeks if prophylaxis was stopped by 6 weeks (54.5 vs. 85.7%, P = 0.007) but not if prophylaxis was continued beyond 6 weeks (83.3 vs. 87.5%, P= 1.00). Conclusion: Addition of extended ZDV to extended NVP prophylaxis significantly reduced the risk of NVP resistance at 14 weeks in infants who were HIV-infected in utero, provided that HIV infection was diagnosed and the prophylaxis was stopped by 6 weeks of age. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Lidstrom, Jessica] Johns Hopkins Univ, Dept Pathol, Sch Med, Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Li, Qing; Kumwenda, Newton; Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Healthcare Policy & Aging Res, Piscataway, NJ USA. [Kafulafula, George] Univ Malawi, Malawi Coll Med, Blantyre, Malawi. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Fowler, Mary G.; Thigpen, Michael C.] Ctr Dis Control & Prevent, Epidemiol Branch, Div HIV AIDS Prevent, Atlanta, GA USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Dept Pathol, Sch Med, Johns Hopkins Med Inst, Ross Bldg 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD) [R03HD061299]; National Institute on Drug Abuse; National Institute of Mental Health; National Institutes of Health (NIH); Department of Health and Human Services (DHHS) [U01AI068613]; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network [U01AI068633]; Centers for Disease Control and Prevention (CDC) Cooperative Agreement [U50/CCU022061] FX This work was supported by the HIV Prevention Trials Network (HPTN) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS) (U01AI068613), the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network (U01AI068633), NIHCHD R03HD061299, and Centers for Disease Control and Prevention (CDC) Cooperative Agreement U50/CCU022061. NR 15 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 28 PY 2010 VL 24 IS 3 BP 381 EP 386 DI 10.1097/QAD.0b013e3283352ef1 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 553NU UT WOS:000274374900009 PM 19996936 ER PT J AU Kang, EM Choi, U Theobald, N Linton, G Priel, DAL Kuhns, D Malech, HL AF Kang, Elizabeth M. Choi, Uimook Theobald, Narda Linton, Gilda Priel, Debra A. Long Kuhns, Doug Malech, Harry L. TI Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils SO BLOOD LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; REPOPULATING CELLS; INSERTIONAL MUTAGENESIS; LENTIVECTOR CORRECTS; LENTIVIRAL VECTOR; CD34(+) CELLS; MURINE; GP91(PHOX) AB Chronic granulomatous disease (CGD) is associated with significant morbidity and mortality from infection. The first CGD gene therapy trial resulted in only short-term marking of 0.01% to 0.1% of neutrophils. A recent study, using busulfan conditioning and an SFFV retrovirus vector, achieved more than 20% marking in 2 patients with X-linked CGD. However, oxidase correction per marked neutrophil was less than normal and not sustained. Despite this, patients clearly benefited in that severe infections resolved. As such, we initiated a gene therapy trial for X-CGD to treat severe infections unresponsive to conventional therapy. We treated 3 adult patients using busulfan conditioning and an MFGS retroviral vector encoding gp91(phox), achieving early marking of 26%, 5%, and 4% of neutrophils, respectively, with sustained long-term marking of 1.1% and 0.03% of neutrophils in 2 of the patients. Gene-marked neutrophils have sustained full correction of oxidase activity for 34 and 11 months, respectively, with full or partial resolution of infection in those 2 patients. Gene marking is polyclonal with no clonal dominance. We conclude that busulfan conditioning together with an MFGS vector is capable of achieving long-term correction of neutrophil oxidase function sufficient to provide benefit in management of severe infection. This study was registered at www.clinicaltrials.gov as #NCT00394316. (Blood. 2010;115:783-791) C1 [Kang, Elizabeth M.; Choi, Uimook; Theobald, Narda; Linton, Gilda; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Priel, Debra A. Long; Kuhns, Doug] SAIC Frederick, Neutrophil Monitoring Lab, Frederick, MD USA. RP Kang, EM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10-CRC,6W Rm 6-3752,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ekang@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775 NR 45 TC 80 Z9 82 U1 2 U2 3 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 JAN 28 PY 2010 VL 115 IS 4 BP 783 EP 791 DI 10.1182/blood-2009-05-222760 PG 9 WC Hematology SC Hematology GA 549XA UT WOS:000274086600010 PM 19965657 ER PT J AU Lin, YW Beharry, ZM Hill, EG Song, JH Wang, WX Xia, ZP Zhang, ZH Aplan, PD Aster, JC Smith, CD Kraft, AS AF Lin, Ying-Wei Beharry, Zanna M. Hill, Elizabeth G. Song, Jin H. Wang, Wenxue Xia, Zuping Zhang, Zhenhua Aplan, Peter D. Aster, Jon C. Smith, Charles D. Kraft, Andrew S. TI A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma SO BLOOD LA English DT Article ID CONSTITUTIVELY ACTIVATED FLT3; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; PROSTATE-CANCER; TRANSGENIC MICE; PHOSPHORYLATES BAD; MAMMALIAN TARGET; FACTOR-I; N-MYC; APOPTOSIS AB The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL. (Blood. 2010;115:824-833) C1 [Kraft, Andrew S.] Med Univ S Carolina, Hollings Canc Ctr, Dept Med, Charleston, SC 29425 USA. [Lin, Ying-Wei] Med Univ S Carolina, Hollings Canc Ctr, Dept Pediat, Charleston, SC 29425 USA. [Beharry, Zanna M.; Wang, Wenxue; Xia, Zuping; Smith, Charles D.] Med Univ S Carolina, Hollings Canc Ctr, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Hill, Elizabeth G.] Med Univ S Carolina, Hollings Canc Ctr, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Song, Jin H.] Med Univ S Carolina, Hollings Canc Ctr, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Zhang, Zhenhua; Aplan, Peter D.] NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Aster, Jon C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Kraft, AS (reprint author), Med Univ S Carolina, Hollings Canc Ctr, Dept Med, 86 Jonathan Lucas St, Charleston, SC 29425 USA. EM kraft@musc.edu RI Aplan, Peter/K-9064-2016 FU Cancer Center [P30 CA138313] FX We thank Drs Paul B. Rothman, University of Iowa, and Anton Berns, The Netherlands Cancer Institute, for the gift of the Pim knockout mice. We thank Sarah L'Heureux of Harvard Medical School for technical advice on the culture of human pre-T-LBL cell lines. Tracy van den Berg of the Hollings Cancer Center Drug Metabolism & Clinical Pharmacology Shared Resource was very helpful in providing the complete blood count and blood chemistry analysis. We are also grateful to Kylie Martin and Richard Peppler of the Hollings Cancer Center Flow Cytometry & Cell Sorting Shared Resource for carrying out cell-cycle analyses, apoptosis analyses, and phenotyping. These shared resources are supported in part by a Cancer Center Support Grant (P30 CA138313). We thank Vortex Biotechnology for supplying SMIs of Pim kinases. We also thank our colleagues Drs Bo Cen, Sandeep Mahajan, and Marina Zemskova for discussions during this work. NR 47 TC 56 Z9 57 U1 4 U2 7 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 JAN 28 PY 2010 VL 115 IS 4 BP 824 EP 833 DI 10.1182/blood-2009-07-233445 PG 10 WC Hematology SC Hematology GA 549XA UT WOS:000274086600014 PM 19965690 ER PT J AU Crooks, DR Ghosh, MC Haller, RG Tong, WH Rouault, TA AF Crooks, Daniel R. Ghosh, Manik C. Haller, Ronald G. Tong, Wing-Hang Rouault, Tracey A. TI Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery SO BLOOD LA English DT Article ID ERYTHROID 5-AMINOLEVULINATE SYNTHASE; ERYTHROPOIETIC PROTOPORPHYRIA; REGULATORY PROTEIN-2; 2FE-2S CLUSTER; MESSENGER-RNA; MAMMALIAN FERROCHELATASE; CLINICAL-MANIFESTATION; MITOCHONDRIAL LON; DEFICIENCY; EXPRESSION AB Mammalian ferrochelatase, the terminal enzyme in the heme biosynthetic pathway, possesses an iron-sulfur [2Fe-2S] cluster that does not participate in catalysis. We investigated ferrochelatase expression in iron-deficient erythropoietic tissues of mice lacking iron regulatory protein 2, in iron-deficient murine erythro-leukemia cells, and in human patients with ISCU myopathy. Ferrochelatase activity and protein levels were dramatically decreased in Irp2(-/-) spleens, whereas ferrochelatase mRNA levels were increased, demonstrating posttranscriptional regulation of ferrochelatase in vivo. Translation of ferrochelatase mRNA was unchanged in iron-depleted murine erythro-leukemia cells, and the stability of mature ferrochelatase protein was also unaffected. However, the stability of newly formed ferrochelatase protein was dramatically decreased during iron deficiency. Ferrochelatase was also severely depleted in muscle biopsies and cultured myoblasts from patients with ISCU myopathy, a disease caused by deficiency of a scaffold protein required for Fe-S cluster assembly. Together, these data suggest that decreased Fe-S cluster availability because of cellular iron depletion or impaired Fe-S cluster assembly causes reduced maturation and stabilization of apoferrochelatase, providing a direct link between Fe-S biogenesis and completion of heme biosynthesis. We propose that decreased heme biosynthesis resulting from impaired Fe-S cluster assembly can contribute to the pathogenesis of diseases caused by defective Fe-S cluster biogenesis. ( Blood. 2010;115:860-869) C1 [Crooks, Daniel R.; Ghosh, Manik C.; Tong, Wing-Hang; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. [Crooks, Daniel R.] Georgetown Univ, Med Ctr, Dept Biochem Mol & Cellular Biol, Washington, DC 20007 USA. [Haller, Ronald G.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Haller, Ronald G.] Vet Adm N Texas Med Ctr, Dallas, TX USA. [Haller, Ronald G.] Inst Exercise & Environm Med, Neuromuscular Ctr, Dallas, TX USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bldg 18T,Rm 101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM trou@helix.nih.gov FU National Institute of Child Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR050597]; Veterans Affairs Merit Review FX The authors thank Drs Harry Dailey and Manu Hegde for helpful scientific discussions, Dr Eric Shoubridge for providing the primary myoblast cells, and Drs Kuanyu Li, Deliang Zhang, Helge Uhrigshardt, Gennadiy Kovtunovych, and Sharon Cooperman for providing ideas and suggestions that greatly improved the quality of this work.; This work was supported by the National Institute of Child Health and Human Development Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR050597), and a Veterans Affairs Merit Review. NR 49 TC 38 Z9 40 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 28 PY 2010 VL 115 IS 4 BP 860 EP 869 DI 10.1182/blood-2009-09-243105 PG 10 WC Hematology SC Hematology GA 549XA UT WOS:000274086600018 PM 19965627 ER PT J AU Joo, JH Jetten, AM AF Joo, Joung Hyuck Jetten, Anton M. TI Molecular mechanisms involved in farnesol-induced apoptosis SO CANCER LETTERS LA English DT Review DE Farnesol; Apoptosis; Isoprenoid; Chemoprevention; Endoplasmic reticulum stress; Unfolded protein response; CTP:phosphocholine cytidylyltransferase; Nuclear receptor; Cancer; NF-kappa B; Apoptosome; MAP kinase ID ENDOPLASMIC-RETICULUM STRESS; CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; UNFOLDED PROTEIN RESPONSE; NF-KAPPA-B; PHASE-II TRIAL; ADMINISTERED 4 TIMES; ISOPRENOID-MEDIATED INHIBITION; AGENT PERILLYL ALCOHOL; LUNG-CARCINOMA CELLS; SMOOTH-MUSCLE-CELLS AB The isoprenoid alcohol farnesol is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, farnesol has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventative and anti-tumor agent in vivo. A number of different biochemical and cellular processes have been implicated in the growth-inhibitory and apoptosis-inducing effects of farnesol. These include regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and CTP:phosphocholine cytidylyltransferase alpha (CCT alpha), rate-limiting enzymes in the mevalonate pathway and phosphatidylcholine biosynthesis, respectively, and the generation of reactive oxygen species. In some cell types the action of farnesol is mediated through nuclear receptors, including activation of farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARs). Recent studies have revealed that induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) play a critical role in the induction of apoptosis by farnesol in lung carcinoma cells. This induction was found to be dependent on the activation of the MEK1/2-ERK1/2 pathway. In addition, farnesol induces activation of the NF-kappa B signaling pathway and a number of NF-kappa B target genes. Optimal activation of NF-kappa B was reported to depend on the phosphorylation of p65/RelA by the MEK1/2-MSK1 signaling pathway. In a number of cells farnesol-induced apoptosis was found to be linked to activation of the apoptosome. This review provides an overview of the biochemical and cellular processes regulated by farnesol in relationship to its growth-inhibitory, apoptosis-promoting, and anti-tumor effects. Published by Elsevier Ireland Ltd. C1 [Joo, Joung Hyuck; Jetten, Anton M.] Natl Inst Environm Hlth Sci, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), Natl Inst Environm Hlth Sci, Cell Biol Sect, LRB, Div Intramural Res,NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU NIEHS, NIH [Z01-ES-101586] FX The authors would like to thank Drs. Carl Bortner and Gary Zeruth (NIEHS) for their comments on the manuscript. This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-101586). NR 160 TC 64 Z9 66 U1 3 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 28 PY 2010 VL 287 IS 2 BP 123 EP 135 DI 10.1016/j.canlet.2009.05.015 PG 13 WC Oncology SC Oncology GA 554QK UT WOS:000274449300001 PM 19520495 ER PT J AU Kim, RJ Kim, SR Roh, KJ Park, SB Park, JR Kang, KS Kong, G Tang, B Yang, YA Kohn, EA Wakefield, LM Nam, JS AF Kim, Ran-Ju Kim, Soo-Rim Roh, Kyung-Jin Park, Sang-Bum Park, Jeong-Ran Kang, Kyung-Sun Kong, Gu Tang, Binwu Yang, Yu-An Kohn, Ethan A. Wakefield, Lalage M. Nam, Jeong-Seok TI Ras activation contributes to the maintenance and expansion of Sca-1(pos) cells in a mouse model of breast cancer SO CANCER LETTERS LA English DT Article DE Cancer stem cell; Stem cell antigen-1; Ras ID MAMMARY-GLAND DEVELOPMENT; GROWTH-FACTOR-BETA; STEM-CELLS; STEM/PROGENITOR CELLS; SKELETAL-MUSCLE; TUMOR-CELLS; K-RAS; EXPRESSION; MICE; DIFFERENTIATION AB The cancer stem cell (CSC) hypothesis proposes that CSCs are the root of cancer and cause cancer metastasis and recurrence. In this study, we examined whether Ras signaling is associated with sternness of the CSCs population characterized by the stem cell antigen (Sca-1) phenotype in a 4T1 syngeneic mouse model of breast cancer. The Sca-1(pos) putative CSCs had high levels of activated Ras and phosphorylated MEK (p-MEK), compared with counterparts. The Ras farnesylation inhibitor (FTI-277) suppressed the maintenance and expansion of CSCs. Therefore, selective inhibition of Ras activation may be useful for stem-specific cancer therapy. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kim, Ran-Ju; Kim, Soo-Rim; Roh, Kyung-Jin; Park, Jeong-Ran; Nam, Jeong-Seok] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Res Inst, Lab Tumor Suppressor, Inchon, South Korea. [Park, Sang-Bum; Kang, Kyung-Sun] Seoul Natl Univ, Coll Vet Med, Dept Vet Publ Hlth, Lab Stem Cell & Tumor Biol, Seoul, South Korea. [Kong, Gu] Hanyang Univ, Coll Med, Dept Pathol, Seoul 133791, South Korea. [Tang, Binwu; Yang, Yu-An; Kohn, Ethan A.; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Nam, JS (reprint author), Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Res Inst, Lab Tumor Suppressor, Inchon, South Korea. EM namjs@gachon.ac.kr RI Kang, Kyung-Sun/G-6205-2013 FU National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea [0820180] FX This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0820180). NR 45 TC 22 Z9 22 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 28 PY 2010 VL 287 IS 2 BP 172 EP 181 DI 10.1016/j.canlet.2009.06.010 PG 10 WC Oncology SC Oncology GA 554QK UT WOS:000274449300007 PM 19586713 ER PT J AU Rahma, OE Ashtar, E Ibrahim, R Toubaji, A Gause, B Herrin, VE Linehan, WM Steinberg, SM Grollman, F Grimes, G Bernstein, SA Berzofsky, JA Khleif, SN AF Rahma, Osama E. Ashtar, Ed Ibrahim, Ramy Toubaji, Antoun Gause, Barry Herrin, Vincent E. Linehan, W. Marston Steinberg, Seth M. Grollman, Frank Grimes, George Bernstein, Sarah A. Berzofsky, Jay A. Khleif, Samir N. TI A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic Renal Cell Carcinoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID TUMOR-SUPPRESSOR GENE; COLONY-STIMULATING FACTOR; RISING INCIDENCE; INFILTRATING LYMPHOCYTES; ADJUVANT TREATMENT; CANCER STATISTICS; INTERFERON-ALPHA; DENDRITIC CELLS; UNITED-STATES; T-CELLS AB Background: Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides. Methods: Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock. Results: Four out of five evaluablepatients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively. Conclusions: The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. Trial registration: 98C0139 C1 [Rahma, Osama E.; Ashtar, Ed; Ibrahim, Ramy; Toubaji, Antoun; Grollman, Frank; Berzofsky, Jay A.; Khleif, Samir N.] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Gause, Barry; Bernstein, Sarah A.] NNMC, Med Oncol Clin Res Unit, Bethesda, MD USA. [Herrin, Vincent E.; Khleif, Samir N.] Natl Naval Med Ctr, Dept Hematol Oncol, Bethesda, MD USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. [Grimes, George] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. RP Khleif, SN (reprint author), NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM khleifs@mail.nih.gov NR 46 TC 9 Z9 10 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 28 PY 2010 VL 8 AR 8 DI 10.1186/1479-5876-8-8 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 574AC UT WOS:000275959800001 PM 20109232 ER PT J AU Strober, W AF Strober, Warren TI IMMUNOLOGY The expanding T(H)2 universe SO NATURE LA English DT Editorial Material ID CELLS C1 NIAID, Host Def Lab, Mucosal Immun Sect, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Host Def Lab, Mucosal Immun Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 9 TC 12 Z9 13 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 28 PY 2010 VL 463 IS 7280 BP 434 EP 435 DI 10.1038/463434a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548QK UT WOS:000273981100028 PM 20110979 ER PT J AU Landon, MB Spong, CY Thom, E AF Landon, Mark B. Spong, Catherine Y. Thom, Elizabeth TI Treatment for Mild Gestational Diabetes REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ADVERSE PREGNANCY OUTCOMES; HYPERGLYCEMIA; MELLITUS C1 [Landon, Mark B.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Thom, Elizabeth] George Washington Univ, Washington, DC USA. RP Landon, MB (reprint author), Ohio State Univ, Coll Med, Columbus, OH 43210 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 28 PY 2010 VL 362 IS 4 BP 366 EP 367 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 548OT UT WOS:000273975000022 ER PT J AU Stall, B Zach, L Ning, H Ondos, J Arora, B Shankavaram, U Miller, RW Citrin, D Camphausen, K AF Stall, Bronwyn Zach, Leor Ning, Holly Ondos, John Arora, Barbara Shankavaram, Uma Miller, Robert W. Citrin, Deborah Camphausen, Kevin TI Comparison of T2 and FLAIR imaging for target delineation in high grade gliomas SO RADIATION ONCOLOGY LA English DT Article ID LIMITED-VOLUME IRRADIATION; RECURSIVE PARTITIONING ANALYSIS; GLIOBLASTOMA-MULTIFORME; RADIATION-THERAPY; MALIGNANT GLIOMA; RANDOMIZED-TRIAL; BRAIN-TUMORS; RADIOTHERAPY; PATTERNS; FAILURE AB Background: FLAIR and T2 weighted MRIs are used based on institutional preference to delineate high grade gliomas and surrounding edema for radiation treatment planning. Although these sequences have inherent physical differences there is limited data on the clinical and dosimetric impact of using either or both sequences. Methods: 40 patients with high grade gliomas consecutively treated between 2002 and 2008 of which 32 had pretreatment MRIs with T1, T2 and FLAIR available for review were selected for this study. These MRIs were fused with the treatment planning CT. Normal structures, clinical tumor volume (CTV) and planning tumor volume (PTV) were then defined on the T2 and FLAIR sequences. A Venn diagram analysis was performed for each pair of tumor volumes as well as a fractional component analysis to assess the contribution of each sequence to the union volume. For each patient the tumor volumes were compared in terms of total volume in cubic centimeters as well as anatomic location using a discordance index. The overlap of the tumor volumes with critical structures was calculated as a measure of predicted toxicity. For patients with MRI documented failures, the tumor volumes obtained using the different sequences were compared with the recurrent gross tumor volume (rGTV). Results: The FLAIR CTVs and PTVs were significantly larger than the T2 CTVs and PTVs ( p < 0.0001 and p = 0.0001 respectively). Based on the discordance index, the abnormality identified using the different sequences also differed in location. Fractional component analysis showed that the intersection of the tumor volumes as defined on both T2 and FLAIR defined the majority of the union volume contributing 63.6% to the CTV union and 82.1% to the PTV union. T2 alone uniquely identified 12.9% and 5.2% of the CTV and PTV unions respectively while FLAIR alone uniquely identified 25.7% and 12% of the CTV and PTV unions respectively. There was no difference in predicted toxicity to normal structures using T2 or FLAIR. At the time of analysis, 26 failures had occurred of which 19 patients had MRIs documenting the recurrence. The rGTV correlated best with the FLAIR CTV but the percentage overlap was not significantly different from that with T2. There was no statistical difference in the percentage overlap with the rGTV and the PTVs generated using either T2 or FLAIR. Conclusions: Although both T2 and FLAIR MRI sequences are used to define high grade glial neoplasm and surrounding edema, our results show that the volumes generated using these techniques are different and not interchangeable. These differences have bearing on the use of intensity modulated radiation therapy (IMRT) and highly conformal treatment as well as on future clinical trials where the bias of using one technique over the other may influence the study outcome. C1 [Stall, Bronwyn; Zach, Leor; Ning, Holly; Ondos, John; Arora, Barbara; Shankavaram, Uma; Miller, Robert W.; Citrin, Deborah; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10,CRC,Rm B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 34 TC 11 Z9 11 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND J9 RADIAT ONCOL JI Radiat. Oncol. PD JAN 28 PY 2010 VL 5 AR 5 DI 10.1186/1748-717X-5-5 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 562HP UT WOS:000275041100002 PM 20109218 ER PT J AU Lindeblad, MO Bauer, KS Zakharov, AD Hill, JM Green, JS Thomas, BF Schwartz, A Kapetanovic, IM Lyubimov, A AF Lindeblad, Matthew O. Bauer, Kenneth S. Zakharov, Alexander D. Hill, Judith M. Green, Jonathan S. Thomas, Brian F. Schwartz, Arthur Kapetanovic, Izet M. Lyubimov, Alexander TI Pharmacokinetic and tissue distribution study of [C-14]fluasterone in male Beagle dogs following intravenous, oral and subcutaneous dosing routes SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE DHEA; Fluasterone; Pharmacokinetics; Tissue distribution; Chemoprevention; Beagle dog ID METABOLIC SYNDROME; ADIPOSE-TISSUE; DEHYDROEPIANDROSTERONE; MICE; CHEMOPREVENTION; CARCINOGENESIS; INHIBITION; ANALOG; 16-ALPHA-FLUORO-5-ANDROSTEN-17-ONE; SKIN AB The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [C-14]fluasterone following intravenous (iv). subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [C-14]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t(max): however. the observed C-max following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC(0-infinity)). Tissue distribution analysis 2 In post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24h. Elimination of [C-14]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [C-14]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24h. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Lindeblad, Matthew O.; Zakharov, Alexander D.; Lyubimov, Alexander] Univ Illinois, Dept Pharmacol, Toxicol Res Lab, Chicago, IL 60612 USA. [Bauer, Kenneth S.] Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA. [Hill, Judith M.; Green, Jonathan S.; Thomas, Brian F.] Analyt Chem & Pharmaceut Grp RTI Int, Res Triangle Pk, NC 27709 USA. [Schwartz, Arthur] Temple Univ, Sch Med AS, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA. [Kapetanovic, Izet M.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Lyubimov, A (reprint author), Univ Illinois, Dept Pharmacol, Toxicol Res Lab, 808 S Wood St,Rm 1306, Chicago, IL 60612 USA. EM lyubimov@uic.edu OI Thomas, Brian/0000-0002-0097-4804 FU NCI [N01-CN-43306] FX This research was supported by NCI contract N01-CN-43306. NR 23 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD JAN 27 PY 2010 VL 183 IS 2 BP 317 EP 326 DI 10.1016/j.cbi.2009.10.004 PG 10 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 553MH UT WOS:000274370600006 PM 19836365 ER PT J AU Virador, VM Grajeda, JPR Blanco-Labra, A Mendiola-Olaya, E Smith, GM Moreno, A Whitaker, JR AF Virador, Victoria M. Reyes Grajeda, Juan P. Blanco-Labra, Alejandro Mendiola-Olaya, Elizabeth Smith, Gary M. Moreno, Abel Whitaker, John R. TI Cloning, Sequencing, Purification, and Crystal Structure of Grenache (Vitis vinifera) Polyphenol Oxidase SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE Polyphenol oxidase; catechol oxidase; copper enzymes; Vitis vinifera; posttranslational processing; enzymatic browning; activation of proenzyme ID MUSHROOM TYROSINASE; PROTEIN-KINASE; PLANT; GENE; EXPRESSION; DNA; AMPLIFICATION; BIOCHEMISTRY; TRANSCRIPTS; HEMOCYANIN AB The full-length cDNA sequence (P93622_VITVI) of polyphenol oxidase (PPO) cDNA from grape Vitis vinifera L., cv Grenache, was found to encode a translated protein of 607 amino acids with an expected molecular weight of ca. 67 kDa and a predicted pI of 6.83. The translated amino acid sequence was 99%, identical to that of a white grape berry PPO (1) (5 out of 607 amino acid potential sequence differences). The protein was purified from Grenache grape berries by using traditional methods, and it was crystallized with ammonium acetate by the hanging-drop vapor diffusion method. The crystals were orthorhombic, space group C222(1). The structure was obtained at 2.2 angstrom resolution using synchrotron radiation using the 39 kDa isozyme of sweet potato PPO (PDB code: 1BT1) as a phase donor. The basic symmetry of the cell parameters (a, b, and c and alpha, beta, and gamma) as well as in the number of asymmetric units in the unit cell of the crystals of PPO, differed between the two proteins. The structures of the two enzymes are quite similar in overall fold, the location of the helix bundles at the core, and the active site in which three histidines bind each of the two catalytic copper ions, and one of the histidines is engaged in a thioether linkage with a cysteine residue. The possibility that the formation of the Cys-His thioether linkage constitutes the activation step is proposed. No evidence of phosphorylation or glycoslyation was found in the electron density map. The mass of the crystallized protein appears to be only 38.4 kDa, and the processing that occurs in the grape berry that leads to this smaller size is discussed. C1 [Smith, Gary M.; Whitaker, John R.] Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA. [Virador, Victoria M.] NIH, Bethesda, MD 20892 USA. [Reyes Grajeda, Juan P.] Inst Nacl Med Genom, Mexico City 01900, DF, Mexico. [Blanco-Labra, Alejandro; Mendiola-Olaya, Elizabeth] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Unidad Irapuato, Irapuato 36821, Gto, Mexico. [Moreno, Abel] Univ Nacl Autonoma Mexico, Inst Quim, Mexico City 04510, DF, Mexico. RP Smith, GM (reprint author), Univ Calif Davis, Dept Food Sci & Technol, Davis, CA 95616 USA. EM gmsmith@ucdavis.edu FU CONACYT [91999]; DGAPA-UNAiM; Fulbright Fellowship; Brookhaven National Laboratories (USA) FX A.M acknowledges the financial support from CONACYT Project No. 91999 and DGAPA-UNAiM for supporting travel expenses for sabbatical time at the University of Cambridge (U.K.). V.M.V. was supported by a Fulbright Fellowship (1990-1994). We also acknowledge the BNL-NSLS in the USA for the support of the X-ray data collection at Brookhaven National Laboratories (USA). NR 57 TC 58 Z9 63 U1 3 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JAN 27 PY 2010 VL 58 IS 2 BP 1189 EP 1201 DI 10.1021/jf902939q PG 13 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 544PV UT WOS:000273671900070 PM 20039636 ER PT J AU Buch, ER Mars, RB Boorman, ED Rushworth, MFS AF Buch, Ethan R. Mars, Rogier B. Boorman, Erie D. Rushworth, Matthew F. S. TI A Network Centered on Ventral Premotor Cortex Exerts Both Facilitatory and Inhibitory Control over Primary Motor Cortex during Action Reprogramming SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INFERIOR FRONTAL-CORTEX; ACTION SELECTION; DORSAL PREMOTOR; FUNCTIONAL CONNECTIVITY; INDIVIDUAL-DIFFERENCES; MAGNETIC STIMULATION; ONLINE ADJUSTMENTS; PREFRONTAL CORTEX; PARIETAL CORTEX; MONKEY AB Ventral premotor cortex (PMv) is widely accepted to exert an important influence over primary motor cortex (M1) when hand movements are made. Although study of these interactions has typically focused on their excitatory nature, given its strong connections with both ventral and opercular frontal regions, one feature of the influence of PMv over M1 may be inhibitory. Paired-pulse transcranial magnetic stimulation (ppTMS) was used to examine functional interactions between human PMv and M1 during the selection and reprogramming of a naturalistic goal-directed action. One of two cylinders was illuminated on each trial. It was then grasped and picked up. On some trials, however, subjects had to reprogram the action as the illuminated cylinder was switched off and the other illuminated simultaneously with reach initiation. At a neurophysiological level, the PMv paired-pulse effect (PPE) on M1 corticospinal activity was facilitatory after the initial target presentation and during movement initiation. When reprogramming was required, however, the PPE became strongly inhibitory. This context-dependent change from facilitation to inhibition occurred within 75 ms of the change of target. Behaviorally, PMv-M1 ppTMS disrupted reprogramming. Diffusion-weighted magnetic resonance image scans were taken of each subject. Intersubject differences in the facilitation-inhibition contrast of PMv-M1 interactions were correlated with fractional anisotropy of white-matter in ventral prefrontal, premotor, and intraparietal brain areas. These results suggest that a network of brain areas centered on PMv inhibits M1 corticospinal activity associated with undesired movements when action plans change. C1 [Buch, Ethan R.; Mars, Rogier B.; Boorman, Erie D.; Rushworth, Matthew F. S.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Buch, Ethan R.; Mars, Rogier B.; Boorman, Erie D.; Rushworth, Matthew F. S.] Univ Oxford, John Radcliffe Hosp, Ctr Funct Magnet Resonance Imaging Brain, Oxford OX3 9DU, England. [Buch, Ethan R.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, Med Neurol Branch, Bethesda, MD 20892 USA. RP Buch, ER (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. EM ethan.buch@psy.ox.ac.uk RI Buch, Ethan/G-1981-2011 FU Medical Research Council UK; Marie Curie Intra-European Fellowship; sixth European Community Framework Programme; National Institute of Neurological Disorders and Stroke FX This work was supported by the Medical Research Council UK (M.F.S.R.), the award of a Marie Curie Intra-European Fellowship within the sixth European Community Framework Programme (R.B.M.), and the intramural program of the National Institute of Neurological Disorders and Stroke. NR 29 TC 77 Z9 78 U1 3 U2 6 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 JAN 27 PY 2010 VL 30 IS 4 BP 1395 EP 1401 DI 10.1523/JNEUROSCI.4882-09.2010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 549LH UT WOS:000274050000020 PM 20107065 ER PT J AU Hawkins, BT Sykes, DB Miller, DS AF Hawkins, Brian T. Sykes, Destiny B. Miller, David S. TI Rapid, Reversible Modulation of Blood-Brain Barrier P-Glycoprotein Transport Activity by Vascular Endothelial Growth Factor SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; IN-VITRO; CEREBRAL-ISCHEMIA; BETA; VEGF; MODEL; ANGIOGENESIS; CAVEOLIN-1; EXPRESSION AB Increased brain expression of vascular endothelial growth factor (VEGF) is associated with neurological disease, brain injury, and blood-brain barrier (BBB) dysfunction. However, the specific effect of VEGF on the efflux transporter P-glycoprotein, a critical component of the BBB, is not known. Using isolated rat brain capillaries and in situ rat brain perfusion, we determined the effect of VEGF exposure on P-glycoprotein activity in vitro and in vivo. In isolated capillaries, VEGF acutely and reversibly decreased P-glycoprotein transport activity without decreasing transporter protein expression or opening tight junctions. This effect was blocked by inhibitors of the VEGF receptor flk-1 and Src kinase, but not by inhibitors of phosphatidylinositol-3-kinase or protein kinase C. VEGF also increased Tyr-14 phosphorylation of caveolin-1, and this was blocked by the Src inhibitor PP2. Pharmacological activation of Src kinase activity mimicked the effects of VEGF on P-glycoprotein activity and Tyr-14 phosphorylation of caveolin-1. In vivo, intracerebroventricular injection of VEGF increased brain distribution of P-glycoprotein substrates morphine and verapamil, but not the tight junction marker, sucrose; this effect was blocked by PP2. These findings indicate that VEGF decreases P-glycoprotein activity via activation of flk-1 and Src, and suggest Src-mediated phosphorylation of caveolin-1 may play a role in downregulation of P-glycoprotein activity. These findings also imply that P-glycoprotein activity is acutely diminished in pathological conditions associated with increased brain VEGF expression and that BBB VEGF/Src signaling could be targeted to acutely modulate P-glycoprotein activity and thus improve brain drug delivery. C1 [Hawkins, Brian T.; Sykes, Destiny B.; Miller, David S.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Miller, DS (reprint author), NIEHS, Pharmacol Lab, NIH, MD F1-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM miller28@niehs.nih.gov OI Hawkins, Brian/0000-0001-6719-5402 FU National Institutes of Health [Z01 ES080048-18 LP] FX This work was supported by the Intramural Research Program of the National Institutes of Health, Project #Z01 ES080048-18 LP. NR 48 TC 49 Z9 53 U1 1 U2 5 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 JAN 27 PY 2010 VL 30 IS 4 BP 1417 EP 1425 DI 10.1523/JNEUROSCI.5103-09.2010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 549LH UT WOS:000274050000023 PM 20107068 ER PT J AU Krsmanovic, LZ Hu, L Leung, PK Feng, H Catt, KJ AF Krsmanovic, Lazar Z. Hu, Lian Leung, Po-Ki Feng, Hao Catt, Kevin J. TI Pulsatile GnRH secretion: Roles of G protein-coupled receptors, second messengers and ion channels SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Summer Neuropeptide Conference/5th International Symposium on Signal Transduction in Health and Disease (STADY V) CY OCT 22-24, 2008 CL Tel Aviv, ISRAEL DE GnRH; G proteins; Receptors; Signaling; Action potential ID GONADOTROPIN-RELEASING-HORMONE; GREEN FLUORESCENT PROTEIN; HYPOTHALAMIC NEURONS; ADENYLYL-CYCLASE; TRANSGENIC MICE; CROSS-TALK; KINASE-C; CALCIUM; NEUROSECRETION; ACTIVATION AB The pulsatile secretion of GnRH from normal and immortalized hypothalamic GnRH neurons is highly calcium-dependent and is stimulated by cAMP. It is also influenced by agonist activation of the endogenous GnRH receptor (GnRH-R), which couples to multiple G proteins. This autocrine mechanism could serve as a timer to determine the frequency of pulsatile GnRH release by regulating Ca(2+)- and cAMP-dependent signaling and GnRH neuronal firing. The firing of individual and/or bursts of action potentials (APs) in spontaneously active GnRH neurons is followed by afterhyperpolarization (AHP) that lasts from several milliseconds to several seconds. GnRH-induced activation of GnRH neurons causes a significant increase in medium AHP that is partially sensitive to apamin. GnRH-induced modulation of Ca(2+) influx and the consequent changes in AHP current suggest that the GnRH receptors expressed in hypothalamic GnRH neurons are important modulators of their neuronal excitability. The coexistence of multiple regulatory mechanisms could provide a high degree of redundancy in the maintenance of this crucial component of the reproductive process. It is also conceivable that this multifactorial system could reflect the gradation from simple to more complex neuroendocrine control systems for regulating hypothalamo-pituitary function and gonadal activity during the evolution of the GnRH pulse generator. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Krsmanovic, Lazar Z.; Hu, Lian; Leung, Po-Ki; Feng, Hao; Catt, Kevin J.] NICHD, Sect Hormonal Regulat, PDEGEN, NIH, Bethesda, MD 20892 USA. RP Krsmanovic, LZ (reprint author), NICHD, Sect Hormonal Regulat, PDEGEN, NIH, 49 Convent Dr,Bldg 49,Rm 6A20, Bethesda, MD 20892 USA. EM lazar@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 41 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 27 PY 2010 VL 314 IS 2 SI SI BP 158 EP 163 DI 10.1016/j.mce.2009.05.015 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 550CE UT WOS:000274104100002 PM 19486924 ER PT J AU Klein, DC Bailey, MJ Carter, DA Kim, JS Shi, Q Ho, AK Chik, CL Gaildrat, P Morin, F Ganguly, S Rath, MF Moller, M Sugden, D Rangel, ZG Munson, PJ Weller, JL Coon, SL AF Klein, David C. Bailey, Michael J. Carter, David A. Kim, Jong-so Shi, Qiong Ho, Anthony K. Chik, Constance L. Gaildrat, Pascaline Morin, Fabrice Ganguly, Surajit Rath, Martin F. Moller, Morten Sugden, David Rangel, Zoila G. Munson, Peter J. Weller, Joan L. Coon, Steven L. TI Pineal function: Impact of microarray analysis SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Summer Neuropeptide Conference/5th International Symposium on Signal Transduction in Health and Disease (STADY V) CY OCT 22-24, 2008 CL Tel Aviv, ISRAEL DE Pineal; Microarray; Melatonin; Circadian rhythms; Cyclic AMP signaling; Immune response; Inflammation; MAP kinase; RNA splicing ID ARYLALKYLAMINE N-ACETYLTRANSFERASE; ACTIVATED PROTEIN-KINASE; BETA-ADRENERGIC STIMULATION; THYROXINE 5'-DEIODINASE ACTIVITY; INTESTINAL-PEPTIDE STIMULATION; PRIMATE CEREBROSPINAL-FLUID; PHOSPHOLIPASE-C ACTIVITY; OTX2 HOMEOBOX GENE; RAT PINEAL; MELATONIN RHYTHM AB Microarray analysis has provided a new understanding of pineal function by identifying genes that are highly expressed in this tissue relative to other tissues and also by identifying over 600 genes that are expressed on a 24-h schedule. This effort has highlighted surprising similarity to the retina and has provided reason to explore new avenues of study including intracellular signaling, signal transduction, transcriptional cascades, thyroid/retinoic acid hormone signaling, metal biology, RNA splicing, and the role the pineal gland plays in the immune/inflammation response. The new foundation that microarray analysis has provided will broadly support future research on pineal function. Published by Elsevier Ireland Ltd. C1 [Klein, David C.; Weller, Joan L.; Coon, Steven L.] NICHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Bailey, Michael J.] Texas A&M Univ, Dept Poultry Sci, College Stn, TX 77843 USA. [Carter, David A.] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. [Kim, Jong-so] POSTECH, Dept Life Sci, Lab Mol Neurophysiol, Pohang 790784, South Korea. [Shi, Qiong] OriGene Technol Inc, Rockville, MD 20850 USA. [Ho, Anthony K.] Univ Alberta, Fac Med & Dent, Dept Physiol, Edmonton, AB T6G 2H7, Canada. [Chik, Constance L.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Gaildrat, Pascaline] Fac Med, INSERM, U614, Mol Genet Lab, Rouen, France. [Gaildrat, Pascaline] Univ Hosp, Rouen, France. [Morin, Fabrice] Univ Rouen, European Inst Peptide Res, Lab Cellular & Mol Neuroendocrinol, INSERM,U413, Mont St Aignan, France. [Ganguly, Surajit] Inst Mol Med, New Delhi 110020, India. [Rath, Martin F.; Moller, Morten] Univ Copenhagen, Fac Hlth Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Sugden, David] Kings Coll London, Sch Biomed & Hlth Sci, Div Reprod & Endocrinol, London SE1 1UL, England. [Rangel, Zoila G.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), 49 Convent Dr,Bldg 49,Rm 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov RI Carter, David/A-4479-2010; OI Carter, David/0000-0002-8419-3975; Rath, Martin/0000-0002-4047-6324 FU Biotechnology and Biological Sciences Research Council [BB/D52503X/1]; Canadian Institutes of Health Research; Intramural NIH HHS [Z01 HD000095-37, Z01 HD008836-01, Z01 HD008838-01, Z01 HD008837-01]; Wellcome Trust NR 111 TC 28 Z9 29 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 27 PY 2010 VL 314 IS 2 SI SI BP 170 EP 183 DI 10.1016/j.mce.2009.07.010 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 550CE UT WOS:000274104100004 PM 19622385 ER PT J AU Stojilkovic, SS He, ML Koshimizu, TA Balik, A Zemkova, H AF Stojilkovic, Stanko S. He, Mu-Lan Koshimizu, Taka-aki Balik, Ales Zemkova, Hana TI Signaling by purinergic receptors and channels in the pituitary gland SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Summer Neuropeptide Conference/5th International Symposium on Signal Transduction in Health and Disease (STADY V) CY OCT 22-24, 2008 CL Tel Aviv, ISRAEL DE Purinergic receptors; Anterior pituitary; Posterior pituitary; ATP; P2X, P2Y ID ISOLATED NEUROHYPOPHYSEAL TERMINALS; P2X(2) RECEPTOR; ADENOSINE-TRIPHOSPHATE; EXTRACELLULAR ATP; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; FOLLICULOSTELLATE CELLS; INTRACELLULAR CALCIUM; VASOPRESSIN RELEASE; PROLACTIN-RELEASE; PRIMARY CULTURES AB Adenosine 5'-triphosphate is frequently released by cells and acts as an agonist for G protein-coupled P2Y receptors and ligand-gated P2X cationic channels in numerous tissues. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors. In the pituitary gland, adenosine 5'-triphosphate is released from the endings of magnocellular hypothalamic neurons and by anterior pituitary cells through pathway(s) that are still not well characterized. This gland also expresses several members of each family of purinergic receptors. P2X and adenosine receptors are co-expressed in the somata and nerve terminals of vasopressin-releasing neurons as well as in some secretory pituitary cells. P2X receptors stimulate electrical activity and modulate InSP3-dependent calcium release from intracellular stores, whereas adenosine receptors terminate electrical activity. Calcium-mobilizing P2Y receptors are expressed in pituicytes, folliculo-stellate cells and some secretory cells of the anterior pituitary. Published by Elsevier Ireland Ltd. C1 [Stojilkovic, Stanko S.; He, Mu-Lan; Koshimizu, Taka-aki; Balik, Ales; Zemkova, Hana] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Zemkova, Hana/C-1844-2012; Balik, Ales/C-1900-2012; OI Koshimizu, Taka-aki/0000-0001-5292-7535 FU Intramural NIH HHS [Z01 HD000195-14] NR 68 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 27 PY 2010 VL 314 IS 2 SI SI BP 184 EP 191 DI 10.1016/j.mce.2009.05.008 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 550CE UT WOS:000274104100005 PM 19467293 ER PT J AU Dufau, ML Liao, MJ Zhang, Y AF Dufau, Maria L. Liao, Mingjuan Zhang, Ying TI Participation of signaling pathways in the derepression of luteinizing hormone receptor transcription SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Summer Neuropeptide Conference/5th International Symposium on Signal Transduction in Health and Disease (STADY V) CY OCT 22-24, 2008 CL Tel Aviv, ISRAEL DE Luteinizing hormone receptor; Transcription; Epigenetic; Repressor; Co-repressor; Histone deacetylase; Histone acetylation; DNA methylation; Sp1/PKC phosphorylation; Phosphatases ID CHORIONIC-GONADOTROPIN RECEPTORS; NUCLEAR ORPHAN RECEPTORS; GENE-TRANSCRIPTION; REGULATE TRANSCRIPTION; ADENYLYL-CYCLASE; PROTEIN-KINASE; BREAST-CANCER; LH RECEPTOR; EXPRESSION; PROMOTER AB The luteinizing hormone receptor (LHR) transcription is subject to an epigenetic regulatory mode whereby the proximal Sp1 site acts as an anchor to recruit histone deacetylases (HDAC)1/2 and the Sin3A corepressor complex. This results in promoter-localized histone hypo-acetylation that contributes to the silencing of LHR transcriptional expression. Chromatin changes resulting from site-specific acetylation and methylation of histones regulate LHR gene expression. The HDAC inhibitor TSA-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for Sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase C zeta (PI3K/PKC zeta) at Ser641, leading to p107 repressor derecruitment and LHR transcriptional activation. The methylation status of the promoter provides another layer of modulation in a cell-specific manner. Maximal derepression of the LHR gene is dependent on complete DNA demethylation of the promoter in conjunction with histone hyperacetylation and release of repressors (p107 and HDAC/Sin3A). Independently, the PKC-alpha/Erk pathway, participates in LHR gene expression through induction of Sp1 phosphorylation at Ser site(s) other than Ser641. This causes dissociation of the HDAC1/mSin3A from the promoter, recruitment of TFIIB and Pol II, and transcriptional activation. Collectively, these findings demonstrate that LHR gene expression at the transcriptional level is regulated by complex and diverse networks, in which coordination and interactions between these regulatory effectors are crucial for silencing/activation of LHR expression. Published by Elsevier Ireland Ltd. C1 [Dufau, Maria L.; Liao, Mingjuan; Zhang, Ying] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Endocrinol, Program Dev Endocrinol & Genet, NIH, Bldg 49 Rm 6A-36, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov FU Intramural NIH HHS [Z01 HD000150-32] NR 45 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 27 PY 2010 VL 314 IS 2 SI SI BP 221 EP 227 DI 10.1016/j.mce.2009.05.005 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 550CE UT WOS:000274104100009 PM 19464346 ER PT J AU Fox, CS Muntner, P Chen, AY Alexander, KP Roe, MT Cannon, CP Saucedo, JF Kontos, MC Wiviott, SD AF Fox, Caroline S. Muntner, Paul Chen, Anita Y. Alexander, Karen P. Roe, Matthew T. Cannon, Christopher P. Saucedo, Jorge F. Kontos, Michael C. Wiviott, Stephen D. TI Use of Evidence-Based Therapies in Short-Term Outcomes of ST-Segment Elevation Myocardial Infarction and Non-ST-Segment Elevation Myocardial Infarction in Patients With Chronic Kidney Disease A Report From the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network Registry SO CIRCULATION LA English DT Article DE kidney; myocardial infarction; outcomes ID CHRONIC RENAL-INSUFFICIENCY; GLOMERULAR-FILTRATION-RATE; UNITED-STATES; SUBSEQUENT MORTALITY; CREATININE CLEARANCE; DIALYSIS PATIENTS; GLOBAL-REGISTRY; RISK-FACTORS; DYSFUNCTION; IMPACT AB Background-Chronic kidney disease (CKD) is a risk factor for myocardial infarction (MI) and death. Our goal was to characterize the association between CKD severity and short-term outcomes and the use of in-hospital evidence-based therapies among patients with ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI). Methods and Results-The study sample was drawn from the Acute Coronary Treatment and Intervention Outcomes Network registry, a nationwide sample of STEMI (n = 19 029) and NSTEMI (n = 30 462) patients. Estimated glomerular filtration rate was calculated with the Modification of Diet in Renal Disease equation in relation to use of immediate (first 24 hours) therapies and early (first 48 hours) cardiac catheterization as well as in-hospital major bleeding events and death. Overall, 30.5% and 42.9% of patients with STEMI and NSTEMI, respectively, had CKD. Regardless of MI type, patients with progressively more severe CKD had higher rates of death. For STEMI, the odds ratio for stage 3a, 3b, 4, and 5 CKD compared with patients with no CKD was 2.49, 3.72, 4.82, and 7.97, respectively (P(trend) < 0.0001). For NSTEMI, the analogous odds ratios were 1.81, 2.41, 3.50, and 4.09 (P for trend < 0.0001). In addition, patients with progressively more severe CKD were less likely to receive immediate evidence-based therapies including aspirin, beta-blockers, or clopidogrel, were less likely to undergo any reperfusion (STEMI) or revascularization (NSTEMI), and had higher rates of bleeding. Conclusions-Reports over the past decade have highlighted the importance of CKD among patients with MI. Data from this contemporary cohort suggest that patients with CKD still receive fewer evidence-based therapies and have substantially higher mortality rates. (Circulation. 2010;121:357-365.) C1 [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. [Muntner, Paul] Univ Alabama Brmingham, Dept Epidemiol, Birmingham, AL USA. [Muntner, Paul] Univ Alabama Brmingham, Div Nephrol, Dept Med, Birmingham, AL USA. [Chen, Anita Y.; Alexander, Karen P.; Roe, Matthew T.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Saucedo, Jorge F.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Kontos, Michael C.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Cannon, Christopher P.; Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Cannon, Christopher P.; Wiviott, Stephen D.] Brigham & Womens Hosp, Thrombolysis Myocardial Infarct Study Grp, Boston, MA 02115 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Genentech; Schering-Plough Corporation; Amersham/GE; Inovise Technologies; Biosite; Molecular Insight Pharmaceuticals; Accumetrics; AstraZeneca; Bristol-Myers Squibb/Sanofi Partnership; GlaxoSmithKline; Merck; Merck/Schering-Plough Partnership FX The ACTION registry is supported by Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Genentech, and Schering-Plough Corporation.; The authors report the following conflicts of interest: Dr Kontosspeakers' bureau: Sanofi-Aventis, Schering-Plough, Pfizer; consultant: Sanofi-Aventis, Schering-Plough, Pfizer, Inovise Technologies, Molecular Insight Pharmaceuticals; research support: Amersham/GE, Inovise Technologies, Biosite, Molecular Insight Pharmaceuticals. Dr Saucedo-consultant: Eli Lilly, Bristol-Myers Squibb/Sanofi, The Medicines Company; research, honoraria: ScheringPlough; honoraria: Pfizer. Dr Wiviott-consultant: Sanofi-Aventis; research, honoraria: Eli Lilly; research, honoraria: Daiichi Sankyo; honoraria: Astra-Zeneca; research: Schering-Plough; honoraria: Pfizer. Dr Roe-research funding and consultant and member of the speakers' bureau for the companies that fund the ACTION registry via the American College of Cardiology: BMS/Sanofi-Aventis, Schering-Plough. Dr Cannon-research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Merck, Merck/Schering-Plough Partnership; clinical advisor, equity in Automedics Medical Systems. The other authors report no conflicts. NR 37 TC 145 Z9 151 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 26 PY 2010 VL 121 IS 3 BP 357 EP U33 DI 10.1161/CIRCULATIONAHA.109.865352 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 547XF UT WOS:000273922500004 PM 20065168 ER PT J AU Ix, JH Katz, R Peralta, CA de Boer, IH Allison, MA Bluemke, DA Siscovick, DS Lima, JAC Criqui, MH AF Ix, Joachim H. Katz, Ronit Peralta, Carmen A. de Boer, Ian H. Allison, Matthew A. Bluemke, David A. Siscovick, David S. Lima, Joao A. C. Criqui, Michael H. TI A High Ankle Brachial Index Is Associated With Greater Left Ventricular Mass MESA (Multi-Ethnic Study of Atherosclerosis) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; heart failure; left ventricular mass; medial arterial calcification; vascular stiffness ID PERIPHERAL ARTERIAL-DISEASE; CARDIOVASCULAR HEALTH; RISK-FACTORS; CALCIFICATION; PRESSURES; PREVALENCE; MORTALITY; EVENTS; ADULTS AB Objectives This study sought to determine the association of high ankle brachial index (ABI) measurements with left ventricular (LV) mass, and to compare its strength with that of low ABI with LV mass. Background Arterial stiffness leads to LV mass through nonatherosclerotic pathways in mice. In humans, a high ABI indicates stiff peripheral arteries and is associated with cardiovascular disease (CVD) events. Whether high ABI is associated with LV mass in humans and whether this might reflect consequences of arterial stiffness, atherosclerosis, or both is unknown. Methods Among 4,972 MESA (Multi-Ethnic Study of Atherosclerosis) participants without clinical CVD, we used linear regression to evaluate the association of low (<0.90) and high (>1.40 or incompressible) ABI with LV mass by cardiac magnetic resonance imaging (MRI). Intermediate ABIs served as the reference category. To determine the effect of subclinical atherosclerosis, models were adjusted for common and internal carotid intima media thickness (cIMT) and natural log-transformed coronary artery calcification. Results Compared with subjects with intermediate ABI, LV mass was higher with either low (2.70 g/m(2) higher, 95% confidence interval: 0.65 to 4.75) or high ABI (6.84 g/m2 higher, 95% confidence interval: 3.2 to 10.47) after adjustment for traditional CVD risk factors, kidney function, and C-reactive protein. However, further adjustment for cIMT and CAC substantially attenuated the association of low ABI with LV mass index (1.24 g/m(2) higher, 95% confidence interval: -0.84 to 3.33), whereas the association of high ABI was minimally altered (6.01 g/m(2) higher, 95% confidence interval: 2.36 to 9.67). Conclusions High ABI is associated with greater LV mass; an association that is not attenuated with adjustment for subclinical atherosclerosis in nonperipheral arterial beds. High ABI might lead to greater LV mass through nonatherosclerotic pathways. (J Am Coll Cardiol 2010; 55: 342-9) (C) 2010 by the American College of Cardiology Foundation C1 [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, San Diego VA Healthcare Syst, San Diego, CA 92161 USA. [Ix, Joachim H.; Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Div Prevent Med, Dept Family & Prevent, San Diego, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Katz, Ronit] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [de Boer, Ian H.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Peralta, Carmen A.] Univ Calif San Diego, Div Nephrol, Dept Med, San Diego, CA 92161 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Bluemke, David A.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. RP Ix, JH (reprint author), Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, San Diego VA Healthcare Syst, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu OI Bluemke, David/0000-0002-8323-8086; Allison, Matthew/0000-0003-0777-8272 FU National Heart, Lung, and Blood Institute (NHLBI) [R21HL091217, N01-HC-95159, N01-HC-95169]; American Heart Association Fellow to Faculty Transition Award FX From the *Division of Nephrology and Hypertension, Department of Medicine, and the dagger Division of Preventive Medicine, Department of Family and Preventive Medicine, University of California San Diego, San Diego, California; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, California; Collaborative Health Studies Coordinating Center, Department of Biostatistics, ||Division of Nephrology, Department of Medicine, and the Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; #Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California; **San Francisco Veterans Affairs Medical Center, San Francisco, California; dagger dagger Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland; and the Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. This study was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R21HL091217 (to Dr. Ix), an American Heart Association Fellow to Faculty Transition Award, and contracts N01-HC-95159 through N01-HC-95169 from the NHLBI. Michael R. Jaff, MD, served as Guest Editor for this article. NR 28 TC 40 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 26 PY 2010 VL 55 IS 4 BP 342 EP 349 DI 10.1016/j.jacc.2009.11.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 546HP UT WOS:000273802200011 PM 20117440 ER PT J AU Delgado, MR Hirtz, D Aisen, M Ashwal, S Fehlings, DL McLaughlin, J Morrison, LA Shrader, MW Tilton, A Vargus-Adams, J AF Delgado, M. R. Hirtz, D. Aisen, M. Ashwal, S. Fehlings, D. L. McLaughlin, J. Morrison, L. A. Shrader, M. W. Tilton, A. Vargus-Adams, J. TI Practice Parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society SO NEUROLOGY LA English DT Review ID BOTULINUM-TOXIN-A; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; DYNAMIC EQUINUS; UPPER EXTREMITY; MOTOR FUNCTION; UPPER-LIMB; INJECTIONS; DIAZEPAM AB Objective: To evaluate published evidence of efficacy and safety of pharmacologic treatments for childhood spasticity due to cerebral palsy. Methods: A multidisciplinary panel systematically reviewed relevant literature from 1966 to July 2008. Results: For localized/segmental spasticity, botulinum toxin type A is established as an effective treatment to reduce spasticity in the upper and lower extremities. There is conflicting evidence regarding functional improvement. Botulinum toxin type A was found to be generally safe in children with cerebral palsy; however, the Food and Drug Administration is presently investigating isolated cases of generalized weakness resulting in poor outcomes. No studies that met criteria are available on the use of phenol, alcohol, or botulinum toxin type B injections. For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its effect on motor function and its side-effect profile. Tizanidine is possibly effective, but there are insufficient data on its effect on function and its side-effect profile. There were insufficient data on the use of dantrolene, oral baclofen, and intrathecal baclofen, and toxicity was frequently reported. Recommendations: For localized/segmental spasticity that warrants treatment, botulinum toxin type A should be offered as an effective and generally safe treatment ( Level A). There are insufficient data to support or refute the use of phenol, alcohol, or botulinum toxin type B ( Level U). For generalized spasticity that warrants treatment, diazepam should be considered for short-term treatment ( Level B), and tizanidine may be considered ( Level C). There are insufficient data to support or refute use of dantrolene, oral baclofen, or continuous intrathecal baclofen ( Level U). Neurology (R) 2010; 74: 336-343 C1 [Delgado, M. R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Hirtz, D.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Ashwal, S.] Loma Linda Univ, Loma Linda, CA 92350 USA. [Fehlings, D. L.] Bloorview Kids Rehab, Toronto, ON, Canada. [Morrison, L. A.] Univ New Mexico, Albuquerque, NM 87131 USA. [McLaughlin, J.] Univ Washington, Seattle, WA 98195 USA. [Shrader, M. W.] Core Inst, Sun City W, AZ USA. [Tilton, A.] Louisiana State Univ, New Orleans, LA USA. [Vargus-Adams, J.] Cincinnati Childrens Hosp, Cincinnati, OH USA. RP Delgado, MR (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. EM guidelines@aan.com NR 40 TC 68 Z9 79 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 26 PY 2010 VL 74 IS 4 BP 336 EP 343 DI 10.1212/WNL.0b013e3181cbcd2f PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 547YZ UT WOS:000273927100011 ER PT J AU Ashktorab, H Schaffer, AA Daremipouran, M Smoot, DT Lee, E Brim, H AF Ashktorab, Hassan Schaeffer, Alejandro A. Daremipouran, Mohammad Smoot, Duane T. Lee, Edward Brim, Hassan TI Distinct Genetic Alterations in Colorectal Cancer SO PLOS ONE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; ISLAND METHYLATOR PHENOTYPE; MICROSATELLITE INSTABILITY; COLON-CANCER; CHROMOSOMAL INSTABILITY; HUMAN BREAST; AFRICAN-AMERICANS; MLL3 MUTATIONS; CARCINOMA; TUMORS AB Background: Colon cancer (CRC) development often includes chromosomal instability (CIN) leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs) and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. Methodology/Principal Findings: We applied genome-wide array comparative genome hybridization (aCGH) using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes). There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. Conclusions/Significance: Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs. C1 [Ashktorab, Hassan] Howard Univ, Dept Med, Coll Med, Washington, DC 20059 USA. [Ashktorab, Hassan] Howard Univ, Ctr Canc, Coll Med, Washington, DC 20059 USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, DHHS, Bethesda, MD 20892 USA. [Daremipouran, Mohammad; Smoot, Duane T.; Lee, Edward; Brim, Hassan] Howard Univ, Coll Med, Dept Pathol, Washington, DC USA. RP Ashktorab, H (reprint author), Howard Univ, Dept Med, Coll Med, Washington, DC 20059 USA. EM hashktorab@howard.edu RI Schaffer, Alejandro/F-2902-2012 FU National Institutes of Health [CA102681]; NIH; NLM; Howard University FX This work was supported by PHS grant from the National Institutes of Health CA102681, the Intramural Research Program of the NIH, NLM and GCRC award from Howard University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 58 Z9 59 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2010 VL 5 IS 1 AR e8879 DI 10.1371/journal.pone.0008879 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NO UT WOS:000273896500008 PM 20126641 ER PT J AU Kaczmarczyk, SJ Sitaraman, K Hill, T Hartley, JL Chatterjee, DK AF Kaczmarczyk, Stanislaw J. Sitaraman, Kalavathy Hill, Thomas Hartley, James L. Chatterjee, Deb K. TI Tus, an E. coli Protein, Contains Mammalian Nuclear Targeting and Exporting Signals SO PLOS ONE LA English DT Article ID ESCHERICHIA-COLI; TER COMPLEX; DNA-REPLICATION; SEQUENCE; TRANSLOCATION; TERMINATION; BINDING; DOMAIN; LOCALIZATION; RECOMBINASE AB Shuttling of proteins between nucleus and cytoplasm in mammalian cells is facilitated by the presence of nuclear localization signals (NLS) and nuclear export signals (NES), respectively. However, we have found that Tus, an E. coli replication fork arresting protein, contains separate sequences that function efficiently as NLS and NES in mammalian cell lines, as judged by cellular location of GFP-fusion proteins. The NLS was localized to a short stretch of 9 amino acids in the carboxy-terminus of Tus protein. Alterations of any of these basic amino acids almost completely abolished the nuclear targeting. The NES comprises a cluster of leucine/hydrophobic residues located within 21 amino acids at the amino terminus of Tus. Finally, we have shown that purified GFP-Tus fusion protein or GFP-Tus NLS fusion protein, when added to the culture media, was internalized very efficiently into mammalian cells. Thus, Tus is perhaps the first reported bacterial protein to possess both NLS and NES, and has the capability to transduce protein into mammalian cells. C1 [Kaczmarczyk, Stanislaw J.; Sitaraman, Kalavathy; Hartley, James L.; Chatterjee, Deb K.] NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hill, Thomas] Univ N Dakota, Sch Med & Hlth Sci, Dept Microbiol & Immunol, Grand Forks, ND 58201 USA. RP Kaczmarczyk, SJ (reprint author), NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. EM dchatterjee@mail.nih.gov FU National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2010 VL 5 IS 1 AR e8889 DI 10.1371/journal.pone.0008889 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NO UT WOS:000273896500012 PM 20126275 ER PT J AU Fawzi, NL Doucleff, M Suh, JY Clore, GM AF Fawzi, Nicolas L. Doucleff, Michaeleen Suh, Jeong-Yong Clore, G. Marius TI Mechanistic details of a protein-protein association pathway revealed by paramagnetic relaxation enhancement titration measurements SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE enzyme I-histidine containing phosphocarrier protein complex; encounter complex; lowly populated states; NMR; phosphotransferase system ID TRANSIENT ENCOUNTER COMPLEXES; CYTOCHROME-C PEROXIDASE; N-TERMINAL DOMAIN; PHOSPHOTRANSFERASE SYSTEM; BIOLOGICAL MACROMOLECULES; ALPHA-SYNUCLEIN; ENZYME-I; NMR; BINDING; DYNAMICS AB Protein-protein association generally proceeds via the intermediary of a transient, lowly populated, encounter complex ensemble. The mechanism whereby the interacting molecules in this ensemble locate their final stereospecific structure is poorly understood. Further, a fundamental question is whether the encounter complex ensemble is an effectively homogeneous population of nonspecific complexes or whether it comprises a set of distinct structural and thermodynamic states. Here we use intermolecular paramagnetic relaxation enhancement (PRE), a technique that is exquisitely sensitive to lowly populated states in the fast exchange regime, to characterize the mechanistic details of the transient encounter complex interactions between the N-terminal domain of Enzyme I (EIN) and the histidine-containing phosphocarrier protein (HPr), two major bacterial signaling proteins. Experiments were conducted at an ionic strength of 150 mM NaCl to eliminate any spurious nonspecific associations not relevant under physiological conditions. By monitoring the dependence of the intermolecular transverse PRE (Gamma(2)) rates measured on (15)N-labeled EIN on the concentration of paramagnetically labeled HPr, two distinct types of encounter complex configurations along the association pathway are identified and dissected. The first class, which is in equilibrium with and sterically occluded by the specific complex, probably involves rigid body rotations and small translations near or at the active site. In contrast, the second class of encounter complex configurations can coexist with the specific complex to form a ternary complex ensemble, which may help EIN compete with other HPr binding partners in vivo by increasing the effective local concentration of HPr even when the active site of EIN is occupied. C1 [Fawzi, Nicolas L.; Doucleff, Michaeleen; Suh, Jeong-Yong; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008; Fawzi, Nicolas/E-2555-2013 OI Clore, G. Marius/0000-0003-3809-1027; Fawzi, Nicolas/0000-0001-5483-0577 FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Gerhard Hummer for useful discussions. This work was supported by the Intramural Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases, and the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (G.M.C.). NR 37 TC 38 Z9 39 U1 1 U2 11 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 JAN 26 PY 2010 VL 107 IS 4 BP 1379 EP 1384 DI 10.1073/pnas.0909370107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600029 PM 20080627 ER PT J AU Zuo, XB Wang, JB Yu, P Eyler, D Xu, H Starich, MR Tiede, DM Simon, AE Kasprzak, W Schwieters, CD Shapiro, BA Wang, YX AF Zuo, Xiaobing Wang, Jinbu Yu, Ping Eyler, Dan Xu, Huan Starich, Mary R. Tiede, David M. Simon, Anne E. Kasprzak, Wojciech Schwieters, Charles D. Shapiro, Bruce A. Wang, Yun-Xing TI Solution structure of the cap-independent translational enhancer and ribosome-binding element in the 3 ' UTR of turnip crinkle virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE new method; NMR; SAXS; 3 ' UTR RNA; RNA structure ID MINUS-STRAND SYNTHESIS; PLANT VIRAL RNAS; MESSENGER-RNA; GROUP-I; INITIATION; REPLICATION; PSEUDOKNOT; SCATTERING; RIBOZYME; SUBUNIT AB The 3' untranslated region (3' UTR) of turnip crinkle virus (TCV) genomic RNA contains a cap-independent translation element (CITE), which includes a ribosome-binding structural element (RBSE) that participates in recruitment of the large ribosomal subunit. In addition, a large symmetric loop in the RBSE plays a key role in coordinating the incompatible processes of viral translation and replication, which require enzyme progression in opposite directions on the viral template. To understand the structural basis for the large ribosomal subunit recruitment and the intricate interplay among different parts of the molecule, we determined the global structure of the 102-nt RBSE RNA using solution NMR and small-angle x-ray scattering. This RNA has many structural features that resemble those of a tRNA in solution. The hairpins H1 and H2, linked by a 7-nucleotide linker, form the upper part of RBSE and hairpin H3 is relatively independent from the rest of the structure and is accessible to interactions. This global structure provides insights into the three-dimensional layout for ribosome binding, which may serve as a structural basis for its involvement in recruitment of the large ribosomal subunit and the switch between viral translation and replication. The experimentally determined three-dimensional structure of a functional element in the 3' UTR of an RNA from any organism has not been previously reported. The RBSE structure represents a prototype structure of a new class of RNA structural elements involved in viral translation/replication processes. C1 [Zuo, Xiaobing; Wang, Jinbu; Yu, Ping; Xu, Huan; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Yu, Ping; Kasprzak, Wojciech] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Eyler, Dan] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Starich, Mary R.] NCI, Off Chief, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. [Tiede, David M.] Argonne Natl Lab, Chem Sci & Engn Div, Argonne, IL 60439 USA. [Simon, Anne E.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. RP Wang, YX (reprint author), NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, NIH, Frederick, MD 21702 USA. EM wangyunx@mail.nih.gov RI Zuo, Xiaobing/F-1469-2010; ID, BioCAT/D-2459-2012; Simon, Anne/B-8713-2014 FU National Institutes of Health (NIH) [RR-08630]; National Cancer Institute; Center for Cancer Research; CIT Intramural Research Program; U.S. Public Health Service [GM 061515-05A2/G120CD]; National Cancer Institute, NIH [HHSN261200800001E]; Office of Basic Energy Sciences, Department of Energy [DE-AC02-06CH11357, W-31-109-ENG-38] FX We thank Professors R. Green and Samuel E. Butcher for helpful discussions. We thank Drs. L. Guo (BioCAT, sector 18-ID) and S. Seifert (BESSRC, sector 12-ID) at Argonne National Laboratory for their support for synchrotron experiments. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research to B. A. S. and Y-X.W.; by the Intramural Research Program of the NIH, the CIT Intramural Research Program to C. D. S, and U.S. Public Health Service (GM 061515-05A2/G120CD) to A.E.S.. This publication has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under grant HHSN261200800001E to W. K. and P.Y. Work at Argonne National Laboratory (DMT) and the Advanced Photon Source was supported by the Office of Basic Energy Sciences, Department of Energy under contract DE-AC02-06CH11357. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract No. W-31-109-ENG-38. BioCAT is a National Institutes of Health-supported Research Center RR-08630. NR 35 TC 50 Z9 51 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 26 PY 2010 VL 107 IS 4 BP 1385 EP 1390 DI 10.1073/pnas.0908140107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600030 PM 20080629 ER PT J AU Song, H Mak, KK Topol, L Yun, KS Hu, JX Garrett, L Chen, YB Park, O Chang, J Simpson, RM Wang, CY Gao, B Jiang, J Yang, YZ AF Song, Hai Mak, Kinglun Kingston Topol, Lilia Yun, Kangsun Hu, Jianxin Garrett, Lisa Chen, Yongbin Park, Ogyi Chang, Jia Simpson, R. Mark Wang, Cun-Yu Gao, Bin Jiang, Jin Yang, Yingzi TI Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Hippo signaling; tumor suppressor; Yap phosphorylation ID HIPPO SIGNALING PATHWAY; CELL CONTACT INHIBITION; LIVER STEM-CELLS; PROMOTES APOPTOSIS; TRANSCRIPTION FACTOR; PROGENITOR CELLS; TEAD/TEF FAMILY; PROTEIN-KINASE; GROWTH-CONTROL; FEEDBACK LOOP AB Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and promoting cell death. Here we investigated whether mammals also require the Hpo pathway to control organ size and adult tissue homeostasis. We found that Mst1 and Mst2, the two mouse homologs of the Drosophila Hpo, control the sizes of some, but not all organs, in mice, and Mst1 and Mst2 act as tumor suppressors by restricting cell proliferation and survival. We show that Mst1 and Mst2 play redundant roles, and removal of both resulted in early lethality in mouse embryos. Importantly, tumors developed in the liver with a substantial increase of the stem/progenitor cells by 6 months after removing Mst1 and Mst2 postnatally. We show that Mst1 and Mst2 were required in vivo to control Yap phosphorylation and activity. Interestingly, apoptosis induced by TNF alpha was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNF alpha is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNF alpha-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2. C1 [Song, Hai; Mak, Kinglun Kingston; Topol, Lilia; Yun, Kangsun; Hu, Jianxin; Garrett, Lisa; Yang, Yingzi] Natl Human Genome Res Inst, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Chen, Yongbin; Jiang, Jin] UT SW Med Ctr, Dept Dev Biol, Dallas, TX 75390 USA. [Chen, Yongbin; Jiang, Jin] UT SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA. [Park, Ogyi; Gao, Bin] NIAAA, Sect Liver Biol, Bethesda, MD 20892 USA. [Chang, Jia; Wang, Cun-Yu] Univ Calif Los Angeles, Sch Dent, Div Oral Biol & Med, Los Angeles, CA 90095 USA. [Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Yang, YZ (reprint author), Natl Human Genome Res Inst, Genet Dis Res Branch, 49 Convent Dr, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov RI Song, H/C-9965-2011 FU National Human Genome Research Institute; Welch Foundation [I-1603] FX We thank the Yang Laboratory members for stimulating discussions during the course of the work; Drs. Randy Johnson and Dae-Sik Lim for sharing unpublished results; Drs. Zheng-Gang Liu and Xinwei Wang for insights into TNF signaling and liver tumors; and Julia Fekecs for help in preparing the figures. This work is supported by the Intramural Research Program of the National Human Genome Research Institute. (Y.Y.)and the Welch Foundation grant I-1603 (J.J.). NR 63 TC 234 Z9 238 U1 3 U2 36 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 JAN 26 PY 2010 VL 107 IS 4 BP 1431 EP 1436 DI 10.1073/pnas.0911409107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600038 PM 20080598 ER PT J AU Menendez, D Inga, A Resnick, MA AF Menendez, Daniel Inga, Alberto Resnick, Michael A. TI Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE FLT1; noncanonical response element; half-site; transcriptional synergy ID TUMOR-SUPPRESSOR P53; TRANSCRIPTION-FACTOR; RESPONSE ELEMENTS; TETRAMERIC P53; BINDING-SITES; DNA-BINDING; NETWORK; DOMAIN; GENES; DIVERSITY AB p53 is a master regulatory, sequence-specific transcription factor that directly controls expression of over 100 genes in response to various stress signals. Transactivation is generally considered to occur through p53 binding to a consensus response element (RE) composed of two 5'-RRRCWWGYYY-3' decamers. Recently, studying the human angiogenesis-related gene FLT1 we discovered that p53 can mediate limited transactivation at a noncanonical 1/2 site and could synergize with the estrogen receptor (ER) acting in cis at a nearby ER 1/2 site. To address the generality of concerted transactivation by p53 and ER, the 1/2 site in the FLT1 promoter was replaced with a variety of 1/2 sites, as well as canonical weak and strong p53 REs of human target genes. The p53 transactivation of all tested sequences was greatly enhanced by ligand-activated ER acting in cis. Furthermore, enhanced transactivation extends to several cancer-associated p53 mutants with altered function, suggesting ER-dependent mutant p53 activity for at least some REs. The enhanced transactivation was also found with p63 and p73. We propose a general synergistic relationship between p53 family and ER master regulators in transactivation of p53 target canonical and noncanonical REs, which might be poorly responsive to p53 on their own. This relationship greatly expands the transcriptional master network regulated by p53 in terms of genes affected and levels of expression and has implications for the appearance and possible treatments of cancer. C1 [Menendez, Daniel; Resnick, Michael A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Inga, Alberto] Ist Sci Studio & Cura Tumori, Natl Inst Canc Res, Dept Epidemiol & Prevent, Unit Mol Mutagenesis & DNA Repair, I-16132 Genoa, Italy. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov FU National Institute on Environmental Health Sciences [Z01 ES065079]; Italian Association for Cancer Research; Associazione Italiana per la Ricerca sul Cancro FX We appreciate O. Bandele and A. M Jetten for critical comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute on Environmental Health Sciences (Grant Z01 ES065079 to D. M. and M. A. R.) and partially supported by the Italian Association for Cancer Research, Associazione Italiana per la Ricerca sul Cancro (to A. I.). NR 35 TC 31 Z9 34 U1 0 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 JAN 26 PY 2010 VL 107 IS 4 BP 1500 EP 1505 DI 10.1073/pnas.0909129107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600050 PM 20080630 ER PT J AU Benveniste, H Fowler, JS Rooney, WD Scharf, BA Backus, WW Izrailtyan, I Knudsen, GM Hasselbalch, SG Volkow, ND AF Benveniste, Helene Fowler, Joanna S. Rooney, William D. Scharf, Bruce A. Backus, W. Walter Izrailtyan, Igor Knudsen, Gitte M. Hasselbalch, Steen G. Volkow, Nora D. TI Cocaine is pharmacologically active in the nonhuman primate fetal brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain function; in vivo; pregnancy; imaging; in utero ID CEREBRAL GLUCOSE-UTILIZATION; POSITRON EMISSION TOMOGRAPHY; DOPAMINE TRANSPORTER; NORMAL VALUES; MONKEY BRAIN; COMBINED PET; IN-VIVO; METABOLISM; HUMANS; RAT AB Cocaine use during pregnancy is deleterious to the newborn child, in part via its disruption of placental blood flow. However, the extent to which cocaine can affect the function of the fetal primate brain is still an unresolved question. Here we used PET and MRI and show that in third-trimester pregnant nonhuman primates, cocaine at doses typically used by drug abusers significantly increased brain glucose metabolism to the same extent in the mother as in the fetus (similar to 100%). Inasmuch as brain glucose metabolism is a sensitive marker of brain function, the current findings provide evidence that cocaine use by a pregnant mother will also affect the function of the fetal brain. We are also unique in showing that cocaine's effects in brain glucose metabolism differed in pregnant (increased) and nonpregnant (decreased) animals, which suggests that the psychoactive effects of cocaine are influenced by the state of pregnancy. Our findings have clinical implications because they imply that the adverse effects of prenatal cocaine exposure to the newborn child include not only cocaine's deleterious effects to the placental circulation, but also cocaine's direct pharmacological effect to the developing fetal brain. C1 [Benveniste, Helene] SUNY Stony Brook, Hlth Sci Ctr, Dept Anesthesiol, Level 4, Stony Brook, NY 11794 USA. [Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Rooney, William D.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Scharf, Bruce A.] Univ Med & Dent New Jersey, Res Off, Newark, NJ 07101 USA. [Knudsen, Gitte M.; Hasselbalch, Steen G.] Univ Copenhagen, Rigshosp, Neurobiol Res Unit, DK-2100 Copenhagen, Denmark. [Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. RP Benveniste, H (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Dept Anesthesiol, Level 4, Stony Brook, NY 11794 USA. EM Benve-niste@bnl.gov RI Knudsen, Gitte/C-1368-2013; Izrailtyan, Igor/G-8192-2016 OI Knudsen, Gitte/0000-0003-1508-6866; Izrailtyan, Igor/0000-0003-1216-3467 FU Department of Energy Office of Biological and Environmental Research [DE-AC02-98CH10886]; National Institutes of Health; New York State Office of Science, Technology and Academic Research FX We thank Donald Warner and David Alexoff for assistance with the PET scan acquisitions; Pauline Carter, Payton King, and Barbara Hubbard for help with the preparation, anesthesia, and imaging of the nonhuman primates; and Dr. L. Rosenblum for allowing us access to pregnant M. radiata from the Primate Laboratory at State University of New York Downstate. This research was supported by Department of Energy Office of Biological and Environmental Research (Brookhaven National Laboratory Contract DE-AC02-98CH10886), National Institutes of Health, and New York State Office of Science, Technology and Academic Research. NR 41 TC 6 Z9 6 U1 0 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 JAN 26 PY 2010 VL 107 IS 4 BP 1582 EP 1587 DI 10.1073/pnas.0909585107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OQ UT WOS:000273974600064 PM 20080687 ER PT J AU Holmes, EC AF Holmes, Edward C. TI The comparative genomics of viral emergence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; influenza; RNA virus; lethal mutagenesis; mutation rate ID INFLUENZA-A VIRUS; RNA VIRUSES; ADAMANTANE RESISTANCE; PHYLOGENETIC EVIDENCE; LETHAL MUTAGENESIS; UNITED-STATES; H3N2 VIRUSES; HIGH-RATES; EVOLUTION; HOST AB RNA viruses are the main agents of emerging and re-emerging diseases. It is therefore important to reveal the evolutionary processes that underpin their ability to jump species boundaries and establish themselves in new hosts. Here, I discuss how comparative genomics can contribute to this endeavor. Arguably the most important evolutionary process in RNA virus evolution, abundant mutation, may even open up avenues for their control through "lethal mutagenesis." Despite this remarkable mutational power, adaptation to diverse host species remains a major adaptive challenge, such that the most common outcome of host jumps are short-term "spillover" infections. A powerful case study of the utility of genomic approaches to studies of viral evolution and emergence is provided by influenza virus and brought into sharp focus by the ongoing epidemic of swine-origin H1N1 influenza A virus (A/H1N1pdm). Research here reveals a marked lack of surveillance of influenza viruses in pigs, coupled with the possibility of cryptic transmission before the first reported human cases, such that the exact genesis of A/H1N1pdm (where, when, how) is uncertain. C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 67 TC 26 Z9 27 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 26 PY 2010 VL 107 SU 1 BP 1742 EP 1746 DI 10.1073/pnas.0906193106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548OH UT WOS:000273972500009 PM 19858482 ER PT J AU Simunovic, F Yi, M Wang, YL Stephens, R Sonntag, KC AF Simunovic, Filip Yi, Ming Wang, Yulei Stephens, Robert Sonntag, Kai C. TI Evidence for Gender-Specific Transcriptional Profiles of Nigral Dopamine Neurons in Parkinson Disease SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; PROSTATE-CANCER; BIOLOGICAL THEMES; AFRICAN-AMERICAN; ALPHA-SYNUCLEIN; NERVOUS-SYSTEM; BREAST-CANCER; CELL-DEATH; PHENOTYPE; GENOME AB Background: Epidemiological data suggest that the male gender is one of the risks factors for the development of Parkinson Disease (PD). Also, differences in the clinical manifestation and the course of PD have been observed between males and females. However, little is known about the molecular aspects underlying gender-specificity in PD. To address this issue, we determined the gene expression profiles of male and female dopamine (DA) neurons in sporadic PD. Methodology/Principal Findings: We analyzed Affymetrix-based microarrays on laser microdissected DA neurons from postmortem brains of sporadic PD patients and age-matched controls across genders. Pathway enrichment demonstrated that major cellular pathways involved in PD pathogenesis showed different patterns of deregulation between males and females with more prominent downregulation of genes related to oxidative phosporylation, apoptosis, synaptic transmission and transmission of nerve impulse in the male population. In addition, we found upregulation of gene products for metabolic processes and mitochondrial energy consumption in the age-matched male control neurons. On the single cell level, selected data validation using quantitative Real-Time (qRT)-PCR was consistent with microarray raw data and supported some of the observations from data analysis. Conclusions/Significance: On the molecular level, our results provide evidence that the expression profiles of aged normal and PD midbrain DA neurons are gender-specific. The observed differences in the expression profiles suggest a disease bias of the male gender, which could be in concordance with clinical observations that the male gender represents a risk factor for sporadic PD. Validation of gene expression by qRT-PCR supported the microarray results, but also pointed to several caveats involved in data interpretation. C1 [Simunovic, Filip; Sonntag, Kai C.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. [Yi, Ming; Stephens, Robert] NCI, Bioinformat Support Grp, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. [Wang, Yulei] Appl Biosyst Inc, Foster City, CA USA. RP Simunovic, F (reprint author), Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. EM ksonntag@mclean.harvard.edu FU Massachusetts' Alzheimer's Disease Research Center; Harvard NeuroDiscovery Center FX This research was in part supported by a grant from the Massachusetts' Alzheimer's Disease Research Center and the Harvard NeuroDiscovery Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 40 Z9 41 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2010 VL 5 IS 1 AR e8856 DI 10.1371/journal.pone.0008856 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NM UT WOS:000273896300008 PM 20111594 ER PT J AU Vora, S Abbas, A Kim, CJ Summerfield, TLS Kusanovic, JP Iams, JD Romero, R Kniss, DA Ackerman, WE AF Vora, Sonali Abbas, Asad Kim, Chong J. Summerfield, Taryn L. S. Kusanovic, Juan P. Iams, Jay D. Romero, Roberto Kniss, Douglas A. Ackerman, William E. TI Nuclear factor-kappa B localization and function within intrauterine tissues from term and preterm labor and cultured fetal membranes SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article ID GENE-EXPRESSION; NITRIC-OXIDE; HUMAN AMNION; PARTURITION; INFLAMMATION; PREGNANCY; CYCLOOXYGENASE-2; OSCILLATIONS; ACTIVATION; MYOMETRIUM AB Background: The objective of this study was to quantify the nuclear localization and DNA binding activity of p65, the major transactivating nuclear factor-kappa B (NF-kappaB) subunit, in full-thickness fetal membranes (FM) and myometrium in the absence or presence of term or preterm labor. Methods: Paired full-thickness FM and myometrial samples were collected from women in the following cohorts: preterm no labor (PNL, N = 22), spontaneous preterm labor (PTL, N = 21), term no labor (TNL, N = 23), and spontaneous term labor (STL, N = 21). NF-kappaB p65 localization was assessed by immunohistochemistry, and DNA binding activity was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based method. Results: Nuclear p65 labeling was rare in amnion and chorion, irrespective of clinical context. In decidua, nuclear p65 labeling was greater in the STL group relative to the TNL cohort, but there were no differences among the TNL, PTL, and PNL cohorts. In myometrium, diffuse p65 nuclear labeling was significantly associated with both term and preterm labor. There were no significant differences in ELISA-based p65 binding activity in amnion, choriodecidual, and myometrial specimens in the absence or presence of term labor. However, parallel experiments using cultured term fetal membranes demonstrated high levels of p65-like binding even the absence of cytokine stimulation, suggesting that this assay may be of limited value when applied to tissue specimens. Conclusions: These results suggest that the decidua is an important site of NF-kappaB regulation in fetal membranes, and that mechanisms other than cytoplasmic sequestration may limit NF-kappaB activation prior to term. C1 [Vora, Sonali; Summerfield, Taryn L. S.; Kniss, Douglas A.; Ackerman, William E.] Ohio State Univ, Lab Perinatal Res, Dept Obstet & Gynecol, Coll Med, Columbus, OH 43210 USA. [Abbas, Asad; Kim, Chong J.; Kusanovic, Juan P.; Romero, Roberto] Eunice Kenndey Shriver NICHHD, Perinatol Res Branch, NIH, Bethesda, MD USA. [Kim, Chong J.; Kusanovic, Juan P.; Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kim, Chong J.] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Summerfield, Taryn L. S.; Iams, Jay D.; Kniss, Douglas A.; Ackerman, William E.] Ohio State Univ, Dept Obstet & Gynecol, Coll Med, Div Maternal Fetal Med, Columbus, OH 43210 USA. [Kniss, Douglas A.] Ohio State Univ, Coll Engn, Dept Biomed Engn, Columbus, OH 43210 USA. RP Ackerman, WE (reprint author), Ohio State Univ, Lab Perinatal Res, Dept Obstet & Gynecol, Coll Med, Columbus, OH 43210 USA. EM ackerman.72@osu.edu RI Ackerman, William/E-2612-2011 FU NIH [R01 HD35581]; Ohio State University; National Institute of Child Health and Human Development [WSU07043, N01-HD-2-3342]; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS; Mentored Clinical Scientist Development Award [K08 HD049628] FX The authors would like to thank Dr. Martha Lappas (Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Victoria, Australia) for helpful discussions about nuclear protein isolation from tissues and explants cultures. Portions of this work were presented in abstract form at the Annual Meeting of the Society for Gynecologic Investigation, March 26-29, 2008, San Diego, CA. This work was supported in part by NIH R01 HD35581 (DAK), The Ohio State University Perinatal Research and Development Fund, and Subcontract WSU07043 under National Institute of Child Health and Human Development Contract N01-HD-2-3342 and Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. WEA was supported by a Mentored Clinical Scientist Development Award (K08 HD049628). NR 39 TC 10 Z9 11 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD JAN 25 PY 2010 VL 8 AR 8 DI 10.1186/1477-7827-8-8 PG 12 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 577IT UT WOS:000276216900001 PM 20100341 ER PT J AU Jedidi, I Zhang, F Qiu, HF Stahl, SJ Palmer, I Kaufman, JD Nadaud, PS Mukherjee, S Wingfield, PT Jaroniec, CP Hinnebusch, AG AF Jedidi, Iness Zhang, Fan Qiu, Hongfang Stahl, Stephen J. Palmer, Ira Kaufman, Joshua D. Nadaud, Philippe S. Mukherjee, Sujoy Wingfield, Paul T. Jaroniec, Christopher P. Hinnebusch, Alan G. TI Activator Gcn4 Employs Multiple Segments of Med15/Gal11, Including the KIX Domain, to Recruit Mediator to Target Genes in Vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; TRANSCRIPTIONAL ACTIVATION; SACCHAROMYCES-CEREVISIAE; SRB MEDIATOR; AMINO-ACIDS; YEAST; HOLOENZYME; COMPLEX; ASSOCIATION AB Mediator is a multisubunit coactivator required for initiation by RNA polymerase II. The Mediator tail subdomain, containing Med15/Gal11, is a target of the activator Gcn4 in vivo, critical for recruitment of native Mediator or the Mediator tail subdomain present in sin4 Delta cells. Although several Gal11 segments were previously shown to bind Gcn4 in vitro, the importance of these interactions for recruitment of Mediator and transcriptional activation by Gcn4 in cells was unknown. We show that interaction of Gcn4 with the Mediator tail in vitro and recruitment of this subcomplex and intact Mediator to the ARG1 promoter in vivo involve additive contributions from three different segments in the N terminus of Gal11. These include the KIX domain, which is a critical target of other activators, and a region that shares a conserved motif (B-box) with mammalian coactivator SRC-1, and we establish that B-box is a critical determinant of Mediator recruitment by Gcn4. We further demonstrate that Gcn4 binds to the Gal11 KIX domain directly and, by NMR chemical shift analysis combined with mutational studies, we identify the likely binding site for Gcn4 on the KIX surface. Gcn4 is distinctive in relying on comparable contributions from multiple segments of Gal11 for efficient recruitment of Mediator in vivo. C1 [Jedidi, Iness; Zhang, Fan; Qiu, Hongfang; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Stahl, Stephen J.; Palmer, Ira; Kaufman, Joshua D.; Wingfield, Paul T.] NIAMS, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Nadaud, Philippe S.; Mukherjee, Sujoy; Jaroniec, Christopher P.] Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bldg 6A,Rm B1A-13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Jaroniec, Christopher/A-4948-2008; Mukherjee, Sujoy/E-5708-2011; OI Jaroniec, Christopher/0000-0003-0364-2888 FU National Institutes of Health; Ohio State University; Eli Lilly and Company FX This work was supported in part by the Intramural Research Program of the National Institutes of Health.; Supported by a grant from the Ohio State University and a Young Investigator Award from Eli Lilly and Company. NR 63 TC 28 Z9 28 U1 1 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 JAN 22 PY 2010 VL 285 IS 4 BP 2438 EP 2455 DI 10.1074/jbc.M109.071589 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544YP UT WOS:000273697800023 PM 19940160 ER PT J AU Hewitt, SC Li, Y Li, LP Korach, KS AF Hewitt, Sylvia C. Li, Yin Li, Leping Korach, Kenneth S. TI Estrogen-mediated Regulation of Igf1 Transcription and Uterine Growth Involves Direct Binding of Estrogen Receptor alpha to Estrogen-responsive Elements SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID I GENE-TRANSCRIPTION; CROSS-TALK; BREAST-CANCER; SIGNAL TRANSDUCERS; TRANSGENIC MICE; MOUSE UTERUS; PROLIFERATION; EXPRESSION; STAT5B; CELLS AB Estrogen enables uterine proliferation, which depends on synthesis of the IGF1 growth factor. This proliferation and IGF1 synthesis requires the estrogen receptor (ER), which binds directly to target DNA sequences (estrogen-responsive elements or EREs), or interacts with other transcription factors, such as AP1, to impact transcription. We observe neither uterine growth nor an increase in Igf1 transcript in a mouse with a DNA-binding mutated ER alpha (KIKO), indicating that both Igf1 regulation and uterine proliferation require the DNA binding function of the ER. We identified several potential EREs in the Igf1 gene, and chromatin immunoprecipitation analysis revealed ER alpha binding to these EREs in wild type but not KIKO chromatin. STAT5 is also reported to regulate Igf1; uterine Stat5a transcript is increased by estradiol (E(2)), but not in KIKO or alpha ERKO uteri, indicating ER alpha- and ERE-dependent regulation. ER alpha binds to a potential Stat5a ERE. We hypothesize that E2 increases Stat5a transcript through ERE binding; that ER alpha, either alone or together with STAT5, then acts to increase Igf1 transcription; and that the resulting lack of IGF1 impairs KIKO uterine growth. Treatment with exogenous IGF1, alone or in combination with E2, induces proliferation in wild type but not KIKO uteri, indicating that IGF1 replacement does not rescue the KIKO proliferative response. Together, these observations suggest in contrast to previous in vitro studies of IGF-1 regulation involving AP1 motifs that direct ER alpha-DNA interaction is required to increase Igf1 transcription. Additionally, full ER alpha function is needed to mediate other cellular signals of the growth factor for uterine growth. C1 [Hewitt, Sylvia C.; Li, Yin; Korach, Kenneth S.] NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Li, Leping] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM curtiss@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health [Z01ES70065, Z01ES101765] FX This work was supported, in whole or in part, by National Institutes of Health Grants Z01ES70065 (to K. S. K., S. C. H., and Y. L.) and Z01ES101765 (to L. L.). NR 46 TC 55 Z9 56 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 22 PY 2010 VL 285 IS 4 BP 2676 EP 2685 DI 10.1074/jbc.M109.043471 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544YP UT WOS:000273697800046 PM 19920132 ER PT J AU Fujiwara, I Remmert, K Hammer, JA AF Fujiwara, Ikuko Remmert, Kirsten Hammer, John A., III TI Direct Observation of the Uncapping of Capping Protein-capped Actin Filaments by CARMIL Homology Domain 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BARBED END; ARP2/3 COMPLEX; BINDING; DYNAMICS; MOTILITY; YEAST; POLYMERIZATION; IDENTIFICATION; NUCLEATION; MECHANISM AB Bulk solution assays have shown that the isolated CARMIL homology 3 (CAH3) domain from mouse and Acanthamoeba CARMIL rapidly and potently restores actin polymerization when added to actin filaments previously capped with capping protein (CP). To demonstrate this putative uncapping activity directly, we used total internal reflection microscopy to observe single, CP-capped actin filaments before and after the addition of the CAH3 domain from mouse CARMIL-1 (mCAH3). The addition of mCAH3 rapidly restored the polymerization of individual capped filaments, consistent with uncapping. To verify uncapping, filaments were capped with recombinant mouse CP tagged with monomeric green fluorescent protein (mGFP-CP). Restoration of polymerization upon the addition of mCAH3 was immediately preceded by the complete dissociation of mGFP-CP from the filament end, confirming the CAH3-driven uncapping mechanism. Quantitative analyses showed that the percentage of capped filaments that uncapped increased as the concentration of mCAH3 was increased, reaching a maximum of similar to 90% at similar to 250 nM mCAH3. Moreover, the time interval between mCAH3 addition and uncapping decreased as the concentration of mCAH3 increased, with the half-time of CP at the barbed end decreasing from similar to 30 min without mCAH3 to similar to 10 s with a saturating amount of mCAH3. Finally, using mCAH3 tagged with mGFP, we obtained direct evidence that the complex of CP and mCAH3 has a small but measurable affinity for the barbed end, as inferred from previous studies and kinetic modeling. We conclude that the isolated CAH3 domain of CARMIL (and presumably the intact molecule as well) possesses the ability to uncap CP-capped actin filaments. C1 [Fujiwara, Ikuko; Remmert, Kirsten; Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Rm 2523,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov RI Fujiwara, Ikuko/H-5717-2016; OI Fujiwara, Ikuko/0000-0002-9361-636X; Hammer, John/0000-0002-2496-5179 NR 39 TC 28 Z9 28 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 JAN 22 PY 2010 VL 285 IS 4 BP 2707 EP 2720 DI 10.1074/jbc.M109.031203 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544YP UT WOS:000273697800049 PM 19926785 ER PT J AU Nasu-Nishimura, Y Jaffe, H Isaac, JTR Roche, KW AF Nasu-Nishimura, Yukiko Jaffe, Howard Isaac, John T. R. Roche, Katherine W. TI Differential Regulation of Kainate Receptor Trafficking by Phosphorylation of Distinct Sites on GluR6 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EXCITATORY SYNAPTIC-TRANSMISSION; MOSSY FIBER SYNAPSES; ER RETENTION SIGNAL; PROTEIN-KINASE-C; SURFACE EXPRESSION; GLUTAMATE RELEASE; THALAMOCORTICAL SYNAPSES; ENDOPLASMIC-RETICULUM; MOLECULAR-MECHANISMS; SPLICE VARIANTS AB Kainate receptors are widely expressed in the brain, and are present at pre- and postsynaptic sites where they play a prominent role in synaptic plasticity and the regulation of network activity. Within individual neurons, kainate receptors of different subunit compositions are targeted to various locations where they serve distinct functional roles. Despite this complex targeting, relatively little is known about the molecular mechanisms regulating kainate receptor subunit trafficking. Here we investigate the role of phosphorylation in the trafficking of the GluR6 kainate receptor subunit. We identify two specific residues on the GluR6 C terminus, Ser(846) and Ser(868), which are phosphorylated by protein kinase C(PKC) and dramatically regulate GluR6 surface expression. By using GluR6 containing phosphomimetic and nonphosphorylatable mutations for these sites expressed in heterologous cells or in neurons lacking endogenous GluR6, we show that phosphorylation of Ser(846) or Ser(868) regulates receptor trafficking through the biosynthetic pathway. Additionally, Ser(846) phosphorylation dynamically regulates endocytosis of GluR6 at the plasma membrane. Our findings thus demonstrate that phosphorylation of PKC sites on GluR6 regulates surface expression of GluR6 at distinct intracellular trafficking pathways, providing potential molecular mechanisms for the PKC-dependent regulation of synaptic kainate receptor function observed during various forms of synaptic plasticity. C1 [Nasu-Nishimura, Yukiko; Jaffe, Howard; Isaac, John T. R.; Roche, Katherine W.] NINDS, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), Bldg 35,Rm 2C903, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov OI Roche, Katherine/0000-0001-7282-6539 FU National Institutes of Health; Japan Society for the Promotion of Science FX This work was supported, in whole or in part, by the National Institutes of Health NINDS Intramural Research Program and a Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at National Institutes of Health. NR 48 TC 21 Z9 21 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 JAN 22 PY 2010 VL 285 IS 4 BP 2847 EP 2856 DI 10.1074/jbc.M109.081141 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 544YP UT WOS:000273697800060 PM 19920140 ER PT J AU Taubner, LM Bienkiewicz, EA Copie, V Caughey, B AF Taubner, Lara M. Bienkiewicz, Ewa A. Copie, Valerie Caughey, Byron TI Structure of the Flexible Amino-Terminal Domain of Prion Protein Bound to a Sulfated Glycan SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE prion protein; octarepeats; NMR; circular dichroism; pentosan polysulfate ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; ULTRAVIOLET CIRCULAR-DICHROISM; SIDE-CHAIN RESONANCES; SECONDARY STRUCTURE; COPPER-BINDING; C-13-ENRICHED PROTEINS; N-15-LABELED PROTEINS; INSERTION MUTATIONS; C-13 MAGNETIZATION; COORDINATION MODES AB The intrinsically disordered amino-proximal domain of hamster prion protein (PrP) contains four copies of a highly conserved octapeptide sequence, PHGGGWGQ, that is flanked by two polycationic residue clusters. This N-terminal domain mediates the binding of sulfated glycans, which can profoundly influence the conversion of PrP to pathological forms and the progression of prion disease. To investigate the structural consequences of sulfated glycan binding, we performed multidimensional heteronuclear ((1)H, (13)C, (15)N) NMR (nuclear magnetic resonance), circular dichroism (CD), and fluorescence studies on hamster PrP residues 23-106 (PrP 23-106) and fragments thereof when bound to pentosan polysulfate (PPS). While the majority of PrP 23-106 remain disordered upon PPS binding, the octarepeat region adopts a repeating loop-turn structure that we have determined by NMR. The beta-like turns within the repeats are corroborated by CD data demonstrating that these turns are also present, although less pronounced, without PPS. Binding to PPS exposes a hydrophobic surface composed of aligned tryptophan side chains, the spacing and orientation of which are consistent with a self-association or ligand binding site. The unique tryptophan motif was probed by intrinsic tryptophan fluorescence, which displayed enhanced fluorescence of PrP 23-106 when bound to PPS, consistent with the alignment of tryptophan side chains. Chemical-shift mapping identified binding sites on PrP 23-106 for PPS, which include the octarepeat histidine and an N-terminal basic cluster previously linked to sulfated glycan binding. These data may in part explain how sulfated glycans modulate PrP conformational conversions and oligomerizations. Published by Elsevier Ltd. C1 [Taubner, Lara M.; Caughey, Byron] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Bienkiewicz, Ewa A.] Florida State Univ, Dept Biomed Sci, Coll Med, Tallahassee, FL 32306 USA. [Copie, Valerie] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. RP Taubner, LM (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM taubnerl@niaid.nih.gov OI Bienkiewicz, Ewa/0000-0002-5282-6360 FU National Institutes of Health [1-S10RR13878-01] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the Florida State University Council on Research and Creativity (Planning Grant awarded to E.A.B.). The NMR experiments were carried out at the Montana State University NMR Facility on the DRX-600 purchased with funds from the National Institutes of Health (SIG grant 1-S10RR13878-01). We appreciate the critical review of the manuscript conducted by Drs. Suzette Priola, Roger Moore, and Jonathan Speare and the technical assistance provided by Greg Raymond and Lynne Raymond. We thank Drs. John McEwan and David Cullis-Hill of Biopharm Australia for the PPS used in our studies. We also acknowledge Gary Hettrick for his assistance with figure preparation and the Biomedical Proteomics Laboratory of the Florida State Univesity College of Medicine for use of the UV/Vis spectroscopy (Cary 300, Varian, Inc.) and fluorescence (Eclipse, Varian, Inc.) instrumentation. NR 89 TC 28 Z9 29 U1 1 U2 18 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 22 PY 2010 VL 395 IS 3 BP 475 EP 490 DI 10.1016/j.jmb.2009.10.075 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 550ST UT WOS:000274150700003 PM 19913031 ER PT J AU Ellis, RD Martin, LB Shaffer, D Long, CA Miura, K Fay, MP Narum, DL Zhu, DM Mullen, GED Mahanty, S Miller, LH Durbin, AP AF Ellis, Ruth D. Martin, Laura B. Shaffer, Donna Long, Carole A. Miura, Kazutoyo Fay, Michael P. Narum, David L. Zhu, Daming Mullen, Gregory E. D. Mahanty, Siddhartha Miller, Louis H. Durbin, Anna P. TI Phase 1 Trial of the Plasmodium falciparum Blood Stage Vaccine MSP1(42)-C1/Alhydrogel with and without CPG 7909 in Malaria Naive Adults SO PLOS ONE LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; APICAL MEMBRANE ANTIGEN-1; MONTANIDE ISA 720; ANTIBODY-RESPONSES; HEALTHY-ADULTS; TLR9 AGONIST; PROTECTION; SAFETY; IMMUNOGENICITY; ADJUVANT AB Background: Merozoite surface protein 1(42) (MSP1(42)) is a leading blood stage malaria vaccine candidate. In order to induce immune responses that cover the major antigenic polymorphisms, FVO and 3D7 recombinant proteins of MSP1(42) were mixed (MSP1(42)-C1). To improve the level of antibody response, MSP1(42)-C1 was formulated with Alhydrogel plus the novel adjuvant CPG 7909. Methods: A Phase 1 clinical trial was conducted in healthy malaria-naive adults at the Center for Immunization Research in Washington, D. C., to evaluate the safety and immunogenicity of MSP1(42)-C1/Alhydrogel +/- CPG 7909. Sixty volunteers were enrolled in dose escalating cohorts and randomized to receive three vaccinations of either 40 or 160 mu g protein adsorbed to Alhydrogel +/- 560 mu g CPG 7909 at 0, 1 and 2 months. Results: Vaccinations were well tolerated, with only one related adverse event graded as severe (Grade 3 injection site erythema) and all other vaccine related adverse events graded as either mild or moderate. Local adverse events were more frequent and severe in the groups receiving CPG. The addition of CPG enhanced anti-MSP1(42) antibody responses following vaccination by up to 49-fold two weeks after second immunization and 8-fold two weeks after the third immunization when compared to MSP1(42)-C1/Alhydrogel alone (p<0.0001). After the third immunization, functionality of the antibody was tested by an in vitro growth inhibition assay. Inhibition was a function of antibody titer, with an average of 3% (range -2 to 10%) in the non CPG groups versus 14% (3 to 32%) in the CPG groups. Conclusion/Significance: The favorable safety profile and high antibody responses induced with MSP1(42)-C1/Alhydrogel + CPG 7909 are encouraging. MSP1(42)-C1/Alhydrogel is being combined with other blood stage antigens and will be taken forward in a formulation adjuvanted with CPG 7909. C1 [Ellis, Ruth D.; Martin, Laura B.; Miura, Kazutoyo; Narum, David L.; Zhu, Daming; Mullen, Gregory E. D.; Mahanty, Siddhartha; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD USA. [Shaffer, Donna; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. RP Ellis, RD (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD USA. EM ellisru@niaid.nih.gov RI Martin, Laura/N-1789-2013; OI Martin, Laura/0000-0002-4431-4381; Fay, Michael P./0000-0002-8643-9625 FU National Institutes of Health, National Institute of Allergy and Infectious Disease; PATH Malaria Vaccine Initiative (MVI); United States Agency for International Development (USAID) FX This work was supported by the Intramural program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. Support for this project was provided in part by the PATH Malaria Vaccine Initiative (MVI), which also supports the Growth Inhibition Assay (GIA) Reference Center, and by the United States Agency for International Development (USAID) Malaria Vaccine Development Program through a cooperative agreement between USAID and MVI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 41 Z9 45 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 22 PY 2010 VL 5 IS 1 AR e8787 DI 10.1371/journal.pone.0008787 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NK UT WOS:000273896100005 PM 20107498 ER PT J AU Keller, MJ Mesquita, PMM Torres, NM Cho, S Shust, G Madan, RP Cohen, HW Petrie, J Ford, T Soto-Torres, L Profy, AT Herold, BC AF Keller, Marla J. Mesquita, Pedro M. M. Torres, N. Merna Cho, Sylvia Shust, Gail Madan, Rebecca P. Cohen, Hillel W. Petrie, Julie Ford, Tara Soto-Torres, Lydia Profy, Albert T. Herold, Betsy C. TI Postcoital Bioavailability and Antiviral Activity of 0.5% PRO 2000 Gel: Implications for Future Microbicide Clinical Trials SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RANDOMIZED CONTROLLED-TRIAL; HIV-INFECTION; CELLULOSE SULFATE; TOPICAL MICROBICIDES; SEMINAL PLASMA; VAGINAL GEL; HERPES; TRANSMISSION; CELL AB Background: The pharmacokinetics and pharmacodynamics of vaginal microbicides are typically assessed among sexually abstinent women. However, the physical act of sex may modulate gel distribution, and preclinical studies demonstrate seminal plasma interferes with the antiviral activity of several microbicides. This study compared the biological activity and concentration of PRO 2000 in cervicovaginal lavage (CVL) collected in the absence or following coitus. Methods: CVL samples were collected from ten heterosexual couples at baseline, after sex, after a single dose of 0.5% PRO 2000 gel and sex, and after gel application without sex. The impact of CVL on HIV-1 infection of TZM-bl cells and HSV-2 infection of CaSki cells was monitored by luciferase and plaque assay, respectively. PRO 2000 concentrations were measured by fluorescence. Results: CVL collected after PRO 2000 application significantly inhibited HIV-1 and HSV-2 (p = 0.01). However, the antiviral activity was reduced following sex and no significant protective effect was observed in postcoital CVL obtained in the presence compared to the absence of PRO 2000 for HIV (p = 0.45) or HSV-2 (p = 0.56). Less PRO 2000 was recovered in postcoital CVL, which, in conjunction with interference by seminal plasma, may have contributed to lower antiviral activity. Conclusions: Postcoital responses to PRO 2000 differ from precoital measures and the results obtained may provide insights into the clinical trial findings in which there was no significant protection against HIV-1 or HSV-2. Postcoital studies should be incorporated into clinical studies before embarking on large-scale efficacy trials. C1 [Keller, Marla J.; Petrie, Julie; Ford, Tara] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Keller, Marla J.; Herold, Betsy C.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Mesquita, Pedro M. M.; Torres, N. Merna; Cho, Sylvia; Shust, Gail; Madan, Rebecca P.; Herold, Betsy C.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Cohen, Hillel W.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Herold, Betsy C.] Albert Einstein Coll Med, Dept & Microbiol & Immunol, Bronx, NY 10467 USA. [Soto-Torres, Lydia] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Profy, Albert T.] Endo Pharmaceut, Chadds Ford, PA USA. RP Keller, MJ (reprint author), Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. EM betsy.herold@einstein.yu.edu OI Cohen, Hillel/0000-0002-4524-0898; Mesquita, Pedro/0000-0002-6591-4896 FU National Institutes of Health [AI077549, AI065309, UL1RR025750] FX This work was supported by grants from the National Institutes of Health (AI077549, AI065309 and UL1RR025750). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Indevus Pharmaceuticals (now Endo) provided PRO 2000 gel and is the employer of one of the co-authors, Al Profy. Their involvement does not alter our adherence to all the PLoS ONE policies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 45 Z9 46 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 22 PY 2010 VL 5 IS 1 AR e8781 DI 10.1371/journal.pone.0008781 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NK UT WOS:000273896100004 PM 20107502 ER PT J AU MacKellar, J Cushman, SW Periwal, V AF MacKellar, Jennifer Cushman, Samuel W. Periwal, Vipul TI Waves of Adipose Tissue Growth in the Genetically Obese Zucker Fatty Rat SO PLOS ONE LA English DT Article ID CELL-SIZE; ADIPOCYTE SIZE; INSULIN-RESISTANCE; IN-VITRO; CELLULARITY; HYPERPHAGIA; DEPOTS; GENES; DIET; MICE AB Background: In mammals, calories ingested in excess of those used are stored primarily as fat in adipose tissue; consistent ingestion of excess calories requires an enlargement of the adipose tissue mass. Thus, a dysfunction in adipose tissue growth may be a key factor in insulin resistance due to imbalanced fat storage and disrupted insulin action. Adipose tissue growth requires the recruitment and then the development of adipose precursor cells, but little is known about these processes in vivo. Methodology: In this study, adipose cell-size probability distributions were measured in two Zucker fa/fa rats over a period of 151 and 163 days, from four weeks of age, using micro-biopsies to obtain subcutaneous (inguinal) fat tissue from the animals. These longitudinal probability distributions were analyzed to assess the probability of periodic phenomena. Conclusions: Adipose tissue growth in this strain of rat exhibits a striking temporal periodicity of approximately 55 days. A simple model is proposed for the periodicity, with PPAR signaling driven by a deficit in lipid uptake capacity leading to the periodic recruitment of new adipocytes. This model predicts that the observed period will be diet-dependent. C1 [MacKellar, Jennifer; Cushman, Samuel W.] NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP MacKellar, J (reprint author), NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov RI Periwal, Vipul/I-1728-2012 FU National Institutes of Health, National Institute of Diabetes Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 15 Z9 16 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 22 PY 2010 VL 5 IS 1 AR e8197 DI 10.1371/journal.pone.0008197 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 547NK UT WOS:000273896100001 PM 20107501 ER PT J AU Einstein, TL Stasevich, TJ AF Einstein, Theodore L. Stasevich, Timothy J. TI Epitaxial Growth Writ Large SO SCIENCE LA English DT Editorial Material ID FILM GROWTH; MODEL C1 [Einstein, Theodore L.] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Stasevich, Timothy J.] NCI, Fluorescence Imaging Grp, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Einstein, TL (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM einstein@umd.edu; stasevicht@mail.nih.gov OI Einstein, Theodore L./0000-0001-6031-4923 NR 15 TC 13 Z9 13 U1 0 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 22 PY 2010 VL 327 IS 5964 BP 423 EP 424 DI 10.1126/science.1184947 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546BS UT WOS:000273783100026 PM 20093465 ER PT J AU Lucas, AH Rittenhouse-Olson, K Kronenberg, M Apicella, MA Wang, D Schreiber, JR Taylor, CE AF Lucas, A. H. Rittenhouse-Olson, K. Kronenberg, M. Apicella, M. A. Wang, D. Schreiber, J. R. Taylor, C. E. TI Carbohydrate moieties as vaccine candidates: Meeting summary SO VACCINE LA English DT Article DE Vaccine; Carbohydrate; Immunity; Tumor; Adjuvant ID BACILLUS-ANTHRACIS EXOSPORIUM; KILLER T-CELLS; TETRASACCHARIDE SIDE-CHAIN; NECROSIS-FACTOR FAMILY; MEMORY B-CELLS; CRYPTOCOCCUS-NEOFORMANS; MONOCLONAL-ANTIBODY; CHEMOENZYMATIC SYNTHESIS; MAJOR GLYCOPROTEIN; IMMUNE-RESPONSE AB In September 2007, a meeting entitled 'Carbohydrate Moieties as Vaccine Candidates' was held at the National Institutes of Health (Bethesda, MD) This meeting brought together scientists from a number of disciplines to address issues concerning carbohydrate moieties as targets for vaccines for a variety of pathogens and tumors In addition, the meeting participants addressed fundamental topics of glycoimmunology including the recognition of glycotopes by B and T lymphocytes, the ontogeny of anti-carbohydrate immune responses. peptide mimicry, carbohydrate antigen processing pathways and adjuvants One session reported progress in the development of new tools such as computational algorithms, glycan arrays and oligosaccharide synthesis and their application to carbohydrate vaccine research The session titles were (1) immune response to bacterial carbohydrate antigens; (2) immune response to glycolipids. (3) immune response to carbohydrate antigens on other microbes and on tumors, (4) novel vaccine approaches; (5) novel tools in carbohydrate vaccine research: (6) bench to bedside. carbohydrate moieties as vaccine immunopotentiators Published by Elsevier Ltd C1 [Lucas, A. H.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Rittenhouse-Olson, K.] SUNY Buffalo, Buffalo, NY 14260 USA. [Kronenberg, M.] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Apicella, M. A.] Univ Iowa, Iowa City, IA USA. [Wang, D.] Stanford Univ, Stanford, CA 94305 USA. [Schreiber, J. R.] Floating Hosp Children, Tufts Med Ctr, Boston, MA USA. [Taylor, C. E.] NIH, Bethesda, MD 20892 USA. RP Taylor, CE (reprint author), NIAID, Resp Dis Branch, Div Microbiol & Infect Dis, 6610 Rockledge Dr,Room 5045, Rockville, MD 20852 USA. FU NCI NIH HHS [U01 CA128416] NR 109 TC 9 Z9 10 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 JAN 22 PY 2010 VL 28 IS 4 BP 1121 EP 1131 DI 10.1016/j.vaccine.2008.05.055 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 560ZB UT WOS:000274943300039 PM 18579261 ER PT J AU Tang, Y Desierto, MJ Chen, JC Young, NS AF Tang, Yong Desierto, Marie J. Chen, Jichun Young, Neal S. TI The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELL; ANTI-THYMOCYTE GLOBULIN; APLASTIC-ANEMIA; IMMUNOSUPPRESSIVE THERAPY; ANTITHYMOCYTE GLOBULIN; INTERFERON-GAMMA; FAS ANTIGEN; CYCLOSPORINE; EXPRESSION; INFUSION AB The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet(-/-)). In comparison with normal C57BL6 (B6) control mice, T-bet(-/-) mice had normal cellular composition in lymphohematopoietic tissues, but T-bet(-/-) lymphocytes were functionally defective. Infusion of 5 x 10(6) T-bet(-/-) lymph node (LN) cells into sublethally irradiated, major histocompatibility complex-mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet(-/-) LN-cell dose to 10 to 23 x 10(6) per recipient led to only mild hematopoietic deficiency. Recipients of T-bet(-/-) LN cells had no expansion in T cells or interferon-gamma-producing T cells but showed a significant increase in Lin(-)Sca1(+)CD117(+)CD34(-) BM cells. Plasma transforming growth factor-beta and interleukin-17 concentrations were increased in T-bet(-/-) LN-cell recipients, possibly a compensatory upregulation of the Th17 immune response. Continuous infusion of interferon-gamma resulted in hematopoietic suppression but did not cause T-bet(-/-) LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure. (Blood. 2010; 115: 541-548) C1 [Tang, Yong; Desierto, Marie J.; Chen, Jichun; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 Clin Res Ctr Rm 3E-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM youngn@nhlbi.nih.gov NR 37 TC 16 Z9 21 U1 0 U2 3 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 JAN 21 PY 2010 VL 115 IS 3 BP 541 EP 548 DI 10.1182/blood-2009-03-211383 PG 8 WC Hematology SC Hematology GA 546OR UT WOS:000273820600015 PM 19903901 ER PT J AU Zhang, YQ De, S Garner, JR Smith, K Wang, SA Becker, KG AF Zhang, Yonqing De, Supriyo Garner, John R. Smith, Kirstin Wang, S. Alex Becker, Kevin G. TI Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information SO BMC MEDICAL GENOMICS LA English DT Article ID GENOME-WIDE ASSOCIATION; AUTISM SPECTRUM DISORDER; SET ENRICHMENT ANALYSIS; TRANSCRIPTION FACTOR; AUTOIMMUNE-DISEASES; COMPLEX DISEASES; CANDIDATE-GENE; EXPRESSION; PREDICTION; SUSCEPTIBILITY AB Background: The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods: In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results: Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion: This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease. C1 [Zhang, Yonqing; De, Supriyo; Garner, John R.; Smith, Kirstin; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Wang, S. Alex] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Becker, KG (reprint author), NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. EM beckerk@grc.nia.nih.gov OI De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU NIH, National Institute on Aging and Center for Information Technology FX The authors would like to thank Dr. Ilya Goldberg for helpful discussions, and Drs. Goldberg, David Schlessinger, and Chris Cheadle and for critical reading of the manuscript.; This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and Center for Information Technology. NR 58 TC 55 Z9 60 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD JAN 21 PY 2010 VL 3 AR 1 DI 10.1186/1755-8794-3-1 PG 22 WC Genetics & Heredity SC Genetics & Heredity GA 557OB UT WOS:000274677700001 PM 20092628 ER PT J AU Rosta, E Hummer, G AF Rosta, Edina Hummer, Gerhard TI Error and efficiency of simulated tempering simulations SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE Ising model; metastable states; molecular dynamics method; Monte Carlo methods; replica techniques ID EXCHANGE MOLECULAR-DYNAMICS; MONTE-CARLO DATA; REPLICA-EXCHANGE; FLUORESCENCE SPECTROSCOPY; FREE-ENERGY; SYSTEMS; TRANSITIONS; ALGORITHMS; CONSTANTS; WATER AB We derive simple analytical expressions for the error and computational efficiency of simulated tempering (ST) simulations. The theory applies to the important case of systems whose dynamics at long times is dominated by the slow interconversion between two metastable states. An extension to the multistate case is described. We show that the relative gain in efficiency of ST simulations over regular molecular dynamics (MD) or Monte Carlo (MC) simulations is given by the ratio of their reactive fluxes, i.e., the number of transitions between the two states summed over all ST temperatures divided by the number of transitions at the single temperature of the MD or MC simulation. This relation for the efficiency is derived for the limit in which changes in the ST temperature are fast compared to the two-state transitions. In this limit, ST is most efficient. Our expression for the maximum efficiency gain of ST simulations is essentially identical to the corresponding expression derived by us for replica exchange MD and MC simulations [E. Rosta and G. Hummer, J. Chem. Phys. 131, 165102 (2009)] on a different route. We find quantitative agreement between predicted and observed efficiency gains in a test against ST and replica exchange MC simulations of a two-dimensional Ising model. Based on the efficiency formula, we provide recommendations for the optimal choice of ST simulation parameters, in particular, the range and number of temperatures, and the frequency of attempted temperature changes. C1 [Rosta, Edina; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Rosta, E (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; OI Hummer, Gerhard/0000-0001-7768-746X; Rosta, Edina/0000-0002-9823-4766 FU NIDDK, NIH FX We thank Dr. Attila Szabo for many helpful and stimulating discussions and Dr. William Swope for discussions about the effects of integrators. This research was supported by the Intramural Research Program of the NIDDK, NIH. NR 34 TC 21 Z9 21 U1 0 U2 19 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 JAN 21 PY 2010 VL 132 IS 3 AR 034102 DI 10.1063/1.3290767 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 547LS UT WOS:000273890800005 PM 20095723 ER PT J AU Shemesh, N Ozarslan, E Basser, PJ Cohen, Y AF Shemesh, Noam Ozarslan, Evren Basser, Peter J. Cohen, Yoram TI Detecting diffusion-diffraction patterns in size distribution phantoms using double-pulsed field gradient NMR: Theory and experiments SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biodiffusion; biological NMR; biological tissues; emulsions; phantoms; porous materials; rocks ID SPIN-ECHO NMR; POROUS-MEDIA; MAGNETIC-FIELD; STRUCTURAL INFORMATION; PFG-NMR; EXPERIMENTAL PARAMETERS; RESTRICTED DIFFUSION; PGSE NMR; EMULSION SYSTEMS; ROTATIONAL ANGLE AB NMR observable nuclei undergoing restricted diffusion within confining pores are important reporters for microstructural features of porous media including, inter-alia, biological tissues, emulsions and rocks. Diffusion NMR, and especially the single-pulsed field gradient (s-PFG) methodology, is one of the most important noninvasive tools for studying such opaque samples, enabling extraction of important microstructural information from diffusion-diffraction phenomena. However, when the pores are not monodisperse and are characterized by a size distribution, the diffusion-diffraction patterns disappear from the signal decay, and the relevant microstructural information is mostly lost. A recent theoretical study predicted that the diffusion-diffraction patterns in double-PFG (d-PFG) experiments have unique characteristics, such as zero-crossings, that make them more robust with respect to size distributions. In this study, we theoretically compared the signal decay arising from diffusion in isolated cylindrical pores characterized by lognormal size distributions in both s-PFG and d-PFG methodologies using a recently presented general framework for treating diffusion in NMR experiments. We showed the gradual loss of diffusion-diffraction patterns in broadening size distributions in s-PFG and the robustness of the zero-crossings in d-PFG even for very large standard deviations of the size distribution. We then performed s-PFG and d-PFG experiments on well-controlled size distribution phantoms in which the ground-truth is well-known a priori. We showed that the microstructural information, as manifested in the diffusion-diffraction patterns, is lost in the s-PFG experiments, whereas in d-PFG experiments the zero-crossings of the signal persist from which relevant microstructural information can be extracted. This study provides a proof of concept that d-PFG may be useful in obtaining important microstructural features in samples characterized by size distributions. C1 [Shemesh, Noam; Cohen, Yoram] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Chem, IL-69778 Tel Aviv, Israel. [Ozarslan, Evren; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Cohen, Y (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Chem, IL-69778 Tel Aviv, Israel. EM ycohen@post.tau.ac.il RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011; OI Ozarslan, Evren/0000-0003-0859-1311; Shemesh, Noam/0000-0001-6681-5876 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX P.J.B and E.O. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 71 TC 36 Z9 36 U1 0 U2 14 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 JAN 21 PY 2010 VL 132 IS 3 AR 034703 DI 10.1063/1.3285299 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 547LS UT WOS:000273890800030 PM 20095748 ER PT J AU Barr, RG Bluemke, DA Ahmed, FS Carr, JJ Enright, PL Hoffman, EA Jiang, R Kawut, SM Kronmal, RA Lima, JAC Shahar, E Smith, LJ Watson, KE AF Barr, R. Graham Bluemke, David A. Ahmed, Firas S. Carr, J. Jeffery Enright, Paul L. Hoffman, Eric A. Jiang, Rui Kawut, Steven M. Kronmal, Richard A. Lima, Joao A. C. Shahar, Eyal Smith, Lewis J. Watson, Karol E. TI Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PULMONARY BLOOD-FLOW; CHRONIC COR-PULMONALE; RAY CT IMAGES; ATHEROSCLEROSIS MESA; MYOCARDIAL MASS; LUNG-DISEASE; CARDIAC CT; MILD COPD; HYPERTENSION; SMOKERS AB BACKGROUND Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease. METHODS We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects. RESULTS Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction. CONCLUSIONS In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction. C1 [Barr, R. Graham; Ahmed, Firas S.; Jiang, Rui] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10032 USA. [Barr, R. Graham; Jiang, Rui] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Carr, J. Jeffery] Wake Forest Univ, Dept Radiol, Winston Salem, NC 27109 USA. [Enright, Paul L.; Shahar, Eyal] Univ Arizona, Div Epidemiol & Biostat, Tucson, AZ USA. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Kawut, Steven M.] Univ Penn, Sch Med, Penn Cardiovasc Inst, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Smith, Lewis J.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Watson, Karol E.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. RP Barr, RG (reprint author), Columbia Univ, Med Ctr, Div Gen Med, 630 W 168th St,PH 9 E,Rm 105, New York, NY 10032 USA. EM rgb9@columbia.edu RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Smith, Lewis J/0000-0002-4728-1562; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC95159, N01HC95169]; Pfizer; Toshiba Medical Systems and General Electric; [R01-HL077612]; [R01-HL075476]; [R01-HL093081]; [UL1-RR02415] FX Supported by grants (R01-HL077612, R01-HL075476, and R01-HL093081) and contracts (N01-HC95159 through N01HC95169) from the National Heart, Lung, and Blood Institute, with additional support from UL1-RR02415.; Dr. Enright reports receiving consulting fees from Pfizer and Gilead; Dr. Hoffman, having equity ownership in and being a founder of VIDA Diagnostics and receiving lecture fees from Sanofi-Aventis, AstraZeneca, and Chiesi Pharmaceuticals; Dr. Kawut, receiving grant support from Pfizer; Dr. Lima, receiving grant support from Toshiba Medical Systems and General Electric; and Dr. Smith, receiving consulting fees from Merck and KarmelSonix. No other potential conflict of interest relevant to this article was reported. NR 57 TC 211 Z9 214 U1 0 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2010 VL 362 IS 3 BP 217 EP 227 DI 10.1056/NEJMoa0808836 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400008 PM 20089972 ER PT J AU Neaton, JD Levy, Y Lane, HC AF Neaton, James D. Levy, Yves Lane, H. Clifford CA INSIGHT ESPRIT & SILCAAT Sci Comm TI Interleukin-2 Therapy in Patients with HIV Infection REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Neaton, James D.] Univ Minnesota, Minneapolis, MN 55455 USA. [Levy, Yves] Hop Henri Mondor, F-94010 Creteil, France. [Lane, H. Clifford] NIAID, Bethesda, MD 20892 USA. RP Neaton, JD (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM jim@ccbr.umn.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2010 VL 362 IS 3 BP 271 EP 271 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400021 ER PT J AU Coulibaly, YI Nutman, TB Klion, AD AF Coulibaly, Yaya I. Nutman, Thomas B. Klion, Amy D. TI Doxycycline for Mansonella perstans Infection REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Coulibaly, Yaya I.] Univ Bamako, Bamako, Mali. [Nutman, Thomas B.; Klion, Amy D.] NIH, Bethesda, MD 20892 USA. RP Coulibaly, YI (reprint author), Univ Bamako, Bamako, Mali. EM aklion@niaid.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2010 VL 362 IS 3 BP 272 EP 272 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 545NE UT WOS:000273738400023 ER PT J AU Lee, C Lodwick, D Hurtado, J Pafundi, D LWilliams, J Bolch, WE AF Lee, Choonsik Lodwick, Daniel Hurtado, Jorge Pafundi, Deanna LWilliams, Jonathan Bolch, Wesley E. TI The UF family of reference hybrid phantoms for computational radiation dosimetry SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID PEDIATRIC-PATIENTS; HUMAN ANATOMY; MODELS; PATIENT; SERIES; CT; MORPHOMETRY; NEWBORN; ADULT AB Computational human phantoms are computer models used to obtain dose distributions within the human body exposed to internal or external radiation sources. In addition, they are increasingly used to develop detector efficiencies for in vivo whole-body counters. Two classes of computational human phantoms have been widely utilized for dosimetry calculation: stylized and voxel phantoms that describe human anatomy through mathematical surface equations and 3D voxel matrices, respectively. Stylized phantoms are flexible in that changes to organ position and shape are possible given avoidance of region overlap, while voxel phantoms are typically fixed to a given patient anatomy, yet can be proportionally scaled to match individuals of larger or smaller stature, but of equivalent organ anatomy. Voxel phantoms provide much better anatomical realism as compared to stylized phantoms which are intrinsically limited by mathematical surface equations. To address the drawbacks of these phantoms, hybrid phantoms based on non-uniform rational B-spline (NURBS) surfaces have been introduced wherein anthropomorphic flexibility and anatomic realism are both preserved. Researchers at the University of Florida have introduced a series of hybrid phantoms representing the ICRP Publication 89 reference newborn, 15 year, and adult male and female. In this study, six additional phantoms are added to the UF family of hybrid phantoms those of the reference 1 year, 5 year and 10 year child. Head and torso CT images of patients whose ages were close to the targeted ages were obtained under approved protocols. Major organs and tissues were segmented from these images using an image processing software, 3D-DOCTOR (TM). NURBS and polygon mesh surfaces were then used to model individual organs and tissues after importing the segmented organ models to the 3D NURBS modeling software, Rhinoceros (TM). The phantoms were matched to four reference datasets: (1) standard anthropometric data, (2) reference organ masses from ICRP Publication 89, (3) reference elemental compositions provided in ICRP 89 as well as ICRU Report 46, and (4) reference data on the alimentary tract organs given in ICRP Publications 89 and 100. Various adjustments and refinements to the organ systems of the previously described newborn, 15 year and adult phantoms are also presented. The UF series of hybrid phantoms retain the non-uniform scalability of stylized phantoms while maintaining the anatomical realism of patient-specific voxel phantoms with respect to organ shape, depth and inter-organ distance. While the final versions of these phantoms are in a voxelized format for radiation transport simulation, their primary format is given as NURBS and polygon mesh surfaces, thus permitting one to sculpt non-reference phantoms using the reference phantoms as an anatomic template. C1 [Bolch, Wesley E.] Univ Florida, Dept Nucl & Radiol, Gainesville, FL 32611 USA. [Bolch, Wesley E.] Univ Florida, Dept Biomed Engn, Gainesville, FL 32611 USA. [LWilliams, Jonathan] Univ Florida, Dept Radiol, Gainesville, FL 32611 USA. [Lodwick, Daniel; Hurtado, Jorge; Pafundi, Deanna] Univ Florida, Dept Nucl & Radiol Engn, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Bolch, WE (reprint author), Univ Florida, Dept Nucl & Radiol, Gainesville, FL 32611 USA. EM wbolch@ufl.edu RI Lee, Choonsik/C-9023-2015; OI Lee, Choonsik/0000-0003-4289-9870; Lodwick, Daniel/0000-0001-8434-2275 FU National Cancer Institute [RO1 CA116743, CO6 CA059267]; National Institute of Biomedical Imaging and Bioengineering [R01 EB00267]; Radiation Epidemiology Branch of NCI [HHS-N2612-0090-0098P]; TKC Integrated Services, Inc. [TKC 30-06-16601] FX This research was supported in part by grants RO1 CA116743 and CO6 CA059267 from the National Cancer Institute, Grant R01 EB00267 from the National Institute of Biomedical Imaging and Bioengineering, Contract HHS-N2612-0090-0098P from the Radiation Epidemiology Branch of NCI, and Contract TKC 30-06-16601 from TKC Integrated Services, Inc. NR 25 TC 101 Z9 104 U1 0 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 21 PY 2010 VL 55 IS 2 BP 339 EP 363 DI 10.1088/0031-9155/55/2/002 PG 25 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 535IG UT WOS:000272960400002 PM 20019401 ER PT J AU Denton, PW Krisko, JF Powell, DA Mathias, M Kwak, YT Martinez-Torres, F Zou, W Payne, DA Estes, JD Garcia, JV AF Denton, Paul W. Krisko, John F. Powell, Daniel A. Mathias, Melissa Kwak, Youn Tae Martinez-Torres, Francisco Zou, Wei Payne, Deborah A. Estes, Jacob D. Garcia, J. Victor TI Systemic Administration of Antiretrovirals Prior to Exposure Prevents Rectal and Intravenous HIV-1 Transmission in Humanized BLT Mice SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VAGINAL SHIV CHALLENGE; PREEXPOSURE PROPHYLAXIS; REVERSE-TRANSCRIPTASE; SEXUAL TRANSMISSION; IMMUNE-RESPONSES; SIV INFECTION; MACAQUES; CHEMOPROPHYLAXIS; VACCINE AB Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, high-risk women and men who have sex with men. Targeted antiretroviral PrEP could be particularly effective at slowing the spread of HIV-1 if a single antiretroviral combination were found to be broadly protective across multiple routes of transmission. Therefore, we designed our in vivo preclinical study to systematically investigate whether rectal and intravenous HIV-1 transmission can be blocked by antiretrovirals administered systemically prior to HIV-1 exposure. We performed these studies using a highly relevant in vivo model of mucosal HIV-1 transmission, humanized Bone marrow/Liver/Thymus mice (BLT). BLT mice are susceptible to HIV-1 infection via three major physiological routes of viral transmission: vaginal, rectal and intravenous. Our results show that BLT mice given systemic antiretroviral PrEP are efficiently protected from HIV-1 infection regardless of the route of exposure. Specifically, systemic antiretroviral PrEP with emtricitabine and tenofovir disoproxil fumarate prevented both rectal (Chi square = 8.6, df = 1, p = 0.003) and intravenous (Chi square = 13, df = 1, p = 0.0003) HIV-1 transmission. Our results indicate that antiretroviral PrEP has the potential to be broadly effective at preventing new rectal or intravenous HIV transmissions in targeted high risk individuals. These in vivo preclinical findings provide strong experimental evidence supporting the potential clinical implementation of antiretroviral based pre-exposure prophylactic measures to prevent the spread of HIV/AIDS. C1 [Denton, Paul W.; Krisko, John F.; Powell, Daniel A.; Mathias, Melissa; Kwak, Youn Tae; Martinez-Torres, Francisco; Zou, Wei; Garcia, J. Victor] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Payne, Deborah A.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Estes, Jacob D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Denton, PW (reprint author), Univ N Carolina, Ctr AIDS Res, Div Infect Dis, Chapel Hill, NC 27515 USA. EM victor_garcia@med.unc.edu OI Denton, Paul/0000-0003-2458-8147 FU National Institutes of Health [AI073146, AI071940, 5T32AI005284, HHSN266200400088C]; Foundation for AIDS Research (amfAR) [107183-44-RFRL]; UT Southwestern Summer Medical Student Research Program FX This work was supported in part with federal funds from National Institute of Allergy and Infectious Diseases, National Institutes of Health grants AI073146 and AI071940 (J. V. G.), 5T32AI005284 (J. F. K.), and the National Cancer Institute, National Institutes of Health, under contract HHSN266200400088C (J. E. D.). This work was supported in part by fellowship number 107183-44-RFRL from The Foundation for AIDS Research (amfAR) (P. W. D.). M. M. was supported by the UT Southwestern Summer Medical Student Research Program. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 82 Z9 84 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2010 VL 5 IS 1 AR e8829 DI 10.1371/journal.pone.0008829 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AJ UT WOS:000273779100020 PM 20098623 ER PT J AU Drgon, T Zhang, PW Johnson, C Walther, D Hess, J Nino, M Uhl, GR AF Drgon, Tomas Zhang, Ping-Wu Johnson, Catherine Walther, Donna Hess, Judith Nino, Michelle Uhl, George R. TI Genome Wide Association for Addiction: Replicated Results and Comparisons of Two Analytic Approaches SO PLOS ONE LA English DT Article ID SAMPLE-SIZE CALCULATIONS; CELL-ADHESION MOLECULES; MILD MENTAL IMPAIRMENT; NICOTINE DEPENDENCE; POOLED DNA; POLYSUBSTANCE ABUSERS; MACULAR DEGENERATION; SYNAPTIC PLASTICITY; VULNERABILITY LOCI; ALCOHOL DEPENDENCE AB Background: Vulnerabilities to dependence on addictive substances are substantially heritable complex disorders whose underlying genetic architecture is likely to be polygenic, with modest contributions from variants in many individual genes. "Nontemplate" genome wide association (GWA) approaches can identity groups of chromosomal regions and genes that, taken together, are much more likely to contain allelic variants that alter vulnerability to substance dependence than expected by chance. Methodology/Principal Findings: We report pooled "nontemplate" genome-wide association studies of two independent samples of substance dependent vs control research volunteers (n = 1620), one European-American and the other African-American using 1 million SNP (single nucleotide polymorphism) Affymetrix genotyping arrays. We assess convergence between results from these two samples using two related methods that seek clustering of nominally-positive results and assess significance levels with Monte Carlo and permutation approaches. Both "converge then cluster" and "cluster then converge" analyses document convergence between the results obtained from these two independent datasets in ways that are virtually never found by chance. The genes identified in this fashion are also identified by individually-genotyped dbGAP data that compare allele frequencies in cocaine dependent vs control individuals. Conclusions/Significance: These overlapping results identify small chromosomal regions that are also identified by genome wide data from studies of other relevant samples to extents much greater than chance. These chromosomal regions contain more genes related to "cell adhesion" processes than expected by chance. They also contain a number of genes that encode potential targets for anti-addiction pharmacotherapeutics. "Nontemplate" GWA approaches that seek chromosomal regions in which nominally-positive associations are found in multiple independent samples are likely to complement classical, "template" GWA approaches in which "genome wide" levels of significance are sought for SNP data from single case vs control comparisons. C1 [Drgon, Tomas; Zhang, Ping-Wu; Johnson, Catherine; Walther, Donna; Hess, Judith; Nino, Michelle; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Natl Inst Hlth Intramural Res Program, Baltimore, MD USA. RP Drgon, T (reprint author), Natl Inst Drug Abuse, Mol Neurobiol Branch, Natl Inst Hlth Intramural Res Program, Baltimore, MD USA. EM guhl@intra.nida.nih.gov FU National Institutes of Health (NIH) [U01 HG004422, U01HG004438, HHSN268200782096C] FX This study was fully supported by the National Institutes of Health (NIH) Intramural Research Program (National Institute on Drug Abuse). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research was supported financially by the NIH Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services. Support for dbGAP data came from the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422)/Gene Environment Association Studies (GENEVA) which received assistance with phenotype harmonization, genotype cleaning, and study coordination from the GENEVA Coordinating Center (U01 HG004446), assistance with data cleaning from the National Center for Biotechnology Information, and assistance with collection of datasets and samples by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Support for genotyping dbGAP samples at the Johns Hopkins University Center for Inherited Disease Research came through (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). dbGaP datasets were obtained at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id = phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. NR 58 TC 27 Z9 27 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2010 VL 5 IS 1 AR e8832 DI 10.1371/journal.pone.0008832 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AJ UT WOS:000273779100023 PM 20098672 ER PT J AU Heuett, WJ Periwal, V AF Heuett, William J. Periwal, Vipul TI Autoregulation of Free Radicals via Uncoupling Protein Control in Pancreatic beta-Cell Mitochondria SO BIOPHYSICAL JOURNAL LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; SKELETAL-MUSCLE MITOCHONDRIA; INDUCED INSULIN-SECRETION; PROTON LEAK; MINIMAL MODEL; DYSFUNCTION; METABOLISM; ACTIVATION; PARADIGM; OBESITY AB Pancreatic beta-cells sense the ambient blood-glucose concentration and secrete insulin to signal other tissues to take up glucose. Mitochondria play a key role in this response as they metabolize nutrients to produce ATP and reactive oxygen species (ROS), both of which are involved in insulin secretion signaling. Based on data available in the literature and previously developed mathematical models, we present a model of glucose-stimulated mitochondrial respiration, ATP synthesis, and ROS production and control in beta-cells. The model is consistent with a number of experimental observations reported in the literature. Most notably, it captures the nonlinear rise in the proton leak rate at high membrane potential and the increase in this leak due to uncoupling protein (UCP) activation by ROS. The functional forms used to model ROS production and UCP regulation yield insight into these mechanisms, as many details have not yet been unraveled in the experimental literature. We examine short- and long-term effects of UCP activation inhibition and changes in the mitochondrial density on mitochondrial responses to glucose. Results suggest increasing mitochondrial density while decreasing UCP activity may be an effective way to increase glucose-stimulated insulin secretion while decreasing oxidative stress. C1 [Heuett, William J.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Heuett, WJ (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM heuettw@niddk.nih.gov RI Periwal, Vipul/I-1728-2012 FU Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland FX This work Was Supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. NR 32 TC 7 Z9 7 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 20 PY 2010 VL 98 IS 2 BP 207 EP 217 DI 10.1016/j.bpj.2009.10.012 PG 11 WC Biophysics SC Biophysics GA 548OJ UT WOS:000273972700004 PM 20338842 ER PT J AU Calvo, E Sanchez-Vargas, I Favreau, AJ Barbian, KD Pham, VM Olson, KE Ribeiro, JMC AF Calvo, Eric Sanchez-Vargas, Irma Favreau, Amanda J. Barbian, Kent D. Pham, Van M. Olson, Kenneth E. Ribeiro, Jose M. C. TI An insight into the sialotranscriptome of the West Nile mosquito vector, Culex tarsalis SO BMC GENOMICS LA English DT Article ID ADULT FEMALE MOSQUITO; SALIVARY-GLAND TRANSCRIPTOME; YELLOW-FEVER MOSQUITO; HOST IMMUNE-RESPONSE; AEDES-AEGYPTI; ANOPHELES-GAMBIAE; CODON VOLATILITY; BINDING-PROTEIN; ARBOVIRUS TRANSMISSION; SEQUENCE ALIGNMENT AB Background: Saliva of adult female mosquitoes help sugar and blood feeding by providing enzymes and polypeptides that help sugar digestion, control microbial growth and counteract their vertebrate host hemostasis and inflammation. Mosquito saliva also potentiates the transmission of vector borne pathogens, including arboviruses. Culex tarsalis is a bird feeding mosquito vector of West Nile Virus closely related to C. quinquefasciatus, a mosquito relatively recently adapted to feed on humans, and the only mosquito of the genus Culex to have its sialotranscriptome so far described. Results: A total of 1,753 clones randomly selected from an adult female C. tarsalis salivary glands (SG) cDNA library were sequenced and used to assemble a database that yielded 809 clusters of related sequences, 675 of which were singletons. Primer extension experiments were performed in selected clones to further extend sequence coverage, allowing for the identification of 283 protein sequences, 80 of which code for putative secreted proteins. Conclusion: Comparison of the C. tarsalis sialotranscriptome with that of C. quinquefasciatus reveals accelerated evolution of salivary proteins as compared to housekeeping proteins. The average amino acid identity among salivary proteins is 70.1%, while that for housekeeping proteins is 91.2% (P < 0.05), and the codon volatility of secreted proteins is significantly higher than those of housekeeping proteins. Several protein families previously found exclusive of mosquitoes, including only in the Aedes genus have been identified in C. tarsalis. Interestingly, a protein family so far unique to C. quinquefasciatus, with 30 genes, is also found in C. tarsalis, indicating it was not a specific C. quinquefasciatus acquisition in its evolution to optimize mammal blood feeding. C1 [Calvo, Eric; Pham, Van M.; Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Sanchez-Vargas, Irma; Olson, Kenneth E.] Colorado State Univ, Dept Microbiol Immunol Pathol, Ft Collins, CO 80523 USA. [Favreau, Amanda J.; Barbian, Kent D.] NIAID, Rocky Mt Labs, Genom Unit, Res Technol Sect, Hamilton, MT 59840 USA. RP Ribeiro, JMC (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health [R01 AI46435] FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and NIH R01 AI46435 grant to KEO. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the government of the United States of America. We are grateful to NIAID intramural editor Brenda Rae Marshall for assistance. Because E. C., A.J.V, K. D. B, V. M. P, and J.M.C.R. are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U. S. subject to a government use license. NR 84 TC 20 Z9 23 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 20 PY 2010 VL 11 AR 51 DI 10.1186/1471-2164-11-51 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 557HK UT WOS:000274660000001 PM 20089177 ER PT J AU Lu, J Liu, Y AF Lu, Jian Liu, Yie TI Deletion of Ogg1 DNA glycosylase results in telomere base damage and length alteration in yeast SO EMBO JOURNAL LA English DT Article DE DNA glycosylase; oxidative guanine lesion telomere length ID NUCLEOTIDE EXCISION-REPAIR; ONE-ELECTRON OXIDATION; SACCHAROMYCES-CEREVISIAE; CATALYTIC SUBUNIT; GGG TRIPLETS; RAP1; RECOMBINATION; ELONGATION; HELICASE; REPLICATION AB Telomeres consist of short guanine-rich repeats. Guanine can be oxidized to 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). 8-oxoguanine DNA glycosylase (Ogg1) repairs these oxidative guanine lesions through the base excision repair (BER) pathway. Here we show that in Saccharomyces cerevisiae ablation of Ogg1p leads to an increase in oxidized guanine level in telomeric DNA. The ogg1 deletion (ogg1 Delta) strain shows telomere lengthening that is dependent on telomerase and/or Rad52p-mediated homologous recombination. 8-oxoG in telomeric repeats attenuates the binding of the telomere binding protein, Rap1p, to telomeric DNA in vitro. Moreover, the amount of telomere-bound Rap1p and Rif2p is reduced in ogg1 Delta strain. These results suggest that oxidized guanines may perturb telomere length equilibrium by attenuating telomere protein complex to function in telomeres, which in turn impedes their regulation of pathways engaged in telomere length maintenance. We propose that Ogg1p is critical in maintaining telomere length homoeostasis through telomere guanine damage repair, and that interfering with telomere length homoeostasis may be one of the mechanism(s) by which oxidative DNA damage inflicts the genome. The EMBO Journal (2010) 29, 398-409. doi: 10.1038/emboj.2009.355; Published online 26 November 2009 C1 [Lu, Jian; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Liu, Y (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Dr,Suite 100,Rm 06B121, Baltimore, MD 21224 USA. EM liuyie@mail.nih.gov RI Lu, Jian/G-8391-2011 OI Lu, Jian/0000-0001-6522-8485 FU NIA, National Institutes of Health FX We thank Dr Wei Yang for the structure analysis of Rap1's binding with telomeric 8-oxoG; Fang Zhou for technical assistance; Drs Anders Bystrom, Katherine L Friedman, Katsunori Sugimoto, Kyungiae Myung, Leticia Vega, Kurt Runge, and Antony Weil for providing yeast strains and plasmids; Drs Vilhelm Bohr, Lea Harrington, Katherine L Friedman, and Kyungiae Myung for their critical reading of the paper. This study was supported by funds from the Intramural Research Program of the NIA, National Institutes of Health. NR 73 TC 21 Z9 22 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 20 PY 2010 VL 29 IS 2 BP 398 EP 409 DI 10.1038/emboj.2009.355 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 545KO UT WOS:000273731200012 PM 19942858 ER PT J AU Zametkin, AJ AF Zametkin, Alan J. TI Dopamine Reward Pathway in Adult ADHD SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. RP Zametkin, AJ (reprint author), NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. EM zametkin@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 20 PY 2010 VL 303 IS 3 BP 232 EP 233 DI 10.1001/jama.2009.1998 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 544WM UT WOS:000273690600016 PM 20085952 ER PT J AU Volkow, ND Swanson, JM Newcorn, JH AF Volkow, Nora D. Swanson, James M. Newcorn, Jeffrey H. TI Dopamine Reward Pathway in Adult ADHD Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. [Swanson, James M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. [Newcorn, Jeffrey H.] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. RP Volkow, ND (reprint author), NIDA, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 20 PY 2010 VL 303 IS 3 BP 233 EP 234 DI 10.1001/jama.2009.2000 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 544WM UT WOS:000273690600018 ER PT J AU de Gramont, A Hubbard, J Shi, Q O'Connell, MJ Buyse, M Benedetti, J Bot, B O'Callaghan, C Yothers, G Goldberg, RM Blanke, CD Benson, A Deng, QQ Alberts, SR Andre, T Wolmark, N Grothey, A Sargent, D AF de Gramont, Aimery Hubbard, Joleen Shi, Qian O'Connell, Michael J. Buyse, Marc Benedetti, Jacqueline Bot, Brian O'Callaghan, Chris Yothers, Greg Goldberg, Richard M. Blanke, Charles D. Benson, Al Deng, Qiqi Alberts, Steven R. Andre, Thierry Wolmark, Norman Grothey, Axel Sargent, Daniel TI Association Between Disease-Free Survival and Overall Survival When Survival Is Prolonged After Recurrence in Patients Receiving Cytotoxic Adjuvant Therapy for Colon Cancer: Simulations Based on the 20,800 Patient ACCENT Data Set SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC COLORECTAL-CANCER; 18 RANDOMIZED-TRIALS; PHASE-III TRIAL; STAGE-II; 1ST-LINE TREATMENT; PLUS IRINOTECAN; END-POINTS; FLUOROURACIL; LEUCOVORIN; OXALIPLATIN AB Purpose We previously validated disease-free survival (DFS) as a surrogate for overall survival (OS) in fluorouracil-based adjuvant colon cancer clinical trials. New therapies have extended survival after recurrence from 1 to approximately 2 years. We examined the possible impact of this improvement on the DFS/OS association. Methods The Adjuvant Colon Cancer Endpoints (ACCENT) data set of 20,898 patients was analyzed. In an exploratory fashion, time from recurrence to death in patients experiencing recurrence was extended using several algorithms, and the association of DFS after 3 years of median follow-up and OS after varying lengths of follow-up (median of 5, 6, and 7 years) was assessed. Results Seven thousand four hundred two patients (35%) experienced recurrence. Median time from recurrence to death was 24 months in the hypothetical data sets. When times from recurrence to death were doubled, the association between treatment effects on DFS and 5-year OS was modest (R(2) = 0.51 for both 2- and 3-year DFS) but remained strong for DFS and 6-year OS (R(2) = 0.67 for both 2- and 3-year DFS) and 7-year OS (R(2) = 0.70 for both 2-and 3-year DFS). The reduced DFS/OS association with extended survival after recurrence was greater in stage II than stage III patients. Multiple simulations provided consistent findings. Conclusion Extended survival after recurrence reduces the association between treatment effects on 3-year DFS and 5-year OS, particularly in stage II patients; longer follow-up strengthens the association. In modern adjuvant trials, 6 or 7 years may be required to demonstrate OS improvements, further supporting DFS as the preferred primary end point for future adjuvant colon cancer clinical trials. C1 [Sargent, Daniel] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA. Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. Univ Minnesota, Minneapolis, MN USA. NSABP, Operat Off, Pittsburgh, PA USA. NSABP, Ctr Biostat, Pittsburgh, PA USA. SW Oncol Grp, Ctr Stat, Seattle, WA USA. Univ N Carolina, Chapel Hill, NC USA. Northwestern Univ, Chicago, IL 60611 USA. Hop St Antoine, Paris, France. Grp Hosp Pitie Salpetriere, F-75634 Paris, France. Int Inst Drug Dev, Louvain, Belgium. Queens Univ, Clin Trials Grp, Natl Canc Inst Canada, Kingston, ON, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. RP Sargent, D (reprint author), Mayo Clin, Div Med Oncol, 200 1st St SW, Rochester, MN 55905 USA. EM sargent.daniel@mayo.edu RI Goldberg , Richard/M-1311-2013; OI Bot, Brian/0000-0002-2412-6826; Yothers, Greg/0000-0002-7965-7333; Sargent, Daniel/0000-0002-2684-4741 FU National Cancer Institute, Bethesda, MD [CA25224, CA12027, CA69974, CA37372, CA69651] FX Supported by Grants No. CA25224, CA12027, CA69974, CA37372, and CA69651 from the National Cancer Institute, Bethesda, MD. NR 24 TC 37 Z9 38 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2010 VL 28 IS 3 BP 460 EP 465 DI 10.1200/JCO.2009.23.1407 PG 6 WC Oncology SC Oncology GA 544MY UT WOS:000273662700017 PM 20008641 ER PT J AU Croyle, RT AF Croyle, Robert T. TI Increasing the Effectiveness of Tobacco Quitlines SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID INTERVENTION; CESSATION; SMOKERS; TRIAL C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Rm 6138, Bethesda, MD 20892 USA. EM croyler@mail.nih.gov NR 8 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 20 PY 2010 VL 102 IS 2 BP 72 EP 73 DI 10.1093/jnci/djp476 PG 2 WC Oncology SC Oncology GA 549YO UT WOS:000274091200002 PM 20056954 ER PT J AU Grakalic, I Panlilio, LV Quiroz, C Schindler, CW AF Grakalic, I. Panlilio, L. V. Quiroz, C. Schindler, C. W. TI EFFECTS OF ORBITOFRONTAL CORTEX LESIONS ON COCAINE SELF-ADMINISTRATION SO NEUROSCIENCE LA English DT Article DE addiction; dysregulation; reinstatement; drug; food; rat ID STIMULUS-CONTROL ACCOUNT; PREFRONTAL CORTEX; DRUG-ADDICTION; DECISION-MAKING; RATS; TRANSITION; SEEKING; ABUSE; REINFORCEMENT; REINSTATEMENT AB Previous research has implicated limbic and prefrontal cortical areas in the control of drug-seeking behavior. The present study examined the effects of orbitofrontal-cortex (OFC) lesions on acquisition, dose-dependence, within-session patterning, and reinstatement of cocaine self-administration. Rats received OFC or sham lesions before or after acquisition (0.3 mg/kg/injection, paired with a visual stimulus), then were tested with a range of doses (0, 0.03, 0.1, 0.3 and 1). Compared to controls, rats lesioned before acquisition acquired the behavior sooner, responded more at low doses, and responded more on the first day of extinction. Rats that were lesioned after acquisition showed an even larger increase in responding (similar to 250%) at the lowest dose, and they also showed increased timeout responding and drug "loading" at low doses. Pre-acquisition lesions were tested and found to have no effect on cocaine-induced reinstatement. In parallel experiments examining effects of pre-acquisition OFC lesions on food-reinforced responding, lesions did not alter acquisition, maintenance, or reinstatement, but accelerated the course of extinction. The increased cocaine self-administration seen in OFC-lesioned rats did not resemble the dysregulated drug intake observed in long-access models of addiction but might be due to impaired response inhibition or impaired tracking of the reward value of drug-related cues. Published by Elsevier Ltd on behalf of IBRO. C1 [Grakalic, I.; Panlilio, L. V.; Quiroz, C.; Schindler, C. W.] NIDA, DHHS, NIH, Intramural Res Program, Baltimore, MD USA. RP Grakalic, I (reprint author), NIAAA, Div Neurosci & Behav, 5635 Fishers Lane,Room 2050,MSC 9304, Bethesda, MD 20892 USA. EM igrakalic@mail.nih.gov FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. NR 32 TC 8 Z9 9 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 20 PY 2010 VL 165 IS 2 BP 313 EP 324 DI 10.1016/j.neuroscience.2009.10.051 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 545IC UT WOS:000273724700003 PM 19879927 ER PT J AU Smirnov, MS Kiyatkin, EA AF Smirnov, M. S. Kiyatkin, E. A. TI COCAINE ACTION ON PERIPHERAL, NON-MONOAMINE NEURAL SUBSTRATES AS A TRIGGER OF ELECTROENCEPHALOGRAPHIC DESYNCHRONIZATION AND ELECTROMYOGRAPHIC ACTIVATION FOLLOWING IV ADMINISTRATION IN FREELY MOVING RATS SO NEUROSCIENCE LA English DT Article DE arousal; neural activation; sensory effects; cocaine methiodide; procaine; reinforcement ID POWER SPECTRAL-ANALYSIS; CENTRAL-NERVOUS-SYSTEM; INTRAVENOUS COCAINE; ENVIRONMENTAL STIMULI; DOPAMINE TRANSPORTER; POTASSIUM CHANNEL; CONSCIOUS RATS; RHESUS-MONKEYS; IN-VIVO; PROCAINE AB Many important physiological, behavioral and subjective effects of i.v. cocaine (COC) are exceptionally rapid and transient, suggesting a possible involvement of peripheral neural substrates in their triggering. In the present study, we used high-speed electroencephalographic (EEG) and electromyographic (EMG) recordings (4-s resolution) in freely moving rats to characterize the central electrophysiological effects of i.v. COC at low doses within a self-administration range (0.25-1.0 mg/kg). We found that COC induces rapid, strong, and prolonged desynchronization of cortical EEG (decrease in alpha and increase in beta and gamma activity) and activation of the neck EMG that begin within 2-6 s following the start of a 10-s injection; immediate components of both effects were dose-independent. The rapid effects of COC were mimicked by i.v. COC methiodide (COC-MET), a derivative that cannot cross the blood-brain barrier. At equimolar doses (0.33-1.33 mg/kg), COC-MET had equally fast and strong effects on EEG and EMG total powers, decreasing alpha and increasing beta and gamma activities. Rapid EEG desynchronization and EMG activation was also induced by i.v. procaine, a structurally similar, short-acting local anesthetic with virtually no effects on monoamine uptake; at equipotential doses (1.25-5.0 mg/kg), these effects were weaker and shorter in duration than those of COC. Surprisingly, i.v. saline injection delivered during slow-wave sleep (but not during quiet wakefulness) also induced a transient EEG desynchronization but without changes in EMG and motor activity; these effects were significantly weaker and much shorter than those induced by all tested drugs. These data suggest that in awake animals, i.v. COC induces rapid cortical activation and a subsequent motor response via its action on peripheral non-monoamine neural elements, involving neural transmission via visceral sensory pathways. By providing a rapid neural signal and triggering neural activation, such an action might play a crucial role in the sensory effects of COC, thus contributing to the learning and development of drug-taking behavior. Published by Elsevier Ltd on behalf of IBRO. C1 [Smirnov, M. S.; Kiyatkin, E. A.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov OI Smirnov, Michael/0000-0003-2248-8863 FU NIH, NIDA FX The research described in this manuscript was supported by the Intramural Research Program of the NIH, NIDA. NR 65 TC 3 Z9 3 U1 3 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 20 PY 2010 VL 165 IS 2 BP 500 EP 514 DI 10.1016/j.neuroscience.2009.10.037 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 545IC UT WOS:000273724700021 PM 19861149 ER PT J AU Lewis, SS Hutchinson, MR Rezvani, N Loram, LC Zhang, Y Maier, SF Rice, KC Watkins, LR AF Lewis, S. S. Hutchinson, M. R. Rezvani, N. Loram, L. C. Zhang, Y. Maier, S. F. Rice, K. C. Watkins, L. R. TI EVIDENCE THAT INTRATHECAL MORPHINE-3-GLUCURONIDE MAY CAUSE PAIN ENHANCEMENT VIA TOLL-LIKE RECEPTOR 4/MD-2 AND INTERLEUKIN-1 beta SO NEUROSCIENCE LA English DT Article DE minocycline; 17-DMAG; (+)-naloxone; nonstereoselective; allodynia; hyperalgesia ID PROINFLAMMATORY CYTOKINE EXPRESSION; HIV-1 ENVELOPE GLYCOPROTEIN; NEUROPATHIC PAIN; MECHANICAL ALLODYNIA; MORPHINE-METABOLISM; ACTIVATION; RATS; PHARMACOLOGY; HYPERALGESIA; ANALGESIA AB Morphine-3-glucoronide (M3G) is a major morphine metabolite detected in cerebrospinal fluid of humans receiving systemic morphine. M3G has little-to-no affinity for opioid receptors and induces pain by unknown mechanisms. The pain-enhancing effects of M3G have been proposed to significantly and progressively oppose morphine analgesia as metabolism ensues. We have recently documented that morphine activates toll-like receptor 4 (TLR4), beyond its classical actions on mu-opioid receptors. This suggests that M3G may similarly activate TLR4. This activation could provide a novel mechanism for M3G-mediated pain enhancement, as (a) TLR4 is predominantly expressed by microglia in spinal cord and (b) TLR4 activation releases pain-enhancing substances, including interieukin-1 (IL-1). We present in vitro evidence that M3G activates TLR4, an effect blocked by TLR4 inhibitors, and that M3G activates microglia to produce IL-1. In vivo, intrathecal M3G (0.75 mu g) induced potent allodynia and hyperalgesia, blocked or reversed by interleukin-1 receptor antagonist, minocycline (microglial inhibitor), and (+)-and (-)-naloxone. This latter study extends our prior demonstrations that TLR4 signaling is inhibited by naloxone nonstereoselectively. These results with (+)-and (-)-naloxone also demonstrate that the effects cannot be accounted for by actions at classical, stereoselective opioid receptors. Hyperalgesia (allodynia was not tested) and in vitro M3G-induced TLR4 signaling were both blocked by 17-DMAG, an inhibitor of heat shock protein 90 (HSP90) that can contribute to TLR4 signaling. Providing further evidence of proinflammatory activation, M3G upregulated TLR4 and CD11b (microglial/macrophage activation marker) mRNAs in dorsal spinal cord as well as IL-1 protein in the lumbosacral cerebrospinal fluid. Finally, in silico and in vivo data support that the glucuronic acid moiety is capable of inducing TLR4/MD-2 activation and enhanced pain. These data provide the first evidence for a TLR4 and IL-1 mediated component to M3G-induced effects, likely of at least microglial origin. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Lewis, S. S.; Hutchinson, M. R.; Rezvani, N.; Loram, L. C.; Zhang, Y.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Hutchinson, M. R.] Univ Adelaide, Sch Med Sci, Discipline Pharmacol, Adelaide, SA, Australia. [Rice, K. C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, K. C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Lewis, SS (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. EM susannah.lewis@colorado.edu RI Hutchinson, Mark/G-4147-2014 OI Hutchinson, Mark/0000-0003-2154-5950 FU International Association for the Study of Pain; American Australian Association Merck Company Foundation; National Health and Medical Research Council [465423]; NIH [DA015642, DA024044, DE017782]; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship (ID 465423; M.R.H.) and NIH Grants DA015642, DA024044, and DE017782. This work was partially supported by the by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. We thank Avigen (Alameda, CA, USA) for the gift of the HEK293-TLR4 cell line. NR 44 TC 66 Z9 70 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 20 PY 2010 VL 165 IS 2 BP 569 EP 583 DI 10.1016/j.neuroscience.2009.10.011 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 545IC UT WOS:000273724700028 PM 19833175 ER PT J AU Krasnova, IN Justinova, Z Ladenheim, B Jayanthi, S McCoy, MT Barnes, C Warner, JE Goldberg, SR Cadet, JL AF Krasnova, Irina N. Justinova, Zuzana Ladenheim, Bruce Jayanthi, Subramaniam McCoy, Michael T. Barnes, Chanel Warner, John E. Goldberg, Steven R. Cadet, Jean Lud TI Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat SO PLOS ONE LA English DT Article ID BRAIN-SEROTONIN TRANSPORTER; INDUCED NEUROTOXICITY; INTRAVENOUS METHAMPHETAMINE; NEUROCHEMICAL CONSEQUENCES; TYROSINE-HYDROXYLASE; AMPHETAMINE ABUSE; OXIDATIVE STRESS; NULL MUTATION; USERS; IMPAIRMENT AB Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers. C1 [Krasnova, Irina N.; Justinova, Zuzana; Ladenheim, Bruce; Jayanthi, Subramaniam; McCoy, Michael T.; Barnes, Chanel; Warner, John E.; Goldberg, Steven R.; Cadet, Jean Lud] NIDA, NIH, Baltimore, MD USA. [Justinova, Zuzana] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Krasnova, IN (reprint author), NIDA, NIH, Baltimore, MD USA. EM jcadet@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011 OI Justinova, Zuzana/0000-0001-5793-7484 FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services of the United States of America FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services of the United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript. NR 68 TC 52 Z9 52 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2010 VL 5 IS 1 AR e8790 DI 10.1371/journal.pone.0008790 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AI UT WOS:000273779000018 PM 20098750 ER PT J AU Ott, PA Hamilton, A Jones, A Haas, N Shore, T Liddell, S Christos, PJ Doyle, LA Millward, M Muggia, FM Pavlick, AC AF Ott, Patrick A. Hamilton, Anne Jones, Amanda Haas, Naomi Shore, Tsiporah Liddell, Sandra Christos, Paul J. Doyle, L. Austin Millward, Michael Muggia, Franco M. Pavlick, Anna C. TI A Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) in Patients with Metastatic Melanoma SO PLOS ONE LA English DT Article ID ADVANCED MALIGNANT-MELANOMA; COOPERATIVE-ONCOLOGY-GROUP; DOCETAXEL TAXOTERE; PROSTATE-CANCER; CLINICAL-TRIALS; SOLID TUMORS; CHEMOTHERAPY; ANTHRACYCLINE; PACLITAXEL; TAXANE AB Background: Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naive ( previously untreated) and previously treated patients with metastatic melanoma. Methodology/Principal Findings: Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea. Conclusions/Significance: Ixabepilone has no meaningful activity in either chemotherapy-naive (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted. C1 [Ott, Patrick A.; Jones, Amanda; Muggia, Franco M.; Pavlick, Anna C.] NYU, Inst Canc, Dept Med Oncol, New York, NY 10012 USA. [Hamilton, Anne; Liddell, Sandra] Royal Prince Alfred Hosp, Sydney Canc Ctr, Sydney, NSW, Australia. [Hamilton, Anne] Sydney Melanoma Unit, Sydney, NSW, Australia. [Hamilton, Anne] Univ Sydney, Sydney, NSW 2006, Australia. [Haas, Naomi] Univ Penn, Abramson Canc Ctr, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Shore, Tsiporah] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY USA. [Shore, Tsiporah] New York Presbyterian Hosp, New York, NY USA. [Christos, Paul J.] Weill Cornell Med Coll, Div Biostat & Epidemiol, New York, NY USA. [Doyle, L. Austin] NCI, Invest Drug Branch, Bethesda, MD 20892 USA. [Millward, Michael] Charles Gairdner Hosp, Dept Med Oncol, Perth, WA, Australia. [Millward, Michael] Univ Western Australia, Perth, WA 6009, Australia. RP Ott, PA (reprint author), NYU, Inst Canc, Dept Med Oncol, New York, NY 10012 USA. EM anna.pavlick@nyumc.org RI Millward, Michael/H-5456-2014; OI Muggia, Franco/0000-0003-0703-9146 FU United States Department of Health and Human Service [N01-CM-62204]; United States National Institutes of Health [1U01 CA76642] FX Funding was provided by the United States Department of Health and Human Service contract N01-CM-62204 (P.I. Joseph A. Sparano, MD) and United States National Institutes of Health grant 1U01 CA76642 (P.I. Franco Muggia, MD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 10 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2010 VL 5 IS 1 AR e8714 DI 10.1371/journal.pone.0008714 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AI UT WOS:000273779000006 PM 20098694 ER PT J AU Drazen, JM Van Der Weyden, MB Sahni, P Rosenberg, J Marusic, A Laine, C Kotzin, S Horton, R Hebert, PC Haug, C Godlee, F Frizelle, FA de Leeuw, PW DeAngelis, CD AF Drazen, Jeffrey M. Van Der Weyden, Martin B. Sahni, Peush Rosenberg, Jacob Marusic, Ana Laine, Christine Kotzin, Sheldon Horton, Richard Hebert, Paul C. Haug, Charlotte Godlee, Fiona Frizelle, Frank A. de Leeuw, Peter W. DeAngelis, Catherine D. TI Uniform Format for Disclosure of Competing Interests in ICMJE Journals SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Kotzin, Sheldon] Natl Lib Med, Bethesda, MD 20894 USA. [Laine, Christine] Amer Coll Physicians, Philadelphia, PA 19106 USA. RP Laine, C (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. EM claine@mail.acponline.org RI Marusic, Ana/E-7683-2013 OI Marusic, Ana/0000-0001-6272-0917 NR 0 TC 5 Z9 5 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 19 PY 2010 VL 152 IS 2 BP 125 EP 126 DI 10.7326/0000605-200901190-00160 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 548IE UT WOS:000273953000009 PM 20083831 ER PT J AU Cheung, HH Lee, TL Davis, AJ Taft, DH Rennert, OM Chan, WY AF Cheung, H. H. Lee, T. L. Davis, A. J. Taft, D. H. Rennert, O. M. Chan, W. Y. TI Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE DNA methylation; MeDIP-chip; non-coding RNA; intergenic and intronic DMR; TGCT ID GERM-CELL TUMORS; CPG ISLAND METHYLATION; COLORECTAL-CANCER; IN-VITRO; EXPRESSION; MICRORNAS; METASTASIS; PROTOCADHERIN-10; ARABIDOPSIS; CARCINOMAS AB BACKGROUND: Testicular germ cell tumour (TGCT) is the most common malignant tumour in young males. Although aberrant DNA methylation is implicated in the pathophysiology of many cancers, only a limited number of genes are known to be epigenetically changed in TGCT. This report documents the genome-wide analysis of differential methylation in an in vitro model culture system. Interesting genes were validated in TGCT patient samples. METHODS: In this study, we used methylated DNA immunoprecipitation (MeDIP) and whole-genome tiling arrays to identify differentially methylated regions (DMRs). RESULTS: We identified 35 208 DMRs. However, only a small number of DMRs mapped to promoters. A genome-wide analysis of gene expression revealed a group of differentially expressed genes that were regulated by DNA methylation. We identified several candidate genes, including APOLD1, PCDH10 and RGAG1, which were dysregulated in TGCT patient samples. Surprisingly, APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis. We also observed aberrant methylation in the loci of some non-coding RNAs (ncRNAs). One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples, and also in our in vitro model culture system. CONCLUSION: This report is the first application of MeDIP-chip for identifying epigenetically regulated genes and ncRNAs in TGCT. We also demonstrated the function of intergenic and intronic DMRs in the regulation of ncRNAs. British Journal of Cancer (2010) 102, 419-427. doi:10.1038/sj.bjc.6605505 www.bjcancer.com Published online 5 January 2010 (C) 2010 Cancer Research UK C1 [Cheung, H. H.; Lee, T. L.; Davis, A. J.; Taft, D. H.; Rennert, O. M.; Chan, W. Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Clin Genom, Sect Dev Genom, NIH, Bethesda, MD 20892 USA. [Cheung, H. H.; Chan, W. Y.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. RP Chan, WY (reprint author), NICHD, Lab Clin Genom, NIH, 49 Convent Dr,MSC4429,Bldg 49,Room 2A08, Bethesda, MD 20892 USA. EM chanwy@cuhk.edu.hk RI Cheung, Hoi-Hung/G-7605-2011; Lee, Tin-Lap/A-7853-2009; OI Lee, Tin-Lap/0000-0002-6654-0988; Davis, Andrew/0000-0001-9556-4498 FU National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 45 TC 76 Z9 78 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 19 PY 2010 VL 102 IS 2 BP 419 EP 427 DI 10.1038/sj.bjc.6605505 PG 9 WC Oncology SC Oncology GA 545JO UT WOS:000273728500023 PM 20051947 ER PT J AU Kim, HS Patel, K Muldoon-Jacobs, K Bisht, KS Aykin-Burns, N Pennington, JD van der Meer, R Nguyen, P Savage, J Owens, KM Vassilopoulos, A Ozden, O Park, SH Singh, KK Abdulkadir, SA Spitz, DR Deng, CX Gius, D AF Kim, Hyun-Seok Patel, Krish Muldoon-Jacobs, Kristi Bisht, Kheem S. Aykin-Burns, Nukhet Pennington, J. Daniel van der Meer, Riet Nguyen, Phuongmai Savage, Jason Owens, Kjerstin M. Vassilopoulos, Athanassios Ozden, Ozkan Park, Seong-Hoon Singh, Keshav K. Abdulkadir, Sarki A. Spitz, Douglas R. Deng, Chu-Xia Gius, David TI SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress SO CANCER CELL LA English DT Article ID DNA-DAMAGE RESPONSE; GENE-EXPRESSION; BREAST-CANCER; DEPENDENT DEACETYLASE; CALORIE RESTRICTION; HISTOLOGIC GRADE; HOMOLOG; INSTABILITY; PATHWAYS; SIRTUINS AB The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3(-/-) mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3(-/-) MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3(-/-) MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3(-/-) mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor. C1 [Kim, Hyun-Seok; Vassilopoulos, Athanassios; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Patel, Krish; Muldoon-Jacobs, Kristi; Bisht, Kheem S.; Pennington, J. Daniel; Nguyen, Phuongmai; Savage, Jason; Ozden, Ozkan; Park, Seong-Hoon; Gius, David] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Aykin-Burns, Nukhet; Spitz, Douglas R.] Univ Iowa, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA. [van der Meer, Riet; Abdulkadir, Sarki A.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. [Gius, David] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA. [Owens, Kjerstin M.; Singh, Keshav K.] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM chuxiad@mail.nih.gov; david.gius@vanderbilt.edu RI deng, chuxia/N-6713-2016 FU National Institutes of Health [R01CA100045, R01CA133114, P30 CA086862, R01 121904, 116430, F30AG030839, CA094858, CA123484] FX This research was supported (in part) by the Intramural Research Program of the National Institute Diabetes and Digestive and Kidney Diseases, National Cancer Institute, and CCR, National Institutes of Health. D.R.S. and N.A.B. are supported by grants from the National Institutes of Health (R01CA100045, R01CA133114, and P30 CA086862). K.K.S. was supported by R01 121904 and 116430. J.D.S. was supported by F30AG030839. S.A.A. was supported by CA094858 and CA123484. We thank Melissa Stauffer, PhD, of Scientific Editing Solutions, for editorial assistance. NR 34 TC 333 Z9 348 U1 3 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JAN 19 PY 2010 VL 17 IS 1 BP 41 EP 52 DI 10.1016/j.ccr.2009.11.023 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 554YA UT WOS:000274471300008 PM 20129246 ER PT J AU Schnabel, RB Larson, MG Yamamoto, JF Sullivan, LM Pencina, MJ Meigs, JB Tofler, GH Selhub, J Jacques, PF Wolf, PA Magnani, JW Ellinor, PT Wang, TJ Levy, D Vasan, RS Benjamin, EJ AF Schnabel, Renate B. Larson, Martin G. Yamamoto, Jennifer F. Sullivan, Lisa M. Pencina, Michael J. Meigs, James B. Tofler, Geoffrey H. Selhub, Jacob Jacques, Paul F. Wolf, Philip A. Magnani, Jared W. Ellinor, Patrick T. Wang, Thomas J. Levy, Daniel Vasan, Ramachandran S. Benjamin, Emelia J. TI Relations of Biomarkers of Distinct Pathophysiological Pathways and Atrial Fibrillation Incidence in the Community SO CIRCULATION LA English DT Article DE atrial fibrillation; biomarkers; epidemiology; arrhythmia; risk assessment ID NATRIURETIC PEPTIDE LEVELS; POPULATION-BASED COHORT; C-REACTIVE PROTEIN; CARDIOVASCULAR EVENTS; RISK-FACTORS; SECULAR TRENDS; HEART-FAILURE; PREVALENCE; PREDICTORS; STROKE AB Background-Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial. Methods and Results-In 3120 Framingham cohort participants (mean age 58.4 +/- 9.7 years, 54% women), we related 10 biomarkers that represented inflammation (C-reactive protein and fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP] and N-terminal proatrial natriuretic peptide), oxidative stress (homocysteine), the renin-angiotensin-aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion; n = 2673) to incident AF (n = 209, 40% women) over a median follow-up of 9.7 years (range 0.05 to 12.8 years). In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise-selection models (P<0.01 for entry and retention), log-transformed BNP (hazard ratio per SD 1.62, 95% confidence interval 1.41 to 1.85, P<0.0001) and C-reactive protein (hazard ratio 1.25, 95% confidence interval 1.07 to 1.45, P<0.004) were chosen. The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95% confidence interval 0.75 to 0.81) to 0.80 (95% confidence interval 0.78 to 0.83) and showed an integrated discrimination improvement of 0.03 (95% confidence interval 0.02 to 0.04, P<0.0001), with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and C-reactive protein did not appreciably improve risk prediction over the model that incorporated BNP in addition to the risk factors. Conclusions-BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention requires further investigation. (Circulation. 2010; 121: 200-207.) C1 [Schnabel, Renate B.; Larson, Martin G.; Wolf, Philip A.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Framingham Study, Framingham, MA 01702 USA. [Schnabel, Renate B.; Larson, Martin G.; Wolf, Philip A.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Larson, Martin G.; Pencina, Michael J.] Boston Univ, Sch Med, Dept Math & Stat, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Evans Mem Med Dept, Boston, MA 02118 USA. [Magnani, Jared W.; Levy, Daniel; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Neurol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Yamamoto, Jennifer F.; Sullivan, Lisa M.; Pencina, Michael J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Ellinor, Patrick T.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. [Selhub, Jacob; Jacques, Paul F.] Tufts Univ, Jean Mayer Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM emelia@bu.edu RI Schnabel, Renate/F-6527-2014; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-IIC-25195, 6R01-NS 17950]; National Institutes of Health [1R01HL092577-01A1, HL064753, HL076784, AG028321, 1 RO1HL71039, K24 HL04334, K24, DK080140]; American Diabetes Association; Deutsche Forschungsgemeinschaft (German Research Foundation) [SCHN 1149/1-1] FX This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute contracts N01-IIC-25195 and 6R01-NS 17950; National Institutes of Health grants 1R01HL092577-01A1 (Drs Ellinor and Benjamin), HL064753, HL076784, and AG028321 (Dr Benjamin), and 1 RO1HL71039 (Dr Vasan); National Institutes of Health Research career award K24 HL04334 (Dr Vasan) and K24, DK080140 (Dr Meigs); an American Diabetes Association career development award (Dr Meigs); and Deutsche Forschungsgemeinschaft (German Research Foundation) research fellowship SCHN 1149/1-1 (Dr Schnabel). NR 45 TC 119 Z9 127 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 19 PY 2010 VL 121 IS 2 BP 200 EP U45 DI 10.1161/CIRCULATIONAHA.109.882241 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 544XK UT WOS:000273693500005 PM 20048208 ER PT J AU Rodriguez, CJ Diez-Roux, AV Moran, A Jin, ZZ Kronmal, RA Lima, J Homma, S Bluemke, DA Barr, RG AF Rodriguez, Carlos J. Diez-Roux, Ana V. Moran, Andrew Jin, Zhezhen Kronmal, Richard A. Lima, Joao Homma, Shunichi Bluemke, David A. Barr, R. Graham TI Left Ventricular Mass and Ventricular Remodeling Among Hispanic Subgroups Compared With Non-Hispanic Blacks and Whites MESA (Multi-Ethnic Study of Atherosclerosis) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE hypertension; hypertrophy; remodeling; epidemiology; Hispanics; magnetic resonance imaging ID NORTHERN MANHATTAN; UNITED-STATES; RISK-FACTORS; PROGNOSTIC IMPLICATIONS; CARDIOVASCULAR-DISEASE; ESSENTIAL-HYPERTENSION; GEOMETRIC PATTERNS; HEALTH; PREVALENCE; MORTALITY AB Objectives The purpose of this study was to examine the prevalence of left ventricular hypertrophy (LVH) and left ventricular (LV) remodeling patterns within Hispanic subgroups compared with non-Hispanic whites in the MESA (Multi-Ethnic Study of Atherosclerosis). Background Hispanics are the largest and fastest-growing ethnic minority in the U.S., but there are no data on LVH and LV geometry among Hispanic subgroups. Methods Cardiac magnetic resonance imaging was performed in 4,309 men and women age 45 to 84 years without clinical cardiovascular disease. Hispanics were categorized into subgroups based on self-reported ancestry. LVH was defined as the upper 95th percentile of indexed LV mass in a reference normotensive, nondiabetic, nonobese population, and LV remodeling according to the presence/absence of LVH and abnormal/normal LV mass to LV end-diastolic volume ratio. Results Among Hispanic participants, 574 were of Mexican origin, 329 were of Caribbean origin, and 161 were of Central/South American origin. On unadjusted analysis, only Caribbean-origin Hispanics (prevalence ratio = 1.2; 95% confidence interval [CI]: 1.03 to 1.4) had greater prevalence of hypertension than non-Hispanic whites. Hispanic subgroups were more likely to have LVH than non-Hispanic whites after adjustment for hypertension and other covariates (Caribbean-origin Hispanics = odds ratio [OR]: 1.8, 95% CI: 1.1 to 3.0; Mexican-origin Hispanics = OR: 2.2, 95% CI: 1.4 to 3.3; Central/South Americans = OR: 1.5, 95% CI: 0.7 to 3.1). All Hispanic subgroups also had a higher prevalence of concentric and eccentric hypertrophy compared with non-Hispanic whites (p < 0.001). Conclusions Caribbean-origin Hispanics had a higher prevalence of LVH and abnormal LV remodeling compared with non-Hispanic whites. A higher prevalence of LVH and abnormal LV remodeling was also observed among Mexicanorigin Hispanics, despite a lower prevalence of hypertension. Differences among Hispanic subgroups regarding LVH and LV remodeling should be taken into account when evaluating cardiovascular risk in this population. (J Am Coll Cardiol 2010; 55: 234-42) (C) 2010 by the American College of Cardiology Foundation C1 [Rodriguez, Carlos J.; Moran, Andrew; Homma, Shunichi; Barr, R. Graham] Columbia Univ, Dept Med, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Jin, Zhezhen] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Rodriguez, Carlos J.; Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Diez-Roux, Ana V.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Kronmal, Richard A.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Lima, Joao] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Barr, RG (reprint author), Columbia Univ, Dept Med, Mailman Sch Publ Hlth, PH 9 E Room 105,622 W 168th St, New York, NY 10032 USA. EM rgb9@columbia.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95168]; Robert Wood Johnson Harold Amos Medical Faculty; National Heart, Lung, and Blood Institute's [K23HL079343-01A2] FX This research was supported by contracts N01-HC-95159 and N01-HC-95168 from the National Heart, Lung, and Blood Institute. Dr. Rodriguez is supported by the Robert Wood Johnson Harold Amos Medical Faculty Development Program and a National Heart, Lung, and Blood Institute's Mentored Patient-Oriented Research Career Development Award (K23HL079343-01A2). Christopher M. Kramer, MD, served as Guest Editor for this article. NR 40 TC 47 Z9 48 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 19 PY 2010 VL 55 IS 3 BP 234 EP 242 DI 10.1016/j.jacc.2009.08.046 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 543XI UT WOS:000273613100009 PM 20117402 ER PT J AU Voon, V Gallea, C Hattori, N Bruno, M Ekanayake, V Hallett, M AF Voon, V. Gallea, C. Hattori, N. Bruno, M. Ekanayake, V. Hallett, M. TI The involuntary nature of conversion disorder SO NEUROLOGY LA English DT Article ID OF-BODY EXPERIENCE; TEMPORO-PARIETAL JUNCTION; TEMPOROPARIETAL JUNCTION; PARALYSIS; MOVEMENT; CONSEQUENCES; INTENTION; SYMPTOMS; CORTEX; FMRI AB Background: What makes a movement feel voluntary, and what might make it feel involuntary? Motor conversion disorders are characterized by movement symptoms without a neurologic cause. Conversion movements use normal voluntary motor pathways, but the symptoms are paradoxically experienced as involuntary, or lacking in self-agency. Self-agency is the experience that one is the cause of one's own actions. The matched comparison between the prediction of the action consequences (feed-forward signal) and actual sensory feedback is believed to give rise to self-agency and has been in part associated with the right inferior parietal cortex. Using fMRI, we assessed the correlates of self-agency during conversion tremor. Methods: We used a within-subject fMRI block design to compare brain activity during conversion tremor and during voluntary mimicked tremor in 8 patients. Results: The random effects group analysis showed that conversion tremor compared with voluntary tremor had right temporoparietal junction (TPJ) hypoactivity ( p < 0.05 family-wise error whole brain corrected) and lower functional connectivity between the right TPJ, sensorimotor regions ( sensorimotor cortices and cerebellar vermis), and limbic regions ( ventral anterior cingulate and right ventral striatum). Conclusions: The right TPJ has been implicated as a general comparator of internal predictions with actual events. We propose that the right TPJ hypoactivity and lower TPJ and sensorimotor cortex interactions may reflect the lack of an appropriate sensory prediction signal. The lack of a match for the proprioceptive feedback would lead to the perception that the conversion movement is not self-generated. Neurology (R) 2010; 74: 223-228 C1 [Voon, V.; Gallea, C.; Hattori, N.; Bruno, M.; Ekanayake, V.; Hallett, M.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Voon, V.] UCL, Inst Neurol, Wellcome Trust Ctr Neuroimaging, London WC1E 6BT, England. RP Voon, V (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 10 Ctr Dr,Bldg 10,Room 7D42, Bethesda, MD 20892 USA. EM voonval@gmail.com FU National Institute of Neurological Disorders and Stroke, NIH; Japan Science and Technology Agency; Neurotoxin Institute; Ariston Pharmaceuticals; US Department of Defense FX The study was supported and conducted at the National Institute of Neurological Disorders and Stroke, NIH.; Dr. Voon serves on a scientific advisory board for Boehringer Ingelheim; serves on the editorial board of Movement Disorders; and was supported by an intramural National Institute of Neurological Disorders and Stroke fellowship. Dr. Gallea is supported by an intramural National Institute of Neurological Disorders and Stroke fellowship. Dr. Hattori receives research support from the Japan Science and Technology Agency. Dr. Bruno reports no disclosures. Dr. Hallett serves as Chair of the Medical Advisory Board for and receives funding for travel from the Neurotoxin Institute; serves as Chair of the Medical Advisory Board of the Benign Essential Blepharospasm Foundation; has received honoraria and/or funding for travel for lectures or educational activities not funded by industry; serves on editorial advisory boards for Clinical Neurophysiology, Western Hemisphere, Brain, Acta Neurologica Scandinavica, Journal of Clinical Neurophysiology, Italian Journal of Neurological Sciences, Medical Problems of Performing Artists, Annals of Neurology, Neurology and Clinical Neurophysiology, The Cerebellum, NeuroRx, Current Trends in Neurology, Faculty of 1000 Biology, European Neurology, Faculty of 1000 Medicine, Brain Stimulation, Journal of Movement Disorders ( Korea), and World Neurology; may accrue revenue on US Patent 6,780,413 B2 ( Issued: August 24, 2004): Immunotoxin (MAB-Ricin) for the treatment of focal movement disorders, and US Patent 7,407,478 ( Issued: August 5, 2008): Coil for magnetic stimulation and methods for using the same; receives royalties from publishing from Blackwell Publisher, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, and Elsevier; receives research support from Ariston Pharmaceuticals, NIH/NINDS ( Intramural Program) and the US Department of Defense ( Army); has received license fee payments from the NIH ( from Brainsway) for licensing the patent for the H-coil; and with his spouse held stock in Agilent Technologies, Amgen, Amylin Pharmaceuticals, Merck & Co., Monsanto Co New Del, sanofi-aventis, Coventry Health Care Inc., Sigma Aldrich Corp., Warner Chilcott Ltd., Pfizer Inc, Genentech, Inc., United Health Group, St. Jude Medical, and Eli Lilly and Company. NR 25 TC 80 Z9 80 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 19 PY 2010 VL 74 IS 3 BP 223 EP 228 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 545BR UT WOS:000273707900010 PM 20083798 ER PT J AU Goldstein, DS Sewell, L Holmes, C AF Goldstein, David S. Sewell, LaToya Holmes, Courtney TI Association of anosmia with autonomic failure in Parkinson disease SO NEUROLOGY LA English DT Article ID CARDIAC SYMPATHETIC DENERVATION; CENTRAL DOPAMINE DEFICIENCY; MULTIPLE SYSTEM ATROPHY; ORTHOSTATIC HYPOTENSION; ODOR IDENTIFICATION; SIGNS AB Background: Olfactory dysfunction and autonomic failure are gaining recognition as nonmotor manifestations of Parkinson disease (PD). This observational study assessed whether in PD anosmia and autonomic failure are related to each other or to neuroimaging evidence of striatal dopamine deficiency. Methods: Olfactory function was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) in 23 patients with sporadic PD. Baroreflex-cardiovagal gain was quantified from the relationship between cardiac interbeat interval and systolic pressure during the Valsalva maneuver and baroreflex-sympathoneural function by responses of systolic pressure to the Valsalva maneuver and of hemodynamics and plasma norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels to orthostasis. 6-[(18)F] Fluorodopamine PET and plasma and skeletal muscle microdialysate NE and DHPG were used to indicate cardiac and extracardiac noradrenergic innervation and brain 6-[(18)F] fluorodopa PET to indicate striatal dopaminergic innervation. Parkinsonism was assessed by UPDRS scores. Results: Compared to patients with PD and normal to moderately decreased sense of smell, patients with anosmic PD had lower mean baroreflex-cardiovagal gain (p = 0.04), larger falls in systolic pressure during the Valsalva maneuver and orthostasis (p = 0.04, p = 0.02), smaller orthostatic increments in plasma NE and DHPG (p = 0.003, p = 0.03), lower cardiac septal: hepatic and renal cortical: hepatic ratios of 6-[(18)F] fluorodopamine-derived radioactivity (p = 0.01, p = 0.06), and lower microdialysate NE and DHPG (p = 0.01; p = 0.006). Neither clinical severity of parkinsonism nor the putamen: occipital cortex ratio of 6-[(18)F] fluorodopa-derived radioactivity was related to the UPSIT category. Conclusions: In Parkinson disease, anosmia is associated with baroreflex failure and cardiac and organ-selective extracardiac noradrenergic denervation, independently of parkinsonism or striatal dopaminergic denervation. Neurology (R) 2010; 74: 245-251 C1 [Goldstein, David S.; Sewell, LaToya; Holmes, Courtney] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, 10 Ctr Dr,MSC 1620,Bldg 10,Room 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Bakken Heart-Brain Institute FX Dr. Goldstein received the Pioneer Award from the Bakken Heart-Brain Institute; has received funding for sponsored travel for official US Government duties; and receives royalties from publication of the books Stress, Catecholamines, and Cardiovascular Disease (Oxford University Press, 1995), The Autonomic Nervous System in Health and Disease (Taylor & Francis, 2000), and Adrenaline and the Inner World: An Introduction to Scientific Integrative Medicine (The Johns Hopkins University Press, 2006). L. Sewell and C. Holmes report no disclosures. NR 19 TC 22 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 19 PY 2010 VL 74 IS 3 BP 245 EP 251 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 545BR UT WOS:000273707900013 PM 20083801 ER PT J AU Panguluri, SK Bhatnagar, S Kumar, A McCarthy, JJ Srivastava, AK Cooper, NG Lundy, RF Kumar, A AF Panguluri, Siva K. Bhatnagar, Shephali Kumar, Akhilesh McCarthy, John J. Srivastava, Apurva K. Cooper, Nigel G. Lundy, Robert F. Kumar, Ashok TI Genomic Profiling of Messenger RNAs and MicroRNAs Reveals Potential Mechanisms of TWEAK-Induced Skeletal Muscle Wasting in Mice SO PLOS ONE LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; DUCHENNE MUSCULAR-DYSTROPHY; MYOGENIC DIFFERENTIATION; SARCOMERIC PROTEIN; SIGNALING PATHWAYS; ADAPTIVE IMMUNITY; CANCER CACHEXIA; DISUSE ATROPHY; WEAK INDUCER AB Background: Skeletal muscle wasting is a devastating complication of several physiological and pathophysiological conditions. Inflammatory cytokines play an important role in the loss of skeletal muscle mass in various chronic diseases. We have recently reported that proinflammatory cytokine TWEAK is a major muscle-wasting cytokine. Emerging evidence suggests that gene expression is regulated not only at transcriptional level but also at post-transcriptional level through the expression of specific non-coding microRNAs (miRs) which can affect the stability and/or translation of target mRNA. However, the role of miRs in skeletal muscle wasting is unknown. Methodology/Principal Findings: To understand the mechanism of action of TWEAK in skeletal muscle, we performed mRNA and miRs expression profile of control and TWEAK-treated myotubes. TWEAK increased the expression of a number of genes involved in inflammatory response and fibrosis and reduced the expression of few cytoskeletal gene (e. g. Myh4, Ankrd2, and TCap) and metabolic enzymes (e. g. Pgam2). Low density miR array demonstrated that TWEAK inhibits the expression of several miRs including muscle-specific miR-1-1, miR-1-2, miR-133a, miR-133b and miR-206. The expression of a few miRs including miR-146a and miR-455 was found to be significantly increased in response to TWEAK treatment. Ingenuity pathway analysis showed that several genes affected by TWEAK are known/putative targets of miRs. Our cDNA microarray data are consistent with miRs profiling. The levels of specific mRNAs and miRs were also found to be similarly regulated in atrophying skeletal muscle of transgenic mice (Tg) mice expressing TWEAK. Conclusions/Significance: Our results suggest that TWEAK affects the expression of several genes and microRNAs involved in inflammatory response, fibrosis, extracellular matrix remodeling, and proteolytic degradation which might be responsible for TWEAK-induced skeletal muscle loss. C1 [Panguluri, Siva K.; Bhatnagar, Shephali; Kumar, Akhilesh; Cooper, Nigel G.; Lundy, Robert F.; Kumar, Ashok] Univ Louisville, Sch Med, Dept Anat Sci & Neurobiol, Louisville, KY 40292 USA. [McCarthy, John J.] Univ Kentucky, Coll Med, Dept Physiol, Lexington, KY USA. [Srivastava, Apurva K.] NCI, Lab Human Toxicol & Pharmacol, Appl & Dev Res Directorate SAIC Frederick, Frederick, MD 21701 USA. RP Panguluri, SK (reprint author), Univ Louisville, Sch Med, Dept Anat Sci & Neurobiol, Louisville, KY 40292 USA. EM ashok.kumar@louisville.edu RI Panguluri, Siva Kumar/A-3084-2008 FU National Institutes of Health [RO1 AG129623]; NCRR [P20RR16481] FX This work was supported by National Institutes of Health grant RO1 AG129623 to AK. Support from NCRR award P20RR16481 is also gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 42 Z9 49 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 19 PY 2010 VL 5 IS 1 AR e8760 DI 10.1371/journal.pone.0008760 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 546AH UT WOS:000273778900006 PM 20098732 ER PT J AU Tildesley, MJ House, TA Bruhn, MC Curry, RJ O'Neil, M Allpress, JLE Smith, G Keeling, MJ AF Tildesley, Michael J. House, Thomas A. Bruhn, Mark C. Curry, Ross J. O'Neil, Maggie Allpress, Justine L. E. Smith, Gary Keeling, Matt J. TI Impact of spatial clustering on disease transmission and optimal control SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE foot-and-mouth; modeling ID MOUTH-DISEASE; VACCINATION STRATEGIES; GREAT-BRITAIN; FOOT; EPIDEMIC; DYNAMICS; SPREAD; UK; ENVIRONMENTS; DISPERSAL AB Spatial heterogeneities and spatial separation of hosts are often seen as key factors when developing accurate predictive models of the spread of pathogens. The question we address in this paper is how coarse the resolution of the spatial data can be for a model to be a useful tool for informing control policies. We examine this problem using the specific case of foot-and-mouth disease spreading between farms using the formulation developed during the 2001 epidemic in the United Kingdom. We show that, if our model is carefully parameterized to match epidemic behavior, then using aggregate county-scale data from the United States is sufficient to closely determine optimal control measures (specifically ring culling). This result also holds when the approach is extended to theoretical distributions of farms where the spatial clustering can be manipulated to extremes. We have therefore shown that, although spatial structure can be critically important in allowing us to predict the emergent population-scale behavior from a knowledge of the individual-level dynamics, for this specific applied question, such structure is mostly subsumed in the parameterization allowing us to make policy predictions in the absence of high-quality spatial information. We believe that this approach will be of considerable benefit across a range of disciplines where data are only available at intermediate spatial scales. C1 [Tildesley, Michael J.] Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. [Tildesley, Michael J.] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. [House, Thomas A.; Keeling, Matt J.] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. [Bruhn, Mark C.; Curry, Ross J.; O'Neil, Maggie; Allpress, Justine L. E.] RTI Int, Res Triangle Pk, NC 27709 USA. [Smith, Gary] Univ Penn, Sch Vet Med, Sect Epidemiol & Publ Hlth, Kennett Sq, PA 19348 USA. RP Tildesley, MJ (reprint author), Univ Edinburgh, Sch Biol Sci, Ctr Immun Infect & Evolut, W Mains Rd, Edinburgh EH9 3JT, Midlothian, Scotland. EM michael.tildesley@ed.ac.uk RI Keeling, Matt/J-9280-2012; OI Keeling, Matt/0000-0003-4639-4765 FU Models of Infectious Disease Agent Study (National Institute of General Medical Sciences, National Institutes of Health); Wellcome Trust; Scottish Funding Council/Department for the Environment, Food, and Rural Affairs; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center; National Institutes of Health FX This work was funded by the Models of Infectious Disease Agent Study (National Institute of General Medical Sciences, National Institutes of Health), the Wellcome Trust, the Scottish Funding Council/Department for the Environment, Food, and Rural Affairs Veterinary Research Training Initiative Programme, the Research and Policy for Infectious Disease Dynamics Program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. Support for M.J.T was also provided through a Wellcome Trust strategic award for the Centre for Immunology, Infection and Evolution, University of Edinburgh. NR 32 TC 35 Z9 35 U1 3 U2 32 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 JAN 19 PY 2010 VL 107 IS 3 BP 1041 EP 1046 DI 10.1073/pnas.0909047107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100019 PM 19955428 ER PT J AU Best, RB Hummer, G AF Best, Robert B. Hummer, Gerhard TI Coordinate-dependent diffusion in protein folding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE coordinate transformation; internal friction; kinetic prefactor; projected dynamics; reaction coordinate ID UNFOLDED POLYPEPTIDE-CHAINS; BETA-HAIRPIN FORMATION; SPEED LIMIT; ENERGY LANDSCAPE; INTERNAL-FRICTION; TRANSITION-STATES; SOLVENT VISCOSITY; CONTACT FORMATION; 3-HELIX BUNDLE; LOOP FORMATION AB Diffusion on a low-dimensional free-energy surface is a remarkably successful model for the folding dynamics of small single-domain proteins. Complicating the interpretation of both simulations and experiments is the expectation that the effective diffusion coefficient D will in general depend on the position along the folding coordinate, and this dependence may vary for different coordinates. Here we explore the position dependence of D, its connection to protein internal friction, and the consequences for the interpretation of single-molecule experiments. We find a large decrease in D from unfolded to folded, for reaction coordinates that directly measure fluctuations in Cartesian configuration space, including those probed in single-molecule experiments. In contrast, D is almost independent of Q, the fraction of native amino acid contacts: Near the folded state, small fluctuations in position cause large fluctuations in Q, and vice versa for the unfolded state. In general, position-dependent free energies and diffusion coefficients for any two good reaction coordinates that separate reactant, product, and transition states, are related by a simple transformation, as we demonstrate. With this transformation, we obtain reaction coordinates with position-invariant D. The corresponding free-energy surfaces allow us to justify the assumptions used in estimating the speed limit for protein folding from experimental measurements of the reconfiguration time in the unfolded state, and also reveal intermediates hidden in the original free-energy projection. Lastly, we comment on the design of future single-molecule experiments that probe the position dependence of D directly. C1 [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM rbb24@cam.ac.uk; hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Royal Society University Research Fellowship; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX We thank Dr. William A. Eaton and Prof. Ben Schuler for helpful comments on the manuscript. R. B. is supported by a Royal Society University Research Fellowship. G. H. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 66 TC 135 Z9 135 U1 2 U2 35 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 JAN 19 PY 2010 VL 107 IS 3 BP 1088 EP 1093 DI 10.1073/pnas.0910390107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100027 PM 20080558 ER PT J AU Pancera, M Majeed, S Ban, YEA Chen, L Huang, CC Kong, L Kwon, YD Stuckey, J Zhou, TQ Robinson, JE Schief, WR Sodroski, J Wyatt, R Kwong, PD AF Pancera, Marie Majeed, Shahzad Ban, Yih-En Andrew Chen, Lei Huang, Chih-chin Kong, Leopold Kwon, Young Do Stuckey, Jonathan Zhou, Tongqing Robinson, James E. Schief, William R. Sodroski, Joseph Wyatt, Richard Kwong, Peter D. TI Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV-1 viral spike; molecular motion; protein architecture; receptor-triggered entry; type 1 fusion protein ID MEMBRANE-FUSION; BINDING-SITE; VIRAL ENTRY; GLYCOPROTEIN; ANTIBODY; NEUTRALIZATION; CD4; HEMAGGLUTININ; RECEPTOR; DEFINITION AB The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug-and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate-and structurally plastic-layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanismin which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions. C1 [Pancera, Marie; Majeed, Shahzad; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Wyatt, Richard; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Ban, Yih-En Andrew; Schief, William R.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Robinson, James E.] Tulane Univ, Med Ctr, Dept Pediat, New Orleans, LA 70112 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the NIH; Melinda Gates Foundation Grand Challenges in Global Heath Initiative; NIH; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank A. Finzi, M. Gerstein, B. Korber, H. Langedijk, G. Nabel, R. Sanders, Q. Sattentau, L. Shapiro, M. Shastri, I. Wilson, and members of the Structural Biology Section, Vaccine Research Center, for discussions or comments on the manuscript; J. Skinner for assistance with statistical analysis; S. Subramaniam for ligand-oriented cryoelectron tomograms; D. Dimitrov for antibodies X5, m6, and m9; M. Fung for antibody 5A8, M. Posner for antibody F105, W. Hendrickson for support, advice, and guidance during the early stages of the project, and the NIH AIDS Research and Reference Reagent Program for CD4. Support for this work was provided by the Intramural Research Program of the NIH, by the International AIDS Vaccine Initiative, by a grant from the Bill and Melinda Gates Foundation Grand Challenges in Global Heath Initiative, and by grants from the NIH. Use of insertion device 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract no. W-31-109-Eng-38. Atomic coordinates and structure factors for the structure of gp120with intact gp41-interactive region in complex with CD4 and antibody 48d for both orthorhombic and tetragonal crystal forms have been deposited with the Protein Data Bank under the accession codes 3JWD and 3JWO, respectively. NR 35 TC 184 Z9 188 U1 4 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 19 PY 2010 VL 107 IS 3 BP 1166 EP 1171 DI 10.1073/pnas.0911004107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100040 PM 20080564 ER PT J AU Kubler-Kielb, J Majadly, F Biesova, Z Mocca, CP Guo, CY Nussenzweig, R Nussenzweig, V Mishra, S Wu, YM Miller, LH Keith, JM Liu, TY Robbins, JB Schneerson, R AF Kubler-Kielb, Joanna Majadly, Fathy Biesova, Zuzana Mocca, Christopher P. Guo, Chunyan Nussenzweig, Ruth Nussenzweig, Victor Mishra, Satish Wu, Yimin Miller, Louis H. Keith, Jerry M. Liu, Teh-Yung Robbins, John B. Schneerson, Rachel TI A bicomponent Plasmodium falciparum investigational vaccine composed of protein-peptide conjugates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE malaria; circumsporozoite protein; Asn-Ala-Asn-Pro; Plasmodium falciparum ookinete surface protein 25 ID MALARIA VACCINE; IMPORTED MALARIA; IMMUNIZATION; RESPONSES; EFFICACY; BURDEN AB There is yet no licensed vaccine against malaria, a serious human disease affecting mostly children, with an annual death rate of about one million. Plasmodia, the malaria-causing parasites, have two obligatory hosts: mammals or birds, in which they multiply asexually, and mosquitoes with sexual multiplication. The most common and serious type of malaria is caused by Plasmodium falciparum. The circumsporozoite protein (CSP), a major surface antigen of sporozoites, is a protective antigen. A unique feature of P. falciparum CSP is its large central domain composed of over 30 tetrapeptide repeats of Asn-Ala-Asn-Pro (NANP). Several NANP peptide-protein conjugates were tested clinically but elicited a low level of CSP antibodies for a short duration. To provide a CSP-based candidate vaccine, we investigated recombinant CSP and NANP conjugates of various peptide lengths, with different N-terminal amino acids, bound at different ratios to various carrier proteins. Injected into mice, CSP alone and CSP or NANP conjugates induced antibodies with booster responses and were positive by the sporozoite imunofluorescent assay. The use of the mosquito stage P. falciparum ookinete surface protein, Pfs25, cross-linked onto itself as a carrier for NANP, induced in mice high levels of uniquely long-lasting antibodies to both vaccine components with secondary biological activities, that will provide immunity to liver infection by sporozoites and block transmission by mosquitoes. C1 [Kubler-Kielb, Joanna; Majadly, Fathy; Biesova, Zuzana; Mocca, Christopher P.; Guo, Chunyan; Keith, Jerry M.; Liu, Teh-Yung; Robbins, John B.; Schneerson, Rachel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. [Nussenzweig, Ruth; Nussenzweig, Victor; Mishra, Satish] NYU, Sch Med, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. [Wu, Yimin; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Robbins, JB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. EM robbinsjo@nichd.nih.gov; schneerr@mail.nih.gov RI Mishra, Satish/K-7473-2015 OI Mishra, Satish/0000-0002-8942-6416 FU Intramural Research Program of the National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases. NR 21 TC 20 Z9 24 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 JAN 19 PY 2010 VL 107 IS 3 BP 1172 EP 1177 DI 10.1073/pnas.0913374107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100041 PM 20080619 ER PT J AU Therrien, JP Kim, SM Terunuma, A Qin, Y Tock, CL Pfutzner, W Ohyama, M Schnermann, J Vogel, JC AF Therrien, Jean-Philippe Kim, Soo Mi Terunuma, Atsushi Qin, Yan Tock, Christine L. Pfuetzner, Wolfgang Ohyama, Manabu Schnermann, Jurgen Vogel, Jonathan C. TI A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE keratinocytes; human engineered skin; hypertension; multi-drug resistance gene; retroviral vectors ID ATRIAL-NATRIURETIC-FACTOR; PRIMARY HUMAN KERATINOCYTES; MULTIDRUG-RESISTANCE GENE; EXPRESSION IN-VIVO; STEM-CELLS; EPIDERMAL-KERATINOCYTES; ARTERIAL-PRESSURE; PEPTIDE; INFUSION; DELIVERY AB The use of bioengineered human skin as a bioreactor to deliver therapeutic factors has a number of advantages including accessibility that allows manipulation and monitoring of genetically modified cells. We demonstrate a skin gene therapy approach that can regulate blood pressure and treat systemic hypertension by expressing atrial natriuretic peptide (ANP), a hormone able to decrease blood pressure, in bioengineered human skin equivalents (HSE). Additionally, the expression of a selectable marker gene, multidrug resistance (MDR) type 1, is linked to ANP expression on a bicistronic vector and was coexpressed in the human keratinocytes and fibroblasts of the HSE that were grafted on to immunocompromised mice. Topical treatments of grafted HSE with the antimitotic agent colchicine select for keratinocyte progenitors that express both MDR and ANP. Significant plasma levels of human ANP were detected in mice grafted with HSE expressing ANP from either keratinocytes or fibroblasts, and topical selection of grafted HSE resulted in persistent high levels of ANP expression in vivo. Mice with elevated plasma levels of human ANP showed lower renin levels and, correspondingly, had lower systemic blood pressure than controls. Furthermore, mice with HSE grafts expressing human ANP did not develop elevated blood pressure when fed a high-salt diet. These findings illustrate the potential of this human skin gene therapy approach to deliver therapeutic molecules systemically for long-term treatment of diverse diseases. C1 [Therrien, Jean-Philippe; Terunuma, Atsushi; Tock, Christine L.; Ohyama, Manabu; Vogel, Jonathan C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Kim, Soo Mi; Qin, Yan; Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD 20892 USA. [Pfuetzner, Wolfgang] Univ Giessen & Marburg, Dept Dermatol & Allogol, D-35037 Marburg, Germany. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N260,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM jonvogel@mail.nih.gov RI Ohyama, Manabu/J-5524-2014 OI Ohyama, Manabu/0000-0002-2662-5717 FU Center for Cancer Research; NCI; NIDDK; Canadian Institutes of Health Research FX We thank Mark Udey, Carole Yee, and Girish Patel of the Dermatology Branch, National Cancer Institute (NCI), National Institutes of Health, for critical input and review of the manuscript (M. U.) and for technical assistance and helpful discussion of experimental design (C. Y. and G. P.). We thank Diane Milenic of the Radiation Oncology Branch, NCI, for assistance with the gamma-counter and Diane Mizel of the Renal Function and Injury Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), for assistance with the renin assay. We also thank John Dennis and the animal facility staff for helpful advice regarding the animal studies. This research was supported by the Center for Cancer Research, NCI, and the NIDDK, NIH. J.-P. T. was the recipient of a fellowship from Canadian Institutes of Health Research. NR 36 TC 7 Z9 7 U1 0 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 JAN 19 PY 2010 VL 107 IS 3 BP 1178 EP 1183 DI 10.1073/pnas.0908882107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 548BP UT WOS:000273934100042 PM 20080656 ER PT J AU Wang, XQ Tian, XY Liu, FF Zhao, YQ Sun, M Chen, DF Lu, CD Wang, Z Shi, XT Zhang, QY Zhang, DH Shen, ZY Li, F Harris, CC Cai, H Ke, Y AF Wang, Xueqian Tian, Xiuyun Liu, Fangfang Zhao, Yiqiang Sun, Min Chen, Dafang Lu, Changdong Wang, Zhong Shi, Xiaotian Zhang, Qingying Zhang, Donghong Shen, Zhongying Li, Feng Harris, Curtis C. Cai, Hong Ke, Yang TI Detection of HPV DNA in esophageal cancer specimens from different regions and ethnic groups: a descriptive study SO BMC CANCER LA English DT Article ID HUMAN-PAPILLOMAVIRUS DNA; POLYMERASE-CHAIN-REACTION; SQUAMOUS-CELL CARCINOMAS; HIGH-RISK AREA; CHINA; LINXIAN; ASSOCIATION; INFECTION; TYPE-16; ABSENCE AB Background: HPV has been found repeatedly in esophageal carcinoma tissues. However, reported detection rates of HPV DNA in these tumors have varied markedly. Differences in detection methods, sample types, and geographic regions of sample origin have been suggested as potential causes of this discrepancy. Methods: HPV L1 DNA and HPV genotypes were evaluated in 435 esophageal carcinoma specimens collected from four geographic regions with different ethnicities including Anyang in north China, Shantou in south China, Xinjiang in west China, and the United States. The HPV L1 fragment was detected using SPF1/GP6+ primers. HPV genotyping was performed using genotype specific PCR. Results: Two hundred and forty four of 435 samples (56.1%) tested positive for HPV L1. Significant differences in detection rate were observed neither among the three areas of China nor between China and the US. HPV6, 16, 18, 26, 45, 56, 57, and 58 were identified in L1 positive samples. HPV16 and 57 were the most common types in all regions, followed by HPV26 and HPV18. Conclusions: HPV infection is common in esophageal carcinoma independent of region and ethnic group of origin. Findings in this study raise the possibility that HPV is involved in esophageal carcinogenesis. Further investigation with a larger sample size over broader geographic areas may be warranted. C1 [Wang, Xueqian; Tian, Xiuyun; Liu, Fangfang; Zhao, Yiqiang; Sun, Min; Cai, Hong; Ke, Yang] Peking Univ, Beijing Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ,Sch Oncol, Beijing 100142, Peoples R China. [Ke, Yang] Peking Univ, Dept Cell Biol, Hlth Sci Ctr, Beijing 100191, Peoples R China. [Chen, Dafang] Peking Univ, Sch Publ Hlth, Hlth Sci Ctr, Beijing 100191, Peoples R China. [Lu, Changdong; Wang, Zhong; Shi, Xiaotian] Anyang Canc Hosp, Anyang 455000, Henan, Peoples R China. [Zhang, Qingying; Zhang, Donghong; Shen, Zhongying] Shantou Univ, Sch Med, Shantou 515031, Shandong, Peoples R China. [Li, Feng] Shihezi Med Sch, Shihezi 832002, Xinjiang, Peoples R China. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Cai, H (reprint author), Peking Univ, Beijing Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Minist Educ,Sch Oncol, 52 Fucheng Rd, Beijing 100142, Peoples R China. EM drhcai@yahoo.com; keyang@bjmu.edu.cn FU Natural Science Foundation of China [30430710, 30872937]; "863" Key Projects of National Ministry of Science and Technology [2006AA2Z467, 2006AA02A403]; Beijing Project on Science and Technology Commission [Z09050703080902] FX This work was supported by grants from Natural Science Foundation of China ( No. 30430710 and No. 30872937), "863" Key Projects of National Ministry of Science and Technology ( No. 2006AA2Z467 and No. 2006AA02A403) and Beijing Project on Science and Technology Commission ( No. Z09050703080902) to Yang Ke. We would also like to thank Dr. Michael A. McNutt for proofreading and correction of this manuscript. NR 27 TC 49 Z9 51 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 16 PY 2010 VL 10 AR 19 DI 10.1186/1471-2407-10-19 PG 8 WC Oncology SC Oncology GA 564IX UT WOS:000275207600001 PM 20078887 ER PT J AU Nagababu, E Mohanty, JG Bhamidipaty, S Ostera, GR Rifkind, JM AF Nagababu, Enika Mohanty, Joy G. Bhamidipaty, Surya Ostera, Graciela R. Rifkind, Joseph M. TI Role of the membrane in the formation of heme degradation products in red blood cells SO LIFE SCIENCES LA English DT Article DE Red blood cells; Hemoglobin; Membrane; Heme degradation; Fluorescence; Oxidative stress; Autoxidation; Hydrogen peroxide ID HYDROGEN-PEROXIDE; OXIDATIVE STRESS; GLUTATHIONE-PEROXIDASE; ANTIOXIDANT ENZYMES; LIPID-PEROXIDATION; HEMOGLOBIN-C; ERYTHROCYTE; DISEASE; DENATURATION; AUTOXIDATION AB Aims: Red blood cells (RBCs) have an extensive antioxidant system designed to eliminate the formation of reactive oxygen species (ROS). Nevertheless, RBC oxidant stress has been demonstrated by the formation of a fluorescent heme degradation product (excitation (ex) 321 nm, emission (em) 465 nm) both in vitro and in vivo. We investigated the possibility that the observed heme degradation results from ROS generated on the membrane surface that are relatively inaccessible to the cellular antioxidants. Main methods: Membrane and cytosol were separated by centrifugation and the fluorescence intensity and emission maximum were measured. The effect on the maximum emission of adding oxidized and reduced hemoglobin to the fluorescent product formed when hemin is degraded by hydrogen peroxide (H(2)O(2)) was studied. Key findings: 90% of the fluorescent heme degradation products in hemolysates are found on the membrane. Furthermore, these products are not transferred from the cytosol to the membrane and must, therefore, be formed on the membrane. We also showed that the elevated level of heme degradation in HbCC cells that is attributed to increased oxidative stress was found on the membrane. Significance: These results suggest that, although ROS generated in the cytosol are neutralized by antioxidant enzymes, H(2)O(2) generated by the membrane bound hemoglobin is not accessible to the cytosolic antioxidants and reacts to generate fluorescent heme degradation products. The formation of H(2)O(2) on the membrane surface can explain the release of ROS from the RBC to other tissues and ROS damage to the membrane that can alter red cell function and lead to the removal of RBCs from circulation by macrophages. (C) 2009 Published by Elsevier Inc. C1 [Nagababu, Enika; Mohanty, Joy G.; Bhamidipaty, Surya; Rifkind, Joseph M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. [Ostera, Graciela R.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Rifkind, JM (reprint author), NIA, Mol Dynam Sect, NIH, 251 Bay View Blvd, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov FU Intramural NIH HHS [Z01 AG000047-37] NR 35 TC 28 Z9 30 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JAN 16 PY 2010 VL 86 IS 3-4 BP 133 EP 138 DI 10.1016/j.lfs.2009.11.015 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 546SY UT WOS:000273833200009 PM 19958781 ER PT J AU Farasat, SM Bolger, DT Shetty, V Menachery, EP Gerstenblith, G Kasper, EK Najjar, SS AF Farasat, S. Morteza Bolger, Dennis T. Shetty, Veena Menachery, Elizabeth P. Gerstenblith, Gary Kasper, Edward K. Najjar, Samer S. TI Effect of Beta-Blocker Therapy on Rehospitalization Rates in Women Versus Men With Heart Failure and Preserved Ejection Fraction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SYSTOLIC FUNCTION; OLDER PATIENTS; LEFT-VENTRICLE; EXERCISE; MORTALITY; NEBIVOLOL; OUTCOMES; REGISTRY; SENIORS; IMPACT AB Beta blockers are empirically used in many patients with heart failure (HF) and preserved ejection fraction (HFpEF) because they allow more time for diastolic filling and because they improve outcomes in patients with systolic HF. However, recent data suggest that impaired chronotropic and vasodilator responses to exercise, which can worsen with beta blockade, may play a key role in the pathophysiology of HFpEF. We prospectively examined the association between beta-blocker therapy after hospitalization for decompensated HF and HF rehospitalization at 6 months in 66 consecutive patients with HFpEF (71 +/- 13 years old, 68% women, 42% Black). Subjects were stratified based on receiving (BB+; 15 men, 28 women) or not receiving (BB) beta-blockers at hospital discharge. In men, HF rehospitalization occurred less frequently in the BB+ than in the BB- group, albeit nonsignificantly (20% vs 50%, p = 0.29). In women, HF rehospitalization occurred more frequently in the BB+ than in the BB- group (75% vs 18%, p <0.001). In univariate analyses, discharge beta-blocker was associated with HF rehospitalization in women (odds ratio [OR] 14.00, 95% confidence interval [CI] 3.09 to 63.51, p = 0.001), but not in men (OR 0.25, 95% CI 0.03 to 1.92, p = 0.18). In a forward logistic regression model that offered all univariate predictors of HF rehospitalization, discharge 13 blocker remained an independent predictor of HF rehospitalization in women (OR 11.06, 95% CI 1.98 to 61.67, p = 0.006). In conclusion, this small observational study suggests that beta-blocker therapy may be associated with a higher risk of HF rehospitalization in women with HFpEF. The risks and benefits of beta-blocker therapy in patients with HFpEF should be evaluated in randomized, controlled trials. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:229-234) C1 [Najjar, Samer S.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Bolger, Dennis T.; Menachery, Elizabeth P.; Gerstenblith, Gary; Kasper, Edward K.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Farasat, S. Morteza; Shetty, Veena] Johns Hopkins Univ, MedStar Res Inst, Baltimore, MD USA. RP Najjar, SS (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM najjarsa@mail.nih.gov FU National Institutes of Health, National Institute on Aging, Baltimore, Maryland FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, Baltimore, Maryland, a portion of which was through a Research and Development Contract with MedStar Research Institute, Baltimore. NR 29 TC 18 Z9 18 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2010 VL 105 IS 2 BP 229 EP 234 DI 10.1016/j.amjcard.2009.09.008 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JW UT WOS:000278136400018 PM 20102924 ER PT J AU Castle, PE Schiffman, M Wheeler, CM Wentzensen, N Gravitt, PE AF Castle, Philip E. Schiffman, Mark Wheeler, Cosette M. Wentzensen, Nicolas Gravitt, Patti E. TI Impact of Improved Classification on the Association of Human Papillomavirus With Cervical Precancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cervical intraepithelial neoplasia; misclassification; papillomavirus infections; uterine cervical neoplasms ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; INTRAEPITHELIAL LESION TRIAGE; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; CYTOLOGY INTERPRETATIONS; EPIDEMIOLOGIC EVIDENCE; MANAGEMENT STRATEGIES; CANCER; DNA AB Misclassification of exposure and surrogate endpoints of disease can obscure causal relations. Using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS, 1997-2001), the authors explored the impact of exposure (human papillomavirus (HPV) detection) and endpoint (histologic cervical precancer) classification on their mutual association. Women referred into this study with an atypical squamous cells of undetermined significance Papanicolaou test with satisfactory results for all 4 HPV tests were included in this analysis (n = 3,215; 92.2%). HPV testing results were related to different definitions of cervical precancer, based on paired, worst 2-year histologic diagnoses, by calculating clinical sensitivity, specificity, and odds ratios. The authors found that HPV test sensitivity increased and specificity decreased with increasing certainty of cervical precancer, with HPV testing having the highest sensitivity (92%-98%) and lowest specificity (46%-54%) for consensus cervical intraepithelial neoplasia grade 3 (CIN 3). The overall accuracy of each HPV test, as measured by odds ratios, was greatest for consensus CIN-3 diagnoses, from 2- to 4-fold greater than for a less stringent precancer definition of any diagnosis of CIN 2 or more severe. In summary, there was convergence of greater certainty of carcinogenic HPV with greater certainty of a precancerous diagnosis, such that all 4 HPV tests almost always tested positive in women most likely to have cervical precancer. Finding increasingly strong associations when both test and diagnostic misclassification are reduced is a useful sign of "true association" in molecular epidemiology. C1 [Castle, Philip E.; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CN055105, N01 CN055157, N01 CN055154, N01 CN055159, N01 CN055153, N01 CN055158, N01 CN055156, N01 CN055155] NR 51 TC 15 Z9 15 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2010 VL 171 IS 2 BP 155 EP 163 DI 10.1093/aje/kwp390 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 539AD UT WOS:000273224700002 PM 20007673 ER PT J AU Meinhold, CL Ron, E Schonfeld, SJ Alexander, BH Freedman, DM Linet, MS de Gonzalez, AB AF Meinhold, Cari L. Ron, Elaine Schonfeld, Sara J. Alexander, Bruce H. Freedman, D. Michal Linet, Martha S. de Gonzalez, Amy Berrington TI Nonradiation Risk Factors for Thyroid Cancer in the US Radiologic Technologists Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; hormones; motor activity; prospective studies; reproduction; smoking; thyroid diseases; thyroid neoplasms ID BODY-MASS INDEX; POOLED ANALYSIS; REPRODUCTIVE FACTORS; ANTHROPOMETRIC FACTORS; STIMULATING HORMONE; CIGARETTE-SMOKING; TOBACCO SMOKING; NATIONAL-HEALTH; BREAST DISEASE; UNITED-STATES AB The incidence of thyroid cancer has been rapidly increasing in the United States, but few risk factors have been established. The authors prospectively examined the associations of self-reported medical history, anthropometric factors, and behavioral factors with thyroid cancer risk among 90,713 US radiologic technologists (69,506 women and 21,207 men) followed from 1983 through 2006. Incident thyroid cancers in 242 women and 40 men were reported. Elevated risks were observed for women with benign thyroid conditions (hazard ratio (HR) - 2.35, 95% confidence interval (CI): 1.73, 3.20), benign breast disease (HR = 1.56, 95% CI: 1.08, 2.26), asthma (HR = 1.68, 95% CI: 1.00, 2.83), and body mass index >= 35.0 versus 18.5-24.9 kg/m(2) (HR = 1.74, 95% CI: 1.03, 2.94; P-trend = 0.04). Current smoking was inversely associated with thyroid cancer risk (HR = 0.54). No clear associations emerged for reproductive factors, other medical conditions, alcohol intake, or physical activity. Despite few thyroid cancers in men, men with benign thyroid conditions had a significantly increased risk of thyroid cancer (HR = 4.65, 95% CI: 1.62, 13.34), and results for other risk factors were similar to those for women. Consistent with prior studies, obesity and benign thyroid conditions increased and current smoking decreased the risk of thyroid cancer. The novel findings for benign breast disease and asthma warrant further investigation. C1 [Meinhold, Cari L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Alexander, Bruce H.] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA. RP Meinhold, CL (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd, Rockville, MD 20852 USA. EM meinholdc@mail.nih.gov RI Kitahara, Cari/R-8267-2016 FU National Institutes of Health/National Cancer Institute FX This research was supported in part by the Intramural Research Program of the lNational Institutes of Health/National Cancer Institute. NR 60 TC 62 Z9 66 U1 3 U2 8 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 JAN 15 PY 2010 VL 171 IS 2 BP 242 EP 252 DI 10.1093/aje/kwp354 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 539AD UT WOS:000273224700012 PM 19951937 ER PT J AU Caban-Martinez, AJ Louie, GH Ward, MM Tektonidou, MG AF Caban-Martinez, Alberto J. Louie, Grant H. Ward, Michael M. Tektonidou, Maria G. TI Measures of psychological distress in patients with arthritis: comment on the article by Fuller-Thomson and Shaked SO ARTHRITIS CARE & RESEARCH LA English DT Letter ID DEPRESSION C1 [Caban-Martinez, Alberto J.; Louie, Grant H.; Ward, Michael M.; Tektonidou, Maria G.] NIAMSD, Bethesda, MD 20892 USA. [Caban-Martinez, Alberto J.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Tektonidou, Maria G.] Euroclin Hosp, Athens, Greece. RP Caban-Martinez, AJ (reprint author), NIAMSD, Bethesda, MD 20892 USA. OI Caban-Martinez, Alberto/0000-0002-5960-1308 NR 6 TC 0 Z9 0 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JAN 15 PY 2010 VL 62 IS 1 BP 140 EP 141 DI 10.1002/acr.20030 PG 3 WC Rheumatology SC Rheumatology GA 639MI UT WOS:000280978500024 PM 20191507 ER PT J AU von Marschall, Z Fisher, LW AF von Marschall, Zofia Fisher, Larry W. TI Decorin is processed by three isoforms of bone morphogenetic protein-1 (BMP1) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Decorin; Biglycan; BMP1; mTLD; BMP1-5 ID GROWTH-FACTOR-BETA; PROTEOGLYCAN-II DECORIN; GENE-THERAPY; BIGLYCAN; IDENTIFICATION; BIOSYNTHESIS; EXPRESSION; HOMOLOGY; SKELETAL; COLLAGEN AB The secreted small proteoglycan, decorin, modulates collagen fibril formation as well as the bioactivity of various members of the transforming growth factor-beta (TGF beta) superfamily. Indeed, recombinant prodecorin has been used in several gene therapy experiments to inhibit unwanted fibrosis in model diseases of the kidney, heart, and other tissues although the status of the propeptide within the target tissues is unknown. Currently the protease that removes the highly conserved propeptide from decorin is unprousing a variety of approaches, we show that three isoforms of the Tolloid-related bone morphogenetic protein-1 (BMP1) can effectively remove the propeptide from human prodecorin resulting in the well-established mature proteoglycan. Classic BMP1, the full-length gene transcript mTLD (BMP1-3), and BMP1-5 (isoform lacking the CUB3 domain thought to be important for efficient type 1 collagen C-propeptidase activity) all removed the analogous propeptides from both recombinant human prodecorin and murine probiglycan. Furthermore, the timed removal of the propeptide was found to not be necessary for the addition of decorin's single glycosaminoglycan chain. Decorin therefore joins the growing list of matrix and bioactive molecules processed/activated by the BMP1/Tolloid family. Since the third member of the Class I small leucine-rich proteooglycan (SLRP) superfamily, asporin, also contains a similar cleavage motif at the appropriate location, we propose that the removal of these propeptides by members of the BMP1 family is an additional characteristic of Class I SLRP. Published by Elsevier Inc. C1 [von Marschall, Zofia; Fisher, Larry W.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD USA. RP Fisher, LW (reprint author), Room 228,Bldg 30,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lfisher@dir.nidcr.nih.gov FU Division of intramural Research, NIDCR, of the Intramural Research Program, NIH, DHHS FX This work was Supported by the Division of intramural Research, NIDCR, of the Intramural Research Program, NIH, DHHS. NR 27 TC 19 Z9 19 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 15 PY 2010 VL 391 IS 3 BP 1374 EP 1378 DI 10.1016/j.bbrc.2009.12.067 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 550AL UT WOS:000274097800014 PM 20026052 ER PT J AU Venancio, TM Aravind, L AF Venancio, Thiago M. Aravind, L. TI CYSTM, a novel cysteine-rich transmembrane module with a role in stress tolerance across eukaryotes SO BIOINFORMATICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; PROTEIN; LOCALIZATION; YEAST AB Using sensitive sequence profile analysis, we identify a hitherto uncharacterized cysteine-rich, transmembrane (TM) module, CYSTM, found in a wide range of tail-anchored membrane proteins across eukaryotes. This superfamily includes Schizosaccharomyces Uvi15, Arabidopsis PCC1, Digtaria CDT1 and Saccharomyces proteins YDL012C and YDR210W, which have all been implicated in resistance/response to stress or pathogens. Based on the pattern of conserved cysteines and data from different chemical genetics studies, we suggest that CYSTM proteins might have critical role in responding to deleterious compounds at the plasma membrane via chelation or redox-based mechanisms. Thus, CYSTM proteins are likely to be part of a novel cellular protective mechanism that is widely active in eukaryotes, including humans. C1 [Venancio, Thiago M.; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nih.gov RI Venancio, Thiago/B-5003-2011; Entomologiamolecular, Inct/J-8214-2013 FU National Institutes of Health, USA FX Intramural Research Program of the National Institutes of Health, USA. NR 22 TC 12 Z9 14 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JAN 15 PY 2010 VL 26 IS 2 BP 149 EP 152 DI 10.1093/bioinformatics/btp647 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 544YJ UT WOS:000273696900001 PM 19933165 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI Pioneering First Steps and Cautious Conclusions SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID STAR-ASTERISK-D; ANTIDEPRESSANT TREATMENT; DEPRESSION; POLYMORPHISMS; ASSOCIATION; CITALOPRAM; GENETICS C1 [McMahon, Francis J.] NIMH, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), 35 Convent Dr,Room 1A202, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS NR 20 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2010 VL 67 IS 2 BP 99 EP 100 DI 10.1016/j.biopsych.2009.11.010 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 538RN UT WOS:000273201800002 PM 20006745 ER PT J AU Tosh, DK Chinn, M Yoo, LS Kang, DW Luecke, H Gao, ZG Jacobson, KA AF Tosh, Dilip K. Chinn, Moshe Yoo, Lena S. Kang, Dong Wook Luecke, Hans Gao, Zhan-Guo Jacobson, Kenneth A. TI 2-Dialkynyl derivatives of (N)-methanocarba nucleosides: 'Clickable' A(3) adenosine receptor-selective agonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE G protein-coupled receptor; Purines; Azide; Structure-activity relationship; Radioligand binding ID CHEMISTRY; CELLS; ANTAGONISTS; LIGANDS; POTENT; FLUORESCENCE; RADIOLIGAND; BINDING; DESIGN; FLUID AB We modified a series of (N)-methanocarba nucleoside 5'-uronamides to contain dialkyne groups on an extended adenine C2 substituent, as synthetic intermediates leading to potent and selective A(3) adenosine receptor (AR) agonists. The proximal alkyne was intended to promote receptor recognition, and the distal alkyne reacted with azides to form triazole derivatives (click cycloaddition). Click chemistry was utilized to couple an octadiynyl A(3)AR agonist to azido-containing fluorescent, chemically reactive, biotinylated, and other moieties with retention of selective binding to the A(3)AR. A bifunctional thiol-reactive crosslinking reagent was introduced. The most potent and selective novel compound was a 1-adamantyl derivative (K-i 6.5 nM), although some of the click products had K-i values in the range of 200-400 nM. Other potent, selective derivatives (K-i at A(3)AR in nM) were intended as possible receptor affinity labels: 3-nitro-4-fluorophenyl (10.6), alpha-bromophenacyl (9.6), thiol-reactive isothiazolone (102), and arylisothiocyanate (37.5) derivatives. The maximal functional effects in inhibition of forskolin-stimulated cAMP were measured, indicating that this class of click adducts varied from partial to full A(3)AR agonist compared to other widely used agonists. Thus, this strategy provides a general chemical approach to linking potent and selective A(3)AR agonists to reporter groups of diverse structure and to carrier moieties. Published by Elsevier Ltd. C1 [Tosh, Dilip K.; Chinn, Moshe; Yoo, Lena S.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIDDKD,NIH,LBC, Bethesda, MD 20892 USA. [Kang, Dong Wook; Luecke, Hans] NIDDKD, Gene Regulat Grp, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIDDKD,NIH,LBC, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. We thank Arunkumar Easwaran, Ph. D., Molecular Targeting Technologies, Inc. West Chester, PA for helpful discussions. NR 41 TC 18 Z9 21 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 15 PY 2010 VL 18 IS 2 BP 508 EP 517 DI 10.1016/j.bmc.2009.12.018 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 543XK UT WOS:000273613500003 PM 20036562 ER PT J AU Jozwiak, K Woo, AYH Tanga, MJ Toll, L Jimenez, L Kozocas, JA Plazinska, A Xiao, RP Wainer, IW AF Jozwiak, Krzysztof Woo, Anthony Yiu-Ho Tanga, Mary J. Toll, Lawrence Jimenez, Lucita Kozocas, Joseph A. Plazinska, Anita Xiao, Rui-Ping Wainer, Irving W. TI Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Comparative molecular fields analysis; beta(2) selective agonist; Drug design ID HIGH-AFFINITY BINDING; ADRENERGIC-RECEPTOR; 3-DIMENSIONAL MODELS; COMPLEXES AB Purpose: To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor. Results: Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities. Conclusion: the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K-i beta(2)-AR = 0.28 mu m, K-i beta(1)-AR/K-i beta(2)-AR = 573, EC50cAMP = 3.9 nm, EC50cardio = 16 nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Jozwiak, Krzysztof; Plazinska, Anita] Med Univ Lublin, Dept Chem, Lublin, Poland. [Woo, Anthony Yiu-Ho; Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Tanga, Mary J.; Toll, Lawrence; Jimenez, Lucita; Kozocas, Joseph A.] SRI Int, Menlo Pk, CA 94025 USA. [Wainer, Irving W.] NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Jozwiak, K (reprint author), Med Univ Lublin, Dept Chem, Lublin, Poland. EM krzysztof.jozwiak@umlub.pl RI Woo, Anthony/D-4305-2014 OI Woo, Anthony/0000-0003-0662-698X FU National Institute on Aging, Intramural Research Program, NIA [N01-AG-3-1009]; Foundation for Polish Science [FOCUS 4/2006] FX This work was supported in part by funds from the National Institute on Aging, Intramural Research Program, NIA Contract N01-AG-3-1009 and the Foundation for Polish Science (FOCUS 4/2006 programme) NR 18 TC 28 Z9 29 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 15 PY 2010 VL 18 IS 2 BP 728 EP 736 DI 10.1016/j.bmc.2009.11.062 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 543XK UT WOS:000273613500025 PM 20036561 ER PT J AU Bharate, SB Guo, LL Reeves, TE Cerasoli, DM Thompson, CM AF Bharate, Sandip B. Guo, Lilu Reeves, Tony E. Cerasoli, Douglas M. Thompson, Charles M. TI Bisquaternary pyridinium oximes: Comparison of in vitro reactivation potency of compounds bearing aliphatic linkers and heteroaromatic linkers for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Organophosphorus; Acetylcholinesterase; Bisquaternary oximes; Reactivation; Paraoxon ID BISPYRIDINIUM COMPOUNDS BEARING; TETRAETHYL PYROPHOSPHATE; (E)-BUT-2-ENE LINKER; NERVE AGENTS; SERIES; SALTS; SOMAN; TABUN; ALDOXIMES; ESTERASE AB Oxime reactivators are the drugs of choice for the post-treatment of OP ( organophosphorus) intoxication and used widely for mechanistic and kinetic studies of OP-inhibited cholinesterases. The purpose of the present study was to evaluate new oxime compounds to reactivate acetylcholinesterase (AChE) inhibited by the OP paraoxon. Several new bisquaternary pyridinium oximes with heterocyclic linkers along with some known bisquaternary pyridinium oximes bearing aliphatic linkers were synthesized and evaluated for their in vitro reactivation potency against paraoxon-inhibited electric eel acetylcholinesterase (EeAChE) and recombinant human acetylcholinesterase (rHuAChE). Results herein indicate that most of the compounds are better reactivators of EeAChE than of rHuAChE. The reactivation potency of two different classes of compounds with varying linker chains was compared and observed that the structure of the connecting chain is an important factor for the activity of the reactivators. At a higher concentration (10 (3) M), compounds bearing aliphatic linker showed better reactivation than compounds with heterocyclic linkers. Interestingly, oximes with a heterocyclic linker inhibited AChE at higher concentration (10 (3) M), whereas their ability to reactivate was increased at lower concentrations (10 (4) M and 10 (5) M). Compounds bearing either a thiophene linker 26, 46 or a furan linker 31 showed 59%, 49% and 52% reactivation of EeAChE, respectively, at 10 (5) M. These compounds showed 14%, 6% and 15% reactivation of rHuAChE at 10 (4) M. Amongst newly synthesized analogs with heterocyclic linkers (26-35 and 45-46), compound 31, bearing furan linker chain, was found to be the most effective reactivator with a k(r) 0.042 min (1), which is better than obidoxime (3) for paraoxon-inhibited EeAChE. Compound 31 showed a k(r) 0.0041 min (1) that is near equal to pralidoxime (1) for paraoxon-inhibited rHuAChE. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Bharate, Sandip B.; Thompson, Charles M.] Univ Montana, Dept Biomed & Pharmaceut Sci, NIH COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. [Guo, Lilu; Thompson, Charles M.] ATERIS Technol LLC, Missoula, MT 59802 USA. [Reeves, Tony E.; Cerasoli, Douglas M.] USAMRICD, Div Res, Physiol & Immunol Branch, Aberdeen Proving Ground, MD 21010 USA. RP Thompson, CM (reprint author), Univ Montana, Dept Biomed & Pharmaceut Sci, NIH COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. EM charles.thompson@umontana.edu FU NIH [UO1-ES016102, P30-NS055022, P20-RR015583]; SBIR grants to ATERIS Technologies LLC [R43 ES016392, U44 NS058229] FX This research was supported by NIH UO1-ES016102 ( C. M. T.) and SBIR grants to ATERIS Technologies LLC (R43 ES016392 and U44 NS058229). Support from the Core Laboratory for Neuromolecular Production (NIH P30-NS055022) and the Center for Structural and Functional Neuroscience (NIH P20-RR015583) is appreciated.; Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U. S. Army or the Department of Defense. NR 34 TC 17 Z9 17 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 15 PY 2010 VL 18 IS 2 BP 787 EP 794 DI 10.1016/j.bmc.2009.11.052 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 543XK UT WOS:000273613500031 PM 20005727 ER PT J AU Kong, YL Wang, K Edler, MC Hamel, E Mooberry, SL Paige, MA Brown, ML AF Kong, Yali Wang, Kan Edler, Michael C. Hamel, Ernest Mooberry, Susan L. Paige, Mikell A. Brown, Milton L. TI A boronic acid chalcone analog of combretastatin A-4 as a potent anti-proliferation agent SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Chalcone; Boronic acid; Combretastatin A-4; Tubulin polymerization; Anti-tumor agent ID AROMATIC ALDEHYDES; ANTIMITOTIC AGENTS; CANCER CELLS; TUBULIN; GROWTH; COLCHICINE AB Chalcones represent a class of natural products that inhibits tubulin assembly. In this study we designed and synthesized boronic acid analogs of chalcones in an effort to compare biological activities with combretastatin A-4, a potent inhibitor of tubulin polymerization. Systematic evaluation of the positional effects of the carbonyl moiety towards inhibition of tubulin polymerization, cancer cell proliferation and angiogenesis revealed that placement of the carbonyl adjacent to the trimethoxybenzene A-ring resulted in more active compounds than when the carbonyl group was placed adjacent to the C-ring. Our study identified a boronic acid chalcone with inhibition towards 16 human cancer cell lines in the 10-200 nM range, and another three cell lines with GI(50)-values below 10 nM. Furthermore, this drug has significant anti-angiogenesis effects demonstrated by HUVEC tube formation and aortic ring assay. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Kong, Yali; Wang, Kan; Paige, Mikell A.; Brown, Milton L.] Georgetown Univ, Med Ctr, Dept Oncol, Drug Discovery Program, Washington, DC 20057 USA. [Wang, Kan; Edler, Michael C.] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Mooberry, Susan L.] SW Fdn Biomed Res, Dept Physiol & Med, San Antonio, TX 78245 USA. RP Brown, ML (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Drug Discovery Program, 3970 Reservoir Rd, Washington, DC 20057 USA. EM mb544@georgetown.edu FU National Cancer Institute's Developmental Therapeutics Program; Georgetown Medical Center Drug Discovery Program; Lombardi Comprehensive Cancer Center FX We thank the National Cancer Institute's Developmental Therapeutics Program for evaluating compound 4 in the human cancer cell screen, the Georgetown Medical Center Drug Discovery Program and Lombardi Comprehensive Cancer Center for financial support. NR 20 TC 46 Z9 51 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 15 PY 2010 VL 18 IS 2 BP 971 EP 977 DI 10.1016/j.bmc.2009.11.003 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 543XK UT WOS:000273613500052 PM 20006519 ER PT J AU Malhotra, SV Kumar, V AF Malhotra, Sanjay V. Kumar, Vineet TI A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Ionic liquids; Anti-tumor; Anti-cancer; Cytotoxicity ID CELL-LINE HELA; CYTOTOXICITY; THALIDOMIDE; CANCER; SCREEN AB The anti-cancer activity and cytotoxicity of imidazolium-based ionic liquids has been determined for the first time via NCI's in vitro 60 human tumor cell lines. The preliminary SAR showed that the chain length of alkyl substitution at N-3 position of imidazole ring plays crucial role towards anti-tumor activity and cytotoxicity of these ionic liquids. The ionic liquids with alkyl substitution of C-12 chain length were found to be effective against all 60 tumor cell lines and show very low cytotoxicity in most of the cases. Further increase in chain length resulted in enhanced growth inhibition of tumor cell lines as well as high cytotoxicity. Interestingly, active compounds 1-dodecyl-3-methylimidazolium chloride (8), 1-dodecyl-3-methylimidazolium tetrafluoroborate (9), 1-hexadecyl-3-methylimidazoium chloride (10), 1-octadecyl-3-methylimidazolium chloride (11), 1-octadecyl-3-methylimidazolium hexafluorophosphate (12), 1-octadecyl-3-methylimidazolium bis(triflic)imide (13) and 1-octadecyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate (14) were highly active against leukemia cell lines, especially compounds 13 and 14 where the cytotoxicity was also very low as given by LC(50) > 100 mu M in all six leukemia cell lines. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Malhotra, Sanjay V.; Kumar, Vineet] NCI, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Malhotra, SV (reprint author), NCI, Lab Synthet Chem, SAIC Frederick Inc, 1050 Boyles St, Frederick, MD 21702 USA. EM malhotrasa@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HSN261200800001E] FX The authors would like to thank the NCI Developmental Therapeutics Program for 60 cell line screen of compounds described in this paper. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 30 TC 45 Z9 46 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2010 VL 20 IS 2 BP 581 EP 585 DI 10.1016/j.bmcl.2009.11.085 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 534ZK UT WOS:000272936000031 PM 20006501 ER PT J AU Nishizawa, R Nishiyama, T Hisaichi, K Hirai, K Habashita, H Takaoka, Y Tada, H Sagawa, K Shibayama, S Maeda, K Mitsuya, H Nakai, H Fukushima, D Toda, M AF Nishizawa, Rena Nishiyama, Toshihiko Hisaichi, Katsuya Hirai, Keisuke Habashita, Hiromu Takaoka, Yoshikazu Tada, Hideaki Sagawa, Kenji Shibayama, Shiro Maeda, Kenji Mitsuya, Hiroaki Nakai, Hisao Fukushima, Daikichi Toda, Masaaki TI Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE CCR5; Chemokine; Anti HIV-1 ID HIV-1 INFECTION; RECEPTOR; ENTRY; CORECEPTOR; COFACTOR; POTENT AB Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Nishizawa, Rena; Nishiyama, Toshihiko; Hisaichi, Katsuya; Hirai, Keisuke; Habashita, Hiromu; Nakai, Hisao; Fukushima, Daikichi; Toda, Masaaki] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan. [Tada, Hideaki; Shibayama, Shiro] Ono Pharmaceut Co Ltd, Tsukuba Res Inst, Ibaraki 300424, Japan. [Takaoka, Yoshikazu] Ono Pharmaceut Co Ltd, Fukui Res Inst, Fukui 9138538, Japan. [Sagawa, Kenji] Ono Pharmaceut Co Ltd, Osaka 5410056, Japan. [Maeda, Kenji; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan. [Maeda, Kenji; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Nishizawa, R (reprint author), Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan. EM r.nishizawa@ono.co.jp NR 15 TC 12 Z9 12 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2010 VL 20 IS 2 BP 763 EP 766 DI 10.1016/j.bmcl.2009.11.018 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 534ZK UT WOS:000272936000070 PM 20005712 ER PT J AU Fox, ER Benjamin, EJ Sarpong, DF Nagarajarao, H Taylor, JK Steffes, MW Salahudeen, AK Flessner, MF Akylbekova, EL Fox, CS Garrison, RJ Taylor, HA AF Fox, Ervin R. Benjamin, Emelia J. Sarpong, Daniel F. Nagarajarao, Harsha Taylor, Jason K. Steffes, Michael W. Salahudeen, Abdullah K. Flessner, Michael F. Akylbekova, Ermeg L. Fox, Caroline S. Garrison, Robert J. Taylor, Herman A., Jr. TI The relation of C - reactive protein to chronic kidney disease in African Americans: the Jackson Heart Study SO BMC NEPHROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; CARDIOVASCULAR-DISEASE; DIABETIC-NEPHROPATHY; RENAL-FUNCTION; US POPULATION; UNITED-STATES; INFLAMMATION; MARKERS; HYPERTENSION; PREVALENCE AB Background: African Americans have an increased incidence and worse prognosis with chronic kidney disease (CKD - estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)) than their counterparts of European-descent. Inflammation has been related to renal disease in non-Hispanic whites, but there are limited data on the role of inflammation in renal dysfunction in African Americans in the community. Methods: We examined the cross-sectional relation of log transformed C-reactive protein (CRP) to renal function (eGFR by Modification of Diet and Renal Disease equation) in African American participants of the community-based Jackson Heart Study's first examination (2000 to 2004). We conducted multivariable linear regression relating CRP to eGFR adjusting for age, sex, body mass index, systolic and diastolic blood pressure, diabetes, total/HDL cholesterol, triglycerides, smoking, antihypertensive therapy, lipid lowering therapy, hormone replacement therapy, and prevalent cardiovascular disease events. In a secondary analysis we assessed the association of CRP with albuminuria (defined as albumin-to-creatinine ratio >30 mg/g). Results: Participants (n = 4320, 63.2% women) had a mean age +/- SD of 54.0 +/- 12.8 years. The prevalence of CKD was 5.2% (n = 228 cases). In multivariable regression, CRP concentrations were higher in those with CKD compared to those without CKD (mean CRP 3.2 +/- 1.1 mg/L vs. 2.4 +/- 1.0 mg/L, respectively p < 0.0001). CRP was significantly associated with albuminuria in sex and age adjusted model however not in the multivariable adjusted model (p > 0.05). Conclusion: CRP was associated with CKD however not albuminuria in multivariable-adjusted analyses. The study of inflammation in the progression of renal disease in African Americans merits further investigation. C1 [Fox, Ervin R.; Nagarajarao, Harsha; Taylor, Jason K.; Flessner, Michael F.; Akylbekova, Ermeg L.; Garrison, Robert J.; Taylor, Herman A., Jr.] Univ Mississippi, Sch Med, Dept Med, Jackson, MS USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Sch Publ Hlth, Boston, MA USA. [Sarpong, Daniel F.; Akylbekova, Ermeg L.; Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS USA. [Steffes, Michael W.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Salahudeen, Abdullah K.] Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Nephrol Sect, Houston, TX 77030 USA. [Fox, Caroline S.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Fox, ER (reprint author), Univ Mississippi, Sch Med, Dept Med, Jackson, MS USA. EM efox@medicine.umsmed.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU NIH [N01 HC 95170, N01 HC-951/1, N01-HC-951/2, HL0/6/84]; National Center for Minority Health and Health Disparities [AG028321] FX The Jackson Heart Study is supported by NIH contracts N01 HC 95170, N01 HC-951/1, and N01-HC-951/2, HL0/6/84 provided by the National Heart, Lung, and Blood Institute and the National Center for Minority Health and Health Disparities and AG028321 provided by the National Institute of Aging. NR 36 TC 32 Z9 34 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JAN 15 PY 2010 VL 11 AR 1 DI 10.1186/1471-2369-11-1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 669IF UT WOS:000283340400001 PM 20078870 ER PT J AU Smirnov, MS Kiyatkin, EA AF Smirnov, Michael S. Kiyatkin, Eugene A. TI Phasic and tonic fluctuations in brain, muscle, and skin temperatures during motivated drinking behavior in rats: Physiological correlates of motivation and reward SO BRAIN RESEARCH LA English DT Article DE Brain metabolism; Brain temperature; Vasoconstriction; Neural activation; Appetitive motivated behavior; Consumption; Reward ID FEEDING-BEHAVIOR; NEURAL ACTIVITY; COCAINE; HYPERTHERMIA; STIMULATION; DOPAMINE; MONKEY; CLUES; FOOD AB Since brain metabolism is accompanied by heat production, measurement of brain temperature offers a method for assessing global alterations in metabolic neural activity. This approach, high-resolution (5-s bin) temperature recording from the nucleus accumbens (NAcc), temporal muscle, and facial skin, was used to study motivated drinking behavior in rats. Experienced animals were presented with a cup containing 5-ml of Coca-Cola (R) (Coke) beverage that resulted, within certain latencies, in initiation of a continuous chain of licking until all liquid was fully consumed. While cup presentation induced rapid, gradual NAcc temperature increase peaking at the start of drinking, temperatures slowly decreased during Coke consumption, but phasically increased again in the post-consumption period when rats were hyperactive, showing multiple interactions with an empty cup. Muscle temperatures followed a similar pattern, but the changes were weaker and delayed compared to those in the brain. Skin temperature rapidly dropped after cup presentation, steadily maintained at low levels during consumption, and slowly restored during the post-consumption period. Substitution of the expected Coke with either sugar-free Diet Coke (R) or water resulted in numerous drinking attempts but ultimately no consumption. During these tests, locomotor activation was much greater and more prolonged, brain and muscle temperatures increased monophasically, and their elevation was significantly greater than that with regular Coke tests. Food deprivation decreased drinking latencies, did not change the pattern of temperature fluctuations during Coke consumption, but temperature elevations were greater than in controls. Our data suggest sustained neural activation triggered by appetitive stimuli and associated with activational (seeking) aspects of appetitive motivated behavior. This seeking-related activation is rapidly ceased following consumption, suggesting this change as a neural correlate of reward. in contrast, inability to obtain an expected reward maintains neural activation and seeking behavior, resulting in larger deviations in physiological parameters. Published by Elsevier B.V. C1 [Smirnov, Michael S.; Kiyatkin, Eugene A.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov OI Smirnov, Michael/0000-0003-2248-8863 FU NIH, NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. We wish to thank Dr. Mary Pfeiffer and Jeremy Tang for language editing of this manuscript. NR 33 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 15 PY 2010 VL 1310 BP 87 EP 102 DI 10.1016/j.brainres.2009.11.036 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 554RA UT WOS:000274450900010 PM 19932691 ER PT J AU Housri, N Yarchoan, R Kaushal, A AF Housri, Nadine Yarchoan, Robert Kaushal, Aradhana TI Radiotherapy for Patients With the Human Immunodeficiency Virus: Are Special Precautions Necessary? SO CANCER LA English DT Review DE human immunodeficiency virus (HIV); acquired immunodeficiency syndrome (AIDS); radiation; cancer; malignancy; antiretroviral therapy ID ACTIVE ANTIRETROVIRAL THERAPY; SQUAMOUS-CELL CARCINOMA; HIV-POSITIVE PATIENTS; OF-THE-LITERATURE; NERVOUS-SYSTEM LYMPHOMA; NON-HODGKINS-LYMPHOMA; COMBINED-MODALITY THERAPY; RADIATION-THERAPY; LUNG-CANCER; KAPOSIS-SARCOMA AB Shortly after the onset of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s, reports of radiation-associated toxicity in patients with the human immunodeficiency virus (HIV) and AIDS began to appear in the medical literature. Although the majority of reports have focused on AIDS-defining malignancies such as Kaposi sarcoma, greater-than-expected toxicity after a course of radiotherapy or chemoradiotherapy has also been documented in cancers not generally classified as being related to HIV. With improved antiretroviral therapies, HIV patients are living longer and have the potential to develop a variety of HIV-associated and nonassociated malignancies that require treatment, including radiotherapy. This review reports the published data regarding the interactions of HIV, AIDS, and antiretroviral therapy with radiotherapy and implications for the management of malignancies in patients with HIV. Cancer 2010;116:273-83. Published 2010 by the American Cancer Society.* C1 [Housri, Nadine; Kaushal, Aradhana] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kaushal, A (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bldg 10 CRC,B2-3500, Bethesda, MD 20892 USA. EM kaushala@mail.nih.gov FU National Institutes of Health (NTH); National Cancer Institute; NIH; Pfizer Inc FX Supported in part by the Intramural Research Program of the National Institutes of Health (NTH), National Cancer Institute, Center for Cancer Research. Dr. Housri was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NTH and Pfizer Inc (via a grant to the Foundation for the NIH from Pfizer Inc). NR 104 TC 24 Z9 24 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2010 VL 116 IS 2 BP 273 EP 283 DI 10.1002/cncr.24878 PG 11 WC Oncology SC Oncology GA 546QT UT WOS:000273826000006 PM 20014399 ER PT J AU Farley, JH Tian, CQ Rose, GS Brown, CL Birrer, M Risinger, JI Thigpen, JT Fleming, GF Gallion, HH Maxwell, GL AF Farley, John H. Tian, Chunqiao Rose, G. Scott Brown, Carol L. Birrer, Michael Risinger, John I. Thigpen, J. Tate Fleming, Gini F. Gallion, Holly H. Maxwell, G. Larry TI Chemotherapy Intensity and Toxicity Among Black and White Women With Advanced and Recurrent Endometrial Cancer A Gynecologic Oncology Group Study SO CANCER LA English DT Article DE endometrial cancer; chemotherapy; GOG ID DOXORUBICIN PLUS CISPLATIN; PHASE-III TRIAL; RACIAL DISPARITY; AFRICAN-AMERICAN; ADJUVANT CHEMOTHERAPY; BREAST-CANCER; STAGE; CARCINOMA; SURVIVAL; OVEREXPRESSION AB BACKGROUND: The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival. METHODS: A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles >= 7 were defined as treatment completion. RESULTS. Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients. CONCLUSIONS: Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology. Cancer 2010;116:355-61. (C) 2070 American Cancer Society. C1 [Farley, John H.; Rose, G. Scott] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20832 USA. [Tian, Chunqiao] Roswell Pk Canc Inst, Gynecol Oncol Grp, Stat & Data Ctr, Buffalo, NY 14263 USA. [Brown, Carol L.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, Div Gynecol Oncol,Dept Obstet & Gynecol, New York, NY 10021 USA. [Birrer, Michael] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Risinger, John I.] Mem Hlth Univ Med Ctr, Dept Lab Oncol Res, Curtis & Elizabeth Anderson Canc Inst, Savannah, GA 31404 USA. [Thigpen, J. Tate] Univ Mississippi, Div Oncol, Dept Med, Sch Med, Jackson, MS 39216 USA. [Fleming, Gini F.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Gallion, Holly H.] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet & Gynecol & Reprod Serv, Pittsburgh, PA USA. [Maxwell, G. Larry] Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Washington, DC 20307 USA. [Maxwell, G. Larry] Walter Reed Army Med Ctr, US Mil Canc Inst, Washington, DC 20307 USA. RP Farley, JH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, 4301 Jones Bridge Rd, Bethesda, MD 20832 USA. EM john.farley@us.army.mil FU National Cancer Institute [CA 27,469]; Gynecologic Oncology Group Statistical Office [CA 37,517] FX This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27,469) and the Gynecologic Oncology Group Statistical Office (CA 37,517). NR 26 TC 7 Z9 7 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2010 VL 116 IS 2 BP 355 EP 361 DI 10.1002/cncr.24769 PG 7 WC Oncology SC Oncology GA 546QT UT WOS:000273826000016 PM 19924790 ER PT J AU De Siervi, A De Luca, P Byun, JS Di, LJ Fufa, T Haggerty, CM Vazquez, E Moiola, C Longo, DL Gardner, K AF De Siervi, Adriana De Luca, Paola Byun, Jung S. Di, Li Jun Fufa, Temesgen Haggerty, Cynthia M. Vazquez, Elba Moiola, Cristian Longo, Dan L. Gardner, Kevin TI Transcriptional Autoregulation by BRCA1 SO CANCER RESEARCH LA English DT Article ID DNA-DAMAGE RESPONSE; BREAST-CANCER; CELL-CYCLE; GENETIC INSTABILITY; REPRESSOR COMPLEX; DOWN-REGULATION; GROWTH ARREST; IN-VIVO; EXPRESSION; PROMOTER AB The BRCA1 gene product plays numerous roles in regulating genome integrity. Its role in assembling supermolecular complexes in response to DNA damage has been extensively studied; however, much less is understood about its role as a transcriptional coregulator. Loss or mutation is associated with hereditary breast and ovarian cancers, whereas altered expression occurs frequently in sporadic forms of breast cancer, suggesting that the control of BRCA1 transcription might be important to tumorigenesis. Here, we provide evidence of a striking linkage between the roles for BRCA1 as a transcriptional coregulator with control of its expression via an autoregulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multicomponent transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress, resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent upregulation of BRCA1 transcription. Cells depleted of BRCA1 respond by upregulating BRCA1 transcripts, whereas cells overexpressing BRCA1 respond by downregulating BRCA1 transcripts. Tandem chromatin immmunoprecipitation studies show that BRCA1 is regulated by a dynamic coregulatory complex containing BRCA1, E2F1, and Rb at the BRCA1 promoter that is disrupted by DNA-damaging agents to increase its transcription. These results define a novel transcriptional mechanism of autoregulated homeostasis of BRCA1 that selectively titrates its levels to maintain genome integrity in response to genotoxic insult. Cancer Res; 70(2); 532-42. (C)2010 AACR. C1 [De Siervi, Adriana; Byun, Jung S.; Di, Li Jun; Fufa, Temesgen; Haggerty, Cynthia M.; Gardner, Kevin] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [De Siervi, Adriana; De Luca, Paola; Vazquez, Elba; Moiola, Cristian] Univ Buenos Aires, Sch Sci, Dept Biol Chem, Buenos Aires, DF, Argentina. [Longo, Dan L.] NIA, Immunol Lab, Baltimore, MD 21224 USA. RP Gardner, K (reprint author), NCI, Lab Receptor Biol & Gene Express, 41 Lib Dr,Bldg 41-D305, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov RI Di, Li-jun/D-6160-2013; Di, Li-jun/B-3352-2011 FU NIH, National Cancer Institute; NIH, National Institute on Aging FX Grant Support; Intramural Research Program of the NIH, National Cancer Institute, and National Institute on Aging. NR 47 TC 36 Z9 37 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2010 VL 70 IS 2 BP 532 EP 542 DI 10.1158/0008-5472.CAN-09-1477 PG 11 WC Oncology SC Oncology GA 607FW UT WOS:000278485500013 PM 20068145 ER PT J AU Ma, HY Wang, YP Sullivan-Halley, J Weiss, L Marchbanks, PA Spirtas, R Ursin, G Burkman, RT Simon, MS Malone, KE Strom, BL McDonald, JA Press, MF Bernstein, L AF Ma, Huiyan Wang, Yaping Sullivan-Halley, Jane Weiss, Linda Marchbanks, Polly A. Spirtas, Robert Ursin, Giske Burkman, Ronald T. Simon, Michael S. Malone, Kathleen E. Strom, Brian L. McDonald, Jill A. Press, Michael F. Bernstein, Leslie TI Use of Four Biomarkers to Evaluate the Risk of Breast Cancer Subtypes in the Women's Contraceptive and Reproductive Experiences Study SO CANCER RESEARCH LA English DT Article ID AFRICAN-AMERICAN WOMEN; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTOR; HORMONE-RECEPTOR; PROTEIN OVEREXPRESSION; MONOCLONAL-ANTIBODIES; P53 EXPRESSION; HER-2/NEU GENE; MUTATIONS; CARCINOMA AB Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER(-)/PR(-)/HER2(-)) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER(+) or PR(+), HER2(-)), luminal B (ER(+) or PR(+)/HER2(+)), and ER(-)/PR(-)/HER2(+) tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer. Cancer Res; 70(2); 575-87. (C)2010 AACR. C1 [Ma, Huiyan; Sullivan-Halley, Jane; Bernstein, Leslie] City Hope Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Wang, Yaping; Ursin, Giske; Bernstein, Leslie] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Weiss, Linda] NCI, Canc Ctr Branch, Bethesda, MD 20892 USA. [Spirtas, Robert] NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD 20892 USA. [Marchbanks, Polly A.; McDonald, Jill A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. [Ursin, Giske] Univ Oslo, Dept Nutr, Oslo, Norway. [Burkman, Ronald T.] Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Div Hematol Oncol, Detroit, MI USA. [Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Strom, Brian L.] Univ Penn, Sch Med, Ctr Educ & Res Therapeut, Dept Biostat & Epidemiol,Ctr Clin Epidemiol & Bio, Philadelphia, PA 19104 USA. RP Bernstein, L (reprint author), City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM LBernstein@coh.org FU National Institute for Child Health and Human Development [NO1-HD-3-3175]; National Cancer Institute [CA48780]; National Institute of Child Health and Human Development and National Cancer Institute, NIH, through Emory University [N01-HD-3-3168]; Fred Hutchinson Cancer Research Center [N01-HD-2-3166]; Karmanos Cancer Institute at Wayne State University [N01-HD-3-3174]; University of Pennsylvania [NO1-HD-3-3276]; University of Southern California [N01-HD-3-3175]; Interagency Agreement with Centers for Disease Control and Prevention [Y01-HD-7022]; California Department of Health Services [103885]; [N01-PC-67006 (Atlanta)]; [N01-CN-65064 (Detroit)]; [N01-PC-67010 (LA)]; [N01-CN-0532 (Seattle)] FX Grant Support; National Institute for Child Health and Human Development grant NO1-HD-3-3175 and National Cancer Institute grant CA48780. Data collection for the Women's CARE Study was supported by the National Institute of Child Health and Human Development and National Cancer Institute, NIH, through contracts with Emory University (N01-HD-3-3168), Fred Hutchinson Cancer Research Center (N01-HD-2-3166), Karmanos Cancer Institute at Wayne State University (N01-HD-3-3174), University of Pennsylvania (NO1-HD-3-3276), and University of Southern California (N01-HD-3-3175) and Interagency Agreement with Centers for Disease Control and Prevention (Y01-HD-7022). Collection of cancer incidence data in LA County by University of Southern California was supported by California Department of Health Services as part of statewide cancer reporting program mandated by California Health and Safety Code, Section 103885. Support for use of SEER cancer registries through contracts N01-PC-67006 (Atlanta), N01-CN-65064 (Detroit), N01-PC-67010 (LA), and N01-CN-0532 (Seattle). NR 50 TC 50 Z9 50 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2010 VL 70 IS 2 BP 575 EP 587 DI 10.1158/0008-5472.CAN-09-3460 PG 13 WC Oncology SC Oncology GA 607FW UT WOS:000278485500018 PM 20068186 ER PT J AU Novosyadlyy, R Lann, DE Vijayakumar, A Rowzee, A Lazzarino, DA Fierz, Y Carboni, JM Gottardis, MM Pennisi, PA Molinolo, AA Kurshan, N Mejia, W Santopietro, S Yakar, S Wood, TL LeRoith, D AF Novosyadlyy, Ruslan Lann, Danielle E. Vijayakumar, Archana Rowzee, Anne Lazzarino, Deborah A. Fierz, Yvonne Carboni, Joan M. Gottardis, Marco M. Pennisi, Patricia A. Molinolo, Alfredo A. Kurshan, Naamit Mejia, Wilson Santopietro, Stefania Yakar, Shoshana Wood, Teresa L. LeRoith, Derek TI Insulin-Mediated Acceleration of Breast Cancer Development and Progression in a Nonobese Model of Type 2 Diabetes SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; 7,12-DIMETHYLBENZ(A)ANTHRACENE-INDUCED MAMMARY-CARCINOMA; SIGNALING PATHWAYS; METABOLIC SYNDROME; TRANSGENIC MOUSE; CELL-LINES; IGF-I; RECEPTOR; MICE; METAANALYSIS AB Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis, and that the IR and/or the IGF-IR are major mediators of these effects. Cancer Res; 70(2); 741-51. (C)2010 AACR. C1 [Novosyadlyy, Ruslan; Lann, Danielle E.; Vijayakumar, Archana; Fierz, Yvonne; Kurshan, Naamit; Mejia, Wilson; Yakar, Shoshana; LeRoith, Derek] Mt Sinai Sch Med, Samuel Bronfman Dept Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Rowzee, Anne; Lazzarino, Deborah A.; Wood, Teresa L.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Carboni, Joan M.; Gottardis, Marco M.] Bristol Myers Squibb Res Inst, Oncol Drug Discovery, Princeton, NJ USA. [Pennisi, Patricia A.; Santopietro, Stefania] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Molinolo, Alfredo A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP LeRoith, D (reprint author), Mt Sinai Sch Med, Samuel Bronfman Dept Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. EM derek.leroith@mssm.edu FU National Cancer Institute [1RO1CA128799-O1A1]; Gerald J. and Dorothy R. Friedman Foundation; NIH [T32 DK007792]; Swiss National Science Foundation [PBBSB-120851]; Novartis Foundation; Roche Research Foundation FX Grant Support; National Cancer Institute grant 1RO1CA128799-O1A1 and Gerald J. and Dorothy R. Friedman Foundation. D. E. Lann was supported by NIH grant T32 DK007792. Y. Fierz was funded by Swiss National Science Foundation grant PBBSB-120851, Novartis Foundation and Roche Research Foundation. NR 47 TC 142 Z9 146 U1 2 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2010 VL 70 IS 2 BP 741 EP 751 DI 10.1158/0008-5472.CAN-09-2141 PG 11 WC Oncology SC Oncology GA 607FW UT WOS:000278485500034 PM 20068149 ER PT J AU Sordet, O Nakamura, AJ Redon, CE Pommier, Y AF Sordet, Olivier Nakamura, Asako J. Redon, Christophe E. Pommier, Yves TI DNA double-strand breaks and ATM activation by transcription-blocking DNA lesions SO CELL CYCLE LA English DT Article DE ATM; DNA double-strand breaks; R-loop; topoisomerase; transcription ID RNA-POLYMERASE-II; TOPOISOMERASE-I; DAMAGE RESPONSE; SPINOCEREBELLAR ATAXIA; CLEAVAGE COMPLEXES; NEURONAL DEATH; REPAIR; PHOSPHORYLATION; CAMPTOTHECIN; MECHANISM AB A taxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA double-strand break (DSB) response. We recently showed that transcription-blocking topoisomerase I cleavage complexes (TOP1cc) produce DSBs related to R-loop formation and activate ATM in post-mitotic neurons and lymphocytes. Here we discuss how TOP1cc can produce transcription arrest with R-loop formation and generate DSBs that activate ATM, as well as data suggesting that those transcription-dependent DSBs tend to form at the IgH locus and at specific genomic sites. We also address the potential roles of ATM in response to transcription-blocking TOP1cc. C1 [Sordet, Olivier; Nakamura, Asako J.; Redon, Christophe E.; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Sordet, Olivier/M-3271-2014 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Dr. A. Nussenzweig for providing the IgH DNA FISH probe. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 49 TC 24 Z9 24 U1 0 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2010 VL 9 IS 2 BP 274 EP 278 PG 5 WC Cell Biology SC Cell Biology GA 550PG UT WOS:000274139800024 PM 20023421 ER PT J AU Nakamura, AJ Rao, VA Pommier, Y Bonner, WM AF Nakamura, Asako J. Rao, V. Ashutosh Pommier, Yves Bonner, William M. TI The complexity of phosphorylated H2AX foci formation and DNA repair assembly at DNA double-strand breaks SO CELL CYCLE LA English DT Article DE DNA double strand breaks; phosphorylated H2AX; MDC1; 53BP1; NBS1 ID DAMAGE RESPONSE; HISTONE H2AX; HOMOLOGOUS RECOMBINATION; IONIZING-RADIATION; GAMMA-H2AX; 53BP1; ATM; MDC1; RECRUITMENT; IRRADIATION AB The maintenance of genome stability requires efficient DNA double-stranded break (DSB) repair mediated by the phosphorylation of multiple histone H2AX molecules near the break sites. The phosphorylated H2AX (gamma H2AX) molecules form foci covering many megabases of chromatin. The formation of gamma-H2AX foci is critical for efficient DNA damage response (DDR) and for the maintenance of genome stability, however, the mechanisms of protein organization in foci is largely unknown. To investigate the nature of gamma H2AX foci formation, we analyzed the distribution of gamma H2AX and other DDR proteins at DSB sites using a variety of techniques to visualize, expand and partially disrupt chromatin. We report here that gamma H2AX foci change composition during the cell cycle, with proteins 53BP1, NBS1 and MRE11 dissociating from foci in G 2 and mitosis to return at the beginning of the following G(1). In contrast, MDC1 remained colocalized with gamma-H2AX during mitosis. In addition, while gamma H2AX was found to span large domains flanking DSB sites, 53BP1 and NBS1 were more localized and MDC1 colocalized in doublets in foci. H2AX and MDC1 were found to be involved in chromatin relaxation after DSB formation. Our data demonstrates that the DSB repair focus is a heterogeneous and dynamic structure containing internal complexity. C1 [Nakamura, Asako J.; Pommier, Yves; Bonner, William M.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Rao, V. Ashutosh] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. RP Nakamura, AJ (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM nakamuraa@mail.nih.gov FU National Cancer Institute; CCR; NIH FX We thank Jennifer S. Dickey, Christophe E. Redon and Olga A. Sedelnikova, for critical reading of this manuscript, and other members of Laboratory of Molecular Pharmacology for help in this work. We thank Brittany Flood for technical assistance. We are grateful to Peter Franklin with the technical support for DeltaVision OMX (TM) 3D-SIM (TM) Super Resolution Imaging System. This work was supported by the Intramural Research Program of the National Cancer Institute, CCR, NIH. NR 45 TC 57 Z9 60 U1 3 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2010 VL 9 IS 2 BP 389 EP 397 PG 9 WC Cell Biology SC Cell Biology GA 550PG UT WOS:000274139800036 PM 20046100 ER PT J AU Landi, MT Zhao, YD Rotunno, M Koshiol, J Liu, H Bergen, AW Rubagotti, M Goldstein, AM Linnoila, I Marincola, FM Tucker, MA Bertazzi, PA Pesatori, AC Caporaso, NE McShane, LM Wang, E AF Landi, Maria Teresa Zhao, Yingdong Rotunno, Melissa Koshiol, Jill Liu, Hui Bergen, Andrew W. Rubagotti, Maurizia Goldstein, Alisa M. Linnoila, Ilona Marincola, Francesco M. Tucker, Margaret A. Bertazzi, Pier Alberto Pesatori, Angela C. Caporaso, Neil E. McShane, Lisa M. Wang, Ena TI MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID REAL-TIME PCR; HYBRIDIZATION ARRAY ANALYSIS; FACTOR RECEPTOR GENE; STEM-CELLS; FAMILY; GROWTH; MUTATIONS; SIGNATURE; PROGNOSIS; RNA AB Purpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non-small cell lung cancer. Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics. Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (P(global) < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ. Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. Clin Cancer Res; 16(2); 430-41. (C)2010 AACR. C1 [Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Zhao, Yingdong; McShane, Lisa M.] NCI, Div Canc Treatment & Diag, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Linnoila, Ilona] NCI, Ctr Canc Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Liu, Hui; Marincola, Francesco M.; Wang, Ena] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Liu, Hui; Marincola, Francesco M.; Wang, Ena] NIH, Ctr Human Immunol, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Rubagotti, Maurizia; Bertazzi, Pier Alberto; Pesatori, Angela C.] Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. [Rubagotti, Maurizia; Bertazzi, Pier Alberto; Pesatori, Angela C.] Osped Maggiore Policlin Mangiagalli & Regina Elen, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Tucker, Margaret/B-4297-2015; bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 FU NIH, NCI, Division of Cancer Epidemiology and Genetics; NCI Director's Innovation Award FX Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics, and a 2006 NCI Director's Innovation Award to M.T.L. NR 58 TC 175 Z9 191 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 430 EP 441 DI 10.1158/1078-0432.CCR-09-1736 PG 12 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000009 PM 20068076 ER PT J AU Du, JA Martin, SM Levine, M Wagner, BA Buettner, GR Wang, SH Taghiyev, AF Du, CB Knudson, CM Cullen, JJ AF Du, Juan Martin, Sean M. Levine, Mark Wagner, Brett A. Buettner, Garry R. Wang, Sih-han Taghiyev, Agshin F. Du, Changbin Knudson, Charles M. Cullen, Joseph J. TI Mechanisms of Ascorbate-Induced Cytotoxicity in Pancreatic Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DEPRIVATION-INDUCED CYTOTOXICITY; VITAMIN-C PHARMACOKINETICS; TERMINAL HUMAN CANCER; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; CELL-DEATH; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT; SURVIVAL TIMES; CLINICAL-TRIAL AB Purpose: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%. Experimental Design: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks. Results: There was a time- and dose-dependent increase in measured H(2)O(2) production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H(2)O(2). Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival. Conclusions: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer. Clin Cancer Res; 16(2); 509-20. (C)2010 AACR. C1 [Cullen, Joseph J.] Univ Iowa, Coll Med, Dept Surg, Iowa City, IA 52242 USA. [Du, Juan; Wagner, Brett A.; Buettner, Garry R.; Du, Changbin; Cullen, Joseph J.] Univ Iowa, Coll Med, Dept Radiat Oncol, Iowa City, IA 52242 USA. [Martin, Sean M.; Wang, Sih-han; Taghiyev, Agshin F.; Knudson, Charles M.] Univ Iowa, Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Buettner, Garry R.; Cullen, Joseph J.] Holden Comprehens Canc Ctr, Iowa City, IA USA. [Cullen, Joseph J.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Levine, Mark] NIDDKD, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Cullen, JJ (reprint author), Univ Iowa Hosp & Clin, 4605 JCP, Iowa City, IA 52242 USA. EM joseph-cullen@uiowa.edu OI Buettner, Garry/0000-0002-5594-1903 FU NIH [CA115785]; Medical Research Service; Department of Veterans Affairs FX NIH grant CA115785; Medical Research Service; Department of Veterans Affairs; and Susan L. Bader Foundation of Hope and the Intramural Research Program, NIH. NR 46 TC 70 Z9 73 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 509 EP 520 DI 10.1158/1078-0432.CCR-09-1713 PG 12 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000016 PM 20068072 ER PT J AU Shimamura, T Fujisawa, T Husain, SR Joshi, B Puri, RK AF Shimamura, Takeshi Fujisawa, Toshio Husain, Syed R. Joshi, Bharat Puri, Raj K. TI Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor alpha 2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID CHIMERIC FUSION PROTEINS; CARCINOMA-CELLS; NECK-CANCER; HUMAN HEAD; CHAIN; GROWTH; MODEL; EXPRESSION; TARGET; GLIOMA AB Purpose: Interleukin-13 receptor alpha 2 (IL-13R alpha 2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13R alpha 2 in cancer. Experimental Design: The expression of IL-13R alpha 2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13R alpha 2 was examined by IL-13-induced signaling in pancreatic cancer cell lines. IL-13R alpha 2-positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer. Results: Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13R alpha 2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-beta 1 promoter activity in IL-13R alpha 2-positive tumor cells and in cells engineered to express IL-13R alpha 2 but not in IL-13R alpha 2-negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13R alpha 2-positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample. Conclusions: These results indicate that IL-13R alpha 2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-beta activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Clin Cancer Res; 16(2); 577-86. (C)2010 AACR. C1 [Shimamura, Takeshi; Fujisawa, Toshio; Husain, Syed R.; Joshi, Bharat; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN20 HFM-735,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov NR 31 TC 24 Z9 26 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 577 EP 586 DI 10.1158/1078-0432.CCR-09-2015 PG 10 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000022 PM 20068108 ER PT J AU Rasool, N LaRochelle, W Zhong, HH Ara, G Cohen, J Kohn, EC AF Rasool, Nabila LaRochelle, William Zhong, Haihong Ara, Gulshan Cohen, Joshua Kohn, Elise C. TI Secretory Leukocyte Protease Inhibitor Antagonizes Paclitaxel in Ovarian Cancer Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID SIGNAL-REGULATED KINASE; AZD6244 ARRY-142886; PROTEINASE-INHIBITOR; LUNG-CANCER; IN-VITRO; EGLIN-C; ELASTASE; PATHWAY; SLPI; ACTIVATION AB Purpose: Ovarian cancer recurrence with the development of paclitaxel resistance is an obstacle to long-term survival. We showed that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer. We hypothesize that SLPI may antagonize paclitaxel injury. Experimental Design: Differential SLPI induction in response to paclitaxel and in response to stable forced expression of SLPI was shown in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22, and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MAP/extracellular signal-regulated kinase (ERK) kinase inhibitor, U0126, and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo. Results: SLPI expression was lower in A2780-1A9 ovarian cancer cells than in PTX10 and PTX22, and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (P = 0.01); expression of and response to SLPI in OVCAR3 cells were abrogated by exposure to CR012. SLPI reduced the paclitaxel susceptibility of 1A9 and HEY-A8 cells (P <= 0.05), and SLPI expression did not increase the resistance of PTX10 and PTX22 cells. Both paclitaxel and SLPI overexpression induced ERK activation. Inhibition of MAP/ERK kinase with U0126 increased paclitaxel injury and overcame SLPI-mediated cell protection. It did not reinstate PTX10 sensitivity to paclitaxel, which was associated with AKT activation. Significant inhibition of OVCAR3 xenograft growth was observed with CR012 and paclitaxel, over single agents (P <= 0.001). Conclusions: A two-pronged approach confirmed that SLPI overcomes paclitaxel in part through activation of ERK1/2. These results credential SLPI as a molecular target for ovarian cancer and suggest CR012 as a tool for proof of concept. Clin Cancer Res; 16(2); 600-9. (C) 2010 AACR. C1 [Rasool, Nabila; Cohen, Joshua; Kohn, Elise C.] NCI, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [LaRochelle, William; Zhong, Haihong; Ara, Gulshan] CuraGen Corp, Branford, CT USA. RP Kohn, EC (reprint author), 10 Ctr Dr,MSC1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX N. Rasool, J. Cohen, ND, and E. C. Kohn are supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project is a research collaboration with the CuraGen investigators. NR 38 TC 13 Z9 13 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 600 EP 609 DI 10.1158/1078-0432.CCR-09-1979 PG 10 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000024 PM 20068074 ER PT J AU Annunziata, CM Walker, AJ Minasian, L Yu, MS Kotz, H Wood, BJ Calvo, K Choyke, P Kimm, D Steinberg, SM Kohn, EC AF Annunziata, Christina M. Walker, Amanda J. Minasian, Lori Yu, Minshu Kotz, Herbert Wood, Bradford J. Calvo, Katherine Choyke, Peter Kimm, Daniel Steinberg, Seth M. Kohn, Elise C. TI Vandetanib, Designed to Inhibit VEGFR2 and EGFR Signaling, Had No Clinical Activity as Monotherapy for Recurrent Ovarian Cancer and No Detectable Modulation of VEGFR2 SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; RANDOMIZED PHASE-II; PROTEIN MICROARRAYS; JAPANESE PATIENTS; TARGETED THERAPY; BEVACIZUMAB; TOXICITY; ZD6474; GEFITINIB; CARCINOMA AB Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. Experimental Design: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples. Results: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed. Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib. Clin Cancer Res; 16(2); 664-72. (C) 2010 AACR. C1 [Annunziata, Christina M.] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Choyke, Peter] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Calvo, Katherine] NIH, Hematol Serv, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Annunziata, CM (reprint author), NCI, NIH, Med Oncol Branch, Room 12N226,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Calvo, Katherine/A-8109-2009; Annunziata, Christina/L-3219-2016; OI Annunziata, Christina/0000-0003-2033-6532; Calvo, Katherine/0000-0002-0771-4191 FU Center for Cancer Research, National Cancer Institute FX Intramural Program of the Center for Cancer Research, National Cancer Institute. NR 28 TC 46 Z9 47 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 664 EP 672 DI 10.1158/1078-0432.CCR-09-2308 PG 9 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000030 PM 20068097 ER PT J AU Freidlin, B Jiang, WY Simon, R AF Freidlin, Boris Jiang, Wenyu Simon, Richard TI The Cross-Validated Adaptive Signature Design SO CLINICAL CANCER RESEARCH LA English DT Article ID ERROR ESTIMATION; BREAST-CANCER; EXPRESSION; PREDICTORS AB Purpose: Many anticancer therapies benefit only a subset of treated patients and may be overlooked by the traditional broad eligibility approach to design phase III clinical trials. New biotechnologies such as microarrays can be used to identify the patients that are most likely to benefit from anticancer therapies. However, due to the high-dimensional nature of the genomic data, developing a reliable classifier by the time the definitive phase III trail is designed may not be feasible. Experimental Design: Previously, Freidlin and Simon (Clinical Cancer Research, 2005) introduced the adaptive signature design that combines a prospective development of a sensitive patient classifier and a properly powered test for overall effect in a single pivotal trial. In this article, we propose a cross-validation extension of the adaptive signature design that optimizes the efficiency of both the classifier development and the validation components of the design. Results: The new design is evaluated through simulations and is applied to data from a randomized breast cancer trial. Conclusion: The cross-validation approach is shown to considerably improve the performance of the adaptive signature design. We also describe approaches to the estimation of the treatment effect for the identified sensitive subpopulation. Clin Cancer Res; 16(2); 691-8. (C) 2010 AACR. C1 [Freidlin, Boris; Simon, Richard] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Jiang, Wenyu] Queens Univ, Dept Math & Stat, Kingston, ON K7L 3N6, Canada. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN 8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 14 TC 70 Z9 71 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 691 EP 698 DI 10.1158/1078-0432.CCR-09-1357 PG 8 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000033 PM 20068112 ER PT J AU O'Connor, OA Portlock, C Moskowitz, C Hamlin, P Straus, D Gerecitano, J Gonen, M Dumitrescu, O Sarasohn, D Butos, J Neylon, E Cortelli, BMG Blumel, S Evens, AM Zelenetz, AD Wright, J Cooper, B Winter, J Vose, J AF O'Connor, Owen A. Portlock, Carol Moskowitz, Craig Hamlin, Paul Straus, David Gerecitano, John Gonen, Mithat Dumitrescu, Otilia Sarasohn, Debra Butos, John Neylon, Ellen Cortelli, Barbara Mac-Gregor Blumel, Susan Evens, Andrew M. Zelenetz, Andrew D. Wright, John Cooper, Brenda Winter, Jane Vose, Julie TI Time to Treatment Response in Patients with Follicular Lymphoma Treated with Bortezomib Is Longer Compared with Other Histologic Subtypes SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; NON-HODGKINS-LYMPHOMA; MANTLE CELL LYMPHOMA; PHASE-II; HEMATOLOGIC MALIGNANCIES; CLINICAL-EXPERIENCE; EXPRESSION; SURVIVAL; THERAPY; TRIAL AB Purpose: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma. Experimental Design: Patients with follicular lymphoma (FL), marginal zone lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia were eligible for study. Bortezomib was given at a dose of 1.5 mg/m(2) as an i.v. push on days 1, 4, 8, and 11 of a 21-day cycle. Eligibility included the following: (a) no more than three prior therapies, (b) at least 1 month since prior chemotherapy, (c) measurable disease, and (d) an absolute neutrophil count of >1,000/mu L and a platelet count >50,000/mu L for the first dose of any cycle. Results: Seventy-seven patients were registered, of which 69 were assessable for response based on the completion of two cycles of therapy. Subtypes included FL (59.5%), mantle cell lymphoma (52%), small lymphocytic lymphoma/chronic lymphocytic leukemia (16.2%), marginal zone lymphoma (21.6%), and one Waldenstrom's macroglobulinemia. The median number of prior therapies was three. The most common grade 3 toxicity was lymphopenia (35%) and thrombocytopenia (31%). Twenty-five patients experienced grade <= 2 sensory neuropathy (32), and 8% experienced grade 3 neurosensory toxicity. The overall response rate was 45% (40% on an intention to treat) including 10 complete remissions. Of 18 patients with FL, 9 responded with 4 complete response. The median time to treatment response for FL was 12 weeks, whereas the median time to treatment response for other subtypes of non-Hodgkin's lymphoma was only 4 weeks. Conclusions: These data suggest that bortezomib has significant single agent activity in patients with FL, and that longer durations of treatment may improve overall response. Clin Cancer Res; 16(2); 719-26. (C) 2010 AACR. C1 [Portlock, Carol; Moskowitz, Craig; Hamlin, Paul; Straus, David; Gerecitano, John; Butos, John; Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, Lymphoma Serv, New York, NY 10021 USA. [Gonen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Stat, New York, NY 10021 USA. [Dumitrescu, Otilia; Sarasohn, Debra] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Blumel, Susan; Vose, Julie] Univ Nebraska, Dept Med, Omaha, NE 68182 USA. [Evens, Andrew M.; Winter, Jane] Northwestern Univ, Dept Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Wright, John] NCI, Drug Dev Branch, CTEP, Bethesda, MD 20892 USA. [Cooper, Brenda] Case Western Reserve Univ, Univ Hosp Cleveland, Dept Med, Ctr Comprehens Canc, Cleveland, OH 44106 USA. RP O'Connor, OA (reprint author), Columbia Univ, Lymphoid Dev & Malignancy Program, Herbert Irving Comprehens Canc Ctr, Lymphoma Serv,Coll Phys & Surg,New York Presbyter, 1130 St Nicholas Ave,Room 216, New York, NY 10032 USA. EM oo2130@columbia.edu RI Gonen, Mithat/E-4826-2012; OI Zelenetz, Andrew/0000-0003-1403-6883; Sarasohn, Debra/0000-0002-8790-5528 FU Leukemia and Lymphoma Society Scholar in Research Award [K23 CA109613]; National Cancer Institute [UO1 CA 69913]; Lymphoma Research Foundation FX The Leukemia and Lymphoma Society Scholar in Research Award (O.A. O'Connor) and K23 CA109613 (A. M. Evens). This work was supported under a National Cancer Institute Phase II grant (UO1 CA 69913) and in part by a grant from the Lymphoma Research Foundation. NR 27 TC 33 Z9 33 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 719 EP 726 DI 10.1158/1078-0432.CCR-08-2647 PG 8 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000036 PM 20068103 ER PT J AU Sportes, C Babb, RR Krumlauf, MC Hakim, FT Steinberg, SM Chow, CK Brown, MR Fleisher, TA Noel, P Maric, I Stetler-Stevenson, M Engel, J Buffet, R Morre, M Amato, RJ Pecora, A Mackall, CL Gress, RE AF Sportes, Claude Babb, Rebecca R. Krumlauf, Michael C. Hakim, Frances T. Steinberg, Seth M. Chow, Catherine K. Brown, Margaret R. Fleisher, Thomas A. Noel, Pierre Maric, Irina Stetler-Stevenson, Maryalice Engel, Julie Buffet, Renaud Morre, Michel Amato, Robert J. Pecora, Andrew Mackall, Crystal L. Gress, Ronald E. TI Phase I Study of Recombinant Human Interleukin-7 Administration in Subjects with Refractory Malignancy SO CLINICAL CANCER RESEARCH LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; EARLY LYMPHOCYTE RECOVERY; METASTATIC BREAST-CANCER; VERSUS-HOST-DISEASE; B-LINEAGE CELLS; T-CELLS; PROLONGED SURVIVAL; POTENTIAL ROLE; HUMAN IL-7 AB Purpose: Interleukin-7 (IL-7) has critical and nonredundant roles in T-cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans. Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 mu g/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects. Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3(+), CD4(+), and CD8(+) lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving >= 10 mu g/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells. Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications. Clin Cancer Res; 16(2); 727-35. (C) 2010 AACR. C1 [Sportes, Claude; Babb, Rebecca R.; Krumlauf, Michael C.; Hakim, Frances T.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chow, Catherine K.] NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Engel, Julie; Buffet, Renaud; Morre, Michel] Cytheris Inc, Rockville, MD USA. [Amato, Robert J.] Methodist Hosp, Texas Med Ctr, Houston, TX 77030 USA. [Pecora, Andrew] Hackensack Univ, Med Ctr, Ctr Canc, Hackensack, NJ USA. [Brown, Margaret R.; Fleisher, Thomas A.; Noel, Pierre; Maric, Irina] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Sportes, C (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,CRC Room 43142, Bethesda, MD 20892 USA. EM csportes@mail.nih.gov FU National Cancer Institute, NIH, Department of Health and Human Services [01649] FX National Cancer Institute, NIH, Department of Health and Human Services in collaboration with Cytheris under a Cooperative Research and Development Agreement grant 01649. NR 38 TC 78 Z9 78 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 727 EP 735 DI 10.1158/1078-0432.CCR-09-1303 PG 9 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000037 PM 20068111 ER PT J AU Jacobs, S Fox, E Krailo, M Hartley, G Navid, F Wexler, L Blaney, SM Goodwin, A Goodspeed, W Balis, FM Adamson, PC Widemann, BC AF Jacobs, Shana Fox, Elizabeth Krailo, Mark Hartley, Gwen Navid, Fariba Wexler, Leonard Blaney, Susan M. Goodwin, Anne Goodspeed, Wendy Balis, Frank M. Adamson, Peter C. Widemann, Brigitte C. TI Phase II Trial of Ixabepilone Administered Daily for Five Days in Children and Young Adults with Refractory Solid Tumors: A Report from the Children's Oncology Group SO CLINICAL CANCER RESEARCH LA English DT Article ID EPOTHILONE-B ANALOG; METASTATIC BREAST-CANCER; CLINICAL-TRIAL; PEDIATRIC-PATIENTS; BMS-247550; PACLITAXEL; DOCETAXEL; INSTITUTE; SCHEDULE; BRANCH AB Purpose: Ixabepilone is a microtubule-stabilizing agent with activity in adult solid tumors and in pediatric tumor xenograft models that are resistant to paclitaxel. The maximum tolerated dose on the daily-for-5-days i.v. schedule was 6 mg/m(2)/dose in adults and 8 mg/m(2)/dose in children, and the primary dose-limiting toxicity (DLT) was neutropenia. This study aimed to determine the response rate to ixabepilone in six solid tumor strata in children and young adults. Experimental Design: We conducted a phase II trial of ixabepilone (8 mg/m(2)/dose for 5 days every 21 days) using a two-stage design in taxane-naive children and young adults with treatment-refractory, measurable rhabdomyosarcoma, Ewing sarcoma family tumors, osteosarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor, neuroblastoma, and Wilms tumor. Results: Sixty-one eligible patients (36 male) were enrolled. Median (range) age was 13 years (range, 336). Fifty-nine patients were fully evaluable for toxicity and response. DLTs, most commonly myelosuppression, occurred in 11 patients (15% incidence in 3-18 years old and 33% in 19-36 years old; P = 0.2) during cycle 1. The median (range) number of cycles was 2 (range, 1-38). No partial or complete responses (response evaluation criteria in solid tumors) were observed. Seven patients received >= 3 cycles, and two had prolonged stable disease (Wilms' tumor, 38 cycles; synovial sarcoma, 8 cycles). Conclusions: Ixabepilone at 8 mg/m(2)/dose daily for 5 days was tolerable in children and adolescents, but did not show evidence of clinical activity in the childhood solid tumors studied. Clin Cancer Res; 16(2); 750-4. (C) 2010 AACR. C1 [Jacobs, Shana] Childrens Natl Med Ctr, Washington, DC 20020 USA. [Fox, Elizabeth; Goodwin, Anne; Goodspeed, Wendy; Balis, Frank M.; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Krailo, Mark; Hartley, Gwen] Childrens Oncol Grp, Arcadia, CA USA. [Navid, Fariba] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Wexler, Leonard] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Blaney, Susan M.] Texas Childrens Canc Ctr, Houston, TX USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Krailo, Mark] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Jacobs, S (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20020 USA. EM jacobss@cnmc.org FU National Cancer Institute [U10 CA 98543]; NIH, National Cancer Institute, Center for Cancer Research FX National Cancer Institute Grant No. U10 CA 98543 and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 21 TC 20 Z9 21 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2010 VL 16 IS 2 BP 750 EP 754 DI 10.1158/1078-0432.CCR-09-1906 PG 5 WC Oncology SC Oncology GA 607ZE UT WOS:000278545000040 PM 20068084 ER PT J AU Zhao, YG Mailloux, CM Hermesz, E Palkovits, M Westphal, H AF Zhao, Yangu Mailloux, Christina M. Hermesz, Edit Palkovits, Miklos Westphal, Heiner TI A role of the LIM-homeobox gene Lhx2 in the regulation of pituitary development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Pituitary; Rathke's pouch; Infundibulum; LIM-homeobox; Lhx2; Transcription factor; Endocrine cell lineages; Organogenesis; Differentiation; Cell proliferation; Apoptosis; Transgenic ID RATHKES POUCH; LINEAGE DETERMINATION; CELL DIFFERENTIATION; ANTERIOR-PITUITARY; PROGENITOR CELLS; BINDING PROTEIN; CEREBRAL-CORTEX; ORGANOGENESIS; EXPRESSION; SPECIFICATION AB The mammalian pituitary gland originates from two separate germinal tissues during embryonic development. The anterior and intermediate lobes of the pituitary are derived from Rathke's pouch, a pocket formed by an invagination of the oral ectoderm. The posterior lobe is derived from the infundibulum, which is formed by evagination of the neuroectoderm in the ventral diencephalon. Previous studies have shown that development of Rathke's pouch and the generation of distinct populations of hormone-producing endocrine cell lineages in the anterior/intermediate pituitary lobes is regulated by a number of transcription factors expressed in the pouch and by inductive signals from the ventral diencephalon/infundibulum. However, little is known about factors that regulate the development of the posterior pituitary lobe. In this study, we show that the LIM-homeobox gene Lhx2 is extensively expressed in the developing ventral diencephalon, including the infundibulum and the posterior lobe of the pituitary. Deletion of Lhx2 gene results in persistent cell proliferation, a complete failure of evagination of the neuroectoderm in the ventral diencephalon, and defects in the formation of the distinct morphological features of the infundibulum and the posterior pituitary lobe. Rathke's pouch is formed and endocrine cell lineages are generated in the anterior/intermediate pituitary lobes of the Lhx2 mutant. However, the shape and organization of the pouch and the anterior/intermediate pituitary lobes are severely altered due to the defects in development of the infundibulum and the posterior lobe. Our study thus reveals an essential role for Lhx2 in the regulation of posterior pituitary development and suggests a mechanism whereby development of the posterior lobe may affect the development of the anterior and intermediate lobes of the pituitary gland. Published by Elsevier Inc. C1 [Zhao, Yangu; Mailloux, Christina M.; Hermesz, Edit; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Program Genom Dev, NIH, Bethesda, MD 20892 USA. [Hermesz, Edit] Univ Szeged, Dept Biochem & Mol Biol, H-6701 Szeged, Hungary. [Palkovits, Miklos] Semmelweis Univ, Lab Neuromorphol, H-1094 Budapest, Hungary. RP Westphal, H (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Program Genom Dev, NIH, Room 413,Bldg 6B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hw@mail.nih.gov RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 FU NICHD FX This work was supported by funds from the Intramural Research Program of NICHD. We would like to thank Drs. Jacques Drouin, Jeff Murray, and Michael Klymkowsky for providing the Pitx1, Pitx2, and Sox3 antibodies, respectively. The Islet1 and Lhx3 antibodies developed by Dr. Thomas Jessell were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of NICHD and maintained by the Department of Biology, University of Iowa, Iowa City, IA 52242. The antibodies to GH, MSH, and PRL were obtained from Dr. A. F. Parlow, the National Hormone and Peptide Program, NIDDK. NR 54 TC 27 Z9 29 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 JAN 15 PY 2010 VL 337 IS 2 BP 313 EP 323 DI 10.1016/j.ydbio.2009.11.002 PG 11 WC Developmental Biology SC Developmental Biology GA 548GO UT WOS:000273948300012 PM 19900438 ER PT J AU Liang, JK Bok, J Wu, DK AF Liang, Jennifer K. Bok, Jinwoong Wu, Doris K. TI Distinct contributions from the hindbrain and mesenchyme to inner ear morphogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Inner ear morphogenesis; Axial specification; Hindbrain; Rhombomere; Mesenchyme; Basilar papilla; Semicircular canals; Chicken ID AXIAL SPECIFICATION; NEURAL CREST; GENE; CHICK; EXPRESSION; COCHLEA; MICE; PROLIFERATION; SEGMENTATION; HEDGEHOG AB A mature inner ear is a complex structure consisting of vestibular and auditory components. Microsurgical ablations, rotations, and translocations were performed in ovo to identify the tissues that control inner ear morphogenesis. We show that mesenchyme/ectoderm adjacent to the developing ear specifically governs the shape of vestibular components - the semicircular canals and ampullae - by conferring anteroposterior axial information to these structures. In contrast, removal of individual hindbrain rhombomeres adjacent to the developing ear preferentially affects the growth and morphogenesis of the auditory subdivision, the cochlear duct, or basilar papilla. Removal of rhombomere 5 affects cochlear duct growth, while rhombomere 6 removal affects cochlear growth and morphogenesis. Rotating rhombomeres 5 and 6 along the anteroposterior axis also impacts cochlear duct morphogenesis but has little effect on the vestibular components. Our studies indicate that discrete tissues, acting at a distance. control the morphogenesis of distinct elements of the inner ear. These results provide a basis for identifying factors that are essential to vestibular and auditory development in vertebrates. (C) 2009 Published by Elsevier Inc. C1 [Liang, Jennifer K.; Wu, Doris K.] Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. [Bok, Jinwoong] Yonsei Univ, Coll Med, Dept Anat, Brain Korea Project Med Sci 21, Seoul 120752, South Korea. RP Bok, J (reprint author), NIDCD, 5 Res Court,Rm 2B34, Rockville, MD 20850 USA. EM bokj@yuhs.ac; wud@nidcd.nih.gov RI Bok, Jinwoong/B-8982-2016 OI Bok, Jinwoong/0000-0003-1958-1872 FU NIDCD FX We are grateful to Drs. Jennifer Hill and Steven Raft and the rest of the Wu Lab for comments and discussion throughout the writing process. We thank Dr. Yutzey for Hoxd4 plasmid. In addition, we wish to thank Drs. Andrew Griffith and Thomas Friedman for critical reading of this manuscript. This project was funded by the NIDCD Intramural Program. NR 32 TC 15 Z9 17 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2010 VL 337 IS 2 BP 324 EP 334 DI 10.1016/j.ydbio.2009.11.001 PG 11 WC Developmental Biology SC Developmental Biology GA 548GO UT WOS:000273948300013 PM 19896934 ER PT J AU Talamillo, A Delgado, I Nakamura, T De-Vega, S Yoshitomi, Y Unda, F Birchmeier, W Yamada, Y Ros, MA AF Talamillo, Ana Delgado, Irene Nakamura, Takashi de-Vega, Susana Yoshitomi, Yasuo Unda, Fernando Birchmeier, Walter Yamada, Yoshihiko Ros, Maria A. TI Role of Epiprofin, a zinc-finger transcription factor, in limb development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Epiprofin; Sp6; Sp/KLF; Limb development; Apical ectodermal ridge; AER; Syndactyly; Oligodactyly; WNT/b-CATENIN; BMP ID APICAL ECTODERMAL RIDGE; PROGRAMMED CELL-DEATH; VERTEBRATE LIMB; MOUSE LIMB; NEGATIVE REGULATOR; BETA-CATENIN/TCF; FEEDBACK LOOP; CHICK-EMBRYO; BUD MESODERM; OUTGROWTH AB The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. In the present work, we have investigated the role of Epiprofin (Epfn/Sp6), a member of the SP/KLF transcription factor family that is expressed in the limb ectoderm and the AER, during limb development. Epfn mutant mice have a defective autopod that shows mesoaxial syndactyly in the forelimb and synostosis (bony fusion) in the hindlimb and partial bidorsal digital tips. Epfn mutants also show a defect in the maturation of the AER that appears flat and broad, with a double ridge phenotype. By genetic analysis, we also show that Epfn is controlled by WNT/b-CATENIN signaling in the limb ectoderm. Since the less severe phenotypes of the conditional removal of b-catenin in the limb ectoderm strongly resemble the limb phenotype of Epfn mutants, we propose that EPFN very likely functions as a modulator of WNT signaling in the limb ectoderm. (C) 2009 Elsevier Inc. All rights reserved. C1 [Delgado, Irene; Ros, Maria A.] CSIC UC IDICAN, Fac Med, Inst Biomed & Biotecnol Cantabria IBBTEC, Santander 39011, Spain. [Nakamura, Takashi; de-Vega, Susana; Yoshitomi, Yasuo; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Unda, Fernando] Univ Basque Country, Fac Med & Odontol, Dept Biol Celular & Histol, Leioa 48490, Spain. [Birchmeier, Walter] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Talamillo, Ana; Delgado, Irene; Ros, Maria A.] Univ Cantabria, Fac Med, Dept Anat & Biol Celular, Santander 39011, Spain. RP Ros, MA (reprint author), CSIC UC IDICAN, Fac Med, Inst Biomed & Biotecnol Cantabria IBBTEC, Santander 39011, Spain. EM rosm@unican.es RI Ros, Maria /K-8160-2014; Delgado, Irene/L-9424-2014; Nakamura, Takashi/P-7796-2016 OI Ros, Maria /0000-0002-1224-7671; Delgado, Irene/0000-0002-0493-8261; Nakamura, Takashi/0000-0001-9904-1037 FU Spanish Ministry of Education and Science [BFU2008-00397]; IFIMAV [API 05/27]; NIDCR; University of the Basque Country [GIU05/27]; Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV) FX We are very grateful to G. Martin and F. Mariani for the double Fgf4;Fgf8 mutant embryos and to J. Galceran, A. Joyner, G. Martin, A. McMahon and C. Niehrs for generously providing reagents. This work was supported by grant BFU2008-00397 from the Spanish Ministry of Education and Science and grant API 05/27 from the IFIMAV to M.R., the Intramural Research Program of the NIDCR, NIH to Y.Y. and grant GIU05/27 from the University of the Basque Country to F.U. A.T. had a postdoctoral fellowship from the Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV). We acknowledge the excellent technical assistance of Marisa Junco. NR 70 TC 13 Z9 13 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2010 VL 337 IS 2 BP 363 EP 374 DI 10.1016/j.ydbio.2009.11.007 PG 12 WC Developmental Biology SC Developmental Biology GA 548GO UT WOS:000273948300016 PM 19913006 ER PT J AU Fujimoto, VY Luke, B Brown, MB Jain, T Armstrong, A Grainger, DA Hornstein, MD AF Fujimoto, Victor Y. Luke, Barbara Brown, Morton B. Jain, Tarun Armstrong, Alicia Grainger, David A. Hornstein, Mark D. CA Soc Assisted Reproductive Technol TI Racial and ethnic disparities in assisted reproductive technology outcomes in the United States SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 64th Annual Meeting of the American-Society-for-Reproductive-Medicine CY NOV 08-12, 2008 CL San Francisco, CA SP Amer Soc Reprod Med DE Ethnic disparities; racial disparities; Asian; black; Hispanic; ART outcomes; IVF outcomes; IVF pregnancy rates; IVF live birth rates; prematurity; growth restriction ID IN-VITRO FERTILIZATION; ADVERSE PREGNANCY OUTCOMES; LOW-BIRTH-WEIGHT; INTRAUTERINE GROWTH-CURVES; GLUCOSE-TOLERANCE TEST; BODY-MASS INDEX; GESTATIONAL-AGE; WHITE WOMEN; PERINATAL OUTCOMES; AFRICAN-AMERICAN AB Objective: To evaluate ethnic differences in assisted reproductive technology (ART) outcomes in the United States. Design: Historical cohort study. Setting: Clinic-based data. Patient(s): A total of 139,027 ART cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System online database for 2004-2006, limited to white, Asian, black, and Hispanic women. Intervention(S): None. Main Outcome Measure(s): Logistic regression was used to model the odds of pregnancy and live birth; among singletons and twins, the odds of preterm birth and fetal growth restriction. Results are presented as adjusted odds ratios, with white women as the reference group. Result(S): The odds of pregnancy were reduced for Asians (0.86), and the odds of live birth were reduced for all 1 groups: Asian (0.90), black (0.62), and Hispanic (0.87) women. Among singletons, moderate and severe growth restriction were increased for all infants in all three minority groups (Asians [1.78, 2.05]; blacks [1.81, 2.17]; Hispanics [1.36, 1.64]), and preterm birth was increased among black (1.79) and Hispanic women (1.22). Among twins, the odds for moderate growth restriction were increased for infants of Asian (1.30) and black women (1.97). and severe growth restriction was increased among black women (3.21). The odds of preterm birth were increased for blacks (1.64) and decreased for Asians (0.70). Conclusion(S): There are significant disparities in ART outcomes according to ethnicity. (Fertil Steril (R) 2010; 93:382-90. (C)2010 by American Society for Reproductive Medicine.) C1 [Fujimoto, Victor Y.] Univ Calif San Francisco, Ctr Reprod Hlth, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94115 USA. [Luke, Barbara] Michigan State Univ, Dept Obstet Gynecol & Reprod Biol, E Lansing, MI 48824 USA. [Luke, Barbara] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Brown, Morton B.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Jain, Tarun] Univ Illinois, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Chicago, IL 60612 USA. [Armstrong, Alicia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Grainger, David A.] Univ Kansas, Sch Med, Dept Obstet & Gynecol, Wichita, KS 67214 USA. [Grainger, David A.] Univ Kansas, Sch Med, Ctr Reprod Med, Wichita, KS 67214 USA. [Hornstein, Mark D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Fujimoto, VY (reprint author), Univ Calif San Francisco, Ctr Reprod Hlth, Dept Obstet Gynecol & Reprod Sci, 2356 Sutter St,7th Floor, San Francisco, CA 94115 USA. EM fujimotov@obgyn.ucsf.edu OI Jain, Tarun/0000-0002-8889-084X FU Intramural NIH HHS [Z99 HD999999] NR 64 TC 59 Z9 59 U1 0 U2 1 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 JAN 15 PY 2010 VL 93 IS 2 BP 382 EP 390 DI 10.1016/j.fertnstert.2008.10.061 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 554KL UT WOS:000274433800011 PM 19081561 ER PT J AU Hill, MJ Miller, KA Frattarelli, JL AF Hill, Micah J. Miller, Kathleen A. Frattarelli, John L. TI A GnRH agonist and exogenous hormone stimulation protocol has a higher live-birth rate than a natural endogenous hormone protocol for frozen-thawed blastocyst-stage embryo transfer cycles: an analysis of 1391 cycles SO FERTILITY AND STERILITY LA English DT Article DE In vitro fertilization; cryopreserved; blastocyst; natural cycle; synthetic cycle; embryo transfer ID REPLACEMENT CYCLES; SUPPRESSION; PREEMBRYOS; STEROIDS AB Objective: To compare embryo and birth data in cryopreserved-thawed blastocyst-stage ET cycles between natural endogenous hormone cycles and exogenous hormone stimulation cycles. Design: Retrospective cohort analysis. Setting: Large academic assisted reproductive technology center. Patient(s): One thousand three hundred ninety-one patient cycles undergoing frozen-thawed blastocyst-stage ET cycles. Main Outcome Measure(s): Live-birth rate. Intervention(s): The synthetic protocol used GnRH agonist followed by estrogen and P. The natural protocol used monitoring and post-transfer P. Result(S): The patients in the two protocols had similar baseline characteristics. Multiple linear regression showed the synthetic protocol to have a higher live-birth rate (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.02-2.09). In patients having two embryos transferred, the synthetic stimulation protocol resulted in a higher live-birth rate per cycle start (32.3% vs. 20.4%; relative risk [RR], 1.58; 95% CI, 1.22-2.06). Similarly, patients with one or two embryos transferred who had additional cryopreserved blastocysts available also had a higher live-birth rate per cycle start (36.1% vs. 12.1; RR, 2.98; 95% CI, 1.16-7.63). Conclusion(S): The synthetic hormone protocol was associated with a higher live-birth rate when compared with a natural cycle protocol for frozen-thawed blastocyst-stage ET cycles. This improvement persisted when analysis was controlled for cycle cancellation. The synthetic stimulation protocol for frozen-thawed embryo cycles offers improved outcome results for patients. (Fertil Steril (R) 2010:93:416-22. (C)2010 by American Society for Reproductive Medicine.) C1 [Hill, Micah J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. [Miller, Kathleen A.; Frattarelli, John L.] Reprod Med Associates New Jersey, Morristown, NJ USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, NIH, Bldg 10,CRC,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov NR 14 TC 18 Z9 23 U1 0 U2 6 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 JAN 15 PY 2010 VL 93 IS 2 BP 416 EP 422 DI 10.1016/j.fertnstert.2008.11.027 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 554KL UT WOS:000274433800015 PM 19171338 ER PT J AU Samuni, Y Flores-Santana, W Krishna, MC Mitchell, JB Wink, DA AF Samuni, Yuval Flores-Santana, Wilmarie Krishna, Murali C. Mitchell, James B. Wink, David A. TI The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation (vol 47, pg 419, 2009) SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Correction C1 [Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C.; Mitchell, James B.; Wink, David A.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM murali@helix.nih.gov NR 1 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2010 VL 48 IS 2 BP 372 EP 372 DI 10.1016/j.freeradbiomed.2009.10.001 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 547JQ UT WOS:000273883800022 ER PT J AU Yakovlev, A Khafizova, M Abdullaev, Z Loukinov, D Kondratyev, A AF Yakovlev, Alexander Khafizova, Maryam Abdullaev, Ziedulla Loukinov, Dmitri Kondratyev, Alexei TI Epigenetic regulation of caspase-3 gene expression in rat brain development SO GENE LA English DT Article DE DNA methylation; Histone acetylation; Caspase-3; Promoter; Rat brain ID DNA METHYLATION; HISTONE ACETYLATION; TRANSCRIPTIONAL ACTIVITY; TARGET GENES; PROMOTER; APOPTOSIS; CANCER; ACTIVATION; CHROMATIN; IDENTIFICATION AB The expression levels of caspase-3, a major contributor to the execution of neuronal apoptosis, markedly decrease in the process of brain maturation. We have previously cloned the rat caspase-3 gene promoter and identified its essential regulatory elements. In the present study, we extended previous findings by examining transcriptional regulation of caspase-3 expression in the rat brain of two different ages, corresponding to the immature and mature brain. In particular, we determined that the rate of transcription initiation substantially declines during brain maturation. Furthermore, we established that mRNA levels of Ets1, Ets2, and Sp1 do not change in the brain with maturation, suggesting that these transcription factors do not contribute to age-dependent caspase-3 down-regulation. Hence, we examined a role of DNA methylation and histone modification in this process. Utilizing bisulfite DNA sequencing, we determined the presence of age-dependent differentially methylated fragments within the caspase-3 promoter region. Strikingly, differentially methylated CpG sites correspond to the predicted binding sites for a number of transcription factors that have been previously shown to be involved in neuronal development and differentiation. Moreover, using chromatin immunoprecipitation, we found that mature brains displayed significantly lower levels of histone 3 acetylated Lys14 and histone 4 acetylated Lys5, 8, 12, and 16. This observation is consistent with the decreased level of expression of caspase-3 in the mature brain. Together with our observation that histone deacetylase inhibitor, trichostatin A, increased the level of caspase-3 mRNA in cortical neurons in vitro, these results further indicate an important role of epigenetic factors in the regulation of caspase-3 gene expression. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kondratyev, Alexei] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. [Kondratyev, Alexei] Georgetown Univ, Dept Pharmacol, Washington, DC 20057 USA. [Yakovlev, Alexander; Khafizova, Maryam] Georgetown Univ, Dept Neurosci, Washington, DC 20057 USA. [Abdullaev, Ziedulla; Loukinov, Dmitri] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Kondratyev, A (reprint author), Georgetown Univ, Dept Pediat, W208 Res Bldg,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM kondrata@georgetown.edu FU National Institute of Neurological Disorders and Stroke [NS048974, NS056057]; National Institute of Allergy and Infectious Disease FX This study was supported by the grants NS048974 and NS056057 from the National Institute of Neurological Disorders and Stroke. The work was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Disease. The authors thank Mr. Guillermo Palchik for help in preparation of the manuscript. NR 46 TC 17 Z9 19 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 15 PY 2010 VL 450 IS 1-2 BP 103 EP 108 DI 10.1016/j.gene.2009.10.008 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 547YF UT WOS:000273925100014 PM 19909801 ER PT J AU Lehotzky, A Lau, P Tokeso, N Muja, N Hudson, LD Ovadv, J AF Lehotzky, Attila Lau, Pierre Tokeso, Natalia Muja, Naser Hudson, Lynn D. Ovadv, Judit TI Tubulin Polymerization-Promoting Protein (TPPP/p25) is Critical for Oligodendrocyte Differentiation SO GLIA LA English DT Article DE TPPP/p25; oligodendrocytes; cytoskeleton; microRNA ID MULTIPLE SYSTEM ATROPHY; RAT-BRAIN; GENE-EXPRESSION; NERVOUS-SYSTEM; MICRORNA; IDENTIFICATION; CELLS; ASTROCYTES; BLOCKS; SITES AB TPPP/p25, a recently identified tubulin polyinerization-promoting protein (TPPP), is expressed mainly in myelinating oligodendrocytes of the CNS. Here, we show that TPPP/p25 is strongly upregulated during the differentiation of primary oligodendrocyte cells as well as the CG-4 cell line. The microRNA expression profile of CG-4 cells before and after induction of differentiation was established and revealed differential regulation of a limited subset of microRNAs. miR-206, a microRNA predicted to target TPPP/p25 was not detected in oligodendrocytes. Overexpression of miR-206 led to downreg-ulation of TPPP/p25 resulting in inhibition of differentiation. Transfection of siRNAs against TPPP/p25 also inhibited cell differentiation and promoted cell proliferation, providing evidence for an important role of TPPP/p25 during oligodendrogenesis. These results support an essential role for TPPP/p25 in oligodendrocyte differentiation likely via rearrangement of the microtubule system during the process elongation prior to the onset of myelination. (C) 2009 Wiley-Liss, Inc. C1 [Lehotzky, Attila; Tokeso, Natalia; Ovadv, Judit] Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, H-1113 Budapest, Hungary. [Lau, Pierre; Muja, Naser; Hudson, Lynn D.] NINDS, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Ovadv, J (reprint author), Hungarian Acad Sci, Inst Enzymol, Biol Res Ctr, Karolina Ut 29, H-1113 Budapest, Hungary. EM ovadi@enzim.hu OI Attila, Lehotzky/0000-0001-5235-1812 FU Hungarian National Scientific Research Fund [OTKA T-067963]; BioSim [FP6-2003-LIFESCIHEA-LTH-I]; NIH/NUNDS FX Hungarian National Scientific Research Fund; Grant number: OTKA T-067963 (to J.O.); Grant sponsors: BioSim (FP6-2003-LIFESCIHEA-LTH-I; to J.O.), NIH/NUNDS (to L.D.H.). NR 38 TC 51 Z9 53 U1 0 U2 15 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD JAN 15 PY 2010 VL 58 IS 2 BP 157 EP 168 DI 10.1002/glia.20909 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 528UK UT WOS:000272472300004 PM 19606501 ER PT J AU Chang, WZ Barnes, AM Cabral, WA Bodurtha, JN Marini, JC AF Chang, Weizhong Barnes, Aileen M. Cabral, Wayne A. Bodurtha, Joann N. Marini, Joan C. TI Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex SO HUMAN MOLECULAR GENETICS LA English DT Article ID CARTILAGE-ASSOCIATED PROTEIN; RECESSIVE OSTEOGENESIS IMPERFECTA; CYCLOPHILIN-B; IN-VITRO; TRIPLE-HELIX; BETA-SUBUNIT; MUTATIONS; HYDROXYLYSINE; GLYCOSYLATION; 4-HYDROXYLASE AB Null mutations in cartilage-associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) cause types VII and VIII OI, respectively, two novel recessive forms of osteogenesis imperfecta (OI) with severe to lethal bone dysplasia and overmodification of the type I collagen helical region. CRTAP and P3H1 form a complex with cyclophilin B (CyPB) in the endoplasmic reticulum (ER) which 3-hydroxylates the Pro986 residue of alpha 1(I) and alpha 1(II) collagen chains. We investigated the interaction of complex components in fibroblasts from types VII and VIII OI patients. Both CRTAP and P3H1 are absent or reduced on western blots and by immunofluorescence microscopy in cells containing null mutations in either gene. Levels of LEPRE1 or CRTAP transcripts, however, are normal in CRTAP- or LEPRE1-null cells, respectively. Stable transfection of a CRTAP or LEPRE1 expression construct into cells with null mutations for the transfected cDNA restored both CRTAP and P3H1 protein levels. Normalization of collagen helical modification in transfected CRTAP-null cells demonstrated that the restored proteins functioned effectively as a complex. These data indicate that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex. CyPB levels were unaffected by mutations in either CRTAP or LEPRE1. Proteasomal inhibitors partially rescue P3H1 protein in CRTAP-null cells. In LEPRE1-null cells, secretion of CRTAP is increased compared with control cells and accounts for 15-20% of the decreased CRTAP detected in cells. Thus, mutual stabilization of P3H1 and CRTAP in the ER collagen modification complex is an underlying mechanism for the overlapping phenotype of types VII and VIII OI. C1 [Chang, Weizhong; Barnes, Aileen M.; Cabral, Wayne A.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Bodurtha, Joann N.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA. RP Marini, JC (reprint author), NICHD, Bone & Extracellular Matrix Branch, NIH, Bldg 10,Room 10N260,9000 Rockville Pike, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov FU NICHD Intramural Funds FX This work was supported by NICHD Intramural Funds to J.C.M. NR 50 TC 29 Z9 31 U1 0 U2 1 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 JAN 15 PY 2010 VL 19 IS 2 BP 223 EP 234 DI 10.1093/hmg/ddp481 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 537LJ UT WOS:000273114100002 PM 19846465 ER PT J AU Li, Q Anver, MR Li, ZT Butcher, DO Gildersleeve, JC AF Li, Qian Anver, Miriam R. Li, Zhitao Butcher, Donna O. Gildersleeve, Jeffrey C. TI GalNAc alpha 1-3Gal, a new prognostic marker for cervical cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE carbohydrate; prognostic marker; cervical cancer; glycan array ID TN ANTIGEN; NEOPLASTIC TRANSFORMATION; CARBOHYDRATE ANTIGENS; VACCINE DEVELOPMENT; IMMUNOREACTIVE T; EXPRESSION; ANTIBODIES; CARCINOMA; LECTINS; SPECIFICITY AB Cancer cells undergo significant changes in carbohydrate expression, and these alterations can be useful as biomarkers and therapeutic targets. In this study, we investigated the expression of carbohydrate antigens containing a terminal GalNac alpha-1-3Gal or GalNAc alpha 1-6Gal on human cervix and cervical carcinoma. Monoclonal antibodies to each of these carbohydrates were generated by immunizing rabbits with the corresponding antigen conjugated to KLH followed by hybridoma production. Antibodies were screened and evaluated using a combination of carbohydrate microarray profiting, ELISA, dot blot and immunohistochemical staining to verify specificity. Antibody 132-3 was found to selectively recognize GalNAc alpha 1-3Gal with little cross-reactivity to other structurally similar antigens such as GalNAc alpha 1-6Gal, blood group A, Forssman antigen and the Tn antigen on both solution assays and human tissue. Although GalNac alpha 1-6Gal expression was not detected, GalNac alpha 1-6Gal expression was found on 55% of squamous cell carcinomas. Expression in normal tissue was observed but was restricted to the suprabasal epithelial layer. Importantly, we found expression of the antigen on cervical cancer had a statistically significant correlation with the 5-year survival rate of the patients (48 vs. 85% for antigen negative vs. positive, p = 0.017). Expression of GalNAc alpha 1-3Gal did not correlate with other clinical factors including tumor stage, size and lymph node metastasis, indicating the antigen is a new, independent biomarker for the prognosis of cervical cancer. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America. C1 [Li, Qian; Li, Zhitao; Gildersleeve, Jeffrey C.] NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. [Anver, Miriam R.; Butcher, Donna O.] NCI, SAIC, Pathol Histotechnol Lab, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. EM gildersleevej@ncifcrf.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Grant sponsor: National Cancer Institute, National Institutes of Health (in part); Grant number: HHSN261200800001E; Grant sponsor: National Cancer Institute, Center for Cancer Research, NIH (Intramural Research program) NR 37 TC 19 Z9 19 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2010 VL 126 IS 2 BP 459 EP 468 DI 10.1002/ijc.24716 PG 10 WC Oncology SC Oncology GA 538NC UT WOS:000273190200016 PM 19585575 ER PT J AU Zhang, L Ren, J Pan, KF Ma, JL Li, JY Shen, L Zhang, XD Li, J Fan, DM Gail, M You, WC AF Zhang, Lian Ren, Jun Pan, Kaifeng Ma, Junling Li, Jiyou Shen, Lin Zhang, Xiaodong Li, Jie Fan, Daiming Gail, Mitchell You, Weicheng TI Detection of gastric carcinoma-associated MG7-Ag by serum immuno-PCR assay in a high-risk Chinese population, with implication for screening SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gastric cancer; screening; MG7-Ag; Immuno-PCR assay ID CANCER; ANTIGEN; LESIONS; IDENTIFICATION; CLASSIFICATION; PEPSINOGENS AB To evaluate gastric carcinoma-associated antigen, MG7-Ag, for detection of gastric cancer in a high-risk population, a population-based screening of gastric cancer was conducted in Linqu County, Shandong Province, China. In 2002 and 2003, a total of 2,710 participants aged 35-65 years received an endoscopic examination with 5 biopsies taken from standard sites with pathological diagnosis, and serum samples were collected to detect MG7-Ag by serum-based Immunopolymerase chain reaction (PCR) assay. The sensitivity and specificity of MG7-Ag Immuno-PCR assay in detecting of gastric cancer were assessed. Of 2,710 participants, 148 (5.46%) were determined to be MG7-Ag positive. The sensitivity of MG7-Ag Immuno-PCR assay for the detection of gastric cancer was 77.5% (31 of 40 gastric cancer cases), the specificity was 95.62% (2,553 of 2,670 nongastric cancer subjects) and the accuracy was 73.12%. A total of 24 gastric cancer cases were in Stage I or II, of which 17 (70.8%) were MG7-Ag positive. However, the proportion of MG7-Ag positivity in subjects with superficial gastritis, chronic atrophic gastritis, intestinal metaplasia, indefinite dysplasia or dysplasia was ranged from 3.00% to 5.61% in comparison with 77.5% in those with gastric cancer. Our findings suggest that MG7-Ag was a sensitive and specific serum biomarker and may have a potential for gastric cancer screening in the high-risk population. C1 [Zhang, Lian; Ren, Jun; Pan, Kaifeng; Ma, Junling; Li, Jiyou; Shen, Lin; Zhang, Xiaodong; Li, Jie; You, Weicheng] Peking Univ, Beijing Canc Hosp & Inst, Sch Oncol,Minist Educ, Dept Canc Epidemiol,Key Lab Carcinogenesis & Tran, Beijing 100142, Peoples R China. [Fan, Daiming] Fourth Mil Med Univ, Dept Digest Dis, Xian 710032, Peoples R China. [Gail, Mitchell] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP You, WC (reprint author), Peking Univ, Beijing Canc Hosp & Inst, Sch Oncol,Minist Educ, Dept Canc Epidemiol,Key Lab Carcinogenesis & Tran, 52 Fu Cheng Rd, Beijing 100142, Peoples R China. EM weichengyou@yahoo.com FU National Basic Research Program of China [2004CB518702, 2010CB529303]; National 10.5 program [2004BA703B04] FX Grant sponsor: National Basic Research Program of China (973 program); Grant numbers: 2004CB518702 and 2010CB529303; Grant sponsor: National 10.5 program; Grant number: 2004BA703B04 NR 24 TC 7 Z9 10 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2010 VL 126 IS 2 BP 469 EP 473 DI 10.1002/ijc.24739 PG 5 WC Oncology SC Oncology GA 538NC UT WOS:000273190200017 PM 19588495 ER PT J AU Kurtoglu, YE Mishra, MK Kannan, S Kannan, RM AF Kurtoglu, Yunus E. Mishra, Manoj K. Kannan, Sujatha Kannan, Rangaramanujam M. TI Drug release characteristics of PAMAM dendrimer-drug conjugates with different linkers SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE PAMAM; Dendrimer-drug conjugate; Ibuprofen; PEG-drug conjugate; Drug release ID BIOMEDICAL APPLICATIONS; CELLULAR-TRANSPORT; DELIVERY; POLYMERS; PRODRUGS AB Drug release from polymer-drug conjugates plays a crucial role on the efficacy. This is especially true for dendrimers where there is a steric crowding at the surface. The drug release characteristics of G4-polyamidoamine (PAMAM) dendrimer-ibuprofen conjugates with ester, amide, and peptide linkers were investigated, in addition to a linear PEG-ibuprofen conjugate to understand the effect of architecture and linker on drug release. lbuprofen was directly conjugated to NH(2)-terminated dendrimer by an amide bond and OH-terminated dendrimer by an ester bond. A tetra-peptide-linked dendrimer conjugate and a linear mPEG-ibuprofen conjugate were also studied for comparison to direct linked dendrimer conjugates. Amide-linked conjugates were relatively stable against hydrolysis, whereas the ester-linked conjugates showed pH-dependent release and the extent of release varied with pH from 3% (pH 5) to 38% (pH 8.5) for the 10-day period studied. Direct amide- and ester-linked conjugates did not release ibuprofen enzymatically in cathepsin B buffer and diluted human plasma. In contrast, mPEG conjugate released 65% of its payload within 12 h in diluted plasma by esterase activity, and the peptide-linked dendrimer conjugate released 40% of its payload within 48 h by cathepsin B activity. It is demonstrated that the steric crowding at the surface of PAMAM dendrimer-drug conjugates, along with linking chemistry govern the drug release mechanisms as well as kinetics. Understanding these structural and steric effects on their drug release characteristics is crucial for the design of dendrimer conjugates with high efficacy. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kurtoglu, Yunus E.; Mishra, Manoj K.; Kannan, Rangaramanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. [Kurtoglu, Yunus E.; Kannan, Sujatha; Kannan, Rangaramanujam M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kannan, Sujatha] Wayne State Univ, Dept Pediat Crit Care Med, Childrens Hosp Michigan, Detroit, MI 48202 USA. RP Kannan, RM (reprint author), Wayne State Univ, Dept Chem Engn & Mat Sci, Detroit, MI 48202 USA. EM rkannan@eng.wayne.edu FU Wayne State University Wilson Foundation FX This study was supported by the Wayne State University Wilson Foundation and Wayne Sate University nanotechnology effort. NR 18 TC 70 Z9 80 U1 4 U2 53 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JAN 15 PY 2010 VL 384 IS 1-2 BP 189 EP 194 DI 10.1016/j.ijpharm.2009.10.017 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 547WU UT WOS:000273921200026 PM 19825406 ER PT J AU Alper, S McElwee, MK Apfeld, J Lackford, B Freedman, JH Schwartz, DA AF Alper, Scott McElwee, Matthew K. Apfeld, Javier Lackford, Brad Freedman, Jonathan H. Schwartz, David A. TI The Caenorhabditis elegans Germ Line Regulates Distinct Signaling Pathways to Control Lifespan and Innate Immunity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-ELEGANS; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; POLYMORPHIC VARIANTS; SERRATIA-MARCESCENS; RESISTANT MUTANTS; VIRULENCE FACTORS; HUMAN LONGEVITY; I RECEPTOR; INSULIN AB The relationship between the mechanisms that control an organism's lifespan and its ability to respond to environmental challenges are poorly understood. In Caenorhabditis elegans, an insulin-like signaling pathway modulates lifespan and the innate immune response to bacterial pathogens via a common mechanism involving transcriptional regulation by the DAF-16/FOXO transcription factor. The C. elegans germ line also modulates lifespan in a daf-16-dependent manner. Here, we show that the germ line controls the innate immune response of C. elegans somatic cells to two different Gram-negative bacteria. In contrast to the insulin-like signaling pathway, the germ line acts via distinct signaling pathways to control lifespan and innate immunity. Under standard nematode culture conditions, the germ line regulates innate immunity in parallel to a known p38 MAPK signaling pathway, via a daf-16-independent pathway. Our findings indicate that a complex regulatory network integrates inputs from insulin-like signaling, p38 MAPK signaling, and germ line stem cells to control innate immunity in C. elegans. We also confirm that innate immunity and lifespan in C. elegans are distinct processes, as nonoverlapping regulatory networks control survival in the presence of pathogenic and nonpathogenic bacteria. Finally, we demonstrate that the p38 MAPK pathway in C. elegans is activated to a similar extent by both pathogenic and nonpathogenic bacteria, suggesting that both can induce the nematode innate immune response. C1 [Alper, Scott] Natl Jewish Hlth, Integrated Dept Immunol, Denver, CO 80206 USA. [Schwartz, David A.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [McElwee, Matthew K.; Freedman, Jonathan H.] NIEHS, Mol Toxicol Lab, NIH, Durham, NC 27709 USA. [Lackford, Brad] NIEHS, Mol Carcinogenesis Lab, NIH, Durham, NC 27709 USA. [Apfeld, Javier] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [McElwee, Matthew K.] Duke Univ, Nicholas Sch Environm, Durham, NC 27707 USA. RP Alper, S (reprint author), Natl Jewish Hlth, Integrated Dept Immunol, 1400 Jackson St,A640, Denver, CO 80206 USA. EM alpers@njhealth.org OI Apfeld, Javier/0000-0001-9897-5671 FU NHLBI; National Institutes of Health, NIEHS; National Institutes of Health; National Toxicology Program FX This work was supported by the Intramural Research Program of NHLBI, National Institutes of Health, NIEHS, National Institutes of Health, and the National Toxicology Program. NR 61 TC 29 Z9 35 U1 2 U2 7 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 JAN 15 PY 2010 VL 285 IS 3 BP 1822 EP 1828 DI 10.1074/jbc.M109.057323 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541PJ UT WOS:000273429100028 PM 19923212 ER PT J AU Redmond, TM Poliakov, E Kuo, S Chander, P Gentleman, S AF Redmond, T. Michael Poliakov, Eugenia Kuo, Stephanie Chander, Preethi Gentleman, Susan TI RPE65, Visual Cycle Retinol Isomerase, Is Not Inherently 11-cis-specific SUPPORT FOR A CARBOCATION MECHANISM OF RETINOL ISOMERIZATION SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LEBERS CONGENITAL AMAUROSIS; PIGMENT EPITHELIAL-CELLS; CATION-PI INTERACTIONS; ALL-TRANS-RETINOL; BETA-CAROTENE; VITAMIN-A; BINDING PROTEIN; ENERGY-SOURCE; GENE-THERAPY; CIS-RETINOLS AB The mechanism of retinol isomerization in the vertebrate retina visual cycle remains controversial. Does the isomerase enzyme RPE65 operate via nucleophilic addition at C(11) of the all-trans substrate, or via a carbocation mechanism? To determine this, we modeled the RPE65 substrate cleft to identify residues interacting with substrate and/or intermediate. We find that wild-type RPE65 in vitro produces 13-cis and 11-cis isomers equally robustly. All Tyr-239 mutations abolish activity. Trp-331 mutations reduce activity (W331Y to similar to 75% of wild type, W331F to similar to 50%, and W331L and W331Q to 0%) establishing a requirement for aromaticity, consistent with cation-pi carbocation stabilization. Two cleft residues modulate isomerization specificity: Thr-147 is important, because replacement by Ser increases 11-cis relative to 13-cis by 40% compared with wild type. Phe-103 mutations are opposite in action: F103L and F103I dramatically reduce 11-cis synthesis relative to 13-cis synthesis compared with wild type. Thr-147 and Phe-103 thus may be pivotal in controlling RPE65 specificity. Also, mutations affecting RPE65 activity coordinately depress 11-cis and 13-cis isomer production but diverge as 11-cis decreases to zero, whereas 13-cis reaches a plateau consistent with thermal isomerization. Lastly, experiments using labeled retinol showed exchange at 13-cis-retinol C(15) oxygen, thus confirming enzymatic isomerization for both isomers. Thus, RPE65 is not inherently 11-cis-specific and can produce both 11- and 13-cis isomers, supporting a carbocation (or radical cation) mechanism for isomerization. Specific visual cycle selectivity for 11-cis isomers instead resides downstream, attributable to mass action by CRALBP, retinol dehydrogenase 5, and high affinity of opsin apoproteins for 11-cis-retinal. C1 [Redmond, T. Michael; Poliakov, Eugenia; Kuo, Stephanie; Chander, Preethi; Gentleman, Susan] NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bldg 6,Room 117A, Bethesda, MD 20892 USA. EM redmond@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program of NEI. NR 55 TC 28 Z9 28 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 15 PY 2010 VL 285 IS 3 BP 1919 EP 1927 DI 10.1074/jbc.M109.027458 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541PJ UT WOS:000273429100038 PM 19920137 ER PT J AU Chung, NPY Breun, SKJ Bashirova, A Baumann, JG Martin, TD Karamchandani, JM Rausch, JW Le Grice, SFJ Wu, L Carrington, M KewalRamani, VN AF Chung, Nancy P. Y. Breun, Sabine K. J. Bashirova, Arman Baumann, Joerg G. Martin, Thomas D. Karamchandani, Jaideep M. Rausch, Jason W. Le Grice, Stuart F. J. Wu, Li Carrington, Mary KewalRamani, Vineet N. TI HIV-1 Transmission by Dendritic Cell-specific ICAM-3-grabbing Nonintegrin (DC-SIGN) Is Regulated by Determinants in the Carbohydrate Recognition Domain That Are Absent in Liver/Lymph Node-SIGN (L-SIGN) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; C-TYPE LECTIN; RESPIRATORY SYNDROME CORONAVIRUS; T-CELLS; ENDOTHELIAL-CELLS; ADHESION RECEPTOR; STRUCTURAL BASIS; TRANS-INFECTION; BINDING-SITES; DENGUE VIRUS AB In this study, we identify determinants in dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) necessary for human immunodeficiency virus, type 1 (HIV-1), transmission. Although human B cell lines expressing DC-SIGN efficiently capture and transmit HIV-1 to susceptible target cells, cells expressing the related molecule liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) do not. To understand the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions, we developed Raji B cell lines expressing different DC-SIGN/L-SIGN chimeras. Testing of the chimeras demonstrated that replacement of the DC-SIGN carbohydrate-recognition domain (CRD) with that of L-SIGN was sufficient to impair virus binding and prevent transmission. Conversely, the ability to bind and transmit HIV-1 was conferred to L-SIGN chimeras containing the DC-SIGN CRD. We identified Trp-258 in the DC-SIGN CRD to be essential for HIV-1 transmission. Although introduction of a K270W mutation at the same position in L-SIGN was insufficient for HIV-1 binding, an L-SIGN mutant molecule with K270W and a C-terminal DC-SIGN CRD subdomain transmitted HIV-1. These data suggest that DC-SIGN structural elements distinct from the oligosaccharide-binding site are required for HIV-1 glycoprotein selectivity. C1 [Chung, Nancy P. Y.; Martin, Thomas D.; Karamchandani, Jaideep M.; Rausch, Jason W.; Le Grice, Stuart F. J.; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Breun, Sabine K. J.; Baumann, Joerg G.] Fraunhofer Inst Cell Therapy & Immunol, D-04103 Leipzig, Germany. [Bashirova, Arman; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick,NIH, Frederick, MD 21702 USA. [Wu, Li] Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. RP KewalRamani, VN (reprint author), NCI, HIV Drug Resistance Program, NIH, 1050 Boyles St, Frederick, MD 21702 USA. EM vineet@mail.nih.gov RI Wu, Li/E-4330-2011 OI Wu, Li/0000-0002-5468-2487 FU National Institutes of Health [HHSN261200800001E]; NCI Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Grant HHSN261200800001E from NCI, NCI Intramural Research Program, and NCI Center for Cancer Research. NR 50 TC 8 Z9 8 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 JAN 15 PY 2010 VL 285 IS 3 BP 2100 EP 2112 DI 10.1074/jbc.M109.030619 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 541PJ UT WOS:000273429100054 PM 19833723 ER PT J AU Lewis, BA AF Lewis, Brian A. TI Understanding large multiprotein complexes: applying a multiple allosteric networks model to explain the function of the Mediator transcription complex SO JOURNAL OF CELL SCIENCE LA English DT Article DE Mediator; Graph theory; Networks; Transcription ID RNA-POLYMERASE-II; COACTIVATOR COMPLEXES; CONFORMATIONAL SPREAD; PROTEIN-INTERACTION; NUCLEAR RECEPTORS; YEAST; ACTIVATOR; HOLOENZYME; ORGANIZATION; RESIDUES AB The regulation of transcription and of many other cellular processes involves large multi-subunit protein complexes. In the context of transcription, it is known that these complexes serve as regulatory platforms that connect activator DNA-binding proteins to a target promoter. However, there is still a lack of understanding regarding the function of these complexes. Why do multi-subunit complexes exist? What is the molecular basis of the function of their constituent subunits, and how are these subunits organized within a complex? What is the reason for physical connections between certain subunits and not others? In this article, I address these issues through a model of network allostery and its application to the eukaryotic RNA polymerase II Mediator transcription complex. The multiple allosteric networks model (MANM) suggests that protein complexes such as Mediator exist not only as physical but also as functional networks of interconnected proteins through which information is transferred from subunit to subunit by the propagation of an allosteric state known as conformational spread. Additionally, there are multiple distinct sub-networks within the Mediator complex that can be defined by their connections to different subunits; these sub-networks have discrete functions that are activated when specific subunits interact with other activator proteins. C1 NCI, Transcript Regulat & Biochem Unit, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lewis, BA (reprint author), NCI, Transcript Regulat & Biochem Unit, Metab Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lewisbri@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Special thanks to Patrick Trojer, Robert Sims, Michael Hampsey, Joseph Fondell, David Levens, and Dinah Singer for critical reading of the manuscript. NR 46 TC 2 Z9 2 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2010 VL 123 IS 2 BP 159 EP 163 DI 10.1242/jcs.057216 PG 5 WC Cell Biology SC Cell Biology GA 539MN UT WOS:000273258900002 PM 20048337 ER PT J AU Phillips, TM AF Phillips, Terry M. TI Immunoaffinity techniques in analysis Preface SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Editorial Material ID BIOMARKERS C1 NIH, Bethesda, MD 20892 USA. RP Phillips, TM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM phillipt@mail.nih.gov FU Intramural NIH HHS [NIH0010602809]; PHS HHS [NIH0010602809] NR 7 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2010 VL 878 IS 2 SI SI BP 113 EP 114 DI 10.1016/j.jchromb.2009.12.001 PG 2 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 551PG UT WOS:000274220900001 PM 20022568 ER PT J AU Ito, Y Qi, L AF Ito, Yoichiro Qi, Lin TI Centrifugal precipitation chromatography SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Review DE Centerifugal precipitation chromatography; Protein purification by ammonium sulfate; Rotary-seal-free flow-through centrifuge; Separation of proteins ID AMMONIUM-SULFATE; PREPARATIVE SEPARATION; PLASMID DNA; FRACTIONATION; PROTEIN; SOLUBILITY; RNA; TEA AB Centrifugal precipitation chromatography separates analytes according their solubility in ammonium sulfate(AS)solution and other precipitants. The separation column is made from a pair of long spiral channels partitioned with a semipermeable membrane. In a typical separation, concentrated ammonium sulfate is eluted through one channel while water is eluted through the other channel in the opposite direction This countercurrent process forms an exponential AS concentration gradient through the water channel. Consequently, protein samples injected into the water channel is subjected to a steadily increasing AS concentration and at the critical AS concentration they are precipitated and deposited in the channel bed by the centrifugal force Then the chromatographic separation is started by gradually reducing the AS concentration in the AS channel which lowers the AS gradient concentration in the water channel This results in dissolution of deposited proteins which are again precipitated at an advanced critical point as they move through the channel. Consequently, proteins repeat precipitation and dissolution through a long channel and finally eluted out front the column in the order of their solubility in the AS solution The present method has been successfully applied to a number of analytes including human serum proteins. recombinant ketosteroid isomerase, carotenoid cleavage enzymes, plasmid DNA, polysaccharide. polymerized pigments, PEG-protein conjugates. etc. The method is capable to single out the target species of proteins by affinity ligand or immunoaffinity separation. Published by Elsevier B.V. C1 [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Qi, Lin] US FDA, CDER, OPS, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, 10 Ctr Dr,Bldg 10,Room 8N230, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL001047-09] NR 20 TC 8 Z9 8 U1 4 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 EI 1873-376X J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2010 VL 878 IS 2 SI SI BP 154 EP 164 DI 10.1016/j.jchromb.2009.05.055 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 551PG UT WOS:000274220900005 PM 19541553 ER PT J AU Kalish, H Phillips, TM AF Kalish, Heather Phillips, Terry M. TI Analysis of neurotrophins in human serum by immunoaffinity capillary electrophoresis (ICE) following traumatic head injury" SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE CE; Head trauma; Immunoaffinity; Neurotrophins; Serum ID INDUCED FLUORESCENCE DETECTION; NERVE GROWTH-FACTOR; BRAIN-INJURY; MASS-SPECTROMETRY; FACTOR EXPRESSION; UP-REGULATION; RAT-BRAIN; CHILDREN; NEURONS; BDNF AB Neurotrophins, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), neutrotrophin-3 (NT-3), neurotrophin-4 (NT-4). anti beta-nerve growth factor (beta-NGF), play an active role in the development. maintenance and survival of cells of the central nervous system (CNS). Previous research has indicated that a decrease in concentrations of these neurotrophins is often associated with cell death and ultimately patient demise. However, much of the research conducted analyses of samples taken directly from the CNS, ie., of samples that are not readily available in clinical trauma centers. In an attempt to obtain a method for evaluating neurotrophins in a more readily accessible matrix, i.e. serum, a precise and accurate immunoaffinity capillary electrophoresis (ICE) method was developed and applied to measure neurotrophins in serum from patients with various degrees of head injury. The five neurotrophins of interest were extracted and concentrated by specific immunochemically immobilized antibodies. bound directly to the capillary wall, and eluted and separated in approximately 10 min. NT-3, BDNF. CNTF and beta-NGF showed a marked decrease in concentration as the severity of the head injury increased: mild versus severe: 91% decrease tot NT-3; 93 % decrease for BDNF; 93 % decrease for CNTF, and a 87% decrease for beta-NGF. This decrease in concentration is consistent with the neuro-protective roles that neurotrophins play in the maintenance and survival of neuronal cells. The results obtained by the ICE method were closely comparable with those generated by a commercially available ELISA method. Published by Elsevier B V. C1 [Kalish, Heather; Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Kalish, H (reprint author), Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bldg 13,Room 3E42,13 South Dr, Bethesda, MD USA. FU National Institute of Biomedical Imaging and Bioengineering, NIH FX This research was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, NIH. NR 40 TC 13 Z9 13 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 15 PY 2010 VL 878 IS 2 SI SI BP 194 EP 200 DI 10.1016/j.jchromb.2009.10.022 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 551PG UT WOS:000274220900010 PM 19896422 ER PT J AU Grebe, KM Takeda, K Hickman, HD Bailey, AM Embryo, AC Bennink, JR Yewdell, JW AF Grebe, Kristie M. Takeda, Kazuyo Hickman, Heather D. Bailey, Adam M. Embryo, Alan C. Bennink, Jack R. Yewdell, Jonathan W. TI Cutting Edge: Sympathetic Nervous System Increases Proinflammatory Cytokines and Exacerbates Influenza A Virus Pathogenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VIRAL-INFECTION; RESTRAINT STRESS; T-CELLS; MICE; LYMPHOCYTES; MODULATION; CLEARANCE; RESPONSES; STRAIN AB Although the sympathetic nervous system innervates the lung, little is known about its participation in host immunity to pulmonary pathogens. In this study, we show that peripheral sympathectomy reduces mouse morbidity and mortality from influenza A virus-induced pneumonia due to reduced inflammatory influx of monocytes, neutrophils, and NK cells. Mortality was also delayed by treating mice with an alpha-adrenergic antagonist. Sympathectomy diminished the immediate innate cytokine responses, particularly IL-1, which was profoundly reduced. These findings demonstrate an unexpected role for the sympathetic nervous system in innate antiviral immunity and in exacerbating the pathology of a virus of great significance to human and animal health. The Journal of Immunology, 2010, 184: 540-544. C1 [Yewdell, Jonathan W.] NIAID, Labs Viral Dis, NIH, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Labs Viral Dis, NIH, Room 2E13C-1,Bldg 33,33 N Dr, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was generously supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases. NR 20 TC 38 Z9 38 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2010 VL 184 IS 2 BP 540 EP 544 DI 10.4049/jimmunol.0903395 PG 5 WC Immunology SC Immunology GA 541UT UT WOS:000273447100002 PM 20018617 ER PT J AU Radinger, M Kuehn, HS Kim, MS Metcalfe, DD Gilfillan, AM AF Radinger, Madeleine Kuehn, Hye Sun Kim, Mi-Sun Metcalfe, Dean D. Gilfillan, Alasdair M. TI Glycogen Synthase Kinase 3 beta Activation Is a Prerequisite Signal for Cytokine Production and Chemotaxis in Human Mast Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; PROTEIN-TYROSINE KINASE; RICTOR-MTOR COMPLEX; FACTOR-RECEPTOR; C-KIT; SUBSTRATE-SPECIFICITY; PHOSPHORYLATION; GROWTH; GSK-3; MIGRATION AB In addition to regulating mast cell homeostasis, the activation of KIT following ligation by stem cell factor promotes a diversity of mast cell responses, including cytokine production and chemotaxis. Although we have previously defined a role for the mammalian target of rapamycin complex 1 in these responses, it is clear that other signals are also required for maximal KIT-dependent cytokine production and chemotaxis. In this study, we provide evidence to support a role for glycogen synthase kinase 3 beta (GSK3 beta) in such regulation in human mast cells (HuMCs). GSK3 beta was observed to be constitutively activated in HuMCs. This activity was inhibited by knockdown of GSK3 beta protein following transduction of these cells with GSK3 beta-targeted shRNA. This resulted in a marked attenuation in the ability of KIT to promote chemotaxis and, in synergy with Fc epsilon RI-mediated signaling, cytokine production. GSK3 beta regulated KIT-dependent mast cell responses independently of mammalian target of rapamycin. However, evidence from the knockdown studies suggested that GSK3 beta was required for activation of the MAPKs, p38, and JNK and downstream phosphorylation of the transcription factors, Jun and activating transcription. factor 2, in addition to activation of the transcription factor NF-kappa B. These studies provide evidence for a novel prerequisite priming mechanism for KIT-dependent responses regulated by GSK3 beta in HuMCs. The Journal of Immunology, 2010, 184: 564-572. C1 [Radinger, Madeleine; Kuehn, Hye Sun; Kim, Mi-Sun; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C206,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Swedish Heart-Lung Foundation FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. M.R. is grateful for support from the Swedish Heart-Lung Foundation. NR 39 TC 14 Z9 15 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2010 VL 184 IS 2 BP 564 EP 572 DI 10.4049/jimmunol.0902931 PG 9 WC Immunology SC Immunology GA 541UT UT WOS:000273447100006 PM 20008284 ER PT J AU Bem, RA van Woensel, JBM Lutter, R Domachowske, JB Medema, JP Rosenberg, HF Bos, AP AF Bem, Reinout A. van Woensel, Job B. M. Lutter, Rene Domachowske, Joseph B. Medema, Jan Paul Rosenberg, Helene F. Bos, Albert P. TI Granzyme A- and B-Cluster Deficiency Delays Acute Lung Injury in Pneumovirus-Infected Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; GRANULE-MEDIATED CYTOTOXICITY; PNEUMONIA VIRUS; DISTRESS-SYNDROME; TARGET-CELLS; CYTOLYTIC LEUKOCYTES; CYTOSOLIC DELIVERY; T-CELLS; APOPTOSIS; CHILDREN AB Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease in humans is associated with activation of the granzyme pathway by effector lymphocytes, which may promote pathology by exaggerating proapoptotic caspase activity and proinflammatory activity. The main goal of this study was to determine whether granzymes contribute to the development of acute lung injury in pneumovirus-infected mice. Granzyme-expressing mice and granzyme A- and B-cluster single- and double-knockout mice were inoculated with the rodent pneumovirus pneumonia virus of mice strain J3666, and were studied for markers of lung inflammation and injury. Expression of granzyme A and B is detected in effector lymphocytes in mouse lungs in response to pneumovirus infection. Mice deficient for granzyme A and the granzyme B cluster have unchanged virus titers in the lungs but show a significantly delayed clinical response to fatal pneumovirus infection, a feature that is associated with delayed neutrophil recruitment, diminished activation of caspase-3, and reduced lung permeability. We conclude that granzyme A- and B-cluster deficiency delays the acute progression of pneumovirus disease by reducing alveolar injury. The Journal of Immunology, 2010, 184: 931-938. C1 [Bem, Reinout A.; van Woensel, Job B. M.; Bos, Albert P.] Acad Med Ctr, Pediat Intens Care Unit, Emma Childrens Hosp, NL-1100 DD Amsterdam, Netherlands. [Lutter, Rene] Acad Med Ctr, Dept Pulmonol, NL-1100 DD Amsterdam, Netherlands. [Lutter, Rene] Acad Med Ctr, Dept Expt Immunol, NL-1100 DD Amsterdam, Netherlands. [Medema, Jan Paul] Acad Med Ctr, Lab Expt Oncol & Radiobiol, NL-1100 DD Amsterdam, Netherlands. [Domachowske, Joseph B.] Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. [Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20814 USA. RP Bem, RA (reprint author), Acad Med Ctr, Pediat Intens Care Unit, Emma Childrens Hosp, POB 22660, NL-1100 DD Amsterdam, Netherlands. EM r.a.bem@amc.uva.nl FU Donandi and National Institute of Allergy and Infections Diseases Division of Intramural Research [Z01-AI000943] FX This work was supported in part by Ars Donandi and National Institute of Allergy and Infections Diseases Division of Intramural Research Grant Z01-AI000943 (to. H.F.R.). NR 50 TC 12 Z9 13 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2010 VL 184 IS 2 BP 931 EP 938 DI 10.4049/jimmunol.0903029 PG 8 WC Immunology SC Immunology GA 541UT UT WOS:000273447100045 PM 20018616 ER PT J AU Munford, RS AF Munford, Robert S. TI Murine Responses to Endotoxin: Another Dirty Little Secret? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID INFECTIOUS-DISEASES; TOLERANCE; COMPARTMENTALIZATION C1 NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Munford, RS (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. EM munfordrs@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 22 TC 22 Z9 22 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 JAN 15 PY 2010 VL 201 IS 2 BP 175 EP 177 DI 10.1086/649558 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200002 PM 20001601 ER PT J AU Lim, JK McDermott, DH Lisco, A Foster, GA Krysztof, D Follmann, D Stramer, SL Murphy, PM AF Lim, Jean K. McDermott, David H. Lisco, Andrea Foster, Gregory A. Krysztof, David Follmann, Dean Stramer, Susan L. Murphy, Philip M. TI CCR5 Deficiency Is a Risk Factor for Early Clinical Manifestations of West Nile Virus Infection but not for Viral Transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; HIV-1 INFECTION; BLOOD-DONORS; NEW-YORK; EPIDEMIC; GENE; ENCEPHALITIS; METAANALYSIS; PROGRESSION; DELETION AB Background. West Nile virus (WNV) is a neurotropic flavivirus transmitted to humans by mosquito vectors. Homozygosity for CCR5 Delta 32, a complete loss-of-function mutation in CC chemokine receptor 5 (CCR5), has been previously associated with severe symptomatic WNV infection in patients who present with clinical disease; however, whether it acts at the level of initial infection or in promoting clinical progression is unknown. Methods. Here, we address this gap in knowledge by comparing CCR5 Delta 32 distribution among US blood donors identified through a comprehensive blood supply screening program (34,766,863 donations from 2003 through 2008) as either WNV true positive (634 WNV-positive cases) or false positive (422 WNV-negative control participants). All subjects self-reported symptoms occurring during the 2 weeks following blood donation using a standardized questionnaire. Results. No difference was observed in CCR5 Delta 32 homozygous frequency between the WNV-positive cases and WNV-negative control participants. However, CCR5 Delta 32 homozygosity was associated in cases but not controls with clinical symptoms consistent with WNV infection (P=.002). Conclusions. CCR5 deficiency is not a risk factor for WNV infection per se, but it is a risk factor for both early and late clinical manifestations after infection. Thus, CCR5 may function normally to limit disease due to WNV infection in humans. C1 [Lisco, Andrea] NICHHD, Sect Intercellular Interact, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Follmann, Dean] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Foster, Gregory A.; Krysztof, David; Stramer, Susan L.] Amer Red Cross, Gaithersburg, MD USA. [Lim, Jean K.; McDermott, David H.; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NICHHD, Sect Intercellular Interact, Cellular & Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 10,Rm 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov OI McDermott, David/0000-0001-6978-0867 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 25 TC 64 Z9 64 U1 0 U2 4 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 JAN 15 PY 2010 VL 201 IS 2 BP 178 EP 185 DI 10.1086/649426 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200003 PM 20025530 ER PT J AU Ganesan, A Chattopadhyay, PK Brodie, TM Qin, J Gu, WJ Mascola, JR Michael, NL Follmann, DA Roederer, M AF Ganesan, Anuradha Chattopadhyay, Pratip K. Brodie, Tess M. Qin, Jing Gu, Wenjuan Mascola, John R. Michael, Nelson L. Follmann, Dean A. Roederer, Mario CA Infect Dis Clinical Res Program HI TI Immunologic and Virologic Events in Early HIV Infection Predict Subsequent Rate of Progression SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CD8(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; VIRUS TYPE-1 INFECTION; ACUTE SIV INFECTION; IMMUNE ACTIVATION; INTERLEUKIN-7 RECEPTOR; DISEASE PROGRESSION; HIV-1-INFECTED PATIENTS; COLLABORATIVE ANALYSIS AB Background. Variability in human immunodeficiency virus (HIV) disease progression cannot be fully predicted by CD4(+) T cell counts or viral load (VL). Because central memory T (T(CM)) cells play a critical role in the pathogenesis of simian immunodeficiency virus disease, we hypothesized that quantifying these cells in early HIV infection could provide prognostic information. Methods. We measured expression of CD45RO, chemokine (C-C motif) receptor (CCR) 5, CCR7, CD27, and CD28 to enumerate naive and memory subsets in samples from recently infected individuals. We also quantified proliferation, CD127 expression, and cell-associated VL. Disease progression was compared across subgroups defined by these measurements, using Kaplan-Meier survival curves and multivariate Cox proportional hazards regression. Results. Four hundred sixty-six subjects contributed 101 events. The proportion or absolute count of T(CM) cells did not correlate with disease progression, defined as the time to AIDS or death. However, significant associations were observed for proliferation within CD4(+) or CD8(+) T cells, loss of naive or CD127(+) memory CD8(+) T cells, and CD4(+) T cell-associated VL. Conclusions. Our results demonstrate that the extent of the immunopathogenesis established early in HIV infection predicts the course of future disease. Because antiretroviral drug treatment reverses such defects in part, our study provides mechanistic clues to why early use of antiretrovirals may prove beneficial. C1 [Ganesan, Anuradha] Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Infect Dis Clin Res Program, Bethesda, MD USA. [Chattopadhyay, Pratip K.; Brodie, Tess M.; Mascola, John R.; Roederer, Mario] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Follmann, Dean A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Gu, Wenjuan] Sci Applicat Int Corp, Biostat Res Branch, Frederick, MD USA. [Michael, Nelson L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. RP Roederer, M (reprint author), NIH, ImmunoTechnol Sect, Vaccine Res Ctr, 40 Convent Dr,Rm 5509, Bethesda, MD 20892 USA. EM Roederer@nih.gov RI Chattopadhyay, Pratip/B-9227-2008; Marconi, Vincent/N-3210-2014; OI Marconi, Vincent/0000-0001-8409-4689; Agan, Brian/0000-0002-5114-1669; Chattopadhyay, Pratip/0000-0002-5457-9666 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z99 AI999999, ZIA AI005021-08]; NCI NIH HHS [HHSN261200800001E] NR 49 TC 45 Z9 48 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2010 VL 201 IS 2 BP 272 EP 284 DI 10.1086/649430 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200014 PM 20001854 ER PT J AU Permar, SR Kang, HH Carville, A Wilks, AB Mansfield, KG Rao, SS Letvin, NL AF Permar, Sallie R. Kang, Helen H. Carville, Angela Wilks, Andrew B. Mansfield, Keith G. Rao, Srinivas S. Letvin, Norman L. TI Preservation of Memory CD4(+) T Lymphocytes in Breast Milk of Lactating Rhesus Monkeys during Acute Simian Immunodeficiency Virus Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID EXPRESS HIGH-LEVELS; GASTROINTESTINAL-TRACT; CELL DEPLETION; LAMINA PROPRIA; SIV INFECTION; HIV; REPLICATION; RESPONSES; MACAQUES; TISSUES AB Acute human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection is associated with a massive depletion of memory CD4(+) T lymphocytes in the gastrointestinal tract. To define the dynamics of the CD4(+) T lymphocyte subpopulations in breast milk during acute HIV or SIV infection, lymphocyte populations were monitored in blood and milk of 4 Mamu-A*01(+) rhesus monkeys after SIVmac251 inoculation. Strikingly, although the CD4(+) T lymphocytes in blood were depleted during the peak of viremia, the milk CD4(+) T lymphocyte counts remained unchanged, despite active virus replication in the breast milk compartment. Moreover, CD4(+) memory T lymphocytes were preserved in breast milk during acute infection. CD4(+) T lymphocytes in breast milk and other mucosal compartments of uninfected monkeys were similar in their memory phenotype, activation status, and chemokine (C-C motif) receptor 5 expression. Interestingly, the number and proportion of effector CD8(+) T lymphocytes in milk were increased during acute SIV infection, suggesting effective control of virus-mediated CD4(+) T lymphocyte destruction in the breast milk compartment. C1 [Permar, Sallie R.; Kang, Helen H.; Wilks, Andrew B.; Letvin, Norman L.] Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02115 USA. [Permar, Sallie R.] Harvard Univ, Sch Med, Div Infect Dis, Childrens Hosp Boston, Boston, MA USA. [Carville, Angela; Mansfield, Keith G.] Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Southborough, MA USA. [Rao, Srinivas S.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Permar, SR (reprint author), Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, 330 Brookline Ave,E CLS 10, Boston, MA 02115 USA. EM sallie.permar@childrens.harvard.edu FU Center for HIV/AIDS Vaccine Immunology [AI067854]; Fred Lovejoy Research and Education Fund; Children's Hospital House Officer Research; Pediatric Infectious Disease Society/St. Jude Children's Hospital Basic Science Research FX Financial support: Center for HIV/AIDS Vaccine Immunology (grant AI067854 to S. R. P. and N. L. L.), Fred Lovejoy Research and Education Fund (S. R. P.), Children's Hospital House Officer Research Award (S. R. P.), Pediatric Infectious Disease Society/St. Jude Children's Hospital Basic Science Research Award (S. R. P.). NR 19 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2010 VL 201 IS 2 BP 302 EP 310 DI 10.1086/649229 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 536NN UT WOS:000273051200018 PM 20001855 ER PT J AU Rau, DC Sidorova, NY AF Rau, Donald C. Sidorova, Nina Y. TI Diffusion of the Restriction Nuclease EcoRI along DNA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA-protein complex; dissociation rate; one-dimensional diffusion; EcoRI; nonspecific; binding ID REPRESSOR-OPERATOR INTERACTION; ONE-DIMENSIONAL DIFFUSION; PROTEIN TRANSLOCATION; DRIVEN MECHANISMS; LINEAR DIFFUSION; NONSPECIFIC DNA; KINETIC CHARACTERIZATION; OSMOTIC-STRESS; WATER RELEASE; BINDING AB Many specific sequence DNA binding proteins locate their target sequence by first binding to DNA nonspecifically, then by linearly diffusing or hopping along DNA until either the protein dissociates from the DNA or it finds the recognition sequence. We have devised a method for measuring one-dimensional diffusion along DNA based on the ratio of the dissociation rate of protein from DNA fragments containing one specific binding site to the dissociation rate from DNA fragments containing two specific binding sites. Our extensive measurements of dissociation rates and specific-nonspecific relative binding constants of the restriction nuclease EcoRI enable us to determine the diffusion rate of nonspecifically bound protein along the DNA. By varying the distance between the two binding sites, we confirm a linear diffusion mechanism. The sliding rate is relatively insensitive to salt concentration and osmotic pressure, indicating that the protein moves smoothly along the DNA probably following the helical phosphate-sugar backbone of DNA. We calculate a diffusion coefficient for EcoRI of 3 x 10(4) bp(2) s(-1) EcoRI is able to diffuse similar to 150 bp, on average, along the DNA in 1 s. This diffusion rate is about 2000-fold slower than the diffusion of free protein in solution. A factor of 40-50 can be accounted for by rotational friction resulting from following the helical path of the DNA backbone. Two possibilities could account for the remaining activation energy: salt bridges between the DNA and the protein are transiently broken, or the water structure at the protein-DNA interface is disrupted as the two surfaces move past each other. Published by Elsevier Ltd. C1 [Rau, Donald C.; Sidorova, Nina Y.] Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Rau, DC (reprint author), Eunice Kennedy Shriver Natl Inst Hlth & Human Dev, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM raud@mail.nih.gov FU Intramural NIH HHS [Z01 HD008811-02] NR 37 TC 24 Z9 25 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 15 PY 2010 VL 395 IS 2 BP 408 EP 416 DI 10.1016/j.jmb.2009.10.049 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 556QJ UT WOS:000274605900015 PM 19874828 ER PT J AU Jin, P Han, TH Ren, JQ Saunders, S Wang, E Marincola, FM Stroncek, DF AF Jin, Ping Han, Tae Hee Ren, Jiaqiang Saunders, Stefanie Wang, Ena Marincola, Francesco M. Stroncek, David F. TI Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID T-CELLS; EXPRESSION; MATURATION; GENERATION; MONOCYTES; CANCER; IDENTIFICATION; IMMUNOTHERAPY; PRODUCTS; VACCINES AB Background: Dendritic cells (DCs) are often produced by granulocyte-macrophage colony-stimulating factor (GMCSF) and interleukin-4 (IL-4) stimulation of monocytes. To improve the effectiveness of DC adoptive immune cancer therapy, many different agents have been used to mature DCs. We analyzed the kinetics of DC maturation by lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) induction in order to characterize the usefulness of mature DCs (mDCs) for immune therapy and to identify biomarkers for assessing the quality of mDCs. Methods: Peripheral blood mononuclear cells were collected from 6 healthy subjects by apheresis, monocytes were isolated by elutriation, and immature DCs (iDCs) were produced by 3 days of culture with GM-CSF and IL-4. The iDCs were sampled after 4, 8 and 24 hours in culture with LPS and IFN-gamma and were then assessed by flow cytometry, ELISA, and global gene and microRNA (miRNA) expression analysis. Results: After 24 hours of LPS and IFN-gamma stimulation, DC surface expression of CD80, CD83, CD86, and HLA Class II antigens were up-regulated. Th1 attractant genes such as CXCL9, CXCL10, CXCL11 and CCL5 were up-regulated during maturation but not Treg attractants such as CCL22 and CXCL12. The expression of classical mDC biomarker genes CD83, CCR7, CCL5, CCL8, SOD2, MT2A, OASL, GBP1 and HES4 were up-regulated throughout maturation while MTIB, MTIE, MTIG, MTIH, GADD45A and LAMP3 were only up-regulated late in maturation. The expression of miR-155 was up-regulated 8-fold in mDCs. Conclusion: DCs, matured with LPS and IFN-gamma, were characterized by increased levels of Th1 attractants as opposed to Treg attractants and may be particularly effective for adoptive immune cancer therapy. C1 [Jin, Ping; Han, Tae Hee; Ren, Jiaqiang; Saunders, Stefanie; Wang, Ena; Marincola, Francesco M.; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Han, Tae Hee] Inje Univ, Sanggye Paik Hosp, Dept Lab Med, Seoul, South Korea. RP Jin, P (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM pjin@cc.nih.gov OI HAN, TAE HEE/0000-0002-9063-4052 FU Department of Transfusion Medicine, Clinical Center, NIH FX We thank the staff of the NIH, Clinical Center, Dowling Clinic, Department of Transfusion Medicine, Clinical Center, NIH for collecting the cells and the Cell Processing Laboratory, Department of Transfusion Medicine, Clinical Center, NIH for preparing the elutriated cells. These studies were funded by the Department of Transfusion Medicine, Clinical Center, NIH. NR 25 TC 38 Z9 43 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 15 PY 2010 VL 8 AR 4 DI 10.1186/1479-5876-8-4 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 571DJ UT WOS:000275731200001 PM 20078880 ER PT J AU Jadwin, JA Rudd, V Sette, P Challa, S Bouamr, F AF Jadwin, Joshua A. Rudd, Victoria Sette, Paola Challa, Swathi Bouamr, Fadila TI Late Domain-Independent Rescue of a Release-Deficient Moloney Murine Leukemia Virus by the Ubiquitin Ligase Itch SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-SORTING PATHWAY; LATE-BUDDING DOMAINS; ROUS-SARCOMA-VIRUS; IMMUNODEFICIENCY-VIRUS; TYPE-1 GAG; ESCRT-III; TSG101; MOTIFS; TRAFFICKING; RECOGNITION AB Moloney murine leukemia virus (MoMLV) Gag utilizes its late (L) domain motif PPPY to bind members of the Nedd4-like ubiquitin ligase family. These interactions recruit components of the cell's budding machinery that are critical for virus release. MoMLV Gag contains two additional L domains, PSAP and LYPAL, that are believed to drive residual MoMLV release via interactions with cellular proteins Tsg101 and Alix, respectively. We found that overexpression of Tsg101 or Alix failed to rescue the release of PPPY-deficient MoMLV via these other L domains. However, low-level expression of the ubiquitin ligase Itch potently rescued the release and infectivity of MoMLV lacking PPPY function. In contrast, other ubiquitin ligases such as WWP1, Nedd4.1, Nedd4.2, and Nedd4.2s did not rescue this release-deficient virus. Efficient rescue required the ubiquitin ligase activity of Itch and an intact C2 domain but not presence of the endophilin-binding site. Additionally, we found Itch to immunoprecipitate with MoMLV Gag lacking the PPPY motif and to be incorporated into rescued MoMLV particles. The PSAP and LYPAL motifs were dispensable for Itch-mediated virus rescue, and their absence did not affect the incorporation of Itch into the rescued particles. Itch-mediated rescue of release-defective MoMLV was sensitive to inhibition by dominant-negative versions of ESCRT-III components and the VPS4 AAA ATPase, indicating that Itch-mediated correction of MoMLV release defects requires the integrity of the host vacuolar sorting protein pathway. RNA interference knockdown of Itch suppressed the residual release of the MoMLV lacking the PPPY motif. Interestingly, Itch stimulation of the PPPY-deficient MoMLV release was accompanied by the enhancement of Gag ubiquitination and the appearance of new ubiquitinated Gag proteins in virions. Together, these results suggest that Itch can facilitate MoMLV release in an L domain-independent manner via a mechanism that requires the host budding machinery and involves Gag ubiquitination. C1 [Jadwin, Joshua A.; Rudd, Victoria; Sette, Paola; Challa, Swathi; Bouamr, Fadila] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM bouamrf@mail.nih.gov FU NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 63 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 JAN 15 PY 2010 VL 84 IS 2 BP 704 EP 715 DI 10.1128/JVI.01319-09 PG 12 WC Virology SC Virology GA 535TN UT WOS:000272994300004 PM 19864377 ER PT J AU Sall, AA Faye, O Diallo, M Firth, C Kitchen, A Holmes, EC AF Sall, Amadou A. Faye, Ousmane Diallo, Mawlouth Firth, Cadhla Kitchen, Andrew Holmes, Edward C. TI Yellow Fever Virus Exhibits Slower Evolutionary Dynamics than Dengue Virus SO JOURNAL OF VIROLOGY LA English DT Article ID TRANS-OVARIAL TRANSMISSION; AEDES-AEGYPTI; VERTICAL TRANSMISSION; EASTERN SENEGAL; RNA VIRUSES; AFRICA; MOSQUITOS; DISEASE; VECTOR; SUBSTITUTION AB Although yellow fever has historically been one of the most important viral infections of humans, relatively little is known about the evolutionary processes that shape its genetic diversity. Similarly, there is limited information on the molecular epidemiology of yellow fever virus (YFV) in Africa even though it most likely first emerged on this continent. Through an analysis of complete E gene sequences, including a newly acquired viral collection from Central and West Africa (Senegal, Cameroon, Central African Republic, Cote d'Ivoire, Mali, and Mauritania), we show that YFV exhibits markedly lower rates of evolutionary change than dengue virus, despite numerous biological similarities between these two viruses. From this observation, along with a lack of clock-like evolutionary behavior in YFV, we suggest that vertical transmission, itself characterized by lower replication rates, may play an important role in the evolution of YFV in its enzootic setting. Despite a reduced rate of nucleotide substitution, phylogenetic patterns and estimates of times to common ancestry in YFV still accord well with the dual histories of colonialism and the slave trade, with areas of sylvatic transmission (such as Kedougou, Senegal) acting as enzootic/epidemic foci. C1 [Firth, Cadhla; Kitchen, Andrew; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Sall, Amadou A.; Faye, Ousmane; Diallo, Mawlouth] Inst Pasteur, Dakar, Senegal. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 FU NIH [GM080533] FX This work was in part funded by NIH grant GM080533. NR 44 TC 25 Z9 26 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2010 VL 84 IS 2 BP 765 EP 772 DI 10.1128/JVI.01738-09 PG 8 WC Virology SC Virology GA 535TN UT WOS:000272994300009 PM 19889759 ER PT J AU Gherghe, C Leonard, CW Gorelick, RJ Weeks, KM AF Gherghe, Cristina Leonard, Christopher W. Gorelick, Robert J. Weeks, Kevin M. TI Secondary Structure of the Mature Ex Virio Moloney Murine Leukemia Virus Genomic RNA Dimerization Domain SO JOURNAL OF VIROLOGY LA English DT Article ID SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; ACID-CHAPERONE ACTIVITY; PRIMER EXTENSION SHAPE; REVERSE TRANSCRIPTION; PACKAGING SIGNAL; MOLECULAR-WEIGHT; DIMERIC RNA; VIRAL-RNA; TYPE-1 AB Retroviral genomes are dimeric, comprised of two sense-strand RNAs linked at their 5' ends by noncovalent base pairing and tertiary interactions. Viral maturation involves large-scale morphological changes in viral proteins and in genomic RNA dimer structures to yield infectious virions. Structural studies have largely focused on simplified in vitro models of genomic RNA dimers even though the relationship between these models and authentic viral RNA is unknown. We evaluate the secondary structure of the minimal dimerization domain in genomes isolated from Moloney murine leukemia virions using a quantitative and single nucleotide resolution RNA structure analysis technology (selective 2'-hydroxyl acylation analyzed by primer extension, or SHAPE). Results are consistent with an architecture in which the RNA dimer is stabilized by four primary interactions involving two sets of intermolecular base pairs and two loop-loop interactions. The dimerization domain can independently direct its own folding since heating and refolding reproduce the same structure as visualized in genomic RNA isolated from virions. Authentic ex virio RNA has a SHAPE reactivity profile similar to that of a simplified transcript dimer generated in vitro, with the important exception of a region that appears to form a compact stem-loop only in the virion-isolated RNA. Finally, we analyze the conformational changes that accompany folding of monomers into dimers in vitro. These experiments support well-defined structural models for an authentic dimerization domain and also emphasize that many features of mature genomic RNA dimers can be reproduced in vitro using properly designed, simplified RNAs. C1 [Gherghe, Cristina; Leonard, Christopher W.; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, A008 Kenan Labs,CB 3290, Chapel Hill, NC 27599 USA. EM weeks@unc.edu FU U.S. National Institutes of Health [GM064803]; National Cancer Institute [N01-CO-12400] FX This work was supported by the U.S. National Institutes of Health (GM064803 to K. M. W.) and with federal funds from the National Cancer Institute (under contract N01-CO-12400 to R.J.G.). NR 51 TC 20 Z9 20 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JAN 15 PY 2010 VL 84 IS 2 BP 898 EP 906 DI 10.1128/JVI.01602-09 PG 9 WC Virology SC Virology GA 535TN UT WOS:000272994300021 PM 19889760 ER PT J AU Basavapathruni, A Yeh, WW Coffey, RT Whitney, JB Hraber, PT Giri, A Korber, BT Rao, SS Nabel, GJ Mascola, JR Seaman, MS Letvin, NL AF Basavapathruni, Aravind Yeh, Wendy W. Coffey, Rory T. Whitney, James B. Hraber, Peter T. Giri, Ayush Korber, Bette T. Rao, Srinivas S. Nabel, Gary J. Mascola, John R. Seaman, Michael S. Letvin, Norman L. TI Envelope Vaccination Shapes Viral Envelope Evolution following Simian Immunodeficiency Virus Infection in Rhesus Monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID ANTIBODY-MEDIATED NEUTRALIZATION; SUBTYPE-C INFECTION; GLYCOSYLATION SITES; SEQUENCE VARIATION; TYPE-1 INFECTION; V1 REGION; AIDS; GLYCOPROTEIN; MACAQUES; GP120 AB The evolution of envelope mutations by replicating primate immunodeficiency viruses allows these viruses to escape from the immune pressure mediated by neutralizing antibodies. Vaccine-induced anti-envelope antibody responses may accelerate and/or alter the specificity of the antibodies, thus shaping the evolution of envelope mutations in the replicating virus. To explore this possibility, we studied the neutralizing antibody response and the envelope sequences in rhesus monkeys vaccinated with either gag-pol-nef immunogens or gag-pol-nef immunogens in combination with env and then infected with simian immunodeficiency virus (SIV). Using a pseudovirion neutralization assay, we demonstrate that envelope vaccination primed for an accelerated neutralizing antibody response following virus challenge. To monitor viral envelope evolution in these two cohorts of monkeys, full-length envelopes from plasma virus isolated at weeks 37 and 62 postchallenge were sequenced by single genome amplification to identify sites of envelope mutations. We show that env vaccination was associated with a change in the pattern of envelope mutations. Prevalent mutations in sequences from gag-pol-nef vaccinees included deletions in both variable regions 1 and 4 (V1 and V4), whereas deletions in the env vaccinees occurred only in V1. These data show that env vaccination altered the focus of the antibody-mediated selection pressure on the evolution of envelope following SIV challenge. C1 [Basavapathruni, Aravind; Yeh, Wendy W.; Coffey, Rory T.; Whitney, James B.; Giri, Ayush; Seaman, Michael S.; Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis,Dept Med, Boston, MA 02215 USA. [Hraber, Peter T.; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Rao, Srinivas S.; Nabel, Gary J.; Mascola, John R.; Letvin, Norman L.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis,Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu OI Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Vaccine Research Center, NIAID, NIH; NIH [N01-AI30033, K08-AI06995]; Bill and Melinda Gates Collaboration for AIDS Vaccine Discovery Vaccine Immune Monitoring Consortium [38619] FX TZM. bl cells were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH, from John C. Kappes, Xiaoyun Wu, and Tranzyme, Inc. (4, 23, 26). We are grateful to Yair Benita for helpful discussions regarding sequencing results, Alida Ault and John Paul Todd for coordinating animal procedure logistics, Alan Dodson and Tammy Jenkins at BioQual, Inc., for housing and care of the nonhuman primates used in the study, Rebecca Gelman for help with statistical analyses, Richard M. White for help with Mutation Surveyor, and Joseph Sodroski for manuscript preparation.; This work was supported in part by funds from the intramural research program of the Vaccine Research Center, NIAID, NIH; NIH grant N01-AI30033; K08-AI06995 (W.W.Y.); and the Bill and Melinda Gates Collaboration for AIDS Vaccine Discovery Vaccine Immune Monitoring Consortium grant 38619 to M. S. S. NR 40 TC 9 Z9 9 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 JAN 15 PY 2010 VL 84 IS 2 BP 953 EP 963 DI 10.1128/JVI.01679-09 PG 11 WC Virology SC Virology GA 535TN UT WOS:000272994300026 PM 19906933 ER PT J AU Freundt, EC Yu, L Goldsmith, CS Welsh, S Cheng, A Yount, B Liu, W Frieman, MB Buchholz, UJ Screaton, GR Lippincott-Schwartz, J Zaki, SR Xu, XN Baric, RS Subbarao, K Lenardo, MJ AF Freundt, Eric C. Yu, Li Goldsmith, Cynthia S. Welsh, Sarah Cheng, Aaron Yount, Boyd Liu, Wei Frieman, Matthew B. Buchholz, Ursula J. Screaton, Gavin R. Lippincott-Schwartz, Jennifer Zaki, Sherif R. Xu, Xiao-Ning Baric, Ralph S. Subbarao, Kanta Lenardo, Michael J. TI The Open Reading Frame 3a Protein of Severe Acute Respiratory Syndrome-Associated Coronavirus Promotes Membrane Rearrangement and Cell Death SO JOURNAL OF VIROLOGY LA English DT Article ID SARS-ASSOCIATED CORONAVIRUS; VERO E6 CELLS; LINKED-IMMUNOSORBENT-ASSAY; TRANS-GOLGI NETWORK; ENDOPLASMIC-RETICULUM; REPLICATION COMPLEX; VIRUS-REPLICATION; BREFELDIN-A; POLIOVIRUS INFECTION; ORGANELLE STRUCTURE AB The genome of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) contains eight open reading frames (ORFs) that encode novel proteins. These accessory proteins are dispensable for in vitro and in vivo replication and thus may be important for other aspects of virus-host interactions. We investigated the functions of the largest of the accessory proteins, the ORF 3a protein, using a 3a-deficient strain of SARS-CoV. Cell death of Vero cells after infection with SARS-CoV was reduced upon deletion of ORF 3a. Electron microscopy of infected cells revealed a role for ORF 3a in SARS-CoV induced vesicle formation, a prominent feature of cells from SARS patients. In addition, we report that ORF 3a is both necessary and sufficient for SARS-CoV-induced Golgi fragmentation and that the 3a protein accumulates and localizes to vesicles containing markers for late endosomes. Finally, overexpression of ADP-ribosylation factor 1 (Arf1), a small GTPase essential for the maintenance of the Golgi apparatus, restored Golgi morphology during infection. These results establish an important role for ORF 3a in SARS-CoV-induced cell death, Golgi fragmentation, and the accumulation of intracellular vesicles. C1 [Freundt, Eric C.; Yu, Li; Welsh, Sarah; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Cheng, Aaron; Buchholz, Ursula J.; Zaki, Sherif R.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Goldsmith, Cynthia S.] Ctr Dis Control & Prevent, Infect Dis Pathol Branch, Div Viral & Rickettsial Dis, Atlanta, GA 30333 USA. [Yount, Boyd; Frieman, Matthew B.; Baric, Ralph S.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Liu, Wei; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Screaton, Gavin R.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London W12 0NN, England. [Freundt, Eric C.; Xu, Xiao-Ning] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Med Res Council,Human Immunol Unit, Oxford OX3 9DS, England. RP Yu, L (reprint author), Tsinghua Univ, Dept Biol Sci & Biotechnol, Beijing 100084, Peoples R China. EM liyulab@mail.tsinghua.edu.cn OI Screaton, Gavin/0000-0002-3549-4309 FU National Institutes of Health-University of Oxford; National Institutes of Allergy and Infectious Diseases; National Institutes of Health; NIH AID [AI059136] FX The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency. NR 69 TC 12 Z9 14 U1 1 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 JAN 15 PY 2010 VL 84 IS 2 BP 1097 EP 1109 DI 10.1128/JVI.01662-09 PG 13 WC Virology SC Virology GA 535TN UT WOS:000272994300040 PM 19889773 ER PT J AU Umbach, JL Wang, K Tang, S Krause, PR Mont, EK Cohen, JI Cullen, BR AF Umbach, Jennifer L. Wang, Kening Tang, Shuang Krause, Philip R. Mont, Erik K. Cohen, Jeffrey I. Cullen, Bryan R. TI Identification of Viral MicroRNAs Expressed in Human Sacral Ganglia Latently Infected with Herpes Simplex Virus 2 SO JOURNAL OF VIROLOGY LA English DT Article ID HERPES-SIMPLEX-VIRUS-1; SEQUENCE AB Deep sequencing of small RNAs isolated from human sacral ganglia latently infected with herpes simplex virus 2 (HSV-2) was used to identify HSV-2 microRNAs (miRNAs) expressed during latent infection. This effort resulted in the identification of five distinct HSV-2 miRNA species, two of which, miR-H3/miR-I and miR-H4/miR-II, have been previously reported. Three novel HSV-2 miRNAs were also identified, and two of these, miR-H7 and miR-H9, are derived from the latency-associated transcript (LAT) and are located antisense to the viral transcript encoding transactivator ICP0. A third novel HSV-2 miRNA, miR-H10, is encoded within the unique long (U(L)) region of the genome, 3' to the U(L)15 open reading frame, and is presumably excised from a novel, latent HSV-2 transcript distinct from LAT. C1 [Umbach, Jennifer L.; Cullen, Bryan R.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. [Umbach, Jennifer L.; Cullen, Bryan R.] Duke Univ, Med Ctr, Ctr Virol, Durham, NC 27710 USA. [Wang, Kening; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Tang, Shuang; Krause, Philip R.] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Off Vaccines Res & Review, Bethesda, MD 20892 USA. [Mont, Erik K.] Miami Dade Cty Med Examiner Dept, Miami, FL 33136 USA. RP Cullen, BR (reprint author), Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. EM bryan.cullen@duke.edu RI Tang, Shuang/F-9115-2014; OI Tang, Shuang/0000-0002-3084-0903; Krause, Philip/0000-0002-1045-7536 FU National Institute of Allergy and Infectious Diseases [AI067968]; National Institute of Allergy and Infectious Diseases; National Cancer Institute [T32-CA009111] FX This work was supported by Public Health Service grant AI067968 from the National Institute of Allergy and Infectious Diseases to B. R. C. and the intramural research program of the National Institute of Allergy and Infectious Diseases. J. L. U. was supported by NIH training grant T32-CA009111 from the National Cancer Institute. NR 14 TC 35 Z9 43 U1 2 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 JAN 15 PY 2010 VL 84 IS 2 BP 1189 EP 1192 DI 10.1128/JVI.01712-09 PG 4 WC Virology SC Virology GA 535TN UT WOS:000272994300049 PM 19889786 ER PT J AU Tell, G Wilson, DM Lee, CH AF Tell, Gianluca Wilson, David M., III Lee, Chow H. TI Intrusion of a DNA Repair Protein in the RNome World: Is This the Beginning of a New Era? SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID BASE EXCISION-REPAIR; APURINIC APYRIMIDINIC SITES; AP-ENDONUCLEASE APE1/REF-1; MESSENGER-RNA; ABASIC ENDONUCLEASE; FLAP ENDONUCLEASE-1; EXONUCLEASE-III; DAMAGE; IDENTIFICATION; BINDING AB Apurinic/apyrimidinic endonuclease 1 (APE1), an essential protein in mammals, is known to be involved in base excision DNA repair, acting as the major abasic endonuclease; the protein also functions as a redox coactivator of several transcription factors that regulate gene expression. Recent findings highlight a novel role for APE1 in RNA metabolism. The new findings are as follows: (i) APE1 interacts with rRNA and ribosome processing protein NPM1 within the nucleolus; (ii) APE1 interacts with proteins involved in ribosome assembly (i. e., RLA0, RSSA) and RNA maturation (i. e., PRP19, MEP50) within the cytoplasm; (iii) APE1 cleaves abasic RNA; and (iv) APE1 cleaves a specific coding region of c-myc mRNA in vitro and influences c-myc mRNA level and half-life in cells. Such findings on the role of APE1 in the post-transcriptional control of gene expression could explain its ability to influence diverse biological processes and its relocalization to cytoplasmic compartments in some tissues and tumors. In addition, we propose that APE1 serves as a "cleansing" factor for oxidatively damaged abasic RNA, establishing a novel connection between DNA and RNA surveillance mechanisms. In this review, we introduce questions and speculations concerning the role of APE1 in RNA metabolism and discuss the implications of these findings in a broader evolutionary context. C1 [Tell, Gianluca] Univ Udine, Dept Biomed Sci & Technol, I-33100 Udine, Italy. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Lee, Chow H.] Univ No British Columbia, Chem Program, Prince George, BC V2N 4Z9, Canada. RP Tell, G (reprint author), Univ Udine, Dept Biomed Sci & Technol, Piazzale Kolbe 4, I-33100 Udine, Italy. EM gianluca.tell@uniud.it; leec@unbc.ca OI Tell, Gianluca/0000-0001-8845-6448 FU MIUR [FIRB RBRN07BMCT_008]; NSERC [227158]; NIH, National Institute on Aging FX This work was supported by grants from MIUR (FIRB RBRN07BMCT_008) to G. T., NSERC Discovery Grant ( grant no. 227158) to C. H. L., and the Intramural Research Program of NIH, National Institute on Aging to D. M. W. NR 44 TC 47 Z9 47 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 JAN 15 PY 2010 VL 30 IS 2 BP 366 EP 371 DI 10.1128/MCB.01174-09 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 535GL UT WOS:000272955200001 PM 19901076 ER PT J AU Checkley, MA Nagashima, K Lockett, SJ Nyswaner, KM Garfinkel, DJ AF Checkley, Mary Ann Nagashima, Kunio Lockett, Stephen J. Nyswaner, Katherine M. Garfinkel, David J. TI P-Body Components Are Required for Ty1 Retrotransposition during Assembly of Retrotransposition-Competent Virus-Like Particles SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CYTOPLASMIC PROCESSING BODIES; SACCHAROMYCES-CEREVISIAE GENOME; MESSENGER-RNA; REVERSE-TRANSCRIPTASE; HOST GENES; TRANSPOSITION; PROTEIN; ELEMENTS; LOCALIZATION; COLOCALIZATION AB Ty1 is a retrovirus-like retrotransposon whose replication is influenced by diverse cellular processes in Saccharomyces cerevisiae. We have identified cytoplasmic P-body components encoded by DHH1, KEM1, LSM1, and PAT1 as cofactors that posttranscriptionally enhance Ty1 retrotransposition. Using fluorescent in situ hybridization and immunofluorescence microscopy, we found that Ty1 mRNA and Gag colocalize to discrete cytoplasmic foci in wild-type cells. These foci, which are distinct from P-bodies, do not form in P-body component mutants or under conditions suboptimal for retrotransposition. Our immunoelectron microscopy (IEM) data suggest that mRNA/Gag foci are sites where virus-like particles (VLPs) cluster. Overexpression of Ty1 leads to a large increase in retrotransposition in wild-type cells, which allows VLPs to be detected by IEM. However, retrotransposition is still reduced in P-body component mutants under these conditions. Moreover, the percentage of Ty1 mRNA/Gag foci and VLP clusters and levels of integrase and reverse transcriptase are reduced in these mutants. Ty1 antisense RNAs, which have been reported to inhibit Ty1 transposition, are more abundant in the kem1 Delta mutant and colocalize with Ty1 mRNA in the cytoplasm. Therefore, Kem1p may prevent the aggregation of Ty1 antisense and mRNAs. Overall, our results suggest that P-body components enhance the formation of retrotransposition-competent Ty1 VLPs. C1 [Checkley, Mary Ann; Nyswaner, Katherine M.; Garfinkel, David J.] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Nagashima, Kunio; Lockett, Stephen J.] NCI, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Garfinkel, DJ (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM garfinkd@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project was also funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. NR 63 TC 44 Z9 45 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN 15 PY 2010 VL 30 IS 2 BP 382 EP 398 DI 10.1128/MCB.00251-09 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 535GL UT WOS:000272955200003 PM 19901074 ER PT J AU Kim, JS Bailey, MJ Weller, JL Sugden, D Rath, MF Moller, M Klein, DC AF Kim, Jong-So Bailey, Michael J. Weller, Joan L. Sugden, David Rath, Martin F. Moller, Morten Klein, David C. TI Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4) SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Drd4; Thyroid hormone; Pineal gland; cAMP; Norepinephrine; Circadian ID N-ACETYLTRANSFERASE ACTIVITY; PARAVENTRICULAR NUCLEUS AREA; II IODOTHYRONINE DEIODINASE; RAT PINEAL; CIRCADIAN EXPRESSION; MELATONIN SYNTHESIS; MESSENGER-RNA; PHOTORECEPTOR CELLS; NOCTURNAL INCREASE; D-4 RECEPTORS AB Dopamine plays diverse and important roles in vertebrate biology, impacting behavior and physiology through actions mediated by specific G-protein-coupled receptors, one of which is the dopamine receptor D4 (Drd4). Here we present studies on the >100-fold daily rhythm in rat pineal Drd4 expression. Our studies indicate that Drd4 is the dominant dopamine receptor gene expressed in the pineal gland. The gene is expressed in pinealocytes at levels which are similar to 100-fold greater than in other tissues, except the retina, in which transcript levels are similar. Pineal Drd4 expression is circadian in nature and under photoneural control. Whereas most rhythmically expressed genes in the pineal are controlled by adrenergic/cAMP signaling, Drd4 expression also requires thyroid hormone. This advance raises the questions of whether Drd4 expression is regulated by this mechanism in other systems and whether thyroid hormone controls expression of other genes in the pineal gland. Published by Elsevier Ireland Ltd. C1 [Kim, Jong-So; Bailey, Michael J.; Weller, Joan L.; Klein, David C.] NIH, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Sugden, David] Kings Coll London, Div Reprod & Endocrinol, Sch Biomed & Hlth Sci, London SE1 1UL, England. [Rath, Martin F.; Moller, Morten] Univ Copenhagen, Dept Neurosci & Pharmacol, Panum Inst 24 3, DK-2200 Copenhagen, Denmark. [Kim, Jong-So] POSTECH, Dept Life Sci, Pohang 790784, South Korea. [Bailey, Michael J.] Texas A&M Univ, Dept Poultry Sci, College Stn, TX 77843 USA. RP Klein, DC (reprint author), NIH, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, Bldg 49,Room 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov OI Rath, Martin/0000-0002-4047-6324 FU NIH; NICHD; BBSRC; Danish Agency for Science Technology and Innovation; The Lundbeck Foundation; The Novo Nordisk Foundation FX The veterinary support provided by Daniel T. Abebe and the expert histological assistance by Mrs. Ursula Rentzmann are greatly appreciated. This research was supported by the Intramural Research Program of the NIH, NICHD (J-SK, JLW, MJB and DCK), a BBSRC Research Equipment Initiative grant (DS): and, grants from the Danish Agency for Science Technology and Innovation, The Lundbeck Foundation and The Novo Nordisk Foundation (MM and MFR). NR 59 TC 14 Z9 15 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 15 PY 2010 VL 314 IS 1 BP 128 EP 135 DI 10.1016/j.mce.2009.05.013 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 523VC UT WOS:000272101700015 PM 19482058 ER PT J AU Iwasaki, O Tanaka, A Tanizawa, H Grewal, SIS Noma, K AF Iwasaki, Osamu Tanaka, Atsunari Tanizawa, Hideki Grewal, Shiv I. S. Noma, Ken-ichi TI Centromeric Localization of Dispersed Pol III Genes in Fission Yeast SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RNA-POLYMERASE-III; SCHIZOSACCHAROMYCES-POMBE; CHROMOSOME CONDENSATION; CHROMATIN-STRUCTURE; NUCLEAR SPECKLES; SMC PROTEINS; TRANSCRIPTION; GENOME; ORGANIZATION; MITOSIS AB The eukaryotic genome is a complex three-dimensional entity residing in the nucleus. We present evidence that Pol III-transcribed genes such as tRNA and 5S rRNA genes can localize to centromeres and contribute to a global genome organization. Furthermore, we find that ectopic insertion of Pol III genes into a non-Pol III gene locus results in the centromeric localization of the locus. We show that the centromeric localization of Pol III genes is mediated by condensin, which interacts with the Pol III transcription machinery, and that transcription levels of the Pol III genes are negatively correlated with the centromeric localization of Pol III genes. This centromeric localization of Pol III genes initially observed in interphase becomes prominent during mitosis, when chromosomes are condensed. Remarkably, defective mitotic chromosome condensation by a condensin mutation, cut3-477, which reduces the centromeric localization of Pol III genes, is suppressed by a mutation in the sfc3 gene encoding the Pol III transcription factor TFIIIC subunit, sfc3-1. The sfc3-1 mutation promotes the centromeric localization of Pol III genes. Our study suggests there are functional links between the process of the centromeric localization of dispersed Pol III genes, their transcription, and the assembly of condensed mitotic chromosomes. C1 [Iwasaki, Osamu; Tanaka, Atsunari; Tanizawa, Hideki; Noma, Ken-ichi] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Noma, K (reprint author), Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. EM noma@wistar.org RI Tanizawa, Hideki/B-2631-2008; Tanaka, Atsunari/F-4950-2013 FU National Institutes of Health [CA010815, DP2-OD004348] FX We thank the Sanger Institute for cosmid clones, Richard Maraia and Yeast Genetic Resource Center (YGRC) for fission yeast strains, Keith Gull (University of Oxford) for anti-tubulin TAT1 antibody, and the Wistar Bioinformatics facility for statistical analysis of microscopic results. We also thank Louise Showe, Ronen Marmorstein, and Hugh Cam for comments on the manuscript. We are grateful to Andrew Kossenkov, Tomomi Hayashi, Lisa Bain, and Marion Sacks for technical and institutional assistance. This work was supported by National Institutes of Health Grant CA010815 and funded by the NIH Director's New Innovator Award Program, DP2-OD004348. NR 62 TC 61 Z9 61 U1 0 U2 2 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 JAN 15 PY 2010 VL 21 IS 2 BP 254 EP 265 DI 10.1091/mbc.E09-09-0790 PG 12 WC Cell Biology SC Cell Biology GA 543SO UT WOS:000273598900004 PM 19910488 ER PT J AU Kumfer, KT Cook, SJ Squirrell, JM Eliceiri, KW Peel, N O'Connell, KF White, JG AF Kumfer, Kraig T. Cook, Steven J. Squirrell, Jayne M. Eliceiri, Kevin W. Peel, Nina O'Connell, Kevin F. White, John G. TI CGEF-1 and CHIN-1 Regulate CDC-42 Activity during Asymmetric Division in the Caenorhabditis elegans Embryo SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ANTERIOR-POSTERIOR POLARITY; PAR PROTEIN LOCALIZATION; C-ELEGANS; CELL POLARITY; ANTEROPOSTERIOR AXIS; ESTABLISHMENT; POLARIZATION; MAINTENANCE; CDC42; KINASE AB The anterior-posterior axis of the Caenorhabditis elegans embryo is elaborated at the one-cell stage by the polarization of the partitioning (PAR) proteins at the cell cortex. Polarization is established under the control of the Rho GTPase RHO-1 and is maintained by the Rho GTPase CDC-42. To understand more clearly the role of the Rho family GTPases in polarization and division of the early embryo, we constructed a fluorescent biosensor to determine the localization of CDC-42 activity in the living embryo. A genetic screen using this biosensor identified one positive (putative guanine nucleotide exchange factor [GEF]) and one negative (putative GTPase activating protein [GAP]) regulator of CDC-42 activity: CGEF-1 and CHIN-1. CGEF-1 was required for robust activation, whereas CHIN-1 restricted the spatial extent of CDC-42 activity. Genetic studies placed CHIN-1 in a novel regulatory loop, parallel to loop described previously, that maintains cortical PAR polarity. We found that polarized distributions of the nonmuscle myosin NMY-2 at the cell cortex are independently produced by the actions of RHO-1, and its effector kinase LET-502, during establishment phase and CDC-42, and its effector kinase MRCK-1, during maintenance phase. CHIN-1 restricted NMY-2 recruitment to the anterior during maintenance phase, consistent with its role in polarizing CDC-42 activity during this phase. C1 [Kumfer, Kraig T.; Squirrell, Jayne M.; Eliceiri, Kevin W.; White, John G.] Univ Wisconsin, Mol Biol Lab, Madison, WI 53706 USA. [Cook, Steven J.; Squirrell, Jayne M.; Eliceiri, Kevin W.; White, John G.] Univ Wisconsin, Labs Opt & Computat Instrumentat, Madison, WI 53706 USA. [Peel, Nina; O'Connell, Kevin F.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Kumfer, KT (reprint author), Univ Wisconsin, Mol Biol Lab, Madison, WI 53706 USA. EM kumfer@gmail.com OI Eliceiri, Kevin/0000-0001-8678-670X; Peel, Nina/0000-0002-4277-4106 FU National Institutes of Health [GM-052454]; NIBIB [EB000184]; NIH [5 T32 GM-08349] FX We thank Kenneth Kemphues, Ellen Batchelder, and Julie Ahringer for helpful comments and suggestions on this work. We are grateful to Drs. Yuji Kohara, Anjon Audhya, Donato Aceto, Kenneth Kemphues, and Julie Ahringer as well as the Caenorhabditis Genetics Center and National BioResource Project of Japan for reagents and constructs. We thank Long Yan, Muhammad Nazir, and Steve Trier for advice on FLIM and Jens Eickhoff for assistance with logistic regression analysis. This work was supported by National Institutes of Health grants GM-052454 (to J. G. W.) and NIBIB EB000184 (to K. W. E. and J. G. W.). K. T. K. was supported by the Biotechnology Training Program (NIH 5 T32 GM-08349) at the University of Wisconsin-Madison. NR 54 TC 27 Z9 49 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 15 PY 2010 VL 21 IS 2 BP 266 EP 277 DI 10.1091/mbc.E09-01-0060 PG 12 WC Cell Biology SC Cell Biology GA 543SO UT WOS:000273598900005 PM 19923324 ER PT J AU Chuang, KH Belluscio, L Koretsky, AP AF Chuang, Kai-Hsiang Belluscio, Leonardo Koretsky, Alan P. TI In vivo detection of individual glomeruli in the rodent olfactory bulb using manganese enhanced MRI SO NEUROIMAGE LA English DT Article DE Olfactory glomerulus; Magnetic resonance imaging; Neuroanatomy; Molecular imaging ID FUNCTIONAL MRI; MOUSE-BRAIN; RAT-BRAIN; RESOLUTION; CONTRAST; INFORMATION; PERFORMANCE; TOPOGRAPHY; MICROSCOPY; INTENSITY AB MRI contrast based on relaxation times, proton density, or signal phase have been applied to delineate neural structures in the brain. However, neural units such as cortical layers and columns have been difficult to identify using these methods. Manganese ion delivered either systemically or injected directly has been shown to accumulate specifically within cellular areas of the brain enabling the differentiation of layers within the hippocampus, cortex, cerebellum, and olfactory bulb in vivo. Here we show the ability to detect individual olfactory glomeruli using manganese enhanced MRI (MEMRI) Glomeruli are anatomically distinct structures (similar to 150 mu m in diameter) on the surface of the olfactory bulb that represent the first processing units for olfactory sensory information. Following systemic delivery of MnCl(2) we used 3D-MRI with 50 mu m isotropic resolution to detect discrete spots of increased signal intensity between 100 and 200 mu m in diameter in the glomerular layer of the rat olfactory bulb. Inflow effects of arterial blood and susceptibility effects of venous blood were suppressed and were evaluated by comparing the location of vessels in the bulb to areas of manganese enhancement using iron oxide to increase vessel contrast. These potential vascular effects did not explain the contrast detected. Nissl staining of individual glomeruli were also compared to MEMRI images from the same animals clearly demonstrating that many of the manganese enhanced regions corresponded to individual olfactory glomeruli. Thus, MEMRI can be used as a non-invasive means to detect olfactory glomeruli for longitudinal studies looking at neural plasticity during olfactory development or possible degeneration associated with disease. Published by Elsevier Inc. C1 [Chuang, Kai-Hsiang; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Belluscio, Leonardo] NINDS, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. RP Chuang, KH (reprint author), Singapore Bioimaging Consortium, Lab Mol Imaging, 11 Biopolis Way,02-02, Singapore 138667, Singapore. EM chuang_kai_hsiang@sbic.a-star.edu.sg RI Koretsky, Alan/C-7940-2015 OI Chuang, Kai-Hsiang/0000-0002-8356-0657; Koretsky, Alan/0000-0002-8085-4756 FU NINDS; NIH FX The authors thank Nadia Bouraoud for assisting in animal procedures and Steve Dodd for MRI hardware support. This research was supported by the Intramural Research Program of the NINDS, NIH. NR 45 TC 15 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1350 EP 1356 DI 10.1016/j.neuroimage.2009.09.060 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400021 PM 19800011 ER PT J AU Danielian, LE Iwata, NK Thomasson, DM Floeter, MK AF Danielian, Laura E. Iwata, Nobue K. Thomasson, David M. Floeter, Mary Kay TI Reliability of fiber tracking measurements in diffusion tensor imaging for longitudinal study SO NEUROIMAGE LA English DT Article DE Diffusion tensor imaging; Tractography; Fiber tracking; Corticospinal tract; Corpus callosum; Test-retest reliability ID AMYOTROPHIC-LATERAL-SCLEROSIS; WHITE-MATTER TRACTS; HUMAN BRAIN; CORTICOSPINAL TRACT; CORPUS-CALLOSUM; FRACTIONAL ANISOTROPY; UNCINATE FASCICULUS; WALLERIAN DEGENERATION; AXONAL PROJECTIONS; TRACTOGRAPHY AB The statistical reliability of diffusion property measurements was evaluated in ten healthy subjects using deterministic fiber tracking to localize tracts affected in motor neuron disease: corticospinal tract (CST), uncinate fasciculus (UNC), and the Corpus Callosum in its entirety (CC), and its genu (GE), motor (CCM), and splenium (SP) fibers separately. Measurements of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda(1)), transverse diffusivity (lambda(perpendicular to)) and volume of voxels containing fibers (VV) were obtained within each tract. To assess intra-rater and inter-rater reliability, two raters carried out fiber tracking five times on each scan. Scan-rescan and longitudinal reliability were assessed in a subset of four subjects who had six scans, with two sets of three scans separated by 1 year. The statistical reliability of repeated measurements was evaluated using intraclass correlation coefficients (ICC) and coefficients of variation (CV). Spatial agreement of tract shape was assessed using the kappa (kappa) statistic. Results: Repeated same-scan fiber tracking evaluations showed good geometric alignment (intra-rater kappa>0.90, inter-rater kappa>0.76) and reliable diffusion property measurements (intra-rater ICC > 0.92, inter-rater ICC > 0.77). FA, MD, and lambda(perpendicular to) were highly reliable with repeated scans on different days, up to a year apart (ICC > 0.8). VV also exhibited good reliability, but with higher CVs. We were unable to demonstrate reproducibility of lambda(1). Longitudinal reliability after one year was improved by averaging measurements from multiple scans at each time point. Fiber tracking provides a reliable tool for the longitudinal evaluation of white matter diffusion properties. Published by Elsevier Inc. C1 [Danielian, Laura E.; Iwata, Nobue K.; Floeter, Mary Kay] Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, Bethesda, MD 20892 USA. [Thomasson, David M.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Danielian, LE (reprint author), Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, 10 Ctr Dr MSC 1404,Bldg 10,Rm 7-5680, Bethesda, MD 20892 USA. EM danielil@ninds.nih.gov FU Intramural Research Program of the NIH; National Institute of Neurological Disorders and Stroke FX We would like to thank John Ostuni for his invaluable assistance with Linux scripting for FSL image processing. This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. NR 75 TC 51 Z9 53 U1 0 U2 9 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 JAN 15 PY 2010 VL 49 IS 2 BP 1572 EP 1580 DI 10.1016/j.neuroimage.2009.08.062 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400040 PM 19744567 ER PT J AU Iseki, K Hanakawa, T Hashikawa, K Tomimoto, H Nankaku, M Yamauchi, H Hallett, M Fukuyama, H AF Iseki, Kazumi Hanakawa, Takashi Hashikawa, Kazuo Tomimoto, Hidekazu Nankaku, Manabu Yamauchi, Hiroshi Hallett, Mark Fukuyama, Hidenao TI Gait disturbance associated with white matter changes: A gait analysis and blood flow study SO NEUROIMAGE LA English DT Article DE Age-related white matter changes; Vascular parkinsonism; Cerebrovascular; Gait disorder; SPECT; Gait analysis ID SUBCORTICAL VASCULAR ENCEPHALOPATHY; PARKINSONS-DISEASE; OLDER-PEOPLE; BASAL GANGLIA; GLOBUS-PALLIDUS; MOTOR FUNCTION; BRAIN; LESIONS; DISORDERS; ABNORMALITIES AB To clarify the mechanisms underlying gait disturbance secondary to age-related white matter changes (ARWMC), cerebral perfusion was investigated during treadmill walking. Twenty subjects with extensive hyperintensities in the periventricular and deep white matter on T(2)-weighted magnetic resonance images (MRI) were recruited. The ARWMC subjects were classified into gait-disturbed (GD) and non-GD groups according to clinical criteria. All the Subjects underwent gait analyses and cerebral perfusion measurements during both gait and rest by using single photon emission computed tomography. The GD group showed greater double support time/phase and stride width, and slower walking velocity, than the non-GD group. In an analysis of pooled data from all the subjects, gait-induced increases in cerebral perfusion were observed in the supplementary motor areas (SMA), lateral premotor cortex (PMC), primary motor and somatosensory areas, visual areas, basal ganglia and cerebellum. A between-group comparison of gait-induced perfusion changes showed relative underactivation of the SMA, thalamus and basal ganglia, together with relative overactivation of the PMC, in the CD group compared with the non-GD group. In a separate correlation analysis including all the subjects, as the double support phase was longer (that was, gait disturbance was more severe), the gait-induced perfusion changes were proportionally reduced in the SMA, visual cortex, and thalamus. The present study suggests that abnormalities in the basal ganglia-thalamo-cortical loops partly explain gait disturbance observed in a subset of subjects with ARWMC. (C) 2009 Elsevier Inc. All rights reserved. C1 [Hanakawa, Takashi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Cort Funct Disorders, Kodaira, Tokyo 1878502, Japan. [Iseki, Kazumi; Yamauchi, Hiroshi; Fukuyama, Hidenao] Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. [Iseki, Kazumi; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD USA. [Hanakawa, Takashi] JST, PRESTO, Kawaguchi, Saitama, Japan. [Hashikawa, Kazuo] Osaka Minami Med Ctr, Div Stroke, Dept Cardiol 2, Osaka, Japan. [Tomimoto, Hidekazu] Mie Univ, Grad Sch Med, Dept Neurol, Tsu, Mie, Japan. [Nankaku, Manabu] Kyoto Univ, Grad Sch Med, Dept Phys Therapy, Kyoto, Japan. RP Hanakawa, T (reprint author), Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Cort Funct Disorders, 4-1-1 Ogawahigashi, Kodaira, Tokyo 1878502, Japan. EM hanakawa@ncnp.go.jp FU Sumitomo Life Social Welfare Services Foundation; Japan Brain Foundation; Takeda Science Foundation FX The authors are deeply grateful to Drs. Otsuka, Oishi, and Nakatsuka for their contributions to rating patients. The research was partly supported by the Sumitomo Life Social Welfare Services Foundation and the Japan Brain Foundation to K.I. and by a grant-in-aid for Scientific Research on Priority Areas (Emergence of Adaptive Motor Function through Interaction among the Body, Brain, Environment 20033030 and Integrative Brain Research 20019041) and by a grant-in-aid from the Takeda Science Foundation to T.H. NR 46 TC 20 Z9 24 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1659 EP 1666 DI 10.1016/j.neuroimage.2009.09.023 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400049 PM 19770057 ER PT J AU Yu, X Wang, SM Chen, DY Dodd, S Goloshevsky, A Koretsky, AP AF Yu, Xin Wang, Shumin Chen, Der-Yow Dodd, Stephen Goloshevsky, Artem Koretsky, Alan P. TI 3D mapping of somatotopic reorganization with small animal functional MRI SO NEUROIMAGE LA English DT Article ID SOMATOSENSORY CORTEX; NEURONAL-ACTIVITY; HEMODYNAMIC-RESPONSE; ORIENTATION COLUMNS; SENSORY STIMULATION; SPATIAL EXTENT; BRAIN-FUNCTION; BARREL CORTEX; BOLD RESPONSE; RAT-BRAIN AB There are few in vivo noninvasive methods to study neuroplasticity in animal brains. Functional MRI (fMRI) has been developed for animal brain mapping, but few fMRI studies have analyzed functional alteration due to plasticity in animal models. One major limitation is that fMRI maps are characterized by statistical parametric mapping making the apparent boundary dependent on the statistical threshold used. Here, we developed a method to characterize the location of center-of-mass in fMRI maps that is shown not to be sensitive to statistical threshold. Utilizing centers-of-mass as anchor points to fit the spatial distribution of the BOLD response enabled quantitative group analysis of altered boundaries of functional somatosensory maps. This approach was used to study cortical reorganization in the rat primary somatosensory cortex (S1) after sensory deprivation to the barrel cortex by follicle ablation (F.A.). FMRI demonstrated an enlarged nose SI representation in the 3D somatotopic functional maps. This result clearly demonstrates that fMRI enables the spatial mapping of functional changes that can characterize multiple regions of S1 cortex and still be sensitive to changes due to plasticity. Published by Elsevier Inc. C1 [Koretsky, Alan P.] NINDS, LFMI, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, LFMI, NIH, Bldg 10,Rm B1D728 10 Ctr Dr, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural Research Program of the NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. We thank Mss. Nadia Bouraoud and Kathy Sharer for their technical supports and animal surgery protocol preparation. We also thank Dr. David Leopold for his suggestions on the manuscript, and Drs. Daniel Glen, Ziad Saad, and Richard Reynolds for their help and support on image analysis with AFNI. We thank the assistance of the NIH Fellows Editorial Board for editing the manuscript. NR 47 TC 21 Z9 22 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2010 VL 49 IS 2 BP 1667 EP 1676 DI 10.1016/j.neuroimage.2009.09.021 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400050 PM 19770051 ER PT J AU Bergfield, KL Hanson, KD Chen, KW Teipel, SJ Hampel, H Rapoport, SI Moeller, JR Alexander, GE AF Bergfield, Kaitlin L. Hanson, Krista D. Chen, Kewei Teipel, Stefan J. Hampel, Harald Rapoport, Stanley I. Moeller, James R. Alexander, Gene E. TI Age-related networks of regional covariance in MRI gray matter: Reproducible multivariate patterns in healthy aging SO NEUROIMAGE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; VOXEL-BASED MORPHOMETRY; EVENT-RELATED FMRI; ALZHEIMERS-DISEASE; COGNITIVE RESERVE; EXECUTIVE FUNCTION; BRAIN NETWORKS; MEMORY; ADULTS; TASK AB Healthy aging is associated with brain volume reductions that involve the frontal cortex, but also affect other brain regions. We sought to identify an age-related network pattern of MRI gray matter using a multivariate statistical model of regional covariance, the Scaled Subprofile Model (SSM) with voxel based morphometry (VBM) in 29 healthy adults, 23-84 years of age (Group I). In addition, we evaluated the reproducibility of the age-related gray matter pattern derived from a prior SSM VBM study of 26 healthy adults, 22-77 years of age (Group 2; Alexander et al., 2006) in relation to the current sample and tested the ability of the network analysis to extract an age-related pattern from both cohorts combined. The SSM VBM analysis of Group 1 identified a regional pattern of gray matter atrophy associated with healthy aging (R(2) = 0.64, p<0.000001) that included extensive reductions in bilateral dorsolateral and medial frontal, anterior cingulate, insula/perisylvian, precuneus, parietotemporal, and caudate regions with areas of relative preservation in bilateral cerebellum, thalamus, putamen, mid cingulate, and temporal pole regions. The age-related SSM VBM gray matter pattern, previously reported for Group 2, was highly expressed in Group 1 (R(2) = 0.52, p<0.00002). SSM analysis of the combined cohorts extracted a common age-related pattern of gray matter showing reductions involving bilateral medial frontal, insula/perisylvian, anterior cingulate and, to a lesser extent, bilateral dorsolateral prefrontal, lateral temporal, parietal, and caudate brain regions with relative preservation in bilateral cerebellum, temporal pole, and right thalamic regions. The results suggest that healthy aging is associated with a regionally distributed pattern of gray matter atrophy that has reproducible regional features. Whereas the network patterns of atrophy included parietal, temporal, and subcortical regions, involvement of the frontal brain regions showed the most consistently extensive and reliable reductions across samples. Network analysis with SSM VBM can help detect reproducible age-related MRI patterns, assisting efforts in the study of healthy and pathological aging. (C) 2009 Elsevier Inc. All rights reserved. C1 [Hanson, Krista D.; Alexander, Gene E.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Bergfield, Kaitlin L.; Alexander, Gene E.] Univ Arizona, Neurosci Grad Interdisciplinary Program, Tucson, AZ 85721 USA. [Bergfield, Kaitlin L.; Hanson, Krista D.; Alexander, Gene E.] Univ Arizona, Evelyn F McKnight Brain Inst, Tucson, AZ 85721 USA. [Chen, Kewei] Banner Good Samaritan Med Ctr, Banner Alzheimers Inst, Phoenix, AZ 85006 USA. [Chen, Kewei] Banner Good Samaritan Med Ctr, Banner Samaritan PET Ctr, Phoenix, AZ 85006 USA. [Teipel, Stefan J.] Univ Rostock, Dept Psychiat, Rostock, Germany. [Teipel, Stefan J.] DZNE, Bonn, Germany. [Hampel, Harald] Univ Dublin Trinity Coll, Natl Childrens Hosp, Discipline Psychiat, Sch Med, Dublin 2, Ireland. [Hampel, Harald] Univ Dublin Trinity Coll, Natl Childrens Hosp, Adelaide & Meath Hosp, Lab Neuroimaging & Biomarker Res,Inst Neurosci, Dublin 2, Ireland. [Hampel, Harald] Univ Munich, Dept Psychiat, Alzheimers Mem Ctr, D-8000 Munich, Germany. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Moeller, James R.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Bergfield, Kaitlin L.; Hanson, Krista D.; Chen, Kewei; Alexander, Gene E.] Arizona Alzheimers Consortium, Phoenix, AZ 85006 USA. RP Alexander, GE (reprint author), Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. EM gene.alexander@arizona.edu RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU NIA [AG19610, AG025526]; NIA Intramural Research Program; Science Foundation Ireland (SFI) [08/IN.1/B1846]; Health Research Board (HRB) of Ireland; Alzheimer's Association; state of Arizona and Arizona Department of Health Services FX The authors acknowledge grant support for this work from the NIA (AG19610, AG025526), the NIA Intramural Research Program, the Science Foundation Ireland (SFI) investigator neuroimaging program grant (08/IN.1/B1846), a translational investigator program grant by the Health Research Board (HRB) of Ireland, the Alzheimer's Association, and the state of Arizona and Arizona Department of Health Services. An early version of this work was presented, in part, at the meeting of the Society for Neuroscience, Washington, DC, November, 2008. NR 41 TC 52 Z9 54 U1 3 U2 10 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 JAN 15 PY 2010 VL 49 IS 2 BP 1750 EP 1759 DI 10.1016/j.neuroimage.2009.09.051 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 533FF UT WOS:000272808400058 PM 19796692 ER PT J AU Kumar, A Greggio, E Beilina, A Kaganovich, A Chan, D Taymans, JM Wolozin, B Cookson, MR AF Kumar, Azad Greggio, Elisa Beilina, Alexandra Kaganovich, Alice Chan, Diane Taymans, Jean-Marc Wolozin, Benjamin Cookson, Mark R. TI The Parkinson's Disease Associated LRRK2 Exhibits Weaker In Vitro Phosphorylation of 4E-BP Compared to Autophosphorylation SO PLOS ONE LA English DT Article ID AUTOSOMAL-DOMINANT PARKINSONISM; REPEAT KINASE 2; MUTATION; LRRK2/DARDARIN; GENE AB Mutations in the gene encoding Leucine-rich repeat kinase 2 (LRRK2) are the most common cause of inherited Parkinson's disease (PD). LRRK2 is a multi-domain protein kinase containing a central catalytic core and a number of protein-protein interaction domains. An important step forward in the understanding of both the biology and the pathology of LRRK2 would be achieved by identification of its authentic physiological substrates. In the present study we examined phosphorylation of 4E-BP (eukaryotic initiation factor 4E (eIF4E)-binding protein), a recently proposed substrate for LRRKs. We found that LRRK2 is capable of phosphorylating 4E-BP in vitro. The PD related LRRK2-G2019S mutant was similar to 2 fold more active than wild type protein. However, LRRK2 autophosphorylation was stronger than 4E-BP phosphorylation under conditions of molar excess of 4E-BP to LRRK2. We also tested three other kinases (STK3, MAPK14/p38 alpha and DAPK2) and found that MAPK14/p38 alpha could efficiently phosphorylate 4E-BP at the same site as LRRK2 in vitro. Finally, we did not see changes in 4E-BP phosphorylation levels using inducible expression of LRRK2 in HEK cell lines. We also found that MAPK14/p38 alpha phosphorylates 4E-BP in transient overexpression experiments whereas LRRK2 did not. We suggest that increased 4EBP phosphorylation reported in some systems may be related to p38-mediated cell stress rather than direct LRRK2 activity. Overall, our results suggest that 4E-BP is a relatively poor direct substrate for LRRK2. C1 [Kumar, Azad; Greggio, Elisa; Beilina, Alexandra; Kaganovich, Alice; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Chan, Diane; Wolozin, Benjamin] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Chan, Diane; Wolozin, Benjamin] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Taymans, Jean-Marc] Katholieke Univ Leuven, Dept Mol & Cellular Med, Div Mol Med, Lab Neurobiol & Gene Therapy, Louvain, Belgium. RP Kumar, A (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Greggio, Elisa/H-6119-2013; OI Greggio, Elisa/0000-0002-8172-3598; Taymans, Jean-Marc/0000-0001-5503-5524 FU NIH, National Institute on Aging FX Funding: This work was funded by the Intramural Research Program of the NIH, National Institute on Aging. J-MT is a postdoctoral researcher of the Flemish fund for scientific research (FWO, Flanders, Belgium) and a Fulbright research scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 59 Z9 60 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 15 PY 2010 VL 5 IS 1 AR e8730 DI 10.1371/journal.pone.0008730 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 545EI UT WOS:000273714900011 PM 20090955 ER PT J AU Shin, R Cao, JR Webb, SM Ikemoto, S AF Shin, Rick Cao, Junran Webb, Sierra M. Ikemoto, Satoshi TI Amphetamine Administration into the Ventral Striatum Facilitates Behavioral Interaction with Unconditioned Visual Signals in Rats SO PLOS ONE LA English DT Article ID NUCLEUS-ACCUMBENS SHELL; FREELY-MOVING RATS; OLFACTORY TUBERCLE; LOCOMOTOR-ACTIVITY; PLACE PREFERENCE; TEGMENTAL AREA; CONDITIONED REINFORCEMENT; DOPAMINERGIC-NEURONS; INCENTIVE SALIENCE; DRUG SEEKING AB Background: Administration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli. Principal Findings: We found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective) or sulpiride (D2 selective). Conclusions: Our results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli. C1 [Shin, Rick; Cao, Junran; Webb, Sierra M.; Ikemoto, Satoshi] Natl Inst Drug Abuse, Behav Neurosci Res Branch, NIH, US Dept HHS, Baltimore, MD USA. RP Shin, R (reprint author), Natl Inst Drug Abuse, Behav Neurosci Res Branch, NIH, US Dept HHS, Baltimore, MD USA. EM Satoshi.Ikemoto@nih.gov RI Cao, Junran/E-7354-2013; OI Ikemoto, Satoshi/0000-0002-0732-7386 FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health [DA000439-10] FX Funding: This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health (Project number: DA000439-10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 21 Z9 21 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 15 PY 2010 VL 5 IS 1 AR e8741 DI 10.1371/journal.pone.0008741 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 545EI UT WOS:000273714900021 PM 20090902 ER PT J AU Nechaev, S Fargo, DC dos Santos, G Liu, LW Gao, Y Adelman, K AF Nechaev, Sergei Fargo, David C. dos Santos, Gilberto Liu, Liwen Gao, Yuan Adelman, Karen TI Global Analysis of Short RNAs Reveals Widespread Promoter-Proximal Stalling and Arrest of Pol II in Drosophila SO SCIENCE LA English DT Article ID CLEAVAGE FACTOR TFIIS; POLYMERASE-II; TRANSCRIPTION INITIATION; ELONGATION; MELANOGASTER; GENES; NELF; EXPRESSION; STABILITY; INVITRO AB Emerging evidence indicates that gene expression in higher organisms is regulated by RNA polymerase II stalling during early transcription elongation. To probe the mechanisms responsible for this regulation, we developed methods to isolate and characterize short RNAs derived from stalled RNA polymerase II in Drosophila cells. Significant levels of these short RNAs were generated from more than one-third of all genes, indicating that promoter-proximal stalling is a general feature of early polymerase elongation. Nucleotide composition of the initially transcribed sequence played an important role in promoting transcriptional stalling by rendering polymerase elongation complexes highly susceptible to backtracking and arrest. These results indicate that the intrinsic efficiency of early elongation can greatly affect gene expression. C1 [Nechaev, Sergei; dos Santos, Gilberto; Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Lib Serv, NIH, Res Triangle Pk, NC 27709 USA. [Fargo, David C.] NIEHS, Informat Serv, NIH, Res Triangle Pk, NC 27709 USA. [Liu, Liwen] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Gao, Yuan] Virginia Commonwealth Univ, Dept Comp Sci, Richmond, VA 23284 USA. RP Adelman, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov RI Gao, Yuan/E-1706-2011 FU NIH, National Institute of Environmental Health Sciences [Z01 ES101987] FX We thank P. Wade, T. Kunkel, and members of the Adelman laboratory for insightful discussions. We acknowledge S. Dai and J. Grovenstein for computational support. Sequence data are in the Gene Expression Omnibus (GEO) database under accession number GSE18643. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES101987). NR 28 TC 187 Z9 187 U1 1 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 15 PY 2010 VL 327 IS 5963 BP 335 EP 338 DI 10.1126/science.1181421 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 544CM UT WOS:000273629700044 PM 20007866 ER PT J AU Werren, JH Richards, S Desjardins, CA Niehuis, O Gadau, J Colbourne, JK Beukeboom, LW Desplan, C Elsik, CG Grimmelikhuijzen, CJP Kitts, P Lynch, JA Murphy, T Oliveira, DCSG Smith, CD van de Zande, L Worley, KC Zdobnov, EM Aerts, M Albert, S Anaya, VH Anzola, JM Barchuk, AR Behura, SK Bera, AN Berenbaum, MR Bertossa, RC Bitondi, MMG Bordenstein, SR Bork, P Bornberg-Bauer, E Brunain, M Cazzamali, G Chaboub, L Chacko, J Chavez, D Childers, CP Choi, JH Clark, ME Claudianos, C Clinton, RA Cree, AG Cristino, AS Dang, PM Darby, AC de Graaf, DC Devreese, B Dinh, HH Edwards, R Elango, N Elhaik, E Ermolaeva, O Evans, JD Foret, S Fowler, GR Gerlach, D Gibson, JD Gilbert, DG Graur, D Grunder, S Hagen, DE Han, Y Hauser, F Hultmark, D Hunter, HC Jhangian, SN Jiang, HY Johnson, RM Jones, AK Junier, T Kadowaki, T Kamping, A Kapustin, Y Kechavarzi, B Kim, J Kim, J Kiryutin, B Koevoets, T Kovar, CL Kriventseva, EV Kucharski, R Lee, H Lee, SL Lees, K Lewis, LR Loehlin, DW Logsdon, JM Lopez, JA Lozado, RJ Maglott, D Maleszka, R Mayampurath, A Mazur, DJ McClure, MA Moore, AD Morgan, MB Muller, J Munoz-Torres, MC Muzny, DM Nazareth, LV Neupert, S Nguyen, NB Nunes, FMF Oakeshott, JG Okwuonu, GO Pannebakker, BA Pejaver, VR Peng, ZG Pratt, SC Predel, R Pu, LL Ranson, H Raychoudhury, R Rechtsteiner, A Reese, JT Reid, JG Riddle, M Robertson, IM Romero-Severson, J Rosenberg, M Sackton, TB Sattelle, DB Schluns, H Schmitt, T Schneider, M Schuler, A Schurko, AM Shuker, DM Simoes, ZLP Sinha, S Smith, Z Solovyev, V Souvorov, A Springauf, A Stafflinger, E Stage, DE Stanke, M Tanaka, Y Telschow, A Trent, C Vattathil, S Verhulst, EC Viljakainen, L Wanner, KW Waterhouse, RM Whitfield, JB Wilkes, TE Williamson, M Willis, JH Wolschin, F Wyder, S Yamada, T Yi, SV Zecher, CN Zhang, L Gibbs, RA AF Werren, John H. Richards, Stephen Desjardins, Christopher A. Niehuis, Oliver Gadau, Juergen Colbourne, John K. Beukeboom, Leo W. Desplan, Claude Elsik, Christine G. Grimmelikhuijzen, Cornelis J. P. Kitts, Paul Lynch, Jeremy A. Murphy, Terence Oliveira, Deodoro C. S. G. Smith, Christopher D. van de Zande, Louis Worley, Kim C. Zdobnov, Evgeny M. Aerts, Maarten Albert, Stefan Anaya, Victor H. Anzola, Juan M. Barchuk, Angel R. Behura, Susanta K. Bera, Agata N. Berenbaum, May R. Bertossa, Rinaldo C. Bitondi, Marcia M. G. Bordenstein, Seth R. Bork, Peer Bornberg-Bauer, Erich Brunain, Marleen Cazzamali, Giuseppe Chaboub, Lesley Chacko, Joseph Chavez, Dean Childers, Christopher P. Choi, Jeong-Hyeon Clark, Michael E. Claudianos, Charles Clinton, Rochelle A. Cree, Andrew G. Cristino, Alexandre S. Dang, Phat M. Darby, Alistair C. de Graaf, Dirk C. Devreese, Bart Dinh, Huyen H. Edwards, Rachel Elango, Navin Elhaik, Eran Ermolaeva, Olga Evans, Jay D. Foret, Sylvain Fowler, Gerald R. Gerlach, Daniel Gibson, Joshua D. Gilbert, Donald G. Graur, Dan Grunder, Stefan Hagen, Darren E. Han, Yi Hauser, Frank Hultmark, Dan Hunter, Henry C. Jhangian, Shalini N. Jiang, Huaiyang Johnson, Reed M. Jones, Andrew K. Junier, Thomas Kadowaki, Tatsuhiko Kamping, Albert Kapustin, Yuri Kechavarzi, Bobak Kim, Jaebum Kim, Jay Kiryutin, Boris Koevoets, Tosca Kovar, Christie L. Kriventseva, Evgenia V. Kucharski, Robert Lee, Heewook Lee, Sandra L. Lees, Kristin Lewis, Lora R. Loehlin, David W. Logsdon, John M., Jr. Lopez, Jacqueline A. Lozado, Ryan J. Maglott, Donna Maleszka, Ryszard Mayampurath, Anoop Mazur, Danielle J. McClure, Marcella A. Moore, Andrew D. Morgan, Margaret B. Muller, Jean Munoz-Torres, Monica C. Muzny, Donna M. Nazareth, Lynne V. Neupert, Susanne Nguyen, Ngoc B. Nunes, Francis M. F. Oakeshott, John G. Okwuonu, Geoffrey O. Pannebakker, Bart A. Pejaver, Vikas R. Peng, Zuogang Pratt, Stephen C. Predel, Reinhard Pu, Ling-Ling Ranson, Hilary Raychoudhury, Rhitoban Rechtsteiner, Andreas Reese, Justin T. Reid, Jeffrey G. Riddle, Megan Robertson, Il High M. Romero-Severson, Jeanne Rosenberg, Miriam Sackton, Timothy B. Sattelle, David B. Schluens, Helge Schmitt, Thomas Schneider, Martina Schueler, Andreas Schurko, Andrew M. Shuker, David M. Simoes, Zila L. P. Sinha, Saurabh Smith, Zachary Solovyev, Victor Souvorov, Alexandre Springauf, Andreas Stafflinger, Elisabeth Stage, Deborah E. Stanke, Mario Tanaka, Yoshiaki Telschow, Arndt Trent, Carol Vattathil, Selina Verhulst, Eveline C. Viljakainen, Lumi Wanner, Kevin W. Waterhouse, Robert M. Whitfield, James B. Wilkes, Timothy E. Williamson, Michael Willis, Judith H. Wolschin, Florian Wyder, Stefan Yamada, Takuji Yi, Soojin V. Zecher, Courtney N. Zhang, Lan Gibbs, Richard A. CA Nasonia Genome Working Grp TI Functional and Evolutionary Insights from the Genomes of Three Parasitoid Nasonia Species SO SCIENCE LA English DT Article ID WASP NASONIA; DNA METHYLATION; SOCIAL INSECTS; APIS-MELLIFERA; VITRIPENNIS; HYMENOPTERA; GENES; PTEROMALIDAE; DROSOPHILA; HONEYBEE AB We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N. giraulti, and N. longicornis. Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents. C1 [Werren, John H.; Desjardins, Christopher A.; Oliveira, Deodoro C. S. G.; Clark, Michael E.; Edwards, Rachel; Loehlin, David W.; Raychoudhury, Rhitoban; Stage, Deborah E.] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [Richards, Stephen; Worley, Kim C.; Chaboub, Lesley; Chacko, Joseph; Chavez, Dean; Cree, Andrew G.; Dinh, Huyen H.; Fowler, Gerald R.; Han, Yi; Jhangian, Shalini N.; Jiang, Huaiyang; Kamping, Albert; Kovar, Christie L.; Lee, Sandra L.; Lewis, Lora R.; Lozado, Ryan J.; Morgan, Margaret B.; Muzny, Donna M.; Nazareth, Lynne V.; Nguyen, Ngoc B.; Okwuonu, Geoffrey O.; Pu, Ling-Ling; Reid, Jeffrey G.; Vattathil, Selina; Zhang, Lan; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Niehuis, Oliver; Gadau, Juergen; Gibson, Joshua D.; Pratt, Stephen C.; Wolschin, Florian] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. [Colbourne, John K.; Choi, Jeong-Hyeon; Lopez, Jacqueline A.; Rechtsteiner, Andreas; Smith, Zachary] Indiana Univ, Ctr Genom & Bioinformat, Bloomington, IN 47405 USA. [Beukeboom, Leo W.; van de Zande, Louis; Koevoets, Tosca; Pannebakker, Bart A.; Verhulst, Eveline C.] Univ Groningen, Evolutionary Genet Ctr Ecol & Evolutionary Studie, NL-9750 AA Haren, Netherlands. [Desplan, Claude; Rosenberg, Miriam] NYU, Dept Biol, New York, NY 10003 USA. [Elsik, Christine G.; Childers, Christopher P.; Hagen, Darren E.; Munoz-Torres, Monica C.; Reese, Justin T.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Grimmelikhuijzen, Cornelis J. P.; Cazzamali, Giuseppe; Hauser, Frank; Schneider, Martina; Stafflinger, Elisabeth; Williamson, Michael] Univ Copenhagen, Dept Biol, Ctr Comparat & Funct Insect Genom, DK-2100 Copenhagen, Denmark. [Kitts, Paul; Murphy, Terence; Ermolaeva, Olga; Kapustin, Yuri; Kiryutin, Boris; Maglott, Donna; Souvorov, Alexandre] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Lynch, Jeremy A.] Univ Cologne, Inst Entwicklungsphysiol, D-50923 Cologne, Germany. [Smith, Christopher D.; Hunter, Henry C.; Kim, Jay] San Francisco State Univ, Dept Biol, San Francisco, CA 94132 USA. [Smith, Christopher D.] Univ Calif Berkeley, Lawrence Berkeley Lab, Drosophila Heterochromatin Genome Project, Berkeley, CA 94720 USA. [Zdobnov, Evgeny M.; Gerlach, Daniel; Junier, Thomas; Wyder, Stefan] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Zdobnov, Evgeny M.; Gerlach, Daniel] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Zdobnov, Evgeny M.; Waterhouse, Robert M.] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Aerts, Maarten; Devreese, Bart] Univ Ghent, Lab Prot Biochem & Biomol Engn, B-9000 Ghent, Belgium. [Albert, Stefan] Univ Wurzburg, BEEgrp, D-97082 Wurzburg, Germany. [Albert, Stefan] Univ Wurzburg, Inst Pharmaceut Biol, D-97082 Wurzburg, Germany. [Anaya, Victor H.] Humboldt Univ, Inst Theoret Biol, D-10115 Berlin, Germany. [Anzola, Juan M.] Texas A&M Univ, College Stn, TX 77843 USA. [Barchuk, Angel R.] Univ Fed Alfenas, Dept Ciencias Biomed, BR-37130000 Alfenas, MG, Brazil. [Behura, Susanta K.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. [Bera, Agata N.; Jones, Andrew K.; Lees, Kristin; Sattelle, David B.] Univ Oxford, Dept Physiol Anat & Genet, MRC, Funct Genom Unit, Oxford OX1 3QX, England. [Berenbaum, May R.; Robertson, Il High M.; Whitfield, James B.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Bertossa, Rinaldo C.] Univ Groningen, Chronobiol Ctr Behav & Neurosci, NL-9750 AA Haren, Netherlands. [Bitondi, Marcia M. G.; Nunes, Francis M. F.; Simoes, Zila L. P.] Univ Sao Paulo, Dept Biol, Fac Filosofia Ciencias & Letras Ribeirao Pret, BR-14040901 Sao Paulo, Brazil. [Bordenstein, Seth R.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. [Bordenstein, Seth R.; Zecher, Courtney N.] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02536 USA. [Bork, Peer; Muller, Jean; Yamada, Takuji] European Mol Biol Lab, D-69117 Heidelberg, Germany. [Bornberg-Bauer, Erich; Moore, Andrew D.; Romero-Severson, Jeanne; Schueler, Andreas; Telschow, Arndt] Univ Munster, Inst Evolut & Biodivers, D-48143 Munster, Germany. [Brunain, Marleen; de Graaf, Dirk C.] Univ Ghent, Lab Zoophysiol, B-9000 Ghent, Belgium. [Claudianos, Charles; Cristino, Alexandre S.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Clinton, Rochelle A.; McClure, Marcella A.] Montana State Univ, Dept Microbiol, Bozeman, MT 59715 USA. [Clinton, Rochelle A.; McClure, Marcella A.] Montana State Univ, Ctr Computat Biol, Bozeman, MT 59715 USA. [Cristino, Alexandre S.] Univ Sao Paulo, Dept Fis & Informat, Inst Fis Sao Carlos, BR-13560970 Sao Paulo, Brazil. [Dang, Phat M.] ARS, Subtrop Insects Res Unit, USDA, US Hort Res Lab, Ft Pierce, FL 34945 USA. [Darby, Alistair C.; Wilkes, Timothy E.] Univ Liverpool, Sch Biol Sci, Liverpool L69 7ZB, Merseyside, England. [Elango, Navin; Peng, Zuogang; Yi, Soojin V.] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Elhaik, Eran; Graur, Dan] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Evans, Jay D.] ARS, Bee Res Lab, USDA, Beltsville, MD 20705 USA. [Foret, Sylvain] James Cook Univ, Australian Res Council, Ctr Excellence Coral Reef Studies, Townsville, Qld 4811, Australia. [Gilbert, Donald G.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Grunder, Stefan; Springauf, Andreas] Rhein Westfal TH Aachen, Inst Physiol, D-52074 Aachen, Germany. [Hultmark, Dan] Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. [Johnson, Reed M.] Univ Nebraska, Dept Entomol, Lincoln, NE 68583 USA. [Kadowaki, Tatsuhiko] Nagoya Univ, Grad Sch Bioagr Sci, Nagoya, Aichi 4648601, Japan. [Kechavarzi, Bobak; Lee, Heewook; Mayampurath, Anoop; Pejaver, Vikas R.] Indiana Univ, Sch Informat, Bloomington, IN 47405 USA. [Kim, Jaebum; Sinha, Saurabh] Univ Illinois, Dept Comp Sci, Urbana, IL 61801 USA. [Kriventseva, Evgenia V.] Univ Geneva, Sch Med, Dept Struct Biol & Bioinformat, CH-1211 Geneva, Switzerland. [Kucharski, Robert; Maleszka, Ryszard] Australian Natl Univ, Res Sch Biol, Canberra, ACT 2601, Australia. [Logsdon, John M., Jr.; Mazur, Danielle J.; Schurko, Andrew M.] Univ Iowa, Roy J Carver Ctr Comparat Genom, Iowa City, IA 52242 USA. [Logsdon, John M., Jr.; Mazur, Danielle J.; Schurko, Andrew M.] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA. [Munoz-Torres, Monica C.] Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. [Neupert, Susanne; Predel, Reinhard] Univ Jena, Inst Gen Zool, D-7743 Jena, Germany. [Nunes, Francis M. F.] Univ Sao Paulo, Dept Genet, Fac Med Ribeirao Preto, BR-14049900 Sao Paulo, Brazil. [Oakeshott, John G.] CSIRO, Div Entomol, Canberra, ACT 2601, Australia. [Pannebakker, Bart A.] Univ Edinburgh, Sch Biol Sci, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Ranson, Hilary] Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. [Rechtsteiner, Andreas] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Reese, Justin T.] Reese Consulting, Amphur Muang, Nong Khai, Thailand. [Riddle, Megan; Trent, Carol] Western Washington Univ, Dept Biol, Bellingham, WA 98225 USA. [Romero-Severson, Jeanne] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Sackton, Timothy B.] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Schluens, Helge] James Cook Univ, Sch Marine & Trop Biol, Townsville, Qld 4811, Australia. [Schluens, Helge] James Cook Univ, Ctr Comparat Genom, Townsville, Qld 4811, Australia. [Schmitt, Thomas] Univ Freiburg, Dept Evolutionary Biol & Anim Ecol, D-79104 Freiburg, Germany. [Shuker, David M.] Univ St Andrews, Sch Biol, St Andrews KY16 9TH, Fife, Scotland. [Solovyev, Victor] Univ London, Dept Comp Sci, Egham TW20 0EX, Surrey, England. [Stanke, Mario] Univ Gottingen, Inst Mikrobiol & Genet, D-37077 Gottingen, Germany. [Tanaka, Yoshiaki] Natl Inst Agrobiol Sci, Div Insect Sci, Tsukuba, Ibaraki 3058634, Japan. [Viljakainen, Lumi] Univ Oulu, Dept Biol, Oulu 90014, Finland. [Viljakainen, Lumi] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. [Wanner, Kevin W.] Montana State Univ, Dept Plant Sci & Plant Pathol, Bozeman, MT 59717 USA. [Willis, Judith H.] Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA. [Wolschin, Florian] Norwegian Univ Life Sci, Dept Biotechnol Chem & Food Sci, N-1432 As, Norway. RP Werren, JH (reprint author), Univ Rochester, Dept Biol, Rochester, NY 14627 USA. EM werr@mail.rochester.edu; stephenr@bcm.tmc.edu RI Pannebakker, Bart/D-3823-2012; Darby, Alistair/I-6485-2012; Zdobnov, Evgeny/K-1133-2012; Beukeboom, Leo/D-1808-2012; Bornberg-Bauer, Erich/A-1563-2013; Shuker, David/E-8827-2013; Bork, Peer/F-1813-2013; Lopez, Jacqueline/F-9712-2013; Schmitt, Thomas/H-3033-2013; Oakeshott, John/B-5365-2009; Maleszka, Ryszard/A-6078-2008; Evans, Jay/C-8408-2012; Choi, Justin/F-8792-2014; Nunes, Francis/F-5871-2010; Junier, Thomas/A-6748-2011; Pannebakker, Bart/D-1479-2010; Pratt, Stephen/C-5418-2011; Romero-Severson, Jeanne/B-5259-2011; Choi, Jeong-Hyeon/E-3084-2010; Foret, Sylvain/C-7661-2011; Schluns, Helge/B-1753-2009; Peng, Zuogang/D-4448-2011; Devreese, Bart/B-2011-2009; Johnson, Reed/H-3742-2011; Cristino, Alexandre/A-5834-2012; FORET, Sylvain/B-9207-2012; Simoes, Zila/H-7314-2014; Colbourne, John/L-7748-2014; Hauser, Frank/M-2952-2014; Aerts, Maarten/O-6194-2014; Bordenstein, Seth/F-1298-2010; Predel, Reinhard/O-5243-2015; Hultmark, Dan/C-5058-2013; Waterhouse, Robert/A-1858-2010; Verhulst, Eveline/J-2641-2013; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; Bitondi, Marcia/E-8014-2012; Elsik, Christine/C-4120-2017 OI Gerlach, Daniel/0000-0001-9338-3765; Grunder, Stefan/0000-0002-7635-9883; Muller, Jean/0000-0002-7682-559X; Sackton, Timothy/0000-0003-1673-9216; Grimmelikhuijzen, Cornelis/0000-0001-6486-2046; Ranson, Hilary/0000-0003-2332-8247; Wyder, Stefan/0000-0002-3412-0292; Childers, Chris/0000-0002-1253-5550; Solovyev, Victor/0000-0001-8885-493X; Claudianos, Charles/0000-0002-9799-9572; Pannebakker, Bart/0000-0001-8503-3896; Darby, Alistair/0000-0002-3786-6209; Bornberg-Bauer, Erich/0000-0002-1826-3576; Bork, Peer/0000-0002-2627-833X; Maleszka, Ryszard/0000-0003-1855-555X; Evans, Jay/0000-0002-0036-4651; Nunes, Francis/0000-0002-7769-3058; Romero-Severson, Jeanne/0000-0003-4112-7238; Peng, Zuogang/0000-0001-8810-2025; Devreese, Bart/0000-0002-9764-2581; Johnson, Reed/0000-0002-2431-0180; Cristino, Alexandre/0000-0002-3468-0919; Colbourne, John/0000-0002-6966-2972; Hauser, Frank/0000-0001-5563-2345; Aerts, Maarten/0000-0003-0125-6721; Bordenstein, Seth/0000-0001-7346-0954; Hultmark, Dan/0000-0002-6506-5855; Waterhouse, Robert/0000-0003-4199-9052; Verhulst, Eveline/0000-0002-4781-535X; Bitondi, Marcia/0000-0002-5619-6378; Elsik, Christine/0000-0002-4248-7713 FU National Human Genome Research Institute [NHGRI U54 HG003273] FX Genome sequencing, assembly and annotation were funded by the National Human Genome Research Institute (NHGRI U54 HG003273). The whole-genome shotgun project has been deposited at the DNA Databank of Japan (DDBJ)/European Molecular Biology Laboratory (EMBL)/GenBank under accession numbers AAZX00000000 (N. vitripennis), ADAO00000000 (N. giraulti), and ADAP00000000 (N. longicornis). Additional support, acknowledgments, and accession numbers are provided in the supporting online material. NR 39 TC 392 Z9 464 U1 30 U2 232 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 15 PY 2010 VL 327 IS 5963 BP 343 EP 348 DI 10.1126/science.1178028 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 544CM UT WOS:000273629700047 PM 20075255 ER PT J AU Clough, M Justice, CM Marosy, B Miller, NH AF Clough, Mark Justice, Cristina M. Marosy, Beth Miller, Nancy H. TI Males With Familial Idiopathic Scoliosis A Distinct Phenotypic Subgroup SO SPINE LA English DT Article DE chromosome 17; genomic screen; linkage analysis; idiopathic scoliosis ID SURGICAL-TREATMENT; NATURAL-HISTORY; NEUROFIBROMATOSIS; PREVALENCE; LOCUS; BONE; GENE; SUSCEPTIBILITY; IDENTIFICATION; OUTCOMES AB Study Design. Statistical analysis of genomic screening and fine mapping data. Objective. The goals of this study were to analyze a region on chromosome 17 and to identify specific genetic determinants within this region linked to familial idiopathic scoliosis (FIS) in a subgroup of families in which affected males have undergone surgery. Summary of Background Data. The high prevalence and variability of FIS is indicative of genetic heterogeneity. To localize genes related to scoliosis, identification of groups of families with common clinical characteristics is a strategy that reduces genetic heterogeneity. Two independent studies have implicated a region on chromosome 17 as related to FIS. Methods. With approval of the Institutional Review Board, the initial study population consisted of 202 families (1198 individuals), each of which had 2 or more affected individuals; 17 of those families had an affected male who had surgery. Individuals underwent genomic screening and subsequent fine mapping. Results were obtained using model-independent linkage analysis, with scoliosis set as a qualitative and as a quantitative trait, as implemented in SIBPAL (S.A.G.E., v4.5). The level of significance was set at P <= 0.05. Results. The initial study population had significant results at markers d17s975 and d17s2196. Analyses of a subgroup of families with males having undergone surgery using a customized single nucleotide polymorphism panel resulted in increased significance of this region. Conclusion. The data confirm a previously reported genetic locus on chromosome 17 as statistically significant in the etiology of FIS within a subgroup of families in which an affected male had spinal surgery. C1 [Clough, Mark; Marosy, Beth; Miller, Nancy H.] Johns Hopkins Univ, Dept Orthopaed Surg, Baltimore, MD USA. [Justice, Cristina M.] NIH, Genometr Sect, Div Intramural Res, Baltimore, MD USA. [Miller, Nancy H.] Univ Colorado, Childrens Hosp, Hlth Sci Ctr, Dept Orthopaed Surg, Aurora, CO USA. RP Miller, NH (reprint author), Care of Henze EP, Johns Hopkins Bayview Med Ctr, Editorial Serv, Dept Orthopaed Surg, 4940 Eastern Ave,A665, Baltimore, MD 21224 USA. EM ehenze1@jhmi.edu FU National Human Genome Research Institute, National Institutes of Health [1-R01-AR048862-01A1, N01-HG-654035R01AR048862-03]; Scoliosis Research Society; National Scoliosis Foundation; Scoliosis Association, Inc.; Institute de France Foundation Yves Cotrel; Orthopaedic Pediatric Society of North America; Orthopaedic Research and Education Foundation; National Center for Research Resources [1 P41 RR03655] FX Supported, in part, by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Additional grant funding was provided by the Scoliosis Research Society, the National Scoliosis Foundation, Scoliosis Association, Inc., the Institute de France Foundation Yves Cotrel, the Orthopaedic Pediatric Society of North America, the Orthopaedic Research and Education Foundation, and NIH 1-R01-AR048862-01A1.; The genome-wide linkage screen was performed at the Center for Inherited Disease Research (CIDR). CIDR is fully funded through federal contract N01-HG-654035R01AR048862-03 from the National Institutes of Health to the Johns Hopkins University. Some of the results were obtained with the program S. A. G. E., which is supported by grant 1 P41 RR03655 from the National Center for Research Resources. NR 46 TC 4 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JAN 15 PY 2010 VL 35 IS 2 BP 162 EP 168 DI 10.1097/BRS.0b013e3181b7f1a7 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 551WY UT WOS:000274245300006 PM 20081511 ER PT J AU Joo, J Kwak, M Chen, ZH Zheng, G AF Joo, Jungnam Kwak, Minjung Chen, Zehua Zheng, Gang TI Efficiency robust statistics for genetic linkage and association studies under genetic model uncertainty SO STATISTICS IN MEDICINE LA English DT Article DE case-control design; GWAS; Hardy-Weinberg; linkage; MAX; MERT; meta-analysis; restricted inference; trios ID GENOME-WIDE ASSOCIATION; FAMILY-BASED ASSOCIATION; TREND TESTS; NUISANCE PARAMETER; SAMPLE-SIZE; ASYMPTOTIC PROPERTIES; UNIFIED APPROACH; AFFECTED SIBS; P-VALUE; POWER AB When testing genetic linkage and association, test statistics that follow a normal or Chi-square distributions are often used. These statistics are usually derived under a specific mode of inheritance (genetic model). Common genetic models include, but not limited to, the recessive, additive, multiplicative, and dominant models. For many diseases, their underlying genetic models are often unknown. Instead, a family of scientifically plausible genetic models may be available, which includes the four commonly used models. Hence, the optimal test is not available. Employing a single test statistic which is optimal for one model may suffer from substantial loss of power when the model is misspecified. In this situation efficient robust tests are useful. In this tutorial, we first review several commonly used robust statistics, including maximin efficency robust tests, maximal tests, and constrained likelihood ratio tests for three common designs in genetic studies: (i) linkage analysis using affected sib-pairs, (ii) association studies using parents-offspring trios, and (iii) case-control association studies (unmatched and matched). Codes in the R statistical language for applying these robust statistics to test for linkage and association are presented with examples. We also provide some comparisons of the performance of the various robust tests via simulation studies. Guidelines for applications are also given for each study design. Finally, applications of robust tests to genome-wide association studies and meta-analysis are discussed. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Joo, Jungnam; Kwak, Minjung; Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Chen, Zehua] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Room 9200,6701 Rockledge Dr,MSC 7913, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov NR 97 TC 16 Z9 16 U1 2 U2 9 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2010 VL 29 IS 1 BP 158 EP 180 DI 10.1002/sim.3759 PG 23 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 543ZU UT WOS:000273621500013 PM 19918942 ER PT J AU Funderburg, NT Mayne, E Sieg, SF Asaad, R Jiang, W Kalinowska, M Luciano, AA Stevens, W Rodriguez, B Brenchley, JM Douek, DC Lederman, MM AF Funderburg, Nicholas T. Mayne, Elizabeth Sieg, Scott F. Asaad, Robert Jiang, Wei Kalinowska, Magdalena Luciano, Angel A. Stevens, Wendy Rodriguez, Benigno Brenchley, Jason M. Douek, Daniel C. Lederman, Michael M. TI Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation SO BLOOD LA English DT Article ID INTIMA-MEDIA THICKNESS; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; COLI SEPTIC SHOCK; CARDIOVASCULAR-DISEASE; MICROBIAL TRANSLOCATION; CORONARY SYNDROMES; RECEPTOR LIGANDS; ATHEROSCLEROSIS; RISK AB HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV(+) patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection. (Blood. 2010; 115:161-167) C1 [Funderburg, Nicholas T.; Sieg, Scott F.; Asaad, Robert; Jiang, Wei; Kalinowska, Magdalena; Luciano, Angel A.; Rodriguez, Benigno; Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp Cleveland, Dept Med, Div Infect Dis, Cleveland, OH 44106 USA. [Mayne, Elizabeth; Stevens, Wendy] Natl Hlth Lab Serv, Johannesburg, South Africa. [Mayne, Elizabeth; Stevens, Wendy] Univ Witwatersrand, Johannesburg, South Africa. [Luciano, Angel A.] Rainbow Babies & Childrens Hosp, Dept Pediat, Case Med Ctr, Cleveland, OH 44106 USA. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lederman, MM (reprint author), 2109 Adelbert Rd,1048B,BRB Bldg, Cleveland, OH 44106 USA. EM MXL6@case.edu RI Funderburg, Nicholas/L-8022-2013; Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU Center for AIDS Research at Case Western Reserve University [AI-36219]; National Institutes of Health [AI-076174, AI-68636] FX This work was supported by the Center for AIDS Research at Case Western Reserve University (AI-36219) and the National Institutes of Health (grants AI-076174 and AI-68636). NR 36 TC 121 Z9 122 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 14 PY 2010 VL 115 IS 2 BP 161 EP 167 DI 10.1182/blood-2009-03-210179 PG 7 WC Hematology SC Hematology GA 544AE UT WOS:000273622600005 PM 19828697 ER PT J AU Jadhav, A Ferreira, RS Klumpp, C Mott, BT Austin, CP Inglese, J Thomas, CJ Maloney, DJ Shoichet, BK Simeonov, A AF Jadhav, Ajit Ferreira, Rafaela S. Klumpp, Carleen Mott, Bryan T. Austin, Christopher P. Inglese, James Thomas, Craig J. Maloney, David J. Shoichet, Brian K. Simeonov, Anton TI Quantitative Analyses of Aggregation, Autofluorescence, and Reactivity Artifacts in a Screen for Inhibitors of a Thiol Protease SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-THROUGHPUT SCREEN; PROMISCUOUS INHIBITORS; TRYPANOSOMA-CRUZI; FALSE POSITIVES; MECHANISM; LIBRARIES; POTENT; ASSAYS; IDENTIFICATION; INFECTION AB The perceived and actual burden of false positives in high-throughput screening has received considerable attention; however, few studies exist on the contributions of distinct mechanisms of nonspecific effects like chemical reactivity, assay signal interference, and colloidal aggregation. Here, we analyze the outcome of a screen of 197861 diverse compounds in a concentration-response format against the cysteine protease cruzain, a target expected to be particularly sensitive to reactive compounds, and using an assay format with light detection in the short-wavelength region where significant compound autofluorescence is typically encountered. Approximately 1.9% of all compounds screened were detergent-sensitive inhibitors. The contribution from autofluorescence and compounds bearing reactive functionalities was dramatically lower: of all hits, only 1.8% Were autofluorescent and 1.5% contained reactive or undesired functional groups. The distribution of false positives was relatively constant across library sources. The simple step of including detergent in the assay buffer suppressed the nonspecific effect of approximately 93% of the original hits. C1 [Ferreira, Rafaela S.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Jadhav, Ajit; Klumpp, Carleen; Mott, Bryan T.; Austin, Christopher P.; Inglese, James; Thomas, Craig J.; Maloney, David J.; Simeonov, Anton] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Shoichet, BK (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, 1700 4th St, San Francisco, CA 94158 USA. EM shoichet@cgl.ucsf.edu; asimeono@mail.nih.gov RI Ferreira, Rafaela/L-9841-2014 OI Ferreira, Rafaela/0000-0003-3324-0601 FU NIH [GM63815] FX We thank Sam Michael, Adam Yasgar, and Paul Shinn with assistance with the robotic screens and compound management. This research was supported in part by the NIH Roadmap for Medical Research and the Intramural Research Program of the NHGRI, NIH (to C.P.A.) and by NIH grant GM63815 (to B.K.S.). We thank the anonymous reviewers for their valuable comments during the manuscript review process. The authors declare no competing financial interests. NR 37 TC 89 Z9 90 U1 4 U2 18 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 JAN 14 PY 2010 VL 53 IS 1 BP 37 EP 51 DI 10.1021/jm901070c PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 539PL UT WOS:000273268300004 PM 19908840 ER PT J AU Mott, BT Ferreira, RS Simeonov, A Jadhav, A Ang, KKH Leister, W Shen, M Silveira, JT Doyle, PS Arkin, MR McKerrow, JH Inglese, J Austin, CP Thomas, CJ Shoichet, BK Maloney, DJ AF Mott, Bryan T. Ferreira, Rafaela S. Simeonov, Anton Jadhav, Ajit Ang, Kenny Kean-Hooi Leister, William Shen, Min Silveira, Julia T. Doyle, Patricia S. Arkin, Michelle R. McKerrow, James H. Inglese, James Austin, Christopher P. Thomas, Craig J. Shoichet, Brian K. Maloney, David J. TI Identification and Optimization of Inhibitors of Trypanosomal Cysteine Proteases: Cruzain, Rhodesain, and TbCatB SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHAGAS-DISEASE; CATHEPSIN-B; MOUSE MODEL; INFECTION; POTENT; MECHANISM; LIBRARIES; BRUCEI AB Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely oil essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles. which are known inhibitors of other cysteine proteases, its reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against it panel of human cysteine and serine proteases to determine selectivity, and it cocrystal was obtained of our most potent analogue bound to cruzain. C1 [Mott, Bryan T.; Simeonov, Anton; Jadhav, Ajit; Leister, William; Shen, Min; Silveira, Julia T.; Inglese, James; Austin, Christopher P.; Thomas, Craig J.; Maloney, David J.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Ferreira, Rafaela S.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Ang, Kenny Kean-Hooi; Arkin, Michelle R.] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94158 USA. [Ferreira, Rafaela S.] Univ Calif San Francisco, Grad Program Chem & Chem Biol, San Francisco, CA 94158 USA. [Ferreira, Rafaela S.; Doyle, Patricia S.; McKerrow, James H.] Univ Calif San Francisco, Sandler Ctr Basic Res Parasit Dis, San Francisco, CA 94158 USA. RP Maloney, DJ (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM maloneyd@mail.nih.gov RI Ferreira, Rafaela/L-9841-2014 OI Ferreira, Rafaela/0000-0003-3324-0601 FU National Institutes of Health Roadmap for Medical Research; NIH [GM59957]; Sandler Center for Basic Research in Parasitic Diseases FX The authors thank Jeremy Smith, Paul Shinn, and Danielle van Leer for assistance with compound management. We also thank Eaman Balouch for providing the cruzain construct and information oil cruzain expression protocol, and Dr. Linda Brinen for helpful discussions and suggestions. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and by NIH Grant GM59957 (to BKS) and by the Sandler Center for Basic Research in Parasitic Diseases (to J H M). NR 33 TC 50 Z9 50 U1 3 U2 16 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 JAN 14 PY 2010 VL 53 IS 1 BP 52 EP 60 DI 10.1021/jm901069a PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 539PL UT WOS:000273268300005 PM 19908842 ER PT J AU Das, A Ko, H Burianek, LE Barrett, MO Harden, TK Jacobson, KA AF Das, Arijit Ko, Hyojin Burianek, Lauren E. Barrett, Matthew O. Harden, T. Kendall Jacobson, Kenneth A. TI Human P2Y(14) Receptor Agonists: Truncation of the Hexose Moiety of Uridine-5 '-Diphosphoglucose and Its Replacement with Alkyl and Aryl Groups SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID P2Y(6) RECEPTOR; PHOSPHOLIPASE-C; DENDRITIC CELLS; P2 RECEPTORS; NUCLEOTIDES; ANALOGS; POTENCY; IDENTIFICATION; CONFORMATION; SECRETION AB Uridine-5'-diphosphoglucosc (UDPG) activates the P2Y(14) receptor, a neuroinimune system GPCR. P2Y(14) receptor tolerates glucose substitution with sinall alkyl or aryl groups or its truncation to uridine 5'-diphosphate (UDP), a full agonist at the human P2Y(14) receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y(14) vs the P2Y6 receptor, such as 2-thio-UDP4 (EC5() = 1.92 nM at P2Y(14), 224-fold selectivity vs P2Y6)and itsfl-propyloxy ester 18. EC,,() values of tlie -niethyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. -Iert-Butyl ester of 4 was I I-fold more potent than UDPG, but P-aryloxy or larger, branched -alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South rriethanocarba (bicyclo[3. 1.0]hexane) group abolished P2Y(14) receptor agonist activity. ci,p-Methylene and difluoromethylene groups were well tolerated at the P2Y(14) receptor and are expected to provide enhanced stability in biological systems. a,beta-Methylene-2-thio-UDP 11 (EC50 = 0.92 nM) was 2160fold selective versus P2Y6. Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor- C1 [Das, Arijit; Ko, Hyojin; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Burianek, Lauren E.; Barrett, Matthew O.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20, Z99 DK999999]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 30 TC 20 Z9 20 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 14 PY 2010 VL 53 IS 1 BP 471 EP 480 DI 10.1021/jm901432g PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 539PL UT WOS:000273268300040 PM 19902968 ER PT J AU Voon, V Pessiglione, M Brezing, C Gallea, C Fernandez, HH Dolan, RJ Hallett, M AF Voon, Valerie Pessiglione, Mathias Brezing, Christina Gallea, Cecile Fernandez, Hubert H. Dolan, Raymond J. Hallett, Mark TI Mechanisms Underlying Dopamine-Mediated Reward Bias in Compulsive Behaviors SO NEURON LA English DT Article ID TEMPORAL DIFFERENCE MODELS; IMPULSE CONTROL DISORDERS; PARKINSONS-DISEASE; PATHOLOGICAL GAMBLERS; DRUG-USE; STIMULATION; PREDICTION; MEDICATION; ADDICTION; HUMANS AB Pathological behaviors such as problem gambling or shopping are characterized by compulsive choice despite alternative options and negative costs. Reinforcement learning algorithms allow a computation of prediction error, a comparison of actual and expected outcomes, which updates our predictions and influences our subsequent choices. Using a reinforcement learning model, we show data consistent with the idea that dopamine agonists in susceptible individuals with Parkinson's disease increase the rate of learning from gain outcomes. Dopamine agonists also increase striatal prediction error activity, thus signifying a "better than expected" outcome. Thus, our findings are consistent with a model whereby a distorted estimation of the gain cue underpins a choice bias toward gains. C1 [Voon, Valerie; Brezing, Christina; Gallea, Cecile; Hallett, Mark] NIH, Bethesda, MD 20892 USA. [Pessiglione, Mathias] Hop La Pitie Salpetriere, INSERM, F-75013 Paris, France. [Fernandez, Hubert H.] Univ Florida, Gainesville, FL 32610 USA. [Dolan, Raymond J.] UCL, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. RP Voon, V (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM voonval@gmail.com RI Pessiglione, Mathias/E-2141-2017; OI Dolan, Ray/0000-0001-9356-761X FU National Institute of Neurological Disorders and Stroke, National Institutes of Health; NINDS/NIH; Wellcome Trust FX This study was supported and conducted by the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We would like to thank Dr. Grisel Lopez and the Parkinson Disease clinic at the National Institute of Neurological Disorders (NINDS), National Institutes of Health (NIH) for assistance in recruitment and assessment of patients. We would like to thank the patients for their involvement with this study. This study was funded and conducted at intramural NINDS/NIH. R.J.D. is supported by a Wellcome Trust Programme Grant. NR 29 TC 138 Z9 139 U1 2 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 14 PY 2010 VL 65 IS 1 BP 135 EP 142 DI 10.1016/j.neuron.2009.12.027 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 546DZ UT WOS:000273791200014 PM 20152119 ER PT J AU Timofeeva, OA Eddins, D Yakel, JL Blackshear, PJ Levin, ED AF Timofeeva, Olga A. Eddins, Donnie Yakel, Jerrel L. Blackshear, Perry J. Levin, Edward D. TI Hippocampal infusions of MARCKS peptides impair memory of rats on the radial-arm maze SO BRAIN RESEARCH LA English DT Article DE MARCKS Peptide; Memory; Hippocampus ID NICOTINIC ACETYLCHOLINE-RECEPTORS; KINASE SUBSTRATE MARCKS; E-DERIVED PEPTIDES; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; MICE; PROTEIN; BRAIN; ALPHA-7; LOCALIZATION AB In vitro hippocampal studies by Gay et al. (2008) demonstrated that a myristoylated alanine-rich C kinase substrate (MARCKS) peptide comprising the phosphorylation site or effector domain of the protein acts as a powerful inhibitor of alpha 7 nicotinic acetylcholine receptors (nAChRs), which are known to be critically involved in memory function. However, behavioral consequences of hippocampal MARCKS peptide infusions have not been investigated. The purpose of the current study was to determine if local infusions in the rat ventral hippocampus of long (comprising amino acids 151-175) and short (amino acids 159-165) forms of MARCKS peptides could affect memory performance in the 16-arm radial maze. Our results demonstrated a dramatic impairment of both working (changing) and reference (constant) memory with MARCKS(151-175) only. The shorter MARCKS peptide did not affect memory performance. This is in line with in vitro results reported by Gay et al. (2008) that long, but not short, MARCKS peptides inhibit alpha 7 nAChRs. We also found that the effect of the MARCKS(151-175) peptide was dose-dependent, with a robust memory impairment at 10 mu g/side, and smaller inconsistent effects at lower doses. Our present behavioral study, together with the earlier in vitro study by Gay et al. (2008), suggests that effector domain MARCKS peptides could play a significant role in memory regulation and impairment. (C) 2009 Elsevier B.V. All rights reserved. C1 [Timofeeva, Olga A.; Eddins, Donnie; Levin, Edward D.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, US Dept HHS, Bethesda, MD USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, US Dept HHS, Bethesda, MD USA. RP Levin, ED (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 104790 DUMC, Durham, NC 27710 USA. EM edlevin@duke.edu FU NIH-NIEHS FX Supported in part by the Intramural Research Program of the NIH-NIEHS. NR 31 TC 9 Z9 9 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 13 PY 2010 VL 1308 BP 147 EP 152 DI 10.1016/j.brainres.2009.10.040 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 555LT UT WOS:000274513000014 PM 19854162 ER PT J AU Eagel, BA AF Eagel, Barry A. TI The truth about Tamiflu? Zanamivir should be inhaled, not nebulised SO BRITISH MEDICAL JOURNAL LA English DT Letter C1 NCI, SAIC Frederick, Clin Monitoring Res Programme, Frederick, MD 21702 USA. RP Eagel, BA (reprint author), NCI, SAIC Frederick, Clin Monitoring Res Programme, 5705 Ind Lane, Frederick, MD 21702 USA. EM eagelb@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 5 TC 2 Z9 2 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 13 PY 2010 VL 340 AR c131 DI 10.1136/bmj.c131 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 545DA UT WOS:000273711500005 PM 20071426 ER PT J AU Hoffman, AF Laaris, N Kawamura, M Masino, SA Lupica, CR AF Hoffman, Alexander F. Laaris, Nora Kawamura, Masahito Masino, Susan A. Lupica, Carl R. TI Control of Cannabinoid CB1 Receptor Function on Glutamate Axon Terminals by Endogenous Adenosine Acting at A(1) Receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EXCITATORY SYNAPTIC-TRANSMISSION; HIPPOCAMPAL PYRAMIDAL NEURONS; LONG-TERM POTENTIATION; RAT HIPPOCAMPUS; EXTRACELLULAR ADENOSINE; ADENINE-NUCLEOTIDES; INDUCED SEIZURES; RELEASE; BRAIN; INHIBITION AB Marijuana is a widely used drug that impairs memory through interaction between its psychoactive constituent, Delta-9-tetrahydrocannabinol (Delta(9)-THC), and CB1 receptors (CB1Rs) in the hippocampus. CB1Rs are located on Schaffer collateral (Sc) axon terminals in the hippocampus, where they inhibit glutamate release onto CA1 pyramidal neurons. This action is shared by adenosine A(1) receptors (A1Rs), which are also located on Sc terminals. Furthermore, A1Rs are tonically activated by endogenous adenosine (eADO), leading to suppressed glutamate release under basal conditions. Colocalization of A1Rs and CB1Rs, and their coupling to shared components of signal transduction, suggest that these receptors may interact. We examined the roles of A1Rs and eADO in regulating CB1R inhibition of glutamatergic synaptic transmission in the rodent hippocampus. We found that A1R activation by basal or experimentally increased levels of eADO reduced or eliminated CB1R inhibition of glutamate release, and that blockade of A1Rs with caffeine or other antagonists reversed this effect. The CB1R-A1R interaction was observed with the agonists WIN55,212-2 and Delta(9)-THC and during endocannabinoid-mediated depolarization-induced suppression of excitation. A1R control of CB1Rs was stronger in the C57BL/6J mouse hippocampus, in which eADO levels were higher than in Sprague Dawley rats, and the eADO modulation of CB1R effects was absent in A1R knock-out mice. Since eADO levels and A1R activation are regulated by homeostatic, metabolic, and pathological factors, these data identify a mechanism in which CB1R function can be controlled by the brain adenosine system. Additionally, our data imply that caffeine may potentiate the effects of marijuana on hippocampal function. C1 [Hoffman, Alexander F.; Laaris, Nora; Lupica, Carl R.] Natl Inst Drug Abuse, Electrophysiol Res Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kawamura, Masahito; Masino, Susan A.] Trinity Coll, Dept Psychol, Hartford, CT 06106 USA. [Kawamura, Masahito; Masino, Susan A.] Trinity Coll, Neurosci Program, Hartford, CT 06106 USA. [Kawamura, Masahito] Jikei Univ, Sch Med, Dept Pharmacol, Tokyo 1058461, Japan. RP Lupica, CR (reprint author), Natl Inst Drug Abuse, Electrophysiol Res Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM clupica@mail.nih.gov RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institutes of Health; National Institute on Drug Abuse Intramural Research Program; National Science Foundation FX This work supported by the National Institutes of Health, the National Institute on Drug Abuse Intramural Research Program, and the National Science Foundation. We thank Dr. Bertil Fredholm of the Karolinska Institute for helpful comments during the preparation of this manuscript. NR 62 TC 52 Z9 53 U1 1 U2 6 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 JAN 13 PY 2010 VL 30 IS 2 BP 545 EP 555 DI 10.1523/JNEUROSCI.4920-09.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 543OC UT WOS:000273586900013 PM 20071517 ER PT J AU Izquierdo, A Murray, EA AF Izquierdo, Alicia Murray, Elisabeth A. TI Functional Interaction of Medial Mediodorsal Thalamic Nucleus But Not Nucleus Accumbens with Amygdala and Orbital Prefrontal Cortex Is Essential for Adaptive Response Selection after Reinforcer Devaluation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RHESUS-MONKEYS; ORBITOFRONTAL CORTEX; BASOLATERAL AMYGDALA; NEUROTOXIC LESIONS; WORKING-MEMORY; FRONTAL-CORTEX; BASAL GANGLIA; PROJECTIONS; PRIMATE; PERFORMANCE AB In nonhuman primates, reward-based decision making may be assessed through choices of objects overlying two different foods, one of which has been devalued by selective satiation. The most adaptive object choices yield the food of higher value. A large body of data identifies the amygdala and orbital prefrontal cortex (PFo) as neural mediators of adaptive responses to reinforcer devaluation. More recent work in nonhuman primates reveals the critical role of the medial, magnocellular portion of the mediodorsal nucleus of the thalamus (MDm) as well. Because both the nucleus accumbens (NA) and the MDm are anatomically related to the amygdala and PFo, and because both regions are implicated in reward processing, we tested whether either region necessarily interacts with the amygdala and PFo to mediate reinforcer devaluation effects. We used a crossed-disconnection design in which monkeys received amygdala and PFo lesions in one hemisphere combined with either NA or MDm lesions in the contralateral hemisphere. Monkeys that sustained NA disconnection, like controls, showed robust shifts in object choices in response to reinforcer devaluation. In contrast, monkeys that sustained MDm disconnection failed to adjust their object choices. Thus, MDm, but not NA, works together with the amygdala and PFo to support reward-based decision making. C1 [Izquierdo, Alicia; Murray, Elisabeth A.] NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM murraye@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 FU Intramural Research Program of the National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health. We thank Katie Wright and Olga Sheinina for help with behavioral testing, Emily Howland for reconstructing the lesions, and Sarah Rhodes and Peter Rudebeck for comments on an earlier version of this manuscript. NR 52 TC 30 Z9 30 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 13 PY 2010 VL 30 IS 2 BP 661 EP 669 DI 10.1523/JNEUROSCI.3795-09.2010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 543OC UT WOS:000273586900027 PM 20071531 ER PT J AU Puligilla, C Dabdoub, A Brenowitz, SD Kelley, MW AF Puligilla, Chandrakala Dabdoub, Alain Brenowitz, Stephan D. Kelley, Matthew W. TI Sox2 Induces Neuronal Formation in the Developing Mammalian Cochlea SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INNER-EAR; HAIR-CELLS; TRANSCRIPTION FACTORS; DIFFERENTIATION; NEUROGENESIS; EXPRESSION; ORGAN; MATH1; SPECIFICATION; TUBULIN AB In the cochlea, spiral ganglion neurons play a critical role in hearing as they form the relay between mechanosensory hair cells in the inner ear and cochlear nuclei in the brainstem. The proneural basic helix-loop-helix transcription factors Neurogenin1 (Neurog1) and NeuroD1 have been shown to be essential for the development of otocyst-derived inner ear sensory neurons. Here, we show neural competence of nonsensory epithelial cells in the cochlea, as ectopic expression of either Neurog1 or NeuroD1 results in the formation of neuronal cells. Since the high-mobility-group type transcription factor Sox2, which is also known to play a role in neurogenesis, is expressed in otocyst-derived neural precursor cells and later in the spiral ganglion neurons along with Neurog1 and NeuroD1, we used both gain- and loss-of-function experiments to examine the role of Sox2 in spiral ganglion neuron formation. We demonstrate that overexpression of Sox2 results in the production of neurons, suggesting that Sox2 is sufficient for the induction of neuronal fate in nonsensory epithelial cells. Furthermore, spiral ganglion neurons are absent in cochleae from Sox2(Lcc/Lcc) mice, indicating that Sox2 is also required for neuronal formation in the cochlea. Our results indicate that Sox2, along with Neurog1 and NeuroD1, are sufficient to induce a neuronal fate in nonsensory regions of the cochlea. Finally, we demonstrate that nonsensory cells within the cochlea retain neural competence through at least the early postnatal period. C1 [Puligilla, Chandrakala; Dabdoub, Alain; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Sect Dev Neuroscience, Bethesda, MD 20892 USA. [Brenowitz, Stephan D.] Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Sect Synapt Transmiss, Bethesda, MD 20892 USA. [Dabdoub, Alain] Univ Calif San Diego, Sch Med, Dept Surg, Div Otolaryngol, La Jolla, CA 92093 USA. RP Puligilla, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Natl Inst Hlth, Sect Dev Neuroscience, Bethesda, MD 20892 USA. EM puligillac@nidcd.nih.gov; adabdoub@ucsd.edu FU National Institute on Deafness and Other Communication Disorders FX This work was supported by the intramural program at National Institute on Deafness and Other Communication Disorders. We thank Drs. S. Raft, A. Groves, B. Fritzsch, and A. Ryan for reading an earlier version of this manuscript and C. W. Kramer and Drs. W. Chang and B. Jacques for technical assistance. We are grateful to Drs. L. Kan for providing the Sox1 expression vector and Sox1LacZ/LacZ tissue, K. S. E. Cheah for the Sox2Lcc/Lcc tissue, R. Kageyama for the NeuroD1 expression vector, R. Lovell-Badge for Sox3-/- tissue, and L. H. Pevny for providing us with the Sox2 expression vector. NR 39 TC 68 Z9 70 U1 0 U2 6 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 JAN 13 PY 2010 VL 30 IS 2 BP 714 EP 722 DI 10.1523/JNEUROSCI.3852-09.2010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 543OC UT WOS:000273586900032 PM 20071536 ER PT J AU Hu, KN Yau, WM Tycko, R AF Hu, Kan-Nian Yau, Wai-Ming Tycko, Robert TI Detection of a Transient Intermediate in a Rapid Protein Folding Process by Solid-State Nuclear Magnetic Resonance SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID VILLIN HEADPIECE SUBDOMAIN; MOLECULAR-DYNAMICS SIMULATIONS; CONFORMATIONAL DISTRIBUTIONS; WW DOMAIN; NMR; HETEROGENEITY; FRICTION; SCALE AB We describe the use of solid-state NMR spectroscopy to characterize a partially folded state of the 35-residue helical protein HP35 created by rapid freeze-quenching from a thermally unfolded state on the 10-20 mu s time scale. Two-dimensional solid-state 1 3 C NMR spectra of C-13-labeled HP35 in frozen glycerol/water solution exhibit two sets of signals, one corresponding to strongly unfolded protein molecules and the other to an ensemble of molecules having native helical secondary structure but incomplete tertiary structure. The NMR data indicate that secondary structure forms within the freeze-quenching time scale but that full folding involves a slower phase of structural annealing. The similar to 5 mu s folding time observed in earlier studies of HP35 by time-resolved optical techniques may not represent the time scale for full folding. C1 [Hu, Kan-Nian; Yau, Wai-Ming; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. We thank W. A. Eaton and D. A. Torchia for helpful discussions. NR 19 TC 39 Z9 40 U1 2 U2 19 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 JAN 13 PY 2010 VL 132 IS 1 BP 24 EP + DI 10.1021/ja908471n PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 562VW UT WOS:000275084400012 PM 20000466 ER PT J AU Lee, JH Jo, J Hardikar, AA Periwal, V Rane, SG AF Lee, Ji-Hyeon Jo, Junghyo Hardikar, Anandwardhan A. Periwal, Vipul Rane, Sushil G. TI Cdk4 Regulates Recruitment of Quiescent beta-Cells and Ductal Epithelial Progenitors to Reconstitute beta-Cell Mass SO PLOS ONE LA English DT Article ID ISLET PRECURSOR CELLS; DIABETIC MOUSE MODEL; PANCREATIC B-CELL; STEM-CELLS; INSULIN-RESISTANCE; BONE-MARROW; REGENERATION; MICE; PROLIFERATION; ENDOCRINE AB Insulin-producing pancreatic islet beta cells (beta-cells) are destroyed, severely depleted or functionally impaired in diabetes. Therefore, replacing functional beta-cell mass would advance clinical diabetes management. We have previously demonstrated the importance of Cdk4 in regulating beta-cell mass. Cdk4-deficient mice display beta-cell hypoplasia and develop diabetes, whereas beta-cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase. While beta-cell replication appears to be the primary mechanism responsible for beta-cell mass increase, considerable evidence also supports a contribution from the pancreatic ductal epithelium in generation of new beta-cells. Further, while it is believed that majority of beta-cells are in a state of 'dormancy', it is unclear if and to what extent the quiescent cells can be coaxed to participate in the beta-cell regenerative response. Here, we address these queries using a model of partial pancreatectomy (PX) in Cdk4 mutant mice. To investigate the kinetics of the regeneration process precisely, we performed DNA analog-based lineage-tracing studies followed by mathematical modeling. Within a week after PX, we observed considerable proliferation of islet beta-cells and ductal epithelial cells. Interestingly, the mathematical model showed that recruitment of quiescent cells into the active cell cycle promotes beta-cell mass reconstitution in the Cdk4R24C pancreas. Moreover, within 24-48 hours post-PX, ductal epithelial cells expressing the transcription factor Pdx-1 dramatically increased. We also detected insulin-positive cells in the ductal epithelium along with a significant increase of islet-like cell clusters in the Cdk4R24C pancreas. We conclude that Cdk4 not only promotes beta-cell replication, but also facilitates the activation of beta-cell progenitors in the ductal epithelium. In addition, we show that Cdk4 controls beta-cell mass by recruiting quiescent cells to enter the cell cycle. Comparing the contribution of cell proliferation and islet-like clusters to the total increase in insulin-positive cells suggests a hitherto uncharacterized large non-proliferative contribution. C1 [Lee, Ji-Hyeon; Rane, Sushil G.] NIDDK, Regenerat Biol Sect, Diabet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Jo, Junghyo; Periwal, Vipul] NIDDK, Lab Biol Modeling, Natl Inst Hlth, Bethesda, MD USA. [Hardikar, Anandwardhan A.] Natl Ctr Cell Sci, Stem Cells & Diabet Sect, Pune, Maharashtra, India. RP Lee, JH (reprint author), NIDDK, Regenerat Biol Sect, Diabet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM ranes@mail.nih.gov RI Jo, Junghyo/D-4889-2011; Periwal, Vipul/I-1728-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural program FX This work was supported by funds from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural program. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 16 Z9 16 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 13 PY 2010 VL 5 IS 1 AR e8653 DI 10.1371/journal.pone.0008653 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543EV UT WOS:000273554600012 PM 20084282 ER PT J AU Wang, SS Gonzalez, P Yu, K Porras, C Li, QZ Safaeian, M Rodriguez, AC Sherman, ME Bratti, C Schiffman, M Wacholder, S Burk, RD Herrero, R Chanock, SJ Hildesheim, A AF Wang, Sophia S. Gonzalez, Paula Yu, Kai Porras, Carolina Li, Qizhai Safaeian, Mahboobeh Cecilia Rodriguez, Ana Sherman, Mark E. Bratti, Concepcion Schiffman, Mark Wacholder, Sholom Burk, Robert D. Herrero, Rolando Chanock, Stephen J. Hildesheim, Allan TI Common Genetic Variants and Risk for HPV Persistence and Progression to Cervical Cancer SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; DNA-REPAIR GENES; COSTA-RICA; HEPARAN-SULFATE; NEOPLASIA; HOST AB HPV infrequently persists and progresses to cervical cancer. We examined host genetic factors hypothesized to play a role in determining which subset of individuals infected with oncogenic human papillomavirus (HPV) have persistent infection and further develop cervical pre-cancer/cancer compared to the majority of infected individuals who will clear infection. We evaluated 7140 tag single nucleotide polymorphisms (SNPs) from 305 candidate genes hypothesized to be involved in DNA repair, viral infection and cell entry in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 HPV persistent women (median: 25 months), and 425 random controls (RC) from the 10,049 women Guanacaste Costa Rica Natural History study. We used logistic regression to compute odds ratios and p-trend for CIN3/cancer and HPV persistence in relation to SNP genotypes and haplotypes (adjusted for age). We obtained pathway and gene-level summary of associations by computing the adaptive combination of p-values. Genes/regions statistically significantly associated with CIN3/cancer included the viral infection and cell entry genes 29,59 oligoadenylate synthetase gene 3 (OAS3), sulfatase 1 (SULF1), and interferon gamma (IFNG); the DNA repair genes deoxyuridine triphosphate (DUT), dosage suppressor of mck 1 homolog (DMC1), and general transcription factor IIH, polypeptide 3 (GTF2H4); and the EVER1 and EVER2 genes (p<0.01). From each region, the single most significant SNPs associated with CIN3/cancer were OAS3 rs12302655, SULF1 rs4737999, IFNG rs11177074, DUT rs3784621, DMC1 rs5757133, GTF2H4 rs2894054, EVER1/EVER2 rs9893818 (p-trends <= 0.001). SNPs for OAS3, SULF1, DUT, and GTF2H4 were associated with HPV persistence whereas IFNG and EVER1/EVER2 SNPs were associated with progression to CIN3/cancer. We note that the associations observed were less than two-fold. We identified variations DNA repair and viral binding and cell entry genes associated with CIN3/cancer. Our results require replication but suggest that different genes may be responsible for modulating risk in the two critical transition steps important for cervical carcinogenesis: HPV persistence and disease progression. C1 [Wang, Sophia S.] City Hope Natl Med Ctr, Div Etiol, Duarte, CA 91010 USA. [Gonzalez, Paula; Porras, Carolina; Cecilia Rodriguez, Ana; Bratti, Concepcion; Herrero, Rolando] Fdn INCIENSA, San Jose, Costa Rica. [Wang, Sophia S.; Yu, Kai; Li, Qizhai; Safaeian, Mahboobeh; Sherman, Mark E.; Schiffman, Mark; Wacholder, Sholom; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing, Peoples R China. [Burk, Robert D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Chanock, Stephen J.] NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, Adv Technol Program,SAIC Frederick Inc, Frederick, MD 21701 USA. RP Wang, SS (reprint author), City Hope Natl Med Ctr, Div Etiol, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sowang@coh.org RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU Intramural NIH HHS; NCI NIH HHS [CA-78527, CO-12400, CP-21081, CP-31061, N01CO12400, R01 CA078527, U01 CA078527] NR 20 TC 53 Z9 54 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 13 PY 2010 VL 5 IS 1 AR e8667 DI 10.1371/journal.pone.0008667 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543EV UT WOS:000273554600020 PM 20084279 ER PT J AU Peng, XH Ghosh, AK Van Houten, B Greenberg, MM AF Peng, Xiaohua Ghosh, Avik K. Van Houten, Bennett Greenberg, Marc M. TI Nucleotide Excision Repair of a DNA Interstrand Cross-Link Produces Single- and Double-Strand Breaks SO BIOCHEMISTRY LA English DT Article ID DAMAGE; ADDUCTS; UVRB; INCISION; NUCLEASE; COMPLEX; BINDING; CELLS; OLIGONUCLEOTIDES; SENSITIVITY AB The DNA radical resulting from Formal abstraction of a hydrogen atom from the thymidine methyl group, 5-(2'-deoxyuridinyl)methyl radical, forms interstrand cross-links with the opposing 2'-deoxyadenosine. This is the first chemically characterized, radical-mediated cross-link between two opposing nucleotides. In addition, cross-linking between opposing bases in the duplex is less common than between those separated by one or two nucleotides. The first step in cross-link repair was investigated using the UvrABC bacterial nucleotide excision repair system. UvrABC incised both strands of the cross-linked DNA, although the Strand containing the cross-linked purine Was preferred by the enzyme in two different duplexes. The incision sites in one strand were spaced 11-14 nucleotides apart, as Is typical for UvrABC incision. The majority of incisions occur at the third phosphate from the 3'-side of the cross-link and eighth or ninth phosphate on the 5'-side. In addition, cleavage was found to Occur on both strands, producing double-strand breaks in similar to 25-29% or the incision events. This is the first example of double-strand cleavage during nucleotide excision repair of cross-linked DNA that does not already contain a Strand break in the vicinity of the cross-link. C1 [Peng, Xiaohua; Ghosh, Avik K.; Greenberg, Marc M.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Van Houten, Bennett] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Greenberg, MM (reprint author), Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA. EM mgreenberg@jhu.edu FU National Institute of General Medical Sciences [GM-054996] FX We are grateful for support of this research by the National Institute of General Medical Sciences (Grant GM-054996). NR 48 TC 20 Z9 21 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 12 PY 2010 VL 49 IS 1 BP 11 EP 19 DI 10.1021/bi901603h PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539PE UT WOS:000273267300002 PM 20000382 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Taming of the shrewd: novel eukaryotic genes from RNA viruses SO BMC BIOLOGY LA English DT Editorial Material ID DNA FORM; INTEGRATION; SEQUENCES; MECHANISM; EVOLUTION; GENOMES AB Genomes of several yeast species contain integrated DNA copies of complete genomes or individual genes of non-retroviral double-strand RNA viruses as reported in a recent BMC Biology article by Taylor and Bruenn. The integrated virus-specific sequences are at least partially expressed and seem to evolve under pressure of purifying selection, indicating that these are functional genes. Together with similar reports on integrated copies of some animal RNA viruses, these results suggest that integration of DNA copies of non-reverse-transcribing RNA viruses might be much more common than previously thought. The integrated copies could contribute to acquired immunity to the respective viruses. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 23 TC 25 Z9 27 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JAN 12 PY 2010 VL 8 AR 2 DI 10.1186/1741-7007-8-2 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 556MN UT WOS:000274595400001 PM 20067611 ER PT J AU Ghuman, AS McDaniel, JR Martin, A AF Ghuman, Avniel Singh McDaniel, Jonathan R. Martin, Alex TI Face Adaptation without a Face SO CURRENT BIOLOGY LA English DT Article ID VISUAL-ADAPTATION; FUSIFORM GYRUS; PERCEPTION; CORTEX; REPRESENTATION; SELECTIVITY; CONTRAST; BODY; AREA AB Prolonged viewing of a stimulus results in a subsequent perceptual bias [1-3]. This perceptual adaptation and the resulting aftereffect reveal important characteristics regarding how perceptual systems are tuned [2, 4-6]. These aftereffects occur not only for simple stimulus features but also for high-level stimulus properties [7-10]. Here we report a novel cross-category adaptation aftereffect demonstrating that prolonged viewing of a human body without a face shifts the perceptual tuning curve for face gender and face identity. This contradicts a central assumption underlying perceptual adaptation: that adaptation depends on physical similarity between how the adapting and the adapted features are perceived [5]. Additionally, this aftereffect was not due to response bias, because its dependence on adaptation duration resembled traditional perceptual aftereffects. These body-to-face adaptation results demonstrate that bodies alone can alter the tuning properties of neurons that code for the gender and identity of faces. More generally, these results reveal that high-level perceptual adaptation can occur when the property or features being adapted are automatically inferred rather than perceived in the adapting stimulus. C1 [Ghuman, Avniel Singh; McDaniel, Jonathan R.; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Ghuman, AS (reprint author), NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM ghumana@mail.nih.gov RI martin, alex/B-6176-2009; OI Ghuman, Avniel/0000-0003-1746-4656 FU Intramural Program of the National Institutes of Health; National Institute of Mental Health FX We thank D. Leopold and C. Baker for their insightful comments. This work was supported by the Intramural Program of the National Institutes of Health, National Institute of Mental Health. NR 33 TC 38 Z9 41 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 12 PY 2010 VL 20 IS 1 BP 32 EP 36 DI 10.1016/j.cub.2009.10.077 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 544YM UT WOS:000273697500020 PM 20022246 ER PT J AU Ay, H Gungor, L Arsava, EM Rosand, J Vangel, M Benner, T Schwamm, LH Furie, KL Koroshetz, WJ Sorensen, AG AF Ay, H. Gungor, L. Arsava, E. M. Rosand, J. Vangel, M. Benner, T. Schwamm, L. H. Furie, K. L. Koroshetz, W. J. Sorensen, A. G. TI A score to predict early risk of recurrence after ischemic stroke SO NEUROLOGY LA English DT Article ID LONG-TERM RISK; CEREBRAL INFARCTION; SUBTYPE DIAGNOSIS; COMMUNITY STROKE; ATTACK; SEVERITY; SURVIVAL; LEUKOARAIOSIS; PROGNOSIS; PATTERNS AB Background: There is currently no instrument to stratify patients presenting with ischemic stroke according to early risk of recurrent stroke. We sought to develop a comprehensive prognostic score to predict 90-day risk of recurrent stroke. Methods: We analyzed data on 1,458 consecutive ischemic stroke patients using a Cox regression model with time to recurrent stroke as the response and clinical and imaging features typically available to physician at admission as covariates. The 90-day risk of recurrent stroke was calculated by summing up the number of independent predictors weighted by their corresponding beta-coefficients. The resultant score was called recurrence risk estimator at 90 days or RRE-90 score (available at: http://www.nmr.mgh.harvard.edu/RRE-90/). Results: Sixty recurrent strokes (54 had baseline imaging) occurred during the follow-up period. The risk adjusted for time to follow-up was 6.0%. Predictors of recurrence included admission etiologic stroke subtype, prior history of TIA/stroke, and topography, age, and distribution of brain infarcts. The RRE-90 score demonstrated adequate calibration and good discrimination (area under the ROC curve [AUC] = 0.70-0.80), which was maintained when applied to a separate cohort of 433 patients (AUC = 0.70-0.76). The model's performance was also maintained for predicting early (14-day) risk of recurrence (AUC = 0.80). Conclusions: The RRE-90 is a Web-based, easy-to-use prognostic score that integrates clinical and imaging information available in the acute setting to quantify early risk of recurrent stroke. The RRE-90 demonstrates good predictive performance, suggesting that, if validated externally, it has promise for use in creating individualized patient management algorithms and improving clinical practice in acute stroke care. Neurology (R) 2010;74:128-135 C1 [Ay, H.; Rosand, J.; Schwamm, L. H.; Furie, K. L.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Serv, Boston, MA 02115 USA. [Ay, H.; Gungor, L.; Arsava, E. M.; Vangel, M.; Benner, T.; Sorensen, A. G.] Harvard Univ, Sch Med, Dept Radiol, AA Martinos Ctr Biomed Imaging,Massachusetts Gen, Boston, MA 02115 USA. [Rosand, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Rosand, J.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Koroshetz, W. J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Ay, H (reprint author), Harvard Univ, AA Martinos Ctr Biomed Imaging, Sch Med, Massachusetts Gen Hosp, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; OI Arsava, Ethem Murat/0000-0002-6527-4139; Schwamm, Lee/0000-0003-0592-9145 FU NIH [R01-NS059710, R01-NS059727, NINDS P50 NS051343-01, NINDS U01 NS052220 IMS-3, NCRR 1 UL 1 RR025758-01, DHHS/CDC [5 U13 DP001176-02], NINDS NS38477, NCI CA137254, NINDS NS063925, NINDS NS061119]; American Heart Association; Forest Laboratories, Inc; Deane Institute; Millennium Pharmaceuticals, Inc.; Siemens Medical Solutions; AstraZeneca; Genentech Inc; Novartis; Merck Serono; Schering Plough Corp FX Dr. Ay receives research support from the NIH [R01-NS059710 (PI)]. Dr. Gungor and Dr. Arsava report no disclosures. Dr. Rosand receives research support from the NIH [R01-NS059727 (PI)] and from the American Heart Association. Dr. Vangel reports no disclosures. Dr. Benner serves as a consultant for Siemens Medical Solutions and Bayer Schering Pharma. Dr. Schwamm serves on scientific advisory boards for CoAxia, Inc. and Phreesia; has received honoraria and funding for travel for lectures or educational activities not funded by industry; serves on the editorial board of Neurocritical Care; may accrue revenue on US Patent 6,542,769 (filed 2003): Imaging system for obtaining quantitative perfusion indices; his spouse receives royalties from publishing Obstetric Anesthesia (Cambridge Pocket Clinicians, 2007-2009); serves as a consultant to Medtronic, Inc./CryoCath, Research Triangle Inc., and the Massachusetts Department of Public Health; serves on an external scientific review committee for the Canadian Stroke Network; and receives research support from Forest Laboratories, Inc., the NIH [NINDS P50 NS051343-01 (Co-I), NINDS U01 NS052220 IMS-3 (Site PI), and NCRR 1 UL 1 RR025758-01 (CRC Staff)] and the DHHS/CDC [5 U13 DP001176-02 (PI)]. Dr. Furie has served on scientific advisory boards for Novartis and GE Healthcare and receives research support from the NIH/NINDS [R01-HS011392 (PI) and P50-NS051343 (PI)], the American Heart Association, and the Deane Institute. Dr. Koroshetz is a full-time employee of the NIH and holds stock in NeuroLogica. Dr. Sorensen has served on scientific advisory boards for Olea Medical and Breakaway Imaging; has received funding for travel from Genentech, Inc., Siemens Medical Solutions, Millennium Pharmaceuticals, Inc., AstraZeneca, and for speaking and educational activities not funded by industry; serves as a Section Editor of Stroke and on the editorial boards of The Oncologist and the Journal of Clinical Oncology; may accrue revenue on US Patent 7020578 (issued 2001): Method for evaluating novel, stroke treatments using a tissue risk map, US Patent 6542769 (issued 2000): Imaging system for obtaining quantitative perfusion indices, US Patent 10558343 (issued 2004): Delay-compensated calculation of tissue blood flow, US Patent 11075990 (issued: 2005): High-flow oxygen delivery system and methods of use thereof, and US Patent 11417769 (issued: 2006): Magnetic resonance spatial risk map for tissue outcome prediction; receives royalties from publishing Cerebral MR Perfusion Imaging (Thieme, 2000); has received honoraria from Siemens Medical Solutions, Novartis, GE Healthcare, and for speaking and educational activities not funded by industry; has served as a consultant to Mitsubishi Tanabe Pharma Corporation, AstraZeneca, and Genentech, Inc.; receives research support from Millennium Pharmaceuticals, Inc., Siemens Medical Solutions, AstraZeneca, Genentech Inc., Novartis, Merck Serono, Schering Plough Corp, the NIH [NINDS NS38477 (PI), NCI CA137254 (PI), NINDS NS063925 (PI), and NINDS NS061119 (PI)]; and holds stock and stock options in Epix Pharmaceuticals. NR 38 TC 44 Z9 46 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 12 PY 2010 VL 74 IS 2 BP 128 EP 135 DI 10.1212/WNL.0b013e3181ca9cff PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 543HC UT WOS:000273563600007 PM 20018608 ER PT J AU Oleksyk, TK Smith, MW O'Brien, SJ AF Oleksyk, Taras K. Smith, Michael W. O'Brien, Stephen J. TI Genome-wide scans for footprints of natural selection SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE genomes; genome-wide selection scans; whole genome sequences; candidate genes; human populations; vertebrate species ID RECENT POSITIVE SELECTION; ADMIXTURE LINKAGE DISEQUILIBRIUM; MELANOCORTIN-1 RECEPTOR GENE; LACTASE-PHLORHIZIN HYDROLASE; DUFFY-NEGATIVE INDIVIDUALS; ADULT-TYPE HYPOLACTASIA; DNA-SEQUENCE VARIATION; BLOOD-GROUP LOCUS; ACTIVITY IN-VITRO; HAPLOTYPE STRUCTURE AB Detecting recent selected 'genomic footprints' applies directly to the discovery of disease genes and in the imputation of the formative events that molded modern population genetic structure. The imprints of historic selection/adaptation episodes left in human and animal genomes allow one to interpret modern and ancestral gene origins and modifications. Current approaches to reveal selected regions applied in genome-wide selection scans (GWSSs) fall into eight principal categories: (I) phylogenetic footprinting, (II) detecting increased rates of functional mutations, (III) evaluating divergence versus polymorphism, (IV) detecting extended segments of linkage disequilibrium, (V) evaluating local reduction in genetic variation, (VI) detecting changes in the shape of the frequency distribution (spectrum) of genetic variation, (VII) assessing differentiating between populations (FST), and (VIII) detecting excess or decrease in admixture contribution from one population. Here, we review and compare these approaches using available human genome-wide datasets to provide independent verification (or not) of regions found by different methods and using different populations. The lessons learned from GWSSs will be applied to identify genome signatures of historic selective pressures on genes and gene regions in other species with emerging genome sequences. This would offer considerable potential for genome annotation in functional, developmental and evolutionary contexts. C1 [Oleksyk, Taras K.] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00681 USA. [Oleksyk, Taras K.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Smith, Michael W.] NCI, Core Genotyping Facil, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Oleksyk, TK (reprint author), Univ Puerto Rico, Dept Biol, Mayaguez, PR 00681 USA. EM taras.oleksyk@upr.edu; stephen.obrien@nih.gov RI Rinaldi2, Carlos/D-4479-2011; Smith, Michael/B-5341-2012; Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX We thank Drs Colm O'Huigin, Alfred Roca, Sadeep Shrestha and Carlos Driscoll for helpful insights into developing ideas for this manuscript. We also thank Maritta Grau and Allen Kane of Scientific Publications, Graphics and Media, SAIC- Frederick, Inc., for help with editing and figures. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. The project included in this manuscript has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 156 TC 125 Z9 125 U1 10 U2 98 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD JAN 12 PY 2010 VL 365 IS 1537 BP 185 EP 205 DI 10.1098/rstb.2009.0219 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 531ET UT WOS:000272647200018 PM 20008396 ER PT J AU Batlevi, Y Martin, DN Pandey, UB Simon, CR Powers, CM Taylor, JP Baehrecke, EH AF Batlevi, Yakup Martin, Damali N. Pandey, Udai Bhan Simon, Claudio R. Powers, Christine M. Taylor, J. Paul Baehrecke, Eric H. TI Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE macroautophagy; protein degradation; neurodegeneration ID SACCHAROMYCES-CEREVISIAE; SALIVARY-GLAND; MUTATIONS; MICE; MELANOGASTER; MUTANTS; PATHWAY; DISEASE; GROWTH; P62 AB Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 (ddlc1) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration. C1 [Batlevi, Yakup; Powers, Christine M.; Baehrecke, Eric H.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Batlevi, Yakup] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Martin, Damali N.] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD 20852 USA. [Pandey, Udai Bhan; Taylor, J. Paul] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Simon, Claudio R.] Univ Fed Triangulo Mineiro, Dept Biol Sci, Uberaba, MG, Brazil. RP Baehrecke, EH (reprint author), Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. EM eric.baehrecke@umassmed.edu RI Simon, Claudio/J-6015-2014 FU National Institutes of Health [NS053825, AG031587, GM079431] FX We thank V. Budnik, M. Freeman, T. S. Hays, H. Kramer, R. K. Murphey, J. Nambu, T. P. Neufeld, I. Nezis, T. E. Rusten, H. Stenmark, the Bloomington Stock Center, and the Developmental Studies Hybridoma Bank for flies and antibodies; K. Kerr for advice on neuromuscular junction staining; and R. Simin and T. Fortier for technical support. This work was supported by National Institutes of Health Grants NS053825 and AG031587 (to J. P. T.) and GM079431 (to E. H. B.). NR 47 TC 31 Z9 31 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 JAN 12 PY 2010 VL 107 IS 2 BP 742 EP 747 DI 10.1073/pnas.0907967107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FY UT WOS:000273559300042 PM 20080745 ER PT J AU Pos, Z Selleri, S Spivey, TL Wang, JK Liu, H Worschech, A Sabatino, M Monaco, A Leitman, SF Falus, A Wang, E Alter, HJ Marincola, FM AF Pos, Zoltan Selleri, Silvia Spivey, Tara L. Wang, Jeanne K. Liu, Hui Worschech, Andrea Sabatino, Marianna Monaco, Alessandro Leitman, Susan F. Falus, Andras Wang, Ena Alter, Harvey J. Marincola, Francesco M. TI Genomic scale analysis of racial impact on response to IFN-alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE African-American; European American; microarray; signal transducers and activators of transcription; hepatitis C virus ID CHRONIC HEPATITIS-C; GENETIC-VARIATION; VIRUS-INFECTION; INTERFERON; RIBAVIRIN; THERAPY; IL28B; ASSOCIATION; MECHANISMS; CLEARANCE AB Limited responsiveness to IFN-alpha in hepatitis C virus (HCV)-infected African-Americans compared to European Americans (AAs vs. EAs) hinders the management of HCV. Here, we studied healthy non-HCV-infected AA and EA subjects to test whether immune cell response to IFN-alpha is determined directly by race. We compared baseline and IFN-alpha-induced signal transducer and activator of transcription (STAT)-1, STAT-2, STAT-3, STAT-4, and STAT-5 protein and phosphorylation levels in purified T cells, global transcription, and a genomewide single-nucleotide polymorphism (SNP) profile of healthy AA and EA blood donors. In contrast to HCV-infected individuals, healthy AAs displayed no evidence of reduced STAT activation or IFN-alpha-stimulated gene expression compared to EAs. Although >200 genes reacted to IFN-alpha treatment, race had no impact on any of them. The only gene differentially expressed by the two races (NUDT3, P < 10(-7)) was not affected by IFN-alpha and bears no known relationship to IFN-alpha signaling or HCV pathogenesis. Genomewide analysis confirmed the self-proclaimed racial attribution of most donors, and numerous race-associated SNPs were identified within loci involved in IFN-alpha signaling, although they clearly did not affect responsiveness in the absence of HCV. We conclude that racial differences observed in HCV-infected patients in the responsiveness to IFN-alpha are unrelated to inherent racial differences in IFN-alpha signaling and more likely due to polymorphisms affecting the hosts' response to HCV, which in turn may lead to a distinct disease pathophysiology responsible for altered IFN signaling and treatment response. C1 [Pos, Zoltan; Spivey, Tara L.; Liu, Hui; Monaco, Alessandro; Wang, Ena; Alter, Harvey J.; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Pos, Zoltan; Spivey, Tara L.; Liu, Hui; Monaco, Alessandro; Wang, Ena; Alter, Harvey J.; Marincola, Francesco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Selleri, Silvia] Sci Inst HS Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Wang, Jeanne K.] US FDA, Div Med Imaging & Hematol Prod, Off Oncol Drug Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Worschech, Andrea] Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. [Worschech, Andrea] Univ Wurzburg, Inst Biochem, Virchow Ctr Expt Biomed, D-97074 Wurzburg, Germany. [Worschech, Andrea] Univ Wurzburg, Inst Mol Infect Biol, D-97074 Wurzburg, Germany. [Sabatino, Marianna] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Leitman, Susan F.] NIH, Blood Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Falus, Andras] Semmelweis Univ, Dept Genet Cell & Immunobiol, H-1089 Budapest, Hungary. [Falus, Andras] Semmelweis Univ, Hungarian Acad Sci, Inflammat Biol & Immungenom Res Grp, H-1089 Budapest, Hungary. RP Pos, Z (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10,R1C711,9000 Rockville Pike, Bethesda, MD 20892 USA. EM posz@cc.nih.gov; HAlter@cc.nih.gov; Fmarincola@mail.cc.nih.gov RI Worschech, Andrea/I-3919-2012; Pos, Zoltan/C-3623-2014; Monaco, Alessandro/O-5338-2015 OI Worschech, Andrea/0000-0002-4303-8653; Pos, Zoltan/0000-0002-2574-7616; Monaco, Alessandro/0000-0002-9941-7003 NR 20 TC 11 Z9 12 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 JAN 12 PY 2010 VL 107 IS 2 BP 803 EP 808 DI 10.1073/pnas.0913491107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FY UT WOS:000273559300053 PM 20080756 ER PT J AU Olsen, RJ Sitkiewicz, I Ayeras, AA Gonulal, VE Cantu, C Beres, SB Green, NM Lei, BF Humbird, T Greaver, J Chang, E Ragasa, WP Montgomery, CA Cartwright, J McGeer, A Low, DE Whitney, AR Cagle, PT Blasdel, TL DeLeo, FR Musser, JM AF Olsen, Randall J. Sitkiewicz, Izabela Ayeras, Ara A. Gonulal, Vedia E. Cantu, Concepcion Beres, Stephen B. Green, Nicole M. Lei, Benfang Humbird, Tammy Greaver, Jamieson Chang, Ellen Ragasa, Willie P. Montgomery, Charles A. Cartwright, Joiner, Jr. McGeer, Allison Low, Donald E. Whitney, Adeline R. Cagle, Philip T. Blasdel, Terry L. DeLeo, Frank R. Musser, James M. TI Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE group A streptococcus; invasive infection; molecular epidemiology of strain genotype patient phenotype relationships; nonhuman primate ID GROUP-A STREPTOCOCCUS; EXTRACELLULAR CYSTEINE PROTEASE; SOFT-TISSUE INFECTIONS; PYROGENIC EXOTOXIN-B; BACILLUS-SUBTILIS; SEROTYPE M3; PYOGENES; EVASION; DEGRADATION; ACTIVATION AB Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the Delta mtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research. C1 [Musser, James M.] Methodist Hosp, Res Inst, Dept Pathol, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA. [Lei, Benfang] Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. [Humbird, Tammy; Greaver, Jamieson; Blasdel, Terry L.] Univ Houston, Houston, TX 77204 USA. [Montgomery, Charles A.] ComPath, Jay, OK 74346 USA. [Cartwright, Joiner, Jr.] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [McGeer, Allison] Mt Sinai Hosp, Dept Microbiol, Toronto, ON M5G 1X5, Canada. [Low, Donald E.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Low, Donald E.] Ontario Agcy Hlth Protect & Promot, Toronto, ON M5S 1A1, Canada. [Whitney, Adeline R.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), Methodist Hosp, Res Inst, Dept Pathol, Ctr Mol & Translat Human Infect Dis Res, B490,6565 Fannin St, Houston, TX 77030 USA. EM jmmusser@tmhs.org RI Sitkiewicz, Izabela/G-5058-2011; Low, Donald/B-1726-2012; mcgeer, allison /H-7747-2014; OI mcgeer, allison /0000-0001-5647-6137; Sitkiewicz, Izabela/0000-0001-8228-9917; DeLeo, Frank/0000-0003-3150-2516 FU American Heart Association [AHA-0775045N]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank K. Stockbauer for critical review of the manuscript, A. Tart for contributions to experimental design, R. Gonzalez and A. Dayton for technical expertise, and D. Sturdevant, P. Sumby, and S. A. Shelburne III for discussions. This work was supported by American Heart Association Grant AHA-0775045N and the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 29 TC 55 Z9 56 U1 0 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 JAN 12 PY 2010 VL 107 IS 2 BP 888 EP 893 DI 10.1073/pnas.0911811107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FY UT WOS:000273559300068 PM 20080771 ER PT J AU Irarrazabal, CE Gallazzini, M Schnetz, MP Kunin, M Simons, BL Williams, CK Burg, MB Ferraris, JD AF Irarrazabal, Carlos E. Gallazzini, Morgan Schnetz, Michael P. Kunin, Margarita Simons, Brigitte L. Williams, Chester K. Burg, Maurice B. Ferraris, Joan D. TI Phospholipase C-gamma 1 is involved in signaling the activation by high NaCl of the osmoprotective transcription factor TonEBP/OREBP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypertonicity; phosphorylation; proteomics ID NUCLEOTIDE EXCHANGE FACTOR; PROTEIN-KINASE-C; GROWTH-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; NUCLEOCYTOPLASMIC TRAFFICKING; CELLS; GAMMA; PHOSPHORYLATION; SURVIVAL; DOMAINS AB High NaCl elevates activity of the osmoprotective transcription factor TonEBP/OREBP by increasing its phosphorylation, transactivating activity, and localization to the nucleus. We investigated the possible role in this activation of phospholipase C-gamma 1 (PLC-gamma 1), which has a predicted binding site at TonEBP/OREBP-phospho-Y143. We find the following. (i) Activation of TonEBP/OREBP transcriptional activity by high NaCl is reduced in PLC-gamma 1 null cells and in HEK293 cells in which PLC-gamma 1 is knocked down by a specific siRNA. (ii) High NaCl increases phosphorylation of TonEBP/OREBP at Y143. (iii) Wild-type PLC-gamma 1 coimmunoprecipitates with wild-type TonEBP/OREBP but not TonEBP/OREBP-Y143A, and the coimmunoprecipitation is increased by high NaCl. (iv) PLC-gamma 1 is part of the protein complex that associates with TonEBP/OREBP at its DNA binding site. (v) Knockdown of PLC-gamma 1 or overexpression of a PLC-gamma 1-SH3 deletion mutant reduces high NaCl-dependent TonEBP/OREBP transactivating activity. (vi) Nuclear localization of PLC-gamma 1 is increased by high NaCl. (vii) High NaCl-induced nuclear localization of TonEBP/OREBP is reduced if cells lack PLC-gamma 1, if PLC-gamma 1 mutated in its SH2C domain is overexpressed, or if Y143 in TonEBP/OREBP is mutated to alanine. (viii) Expression of recombinant PLC-gamma 1 restores nuclear localization of wild-type TonEBP/OREBP in PLC-gamma 1 null cells but not of TonEBP/OREBP-Y143A. (ix) The PLC-gamma 1 phospholipase inhibitor U72133 inhibits nuclear localization of TonEBP/OREBP but not the increase of its transactivating activity. We conclude that, when NaCl is elevated, TonEBP/OREBP becomes phosphorylated at Y143, resulting in binding of PLC-gamma 1 to that site, which contributes to TonEBP/OREBP transcriptional activity, transactivating activity, and nuclear localization. C1 [Irarrazabal, Carlos E.; Gallazzini, Morgan; Schnetz, Michael P.; Kunin, Margarita; Simons, Brigitte L.; Williams, Chester K.; Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Irarrazabal, Carlos E.] Univ Los Andes, Fac Med, Lab Mol Physiol, Santiago 20106, Chile. [Simons, Brigitte L.] Appl Biosyst MDS SCIEX, Prod Applicat Lab, Concord, ON L4K 4V8, Canada. RP Burg, MB (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, US Dept HHS, 10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM maurice_burg@nih.gov RI Gallazzini, Morgan/E-5465-2011 FU National Heart, Lung, and Blood Institute; National Institutes of Health; University of Los Andes, Chile [FAI-MED 001-08] FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health and by FAI-MED 001-08 from the University of Los Andes, Chile. NR 28 TC 19 Z9 19 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 12 PY 2010 VL 107 IS 2 BP 906 EP 911 DI 10.1073/pnas.0913415107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FY UT WOS:000273559300071 PM 20080774 ER PT J AU Blakesley, RW Hansen, NF Gupta, J McDowell, JC Maskeri, B Barnabas, BB Brooks, SY Coleman, H Haghighi, P Ho, SL Schandler, K Stantripop, S Vogt, JL Thomas, PJ Bouffard, GG Green, ED AF Blakesley, Robert W. Hansen, Nancy F. Gupta, Jyoti McDowell, Jennifer C. Maskeri, Baishali Barnabas, Beatrice B. Brooks, Shelise Y. Coleman, Holly Haghighi, Payam Ho, Shi-Ling Schandler, Karen Stantripop, Sirintorn Vogt, Jennifer L. Thomas, Pamela J. Bouffard, Gerard G. Green, Eric D. CA NISC Comparative Sequencing Progra TI Effort required to finish shotgun-generated genome sequences differs significantly among vertebrates SO BMC GENOMICS LA English DT Article ID IDENTIFICATION; ELEMENTS; REVEALS; EVOLUTION; 1-PERCENT; PROJECT; LOCUS AB Background: The approaches for shotgun-based sequencing of vertebrate genomes are now well-established, and have resulted in the generation of numerous draft whole-genome sequence assemblies. In contrast, the process of refining those assemblies to improve contiguity and increase accuracy (known as 'sequence finishing') remains tedious, labor-intensive, and expensive. As a result, the vast majority of vertebrate genome sequences generated to date remain at a draft stage. Results: To date, our genome sequencing efforts have focused on comparative studies of targeted genomic regions, requiring sequence finishing of large blocks of orthologous sequence (average size 0.5-2 Mb) from various subsets of 75 vertebrates. This experience has provided a unique opportunity to compare the relative effort required to finish shotgun-generated genome sequence assemblies from different species, which we report here. Importantly, we found that the sequence assemblies generated for the same orthologous regions from various vertebrates show substantial variation with respect to misassemblies and, in particular, the frequency and characteristics of sequence gaps. As a consequence, the work required to finish different species' sequences varied greatly. Application of the same standardized methods for finishing provided a novel opportunity to "assay" characteristics of genome sequences among many vertebrate species. It is important to note that many of the problems we have encountered during sequence finishing reflect unique architectural features of a particular vertebrate's genome, which in some cases may have important functional and/or evolutionary implications. Finally, based on our analyses, we have been able to improve our procedures to overcome some of these problems and to increase the overall efficiency of the sequence-finishing process, although significant challenges still remain. Conclusion: Our findings have important implications for the eventual finishing of the draft whole-genome sequences that have now been generated for a large number of vertebrates. C1 [Blakesley, Robert W.; Gupta, Jyoti; McDowell, Jennifer C.; Maskeri, Baishali; Brooks, Shelise Y.; Coleman, Holly; Haghighi, Payam; Ho, Shi-Ling; Schandler, Karen; Stantripop, Sirintorn; Vogt, Jennifer L.; Thomas, Pamela J.; Bouffard, Gerard G.; Green, Eric D.] NHGRI, NIH, Intramural Sequencing Ctr NISC, Bethesda, MD 20892 USA. [Blakesley, Robert W.; Hansen, Nancy F.; Bouffard, Gerard G.; Green, Eric D.; NISC Comparative Sequencing Progra] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Green, ED (reprint author), NHGRI, NIH, Intramural Sequencing Ctr NISC, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov RI Granite, Stephen/J-9487-2013 OI Granite, Stephen/0000-0002-0956-7500 FU National Human Genome Research Institute, National Institutes of Health FX We thank all participants of the NISC Comparative Sequencing Program (participants include A Antonellis, K Ayele, D Bass, SM Beckstrom-Sternberg, CP Brinkley, K Cariaga, G Chu, I Chub, M Dekhtyar, NL Dietrich, J Engle, T Fuksenko, M Gestole, S Granite, M Gregory, X Guan, N Gurson, P Hall, E Han, J Han, A Hargrove, K Hines-Harris, J Hodax, P Hu, B Hurle, JR Idol, T Johnson, E Karlins, P Laric, SQ Lee-Lin, R Legaspi, S Lovett, M Madden, QL Maduro, VB Maduro, EH Margulies, CA Masiello, SD Mastrian, C Montemayor, JC Mullikin, J Myrick, E Novotny, M Park, R Pearson, A Palumbo, ME Portnoy, AB Prasad, O Puri, C Ramsahoye, N Reddix-Dugue, N Riebow, A Sante, B Schmidt, MG Schueler, C Sison, L Smith, A Taye, JW Thomas, EE Tiongson, JW Touchman, C Tsurgeon, V Tsipouri, MA Walker, KD Wetherby, LS Wiggins, TR Withers, and AC Young) for their contributions to the studies described here. We also thank Hatice Abaan, Paul Havlak, and Elliott Margulies (NHGRI) for sharing unpublished Genome Analyzer sequencing data. We thank Kim Kyung and Robert Fulton (WUGSC) for providing sequence of the small gap in our dog BAC [GenBank: AC090445]. We also thank Alice Young (NISC), Rick Myers, and Richards Gibbs for critical feedback about this manuscript. This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 37 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 11 PY 2010 VL 11 AR 21 DI 10.1186/1471-2164-11-21 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 565HC UT WOS:000275279600001 PM 20064230 ER PT J AU Dobolyi, A Palkovits, M Usdin, TB AF Dobolyi, Arpad Palkovits, Miklos Usdin, Ted B. TI The TIP39-PTH2 receptor system: Unique peptidergic cell groups in the brainstem and their interactions with central regulatory mechanisms SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Neuropeptide; Subparafascicular; Posterior intralaminar thalamic; Limbic functions; Endocrine hypothalamic regulations; Nociceptive action; Paralemniscal; Auditory brainstem ID HORMONE-RELATED PEPTIDE; GENE-RELATED PEPTIDE; SUBPARAFASCICULAR THALAMIC NUCLEUS; HUMAN PARATHYROID-HORMONE; CENTRAL-NERVOUS-SYSTEM; PROTEIN-KINASE-C; MALE SEXUAL-BEHAVIOR; 39 RESIDUES TIP39; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; PITUITARY-ADRENOCORTICAL AXIS AB Tuberoinfundibular peptide of 39 residues (TIP39) is the recently purified endogenous ligand of the previously orphan G-protein coupled parathyroid hormone 2 receptor (PTH2R). The TIP39-PTH2R system is a unique neuropeptide-receptor system whose localization and functions in the central nervous system are different from any other neuropeptides. TIP39 is expressed in two brain regions, the subparafascicular area in the posterior thalamus, and the medial paralemniscal nucleus in the lateral pons. Subparafascicular TIP39 neurons seem to divide into a medial and a lateral cell population in the periventricular gray of the thalamus, and in the posterior intralaminar complex of the thalamus, respectively. Periventricular thalamic TIP39 neurons project mostly to limbic brain regions, the posterior intralaminar thalamic TIP39 neurons to neuroendocrine brain areas, and the medial paralemniscal TIP39 neurons to auditory and other brainstem regions, and the spinal cord. The widely distributed axon terminals of TIP39 neurons have a similar distribution as the PTH2R-containing neurons, and their fibers, providing the anatomical basis of a neuromodulatory action of TIP39. Initial functional studies implicated the TIP39-PTH2R system in nociceptive information processing in the spinal cord, in the regulation of different hypophysiotropic neurons in the hypothalamus, and in the modulation of affective behaviors. Recently developed novel experimental tools including mice with targeted mutations of the TIP39-PTH2R system and specific antagonists of the PTH2R will further facilitate the identification of the specific roles of TIP39 and the PTH2R. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Dobolyi, Arpad; Palkovits, Miklos] Semmelweis Univ, Neuromorphol & Neuroendocrine Res Lab, Dept Anat Histol & Embryol, HAS, H-1094 Budapest, Hungary. [Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, NIH, Bethesda, MD 20892 USA. RP Dobolyi, A (reprint author), Semmelweis Univ, Neuromorphol & Neuroendocrine Res Lab, Dept Anat Histol & Embryol, HAS, Tuzolto U 58, H-1094 Budapest, Hungary. EM dobolyi@ana.sote.hu RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 FU Hungarian Academy of Sciences; Hungarian Science Foundation [NKTH-OTKA K67646, NFM-OTKA NNF78219]; OTKA [NK72929]; NIH, National Institute of Mental Health FX The work was supported by the Bolyai Janos Fellowship Grant of the Hungarian Academy of Sciences for AD, the Hungarian Science Foundation NKTH-OTKA K67646 and NFM-OTKA NNF78219 grants for AD, the OTKA NK72929 grant for MP and the Intramural Research Program of the NIH, National Institute of Mental Health for TBU. NR 246 TC 23 Z9 24 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JAN 11 PY 2010 VL 90 IS 1 BP 29 EP 59 DI 10.1016/j.pneurobio.2009.10.017 PG 31 WC Neurosciences SC Neurosciences & Neurology GA 550ZP UT WOS:000274174200003 PM 19857544 ER PT J AU Linday, LA Umhau, JC Shindledecker, RD Dolitsky, JN Holick, MF AF Linday, Linda A. Umhau, John C. Shindledecker, Richard D. Dolitsky, Jay N. Holick, Michael F. TI Cod Liver Oil, the Ratio of Vitamins A and D, Frequent Respiratory Tract Infections, and Vitamin D Deficiency in Young Children in the United States SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Editorial Material ID NUTRITION EXAMINATION SURVEY; MULTIVITAMIN-MINERAL SUPPLEMENT; 3RD NATIONAL-HEALTH; HYPOVITAMINOSIS-D; PILOT RESEARCH; DOUBLE-BLIND; FISH-OIL; RICKETS; INFANTS; CHILDHOOD C1 [Linday, Linda A.] St Lukes Roosevelt Hosp, New York, NY USA. [Umhau, John C.] NIH, Bethesda, MD 20892 USA. [Shindledecker, Richard D.] New York Downtown Hosp, New York, NY USA. [Dolitsky, Jay N.] New York Eye & Ear Infirm, New York, NY 10003 USA. [Holick, Michael F.] Boston Univ, Med Ctr, Boston, MA USA. RP Linday, LA (reprint author), St Lukes Roosevelt Hosp, New York, NY USA. NR 73 TC 4 Z9 6 U1 0 U2 3 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 JAN 10 PY 2010 VL 119 IS 1 BP 64 EP 70 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 544SW UT WOS:000273680600012 PM 20128190 ER PT J AU Anderson, WF Jatoi, I Tse, J Rosenberg, PS AF Anderson, William F. Jatoi, Ismail Tse, Julia Rosenberg, Philip S. TI Male Breast Cancer: A Population-Based Comparison With Female Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; KLINEFELTERS-SYNDROME; TEMPORAL VARIATION; COHORT MODELS; AGE PERIOD; RATES; CARCINOMA; TAMOXIFEN; TRENDS; MEN AB Purpose Because of its rarity, male breast cancer is often compared with female breast cancer. Patients and Methods To compare and contrast male and female breast cancers, we obtained case and population data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program for breast cancers diagnosed from 1973 through 2005. Standard descriptive epidemiology was supplemented with age-period-cohort models and breast cancer survival analyses. Results Of all breast cancers, men with breast cancer make up less than 1%. Male compared with female breast cancers occurred later in life with higher stage, lower grade, and more estrogen receptor-positive tumors. Recent breast cancer incidence and mortality rates declined over time for men and women, but these trends were greater for women than for men. Comparing patients diagnosed from 1996 through 2005 versus 1976 through 1985, and adjusting for age, stage, and grade, cause-specific hazard rates for breast cancer death declined by 28% among men (P = .03) and by 42% among women (P approximate to 0). Conclusion There were three intriguing results. Age-specific incidence patterns showed that the biology of male breast cancer resembled that of late-onset female breast cancer. Similar breast cancer incidence trends among men and women suggested that there are common breast cancer risk factors that affect both sexes, especially estrogen receptor-positive breast cancer. Finally, breast cancer mortality and survival rates have improved significantly over time for both male and female breast cancer, but progress for men has lagged behind that for women. C1 [Anderson, William F.] NCI, DHHS, NIH, DCEG,EPS,BB, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Breast Care Ctr, Natl Naval Med Ctr, Bethesda, MD 20814 USA. Dartmouth Coll, Hanover, NH 03755 USA. RP Anderson, WF (reprint author), NCI, DHHS, NIH, DCEG,EPS,BB, Room 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 51 TC 102 Z9 107 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 232 EP 239 DI 10.1200/JCO.2009.23.8162 PG 8 WC Oncology SC Oncology GA 541LU UT WOS:000273418000011 PM 19996029 ER PT J AU Gunderson, LL Jessup, JM Sargent, DJ Greene, FL Stewart, A AF Gunderson, Leonard L. Jessup, John Milburn Sargent, Daniel J. Greene, Frederick L. Stewart, Andrew TI Revised Tumor and Node Categorization for Rectal Cancer Based on Surveillance, Epidemiology, and End Results and Rectal Pooled Analysis Outcomes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSTOPERATIVE ADJUVANT CHEMOTHERAPY; CIRCUMFERENTIAL MARGIN INVOLVEMENT; RADIATION-THERAPY; PROGNOSTIC-FACTORS; PREOPERATIVE RADIOTHERAPY; CURATIVE SURGERY; LOCAL RECURRENCE; COLORECTAL-CANCER; RANDOMIZED-TRIAL; PHASE-II AB Purpose The sixth edition of the American Joint Committee on Cancer (AJCC) rectal cancer staging subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III as a result of improved survival with T1-2N2 versus T3-4N2 and survival of T4N1 more similar to T3-4N2 than T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion interacts with nodal status to affect survival. Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 35,829 patients with rectal cancer were compared with rectal pooled analysis data (3,791 patients). T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of positive nodes as follows: N1a/N1b (one v two to three nodes) and N2a/N2b (four to six v >= seven nodes). Five-year observed and relative survival rates were obtained for each TN category. Results SEER rectal cancer analyses confirm that T1-2N2 cancers have better prognosis than T3-4N2, T4bN1 have similar prognosis to T4N2, T1-2N1 have similar prognosis to T2N0/T3N0, and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a). Prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects prognosis. Conclusion This SEER population-based rectal cancer analysis validates the rectal pooled analyses and supports the shift of T1-2N2 lesions from IIIC to IIIA or IIIB and T4bN1 from IIIB to IIIC. SEER outcomes support subdividing T4, N1, and N2 and revised substaging of stages II and III. Survival by TN category suggests a complex biologic interaction between depth of invasion and nodal status. C1 Mayo Clin, Ctr Canc, Scottsdale, AZ 85259 USA. NCI, Bethesda, MD 20892 USA. Mayo Clin, Ctr Canc, Rochester, MN USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Amer Coll Surg, Chicago, IL USA. RP Gunderson, LL (reprint author), Mayo Clin, Canc Ctr Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM gunderson.leonard@mayo.edu OI Sargent, Daniel/0000-0002-2684-4741 NR 47 TC 96 Z9 109 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 256 EP 263 DI 10.1200/JCO.2009.23.9194 PG 8 WC Oncology SC Oncology GA 541LU UT WOS:000273418000014 PM 19949015 ER PT J AU Gunderson, LL Jessup, JM Sargent, DJ Greene, FL Stewart, AK AF Gunderson, Leonard L. Jessup, John Milburn Sargent, Daniel J. Greene, Frederick L. Stewart, Andrew K. TI Revised TN Categorization for Colon Cancer Based on National Survival Outcomes Data SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSTOPERATIVE ADJUVANT CHEMOTHERAPY; CIRCUMFERENTIAL MARGIN INVOLVEMENT; AMERICAN JOINT COMMITTEE; RECTAL-CANCER; RADIATION-THERAPY; LYMPH-NODES; PROGNOSTIC-FACTORS; COLORECTAL-CANCER; CURATIVE SURGERY; LOCAL RECURRENCE AB Purpose The sixth edition of American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III because of improved survival for T1-2N2 versus T3-4N2 and T4N1 survival was more similar to T3-4N2 than to T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion and nodal status interact to affect survival. Patients and Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 109,953 colon cancer patients were compared with National Cancer Data Base (NCDB) data on 134,206 patients. T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of involved positive lymph nodes (N+): N1a/N1b (1 v 2-3), N2a/ N2b (4 to 6 v >= 7). Five-year observed and relative survival data were obtained for each TN category. Results SEER colon cancer analyses confirm that patients with T1-2N0 cancers have better survival than T3N0, T3N0 better than T4N0, T1-2N2 better than T3-4N2, and T4bN1 similar to T4N2. Patients with T4a lesions have better survival than T4b by N category. The number of positive nodes affects survival for each T category. Conclusion This SEER population-based colon cancer analysis is highly consistent with rectal cancer pooled analysis and SEER rectal cancer analyses, supporting the shift of T1-2N2 lesions from IIIC to IIIA/IIIB, shifting T4bN1 from IIIB to IIIC, subdividing T4/N1/N2, and revising substaging of stages II/III. Survival outcomes by TN category for colon and rectal cancer are strikingly similar. C1 Mayo Clin, Ctr Canc, Scottsdale, AZ 85259 USA. NCI, Bethesda, MD 20892 USA. Mayo Clin, Ctr Canc, Rochester, MN USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Amer Coll Surg, Chicago, IL USA. RP Gunderson, LL (reprint author), Mayo Clin, Canc Ctr Scottsdale, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM gunderson.leonard@mayo.edu OI Sargent, Daniel/0000-0002-2684-4741 NR 43 TC 194 Z9 201 U1 1 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2010 VL 28 IS 2 BP 264 EP 271 DI 10.1200/JCO.2009.24.0952 PG 8 WC Oncology SC Oncology GA 541LU UT WOS:000273418000015 PM 19949014 ER PT J AU Onder, M Glenn, G Adisen, E Keseroglu, O Sahin, S Ataoglu, O Akkaya, B Toro, JR AF Onder, Meltem Glenn, Gladys Adisen, Esra Keseroglu, Ozge Sahin, Sedef Ataoglu, Omur Akkaya, Bahar Toro, Jorge R. TI Cutaneous papules, uterine fibroids, and renal cell cancer: one family's tale SO LANCET LA English DT Editorial Material ID FUMARATE-HYDRATASE GENE; HEREDITARY LEIOMYOMATOSIS; GERMLINE MUTATIONS C1 [Glenn, Gladys; Toro, Jorge R.] NCI, Genet Epidemiol Branch, Rockville, MD 20892 USA. [Onder, Meltem; Adisen, Esra; Keseroglu, Ozge] Gazi Univ, Dept Dermatol, Ankara, Turkey. [Ataoglu, Omur] Gazi Univ, Dept Pathol, Ankara, Turkey. [Sahin, Sedef] Hacettepe Univ, Dept Dermatol, Ankara, Turkey. [Akkaya, Bahar] Akdeniz Univ, Dept Pathol, TR-07058 Antalya, Turkey. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, 6120 Execut Blvd,Execut Plaza S,Room 7012, Rockville, MD 20892 USA. EM toroj@mail.nih.gov NR 5 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JAN 9 PY 2010 VL 375 IS 9709 BP 170 EP 170 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 544NM UT WOS:000273664500035 PM 20109895 ER PT J AU Bonds, DE Miller, ME Bergenstal, RM Buse, JB Byington, RP Cutler, JA Dudl, RJ Ismail-Beigi, F Kimel, AR Hoogwerf, B Horowitz, KR Savage, PJ Seaquist, ER Simmons, DL Sivitz, WI Speril-Hillen, JM Sweeney, ME AF Bonds, Denise E. Miller, Michael E. Bergenstal, Richard M. Buse, John B. Byington, Robert P. Cutler, Jeff A. Dudl, R. James Ismail-Beigi, Faramarz Kimel, Angela R. Hoogwerf, Byron Horowitz, Karen R. Savage, Peter J. Seaquist, Elizabeth R. Simmons, Debra L. Sivitz, William I. Speril-Hillen, Joann M. Sweeney, Mary Ellen TI The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study SO BRITISH MEDICAL JOURNAL LA English DT Article ID CRITICALLY-ILL PATIENTS; GLYCEMIC CONTROL; GLUCOSE CONTROL; RISK; MELLITUS; EVENTS; TRIALS AB Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control. Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia. Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. C1 [Bonds, Denise E.; Cutler, Jeff A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Miller, Michael E.; Byington, Robert P.; Kimel, Angela R.] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Bergenstal, Richard M.] Int Diabet Ctr Pk Nicollet, Minneapolis, MN 55416 USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC 27514 USA. [Dudl, R. James] Kaiser Permanente, Care Management Inst, Oakland, CA 94612 USA. [Ismail-Beigi, Faramarz; Horowitz, Karen R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Hoogwerf, Byron] Cleveland Clin, Dept Diabet Endocrinol & Metab, Cleveland, OH 44195 USA. [Hoogwerf, Byron] Lilly USA, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Savage, Peter J.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Seaquist, Elizabeth R.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Simmons, Debra L.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Simmons, Debra L.] John L McClellan Mem Vet Adm Med Ctr, Little Rock, AR 72205 USA. [Sivitz, William I.] Univ Iowa Hlth Care, Dept Internal Med, Iowa City, IA 52242 USA. [Speril-Hillen, Joann M.] HealthPartners Res Fdn, Minneapolis, MN 55440 USA. [Sweeney, Mary Ellen] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Sweeney, Mary Ellen] Atlanta Vet Adm Med Ctr, Atlanta, GA 30033 USA. RP Bonds, DE (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM bondsde@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers; Amylin Pharmaceuticals; Abbott Diabetes Care; Bayer; Eli Lilly; Intuity Medical; LifeScan; Mannkind; Medtronic-Minimed; Novo Nordisk; ResMed; Roche; Sanofi-Aventis; Valeritas; UnitedHealth Group; GlaxoSmithKline FX RMB receives research grant support and/or is a member of a scientific advisory board for the following companies: Amylin Pharmaceuticals, Abbott Diabetes Care, Bayer, Eli Lilly, Intuity Medical, LifeScan, Mannkind, Medtronic-Minimed, National Institutes of Health, Novo Nordisk, ResMed, Roche, Sanofi-Aventis, Valeritas, and UnitedHealth Group. All the above activities are performed under contract with the non-profit Park Nicollet Institute and the International Diabetes Center, Minneapolis, MN, USA. RMB receives no personal compensation for any of these activities. He also inherited Merck stock. JBB is a shareholder of Insulet. Under contracts with his employer, JBB has been an investigator, consultant, or speaker for Amylin Pharmaceuticals, Bayhill Therapeutics, Becton, Dickinson and Company Research Laboratories, Bristol-Myers Squibb, Dexcom, Eli Lilly, GlaxoSmithKline, Intekrin, Intuity Medical, Johnson & Johnson, MannKind, Medtronic, Merck, MicroIslet, Novartis, Novo Nordisk, Osiris, Pfizer, Roche, Sanofi-Aventis, Transition Therapeutics, and Wyeth. BH is a full-time employee of Lilly USA (Endocrine), Indianapolis, IN, USA. ERS has been reimbursed by Pfizer for participating in the review of applications for visiting professorships and has been a paid consultant for Merck. WIS receives research funds from GlaxoSmithKline and has been reimbursed by Merck as a consultant at a Global Experts Forum. The remaining authors declare no competing interests. NR 26 TC 378 Z9 392 U1 4 U2 17 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 8 PY 2010 VL 340 AR b4909 DI 10.1136/bmj.b4909 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 542II UT WOS:000273486100001 PM 20061358 ER PT J AU Miller, ME Bonds, DE Gerstein, HC Seaquist, ER Bergenstal, RM Calles-Escandon, J Childress, RD Craven, TE Cuddihy, RM Dailey, G Feinglos, MN Ismail-Beigi, F Largay, JF O'Connor, PJ Paul, T Savage, PJ Schubart, UK Sood, A Genuth, S AF Miller, Michael E. Bonds, Denise E. Gerstein, Hertzel C. Seaquist, Elizabeth R. Bergenstal, Richard M. Calles-Escandon, Jorge Childress, R. Dale Craven, Timothy E. Cuddihy, Robert M. Dailey, George Feinglos, Mark N. Ismail-Beigi, Farmarz Largay, Joe F. O'Connor, Patrick J. Paul, Terri Savage, Peter J. Schubart, Ulrich K. Sood, Ajay Genuth, Saul CA ACCORD Investigators TI The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study SO BRITISH MEDICAL JOURNAL LA English DT Article ID AMERICAN-DIABETES-ASSOCIATION; BLOOD-GLUCOSE CONTROL; TREATMENT MODALITIES; FREQUENCY; TYPE-1; COMPLICATIONS AB Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A(1C)) achieved during therapy. Design Post hoc epidemiological analysis of a double 2x2 factorial, randomised, controlled trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A(1C) concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control. Main outcome measures Severe hypoglycaemia was defined as episodes of "low blood glucose" requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A(1C) concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A(1C) concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). Conclusions A greater drop in haemoglobin A(1C) concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. C1 [Miller, Michael E.; Craven, Timothy E.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Bonds, Denise E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Gerstein, Hertzel C.] McMaster Univ & Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON L8L 2X2, Canada. [Seaquist, Elizabeth R.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Bergenstal, Richard M.; Cuddihy, Robert M.] Int Diabet Ctr Pk Nicollet, Minneapolis, MN 55416 USA. [Calles-Escandon, Jorge] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sect Endocrinol & Metab, Winston Salem, NC 27157 USA. [Childress, R. Dale] Memphis Vet Affairs Med Ctr, Memphis, TN 38104 USA. [Dailey, George] Whittier Inst Diabet & Endocrinol, La Jolla, CA 92037 USA. [Feinglos, Mark N.] Duke Univ, Med Ctr, Div Metab Endocrinol & Nutr, Durham, NC 27710 USA. [Ismail-Beigi, Farmarz; Sood, Ajay; Genuth, Saul] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Largay, Joe F.] Univ N Carolina, Dept Med, Div Endocrinol, Chapel Hill, NC 27514 USA. [O'Connor, Patrick J.] HealthPartners Res Fdn, Minneapolis, MN 55440 USA. [Paul, Terri] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, London, ON N6A 5C1, Canada. [Savage, Peter J.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Schubart, Ulrich K.] Yeshiva Univ Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10461 USA. RP Miller, ME (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA. EM mmiller@wfubmc.edu FU NHLBI NIH HHS [IAA-Y1-HC-1010, IAA-Y1-HC-9035, N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184] NR 23 TC 159 Z9 163 U1 0 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 8 PY 2010 VL 340 AR b5444 DI 10.1136/bmj.b5444 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 542II UT WOS:000273486100002 PM 20061360 ER PT J AU Peng, W Zhang, Y Zheng, M Cheng, HP Zhu, WZ Cao, CM Xiao, RP AF Peng, Wei Zhang, Yan Zheng, Ming Cheng, Heping Zhu, Weizhong Cao, Chun-Mei Xiao, Rui-Ping TI Cardioprotection by CaMKII-delta B Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70 SO CIRCULATION RESEARCH LA English DT Article DE CaMKII isoforms; CaMKII-delta B; oxidative stress; hypoxia; cardiomyocyte apoptosis; iHSP70; HSF1 ID CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; MUSCLE CELL APOPTOSIS; TRANSCRIPTION FACTOR; CARDIAC-HYPERTROPHY; IN-VIVO; BETA(1)-ADRENERGIC STIMULATION; DILATED CARDIOMYOPATHY; INDEPENDENT ACTIVATION; VENTRICULAR MYOCYTES; INHIBITION PROTECTS AB Rationale: Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is a multifunctional kinase involved in vital cellular processes such as Ca(2+) handling and cell fate regulation. In mammalian heart, 2 primary CaMKII isoforms, delta B and delta C, localize in nuclear and cytosolic compartments, respectively. Although previous studies have established an essential role of CaMKII-delta C in cardiomyocyte apoptosis, the functional role of the more abundant isoform, CaMKII-delta B, remains elusive. Objective: Here, we determined the potential role of CaMKII-delta B in regulating cardiomyocyte viability and explored the underlying mechanism. Methods and Results: In cultured neonatal rat cardiomyocytes, the expression of CaMKII-delta B and CaMKII-delta C was inversely regulated in response to H(2)O(2)-induced oxidative stress with a profound reduction of the former and an increase of the later. Similarly, in vivo ischemia/reperfusion (IR) led to an opposite regulation of these CaMKII isoforms in a rat myocardial IR model. Notably, overexpression of CaMKII-delta B protected cardiomyocytes against oxidative stress-, hypoxia-, and angiotensin II-induced apoptosis, whereas overexpression of its cytosolic counterpart promoted apoptosis. Using cDNA microarray, real-time PCR and Western blotting, we demonstrated that overexpression of CaMKII-delta B but not CaMKII-delta C elevated expression of heat shock protein (HSP)70 family members, including inducible (i)HSP70 and its homolog (Hst70). Moreover, overexpression of CaMKII-delta B led to phosphorylation and activation of heat shock factor (HSF)1, the primary transcription factor responsible for HSP70 gene regulation. Importantly, gene silencing of iHSP70, but not Hst70, abolished CaMKII-delta B-mediated protective effect, indicating that only iHSP70 was required for CaMKII-delta B elicited antiapoptotic signaling. Conclusions: We conclude that cardiac CaMKII-delta B and CaMKII-delta C were inversely regulated in response to oxidative stress and IR injury, and that in contrast to CaMKII-delta C, CaMKII-delta B serves as a potent suppressor of cardiomyocyte apoptosis triggered by multiple death-inducing stimuli via phosphorylation of HSF1 and subsequent induction of iHSP70, marking both CaMKII-delta isoforms as promising therapeutic targets for the treatment of ischemic heart disease. (Circ Res. 2010;106:102-110.) C1 [Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. [Peng, Wei; Zhang, Yan; Zheng, Ming; Cheng, Heping; Cao, Chun-Mei] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Zhang, Yan] Peking Univ, Inst Cardiovasc Sci, Beijing 100871, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Caochunmei@pku.edu.cn; Xiaor@grc.nia.nih.gov RI Zhang, Yan/B-2831-2012 FU Peking University; 973 Program [2007CB512100]; NIH; National Institute on Aging FX This work was supported by the Peking University 985 Project (to W. P., Y. Z., M. Z., H. C., C.- M. C.) and 973 Program (2007CB512100) (to C.- M. C., M. Z., and H. C.) and, in part, by the Intramural Research Program of the NIH, National Institute on Aging (to W. Z. and R.- P. X.). NR 48 TC 53 Z9 61 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 8 PY 2010 VL 106 IS 1 BP 102 EP 110 DI 10.1161/CIRCRESAHA.109.210914 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 541GP UT WOS:000273403600018 PM 19910575 ER PT J AU Kaludercic, N Takimoto, E Nagayama, T Feng, N Lai, EW Bedja, D Chen, K Gabrielson, KL Blakely, RD Shih, JC Pacak, K Kass, DA Di Lisa, F Paolocci, N AF Kaludercic, Nina Takimoto, Eiki Nagayama, Takahiro Feng, Ning Lai, Edwin W. Bedja, Djahida Chen, Kevin Gabrielson, Kathleen L. Blakely, Randy D. Shih, Jean C. Pacak, Karel Kass, David A. Di Lisa, Fabio Paolocci, Nazareno TI Monoamine Oxidase A-Mediated Enhanced Catabolism of Norepinephrine Contributes to Adverse Remodeling and Pump Failure in Hearts With Pressure Overload SO CIRCULATION RESEARCH LA English DT Article DE monoamine oxidase A; congestive heart failure; oxidative stress; catecholamines; norepinephrine transporter ID OXIDATIVE STRESS; CARDIAC-HYPERTROPHY; DOWN-REGULATION; MAO-A; VENTRICULAR HYPERTROPHY; OXYGEN; LOCALIZATION; SEROTONIN; APOPTOSIS; MYOCYTES AB Rationale: Monoamine oxidases (MAOs) are mitochondrial enzymes that catabolize prohypertrophic neurotransmitters, such as norepinephrine and serotonin, generating hydrogen peroxide. Because excess reactive oxygen species and catecholamines are major contributors to the pathophysiology of congestive heart failure, MAOs could play an important role in this process. Objective: Here, we investigated the role of MAO-A in maladaptive hypertrophy and heart failure. Methods and Results: We report that MAO-A activity is triggered in isolated neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. All of these in vitro changes occur, in part, independently from alpha- and beta-adrenergic receptor-operated signaling and are inhibited by the specific MAO-A inhibitor clorgyline. In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A is increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevents these changes, and also reverses fetal gene reprogramming, metalloproteinase and caspase-3 activation, as well as myocardial apoptosis. The specific role of MAO-A was further tested in mice expressing a dominant-negative MAO-A (MAO-A(neo)), which were more protected against pressure overload than their wild-type littermates. Conclusions: In addition to adrenergic receptor-dependent mechanisms, enhanced MAO-A activity coupled with increased intramyocardial norepinephrine availability results in augmented reactive oxygen species generation, contributing to maladaptive remodeling and left ventricular dysfunction in hearts subjected to chronic stress. (Circ Res. 2010; 106: 193-202.) C1 [Kaludercic, Nina; Takimoto, Eiki; Nagayama, Takahiro; Feng, Ning; Kass, David A.; Paolocci, Nazareno] Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21205 USA. [Bedja, Djahida; Gabrielson, Kathleen L.] Johns Hopkins Med Inst, Dept Comparat Pathobiol, Baltimore, MD 21205 USA. [Kaludercic, Nina; Di Lisa, Fabio] Univ Padua, Dept Biomed Sci, I-35100 Padua, Italy. [Lai, Edwin W.; Pacak, Karel] NICHD, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. [Chen, Kevin; Shih, Jean C.] Univ So Calif, Keck Sch Med, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90033 USA. [Shih, Jean C.] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA. [Blakely, Randy D.] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN USA. [Blakely, Randy D.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Paolocci, Nazareno] Univ Perugia, Dept Clin Med, I-06100 Perugia, Italy. RP Paolocci, N (reprint author), Johns Hopkins Sch Med, Div Cardiol Ross 858, 720 Rutland Ave, Baltimore, MD 21205 USA. EM npaoloc1@jhmi.edu OI Di Lisa, Fabio/0000-0001-9757-8818; Paolocci, Nazareno/0000-0001-7011-997X FU American Heart Association; Ministero dell'Universita e della Ricerca; Consiglio Nazionale delle Ricerche; NIH [HL093432, HL088649, HL56693, HL-089297, HL-077180, R01HL075265, HL091923]; National Institute of Child Health and Development, NIH; National Institute of Mental Health [R37 MH39085, R01 MH67968]; Boyd and Elsie Welin Professorship Award FX This work was supported by the American Heart Association (Postdoctoral Grant to N. K. and Scientist Development Grant to N. P.); the Ministero dell'Universita e della Ricerca and Consiglio Nazionale delle Ricerche (to F. D. L.); the NIH (grants HL093432 to E. T., HL088649 to K. L. G., HL56693 to R. D. B., HL-089297 and HL-077180 to D. A. K., R01HL075265 and HL091923 to N. P.); and, in part, by the Intramural Research Program of the National Institute of Child Health and Development, NIH; National Institute of Mental Health grants R37 MH39085 (Merit Award) and R01 MH67968; and a Boyd and Elsie Welin Professorship Award (to J. C. S.). NR 57 TC 89 Z9 90 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 8 PY 2010 VL 106 IS 1 BP 193 EP U401 DI 10.1161/CIRCRESAHA.109.198366 PG 19 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 541GP UT WOS:000273403600028 PM 19910579 ER PT J AU Miwa, HE Gerken, TA Jamison, O Tabak, LA AF Miwa, Hazuki E. Gerken, Thomas A. Jamison, Oliver Tabak, Lawrence A. TI Isoform-specific O-Glycosylation of Osteopontin and Bone Sialoprotein by Polypeptide N-Acetylgalactosaminyltransferase-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-ACETYLGALACTOSAMINYLTRANSFERASE FAMILY; MUCIN TANDEM REPEAT; UDP-GALNAC; POSTTRANSLATIONAL MODIFICATIONS; LECTIN DOMAINS; STRUCTURAL-CHARACTERIZATION; MASS-SPECTROMETRY; BINDING-SITE; AMINO-ACID; GLYCOPEPTIDE AB Mucin-type O-glycan biosynthesis is regulated by the family of UDP-GalNAc polypeptide: N-acetylgalactosaminlytransfersases (ppGalNAcTs) that catalyzes the first step in the pathway by transferring GalNAc to Ser or Thr residues in a protein from the sugar donor UDP-GalNAc. Because not all Ser/Thr residues are glycosylated, rules must exist that signal which hydroyxamino acids acquire sugar. To date, no universal consensus signal has emerged. Therefore, strategies to deduce the subset of proteins that will be glycosylated by distinct ppGalNAcTs must be developed. Mucin-type O-glycoproteins are present abundantly in bone, where we found multiple ppGalNAcT isoforms, including ppGalNAcT-1, to be highly expressed. Thus, we compared glycoproteins expressed in wild-type and Galnt1-null mice to identify bone-associated proteins that were glycosylated in a ppGalNAcT-1-dependent manner. A reduction in the apparent molecular masses of two SIBLINGs (small integrin binding ligand N-linked glycoproteins), osteopontin (OPN) and bone sialoprotein (BSP) in the Galnt1-null mice relative to those of the wild-type was observed. Several synthetic peptides derived from OPN and BSP sequences were designed to include either known or predicted (in silico) glycosylation sites. In vitro glycosylation assays of these peptides with recombinant ppGalNAcT-1, ppGalNAcT-2, or ppGalNAcT-3 demonstrated that both SIBLINGs contained Thr/Ser residues that were preferentially glycosylated by ppGalNAcT-1. In addition, lysates prepared from wild-type, but not those from Galnt1-null derived osteoblasts, could glycosylate these peptides efficiently, suggesting that OPN and BSP contain sites that are specific for ppGalNAcT-1. Our study presents a novel and systematic approach for identification of isoform-specific substrates of the ppGalNAcT family and suggests ppGalNAcT-1 to be indispensable for O-glycosylation at specific sites of the bone glycoproteins OPN and BSP. C1 [Miwa, Hazuki E.; Tabak, Lawrence A.] NIDDK, Sect Biol Chem, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gerken, Thomas A.; Jamison, Oliver] Case Western Reserve Univ, Sch Med, WA Bernbaum Ctr Cyst Fibrosis Res, Dept Pediat, Cleveland, OH 44106 USA. [Gerken, Thomas A.; Jamison, Oliver] Case Western Reserve Univ, Sch Med, WA Bernbaum Ctr Cyst Fibrosis Res, Dept Biochem, Cleveland, OH 44106 USA. RP Tabak, LA (reprint author), NIDDK, Sect Biol Chem, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM tabakl@mail.nih.gov FU NIDDK [NCI-RO1CA-78834] FX This work was supported, in whole or in part, by the National Institutes of Health intramural program of NIDDK and Grant NCI-RO1CA-78834 (to T. A. G.). NR 51 TC 22 Z9 22 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 JAN 8 PY 2010 VL 285 IS 2 BP 1208 EP 1219 DI 10.1074/jbc.M109.035436 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539MH UT WOS:000273258200043 PM 19880513 ER PT J AU Sahu, G Wang, DF Chen, CB Zhurkin, VB Harrington, RE Appella, E Hager, GL Nagaich, AK AF Sahu, Geetaram Wang, Difei Chen, Claudia B. Zhurkin, Victor B. Harrington, Rodney E. Appella, Ettore Hager, Gordon L. Nagaich, Akhilesh K. TI p53 Binding to Nucleosomal DNA Depends on the Rotational Positioning of DNA Response Element SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR; GLUCOCORTICOID-RECEPTOR; TUMOR-SUPPRESSOR; CRYSTAL-STRUCTURE; IN-VITRO; STRUCTURAL BASIS; SWI/SNF COMPLEX; DOMAIN PEPTIDES; CORE DOMAIN; PROTEIN AB The sequence-specific binding to DNA is crucial for the p53 tumor suppressor function. To investigate the constraints imposed on p53-DNA recognition by nucleosomal organization, we studied binding of the p53 DNA binding domain (p53DBD) and full-length wild-type p53 protein to a single p53 response element (p53RE) placed near the nucleosomal dyad in six rotational settings. We demonstrate that the strongest p53 binding occurs when the p53RE in the nucleosome is bent in the same direction as observed for the p53-DNA complexes in solution and in co-crystals. The p53RE becomes inaccessible, however, if its orientation in the core particle is changed by similar to 180 degrees. Our observations indicate that the orientation of the binding sites on a nucleosome may play a significant role in the initial p53-DNA recognition and subsequent cofactor recruitment. C1 [Nagaich, Akhilesh K.] US FDA, Chem Lab, Div Therapeut Prot, OBP,OPS,CDER, Bethesda, MD 20892 USA. [Wang, Difei; Zhurkin, Victor B.; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Harrington, Rodney E.] Arizona State Univ, Dept Microbiol, Tempe, AZ 85287 USA. RP Nagaich, AK (reprint author), US FDA, Chem Lab, Div Therapeut Prot, OBP,OPS,CDER, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM akhilesh.nagaich@fda.hhs.gov RI Wang, Difei/E-7066-2010 FU Oak Ridge Institute for Science and Education through an intraagency agreement between the United States Department of Energy and the United States Food and Drug Administration; National Institutes of Health [R01 CA 70274]; National Cancer Institute; Center for Cancer Research FX This work was supported, in whole or in part, by an appointment of G. Sahu to the Postgraduate Research Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an intraagency agreement between the United States Department of Energy and the United States Food and Drug Administration. This work was also supported in part by National Institutes of Health Grant R01 CA 70274 (to R.E.H.) and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 57 TC 20 Z9 20 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 8 PY 2010 VL 285 IS 2 BP 1321 EP 1332 DI 10.1074/jbc.M109.081182 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 539MH UT WOS:000273258200053 PM 19887449 ER PT J AU Anwari, K Poggio, S Perry, A Gatsos, X Ramarathinam, SH Williamson, NA Noinaj, N Buchanan, S Gabriel, K Purcell, AW Jacobs-Wagner, C Lithgow, T AF Anwari, Khatira Poggio, Sebastian Perry, Andrew Gatsos, Xenia Ramarathinam, Sri Harsha Williamson, Nicholas A. Noinaj, Nicholas Buchanan, Susan Gabriel, Kipros Purcell, Anthony W. Jacobs-Wagner, Christine Lithgow, Trevor TI A Modular BAM Complex in the Outer Membrane of the alpha-Proteobacterium Caulobacter crescentus SO PLOS ONE LA English DT Article ID PEPTIDOGLYCAN-ASSOCIATED LIPOPROTEIN; BACTERIAL FLAGELLAR MOTOR; ESCHERICHIA-COLI; CELL-ENVELOPE; PSEUDOMONAS-AERUGINOSA; NEISSERIA-MENINGITIDIS; PROTEIN COMPLEXES; CRYSTAL-STRUCTURE; OMP85 FAMILY; YAET COMPLEX AB Mitochondria are organelles derived from an intracellular alpha-proteobacterium. The biogenesis of mitochondria relies on the assembly of beta-barrel proteins into the mitochondrial outer membrane, a process inherited from the bacterial ancestor. Caulobacter crescentus is an alpha-proteobacterium, and the BAM (beta-barrel assembly machinery) complex was purified and characterized from this model organism. Like the mitochondrial sorting and assembly machinery complex, we find the BAM complex to be modular in nature. A similar to 150 kDa core BAM complex containing BamA, BamB, BamD, and BamE associates with additional modules in the outer membrane. One of these modules, Pal, is a lipoprotein that provides a means for anchorage to the peptidoglycan layer of the cell wall. We suggest the modular design of the BAM complex facilitates access to substrates from the protein translocase in the inner membrane. C1 [Anwari, Khatira; Perry, Andrew; Gabriel, Kipros; Lithgow, Trevor] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia. [Poggio, Sebastian; Jacobs-Wagner, Christine] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Poggio, Sebastian; Jacobs-Wagner, Christine] Yale Univ, Microbial Pathogenesis Sect, New Haven, CT USA. [Gatsos, Xenia; Ramarathinam, Sri Harsha; Williamson, Nicholas A.; Purcell, Anthony W.] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia. [Noinaj, Nicholas; Buchanan, Susan] NIDDK, NIH, Bethesda, MD USA. [Jacobs-Wagner, Christine] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06511 USA. RP Anwari, K (reprint author), Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia. EM trevor.lithgow@med.monash.edu.au RI Ramarathinam, Sri/G-2278-2012; Perry, Andrew/E-5607-2010; Williamson, Nicholas/O-9812-2016; OI Ramarathinam, Sri/0000-0002-2787-1282; Perry, Andrew/0000-0001-9256-6068; Williamson, Nicholas/0000-0002-2173-3452; Purcell, Anthony/0000-0003-0532-8331 FU National Health and Medical Research Council [508911]; ARC [LE0882913]; Monash University; Pew Latin American Fellowship; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [GM065835, GM076698] FX Work in the authors' laboratories is supported by grants from the National Health and Medical Research Council (508911; to AWP and TL), and an ARC Linkage Infrastructure Equipment and Facilities grant (LE0882913). KA is supported by a Monash University Research Scholarship; AP is supported by a National Health and Medical Research Council Training Fellowship; SP is supported by a Pew Latin American Fellowship. SB and NN are supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The CJW laboratory is supported by the National Institutes of Health (GM065835 and GM076698). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 34 Z9 34 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 8 PY 2010 VL 5 IS 1 AR e8619 DI 10.1371/journal.pone.0008619 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541KO UT WOS:000273414200010 PM 20062535 ER PT J AU Bartlett, EJ Cruz, AM Boonyaratanakornkit, J Esker, J Castano, A Skiadopoulos, MH Collins, PL Murphy, BR Schmidt, AC AF Bartlett, Emmalene J. Cruz, Ann-Marie Boonyaratanakornkit, Jim Esker, Janice Castano, Adam Skiadopoulos, Mario H. Collins, Peter L. Murphy, Brian R. Schmidt, Alexander C. TI A novel human parainfluenza virus type 1 (HPIV1) with separated P and C genes is useful for generating C gene mutants for evaluation as live-attenuated virus vaccine candidates SO VACCINE LA English DT Article DE Human parainfluenza virus; C protein; Vaccine candidates ID RESPIRATORY SYNCYTIAL VIRUS; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; AFRICAN-GREEN MONKEYS; L-POLYMERASE PROTEIN; SENDAI-VIRUS; RNA-SYNTHESIS; REVERSE GENETICS; YOUNG-CHILDREN; GENOME REPLICATION AB A novel recombinant human parainfluenza virus type 1 (rHPIV1), rHPIV1-C+P, in which the overlapping open reading frames of the C and P genes were separated in order to introduce mutations into the C gene without affecting P, was generated Infectious rHPIV1-C+P was readily recovered and replicated as efficiently as HPIV1 wild type (wt) in vitro and in African green monkeys (AGMs) rHPIV1-C+P expressed increased levels of C protein and, surprisingly. activated the type I IFN and apoptosis responses more strongly than HPIV1 wt. rHPIV1-C+P provided a useful backbone for recovering an attenuated P/C gene mutation (Delta 84-85), which was previously unrecoverable, likely due to detrimental effects of the deletion on the P protein rHPIV1-C(Delta 84-85) +P and an additional mutant, rHPIV1-C(Delta 169-170)+P. were found to replicate to similar titers in vitro and to activate the type I IFN and apoptosis responses to a similar degree as rHPIV1-C+P rHPIV1-C(Delta 84-85)+P was found to be highly attenuated in AGMs, and all viruses were immunogenic and effective in protecting AGMs against challenge with HPIV1 wt. rHPIV1-C(Delta 84-85)+P will be investigated as a potential live-attenuated vaccine candidate for HPIV1 Published by Elsevier Ltd. C1 [Bartlett, Emmalene J.; Cruz, Ann-Marie; Boonyaratanakornkit, Jim; Esker, Janice; Castano, Adam; Skiadopoulos, Mario H.; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.] NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Schmidt, AC (reprint author), NIAID, Infect Dis Lab, RNA Viruses Sect, NIH,US Dept HHS, Bldg 50,Room 6511,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health; NIAID [AI-5114]; MedImmune [AI-5114] FX This project was funded and supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This project was partly performed under a cooperative research and development agreement (CRADA) between NIAID and MedImmune (CRADA #AI-5114) for the development of live-attenuated viruses for respiratory syncytial viruses, parainfluenza viruses and human metapneumovirus. NR 58 TC 4 Z9 5 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 JAN 8 PY 2010 VL 28 IS 3 BP 767 EP 779 DI 10.1016/j.vaccine.2009.10.069 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 561YE UT WOS:000275015200024 PM 19857454 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, Vivek Aravind, L. TI Novel eukaryotic enzymes modifying cell-surface biopolymers SO BIOLOGY DIRECT LA English DT Article ID OSMOREGULATED PERIPLASMIC GLUCANS; MEMBRANE-PROTEIN; FAMILY; GENE; SUCCINYLATION; ACETYLATION; ARABIDOPSIS; RESISTANCE; TOLERANCE; ENCODES AB Background: Eukaryotic extracellular matrices such as proteoglycans, sclerotinized structures, mucus, external tests, capsules, cell walls and waxes contain highly modified proteins, glycans and other composite biopolymers. Using comparative genomics and sequence profile analysis we identify several novel enzymes that could be potentially involved in the modification of cell-surface glycans or glycoproteins. Results: Using sequence analysis and conservation we define the acyltransferase domain prototyped by the fungal Cas1p proteins, identify its active site residues and unify them to the superfamily of classical 10TM acyltransferases (e. g. oatA). We also identify a novel family of esterases (prototyped by the previously uncharacterized N-terminal domain of Cas1p) that have a similar fold as the SGNH/GDSL esterases but differ from them in their conservation pattern. Conclusions: We posit that the combined action of the acyltransferase and esterase domain plays an important role in controlling the acylation levels of glycans and thereby regulates their physico-chemical properties such as hygroscopicity, resistance to enzymatic hydrolysis and physical strength. We present evidence that the action of these novel enzymes on glycans might play an important role in host-pathogen interaction of plants, fungi and metazoans. We present evidence that in plants (e. g. PMR5 and ESK1) the regulation of carbohydrate acylation by these acylesterases might also play an important role in regulation of transpiration and stress resistance. We also identify a subfamily of these esterases in metazoans (e. g. C7orf58), which are fused to an ATP-grasp amino acid ligase domain that is predicted to catalyze, in certain animals, modification of cell surface polymers by amino acid or peptides. C1 [Anantharaman, Vivek; Aravind, L.] 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 FU National Library of Medicine at the National Institutes of Health, USA FX Work by the authors is supported by the intramural funds of the National Library of Medicine at the National Institutes of Health, USA. NR 20 TC 17 Z9 18 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JAN 7 PY 2010 VL 5 AR 1 DI 10.1186/1745-6150-5-1 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 563YT UT WOS:000275177900001 PM 20056006 ER PT J AU Tanaka, T Roy, CN Yao, WL Matteini, A Semba, RD Arking, D Walston, JD Fried, LP Singleton, A Guralnik, J Abecasis, GR Bandinelli, S Longo, DL Ferrucci, L AF Tanaka, Toshiko Roy, Cindy N. Yao, Wenliang Matteini, Amy Semba, Richard D. Arking, Dan Walston, Jeremy D. Fried, Linda P. Singleton, Andrew Guralnik, Jack Abecasis, Goncalo R. Bandinelli, Stefania Longo, Dan L. Ferrucci, Luigi TI A genome-wide association analysis of serum iron concentrations SO BLOOD LA English DT Article ID HEPCIDIN; METABOLISM; TMPRSS6; HEMOCHROMATOSIS; POPULATION; DEFICIENCY; MUTATIONS AB To investigate genetic variants that affect iron concentrations in persons not affected by overt genetic disorders of iron metabolism, a genome-wide association study was conducted in the InCHIANTI Study (N = 1206) and the Baltimore Longitudinal Study of Aging (N = 713). The top 2 single-nucleotide polymorphisms were examined for replication in the Women's Health and Aging Study (WHAS) I and II (N = 569). The single-nucleotide polymorphism most strongly associated with lower serum iron concentration was rs4820268 (P = 5.12 x 10(-9)), located in exon 13 of the transmembrane protease serine 6 (TMPRSS6) gene, an enzyme that promotes iron absorption and recycling by inhibiting hepcidin antimicrobial peptide transcription. The allele associated with lower iron concentrations was also associated with lower hemoglobin levels, smaller red cells, and more variability in red cell size (high red blood cell distribution width). Our results confirm the association of TMPRSS6 variants with iron level and provide further evidence of association with other anemia-related phenotypes. (Blood. 2010;115:94-96) C1 [Tanaka, Toshiko] NIA, Medstar Res Inst, Clin Res Branch, Baltimore, MD 21250 USA. [Roy, Cindy N.; Yao, Wenliang; Matteini, Amy; Arking, Dan; Walston, Jeremy D.] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Fried, Linda P.] Columbia Univ, Joseph L Mailman Sch Publ Hlth, New York, NY USA. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Tanaka, T (reprint author), NIA, Medstar Res Inst, Clin Res Branch, 3001 S Hanover St, Baltimore, MD 21250 USA. EM tanakato@mail.nih.gov RI Abecasis, Goncalo/B-7840-2010; Singleton, Andrew/C-3010-2009; OI Abecasis, Goncalo/0000-0003-1509-1825 FU National Institutes of Health, National Institute on Aging [263 MD 9164, 263 MD 821336, R37 AG19905, N01-AG12112]; Medstar Research Institute; Italian Ministry of Health [19982000, ICS110.1/RF97.71]; NCRR OPD-GCRC [RR00722] FX The BLSA was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. A portion of that support was through a R&D contract with Medstar Research Institute. The InCHIANTI study baseline (19982000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336). The WHAS was supported by National Institutes of Health (R37 AG19905, contract N01-AG12112, NCRR OPD-GCRC grant RR00722), and the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 25 TC 78 Z9 79 U1 2 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 7 PY 2010 VL 115 IS 1 BP 94 EP 96 DI 10.1182/blood-2009-07-232496 PG 3 WC Hematology SC Hematology GA 541CE UT WOS:000273389600017 PM 19880490 ER PT J AU Reichert, T Chowell, G Nishiura, H Christensen, RA McCullers, JA AF Reichert, Tom Chowell, Gerardo Nishiura, Hiroshi Christensen, Ronald A. McCullers, Jonathan A. TI Does Glycosylation as a modifier of Original Antigenic Sin explain the case age distribution and unusual toxicity in pandemic novel H1N1 influenza? SO BMC INFECTIOUS DISEASES LA English DT Article ID A H1N1; VIRUS INFECTION; HEMAGGLUTININ; CONCURRENT; EPIDEMIC; FAILURE; GENES; CELLS; H3N2 AB Background: A pandemic novel H1N1 swine-origin influenza virus has emerged. Most recently the World Health Organization has announced that in a country-dependent fashion, up to 15% of cases may require hospitalization, often including respiratory support. It is now clear that healthy children and young adults are disproportionately affected, most unusually among those with severe respiratory disease without underlying conditions. One possible explanation for this case age distribution is the doctrine of Original Antigenic Sin, i.e., novel H1N1 may be antigenically similar to H1N1 viruses that circulated at an earlier time. Persons whose first exposure to influenza viruses was to such similar viruses would be relatively immune. However, this principle is not sufficient to explain the graded susceptibility between ages 20 and 60, the reduced susceptibility in children below age 10, and the unusual toxicity observed. Methods: We collected case data from 11 countries, about 60% of all cases reported through mid-July 2009. We compared sequence data for the hemagglutinin of novel H1N1 with sequences of H1N1 viruses from 1918 to the present. We searched for sequence differences that imply loss of antigenicity either directly through amino acid substitution or by the appearance of sites for potential glycosylation proximal to sites known to be antigenic in humans. We also considered T-cell epitopes. Results: In our composite, over 75% of confirmed cases of novel H1N1 occurred in persons <= 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years. The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield antigenic epitopes, while T-cell epitopes were relatively unchanged. Conclusions: In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increasingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity. Several murine studies suggest specific cell types as a likely basis of the unusual toxicity. These studies also point to widely available pharmaceutical agents as plausible candidates for mitigating the toxic effects. The principle of Original Antigenic Sin modified by glycosylation appears to explain both the case age distribution and the unusual toxicity pattern of the novel H1N1 pandemic. In addition, it suggests pharmaceutical agents for immediate investigation for mitigation potential, and provides strategic guidance for the distribution of pandemic mitigation resources of all types. C1 [Reichert, Tom; Christensen, Ronald A.] Entropy Res Inst, Lincoln, MA 01773 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Nishiura, Hiroshi] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. [Nishiura, Hiroshi] Univ Utrecht, NL-3584 CL Utrecht, Netherlands. [McCullers, Jonathan A.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38104 USA. RP Reichert, T (reprint author), Entropy Res Inst, 345 S Great Rd, Lincoln, MA 01773 USA. EM treichert@entropylimited.com RI Nishiura, Hiroshi/D-1426-2011; Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Nishiura, Hiroshi/0000-0003-0941-8537 FU PHS [AI-66349]; ALSAC FX The authors wish to acknowledge financial support from the following sources: Author JAM: PHS grant AI-66349 and ALSAC. Author HN: JST PRESTO program. NR 40 TC 49 Z9 51 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JAN 7 PY 2010 VL 10 AR 5 DI 10.1186/1471-2334-10-5 PG 9 WC Infectious Diseases SC Infectious Diseases GA 557IL UT WOS:000274662700001 PM 20059763 ER PT J AU Miller, JC Davoudi, B Meza, R Slim, AC Pourbohloul, B AF Miller, Joel C. Davoudi, Bahman Meza, Rafael Slim, Anja C. Pourbohloul, Babak TI Epidemics with general generation interval distributions SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Epidemic; Generation interval; Stochastic growth; Deterministic growth ID DEPENDENT BRANCHING PROCESS; INFECTIOUS PERIODS; REALISTIC DISTRIBUTIONS; MODELS; DYNAMICS; EQUATION; DISEASE; AIDS AB We study the spread of susceptible-infected-recovered (SIR) infectious diseases where an individual's infectiousness and probability of recovery depend on his/her "age" of infection. We focus first on early outbreak stages when stochastic effects dominate and show that epidemics tend to happen faster than deterministic calculations predict. If an outbreak is sufficiently large, stochastic effects are negligible and we modify the standard ordinary differential equation (ODE) model to accommodate age-of-infection effects. We avoid the use of partial differential equations which typically appear in related models. We introduce a "memoryless" ODE system which approximates the true solutions. Finally, we analyze the transition from the stochastic to the deterministic phase. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Miller, Joel C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Miller, Joel C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Miller, Joel C.; Davoudi, Bahman; Meza, Rafael; Pourbohloul, Babak] British Columbia Ctr Dis Control, Div Math Modeling, Vancouver, BC, Canada. [Pourbohloul, Babak] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Slim, Anja C.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Miller, JC (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM joel.c.miller.research@gmail.com RI Miller, Joel/C-4229-2015 OI Miller, Joel/0000-0003-4426-0405 FU Canadian Institutes of Health Research (CIHR) [PTL-93146, PAP-93425, MOP-81273]; Michael Smith Foundation for Health Research (MSFHR); Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX BP would like to acknowledge the support of Canadian Institutes of Health Research (CIHR) (Grants nos. PTL-93146, PAP-93425 and MOP-81273) and the Michael Smith Foundation for Health Research (MSFHR) (Senior Scholar Funds). JCM, BD, and RM were supported by these grants.; JCM was additionally supported by the RAPIDD Program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 24 TC 7 Z9 7 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD JAN 7 PY 2010 VL 262 IS 1 BP 107 EP 115 DI 10.1016/j.jtbi.2009.08.007 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 557CR UT WOS:000274646600011 PM 19679141 ER PT J AU Davis, RE Ngo, VN Lenz, G Tolar, P Young, RM Romesser, PB Kohlhammer, H Lamy, L Zhao, H Yang, YD Xu, WH Shaffer, AL Wright, G Xiao, WM Powell, J Jiang, JK Thomas, CJ Rosenwald, A Ott, G Muller-Hermelink, HK Gascoyne, RD Connors, JM Johnson, NA Rimsza, LM Campo, E Jaffe, ES Wilson, WH Delabie, J Smeland, EB Fisher, RI Braziel, RM Tubbs, RR Cook, JR Weisenburger, DD Chan, WC Pierce, SK Staudt, LM AF Davis, R. Eric Ngo, Vu N. Lenz, Georg Tolar, Pavel Young, Ryan M. Romesser, Paul B. Kohlhammer, Holger Lamy, Laurence Zhao, Hong Yang, Yandan Xu, Weihong Shaffer, Arthur L. Wright, George Xiao, Wenming Powell, John Jiang, Jian-Kang Thomas, Craig J. Rosenwald, Andreas Ott, German Muller-Hermelink, Hans Konrad Gascoyne, Randy D. Connors, Joseph M. Johnson, Nathalie A. Rimsza, Lisa M. Campo, Elias Jaffe, Elaine S. Wilson, Wyndham H. Delabie, Jan Smeland, Erlend B. Fisher, Richard I. Braziel, Rita M. Tubbs, Raymond R. Cook, J. R. Weisenburger, Dennis D. Chan, Wing C. Pierce, Susan K. Staudt, Louis M. TI Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma SO NATURE LA English DT Article ID ANTIGEN RECEPTOR; IG-ALPHA; TYROSINE KINASE; INTERNALIZATION; IMMUNOGLOBULIN; INHIBITORS; INITIATION; MOLECULE; SURVIVAL; TARGET AB A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas(1,2) and by engineering mouse models(3), but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappa B pathway activity and survival in ABC DLBCL4. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappa B-5, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wildtype CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules(6) of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies. C1 [Davis, R. Eric; Ngo, Vu N.; Lenz, Georg; Young, Ryan M.; Romesser, Paul B.; Kohlhammer, Holger; Lamy, Laurence; Zhao, Hong; Yang, Yandan; Xu, Weihong; Shaffer, Arthur L.; Wilson, Wyndham H.; Staudt, Louis M.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tolar, Pavel; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Romesser, Paul B.] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. [Wright, George] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Xiao, Wenming; Powell, John] NIH, Bioinformat & Mol Anal Sect, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NHGRI, NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Rosenwald, Andreas; Muller-Hermelink, Hans Konrad] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany. [Gascoyne, Randy D.; Connors, Joseph M.; Johnson, Nathalie A.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Rimsza, Lisa M.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, J. R.] SW Oncol Grp, Ann Arbor, MI 48106 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Delabie, Jan] Rikshosp Univ Hosp, Pathol Clin, N-0310 Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Rikshosp Univ Hosp, Inst Canc Res, N-0310 Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Ctr Canc Biomed, Fac Div, Norwegian Radium Hosp, N-0310 Oslo, Norway. [Fisher, Richard I.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Tubbs, Raymond R.; Cook, J. R.] Cleveland Clin Pathol, Cleveland, OH 44195 USA. [Tubbs, Raymond R.; Cook, J. R.] Inst Lab Med, Cleveland, OH 44195 USA. [Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA. [Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Microbiol, Omaha, NE 68198 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Lenz, Georg/I-6844-2012 OI Romesser, Paul/0000-0001-8268-2903; Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793; FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; National Institute of Allergy and Infectious Disease; National Human Genome Research Institute FX We thank L. Honigberg for PCI-32765, L. Dang for IKK-beta inhibitors, S. Ansher for dasatinib, and S. Tohda for the TMD8 cell line. This research was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, the Center for Cancer Research, the National Institute of Allergy and Infectious Disease, and the National Human Genome Research Institute. P. B. R. was a Howard Hughes Medical Institute-National Institutes of Health Research Scholar. NR 32 TC 583 Z9 602 U1 6 U2 56 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 7 PY 2010 VL 463 IS 7277 BP 88 EP U97 DI 10.1038/nature08638 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 540OV UT WOS:000273344900036 PM 20054396 ER PT J AU Sleiman, PMA Flory, J Imielinski, M Bradfield, JP Annaiah, K Willis-Owen, SAG Wang, K Rafaels, NM Michel, S Bonnelykke, K Zhang, HT Kim, CE Frackelton, EC Glessner, JT Hou, CP Otieno, FG Santa, E Thomas, K Smith, RM Glaberson, WR Garris, M Chiavacci, RM Beaty, TH Ruczinski, I Orange, JM Allen, J Spergel, JM Grundmeier, R Mathias, RA Christie, JD von Mutius, E Cookson, WOC Kabesch, M Moffatt, MF Grunstein, MM Barnes, KC Devoto, M Magnusson, M Li, HZ Grant, SFA Bisgaard, H Hakonarson, H AF Sleiman, Patrick M. A. Flory, James Imielinski, Marcin Bradfield, Jonathan P. Annaiah, Kiran Willis-Owen, Saffron A. G. Wang, Kai Rafaels, Nicholas M. Michel, Sven Bonnelykke, Klaus Zhang, Haitao Kim, Cecilia E. Frackelton, Edward C. Glessner, Joseph T. Hou, Cuiping Otieno, F. George Santa, Erin Thomas, Kelly Smith, Ryan M. Glaberson, Wendy R. Garris, Maria Chiavacci, Rosetta M. Beaty, Terri H. Ruczinski, Ingo Orange, Jordan M. Allen, Julian Spergel, Jonathan M. Grundmeier, Robert Mathias, Rasika A. Christie, Jason D. von Mutius, Erika Cookson, William O. C. Kabesch, Michael Moffatt, Miriam F. Grunstein, Michael M. Barnes, Kathleen C. Devoto, Marcella Magnusson, Mark Li, Hongzhe Grant, Struan F. A. Bisgaard, Hans Hakonarson, Hakon TI Variants of DENND1B Associated with Asthma in Children SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHILDHOOD ASTHMA; SUSCEPTIBILITY GENES; ORMDL3 EXPRESSION; CELL SUBSETS; DROSOPHILA; DENN/MADD; PROTEIN AB BACKGROUND Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P = 8.55 x 10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P = 9.3 x 10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P = 1.6 x 10(-13) for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor. CONCLUSIONS We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma. C1 [Sleiman, Patrick M. A.; Flory, James; Imielinski, Marcin; Bradfield, Jonathan P.; Annaiah, Kiran; Wang, Kai; Zhang, Haitao; Kim, Cecilia E.; Frackelton, Edward C.; Glessner, Joseph T.; Hou, Cuiping; Otieno, F. George; Santa, Erin; Thomas, Kelly; Smith, Ryan M.; Glaberson, Wendy R.; Garris, Maria; Chiavacci, Rosetta M.; Grant, Struan F. A.; Hakonarson, Hakon] Ctr Appl Gen, Philadelphia, PA 19104 USA. [Orange, Jordan M.; Spergel, Jonathan M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Allen, Julian; Grunstein, Michael M.; Hakonarson, Hakon] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Pulm Med, Philadelphia, PA 19104 USA. [Devoto, Marcella; Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Human Genet, Philadelphia, PA 19104 USA. [Grundmeier, Robert] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Christie, Jason D.] Univ Penn, Sch Med, Div Pulm Med, Philadelphia, PA 19104 USA. [Orange, Jordan M.; Spergel, Jonathan M.; Grundmeier, Robert; Grunstein, Michael M.; Magnusson, Mark; Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Li, Hongzhe] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Willis-Owen, Saffron A. G.; Cookson, William O. C.; Moffatt, Miriam F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Rafaels, Nicholas M.; Beaty, Terri H.; Ruczinski, Ingo; Barnes, Kathleen C.] Johns Hopkins Univ, Baltimore, MD USA. [Mathias, Rasika A.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [von Mutius, Erika] Univ Munich, Munich, Germany. [Michel, Sven; Kabesch, Michael] Hannover Med Sch, Clin Paediat Pneumol & Neonatol, D-3000 Hannover, Germany. [Bonnelykke, Klaus; Bisgaard, Hans] Copenhagen Univ Hosp, Fac Hlth Sci, Copenhagen Prospect Studies Asthma Childhood, Gentofte, Denmark. RP Hakonarson, H (reprint author), Ctr Appl Gen, 1216E Abramson Res Ctr,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM hakonarson@email.chop.edu RI Kronow, Joern/B-1054-2011; Bisgaard, Hans/N-4761-2016; OI Bisgaard, Hans/0000-0003-4131-7592; Spergel, Jonathan/0000-0002-4658-5353; von Mutius, Erika/0000-0002-8893-4515 FU Children's Hospital of Philadelphia; state of Pennsylvania [4100042728]; Cotswold Foundation; Lundbeck Foundation; National Human Genome Research Institute, National Institutes of Health; Mary Beryl Patch Turnbull Scholar program FX Supported by an Institute Development Award from Children's Hospital of Philadelphia (to Dr. Hakonarson), a grant from the state of Pennsylvania (4100042728, to Drs. Hakonarson and Grant), a Research Development Award from the Cotswold Foundation (to Drs. Hakonarson and Grant), and grants from the Lundbeck Foundation (to Dr. Sleiman) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (to Dr. Mathias). Dr. Barnes was supported in part by the Mary Beryl Patch Turnbull Scholar program. NR 26 TC 169 Z9 174 U1 0 U2 19 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 7 PY 2010 VL 362 IS 1 BP 36 EP 44 DI 10.1056/NEJMoa0901867 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 540PA UT WOS:000273345500007 PM 20032318 ER PT J AU O'Connell, MP Fiori, JL Xu, M Carter, AD Frank, BP Camilli, TC French, AD Dissanayake, SK Indig, FE Bernier, M Taub, DD Hewitt, SM Weeraratna, AT AF O'Connell, M. P. Fiori, J. L. Xu, M. Carter, A. D. Frank, B. P. Camilli, T. C. French, A. D. Dissanayake, S. K. Indig, F. E. Bernier, M. Taub, D. D. Hewitt, S. M. Weeraratna, A. T. TI The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma SO ONCOGENE LA English DT Article DE Ror2; Wnt5A; melanoma; metastasis; endosome; clathrin ID RECESSIVE ROBINOW-SYNDROME; BREAST-CANCER METASTASIS; BRACHYDACTYLY TYPE-B; GENE-EXPRESSION; PROSTATE-CANCER; CELL-MIGRATION; PATHWAY; INHIBITION; ACTIVATION; MOTILITY AB Tyrosine kinase receptors represent targets of great interest for cancer therapy. Here we show, for the first time, the importance of the orphan tyrosine kinase receptor, ROR2, in melanoma progression. Using melanoma tissue microarrays, we show that ROR2 is expressed predominantly in metastatic melanoma. As ROR2 has been shown to specifically interact with the non-canonical Wnt ligand, Wnt5A, this corroborates our earlier data implicating Wnt5A as a mediator of melanoma metastasis. We show here that increases in Wnt5A cause increases in ROR2 expression, as well as the PKC-dependent, clathrin-mediated internalization of ROR2. WNT5A knockdown by siRNA decreases ROR2 expression, but silencing of ROR2 has no effect on WNT5A levels. ROR2 knockdown does, however, result in a decrease in signaling downstream of Wnt5A. Using in vitro and in vivo metastasis assays, we show that ROR2 is necessary for the Wnt5A-mediated metastasis of melanoma cells. These data imply that ROR2 may represent a novel target for melanoma therapy. C1 [Weeraratna, A. T.] NIA, Immunol Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Fiori, J. L.; Bernier, M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Indig, F. E.] NIA, Confocal Imaging Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Hewitt, S. M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Weeraratna, AT (reprint author), NIA, Immunol Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Rm 08C226, Baltimore, MD 21224 USA. EM prubinstein@nybloodcenter.org OI Hewitt, Stephen/0000-0001-8283-1788; Bernier, Michel/0000-0002-5948-368X FU National Institute on Aging, Baltimore, USA [MD 21224] FX We thank Ms Ana Lustig for assistance with animal experiments. This work was supported by the Intramural Research Program of the National Institute on Aging, Baltimore, MD 21224, USA. NR 36 TC 89 Z9 91 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 7 PY 2010 VL 29 IS 1 BP 34 EP 44 DI 10.1038/onc.2009.305 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 540XE UT WOS:000273373500004 PM 19802008 ER PT J AU Yuan, SA Roney, CA Wierwille, J Chen, CW Xu, BY Griffiths, G Jiang, J Ma, HZ Cable, A Summers, RM Chen, Y AF Yuan, Shuai Roney, Celeste A. Wierwille, Jeremiah Chen, Chao-Wei Xu, Biying Griffiths, Gary Jiang, James Ma, Hongzhou Cable, Alex Summers, Ronald M. Chen, Yu TI Co-registered optical coherence tomography and fluorescence molecular imaging for simultaneous morphological and molecular imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID EARLY BLADDER-CANCER; NEOPLASTIC PROCESSES; WAVELENGTH RANGE; COLON-CANCER; SOFT-TISSUE; 2200 NM; MODEL; SPECTROSCOPY; DYSPLASIA; DIAGNOSIS AB Optical coherence tomography (OCT) provides high-resolution, cross-sectional imaging of tissue microstructure in situ and in real time, while fluorescence molecular imaging (FMI) enables the visualization of basic molecular processes. There is a great deal of interest in combining these two modalities so that the tissue's structural and molecular information can be obtained simultaneously. This could greatly benefit biomedical applications such as detecting early diseases and monitoring therapeutic interventions. In this research, an optical system that combines OCT and FMI was developed. The system demonstrated that it could co-register en face OCT and FMI images with a 2.4 x 2.4 mm(2) field-of-view. The transverse resolutions of OCT and FMI of the system are both similar to 10 mu m. Capillary tubes filled with fluorescent dye Cy 5.5 in different concentrations under a scattering medium are used as the phantom. En face OCT images of the phantoms were obtained and successfully co-registered with FMI images that were acquired simultaneously. A linear relationship between FMI intensity and dye concentration was observed. The relationship between FMI intensity and target fluorescence tube depth measured by OCT images was also observed and compared with theoretical modeling. This relationship could help in correcting reconstructed dye concentration. Imaging of colon polyps of the APC(min) mouse model is presented as an example of biological applications of this co-registered OCT/FMI system. C1 [Roney, Celeste A.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Yuan, Shuai; Wierwille, Jeremiah; Chen, Chao-Wei; Chen, Yu] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. [Xu, Biying; Griffiths, Gary] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. [Jiang, James; Ma, Hongzhou; Cable, Alex] Thorlabs Inc, Newton, NJ 07860 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 1C368X MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov; yuchen@umd.edu RI Yuan, Shuai/A-5783-2011 FU Nano-Biotechnology Award of the State of Maryland; Minta Martin Foundation; University of Maryland; UMB-UMCP SEED Grant Program; Prevent Cancer Foundation; NIH FX This work is supported by the Nano-Biotechnology Award of the State of Maryland, the Minta Martin Foundation, and the General Research Board (GRB) Award of the University of Maryland, the UMB-UMCP SEED Grant Program and the Prevent Cancer Foundation. The authors acknowledge Professor Chi Lee of the Department of Electrical and Computer Engineering at the University of Maryland for equipment support, and Qian Li and Michael Lai for technical assistance. RS acknowledges the support from the intramural research program of the Clinical Center, NIH. NR 45 TC 32 Z9 32 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JAN 7 PY 2010 VL 55 IS 1 BP 191 EP 206 DI 10.1088/0031-9155/55/1/011 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 531BN UT WOS:000272637800011 PM 20009192 ER PT J AU Chen, PW Randazzo, PA Parent, CA AF Chen, Pei-Wen Randazzo, Paul A. Parent, Carole A. TI ACAP-A/B Are ArfGAP Homologs in Dictyostelium Involved in Sporulation but Not in Chemotaxis SO PLOS ONE LA English DT Article ID GTPASE-ACTIVATING PROTEIN; ADP-RIBOSYLATION FACTOR; CELL-MIGRATION; ACTIN CYTOSKELETON; BINDING PROTEINS; ASAP1; LOCALIZATION; GAP; CANCER; PHOSPHORYLATION AB Arfs and Arf GTPase-activating proteins (ArfGAPs) are regulators of membrane trafficking and actin dynamics in mammalian cells. In this study, we identified a primordial Arf, ArfA, and two ArfGAPs (ACAP-A/B) containing BAR, PH, ArfGAP and Ankyrin repeat domains in the eukaryote Dictyostelium discoideum. In vitro, ArfA has similar nucleotide binding properties as mammalian Arfs and, with GTP bound, is a substrate for ACAP-A and B. We also investigated the physiological functions of ACAP-A/B by characterizing cells lacking both ACAP-A and B. Although ACAP-A/B knockout cells showed no defects in cell growth, migration or chemotaxis, they exhibited abnormal actin protrusions and similar to 50% reduction in spore yield. We conclude that while ACAP-A/B have a conserved biochemical mechanism and effect on actin organization, their role in migration is not conserved. The absence of an effect on Dictyostelium migration may be due to a specific requirement for ACAPs in mesenchymal migration, which is observed in epithelial cancer cells where most studies of mammalian ArfGAPs were performed. C1 [Chen, Pei-Wen; Randazzo, Paul A.; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. RP Chen, PW (reprint author), NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov RI Chen, Pei-Wen/B-7142-2015 FU National Cancer Institute, National Institutes of Health [Z01-BC-007365] FX The work was supported by the intramural program of the National Cancer Institute, National Institutes of Health, project Z01-BC-007365. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 7 Z9 7 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 7 PY 2010 VL 5 IS 1 AR e8624 DI 10.1371/journal.pone.0008624 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 541KN UT WOS:000273414100011 PM 20062541 ER PT J AU Nishiura, H Chowell, G Safan, M Castillo-Chavez, C AF Nishiura, Hiroshi Chowell, Gerardo Safan, Muntaser Castillo-Chavez, Carlos TI Pros and cons of estimating the reproduction number from early epidemic growth rate of influenza A (H1N1) 2009 SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Article ID INFECTIOUS-DISEASES; SOCIAL CONTACTS; MODELS; TRANSMISSION; SPREAD; VIRUS; VACCINATION; DYNAMICS; INTERVAL; A(H1N1) AB Background: In many parts of the world, the exponential growth rate of infections during the initial epidemic phase has been used to make statistical inferences on the reproduction number, R, a summary measure of the transmission potential for the novel influenza A (H1N1) 2009. The growth rate at the initial stage of the epidemic in Japan led to estimates for R in the range 2.0 to 2.6, capturing the intensity of the initial outbreak among school-age children in May 2009. Methods: An updated estimate of R that takes into account the epidemic data from 29 May to 14 July is provided. An age-structured renewal process is employed to capture the age-dependent transmission dynamics, jointly estimating the reproduction number, the age-dependent susceptibility and the relative contribution of imported cases to secondary transmission. Pitfalls in estimating epidemic growth rates are identified and used for scrutinizing and re-assessing the results of our earlier estimate of R. Results: Maximum likelihood estimates of R using the data from 29 May to 14 July ranged from 1.21 to 1.35. The next-generation matrix, based on our age-structured model, predicts that only 17.5% of the population will experience infection by the end of the first pandemic wave. Our earlier estimate of R did not fully capture the population-wide epidemic in quantifying the next-generation matrix from the estimated growth rate during the initial stage of the pandemic in Japan. Conclusions: In order to quantify R from the growth rate of cases, it is essential that the selected model captures the underlying transmission dynamics embedded in the data. Exploring additional epidemiological information will be useful for assessing the temporal dynamics. Although the simple concept of R is more easily grasped by the general public than that of the next-generation matrix, the matrix incorporating detailed information (e.g., age-specificity) is essential for reducing the levels of uncertainty in predictions and for assisting public health policymaking. Model-based prediction and policymaking are best described by sharing fundamental notions of heterogeneous risks of infection and death with non-experts to avoid potential confusion and/or possible misuse of modelling results. C1 [Nishiura, Hiroshi] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. [Nishiura, Hiroshi] Univ Utrecht, NL-3584 CL Utrecht, Netherlands. [Chowell, Gerardo; Castillo-Chavez, Carlos] Arizona State Univ, Math & Computat Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85282 USA. [Chowell, Gerardo] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Safan, Muntaser] Mansoura Univ, Fac Sci, Dept Math, Mansoura 35516, Egypt. [Castillo-Chavez, Carlos] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Nishiura, H (reprint author), Japan Sci & Technol Agcy, PRESTO, Honcho 4-1-8, Kawaguchi, Saitama 3320012, Japan. EM h.nishiura@uu.nl RI Chowell, Gerardo/F-5038-2012; Castillo-Chavez, Carlos/E-1412-2014; OI Chowell, Gerardo/0000-0003-2194-2251; Castillo-Chavez, Carlos/0000-0002-1046-3901; Safan, Muntaser/0000-0001-7652-0094; Nishiura, Hiroshi/0000-0003-0941-8537 FU JST PRESTO program FX The work of H Nishiura was supported by the JST PRESTO program. The authors are grateful to the editor and the three reviewers for their useful comments, advices and expediting publication of this article. NR 46 TC 71 Z9 71 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD JAN 7 PY 2010 VL 7 AR 1 DI 10.1186/1742-4682-7-1 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 555DA UT WOS:000274486400001 PM 20056004 ER PT J AU Yu, X Wang, JD Yang, JC Wang, QM Cheng, SZD Nussinov, R Zheng, J AF Yu, Xiang Wang, Jingdai Yang, Jui-Chen Wang, Qiuming Cheng, Stephen Z. D. Nussinov, Ruth Zheng, Jie TI Atomic-Scale Simulations Confirm that Soluble beta-Sheet-Rich Peptide Self-Assemblies Provide Amyloid Mimics Presenting Similar Conformational Properties SO BIOPHYSICAL JOURNAL LA English DT Article ID SOLID-STATE NMR; MOLECULAR-DYNAMICS SIMULATIONS; ALZHEIMERS-DISEASE; FIBRIL FORMATION; SEQUENCE; BETA(2)-MICROGLOBULIN; AGGREGATION; STABILITY; THERMODYNAMICS; PROTOFILAMENTS AB The peptide self-assembly mimic (PSAM) from the outer surface protein A (OspA) can form highly stable but soluble beta-rich self-assembly-like structures similar to those formed by native amyloid-forming peptides. However, unlike amyloids that predominantly form insoluble aggregates, PSAMs are highly water-soluble. Here, we characterize the conformations of these soluble beta-sheet-rich assemblies. We simulate PSAMs with different-sized beta-sheets in the presence and absence of end-capping proteins using all-atom explicit-solvent molecular dynamics, comparing the structural stability, conformational dynamics, and association force. Structural and free-energy comparisons among beta-sheets with different numbers of layers and sequences indicate that in similarity to amyloids, the intersheet side chain-side chain interactions and hydrogen bonds combined with intrasheet salt bridges are the major driving forces in stabilizing the overall structural organization. A detailed structural analysis shows that in similarity to amyloids fibrils, all wild-type and mutated PSAM structures display twisted and bent beta-sheets to some extent, implying that a twisted and bent beta-sheet is a general motif of beta-rich assemblies. Thus, our studies indicate that soluble beta-sheet-rich peptide self-assemblies can provide good amyloid mimics, and as such confirm on the atomic scale that they are excellent systems for amyloid studies. These results provide further insight into the usefulness of such mimics for nanostructure design. C1 [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21701 USA. [Wang, Jingdai] Zhejiang Univ, Dept Chem Engn, Hangzhou 310003, Zhejiang, Peoples R China. [Yu, Xiang; Yang, Jui-Chen; Wang, Qiuming; Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Cheng, Stephen Z. D.] Univ Akron, Dept Polymer Sci, Akron, OH 44325 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21701 USA. EM ruthnu@helix.nih.gov; zhengj@uakron.edu RI Yu, Xiang/A-9765-2012; Zheng, Jie/B-5057-2013; Wang, Qiuming/E-6254-2014 OI Yu, Xiang/0000-0002-0486-1110; Zheng, Jie/0000-0003-1547-3612; FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 42 TC 8 Z9 8 U1 1 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JAN 6 PY 2010 VL 98 IS 1 BP 27 EP 36 DI 10.1016/j.bpj.2009.10.003 PG 10 WC Biophysics SC Biophysics GA 541QQ UT WOS:000273433800004 PM 20085717 ER PT J AU Wess, J AF Wess, Juergen TI More Is Not Always Better: alpha(2A)-Adrenoceptor Expression in Type 2 Diabetes SO CELL METABOLISM LA English DT Editorial Material ID BETA-CELL FUNCTION; IN-VIVO; GLUCOSE-HOMEOSTASIS; INSULIN-SECRETION; KNOCKOUT MICE; RECEPTORS AB Various members of the G protein-coupled receptor (GPCR) superfamily are known to modulate the release of insulin from pancreatic beta cells. Rosengren and colleagues have recently provided convincing evidence for a role of increased expression of the alpha(2A)-adrenoceptor in beta cells in the pathogenesis of type 2 diabetes. C1 NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Mol Signaling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NR 10 TC 3 Z9 3 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JAN 6 PY 2010 VL 11 IS 1 BP 3 EP 5 DI 10.1016/j.cmet.2009.12.002 PG 3 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 543YJ UT WOS:000273617000003 PM 20085729 ER PT J AU McNally, JG Mazza, D AF McNally, James G. Mazza, Davide TI Fractal geometry in the nucleus SO EMBO JOURNAL LA English DT Editorial Material AB In his groundbreaking work, 'The Fractal Geometry of Nature' (Mandelbrot, 1982), Benoit Mandelbrot described how fractals could account for a long list of natural forms ranging from trees to coastlines. Two recent studies in Science and The EMBO Journal have suggested that chromatin and the nucleoplasmic space surrounding it should be added to the fractal list. C1 [McNally, James G.; Mazza, Davide] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP McNally, JG (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov RI Mazza, Davide/F-9536-2011; Mazza, Davide/R-5340-2016 OI Mazza, Davide/0000-0003-2776-4142 NR 5 TC 29 Z9 31 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 6 PY 2010 VL 29 IS 1 BP 2 EP 3 DI 10.1038/emboj.2009.375 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 540SC UT WOS:000273358100002 PM 20051993 ER PT J AU Drazen, JM Van der Weyden, MB Sahni, P Rosenberg, J Marusic, A Laine, C Kotzin, S Horton, R Hebert, PC Haug, C Godlee, F Frizelle, FA de Leeuw, PW DeAngelis, CD AF Drazen, Jeffrey M. Van der Weyden, Martin B. Sahni, Peush Rosenberg, Jacob Marusic, Ana Laine, Christine Kotzin, Sheldon Horton, Richard Hebert, Paul C. Haug, Charlotte Godlee, Fiona Frizelle, Frank A. de Leeuw, Peter W. DeAngelis, Catherine D. TI Uniform Format for Disclosure of Competing Interests in ICMJE Journals SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kotzin, Sheldon] Natl Lib Med, Bethesda, MD 20894 USA. RI Marusic, Ana/E-7683-2013 OI Marusic, Ana/0000-0001-6272-0917 NR 0 TC 17 Z9 18 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 6 PY 2010 VL 303 IS 1 BP 75 EP 76 DI 10.1001/jama.209.1542 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 539YS UT WOS:000273296900026 PM 19826011 ER PT J AU Dobi, A Margolis, EB Wang, HL Harvey, BK Morales, M AF Dobi, Alice Margolis, Elyssa B. Wang, Hui-Ling Harvey, Brandon K. Morales, Marisela TI Glutamatergic and Nonglutamatergic Neurons of the Ventral Tegmental Area Establish Local Synaptic Contacts with Dopaminergic and Nondopaminergic Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RAT SUBSTANTIA-NIGRA; TYROSINE-HYDROXYLASE; IMMUNOCYTOCHEMICAL LOCALIZATION; NEUROMUSCULAR JUNCTION; PHOSPHATE TRANSPORTER; ELECTRON-MICROSCOPY; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; IN-VITRO; SYNAPSES AB The ventral tegmental area (VTA) contributes to reward and motivation signaling. In addition to the well established populations of dopamine (DA) or GABA VTA neurons, glutamatergic neurons were recently discovered in the VTA. These glutamatergic neurons express the vesicular glutamate transporter 2, VGluT2. To investigate whether VTA glutamatergic neurons establish local synapses, we tagged axon terminals from resident VTA neurons by intra-VTA injection of Phaseolus vulgaris leucoagglutinin (PHA-L) or an adenoassociated virus encoding wheat germ agglutinin (WGA) and by immunoelectron microscopy determined the presence of VGluT2 in PHA-L- or WGA-positive terminals. We found that PHA-L- or WGA-positive terminals from tagged VTA cells made asymmetric or symmetric synapses within the VTA. VGluT2 immunoreactivity was detected in the vast majority of PHA-L- or WGA-positive terminals forming asymmetric synapses. These results indicate that both VTA glutamatergic and nonglutamatergic ( likely GABAergic) neurons establish local synapses. To examine the possible DAergic nature of postsynaptic targets of VTA glutamatergic neurons, we did triple immunolabeling with antibodies against VGluT2, tyrosine hydroxylase (TH), and PHA-L. From triple-labeled tissue, we found that double-labeled PHA-L (+)/VGluT2(+) axon terminals formed synaptic contacts on dendrites of both TH-positive and TH-negative cells. Consistent with these anatomical observations, in whole-cell slice recordings of VTA neurons we observed that blocking action potential activity significantly decreased the frequency of synaptic glutamatergic events in DAergic and non-DAergic neurons. These observations indicate that resident VTA glutamatergic neurons are likely to affect both DAergic and non-DAergic neurotransmission arising from the VTA. C1 [Morales, Marisela] NIDA, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Margolis, Elyssa B.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. RP Morales, M (reprint author), NIDA, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mmorales@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010 FU National Institute on Drug Abuse; State of California for medical research on alcohol and substance abuse through the University of California, San Francisco FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse. E.B.M. was supported by funds from the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco. We thank Doug Howard for assistance with viral vector preparation. NR 69 TC 94 Z9 95 U1 0 U2 5 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 JAN 6 PY 2010 VL 30 IS 1 BP 218 EP 229 DI 10.1523/JNEUROSCI.3884-09.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 540PN UT WOS:000273347300023 PM 20053904 ER PT J AU Hartge, P AF Hartge, Patricia TI Designing Early Detection Programs for Ovarian Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Hartge, P (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Rm 8090, Bethesda, MD 20892 USA. EM hartgep@mail.nih.gov NR 2 TC 12 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 6 PY 2010 VL 102 IS 1 BP 3 EP 3 DI 10.1093/jnci/djp450 PG 1 WC Oncology SC Oncology GA 542NH UT WOS:000273500400001 PM 20042718 ER PT J AU Chakrabarti, S Panchenko, AR AF Chakrabarti, Saikat Panchenko, Anna R. TI Structural and Functional Roles of Coevolved Sites in Proteins SO PLOS ONE LA English DT Article ID INFORMATION-THEORETIC ANALYSIS; AMINO-ACID SUBSTITUTIONS; MUTUAL INFORMATION; CORRELATED MUTATIONS; RESIDUES; COEVOLUTION; EVOLUTION; IDENTIFICATION; COVARIATION; ALIGNMENTS AB Background: Understanding the residue covariations between multiple positions in protein families is very crucial and can be helpful for designing protein engineering experiments. These simultaneous changes or residue coevolution allow protein to maintain its overall structural-functional integrity while enabling it to acquire specific functional modifications. Despite the significant efforts in the field there is still controversy in terms of the preferable locations of coevolved residues on different regions of protein molecules, the strength of coevolutionary signal and role of coevolution in functional diversification. Methodology: In this paper we study the scale and nature of residue coevolution in maintaining the overall functionality and structural integrity of proteins. We employed a large scale study to investigate the structural and functional aspects of coevolved residues. We found that the networks representing the coevolutionary residue connections within our dataset are in general of 'small-world' type as they have clustering coefficient values higher than random networks and also show smaller mean shortest path lengths similar and/or lower than random and regular networks. We also found that altogether 11% of functionally important sites are coevolved with any other sites. Active sites are found more frequently to coevolve with any other sites (15%) compared to protein (11%) and ligand (9%) binding sites. Metal binding and active sites are also found to be more frequently coevolved with other metal binding and active sites, respectively. Analysis of the coupling between coevolutionary processes and the spatial distribution of coevolved sites reveals that a high fraction of coevolved sites are located close to each other. Moreover, similar to 80% of charge compensatory substitutions within coevolved sites are found at very close spatial proximity (< = 5 angstrom), pointing to the possible preservation of salt bridges in evolution. Conclusion: Our findings show that a noticeable fraction of functionally important sites undergo coevolution and also point towards compensatory substitutions as a probable coevolutionary mechanism within spatially proximal coevolved functional sites. C1 [Chakrabarti, Saikat; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Chakrabarti, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM chakraba@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov FU National Library of Medicine at National Institutes of Health/DHHS FX This work was supported by the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 22 Z9 22 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2010 VL 5 IS 1 AR e8591 DI 10.1371/journal.pone.0008591 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 540NF UT WOS:000273338600014 PM 20066038 ER PT J AU Kastrinsky, DB Barry, CE AF Kastrinsky, David B. Barry, Clifton E., III TI Synthesis of labeled meropenem for the analysis of M. tuberculosis transpeptidases SO TETRAHEDRON LETTERS LA English DT Article ID BETA-LACTAM RESISTANCE; MYCOBACTERIAL CELL-WALL; ENTEROCOCCUS-FAECIUM; PEPTIDOGLYCAN; ANTIBIOTICS; PENICILLIN; MECHANISM; BIOSYNTHESIS; CLAVULANATE; INHIBITION AB A concise synthesis of (14)C labeled meropenem prepared from (14)C dimethylamine hydrochloride is described. Using a similar reaction sequence, the meropenem nucleus was also attached to biotin providing a probe for protein interaction studies. Published by Elsevier Ltd. C1 [Kastrinsky, David B.; Barry, Clifton E., III] NIAID, NIH, TB Res Sect, Bethesda, MD 20892 USA. RP Barry, CE (reprint author), NIAID, NIH, TB Res Sect, Bethesda, MD 20892 USA. EM cbarry@mail.nih.gov RI Barry, III, Clifton/H-3839-2012 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We gratefully acknowledge Dr. Kriti Arora and Dr. Pradeep Kumar for help with scintillation counts and biological studies. We would like to thank Dr. Bong-Jin Kim of the Korean Research Institute for Chemical Technology (KRICT) for helpful suggestions and Dr. Noel Whittaker of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) for high resolution mass spectral analysis. Funding was provided by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 30 TC 4 Z9 4 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 6 PY 2010 VL 51 IS 1 BP 197 EP 200 DI 10.1016/j.tetlet.2009.10.124 PG 4 WC Chemistry, Organic SC Chemistry GA 551TC UT WOS:000274232200053 PM 20161438 ER PT J AU Kuepper, Y Alexander, N Osinsky, R Mueller, E Schmitz, A Netter, P Hennig, J AF Kuepper, Yvonne Alexander, Nina Osinsky, Roman Mueller, Eva Schmitz, Anja Netter, Petra Hennig, Juergen TI Aggression-Interactions of serotonin and testosterone in healthy men and women SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Aggression; Serotonin; Testosterone; Gender; S-citalopram; Challenge test ID NEUROENDOCRINE CHALLENGE-TESTS; CSF TESTOSTERONE; D-FENFLURAMINE; SELF-ESTEEM; CITALOPRAM; BEHAVIOR; RESPONSIVITY; IMPULSIVITY; HYPOTHESIS; HOSTILITY AB Serotonin (5-HT) and testosterone (T) have both been implicated in the regulation of aggression. Findings in humans however are very inconclusive, with respect to main effects of either system. Animal models implicate T to modulate 5-HT system activity, and furthermore have shown behaviorally relevant interactions of T and 5-HT with respect to aggression. We tested for associations between habitual T-level and 5-HT system activity, as well as behaviorally relevant interactions of T and 5-HT with respect to trait aggression in 48 healthy male and female subjects. 5-HT activity was measured by means of neuroendocrine challenge paradigm with S-citalopram. T-levels were measured in saliva samples. Trait aggression was assessed by self-report measures. T-levels were not associated with indices of central 5-HT activity. Results showed significant interaction effects between 5-HT and T for trait aggression in men only (p < 0.05). Trait aggression was significantly higher in the combinations "high T+high cortisol responses" (indicating decreased 5-HT availability), and "low T+low cortisol responses" (indicating increased 5-HT availability), after S-citalopram. Results support the notion of behaviorally relevant interactions between T and 5-HT, with respect to aggression in humans, but also indicate the need for further studies. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kuepper, Yvonne; Alexander, Nina; Osinsky, Roman; Mueller, Eva; Netter, Petra; Hennig, Juergen] Univ Giessen, Dept Psychol, Ctr Psychobiol & Behav Med, D-35394 Giessen, FRG, Germany. [Schmitz, Anja] NIMH, Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Kuepper, Y (reprint author), Univ Giessen, Dept Psychol, Ctr Psychobiol & Behav Med, Otto Behaghel Str 10, D-35394 Giessen, FRG, Germany. EM yvonne.kuepper@psychol.uni-giessen.de RI Osinsky, Roman/H-5064-2011 FU H. Lundbeck A/S FX This study was sponsored by H. Lundbeck A/S, who were not responsible for study protocol design, data analysis, data interpretation, or writing the manuscript. NR 60 TC 23 Z9 24 U1 3 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 5 PY 2010 VL 206 IS 1 BP 93 EP 100 DI 10.1016/j.bbr.2009.09.006 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 523UI UT WOS:000272099700013 PM 19747510 ER PT J AU Zhang, Y Oliver, B AF Zhang, Yu Oliver, Brian TI An evolutionary consequence of dosage compensation on Drosophila melanogaster female X-chromatin structure? SO BMC GENOMICS LA English DT Article ID HISTONE H4; HYPERSENSITIVE SITES; GENE-EXPRESSION; MSL COMPLEX; CHROMOSOME; GENOME; KINASE; JIL-1; ACETYLATION; MAMMALS AB Background: X chromosomes are subject to dosage compensation in Drosophila males. Dosage compensation requires cis sequence features of the X chromosome that are present in both sexes by definition and trans acting factors that target chromatin modifying machinery to the X specifically in males. The evolution of this system could result in neutral X chromatin changes that will be apparent in females. Results: We find that the general chromatin structure of female X chromosomes is distinct from autosomes. Additionally, specific histone marks associated with dosage compensation and active chromatin marks on the male X chromosome are also enriched on the X chromosomes of females, albeit to a lesser degree. Conclusions: Our data indicate that X chromatin structure is fundamentally different from autosome structure in both sexes. We suggest that the differences between the X chromosomes and autosomes in females are a consequence of mechanisms that have evolved to ensure sufficient X chromosome expression in the soma of males. C1 [Zhang, Yu; Oliver, Brian] NIDDKD, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIDDKD, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM yuzhang@niddk.nih.gov; oliver@helix.nih.gov FU NIH, NIDDK FX We thank the NIDDK genomics core laboratory for solexa sequencing. We also thank Shirley Liu, David Sturgill, and John Malone for discussions and preliminary analysis of DNA-Seq data. The authors are grateful to members of Oliver lab, Brian Charlesworth and the dosage compensation community for many helpful comments. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 52 TC 18 Z9 18 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 5 PY 2010 VL 11 AR 6 DI 10.1186/1471-2164-11-6 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 557BG UT WOS:000274642100001 PM 20051121 ER PT J AU de Gonzalez, AB Curtis, RE Gilbert, E Berg, CD Smith, SA Stovall, M Ron, E AF de Gonzalez, A. Berrington Curtis, R. E. Gilbert, E. Berg, C. D. Smith, S. A. Stovall, M. Ron, E. TI Second solid cancers after radiotherapy for breast cancer in SEER cancer registries SO BRITISH JOURNAL OF CANCER LA English DT Article DE radiotherapy; second primary neoplasms; breast cancer; risk; radiation ID CONTRALATERAL BREAST; LUNG-CARCINOMA; RADIATION-THERAPY; INCREASED RISK; WOMEN; MORTALITY; SURGERY; QUALITY; CARE; IRRADIATION AB BACKGROUND: Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. METHODS: We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. RESULTS: By the end of 2005 (median follow-up = 13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI) = 1.33-1.58) for high-dose second cancer sites (1 + Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04-1.15) for contralateral breast cancer (approximate to 1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5-0.99 Gy, RR = 0.89 (0.74-1.06)) or low doses (<0.5 Gy, RR = 1.01 (0.95-1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI = 69-284) contralateral breast cancers or 5% (2-8%) of the total in all 1 + year survivors, and 292 (222-362) other solid cancers or 6% (4-7%) of the total. CONCLUSIONS: Most second solid cancers in breast cancer survivors are not related to radiotherapy. British Journal of Cancer (2010) 102, 220-226. doi:10.1038/sj.bjc.6605435 www.bjcancer.com Published online 24 November 2009 (C) 2010 Cancer Research UK C1 [de Gonzalez, A. Berrington; Curtis, R. E.; Gilbert, E.; Ron, E.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20814 USA. [Berg, C. D.] NCI, Early Detect Res Grp, Canc Prevent Div, Bethesda, MD 20814 USA. [Smith, S. A.; Stovall, M.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. RP de Gonzalez, AB (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20814 USA. EM berringtona@mail.nih.gov RI Reely, Sandra/A-6135-2010 NR 35 TC 46 Z9 46 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 5 PY 2010 VL 102 IS 1 BP 220 EP 226 DI 10.1038/sj.bjc.6605435 PG 7 WC Oncology SC Oncology GA 543HE UT WOS:000273563800029 ER PT J AU Zuckerbraun, BS Shiva, S Ifedigbo, E Mathier, MA Mollen, KP Rao, J Bauer, PM Choi, JJW Curtis, E Choi, AMK Gladwin, MT AF Zuckerbraun, Brian S. Shiva, Sruti Ifedigbo, Emeka Mathier, Michael A. Mollen, Kevin P. Rao, Jayashree Bauer, Philip M. Choi, Justin J. W. Curtis, Erin Choi, Augustine M. K. Gladwin, Mark T. TI Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide Generation SO CIRCULATION LA English DT Article DE hypoxia; nitric oxide; monocrotaline sodium; pulmonary artery smooth muscle cells; xanthine oxidoreductase ID ACTIVATED-PROTEIN-KINASE; L-ARGININE; CELL-PROLIFERATION; ISCHEMIA/REPERFUSION INJURY; ISCHEMIA-REPERFUSION; EXERCISE CAPACITY; ORGANIC NITRATES; IN-VIVO; EXPRESSION; SYNTHASE AB Background-Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension. Methods and Results-We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well. Conclusion-These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. (Circulation. 2010; 121: 98-109.) C1 [Ifedigbo, Emeka; Choi, Augustine M. K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Zuckerbraun, Brian S.; Mollen, Kevin P.; Rao, Jayashree; Bauer, Philip M.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Shiva, Sruti] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Ifedigbo, Emeka; Choi, Justin J. W.; Choi, Augustine M. K.; Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Mathier, Michael A.] Univ Pittsburgh, Sch Med, Div Cardiol, Pittsburgh, PA USA. [Zuckerbraun, Brian S.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Shiva, Sruti; Choi, Justin J. W.; Curtis, Erin; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Choi, AMK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM amchoi@rics.bwh.harvard.edu; gladwinmt@upmc.edu FU American Heart Association [0535203N] FX This work was supported by the American Heart Association, Scientist Development Grant 0535203N (B.S.Z.). NR 49 TC 99 Z9 104 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 5 PY 2010 VL 121 IS 1 BP 98 EP 109 DI 10.1161/CIRCULATIONAHA.109.891077 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 539PH UT WOS:000273267700014 PM 20026772 ER PT J AU Boyd, WA Crocker, TL Rodriguez, AM Leung, MCK Lehmann, DW Freedman, JH Van Houten, B Meyer, JN AF Boyd, Windy A. Crocker, Tracey L. Rodriguez, Ana M. Leung, Maxwell C. K. Lehmann, D. Wade Freedman, Jonathan H. Van Houten, Ben Meyer, Joel N. TI Nucleotide excision repair genes are expressed at low levels and are not detectably inducible in Caenorhabditis elegans somatic tissues, but their function is required for normal adult life after UVC exposure SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Caenorhabditis elegans; DNA damage response; Nucleotide excision repair; Global gene expression; Gene-environment interaction ID CYCLOBUTANE PYRIMIDINE DIMERS; RADIATION-SENSITIVE MUTANTS; DNA-DAMAGE RESPONSE; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; C-ELEGANS; INDUCED APOPTOSIS; CELL-CYCLE; PATHWAY; MODEL AB We performed experiments to characterize the inducibility of nucleotide excision repair (NER) in Caenorhabditis elegans, and to examine global gene expression in NER-deficient and -proficient strains as well as germline vs. somatic tissues, with and without genotoxic stress. We also carried out experiments to elucidate the importance of NER in the adult life of C elegans under genotoxin-stressed and control conditions. Adult lifespan was not detectably different between wild-type and NER-deficient xpa-1 nematodes under control conditions. However, exposure to 6 J/m(2)/day of ultraviolet C radiation (UVC) decreased lifespan in xpa-1 nematodes more than a dose of 100 J/M(2)/day in wild-type. Similar differential sensitivities were observed for adult size and feeding. Remarkably, global gene expression was nearly identical in young adult wild-type and xpa-1 nematodes, both in control conditions and 3 h after exposure to 50 J/m(2) UVC. Neither NER genes nor repair activity were detectably inducible in young adults that lacked germ cells and developing embryos (glp-1 strain). However, expression levels of dozens of NER and other DNA damage response genes were much (5-30-fold) lower in adults lacking germ cells and developing embryos, suggesting that somatic and post-mitotic cells have a much lower DNA repair ability. Finally, we describe a refinement of our DNA damage assay that allows damage measurement in single nematodes. (C) 2009 Elsevier B.V. All rights reserved. C1 [Crocker, Tracey L.; Leung, Maxwell C. K.; Meyer, Joel N.] Duke Univ, NSOE, Durham, NC 27708 USA. [Boyd, Windy A.] Natl Inst Environm Hlth Sci, Biomol Screening Branch, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. [Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, NIH, Res Triangle Pk, NC USA. [Rodriguez, Ana M.; Lehmann, D. Wade] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, Res Triangle Pk, NC USA. RP Meyer, JN (reprint author), Duke Univ, NSOE, Box 90328, Durham, NC 27708 USA. EM joel.meyer@duke.edu OI Boyd, Windy/0000-0003-3803-3716; Leung, Maxwell/0000-0003-1530-3306 FU National Institutes of Health [P42 ES10356]; National Toxicology Program; National Institute of Environmental Health Sciences; National Center for Research Resources FX We thank Julie Rice and Daniel Snyder for technical assistance with COPAS Biosort experiments and C. elegans maintenance, Danica Ducharme of the NIEHS microarray facility for microarray work, and Marjolein Smith for statistical analysis of growth and feeding data. This work was supported by National Institutes of Health [P42 ES10356 to J.M.]; the National Toxicology Program [to W.B.]; and the Intramural Research Program of the National Institute of Environmental Health Sciences [to J.F.]. All nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources. NR 55 TC 20 Z9 55 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 5 PY 2010 VL 683 IS 1-2 BP 57 EP 67 DI 10.1016/j.mrfmmm.2009.10.008 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 546WP UT WOS:000273845500009 PM 19879883 ER PT J AU Cheng, Y Zhang, ZH Keenan, B Roschke, AV Nakahara, K Aplan, PD AF Cheng, Yue Zhang, Zhenhua Keenan, Bridget Roschke, Anna V. Nakahara, Kenneth Aplan, Peter D. TI Efficient repair of DNA double-strand breaks in malignant cells with structural instability SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE DNA double-strand break (DSB); Chromosomal rearrangement; I-SceI; Ovarian cancer ID CHROMOSOMAL TRANSLOCATIONS; MAMMALIAN CHROMOSOME; ILLEGITIMATE RECOMBINATION; MLL GENE; FUSION; CANCER; EXPRESSION; SUPPRESSION; ABERRATIONS; MECHANISMS AB Aberrant repair of DNA double-strand breaks (DSBs) is thought to be important in the generation of gross chromosomal rearrangements (GCRs). To examine how DNA DSBs might lead to GCRs, we investigated the repair of a single DNA DSB in a structurally unstable cell line. An I-SceI recognition site was introduced into OVCAR-8 cells between a constitutive promoter (EF1 alpha) and the Herpes simplex virus thymidine kinase (TK) gene, which confers sensitivity to gancyclovir (GCV). Expression of I-SceI in these cells caused a single DSB. Clones with aberrant repair could acquire resistance to GCV by separation of the EF1 alpha promoter from the TK gene, or deletion of either the EF1 alpha promoter or the TK gene. All mutations that we identified were interstitial deletions. Treatment of cells with etoposide or bleomycin, agents known to produce DNA DSBs following expression of I-SceI also did not generate GCRs. Because we identified solely interstitial deletions using the aforementioned negative selection system, we developed a positive selection system to produce GCR. A construct containing an I-SceI restriction site immediately followed by a hygromycin phosphotransferase cDNA, with no promoter, was stably integrated into OVCAR-8 cells. DNA DSBs were produced by an I-SceI expression vector. None of the hygromycin resistant clones recovered had linked the hygromycin phosphotransferase cDNA to an endogenous promoter, but had instead captured a portion of the I-SceI expression vector. These results indicate that even in a structurally unstable malignant cell line, the majority of DNA DSBs are repaired by religation of the two broken chromosome ends, without the introduction of a GCR. Published by Elsevier B.V. C1 [Cheng, Yue; Zhang, Zhenhua; Keenan, Bridget; Roschke, Anna V.; Nakahara, Kenneth; Aplan, Peter D.] NCI, Genet Branch, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, Navy 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Cheng, Yue/E-9853-2010; Aplan, Peter/K-9064-2016 OI Cheng, Yue/0000-0002-2472-1879; FU NIH, NCI FX We thank Tamas Varga, Ilan R. Kirsch and Michael Kuehl for suggestions and helpful advice, and Maria Jasin for the gift of the pCBASce expression vector. This work was supported by the Intramural Research Program of the NIH, NCI. NR 28 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JAN 5 PY 2010 VL 683 IS 1-2 BP 115 EP 122 DI 10.1016/j.mrfmmm.2009.10.016 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 546WP UT WOS:000273845500016 PM 19909760 ER PT J AU Bielekova, B Becker, BL AF Bielekova, Bibiana Becker, Brenda L. TI Monoclonal antibodies in MS Mechanisms of action SO NEUROLOGY LA English DT Article ID B-CELL DEPLETION; REGULATORY T-CELLS; REMITTING MULTIPLE-SCLEROSIS; NATURAL-KILLER-CELLS; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; LYMPHOCYTIC-LEUKEMIA CELLS; CEREBROSPINAL-FLUID; RHEUMATOID-ARTHRITIS; AUTOIMMUNE-DISEASES; RITUXIMAB THERAPY AB The development of monoclonal antibodies (mAbs) presents an emerging, highly specific therapeutic strategy for the treatment of multiple sclerosis (MS). mAbs target selective molecules and have shown early promise, along with notable risks, in the treatment of MS and other immune-mediated diseases. The mechanism of action of the 4 mAbs under active investigation for MS (natalizumab, rituximab, alemtuzumab, and daclizumab) are reviewed, with a discussion of how mAb interaction with each target antigen may produce direct and indirect effects (proven and hypothesized) on immune cell activity, CNS-related inflammatory processes, and clinical outcomes. NEUROLOGY 2010;74 (Suppl 1):S31-S40 C1 [Bielekova, Bibiana] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, Neuroimmunol Branch, NIH, Bldg 10,Room 5C-103,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU Teva Neuroscience FX This supplement was supported by an educational grant from Teva Neuroscience. Expert Medical Education contributed to the editorial refinement of this article and to the production of this supplement. NR 82 TC 63 Z9 63 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 JAN 5 PY 2010 VL 74 IS 1 BP S31 EP S40 DI 10.1212/WNL.0b013e3181c97ed3 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 537PW UT WOS:000273126600006 PM 20038761 ER PT J AU Lee, KH Li, MM Michalowski, AM Zhang, XY Liao, HL Chen, LY Xu, Y Wu, XL Huang, J AF Lee, Kyoung-Hwa Li, Mangmang Michalowski, Aleksandra M. Zhang, Xinyue Liao, Hongling Chen, Lingyi Xu, Yang Wu, Xiaolin Huang, Jing TI A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transcription; epigenetic; modifications; DNA binding; neural stem cells ID SELF-RENEWAL; MOUSE EMBRYOS; DNA-DAMAGE; ES CELLS; PLURIPOTENCY; ACTIVATION; DIFFERENTIATION; APOPTOSIS; ACETYLATION; EXPRESSION AB Both p53 and the Wnt signaling pathway play important roles in regulating the differentiation of mouse embryonic stem cells (mESCs). However, it is not known whether they directly and/or functionally crosstalk in mESCs. Here we report a surprising anti-differentiation function of p53 in mESCs through directly regulating the Wnt signaling pathway. A chromatin-immunoprecipitation-based microarray (ChIP-chip) and gene expression microarray assays reveal that the Wnt signaling pathway is significantly (P value, 0.000048) overrepresented in p53-regulated genes in mESCs. The expression of five Wnt ligand genes is robustly induced by various genotoxic and nongenotoxic insults in a p53-dependent manner. Moreover, the induction of these Wnt genes is greatly attenuated in mouse embryonic fibroblast (MEF) cells and ESC-derived neural stem/progenitor cells, suggesting that the induction is mESC specific. It is established that the activation of the Wnt signaling pathway inhibits the differentiation of mESCs. Consistent with this notion, we detected an antidifferentiation activity from the conditioned medium (CM) collected from UV (UV)-treated mESCs. This antidifferentiation activity can be lowered by either the addition of Wnt antagonists into the CM or the reduction of p53 levels in UV-treated mESCs. Therefore, reminiscent of its dual functions on death and survival in somatic cells, p53 appears to regulate both prodifferentiation and antidifferentiation programs in mESCs. Our findings uncover a direct and functional connection between p53 and the Wnt signaling pathway, and expand the catalog of p53 regulated genes in mESCs. C1 [Lee, Kyoung-Hwa; Li, Mangmang; Michalowski, Aleksandra M.; Zhang, Xinyue; Huang, Jing] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Liao, Hongling; Wu, Xiaolin] NCI, Lab Mol Technol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Xu, Yang] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Chen, Lingyi] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China. RP Huang, J (reprint author), NCI, Lab Canc Biol & Genet, 37 Convent Dr,Room 3140, Bethesda, MD 20892 USA. EM huangj3@mail.nih.gov RI Huang, Jing/A-2566-2009; Chen, Lingyi/G-6309-2013; LI, MANGMANG/J-1683-2015 OI Huang, Jing/0000-0002-7163-5156; FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX We thank Bowen Cui for technical advice on ChIPchip assay, and Glenn Merlino, Peter Blumberg, and Li Guo for critically reading the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research. NR 44 TC 51 Z9 51 U1 3 U2 17 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 JAN 5 PY 2010 VL 107 IS 1 BP 69 EP 74 DI 10.1073/pnas.0909734107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200013 PM 20018659 ER PT J AU Verkoczy, L Diaz, M Holl, TM Ouyang, YB Bouton-Verville, H Alam, SM Liao, HX Kelsoe, G Haynes, BF AF Verkoczy, Laurent Diaz, Marilyn Holl, T. Matt Ouyang, Ying-Bin Bouton-Verville, Hilary Alam, S. Munir Liao, Hua-Xin Kelsoe, Garnett Haynes, Barton F. TI Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 2F5; broadly neutralizing antibodies; B cell development; autoantigens ID IMMUNODEFICIENCY-VIRUS TYPE-1; EDITED B-CELLS; IMMUNOGLOBULIN HEAVY; SELF-TOLERANCE; DNA; SELECTION; MICE; 2F5; EXPRESSION; EPITOPE AB We previously reported that some of the rare broadly reactive, HIV-1 neutralizing antibodies are polyreactive, leading to the hypothesis that induction of these types of neutralizing antibody may be limited by immunologic tolerance. However, the notion that such antibodies are sufficiently autoreactive to trigger B cell tolerance is controversial. To test directly whether rare neutralizing HIV-1 antibodies can activate immunologic tolerance mechanisms, we generated a knock-in mouse in which the Ig heavy chain (HC) variable region rearrangement (V(H)DJ(H)) from the polyreactive and broadly neutralizing human monoclonal antibody 2F5 was targeted into the mouse Igh locus. In vitro, this insertion resulted in chimeric human/mouse 2F5 antibodies that were functionally similar to the human 2F5 antibody, including comparable reactivity to human and murine self-antigens. In vivo, the 2F5 V(H)DJ(H) insertion supported development of large-and small pre-B cells that expressed the chimeric human/mouse ig mu chain but not the production of immature B cells expressing membrane IgM. The developmental arrest exhibited in 2F5 V(H)DJ(H) knock-in mice is characteristic of other knock-in strains that express the Ig HC variable region of autoreactive antibodies and is consistent with the loss of immature B cells bearing 2F5 chimeric antibodies to central tolerance mechanisms. Moreover, homozygous 2F5 V(H)DJ(H) knock-in mice support reduced numbers of residual splenic B cells with low surface IgM density, severely diminished serum IgM levels, but normal to elevated quantities of serum IgGs that did not react with autoantigens. These features are consistent with elimination of 2F5 HC autoreactivity by additional negative selection mechanism(s) in the periphery. C1 [Verkoczy, Laurent; Bouton-Verville, Hilary; Alam, S. Munir; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Med Ctr, Durham, NC 27710 USA. [Verkoczy, Laurent; Bouton-Verville, Hilary; Alam, S. Munir; Liao, Hua-Xin; Haynes, Barton F.] Duke Univ, Dept Med, Med Ctr, Durham, NC 27710 USA. [Holl, T. Matt; Kelsoe, Garnett; Haynes, Barton F.] Duke Univ, Dept Immunol, Med Ctr, Durham, NC 27710 USA. [Diaz, Marilyn] NIEHS, Res Triangle Pk, NC 27709 USA. [Ouyang, Ying-Bin] Xenogen Biosci, Cranbury, NJ 08512 USA. RP Verkoczy, L (reprint author), Duke Univ, Duke Human Vaccine Inst, Med Ctr, 106 Res Dr,MSRBII Bldg,Room 3015, Durham, NC 27710 USA. EM laurent.verkoczy@duke.edu FU Bill and Melinda Gates Foundation; Duke Center For AIDS Research; National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Center for HIV/AIDS Vaccine Immunology [AI0678501] FX We thank John Whitesides, Patti McDermott, and Letealia Oliver for expert technical assistance in flow cytometry; Robert Parks for ELISA assays; and Richard Scearce, Jennifer Hutchinson, and Heather Stevenson for assistance with cloning and expression of recombinant antibodies. 3H9 mice on the C57BL/6 background were provided by Dr. Robert Eisenberg (University of Pennsylvania). This study was supported by a Collaboration for AIDS Vaccine Discovery Grant from the Bill and Melinda Gates Foundation (to B. F. H., G. K., and L. V.), an Innovation Grant from the Duke Center For AIDS Research (to L. V.), and by National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS, Center for HIV/AIDS Vaccine Immunology Grant AI0678501 (to G. K. and B. F. H.). NR 47 TC 91 Z9 92 U1 0 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 JAN 5 PY 2010 VL 107 IS 1 BP 181 EP 186 DI 10.1073/pnas.0912914107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200032 PM 20018688 ER PT J AU Jankovic, M Robbiani, DF Dorsett, Y Eisenreich, T Xu, Y Tarakhovsky, A Nussenzweig, A Nussenzweig, MC AF Jankovic, Mila Robbiani, Davide F. Dorsett, Yair Eisenreich, Thomas Xu, Yang Tarakhovsky, Alexander Nussenzweig, Andre Nussenzweig, Michel C. TI Role of the translocation partner in protection against AID-dependent chromosomal translocations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE B lymphocyte; c-myc; cancer; immunoglobulin ID C-MYC ONCOGENE; CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; SINGLE-STRANDED-DNA; B-CELL SURVIVAL; ATM-DEFICIENT MICE; SOMATIC HYPERMUTATION; TRANSGENIC MICE; V(D)J RECOMBINATION; TUMOR SUPPRESSION AB Chromosome translocations between Ig (Ig) and non-Ig genes are frequently associated with B-cell lymphomas in humans and mice. The best characterized of these is c-myc/IgH translocation, which is associated with Burkitt's lymphoma. These translocations are caused by activation-induced cytidine deaminase (AID), which produces double-strand DNA breaks in both genes. c-myc/IgH translocations are rare events, in part because ATM, p53, and p19 actively suppress them. To further define the mechanism of protection against the accumulation of cells that bear c-myc/IgH translocation, we assayed B cells from mice that carry mutations in cell-cycle and apoptosis regulator proteins that act downstream of p53. We find that PUMA, Bim, and PKC delta are required for protection against c-myc/IgH translocation, whereas Bcl-XL and BAFF enhance c-myc/IgH translocation. Whether these effects are general or specific to cmyc/IgH translocation and whether AID produces dsDNA breaks in genes other than c-myc and Ig is not known. To examine these questions, we developed an assay for translocation between IgH and Ig beta, both of which are somatically mutated by AID. Ig beta/IgH, like c-myc/IgH translocations, are AID-dependent, and AID is responsible for lesions on IgH and the non-IgH translocation partners. However, ATM, p53, and p19 do not protect against Ig beta/IgH translocations. Instead, B cells are protected against Ig beta/IgH translocations by a BAFF-and PKC delta-dependent pathway. We conclude that AID-induced double-strand breaks in non-Ig genes other than c-myc lead to their translocation, and that at least two nonoverlapping pathways protect against translocations in primary B cells. C1 [Jankovic, Mila; Robbiani, Davide F.; Dorsett, Yair; Eisenreich, Thomas; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Eisenreich, Thomas; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Xu, Yang] Univ Calif San Diego, Div Biol Sci, San Diego, CA 92093 USA. [Tarakhovsky, Alexander] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10065 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@mail.rockefeller.edu FU NIH [AI037526]; NIH, National Cancer Institute and the Center for Cancer Research FX We thank Klara Velinzon for FACSorting and David Bosque for help in managing the mouse colonies. The work was supported in part by an NIH grant to M. C. N. (AI037526). A. N. was supported by the Intramural Research Program of the NIH, National Cancer Institute and the Center for Cancer Research. M. C. N. is an HHMI Investigator. NR 79 TC 14 Z9 14 U1 0 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 JAN 5 PY 2010 VL 107 IS 1 BP 187 EP 192 DI 10.1073/pnas.0908946107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 543FX UT WOS:000273559200033 PM 19966290 ER PT J AU Sood, CL Moss, B AF Sood, Cindy L. Moss, Bernard TI Vaccinia virus A43R gene encodes an orthopoxvirus-specific late non-virion type-1 membrane protein that is dispensable for replication but enhances intradermal lesion formation SO VIROLOGY LA English DT Article DE Poxvirus; Virulence; Virus-host interaction; Pathogenesis ID VIRULENCE; GLYCOPROTEIN; MODEL; INFECTION; PEPTIDES; ENVELOPE; RECEPTOR; MICE AB The vaccinia virus A43R open reading frame encodes a 168-amino acid protein with a predicted N-terminal signal sequence and a C-terminal transmembrane domain. Although A43R is conserved in all sequenced members of the orthopoxvirus genus, no non-orthopoxvirus homolog or functional motif was recognized. Biochemical and confocal microscopic studies indicated that A43 is expressed at late times following viral DNA synthesis and is a type-1 membrane protein with two Winked oligosaccharide chains. A43 was present in Golgi and plasma membranes but only a trace amount was detected in sucrose gradient purified mature virions and none in CsCl gradient purified enveloped virions. Prevention of A43R expression had no effect on plaque size or virus replication in cell culture and little effect on virulence after mouse intranasal infection. Although the A43 mutant produced significantly smaller lesions in skin of mice than the control, the amounts of virus recovered from the lesions were similar. Published by Elsevier Inc. C1 [Sood, Cindy L.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20814 USA. [Sood, Cindy L.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20814 USA. EM bmoss@nih.gov FU Division of Intramural Research; NIAID; NIH FX We thank Norman Cooper and Catherine Cotter for providing cells, Heather Hickman for demonstration of intradermal injections, David Tscharke for advice regarding the ear pinnae model and Jon Yewdell for suggesting the brefeldin A control. The work was supported by funds from the Division of Intramural Research, NIAID, NIH. NR 24 TC 1 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2010 VL 396 IS 1 BP 160 EP 168 DI 10.1016/j.virol.2009.10.025 PG 9 WC Virology SC Virology GA 531EX UT WOS:000272647600018 PM 19900687 ER PT J AU Chakrabarti, S Lanczycki, CJ Panchenko, AR Przytycka, TM Thiessen, PA Bryant, SH AF Chakrabarti, Saikat Lanczycki, Christopher J. Panchenko, Anna R. Przytycka, Teresa M. Thiessen, Paul A. Bryant, Stephen H. TI State of the art: refinement of multiple sequence alignments (vol 7, pg 499, 2006) SO BMC BIOINFORMATICS LA English DT Correction AB Correction to Chakrabarti S, Lanczycki CJ, Panchenko AR, Przytycka TM, Thiessen PA and Bryant SH: State of the art: refinement of multiple sequence alignments. BMC Bioinformatics 2006, 7:499. C1 [Chakrabarti, Saikat; Lanczycki, Christopher J.; Panchenko, Anna R.; Przytycka, Teresa M.; Thiessen, Paul A.; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Chakrabarti, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM chakraba@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JAN 4 PY 2010 VL 11 AR 3 DI 10.1186/1471-2105-11-3 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 564FJ UT WOS:000275198400001 ER PT J AU Kotova, S Prasad, K Smith, PD Lafer, EM Nossal, R Jin, AJ AF Kotova, Svetlana Prasad, Kondury Smith, Paul D. Lafer, Eileen M. Nossal, Ralph Jin, Albert J. TI AFM visualization of clathrin triskelia under fluid and in air SO FEBS LETTERS LA English DT Article DE Endocytosis; Clathrin triskelion; Biological AFM; Macromolecular assembly; Molecular flexibility ID COATED VESICLES; ENDOCYTOSIS; DOMAIN; PROTEINS; ACTIN; RECRUITMENT; MICROSCOPY; TRIMERS; REGION; ENTRY AB Atomic force microscopy (AFM) is used to characterize the structure and interactions of clathrin triskelia. Time sequence images of individual, wet triskelia resting on mica surfaces clearly demonstrate conformational fluctuations of the triskelia. AFM of dried samples yields images having nanometric resolution comparable to that obtainable by electron microscopy of shadowed samples. Increased numbers of triskelion dimers and assembly intermediates, as well as structures having dimensions similar to those of clathrin cages, are observed when the triskelia were immersed in a low salt, low pH buffer. These entities have been quantified by AFM protein volume computation. C1 [Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, NIH, DHHS, Bethesda, MD 20892 USA. [Kotova, Svetlana; Smith, Paul D.; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, DHHS, Bethesda, MD 20892 USA. [Prasad, Kondury; Lafer, Eileen M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Nossal, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, NIH, DHHS, Bethesda, MD 20892 USA. EM nossalr@mail.nih.gov; jina@mail.nih.gov OI Jin, Albert/0000-0003-3826-1081 FU EML [NS029051]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Biomedical Imaging and Bioengineering (NIBIB) FX We thank Dr. Dan Sackett (NICHD/NIH) for advice, Suping Jin (Univ. Texas HSC) for technical assistance, and Dr. Maria Aronova (NIBIB/NIH) for helpful comments. This work was supported in part by an extramural grant (EML, NS029051) and by the intramural research programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB). NR 32 TC 9 Z9 10 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 4 PY 2010 VL 584 IS 1 BP 44 EP 48 DI 10.1016/j.febslet.2009.11.039 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 538UJ UT WOS:000273209200009 PM 19925798 ER PT J AU Kojima, C Regino, C Umeda, Y Kobayashi, H Kono, K AF Kojima, Chie Regino, Celeste Umeda, Yasuhito Kobayashi, Hisataka Kono, Kenji TI Influence of dendrimer generation and polyethylene glycol length on the biodistribution of PEGylated dendrimers SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Dendrimer; Polyethylene glycol; Biodistribution; Drug delivery; Radiolabel ID TUMOR-BEARING MICE; MR CONTRAST AGENTS; POLYAMIDOAMINE DENDRIMERS; POLY(ETHYLENE GLYCOL); BIOLOGICAL APPLICATIONS; LYSINE DENDRIMERS; DRUGS; CORE AB Dendrimers are a potential drug carrier. Because modification with polyethylene glycol (PEG) is known to improve the blood retention, PEGylated dendrimers have been studied as a useful drug carrier. In this study, three types of PEGylated L-lysine-bearing polyamidoamine dendrimers (PEG2k-Lys-PAMAM (G4), PEG5k-Lys-PAMAM (G4), PEG2k-Lys-PAMAM (G5)) were synthesized, which are composed of a dendrimer of different generations (generations 4 and 5)and PEG chains with different molecular weights (2k and 5k). An acetylated L-lysine-bearing dendrimer was also synthesized as a non-PEGylated dendrimer. Bifunctional diethylenetriaminepentaacetic acid (PSCN-benzyl-DTPA) was bound to the epsilon -amino group of lysine in a dendrimer, to be labeled with radioactive indium-111. These PEGylayed dendrimers showed longer blood retention and lower accumulation in other normal organs such as the kidneys than the non-PEGylated dendrimer. The PEGylated dendrimers with the higher generation and the longer PEG led the greater blood retention. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kojima, Chie] Osaka Prefecture Univ, Res Inst Twenty First Century, Nanosci & Nanotechnol Res Ctr, Dept Appl Chem,Grad Sch Engn,Naka Ku, Osaka 5998570, Japan. [Regino, Celeste; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kojima, C (reprint author), Osaka Prefecture Univ, Res Inst Twenty First Century, Nanosci & Nanotechnol Res Ctr, Dept Appl Chem,Grad Sch Engn,Naka Ku, 1-2 Gakuen Cho, Osaka 5998570, Japan. EM c-kojima@21c.osakafu-u.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) FX We thank Yasuhiro Haba for his support in synthesis. This project was supported by the Program to Accelerate the Internationalization of University Education (Overseas Advanced Educational Research Practice Support Program) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). NR 20 TC 53 Z9 54 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JAN 4 PY 2010 VL 383 IS 1-2 BP 293 EP 296 DI 10.1016/j.ijpharm.2009.09.015 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 533FT UT WOS:000272809800039 PM 19761822 ER PT J AU Hassan, MA Buldakov, MA Ogawa, R Zhao, QL Furusawa, Y Kudo, N Kondo, T Riesz, P AF Hassan, Mariame A. Buldakov, Mikhail A. Ogawa, Ryohei Zhao, Qing-Li Furusawa, Yukihiro Kudo, Nobuki Kondo, Takashi Riesz, Peter TI Modulation control over ultrasound-mediated gene delivery: Evaluating the importance of standing waves SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Gene delivery; Low-intensity ultrasound; Pulse repetition frequency (PRF); Ultrasound streaming; Standing waves ID IN-VITRO; PULSED ULTRASOUND; SUSPENSION CELLS; CANCER-CELLS; SONOPORATION; TRANSFECTION; DNA; MICROBUBBLES; CAVITATION; AGENT AB Low modulation frequencies from 0.5 to 100 Hz were shown to alter the characteristics of the ultrasound field producing solution agitation (<5 Hz; region of "ultrasound streaming" prevalence) or stagnancy (>5 Hz; region of standing waves establishment) (Buldakov et al., Ultrason. Sonochem., 2009). In this study, the same conditions were used to depict the changes in exogenous DNA delivery in these regions. The luciferase expression data revealed that lower modulations were more capable of enhancing delivery at the expense of viability. On the contrary, the viability was conserved at higher modulations whereas delivery was found to be null. Cavitational activity and acoustic streaming were the effecters beyond the observed pattern and delivery enhancement was shown to be mediated mainly through sonopermeation. To promote transfection, the addition of calcium ions or an echo contrast agent (Levovist (R)) was proposed. Depending on the mechanism involved in each approach, differential enhancement was observed in both regions and at the interim zone (5 Hz). In both cases, enhancement in standing waves field was significant reaching 16.0 and 3.3 folds increase, respectively. Therefore, it is concluded that although the establishment of standing waves is not the only prerequisite for high transfection rates, yet, it is a key element in optimization when other factors such as proximity and cavitation are considered. (C) 2009 Elsevier B.V. All rights reserved. C1 [Hassan, Mariame A.; Ogawa, Ryohei; Zhao, Qing-Li; Furusawa, Yukihiro; Kondo, Takashi] Toyama Univ, Grad Sch Med & Pharmaceut, Dept Radiol Sci, Toyama 9300194, Japan. [Hassan, Mariame A.] Cairo Univ, Fac Pharm, Dept Pharmaceut & Ind Pharm, Cairo 11562, Egypt. [Buldakov, Mikhail A.] Russian Acad Med Sci, Siberian Dept, Tomsk Sci Ctr, Canc Res Inst, Tomsk 634009, Russia. [Buldakov, Mikhail A.] Tomsk VV Kuibyshev State Univ, Dept Physiol, Tomsk 634050, Russia. [Buldakov, Mikhail A.] Russian Acad Sci, Siberian Dept, Inst High Current Elect, Tomsk 634055, Russia. [Kudo, Nobuki] Hokkaido Univ, Grad Sch Informat Sci & Technol, Lab Biomed Instrumentat & Measurements, Sapporo, Hokkaido 0600814, Japan. [Riesz, Peter] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Kondo, T (reprint author), Toyama Univ, Grad Sch Med & Pharmaceut, Dept Radiol Sci, Sugitani 2630, Toyama 9300194, Japan. EM kondot@med.u-toyama.ac.jp RI Buldakov, Mikhail/C-7922-2012; Kudo, Nobuki/D-6742-2012 FU Japan Society of Ultrasonics in Medicine FX This study was supported in part by the Research and Development Committee Program of the Japan Society of Ultrasonics in Medicine. NR 33 TC 26 Z9 27 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JAN 4 PY 2010 VL 141 IS 1 BP 70 EP 76 DI 10.1016/j.jconrel.2009.08.020 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 550CF UT WOS:000274104200010 PM 19720097 ER PT J AU Hortin, GL Sviridov, D AF Hortin, Glen L. Sviridov, Denis TI The dynamic range problem in the analysis of the plasma proteome SO JOURNAL OF PROTEOMICS LA English DT Article DE Plasma proteins; Plasma proteomics; Proteomics; Protein abundance ID PROSTATE-SPECIFIC ANTIGEN; C-REACTIVE PROTEIN; HUMAN CHORIONIC-GONADOTROPIN; SERUM; ASSAY; DISORDERS; CANCER; VALUES; LEVEL; TSH AB One of the greatest challenges in analyzing the plasma proteome is the wide range of concentration of different proteins. The current study examines the range of protein concentration for 18 proteins measured over a year in a clinical laboratory to provide data on pathological extremes in protein concentrations. The complete measured range, from upper limits for albumin to lowest values for thyroid-stimulating hormone (TSH), represented more than 10 logs of molar abundance. A number of plasma proteins measured in the clinical laboratory varied over a concentration range spanning more than 4 logs, and limits of detection of clinical assays were inadequate to assess full concentration ranges of several proteins. Considering reported values from studies using higher sensitivity assays suggest that plasma concentrations of prostate-specific antigen (PSA), human chorionic gonadotropin (hCG), and cardiac troponin I vary by more than 7 logs. All of the plasma proteins measured in the present study represent secretory proteins or highly expressed components of specific tissues. Thus, the dynamic range for these components is likely to greatly underestimate the total range of protein concentration in the plasma proteome. (C) 2009 Elsevier B.V. All rights reserved. C1 [Hortin, Glen L.; Sviridov, Denis] NIH, Dept Lab Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Hortin, GL (reprint author), Univ Florida, Dept Pathol Immunol & Lab Med, Coll Med, Gainesville, FL 32610 USA. EM ghortin@pathology.ufl.edu FU NIH Clinical Center FX Studies were supported by the intramural research program of the NIH Clinical Center. We thank Karen Byer for her assistance with the figures. NR 33 TC 39 Z9 41 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD JAN 3 PY 2010 VL 73 IS 3 SI SI BP 629 EP 636 DI 10.1016/j.jprot.2009.07.001 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 555YH UT WOS:000274552400027 PM 19619681 ER PT J AU Malamud, D Wahl, SM AF Malamud, Daniel Wahl, Sharon M. TI The mouth: a gateway or a trap for HIV? SO AIDS LA English DT Review DE glycoprotein 340; HIV; innate immunity; mucosa; secretory leukocyte protease inhibitor ID HUMAN-IMMUNODEFICIENCY-VIRUS; LEUKOCYTE PROTEASE INHIBITOR; ENVELOPE GLYCOPROTEIN GP120; INNATE IMMUNE FACTORS; T-CELLS; SALIVARY AGGLUTININ; DENDRITIC CELLS; ANTIMICROBIAL PEPTIDES; STREPTOCOCCUS-MUTANS; PROTEINASE-INHIBITOR C1 [Malamud, Daniel] NYU, Coll Dent, Dept Basic Sci, HIV AIDS Res Program, New York, NY 10010 USA. [Malamud, Daniel] NYU, Coll Med, Dept Med, New York, NY 10010 USA. [Wahl, Sharon M.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. RP Malamud, D (reprint author), NYU, Coll Dent, Dept Basic Sci, HIV AIDS Res Program, 345 E 24th St,Room 917 Schwartz Bldg, New York, NY 10010 USA. EM daniel.malamud@nyu.edu OI Malamud, Daniel/0000-0002-9094-4122 FU NIH NIDCR; NIAID [U01DE017855, U19DE018385, R01AI050484, R01AI060505]; New York State Foundation for Science, Technology and Innovation (NYSTAR); NIH, National Institute of Dental and Craniofacial Research FX This research was supported by NIH NIDCR and NIAID grant nos. U01DE017855 (D.M.), U19DE018385 (D.M.), R01AI050484 (D.W), R01AI060505 (D.W), a New York State Foundation for Science, Technology and Innovation (NYSTAR, D.M.) and the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research (S.W). The availability of reagents to us and the scientific community from Drs Holmskov and Ligtenberg, the NIH AIDS Research and Reference Reagent program, and vagina/cervical cell lines from Dr Fichorova are gratefully acknowledged. NR 125 TC 17 Z9 17 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 2 PY 2010 VL 24 IS 1 BP 5 EP 16 DI 10.1097/QAD.0b013e328333525f PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 534SP UT WOS:000272917900003 PM 19935380 ER PT J AU Brunetta, E Fogli, M Varchetta, S Bozzo, L Hudspeth, KL Marcenaro, E Moretta, A Mavilio, D AF Brunetta, Enrico Fogli, Manuela Varchetta, Stefania Bozzo, Luisa Hudspeth, Kelly L. Marcenaro, Emanuela Moretta, Alessandro Mavilio, Domenico TI Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection SO AIDS LA English DT Article DE antiretroviral therapy; biomarker; human cytomegalovirus coinfection; natural killer cell subsets; NKG2A/NKG2C ratio ID NK CELLS; RECEPTOR EXPRESSION; INFECTION; INDIVIDUALS AB Background: The HIV-1-induced expansion of highly dysfunctional natural killer (NK) cell subsets represents a strategy to evade NK cell antiviral functions. In this context, the loss of NKG2A(pos) NK cells in chronic viremic HIV-1-infected individuals has also been associated with a dramatic expansion of NKG2C(pos) NK cells. The viral trigger associated with high frequencies of NK cell subsets expressing NKG2C is still being debated. Objective: To confirm that human cytomegalovirus (HCMV) infection is necessary for the expansion of NKG2C(pos) NK cells and to assess whether this phenomenon affects NKG2A/NKG2C ratio on NK cells in patients coinfected with HIV-1 and HCMV. Design: We measured the expression of NKG2A and NKG2C on NK cells from 70 healthy donors, 21 early, 96 chronic and 27 long-term nonprogressor's (LTNPs) HIV-1 infected patients using a multicolor flow cytometric approach. HCMV infection was detected by titrating the serum levels of specific circulating antibodies. Results: A significant expansion of NKG2C(pos) NK cells could be detected only in HCMV-infected patients. This phenotypic feature, together with the HIV-1-mediated downmodulation of NKG2A, pathologically reverses the ratio of NKG2A/NKG2C uniquely on NK cells from chronic viremic HIV-1-infected patients with a concomitant HCMV infection. The normalization of NKG2A/NKG2C ratio to values more than one occurred only after 24 Months Of Suppression of HIV-1 replication following antiretroviral therapy. Conclusion: The inversion of NKG2A/NKG2C ratio characterizes advanced stages of HIV-1 disease in patients showing a concomitant HCMV infection. This NK cell immune parameter renders this cohort of patients distinguishable from LTNPs and early HIV-1-infected individuals. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Brunetta, Enrico; Bozzo, Luisa; Mavilio, Domenico] Ist Clin Humanitas, Clin & Expt Immunol Lab, IRCCS, Milan, Italy. [Brunetta, Enrico; Fogli, Manuela] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Varchetta, Stefania] Policlin San Matteo, Ctr Hepatol & Infect Dis, Pavia, Italy. [Varchetta, Stefania] Univ Pavia, I-27100 Pavia, Italy. [Hudspeth, Kelly L.] Rush Univ, Dept Immunol & Microbiol, Med Ctr, Chicago, IL 60612 USA. [Marcenaro, Emanuela; Moretta, Alessandro] Univ Genoa, Dipartimento Med Sperimentale, Genoa, Italy. RP Mavilio, D (reprint author), Ist Clin Humanitas, Expt Immunol Lab, IRCCS, Via Alessandro Manzoni 113, Milan, Italy. EM domenico.mavilio@humanitas.it OI Varchetta, Stefania/0000-0002-0289-2896; Mavilio, Domenico/0000-0001-6147-0952 FU NIAID, NIH; Istituto Clinico Humanitas FX This research was supported by the intramural research program of NIAID, NIH and by intramural program of Istituto Clinico Humanitas. NR 19 TC 56 Z9 57 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 2 PY 2010 VL 24 IS 1 BP 27 EP 34 DI 10.1097/QAD.0b013e3283328d1f PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 534SP UT WOS:000272917900005 PM 19910789 ER PT J AU Rambold, HA Sheliga, BM Miles, FA AF Rambold, Holger A. Sheliga, Boris M. Miles, Frederick A. TI Evidence from vergence eye movements that disparities defined by luminance and contrast are sensed by independent mechanisms SO JOURNAL OF VISION LA English DT Article DE luminance; contrast; human vision; first-order disparity; second-order disparity; distortion products; disparity vergence ID TRANSIENT-STEREOPSIS SYSTEM; CORTICAL AREA MST; 2ND-ORDER MOTION; SHORT-LATENCY; BINOCULAR DISPARITY; SPATIAL-FREQUENCY; DEPTH-PERCEPTION; ANTICORRELATED STEREOGRAMS; HORIZONTAL DISPARITY; NONLINEAR STEREOPSIS AB We recorded the initial disparity vergence responses (DVRs) elicited by 1-D sinusoidal gratings differing in phase at the two eyes by 1/4 wavelength and defined by luminance modulation (LM) or contrast modulation (CM) of dynamic binary noise. Both LM and CM stimuli elicited DVRs, but those to CM had longer latency (on average by similar to 20 ms). DVRs showed sigmoidal dependence on depth of modulation, with higher thresholds for CM than for LM. With both LM and CM stimuli, fixing the modulation at one eye well above threshold rendered the DVR hypersensitive to low-level modulation at the other eye (dichoptic facilitation). Disparities defined by LM at one eye and CM at the other generated weak DVRs in the "wrong" direction, consistent with mediation entirely by distortion products associated with the CM stimulus. These (reversed) DVRs could be nulled by adding LM to the CM stimulus (in phase), and the greater the depth of the CM, the greater the added LM required for nulling, exactly as predicted by a simple compressive non-linearity. We conclude that disparities defined by LM and by CM are sensed by independent cortical mechanisms, at least for the purposes of generating short-latency vergence eye movements to disparity steps. C1 [Rambold, Holger A.; Sheliga, Boris M.; Miles, Frederick A.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Rambold, Holger A.] Kreiskliniken, Dept Neurol, Altotting Burghausen, Germany. RP Sheliga, BM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU National Eye Institute at the NIH; Alexander von Humboldt Foundation (Germany) FX This research was supported by the Intramural Program of the National Eye Institute at the NIH. HAR was also supported by the Alexander von Humboldt Foundation (Germany). NR 96 TC 1 Z9 1 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 1534-7362 J9 J VISION JI J. Vision PY 2010 VL 10 IS 14 AR 31 DI 10.1167/10.14.31 PG 34 WC Ophthalmology SC Ophthalmology GA 763BV UT WOS:000290529100031 ER PT S AU Yeager, T Ard, TD Carver, FW Holroyd, I Coppola, R AF Yeager, T. Ard, T. D. Carver, F. W. Holroyd, I. Coppola, R. BE Supek, S Susac, A TI MEG Virtual Channel Methods for Movement Prediction and Training SO 17TH INTERNATIONAL CONFERENCE ON BIOMAGNETISM ADVANCES IN BIOMAGNETISM - BIOMAG2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 39th Annual Clinical Aphasiology Conference CT 17th International Conference on Biomagnetism (Biomag 2010) CY MAY 26-30, 2009 CY MAR 28-APR 01, 2010 CL Keystone, CO CL Dubrovnik, CROATIA SP Univ Zagreb, Fac Sci, Dept Phys, Croatian Biophys Soc, Croatian Cardiac Soc, Int Federat Med & Biol Engn, Croatian Inst Brain Res, Croatian Neurol Soc, Croatian Phys Soc, Croatian Soc Med & Biol Engn, Croatian Soc Neurosci, Zagreb Epilepsy Ctr DE MEG; BCI; motor movement; beta band ID EEG AB Using a whole-head MEG system, we investigated the possibility of distinguishing between directions of hand movement in the mu-beta (8-32 Hz) and high gamma (76-100 Hz) frequency bands in the hand knob and surrounding prefrontal gyrus. We found that four cardinal directions (up, down, left, right) in center-out tasks could be distinguished to a statistically significant extent in the beta band. While no statistically significant difference was found in the gamma band, it was possible to discriminate between hand movement and rest based on hand knob-localized event-related synchronization. Analysis of hand movement in the beta band could lead to finer coordination of brain computer interfaces. C1 [Yeager, T.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. [Yeager, T.; Ard, T. D.; Carver, F. W.; Holroyd, I.] NIH, NIMH, Magnetoencephalog Core Facil, Bethesda, MD USA. RP Yeager, T (reprint author), Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15260 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-12196-8 J9 IFMBE PROC PY 2010 VL 28 BP 171 EP + PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials; Physics, Applied SC Engineering; Materials Science; Physics GA BRE15 UT WOS:000282468700037 ER PT S AU Wang, Y Xiang, J Rose, DF Holroyd, T Harris, E deGrauw, TJ AF Wang, Y. Xiang, J. Rose, D. F. Holroyd, T. Harris, E. deGrauw, T. J. BE Supek, S Susac, A TI The Frequency Profile of Somatosensory Evoked Magnetic Fields in the Developing Brain SO 17TH INTERNATIONAL CONFERENCE ON BIOMAGNETISM ADVANCES IN BIOMAGNETISM - BIOMAG2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 39th Annual Clinical Aphasiology Conference CT 17th International Conference on Biomagnetism (Biomag 2010) CY MAY 26-30, 2009 CY MAR 28-APR 01, 2010 CL Keystone, CO CL Dubrovnik, CROATIA SP Univ Zagreb, Fac Sci, Dept Phys, Croatian Biophys Soc, Croatian Cardiac Soc, Int Federat Med & Biol Engn, Croatian Inst Brain Res, Croatian Neurol Soc, Croatian Phys Soc, Croatian Soc Med & Biol Engn, Croatian Soc Neurosci, Zagreb Epilepsy Ctr DE Magnetoencephalography; virtual sensor; beamformer; index finger stimulation ID EPILEPSY; CHILDREN AB The objective of this paper is to study the variations of magnetic fields evoked by index finger stimulation in four age groups (6-9, 10-13, 14-17 and 18-49 years old) of normal population. We recorded magnetic fields during unilateral electrical stimulation of the index finger in 60 healthy children (7+/-1.2, 12+/-1.3 and 15+/-1.1) and 20 healthy adults (30+/-5.7) using a 275-channel whole head magnetoencephalography (MEG) system. Each group consisted of 10 females and males. Electrical stimulation was applied in randomized order to the right or left index finger with two digital rings. One hundred trials were recorded for both the right and left index finger stimulations. MEG data were analyzed in both the time and frequency domains. Brain regions associated with finger stimulations were localized with the equivalent current dipoles (ECDs). Time-frequency analysis was at the source level with a vector beamformer and Morlet wavelets. Our data have revealed evoked neuromagnetic signals in low-frequency ranges (10-40 Hz). In addition, the spectrograms revealed consistent focal increases of spectral power around 120-200 Hz in the left and right hemispheres in children. Furthermore, the neuromagnetic activation above 200 Hz was also observed, which were in the frequency range of 600-890 Hz. The preliminary data suggest that neuromagnetic signals above 120 Hz in the developing brain are noninvasive detectable. C1 [Wang, Y.] Univ Cincinnati, Dept Biomed Engn, Cincinnati, OH 45229 USA. [Wang, Y.; Xiang, J.; Rose, D. F.; deGrauw, T. J.] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. [Holroyd, T.] NIMH, MEG core Fac, Bethesda, MD 20892 USA. [Harris, E.] Cincinnati Childrens Hosp Med Ctr, Div Child Psychiat, Cincinnati, OH 45229 USA. RP Wang, Y (reprint author), Univ Cincinnati, Dept Biomed Engn, Cincinnati, OH 45229 USA. RI Wang, Yingying/A-4694-2011; OI Harris, Elana/0000-0002-5397-3274 FU Trustee Grant from Cincinnati Children's Hospital Medical Center FX This study was supported by a Trustee Grant from Cincinnati Children's Hospital Medical Center. We would like to thank our research technologist, Kendall O'Brien for performing the MRI scan. NR 8 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-12196-8 J9 IFMBE PROC PY 2010 VL 28 BP 254 EP + PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials; Physics, Applied SC Engineering; Materials Science; Physics GA BRE15 UT WOS:000282468700058 ER PT S AU Manurung, A Yoon, J Park, HS AF Manurung, Auralius Yoon, Jungwon Park, Hyung-Soon GP IEEE TI Speed Adaptation Control of a Small-sized Treadmill with State Feedback Controller SO 2010 3RD IEEE RAS AND EMBS INTERNATIONAL CONFERENCE ON BIOMEDICAL ROBOTICS AND BIOMECHATRONICS SE Proceedings of the IEEE RAS-EMBS International Conference on Biomedical Robotics and Biomechatronics LA English DT Proceedings Paper CT 3rd IEEE RAS and EMBS International Conference on Biomedical Robotics and Biomechatronics CY SEP 26-29, 2010 CL Tokyo, JAPAN SP IEEE ID LOCOMOTION INTERFACE; WALKING AB Variable velocity in treadmill training may play an important role in gait rehabilitation where a patient can practice variable walking velocity while the treadmill adjusts to it. In order to adjust the treadmill velocity to the subject's variable walking velocity, we have developed an automatic gait velocity adaptation algorithm implemented on a small-sized commercial treadmill (belt length of 1.2 m and width of 0.5 m) which is widely used at home and health centers. The control objective is to automatically adjust the treadmill velocity so that the subject's position is maintained within the track when the subject walks at a variable velocity. The subject's position with respect to a reference point is measured by a low-cost sonar sensor located on the back of the subject. Based on a encoder sensor measurement at the treadmill motor, a state feedback control algorithm with Kalman filter was implemented to determine the velocity of the treadmill. In order to reduce the unnatural inertia force felt by the subject, a predefined acceleration limit was applied, which generated smooth velocity trajectories. The experimental results demonstrate the effectiveness of the proposed method in providing successful velocity changes in response to variable velocity walking including starting (accelerating) and stopping (decelerating) periods of treadmill exercise without causing significant inertia force to the subject. In the pilot study with three subjects, users could change their walking velocity easily and naturally with small deviations during slow, medium, and fast walking. The proposed automatic velocity adaptation algorithm can potentially be applied to any locomotion interface in an economical way without having to use sophisticated and expensive sensors and larger treadmills. C1 [Manurung, Auralius; Yoon, Jungwon] Gyeongsang Natl Univ, Sch Mech & Aerosp Engn, Jinju, South Korea. [Yoon, Jungwon] NIH, Ctr Neurosci Regenerat Med, Bethesda, MD 20892 USA. [Park, Hyung-Soon] NIH, Bethesda, MD USA. RP Yoon, J (reprint author), Gyeongsang Natl Univ, Sch Mech & Aerosp Engn, Jinju, South Korea. EM jwyoon@gnu.ac.kr; parkhs@cc.nih.gov RI Manurung, Auralius/A-2166-2012; OI Yoon, Jungwon/0000-0003-1350-5334 FU 2nd stage BK 21 and LG Yeonam Foundation Foreigner Research Professor Program FX This work is supported by 2nd stage BK 21 and LG Yeonam Foundation Foreigner Research Professor Program. NR 16 TC 3 Z9 3 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2155-1782 BN 978-1-4244-7709-8 J9 P IEEE RAS-EMBS INT PY 2010 BP 15 EP 20 PG 6 WC Biophysics; Engineering, Biomedical; Robotics SC Biophysics; Engineering; Robotics GA BTS79 UT WOS:000287997100009 ER PT S AU Castro, MA Yao, JH Pang, YX Baker, E Butman, J Thomasson, D AF Castro, Marcelo A. Yao, Jianhua Pang, Yuxi Baker, Eva Butman, John Thomasson, David GP IEEE TI TEMPLATE METHOD TO IMPROVE BRAIN SEGMENTATION FROM INHOMOGENEOUS BRAIN MAGNETIC RESONANCE IMAGES AT HIGH FIELDS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Magnetic resonance imaging; Image registration; Image segmentation; Brain ID INTENSITY NONUNIFORMITY; RADIOFREQUENCY FIELD; STEADY-STATE; COMBINED T-1; FLIP ANGLES; MR-IMAGES; ACCURATE; T1 AB Magnetic resonance imaging of the brain at high fields (e. g. 3T) provides high resolution and high signal to noise ratio images suitable for a wide range of clinical applications. However, radiofrequency (or B-1) inhomogeneity increases with the magnetic field and produces undesired intensity variations responsible for inaccuracies in quantitative analyses. A method to perform brain segmentation using T-1 maps whose inhomogeneity was corrected using previously acquired B-1 maps is described. A library of B-1 maps was created and a method to compensate the T-1 inhomogeneity using a B-1 map from another subject (template) was developed. The performance of the template-based method was evaluated in 19 healthy volunteers. Our method produced significantly better segmentations than the retrospective N3 method and the one without B-1 inhomogeneity correction. C1 [Castro, Marcelo A.; Yao, Jianhua; Pang, Yuxi; Baker, Eva; Butman, John; Thomasson, David] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Castro, MA (reprint author), NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RI Butman, John/J-2780-2013 OI Butman, John/0000-0002-1547-9195 NR 24 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 73 EP 76 DI 10.1109/ISBI.2010.5490410 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400019 ER PT S AU Summers, RM AF Summers, Ronald M. GP IEEE TI CURRENT CONCEPTS IN COMPUTER-AIDED DETECTION FOR CT COLONOGRAPHY SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE colorectal cancer; polyps; shape; curvature ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; POLYP DETECTION; COLONIC POLYPS; FALSE POSITIVES; ASSISTED DETECTION; ILEOCECAL VALVE; REDUCTION; CLASSIFICATION; DIAGNOSIS; SEGMENTATION AB Computer-aided detection (CAD) for CT colonography has been under development for about eleven years. It is now sufficiently accurate that clinically significant polyps 1 cm and larger can be reliably detected with 90% sensitivity. The research focus is now shifting to reducing the number of false positive detections, clinical validation and integrating CAD into clinical practice and applying CAD to the setting of fecal tagging and laxative-free bowel preparations. This is a dynamic research field which requires the use of state-of-the-art image processing and machine learning techniques. C1 NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM rms@nih.gov NR 48 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 269 EP 272 DI 10.1109/ISBI.2010.5490363 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400068 ER PT S AU Sohail, AM Rahman, MM Bhattacharya, P Krishnamurthy, S Mudur, SP AF Sohail, Abu Sayeed Md Rahman, Md Mahmudur Bhattacharya, Prabir Krishnamurthy, Srinivasan Mudur, Sudhir P. GP IEEE TI RETRIEVAL AND CLASSIFICATION OF ULTRASOUND IMAGES OF OVARIAN CYSTS COMBINING TEXTURE FEATURES AND HISTOGRAM MOMENTS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Ultrasound Medical Image Retrieval; Classification of Ultrasound Ovarian Images; Statistical Texture Descriptors; Histogram Moments ID MEDICAL APPLICATIONS AB This paper presents an effective solution for content-based retrieval and classification of ultrasound medical images representing three types of ovarian cysts: Simple Cyst, Endometrioma, and Teratoma. Our proposed solution comprises of the followings: extraction of low level ultrasound image features combining histogram moments with Gray Level Co-Occurrence Matrix (GLCM) based statistical texture descriptors, image retrieval using a similarity model based on Gower's similarity coefficient which measures the relevance between the query image and the target images, and use of multiclass Support Vector Machine (SVM) for classifying the low level ultrasound image features into their corresponding high level categories. Efficiency of the above solution for ultrasound medical image retrieval and classification has been evaluated using an inprogress database, presently consisting of 478 ultrasound ovarian images. Performance-wise, in retrieval of ultrasound images, our proposed solution has demonstrated above 77% and 75% of average precision considering the first 20 and 40 retrieved results respectively, and an average classification accuracy of 86.90%. C1 [Sohail, Abu Sayeed Md; Mudur, Sudhir P.] Concordia Univ, Dept Comp Sci & Software Engn, Montreal, PQ, Canada. [Rahman, Md Mahmudur] Natl Inst Hlth, US Natl Lab Med, Bethesda, MD USA. [Bhattacharya, Prabir] Univ Cincinnati, Dept Comp Sci, Cincinnati, OH USA. [Krishnamurthy, Srinivasan] Royal Victoria Hosp, Dept Obstet & Gynecol, Montreal, PQ, Canada. RP Sohail, AM (reprint author), Concordia Univ, Dept Comp Sci & Software Engn, Montreal, PQ, Canada. EM a_sohai@encs.concordia.ca; mahrahm73@gmail.com; bhattapr@ucmail.uc.edu; krishnaindu@gmail.com; mudur@encs.concordia.ca NR 10 TC 8 Z9 8 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 288 EP 291 DI 10.1109/ISBI.2010.5490352 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400077 ER PT S AU Sussman, DL Yao, JH Summers, RM AF Sussman, Daniel Lewis Yao, Jianhua Summers, Ronald M. GP IEEE TI AUTOMATED MEASUREMENT AND SEGMENTATION OF ABDOMINAL ADIPOSE TISSUE IN MRI SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE abdominal MRI; adipose tissue; segmentation; quantification; intensity inhomogeneity ID UNSUPERVISED ASSESSMENT; BODY-FAT; IMAGES AB Obesity has become widespread in America and has been identified as a risk factor for many illnesses. Measuring adipose tissue (AT) with traditional means is often unreliable and inaccurate. MRI provides a safe and minimally invasive means to measure AT accurately and segment visceral AT from subcutaneous AT. However, MRI is often corrupted by image artifacts which make manual measurements difficult and time consuming. We present a fully automated method to measure and segment abdominal AT in MRI. Our method uses non-parametric non-uniform intensity normalization (N3) to correct for image artifacts and inhomogeneities, fuzzy c-means to cluster AT regions and active contour models to separate subcutaneous and visceral AT. Our method was able to measure images with severe intensity inhomogeneities and demonstrated agreement with two manual users that was close to the agreement between the manual users. C1 [Sussman, Daniel Lewis; Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Sussman, DL (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM sussmandl@mail.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 936 EP 939 DI 10.1109/ISBI.2010.5490141 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400239 ER PT S AU Caban, JJ Rheingans, P AF Caban, Jesus J. Rheingans, Penny GP IEEE TI RELATIONAL STATISTICAL DEFORMATION MODELS FOR MORPHOLOGICAL IMAGE ANALYSIS AND CLASSIFICATION SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Statistical model; morphological analysis; deformation models; classification; Alzheimers disease. AB As medical imaging datasets continue to grow, interest in effective ways to analyze the statistical properties and data variability within those datasets has surged. Accurate analysis of the morphological statistical properties of a group of images has proven to be extremely important in medical imaging. This paper introduces Relational Statistical Deformation Models, or RSDMs, as a generic modeling technique to capture the morphological statistical deformation properties of a collection of images. Deformation fields, such as those obtained from non-linear registration techniques, are used to learn the morphological properties of a group of images and to train a statistical model capable of solving multiple imaging tasks such as image classification. To compensate for noise and registration errors, RSDM treats each local deformation as a random variable and builds the statistical model as a Markov Random Field (MRF). Once an RSDM model has been created, the same model can be used to solve multiple imaging tasks such as image classification, diagnosis, generation, and denoising. The focus of this paper is to introduce RSDM models and illustrate their effectiveness in image classification tasks. To show the advantages and limitations of RSDMs, a collection of brain MR images was used to create a model to automatically identify subjects with Alzheimer's. C1 [Caban, Jesus J.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Rheingans, Penny] Univ Maryland, Dept Comp Sci, College Pk, MD USA. RP Caban, JJ (reprint author), NIH, Natl Lib Med, Bethesda, MD 20892 USA. EM jesus.caban@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 1333 EP 1336 DI 10.1109/ISBI.2010.5490243 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400339 ER PT S AU Aman, JM Yao, JH Summers, RM AF Aman, Javed M. Yao, Jianhua Summers, Ronald M. GP IEEE TI CONTENT-BASED IMAGE RETRIEVAL ON CT COLONOGRAPHY USING ROTATION AND SCALE INVARIANT FEATURES AND BAG-OF-WORDS MODEL SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Content-Based Image Retrieval; CT Colonography; Computer-Aided Detection; Bag-of-Words; Scale Invariant Features ID AIDED POLYP DETECTION; POPULATION AB We present a content-based image retrieval (CBIR) paradigm to enhance computed tomographic colonography computer-aided detection (CTCCAD). Our method uses scale-invariant feature transform (SIFT) features in conjunction with the bag-of-words model to describe and differentiate 3D images of CTCCAD detections. We evaluate the performance of our system using both digital colon phantoms and detections form CTCCAD. Our method shows promise in distinguishing common structures found within the colon. C1 [Aman, Javed M.; Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Aman, JM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Radiol & Imaging Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 4 Z9 4 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 1357 EP 1360 DI 10.1109/ISBI.2010.5490249 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400345 ER PT S AU Girgis, HZ Mitchell, BR Dassopoulos, T Mullin, G Hager, G AF Girgis, H. Z. Mitchell, B. R. Dassopoulos, T. Mullin, G. Hager, G. GP IEEE TI AN INTELLIGENT SYSTEM TO DETECT CROHN'S DISEASE INFLAMMATION IN WIRELESS CAPSULE ENDOSCOPY VIDEOS SO 2010 7TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING: FROM NANO TO MACRO SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 7th IEEE International Symposium on Biomedical Imaging: From Nano to Macro CY APR 14-17, 2010 CL Rotterdam, NETHERLANDS SP IEEE, Engn Med Biol Soc, Signal Processing Soc DE Wireless Capsule Endoscopy; Crohn's disease; inflammation detection and the mean shift algorithm AB A Wireless Capsule Endoscope (WCE) is a small device that is capable of acquiring thousands of images as it travels through the gastrointestinal track. WCE is becoming a widely accepted method which physicians use in the diagnosis of Crohn's disease, an inflammatory disease that occurs mainly in the small intestine. In this article we present a novel method to detect those images showing inflammation among the thousands of images acquired by the WCE. Further, our method is capable of delineating the inflammation region(s) in each detected frame. Our system utilizes the mean-shift algorithm to find centers of candidate regions that may show Crohn's disease inflammation. Then the system classifies these regions by a trained Support Vector Machine. We have trained, validated and tested our method on three mutually exclusive sets. Our system's testing accuracy, specificity and sensitivity are 87%, 93% and 80% respectively. C1 [Girgis, H. Z.; Mitchell, B. R.; Hager, G.] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. [Mullin, G.] Johns Hopkins Univ Hosp, Baltimore, MD USA. [Dassopoulos, T.] Washington Univ, Sch Med, St Louis, MO USA. [Girgis, H. Z.] Natl Inst Hlth, NCBI, Natl Lib Med, Bethesda, MD USA. RP Girgis, HZ (reprint author), Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. OI Mullin, Gerard/0000-0001-5317-6788 FU National Institutes of Health [5R21EB8227-2]; Johns Hopkins University FX This work was supported in part by National Institutes of Health under Grant 5R21EB8227-2 and Johns Hopkins University internal funds. NR 13 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-4126-6 J9 I S BIOMED IMAGING PY 2010 BP 1373 EP 1376 DI 10.1109/ISBI.2010.5490253 PG 4 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Imaging Science & Photographic Technology SC Engineering; Science & Technology - Other Topics; Imaging Science & Photographic Technology GA BTS82 UT WOS:000287997400349 ER PT S AU Horovitz, SG Berman, BD Hallett, M AF Horovitz, Silvina G. Berman, Brian D. Hallett, Mark GP IEEE TI Real time BOLD functional MRI neuro-feedback affects functional connectivity SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID CORTEX; EEG; FMRI AB Functional connectivity in the resting state based on BOLD functional MRI (fMRI) has been used mainly to observe brain networks while subjects 'do nothing'. The same principle, however, can be used for any other steady-state brain condition. In this study, we compared the connectivity of the motor area during simple finger tapping with and without real time neuro-feedback of the activation in the hand motor area. The presence of the neuro-feedback not only induces correlations between the visual and motor areas, but also increases basal ganglia involvement and bilateral motor cortex connectivity. C1 [Horovitz, Silvina G.; Berman, Brian D.; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Horovitz, SG (reprint author), Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. EM horovits@mail.nih.gov; bermanb2@mail.nih.gov; hallettm@mail.nih.gov NR 15 TC 3 Z9 3 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 4270 EP 4273 DI 10.1109/IEMBS.2010.5627170 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964004167 ER PT S AU Tomasi, D Volkow, ND AF Tomasi, Dardo Volkow, Nora D. GP IEEE TI Ultrafast method for mapping local functional connectivity hubs in the human brain SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID RESTING-STATE DATA; SMALL-WORLD; ALZHEIMERS-DISEASE; CORTICAL HUBS; LOW-FREQUENCY; DEFAULT MODE; NETWORKS; FMRI; FLUCTUATIONS; ORGANIZATION AB Brain networks with energy-efficient hubs might support the high cognitive performance of humans and a better understanding of their organization is of relevance not only for studying normal brain development and plasticity but also neuropsychiatric disorders. Here we propose an ultra-fast method to map the distribution of the functional connectivity density (FCD) in the human brain. The method was tested in 972 subjects from a large repository of magnetic resonance imaging (MRI) time series collected in resting conditions. Consistently across research sites, a region located in the ventral precuneus was the area with the highest FCD, which suggest that this is a prominent functional hub in the brain. In addition regions located in the paracentral lobule, cuneus, inferior parietal, and posterior cingulate cortices had localized high FCD, suggesting that these regions also include prominent functional connectivity hubs. C1 [Tomasi, Dardo; Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. RP Tomasi, D (reprint author), NIAAA, Bethesda, MD 20892 USA. EM tomasi@bnl.gov; nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015 NR 26 TC 6 Z9 6 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 4274 EP 4277 DI 10.1109/IEMBS.2010.5626180 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964004168 ER PT S AU Raman, B Stopfer, M AF Raman, Baranidharan Stopfer, Mark GP IEEE TI Analysis of trial-by-trial variability in stimulus-evoked neural activity SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID OLFACTORY-BULB; INFORMATION AB Using standard dimensionality reduction analysis we examined the stimulus-evoked neural activity over time and their variability across trials. Consistent with earlier results, we found that odor pulses evoked spatio-temporal responses distributed throughout an ensemble of simultaneous recorded neurons. Responses clustered based on odor identity despite the presence of a relatively small amount of trial-by-trial variability. We found that this scatter across trials can be reduced using a simple linear projection of the data. C1 [Raman, Baranidharan] Washington Univ, Dept Biomed Engn, St Louis, MO 63136 USA. [Stopfer, Mark] Natl Inst Hlth, Bethesda, MD 20892 USA. RP Raman, B (reprint author), Washington Univ, Dept Biomed Engn, St Louis, MO 63136 USA. EM barani@wustl.edu; stopferm@mail.nih.gov FU Department of Biomedical Engineering at Washington University [NIH-NICHD] FX This work was supported in part by startup funds provided by the Department of Biomedical Engineering at Washington University to Barani Raman and by an intramural grant from NIH-NICHD to Mark Stopfer. NR 9 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 4320 EP 4322 DI 10.1109/IEMBS.2010.5626198 PG 3 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964004179 ER PT S AU Fairley, J Johnson, AN Georgoulas, G Vachtsevanos, G AF Fairley, Jacqueline Johnson, Ashley N. Georgoulas, George Vachtsevanos, George GP IEEE TI Automated polysomnogram artifact compensation using the generalized singular value decomposition algorithm SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) ID EEG AB Manual/visual polysomnogram (psg) analysis is a standard and commonly implemented procedure utilized in the diagnosis and treatment of sleep related human pathologies. Current technological trends in psg analysis focus upon translating manual psg analysis into automated/computerized approaches. A necessary first step in establishing efficient automated human sleep analysis systems is the development of reliable pre-processing tools to discriminate between outlier/artifact instances and data of interest. This paper investigates the application of an automated approach, using the generalized singular value decomposition algorithm, to compensate for specific psg artifacts. C1 [Fairley, Jacqueline] Emory Univ, Sch Med, Dept Neurol, NINDS, Atlanta, GA 30322 USA. [Johnson, Ashley N.; Vachtsevanos, George] Georgia Inst Technol, Atlanta, GA 30332 USA. [Georgoulas, George] Inst Educ Technol Epirus, Dept Informat & commun technol, Epirus, Greece. RP Fairley, J (reprint author), Emory Univ, Sch Med, Dept Neurol, NINDS, Atlanta, GA 30322 USA. EM jafairl@emory.edu; ashley.johnson@gatech.edu; georgoul@teiion.gr; gjv@ece.gatech.edu FU National Institute for Neurological Disorders and Stroke (NINDS) [NS055015-03]; Facilitating Academic Careers in Engineering and Science (FACES); Georgia Institute of Technology and Emory University FX This work was supported in part by the National Institute for Neurological Disorders and Stroke (NINDS) under Grant NS055015-03 and the National Science Foundation sponsored program Facilitating Academic Careers in Engineering and Science (FACES) at the Georgia Institute of Technology and Emory University. NR 14 TC 2 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 5097 EP 5100 DI 10.1109/IEMBS.2010.5626213 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964005121 ER PT S AU Sikdar, S Ortiz, R Gebreab, T Gerber, LH Shah, JP AF Sikdar, Siddhartha Ortiz, Robin Gebreab, Tadesse Gerber, Lynn H. Shah, Jay P. GP IEEE TI Understanding the Vascular Environment of Myofascial Trigger Points using Ultrasonic Imaging and Computational Modeling SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) DE Chronic pain; myofascial trigger points; Doppler ultrasonic imaging; compartment modeling AB Myofascial pain syndrome (MPS) is a common, yet poorly understood, acute and chronic pain condition. MPS is characterized by local and referred pain associated with hyperirritable nodules known as myofascial trigger points (MTrPs) that are stiff, localized spots of exquisite tenderness in a palpable taut band of skeletal muscle. Recently, our research group has developed new ultrasound imaging methods to visualize and characterize MTrPs and their surrounding soft tissue. The goal of this paper was to quantitatively analyze Doppler velocity waveforms in blood vessels in the neighborhood of MTrPs to characterize their vascular environment. A lumped parameter compartment model was then used to understand the physiological origin of the flow velocity waveforms. 16 patients with acute neck pain were recruited for the study and the blood vessels in the upper trapezius muscle in the neighborhood of palpable MTrPs were imaged using Doppler ultrasound. Preliminary findings show that symptomatic MTrPs have significantly higher peak systolic velocities and negative diastolic velocities compared to latent MTrPs and normal muscle sites. Using compartment modeling, we show that a constricted vascular bed and an enlarged vascular volume could explain the observed flow waveforms with retrograde diastolic flow. C1 [Sikdar, Siddhartha] George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Ortiz, Robin] George Mason Univ, Ctr Chron Illness & Disabil, Fairfax, VA 22030 USA. [Gebreab, Tadesse; Gerber, Lynn H.; Shah, Jay P.] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Sikdar, S (reprint author), George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. EM ssikdar@gmu.edu FU NIAMS NIH HHS [R01 AR057348, R01 AR057348-01A1] NR 8 TC 12 Z9 12 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 5302 EP 5305 DI 10.1109/IEMBS.2010.5626326 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964005175 PM 21096064 ER PT S AU Eranki, A Bellini, L Prosser, L Stanley, C Bland, D Alter, K Damiano, D Sikdar, S AF Eranki, Avinash Bellini, Lindsey Prosser, Laura Stanley, Christopher Bland, Daniel Alter, Katharine Damiano, Diane Sikdar, Siddhartha GP IEEE TI Measurement of Tendon Velocities using Vector Tissue Doppler Imaging: A Feasibility Study SO 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 32nd Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBC 10) CY AUG 30-SEP 04, 2010 CL Buenos Aires, ARGENTINA SP IEEE Engn Med & Biol Soc (EMBS) DE Ultrasonography; vector Doppler; tissue motion; tendon motion; musculoskeletal imaging; signal processing ID MUSCLE; ULTRASOUND AB We have developed a vector Doppler ultrasound imaging method to directly quantify the magnitude and direction of muscle and tendon velocities during movement. The goal of this study was to evaluate the feasibility of using vector Tissue Doppler Imaging (vTDI) for estimating the tibialis anterior tendon velocities during dorsiflexion in children with cerebral palsy who have foot drop. Our preliminary results from this study show that tendon velocities estimated using vTDI have a strong linear correlation with the joint angular velocity estimated using a conventional 3D motion capture system. We observed a peak tendon velocity of 5.66 +/- 1.45 cm/s during dorsiflexion and a peak velocity of 8.83 +/- 2.13 cm/s during the passive relaxation phase of movement. We also obtained repeatable results from the same subject 3 weeks apart. Direct measurements of muscle and tendon velocities may be used as clinical outcome measures and for studying efficiency of movement control. C1 [Eranki, Avinash; Sikdar, Siddhartha] George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Bellini, Lindsey; Prosser, Laura; Stanley, Christopher; Bland, Daniel; Alter, Katharine; Damiano, Diane] NIH, Dept Rehabil Med, Funct & Appl Biomech Scet, Bethesda, MD 20892 USA. RP Sikdar, S (reprint author), George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. EM ssikdar@gmu.edu NR 10 TC 5 Z9 5 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4244-4124-2 J9 IEEE ENG MED BIO PY 2010 BP 5310 EP 5313 DI 10.1109/IEMBS.2010.5626323 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BTS36 UT WOS:000287964005177 ER PT S AU Wei, ZS Yao, JH Wang, SJ Summers, RM AF Wei, Zhuoshi Yao, Jianhua Wang, Shijun Summers, Ronald M. BE Matthews, MB TI Haustral Fold Detection for CT Colonography Images Using Gabor Filter SO 2010 CONFERENCE RECORD OF THE FORTY FOURTH ASILOMAR CONFERENCE ON SIGNALS, SYSTEMS AND COMPUTERS (ASILOMAR) SE Conference Record of the Asilomar Conference on Signals Systems and Computers LA English DT Proceedings Paper CT 44th Asilomar Conference on Signals, Systems and Computers CY NOV 07-10, 2010 CL Pacific Grove, CA SP IEEE, IEEE Signal Proc Soc ID POLYP DETECTION AB Haustral folds are anatomically meaningful structures in the human colon. In this paper we present a method for haustral fold detection for CT colonography images. The 3D colon surface is first preprocessed into a 2D flattened colon. Then the image processing is done on 2D images. The proposed method makes used of a 2D Gabor filter to extract the feature of haustral folds. Then Sobel operator is performed on the filtering results to acquire the edge of the folds. Finally the folds are identified using thresholding method. Experimental results show that our method has a satisfactory detection rate on haustral folds. C1 [Wei, Zhuoshi; Yao, Jianhua; Wang, Shijun; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Wei, ZS (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1058-6393 BN 978-1-4244-9721-8 J9 CONF REC ASILOMAR C PY 2010 BP 329 EP 331 PG 3 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA BAW92 UT WOS:000305886000062 ER PT S AU Wang, SM AF Wang, Shumin GP IEEE TI A Quasi Block Cholesky Algorithm for Fast Direct Solution of Integral-Equation Method Based on the PMCHWT Formulation SO 2010 IEEE ANTENNAS AND PROPAGATION SOCIETY INTERNATIONAL SYMPOSIUM SE IEEE Antennas and Propagation Society International Symposium LA English DT Proceedings Paper CT 2010 IEEE International Symposium Antennas and Propagation/CNC-USNC/URSI Radio Science Meeting CY JUL 11-17, 2010 CL Toronto, CANADA SP IEEE, URSI C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Wang, SM (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr 10-B1D728, Bethesda, MD 20892 USA. EM james.wang@ieee.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-3965 BN 978-1-4244-4968-2 J9 IEEE ANTENNAS PROP PY 2010 PG 4 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA BTL34 UT WOS:000287212403166 ER PT S AU Li, HS Kim, E Huang, XL He, L AF Li, Hongsheng Kim, Edward Huang, Xiaolei He, Lei GP IEEE TI Object Matching with a Locally Affine-Invariant Constraint SO 2010 IEEE CONFERENCE ON COMPUTER VISION AND PATTERN RECOGNITION (CVPR) SE IEEE Conference on Computer Vision and Pattern Recognition LA English DT Proceedings Paper CT 23rd IEEE Conference on Computer Vision and Pattern Recognition (CVPR) CY JUN 13-18, 2010 CL San Francisco, CA SP IEEE Comp Soc ID ALGORITHM; SCALE AB In this paper, we present a new object matching algorithm based on linear programming and a novel locally affine-invariant geometric constraint. Previous works have shown possible ways to solve the feature and object matching problem by linear programming techniques [9], [10]. To model and solve the matching problem in a linear formulation, all geometric constraints should be able to be exactly or approximately reformulated into a linear form. This is a major difficulty for this kind of matching algorithms. We propose a novel locally affine-invariant constraint which can be exactly linearized and requires a lot fewer auxiliary variables than the previous work [10] does. The key idea behind it is that each point can be exactly represented by an affine combination of its neighboring points, whose weights can be solved easily by least squares. The resulting overall objective function can then be solved efficiently by linear programming techniques. Our experimental results on both rigid and non-rigid object matching show the advantages of the proposed algorithm. C1 [Li, Hongsheng; Kim, Edward; Huang, Xiaolei] Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA. [He, Lei] Natl Lib Med, Bethesda, MD 20894 USA. RP Li, HS (reprint author), Lehigh Univ, Dept Comp Sci & Engn, Bethlehem, PA 18015 USA. EM h.li@lehigh.edu; edk208@lehigh.edu; xih206@lehigh.edu; lei.he@nih.gov NR 17 TC 20 Z9 20 U1 0 U2 1 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 1063-6919 BN 978-1-4244-6984-0 J9 PROC CVPR IEEE PY 2010 BP 1641 EP 1648 DI 10.1109/CVPR.2010.5539776 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering; Mathematics, Applied; Imaging Science & Photographic Technology SC Computer Science; Mathematics; Imaging Science & Photographic Technology GA BTN70 UT WOS:000287417501087 ER PT S AU Liu, JM White, JM Summers, RM AF Liu, Jiamin White, Jacob M. Summers, Ronald M. GP IEEE TI AUTOMATED DETECTION OF BLOB STRUCTURES BY HESSIAN ANALYSIS AND OBJECT SCALE SO 2010 IEEE INTERNATIONAL CONFERENCE ON IMAGE PROCESSING SE IEEE International Conference on Image Processing ICIP LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 26-29, 2010 CL Hong Kong, PEOPLES R CHINA SP IEEE, IEEE Signal Process Soc DE blob detection; Hessian matrix; object scale ID NODULES AB Automated detection of blob-like structures is desirable in many biomedical applications such as nodule detection in radiographs and CT images, lymph nodes detection in CT images, and cell counting or tracking in biological images. Multiscale analysis of Hessian matrix is widely used for enhancement or detection of blob-like structures in two-dimensional (2D) and three-dimensional (3D) images. We proposed a new blob detector and a new detection response measure, blobness, based on eigenvalues of the Hessian matrix and local object scale. Pixels with higher blobness are clustered as detected blobs. We evaluated our method by comparison with two existing methods on both simulated and real images. Our results indicated that our automated blob detector had better performance on those images especially when the blobs were close to each other. Our method can be easily extended to 3D for computer-aided detection of blob-like structures in medical images. C1 [Liu, Jiamin; White, Jacob M.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Liu, JM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 1C368X,MSC 1182, Bethesda, MD 20892 USA. NR 11 TC 9 Z9 9 U1 1 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 978-1-4244-7994-8 J9 IEEE IMAGE PROC PY 2010 BP 841 EP 844 DI 10.1109/ICIP.2010.5653499 PG 4 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA BTP82 UT WOS:000287728000208 ER PT S AU Strawn, N Yao, JH AF Strawn, Nathaniel Yao, Jianhua GP IEEE TI TRACKING KIDNEY TUMOR DIMENSIONAL MEASUREMENTS VIA IMAGE MORPHING SO 2010 IEEE INTERNATIONAL CONFERENCE ON IMAGE PROCESSING SE IEEE International Conference on Image Processing ICIP LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 26-29, 2010 CL Hong Kong, PEOPLES R CHINA SP IEEE, IEEE Signal Process Soc DE kidney tumor; image morphing; tumor measurement AB Monitoring the evolution of renal cancer is essential in clinical oncology trials. However, manual tumor measurements are subjective and inconsistent. We have developed and implemented an efficient image-morphing-based method to track dimensional measurements in serial medical images. Our method extracts feature blocks centered at edges detected in source and target images, and then applies a fast, approximate nearest-neighbor algorithm to match these features. This matching gives rise to a global feature flow, and this feature flow can be used to track dimensional measurements. C1 [Strawn, Nathaniel; Yao, Jianhua] NIH, Radiol & Image Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Strawn, N (reprint author), NIH, Radiol & Image Sci Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 978-1-4244-7994-8 J9 IEEE IMAGE PROC PY 2010 BP 1721 EP 1724 DI 10.1109/ICIP.2010.5652976 PG 4 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA BTP82 UT WOS:000287728001203 ER PT S AU Chen, XJ Yao, JH Ying, ZG Bagci, U AF Chen, Xinjian Yao, Jianhua Ying Zhuge Bagci, Ulas GP IEEE TI 3D AUTOMATIC ANATOMY SEGMENTATION BASED ON GRAPH CUT-ORIENTED ACTIVE APPEARANCE MODELS SO 2010 IEEE INTERNATIONAL CONFERENCE ON IMAGE PROCESSING SE IEEE International Conference on Image Processing ICIP LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 26-29, 2010 CL Hong Kong, PEOPLES R CHINA SP IEEE, IEEE Signal Proc Soc DE Object Segmentation; Active Appearance Models; Live Wire; Graph Cut ID IMAGE SEGMENTATION; SHAPE MODELS; ALGORITHMS AB In this paper, we propose a novel 3D automatic anatomy segmentation method based on the synergistic combination of active appearance models (AAM), live wire (LW) and graph cut (GC). The proposed method consists of three main parts: model building, initialization and segmentation. For the model building part, an AAM model is constructed and the LW cost function is trained. For the initialization part, an improved iterative model refinement algorithm is proposed for the AAM optimization, which synergistically combines the AAM and LW method (OAAM). And a multi-object strategy is applied to help the object initialization. A pseudo 3D initialization strategy is employed to segment the organs slice by slice via multi-object OAAM method. The model constraints are applied to the initialization result. For the segmentation part, the object shape information generated from the initialization step is integrated into the GC cost computation. And an iterative GCOAAM method is proposed for object delineation. This method is a general method and can be applied to any organ segmentation. The proposed method was tested on the clinical liver and kidney CT data sets. The results showed the following: (a) an overall segmentation accuracy of true positive fraction>93.5%, and false positive fraction<0.2% can be achieved. (b) The initialization performance is improved by combining the AAM and LW. (c) The multi-object strategy greatly helps the initialization due to interobject constraints. C1 [Chen, Xinjian; Yao, Jianhua] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20814 USA. [Ying Zhuge] NIH, NCI, Radiat Oncol Branch, Bethesda, MD 20814 USA. [Bagci, Ulas] Univ Nottingham, Sch Comp Sci, Collaborat Med Image Anal Grp, Nottingham NG8 1PB, England. RP Chen, XJ (reprint author), NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20814 USA. EM chenx6@mail.nih.gov OI Bagci, Ulas/0000-0001-7379-6829 NR 15 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 978-1-4244-7994-8 J9 IEEE IMAGE PROC PY 2010 BP 3653 EP 3656 DI 10.1109/ICIP.2010.5652101 PG 4 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA BTP82 UT WOS:000287728003178 ER PT S AU Chang, KW Liu, JM Yao, JH Summers, RM AF Chang, Kevin W. Liu, Jiamin Yao, Jianhua Summers, Ronald M. GP IEEE TI IMPROVED METHOD FOR PREDICTING POLYP LOCATION FROM CT COLONOGRAPHY FOR OPTICAL COLONOSCOPY SO 2010 IEEE INTERNATIONAL CONFERENCE ON IMAGE PROCESSING SE IEEE International Conference on Image Processing ICIP LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 26-29, 2010 CL Hong Kong, PEOPLES R CHINA SP IEEE, IEEE Signal Process Soc DE CT colonography; Optical colonoscopy; Centerline Fitting; Polyp Detection; B-Spline ID CENTERLINE AB The ability to accurately locate a polyp found on computed tomographic colonography (CTC) at subsequent optical colonoscopy (OC) is an important part of CTC for colorectal cancer screening. A previous study has shown that a polyp's normalized distance along the colon centerline (NDACC) derived from CTC data can be utilized to predict its location at OC. We present a novel and automated method using a high degree uniform B-Spline curve fitting of the colon centerline on CTC to simulate OC colonoscope paths in order to more accurately predict polyp position. This evaluation is to determine whether the B-Spline method produces statistically significant improvement over the NDACC method in terms of prediction errors within 5 and 10 cm (+/- 1 colonoscope mark). Two-tailed Fisher's Exact Tests indicate the B-Spline method is superior to the NDACC method, especially for locating polyps in the central portion of the colon. The ability to predict polyp locations within 5 and 10 cm increased 31.5 % and 10.2 % respectively using the B-Spline method. C1 [Chang, Kevin W.; Liu, Jiamin; Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Radiol & Imaging Sci Dept, Imaging Biomarkers & Comp Aided Diag Lab, Bethesda, MD 20892 USA. RP Chang, KW (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci Dept, Imaging Biomarkers & Comp Aided Diag Lab, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 978-1-4244-7994-8 J9 IEEE IMAGE PROC PY 2010 BP 4365 EP 4368 DI 10.1109/ICIP.2010.5652341 PG 4 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA BTP82 UT WOS:000287728004103 ER PT S AU Krieger, A Iordachita, I Song, SE Cho, NB Guion, P Fichtinger, G Whitcomb, LL AF Krieger, Axel Iordachita, Iulian Song, Sang-Eun Cho, Nathan B. Guion, Peter Fichtinger, Gabor Whitcomb, Louis L. GP IEEE TI Development and Preliminary Evaluation of an Actuated MRI-Compatible Robotic Device for MRI-Guided Prostate Intervention SO 2010 IEEE INTERNATIONAL CONFERENCE ON ROBOTICS AND AUTOMATION (ICRA) SE IEEE International Conference on Robotics and Automation ICRA LA English DT Proceedings Paper CT IEEE International Conference on Robotics and Automation (ICRA) CY MAY 03-08, 2010 CL Anchorage, AK SP IEEE ID TRANSGLUTEAL BIOPSIES; NEEDLE PLACEMENT; FIELD SYSTEM; 1.5 T; CANCER; INTEGRATION; GLAND; BRACHYTHERAPY; FEASIBILITY; MANIPULATOR AB This paper reports the design, development, and magnetic resonance imaging (MRI) compatibility evaluation of an actuated transrectal prostate robot for MRI-guided intervention. The robot employs an actuated needle guide with the goal of reducing interventional procedure times and increasing needle placement accuracy. The design of the robot, employing piezo-ceramic-motor actuated needle guide positioning and manual needle insertion, is reported. Results of a MRI compatibility study show no reduction of MRI image signal-to-noise-ratio (SNR) with the motors disabled and a 40% to 60% reduction in SNR with the motors enabled. The addition of radio-frequency (RF) shielding is shown to significantly reduce image SNR degradation due to the presence of the robotic device. C1 [Krieger, Axel] Sentinelle Med Inc, Toronto, ON, Canada. [Krieger, Axel; Iordachita, Iulian; Song, Sang-Eun; Cho, Nathan B.; Whitcomb, Louis L.] Johns Hopkins Univ, LCSR, Baltimore, MD USA. [Krieger, Axel; Iordachita, Iulian; Song, Sang-Eun; Cho, Nathan B.; Whitcomb, Louis L.] Johns Hopkins Univ, Dept Engn Mech, Baltimore, MD USA. [Fichtinger, Gabor] Queens Univ, Sch Comp, Kingston, ON K7L 3N6, Canada. [Guion, Peter] Natl Inst Hlth, Natl Canc Inst, Radiat Oncol Branch, Bethesda, MD USA. RP Krieger, A (reprint author), Sentinelle Med Inc, Toronto, ON, Canada. RI Whitcomb, Louis/A-3322-2010; Iordachita, Iulian/A-3507-2010 OI Iordachita, Iulian/0000-0002-2510-9008 NR 41 TC 16 Z9 17 U1 0 U2 5 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1050-4729 BN 978-1-4244-5040-4 J9 IEEE INT CONF ROBOT PY 2010 BP 1066 EP 1073 DI 10.1109/ROBOT.2010.5509727 PG 8 WC Automation & Control Systems; Engineering, Electrical & Electronic; Robotics SC Automation & Control Systems; Engineering; Robotics GA BSD39 UT WOS:000284150004001 ER PT S AU Li, M Kapoor, A Mazilu, D Wood, B Horvath, KA AF Li, Ming Kapoor, Ankur Mazilu, Dumitru Wood, Bradford Horvath, Keith A. GP IEEE TI Cardiac Interventions under MRI Guidance using Robotic Assistance SO 2010 IEEE INTERNATIONAL CONFERENCE ON ROBOTICS AND AUTOMATION (ICRA) SE IEEE International Conference on Robotics and Automation ICRA LA English DT Proceedings Paper CT IEEE International Conference on Robotics and Automation (ICRA) CY MAY 03-08, 2010 CL Anchorage, AK SP IEEE ID PROSTATE INTERVENTIONS; IMPLANTATION; PLACEMENT; VALVE AB Transapical aortic valve replacement under MRI guidance in a beating heart is a recent minimally invasive technique that could benefit from a surgical assistant system. We present a robotic surgical assistant system that can precisely and repeatably deliver aortic valve prostheses. The surgical system consists of an imaging system, an Innomotion robotic arm, a 3-DoF valve delivery module and user interfaces. Interactive control allows the physician to remain in the loop and adjust the orientation and position using real-time MR feedback. The 3-DoF valve delivery module is developed to deploy both balloon-expandable and self-expanding stented prostheses. We use a new compact fiducial that can be placed close to the volume of interest and requires a single image plane for image based robot registration. We evaluate the MRI compatible valve delivery module for both types of prostheses. The accuracy for prosthesis delivery is about 0.8 mm and 1.5 mm, for self-expanding and balloon-expandable prostheses, respectively. Preliminary results in ex-vivo experimentation suggest that the robotic system can be translated into animal and clinical models. C1 [Li, Ming; Mazilu, Dumitru; Horvath, Keith A.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Li, M (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lim2@mail.nih.gov; kapooran@mail.nih.gov; mazilud@mail.nih.gov; bwood@mail.nih.gov; horvathka@mail.nih.gov NR 20 TC 4 Z9 4 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1050-4729 BN 978-1-4244-5040-4 J9 IEEE INT CONF ROBOT PY 2010 BP 2574 EP 2579 DI 10.1109/ROBOT.2010.5509151 PG 6 WC Automation & Control Systems; Engineering, Electrical & Electronic; Robotics SC Automation & Control Systems; Engineering; Robotics GA BSD39 UT WOS:000284150000027 ER PT S AU Seidel, J Xi, WZ Kakareka, JW Pohida, TJ Green, MV Choyke, PL AF Seidel, Jurgen Xi, Wenze Kakareka, John W. Pohida, Thomas J. Green, Michael. V. Choyke, Peter L. GP IEEE TI A Positron Projection Imager for Whole-Body Mouse Imaging SO 2010 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD (NSS/MIC) SE IEEE Nuclear Science Symposium Conference Record LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium (NSS)/Medical Imaging Conference (MIC)/17th International Workshop on Room-Temperature Semiconductor X-ray and Gamma-ray Detectors CY OCT 30-NOV 06, 2010 CL Knoxville, TN SP Inst Elect & Elect Engineers, Nucl & Plasma Sci Soc, IEEE AB Certain experimental questions in molecular imaging can be answered with projection imaging systems rather than tomographs. Accordingly, we have designed, assembled and are now testing a projection imaging system able to visualize the whole-body distribution of positron-emitting compounds in mouse-size animals. When completed, this positron projection imager (PPI) will plug into the MONICA portable dual gamma camera system to provide the user with a positron projection imaging capability and all of the data acquisition and analysis features available with MONICA for single photon projection imaging. C1 [Seidel, Jurgen; Xi, Wenze; Green, Michael. V.] NCI, SAIC Frederick, Bethesda, MD 20892 USA. [Xi, Wenze] Thomas Jefferson Natl Accelerator Facil, Newport News, VA 23606 USA. [Kakareka, John W.; Pohida, Thomas J.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Seidel, J (reprint author), NCI, SAIC Frederick, Bethesda, MD 20892 USA. EM jseidel1@mail.nih.gov; wxi@jlab.org; john.kakareka@nih.gov; tom.pohida@nih.gov; greenmich@mail.nih.gov; peter.choyke@nih.gov FU SAIC-Frederick, Inc. under OTS/NCI [HHSN261200800001E]; NIH; NCI FX This work was supported in part by SAIC-Frederick, Inc. under OTS/NCI contract HHSN261200800001E and the Intramural Research Program of the NIH, NCI. NR 1 TC 2 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 978-1-4244-9106-3 J9 IEEE NUCL SCI CONF R PY 2010 BP 2206 EP 2209 PG 4 WC Engineering, Electrical & Electronic; Nuclear Science & Technology; Physics, Applied SC Engineering; Nuclear Science & Technology; Physics GA BBB94 UT WOS:000306402902080 ER PT S AU Kelley, MW AF Kelley, Matthew W. BE Herold, KE Bentley, WE Vossoughi, J TI Hair Cell Regeneration in the Mammalian Ear, Is Gene Therapy the Answer? SO 26TH SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE: SBEC 2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 26th Southern Biomedical Engineering Conference, SBEC 2010 CY APR 30-MAY 02, 2010 CL Univ Maryland, College Park, MD SP Natl Sci Fdn, Biomedical Engn Soc, Natl Canc Inst HO Univ Maryland ID INNER-EAR; MATH1; COCHLEA; EPITHELIUM; HEARING AB In vertebrates the sensation of hearing is dependent on the presence of mechanosensory hair cells located within the coiled cochlea of the inner ear. The apical surface of each hair cell contains a specialized stereociliary bundle that acts to detect sound-induced pressure waves. In mammals, hair cells are only generated during a finite period in embryogenesis. Therefore, hair cell loss, as a result of either genetic or environmental factors, leads to a permanent loss in hearing acuity. Recent results have identified some of the genes that are instructive for the formation of hair cells. In particular, forced expression of the basic helix-loop-helix transcription factor, Atoh1, was found to be sufficient to induce hair cell formation in different cell types within the embryonic inner ear. These findings suggested that expression of Atoh1 within a damaged mammalian inner ear might be sufficient to induce the formation of new hair cells. In fact, studies in mature animals that can spontaneously regenerate hair cells, such as birds, indicates that re-expression of Atoh1 is a key step in this process. In contrast, existing data indicates that Atoh1 is never re-expressed in a mature mammalian ear, regardless of the nature or degree of damage. Based on these observations, it has been suggested that induction of hair cell regeneration might be accomplished through gene therapy. The inner ear is well suited for gene transfer-based treatments as it is a relatively enclosed space with limited communication with the rest of the body. Preliminary results in animals using both adeno- and adeno-associated virus-based vectors have demonstrated that inner ear tissues can be efficiently transfected. Moreover, in one publication, forced expression of Atoh1 resulted in some degree of recovery in deafened animals. These results, while very promising, will require replication by additional laboratories as well as further study. C1 Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD USA. RP Kelley, MW (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD USA. NR 16 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-14997-9 J9 IFMBE PROC PY 2010 VL 32 BP 42 EP 44 PG 3 WC Engineering, Biomedical SC Engineering GA BBO72 UT WOS:000307744700011 ER PT S AU Schuck, P AF Schuck, P. BE Herold, KE Bentley, WE Vossoughi, J TI Fredholm Integral Equations in Biophysical Data Analysis SO 26TH SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE: SBEC 2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 26th Southern Biomedical Engineering Conference, SBEC 2010 CY APR 30-MAY 02, 2010 CL Univ Maryland, College Park, MD SP Natl Sci Fdn, Biomedical Engn Soc, Natl Canc Inst HO Univ Maryland DE regularization; analytical ultracentrifugation; optical biosensing; size distribution; affinity distribution ID SIZE-DISTRIBUTION ANALYSIS; ANALYTICAL ULTRACENTRIFUGATION; DISTRIBUTIONS; MACROMOLECULES; EQUILIBRIUM; KIND AB In the last decade, the abundant availability of computational resources has allowed for significant improvements in the interpretation of data in traditional disciplines of physical biochemistry. In particular, there are many examples where the data are fitted with a model describing a distribution of parameters, taking the form of a Fredholm integral equation. Algorithms traditionally applied in image analysis have proven highly useful to solve the corresponding ill-posed inverse problem. Two examples are presented from optical biosensing and sedimentation velocity analytical ultracentrifugation. In both examples, standard regularization techniques such as Tikhonov and maximum entropy regularization are applied, in conjunction with non-negativity constraints. Further, Bayesian adaptations of the regularization functional are possible that incorporate available prior knowledge on the system under study. Practical limitations and problems will be discussed. C1 Natl Inst Biomed Imaging & Bioengn, LBPS, NIH, Bethesda, MD USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, LBPS, NIH, Bethesda, MD USA. OI Schuck, Peter/0000-0002-8859-6966 NR 17 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-14997-9 J9 IFMBE PROC PY 2010 VL 32 BP 340 EP 343 PG 4 WC Engineering, Biomedical SC Engineering GA BBO72 UT WOS:000307744700087 ER PT S AU Ehler, M Majumdar, Z King, E Dobrosotskaya, J Chew, E Wong, W Cunningham, D Czaja, W Bonner, RF AF Ehler, Martin Majumdar, Zigurts King, Emily Dobrosotskaya, Julia Chew, Emily Wong, Wai Cunningham, Denise Czaja, Wojciech Bonner, Robert F. BE Herold, KE Bentley, WE Vossoughi, J TI High-Resolution Autofluorescence Imaging for Mapping Molecular Processes within the Human Retina SO 26TH SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE: SBEC 2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 26th Southern Biomedical Engineering Conference, SBEC 2010 CY APR 30-MAY 02, 2010 CL Univ Maryland, College Park, MD SP Natl Sci Fdn, Biomed Engn Soc Chongqing, Natl Canc Inst (NCI) HO Univ Maryland DE autofluorescence imaging; retina; macular pigment; multi-spectral; age related macular degeneration ID MACULAR PIGMENT; DEGENERATION AB Age related macular degeneration (AMD) is a common eye disease that often leads to vision loss. High levels of increased accumulation of fluorescent photoproducts appear to induce local retinal pigment epithelium (RPE) dysfunction associated with AMD. Low macular pigment level has also been identified as a risk factor for AMD. We developed multispectral noninvasive fluorescence imaging of the retina by modifying a standard fundus camera with selective filter sets. By exciting the fluorescent photoproducts at two or more wavelengths, we were able to quantify macular pigment. Our image analysis identified artifacts of the camera optics, and we propose a noninvasive modality to obtain a map of the retinal microvascularization. C1 [Ehler, Martin; Majumdar, Zigurts; King, Emily; Bonner, Robert F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, PPB LIMB SMB, Bethesda, MD 20892 USA. [Ehler, Martin; King, Emily; Dobrosotskaya, Julia; Czaja, Wojciech] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Chew, Emily; Wong, Wai; Cunningham, Denise] NIH, NEI, Bethesda, MD 20892 USA. RP Ehler, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, PPB LIMB SMB, Bethesda, MD 20892 USA. RI Bonner, Robert/C-6783-2015; OI Wong, Wai/0000-0003-0681-4016 FU Intramural ResearchProgram of NICHD/NIH; NSF [CBET0854233]; NGA [HM15820810009]; ONR [N000140910144] FX The research was funded by the Intramural ResearchProgram of NICHD/NIH, by NSF (CBET0854233), byNGA (HM15820810009), and by ONR (N000140910144).The authors gratefully acknowledge Prof. John J. Benedetto NR 8 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-14997-9 J9 IFMBE PROC PY 2010 VL 32 BP 344 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BBO72 UT WOS:000307744700088 ER PT S AU Aronova, MA Kim, YC Sousa, AA Zhang, G Leapman, RD AF Aronova, M. A. Kim, Y. C. Sousa, A. A. Zhang, G. Leapman, R. D. BE Herold, KE Bentley, WE Vossoughi, J TI Nanoscale Imaging of Chemical Elements in Biomedicine SO 26TH SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE: SBEC 2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 26th Southern Biomedical Engineering Conference, SBEC 2010 CY APR 30-MAY 02, 2010 CL Univ Maryland, College Park, MD SP Natl Sci Fdn, Biomed Engn Soc Chongqing, Natl Canc Inst (NCI) HO Univ Maryland DE Electron tomography; elemental mapping; energy-filtered imaging; scanning transmission electron microscopy ID ELECTRON; TOMOGRAPHY; CONTRAST; PROTEIN; 3D AB Imaging techniques based on transmission electron microscopy can elucidate the structure and function of macromolecular complexes in a cellular environment. In addition to providing contrast based on structure, electron microscopy combined with electron spectroscopy can also generate nanoscale contrast from endogenous chemical elements present in biomolecules, as well as from exogenous elements introduced into tissues and cells as imaging probes or as therapeutic drugs. These capabilities complement biomedical imaging used in diagnostics while also providing insight into fundamental cell biological processes. We have developed electron tomography (ET) techniques based on unconventional imaging modes in the electron microscope to map specific types of macromolecules within cellular compartments. ET is used to determine the three-dimensional structure from a series of two-dimensional projections acquired successively by tilting a specimen through a range of angles, and then by reconstructing the three-dimensional volume. We have focused on two approaches that combine ET with other imaging modes: energy filtered transmission electron microscopy (EFTEM) based on collection of inelastically scattered electrons, and scanning transmission electron microscopy (STEM) based on collection of elastically scattered electrons. EFTEM tomography provides 3D elemental mapping and STEM tomography provides 3D mapping of heavy atom clusters used to label specific macromolecular assemblies. These techniques are illustrated by EFTEM imaging of the subcellular nucleic acid distribution through measurement of the intrinsic marker, elemental phosphorus; and by STEM imaging of gold clusters used to immunolabel specific proteins within the cell nucleus. We have also used the EFTEM and STEM techniques to characterize nanoparticles that might be used as drug delivery systems. C1 [Aronova, M. A.; Sousa, A. A.; Zhang, G.; Leapman, R. D.] Nat Inst Biomed Imaging & Bioengn, NIH, 9000 Rockville Pike,Bldg 13-3N17, Bethesda, MD USA. [Kim, Y. C.] Ctr Computat Mat Sci, Naval Res Lab, Washington, DC USA. RP Aronova, MA (reprint author), Nat Inst Biomed Imaging & Bioengn, NIH, 9000 Rockville Pike,Bldg 13-3N17, Bethesda, MD USA. EM aronovaa@mail.nih.gov FU NIH FX This work was supported by the intramural research programof the NIH. NR 20 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-14997-9 J9 IFMBE PROC PY 2010 VL 32 BP 357 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BBO72 UT WOS:000307744700091 ER PT S AU Vu, Q Zhao, MH Wellner, E Truong, X Smith, PD Jin, AJ AF Vu, Q. Zhao, M. H. Wellner, E. Truong, X. Smith, P. D. Jin, A. J. BE Herold, KE Bentley, WE Vossoughi, J TI Raman-AFM Instrumentation and Characterization of SERS Substrates and Carbon Nanotubes SO 26TH SOUTHERN BIOMEDICAL ENGINEERING CONFERENCE: SBEC 2010 SE IFMBE Proceedings LA English DT Proceedings Paper CT 26th Southern Biomedical Engineering Conference, SBEC 2010 CY APR 30-MAY 02, 2010 CL Univ Maryland, College Park, MD SP Natl Sci Fdn, Biomedical Engn Soc, Natl Canc Inst HO Univ Maryland DE Atomic Force Microscope (AFM); Raman Spectroscopy; Near-field Optics; Tip-Enhanced Raman Spectroscopy (TERS); Surface-Enhanced Raman Spectroscopy (SERS); Carbon Nanotubes (CNTs) ID ATOMIC-FORCE MICROSCOPY; SPECTROSCOPY; SCATTERING AB Atomic force microscopy (AFM) is a powerful tool for structural determination at sub-nanometer resolution and nano-mechanical characterization with pico-Newton molecular force sensitivity. Raman spectroscopy, on the other hand, can provide fingerprint chemical information of samples with sub-micron resolution. Through in-house engineering and integration of commercial components, we have developed a multi-modality biological AFM and Raman-spectroscopic instrument featuring a number of unique advantages including an independent closed-loop X-Y scanning stage and Z-piezo control, high-performance optical gratings, thermoelectrically cooled and electron-multiplying charge-coupled detectors (EMCCD), active vibration inhibition, and biological environmental controls. With this new instrument, we have obtained correlated surface enhanced Raman spectroscopy (SERS) mapping and AFM topographic images of a home-grown gold-on-mica substrate with putative SERS hot spots. We have also investigated carbon nanotubes (CNTs) via AFM tip enhanced Raman spectroscopy (TERS), where the enhancement factor is quantified from the difference Raman spectrum of the CNT's G-band signature between an engaged and retracted state of a gold-coated AFM tip. The developed instrument can obtain simultaneous nanoscale structural and chemical information under controlled environmental conditions, a capability that is critical for meaningful interpretation of many anticipated biomedical applications. C1 [Vu, Q.; Zhao, M. H.; Wellner, E.; Truong, X.; Smith, P. D.; Jin, A. J.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Jin, AJ (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, 9000 Rockville Pike,Bldg 13,Room 3N18D, Bethesda, MD 20892 USA. EM jina@mail.nih.gov OI Jin, Albert/0000-0003-3826-1081 NR 18 TC 0 Z9 0 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-14997-9 J9 IFMBE PROC PY 2010 VL 32 BP 500 EP 503 PG 4 WC Engineering, Biomedical SC Engineering GA BBO72 UT WOS:000307744700128 ER PT S AU Xie, B Pearson, G AF Xie, Bo Pearson, Glenn GP IEEE TI Usability Testing by Older Americans of a Prototype Google Map Web Site To Select Nursing Homes SO 43RD HAWAII INTERNATIONAL CONFERENCE ON SYSTEMS SCIENCES VOLS 1-5 (HICSS 2010) SE Proceedings of the Annual Hawaii International Conference on System Sciences LA English DT Proceedings Paper CT 43rd Hawaii International Conference on Systems Sciences (HICSS 2010) CY JAN 05-08, 2010 CL Honolulu, HI SP Univ Hawaii, Shidler Coll Business AB We report a usability study of a prototype Google Maps web site - the "Nursing Home Screener" (NHS) site - intended for locating quality nursing homes Usability testing was conducted in April of 2008 at a health-related public library computer training class for older adults. A total of ten older adults between 57-83 years of age that had little computer experience participated in the testing. Data from the interviews, surveys, and observation showed that the Google map page was puzzling to the majority of these older adults, who lacked the knowledge and skills to be effective with it. Age-related declines in vision and fine motor skills and the library setting also contributed to these participants' difficulties in using the NHS site Based on the testing findings, we suggest a number of design and training guidelines that may help to facilitate older adults' adoption and use of Web map applications C1 [Xie, Bo] Univ Maryland, College Pk, MD 20742 USA. [Pearson, Glenn] Natl Lib Med, Bethesda, MD 20894 USA. RP Xie, B (reprint author), Univ Maryland, College Pk, MD 20742 USA. EM boxie@umd.edu; Glenn_Pearson@nlm.nih.gov NR 22 TC 0 Z9 0 U1 1 U2 1 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 1060-3425 BN 978-1-4244-5509-6 J9 P ANN HICSS PY 2010 BP 2423 EP + PG 2 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BRD18 UT WOS:000282391802065 ER PT B AU Jacobson, KA Gao, ZG Tosh, DK Sanjayan, GJ de Castro, S AF Jacobson, Kenneth A. Gao, Zhan-Guo Tosh, Dillip K. Sanjayan, Gangadhar J. de Castro, Sonia BE Borea, PA TI A(3) Adenosine Receptor Agonists: History and Future Perspectives SO A3 ADENOSINE RECEPTORS FROM CELL BIOLOGY TO PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Book Chapter ID SELECTIVE AGONISTS; HIGHLY POTENT; BIOLOGICAL-ACTIVITY; MOLECULAR-CLONING; A(3)-ADENOSINE RECEPTOR; ALLOSTERIC ENHANCERS; ADENINE NUCLEOSIDES; HIGH-AFFINITY; BINDING-SITE; DERIVATIVES C1 [Jacobson, Kenneth A.; Gao, Zhan-Guo; Tosh, Dillip K.; Sanjayan, Gangadhar J.; de Castro, Sonia] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov; ZhanguoG@intra.niddk.nih.gov; ToshD@niddk.nih.gov; sanjayangj@niddk.nih.gov; decastrs@niddk.nih.gov OI Jacobson, Kenneth/0000-0001-8104-1493 NR 72 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-90-481-3143-3 PY 2010 BP 93 EP 120 DI 10.1007/978-90-481-3144-0_6 D2 10.1007/978-90-481-3144-0 PG 28 WC Cell Biology; Pharmacology & Pharmacy SC Cell Biology; Pharmacology & Pharmacy GA BMQ78 UT WOS:000273356400006 ER PT B AU Moro, S Morizzo, E Jacobson, KA AF Moro, Stefano Morizzo, Erika Jacobson, Kenneth A. BE Borea, PA TI Molecular Modeling and Reengineering of A(3) Adenosine Receptors SO A3 ADENOSINE RECEPTORS FROM CELL BIOLOGY TO PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Book Chapter ID PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; LIGAND RECOGNITION; CRYSTAL-STRUCTURE; HUMAN BRAIN; ACTIVATION; IDENTIFICATION; CLONING; PHARMACOLOGY; MECHANISMS C1 [Moro, Stefano; Morizzo, Erika] Univ Padua, Dept Pharmaceut Sci, Mol Modeling Sect MMS, I-35131 Padua, Italy. [Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Moro, S (reprint author), Univ Padua, Dept Pharmaceut Sci, Mol Modeling Sect MMS, Via Marzolo 5, I-35131 Padua, Italy. EM stefano.moro@unipd.it; erika.morizzo@unipd.it; kajacobs@helix.nih.gov OI Jacobson, Kenneth/0000-0001-8104-1493; Moro, Stefano/0000-0002-7514-3802 NR 35 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-90-481-3143-3 PY 2010 BP 149 EP 161 DI 10.1007/978-90-481-3144-0_8 D2 10.1007/978-90-481-3144-0 PG 13 WC Cell Biology; Pharmacology & Pharmacy SC Cell Biology; Pharmacology & Pharmacy GA BMQ78 UT WOS:000273356400008 ER PT B AU Liang, BT Urso, M Zambraski, E Jacobson, KA AF Liang, Bruce T. Urso, Maria Zambraski, Edward Jacobson, Kenneth A. BE Borea, PA TI Adenosine A(3) Receptors in Muscle Protection SO A3 ADENOSINE RECEPTORS FROM CELL BIOLOGY TO PHARMACOLOGY AND THERAPEUTICS LA English DT Article; Book Chapter ID HUMAN SKELETAL-MUSCLE; REPERFUSION INJURY; GENE-EXPRESSION; ISCHEMIA/REPERFUSION INJURY; OXIDATIVE STRESS; MESSENGER-RNA; MAST-CELLS; ISCHEMIA; ACTIVATION; INFARCTION C1 [Liang, Bruce T.] Univ Connecticut, Sch Med, Pat & Jim Calhoun Cardiovasc Ctr, Div Cardiol,Hlth Ctr, Farmington, CT 06030 USA. [Liang, Bruce T.] Univ Connecticut, Sch Med, Ctr Cardiovasc, Farmington, CT 06030 USA. [Urso, Maria; Zambraski, Edward] USA, Environm Med Res Inst, Mil Performance Div, Natick, MA 01760 USA. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Connecticut, Sch Med, Pat & Jim Calhoun Cardiovasc Ctr, Div Cardiol,Hlth Ctr, 263 Farmington Ave, Farmington, CT 06030 USA. EM bliang@uchc.edu; maria.urso@us.army.mil; edward.zambraski@us.army.mil; kajacobs@helix.nih.gov OI Urso, Maria/0000-0001-8906-4673; Jacobson, Kenneth/0000-0001-8104-1493 NR 54 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-90-481-3143-3 PY 2010 BP 257 EP 280 DI 10.1007/978-90-481-3144-0_13 D2 10.1007/978-90-481-3144-0 PG 24 WC Cell Biology; Pharmacology & Pharmacy SC Cell Biology; Pharmacology & Pharmacy GA BMQ78 UT WOS:000273356400013 ER PT J AU Couture, S Brown, TG Tremblay, J Kin, NMKNY Ouimet, MC Nadeau, L AF Couture, Sophie Brown, Thomas G. Tremblay, Jacques Kin, N. M. K. Ng Ying Ouimet, Marie Claude Nadeau, Louise TI Are biomarkers of chronic alcohol misuse useful in the assessment of DWI recidivism status? SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Driving while impaired; DUI; Alcohol; Biomarkers; Recidivism; Assessment ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; GAMMA-GLUTAMYL-TRANSFERASE; CAPILLARY-ELECTROPHORESIS; TIMELINE FOLLOWBACK; LABORATORY MARKERS; DUI RECIDIVISTS; SCREENING-TEST; MAO ACTIVITY; ABUSE; OFFENDERS AB A first driving while impaired by alcohol (DWI) conviction is a key opportunity to identify offenders who are at high risk for recidivism. Detection of alcohol use disorder (AUD) is a major target of current DWI assessments. However, offenders frequently underreport their alcohol consumption, and use of biomarkers has been proposed as a more objective indicator. Among the best established are aspartate aminotranferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), mean corpuscular red blood cell volume (MCV), carbohydrate-deficient transferrin (CDT), and thiamine. To our knowledge, no research has directly verified whether AUD biomarkers predict DWI recidivism status. Using a cross-sectional design, this study tested three hypotheses related to the utility of biomarkers in DWI assessment. Hypotheses: (1) DWI recidivists possess biomarkers indicative of greater prevalence of AUD compared to first-time offenders; (2) multiple biomarkers better differentiate first-time offenders from recidivists compared to individual biomarkers; and (3) biomarkers add significantly to the prediction of recidivism over and above psychosocial questionnaires. Methods: First-time offenders (n = 49) and recidivists (n = 95) participated in the study. In addition to self-reported information on sociodemographic and driving characteristics, data from several AUD questionnaires were gathered: Michigan Alcoholism Screening Test, Alcohol Use Disorders Identification Test, Composite International Diagnostic Interview, and Timeline Follow-Back. Blood samples were collected to measure AST, ALT, GGT, MCV, CDT, and thiamine. Results: AUD biomarkers, taken individually or in combination, did not indicate that recidivists had more frequent AUD compared to first-time offenders. Also, they failed to significantly differentiate first-time offenders from recidivists or predict recidivism status. Finally, the superiority of biomarkers over psychosocial AUD questionnaires was not supported in the laboratory setting. Conclusion: The present findings suggest that biomarkers of chronic patterns of heavy drinking may not be adequate to capture the multiple processes that appear to promote recidivism (e.g., binge drinking, other risky behavioural and personality features). Despite their objectivity, caution is warranted in the interpretation of a positive score on these biomarkers in DWI assessment. Longitudinal research is needed to more comprehensively explore the relationship between positive biomarkers in first-time offenders and their risk of becoming recidivists. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Couture, Sophie; Brown, Thomas G.; Tremblay, Jacques; Kin, N. M. K. Ng Ying; Ouimet, Marie Claude] Douglas Mental Hlth Univ Inst, Addict Res Program, Verdun, PQ H4H 1R3, Canada. [Couture, Sophie] Univ Montreal, Ecole Criminol, Montreal, PQ H3C 3J7, Canada. [Brown, Thomas G.; Tremblay, Jacques; Kin, N. M. K. Ng Ying] McGill Univ, Dept Psychiat, Montreal, PQ H3A 1A1, Canada. [Brown, Thomas G.] Pavil Foster Addict Treatment Program, St Philippe De Laprairie, PQ J0L 2K0, Canada. [Ouimet, Marie Claude] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. [Nadeau, Louise] Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. RP Brown, TG (reprint author), Douglas Mental Hlth Univ Inst, Addict Res Program, 4th Floor,Rm E-4118,6875 LaSalle Blvd, Verdun, PQ H4H 1R3, Canada. EM thomas.brown@mcgill.ca NR 52 TC 5 Z9 5 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD JAN PY 2010 VL 42 IS 1 BP 307 EP 312 DI 10.1016/j.aap.2009.08.016 PG 6 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 528YE UT WOS:000272482100035 PM 19887172 ER PT J AU Resnik, DB Patrone, D Peddada, S AF Resnik, David B. Patrone, Daniel Peddada, Shyamal TI Research Misconduct Policies of Social Science Journals and Impact Factor SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE ethics; impact factor; misconduct policies AB In this study we gathered data on the misconduct policies of social science journals and combined it with the data from our previous study on journal misconduct policies, which did not include enough social science journals for data analysis. Consistent with our earlier finding, impact factor of the journal was the only variable significantly associated with whether a journal had a formal (written) misconduct policy with an odds-ratio of 1.72 (p < 0.01). We did not find that type of science (physical, biomedical, or social) or publisher had a significant effect on whether a journal had a policy. Another important finding is that less than half of the journals that responded to the survey had a formal misconduct policy. C1 [Resnik, David B.; Peddada, Shyamal] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Patrone, Daniel] Union Grad Coll, Mt Sinai Sch Med, New York, NY USA. RP Resnik, DB (reprint author), NIEHS, NIH, Mail Drop CU 03,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX This research was supported by the Intramural Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). It does not represent the views of the NIH, NIEHS, or the U.S. government. We are grateful to Greg Dinse and Bill Schrader for comments on this manuscript. NR 10 TC 22 Z9 22 U1 3 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 J9 ACCOUNT RES JI Account. Res. PY 2010 VL 17 IS 2 BP 79 EP 84 DI 10.1080/08989621003641181 PG 6 WC Medical Ethics SC Medical Ethics GA 599SL UT WOS:000277933300003 PM 20306350 ER PT J AU Resnik, DB Kennedy, CE AF Resnik, David B. Kennedy, Caitlin E. TI Balancing Scientific and Community Interests in Community-Based Participatory Research SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE community based participatory research; data interpretation; data sharing; ethics; objectivity; openness; publication ID PROTECTING COMMUNITIES; ENVIRONMENTAL-HEALTH; BIOMEDICAL-RESEARCH; GENETIC RESEARCH; PUBLIC-HEALTH; POPULATIONS; ETHICS; HIV; MEN AB Community-based participatory research is an approach to studying human populations that emphasizes extensive partnerships between researchers and community members. While there are many advantages of this approach, it also faces a number of conceptual and practical challenges, one of which is managing the conflict that sometimes arises between promoting scientific and community interests. This essay explores the potential conflict between scientific and community interests in several different stages of community-based participatory research, including research design, data interpretation, and publication, and makes some suggestions for practice and policy. To manage potential conflicts between scientific and community interests, investigators and community partners should enter into written agreements at the beginning of the study. In some cases, it may be necessary for a third party, such as a review committee from a supporting institution, the community, or a funding agency, to help investigators and community partners resolve disagreements. It may also be useful, in some situations, to publish a dissenting opinion when investigators and community partners cannot agree on how to interpret findings resulting from a study. These strategies may help address some of the challenges of implementing community-based participatory research. C1 [Resnik, David B.] NIEHS, NIEHS IRB, NIH, Res Triangle Pk, NC 27709 USA. [Kennedy, Caitlin E.] Johns Hopkins Univ, Dept Int Hlth, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Resnik, DB (reprint author), NIEHS, NIEHS IRB, NIH, POB 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported, in part, by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS or NIH. NR 45 TC 15 Z9 15 U1 3 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 J9 ACCOUNT RES JI Account. Res. PY 2010 VL 17 IS 4 BP 198 EP 210 AR PII 923503562 DI 10.1080/08989621.2010.493095 PG 13 WC Medical Ethics SC Medical Ethics GA 633ZD UT WOS:000280545900004 PM 20597018 ER PT J AU Hooker, JM Kim, SW Alexoff, D Xu, YW Shea, C Reid, A Volkow, N Fowler, JS AF Hooker, Jacob M. Kim, Sung Won Alexoff, David Xu, Youwen Shea, Colleen Reid, Alicia Volkow, Nora Fowler, Joanna S. TI Histone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [C-11]MS-275 using Positron Emission Tomography SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE MS-275; entinostat; carbon-11; PET; HDAC; histone deacetylase; epigenetics; brain ID REFRACTORY SOLID TUMORS; P-GLYCOPROTEIN; PHASE-I; DISORDERS; CULTURES; CANCER; MEMORY; CELLS; TRIAL; ROOT AB MS-275 (entinostat) is a histone deacetylase (HDAC) inhibitor currently in clinical trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood brain barrier (BBB) and cause region-specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomography (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we determined that [C-11]MS-275 has low uptake in brain tissue when administered intravenously to nonhuman primates. In rodent studies, we observed that pharmacokinetics and brain accumulation of [C-11]MS-275 were not changed by the coadministration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compounds for peripheral cancer treatment (where CNS exclusion is often advantageous) but also for the treatment of neurological disorders (where CNS penetration is critical). C1 [Hooker, Jacob M.; Kim, Sung Won; Alexoff, David; Xu, Youwen; Shea, Colleen; Reid, Alicia; Volkow, Nora; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Kim, Sung Won; Volkow, Nora] NIAAA, Bethesda, MD 20892 USA. [Reid, Alicia] CUNY Medgar Evers Coll, Sch Sci, Brooklyn, NY 11225 USA. [Volkow, Nora] NIDA, Bethesda, MD 20892 USA. RP Hooker, JM (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM hooker@bnl.gov OI Hooker, Jacob/0000-0002-9394-7708 FU U.S. Department of Energy, Office of Biological and Environmental Research [DE-ACO2-98CH10886]; NIH [1F32EB008320-01]; Goldhaber Distinguished Fellowship program at BNL FX This work was carried out at Brookhaven National Laboratory under contract DE-ACO2-98CH10886 with the U.S. Department of Energy, supported by its Office of Biological and Environmental Research. J.M.H. was supported by an NIH Postdoctoral Fellowship (Grant 1F32EB008320-01) and through the Goldhaber Distinguished Fellowship program at BNL. NR 31 TC 39 Z9 39 U1 3 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD JAN PY 2010 VL 1 IS 1 BP 65 EP 73 DI 10.1021/cn9000268 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 597FY UT WOS:000277743100008 PM 20657706 ER PT J AU Dauter, Z Baker, EN AF Dauter, Zbigniew Baker, Edward N. TI Black sheep among the flock of protein structures SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Editorial Material C1 [Dauter, Zbigniew] NCI, Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. [Baker, Edward N.] Univ Auckland, Sch Biol Sci, Auckland 1, New Zealand. RP Dauter, Z (reprint author), NCI, Argonne Natl Lab, Biosci Div, Bldg 202,Room Q142, Argonne, IL 60439 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2010 VL 66 BP 1 EP 1 DI 10.1107/S0907444909054481 PN 1 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 545TD UT WOS:000273758800001 PM 20057042 ER PT J AU Magracheva, E Pletnev, S Kotenko, S Li, W Wlodawer, A Zdanov, A AF Magracheva, Eugenia Pletnev, Sergei Kotenko, Sergei Li, Wei Wlodawer, Alexander Zdanov, Alexander TI Purification, crystallization and preliminary crystallographic studies of the complex of interferon-lambda 1 with its receptor SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID CYTOKINES; BINDING AB Human interferon-lambda 1 (IFN-lambda 1(Ins)) and the extracellular domain of interferon-lambda 1 receptor (IFN-lambda 1R1) were expressed in Drosophila S2 cells and purified to homogeneity. Both IFN-lambda 1(Ins) and interferon-lambda 1 produced from Escherichia coli (IFN-lambda 1(Bac)) were coupled with IFN-lambda 1R1 at room temperature and the complexes were purified by gel filtration. Both complexes were crystallized; the crystals were flash-frozen at 100 K and diffraction data were collected to 2.16 and 2.1 angstrom, respectively. Although the IFN-lambda 1(Bac)-IFN-lambda 1R1 and IFN-lambda 1(Ins)-IFN-lambda 1R1 complexes differed only in the nature of the expression system used for the ligand, their crystallization conditions and crystal forms were quite different. A search for heavy-atom derivatives as well as molecular-replacement trials are in progress. C1 [Wlodawer, Alexander; Zdanov, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Magracheva, Eugenia] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. [Pletnev, Sergei] Argonne Natl Lab, Basic Res Program, SAIC Frederick Inc, Argonne, IL 60439 USA. [Kotenko, Sergei; Li, Wei] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. RP Zdanov, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM zdanova@mail.nih.gov RI Li, Wei/I-8060-2014 FU National Cancer Institute; NIH [HHSN2612008000001E] FX This project was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and with Federal funds from the National Cancer Institute, NIH under Contract No. HHSN2612008000001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 18 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD JAN PY 2010 VL 66 BP 61 EP 63 DI 10.1107/S1744309109048817 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 536VR UT WOS:000273072500018 PM 20057073 ER PT J AU Haberg, SE Bentdal, YE London, SJ Kvaerner, KJ Nystad, W Nafstad, P AF Haberg, S. E. Bentdal, Y. E. London, S. J. Kvaerner, K. J. Nystad, W. Nafstad, P. TI Prenatal and postnatal parental smoking and acute otitis media in early childhood SO ACTA PAEDIATRICA LA English DT Article DE Acute otitis media; Cohort studies; Norway; Pregnancy; Smoking ID ENVIRONMENTAL TOBACCO-SMOKE; RESPIRATORY HEALTH; MATERNAL SMOKING; RISK-FACTORS; CHILDREN; EXPOSURE; PREGNANCY; AGE; PREDICTOR; VALIDITY AB Aim: To explore the associations between acute otitis media in early childhood and prenatal and postnatal tobacco smoke exposure. Methods: Subjects were 32 077 children born between 2000 and 2005 in the Norwegian Mother and Child Study with questionnaire data on tobacco smoke exposure and acute otitis media up to 18 months of age. Multivariate regression models were used to obtain adjusted relative risks for acute otitis media. Results: Acute otitis media was slightly more common in children exposed to parental smoking. The incidence from 0 to 6 months was 4.7% in unexposed children and 6.0% in children exposed both prenatally and postnatally. After adjusting for postnatal exposure and covariates, the relative risk for acute otitis media 0-6 months when exposed to maternal smoking in pregnancy was 1.34, 95% confidence interval: 1.06-1.69. Maternal smoking in pregnancy was associated with acute otitis media up to 12 months of age. Compared with non-exposed children, there was a slightly increased risk of recurrent acute otitis media for children exposed both prenatally and postnatally with a relative risk of 1.24, 95% confidence interval: 1.01-1.52. Conclusion: Even in a cohort with relatively low exposure levels of parental smoking, maternal smoking in pregnancy was associated with an increased risk of acute otitis media in early childhood. C1 [Haberg, S. E.; Nafstad, P.] Norwegian Inst Publ Hlth, Div Epidemiol, NO-0403 Oslo, Norway. [Bentdal, Y. E.; Kvaerner, K. J.] Univ Oslo, Akershus Univ Hosp, Fac Div, Oslo, Norway. [Bentdal, Y. E.] Akershus Univ Hosp, Dept Otorhinolaryngol, Oslo, Norway. [London, S. J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [London, S. J.] NIEHS, Lab Resp Biol, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. [Kvaerner, K. J.] Univ Oslo, Dept Special Needs Educ, Oslo, Norway. [Nafstad, P.] Univ Oslo, Fac Med, Dept Gen Practice & Community Med, Oslo, Norway. RP Haberg, SE (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, POB 4404, NO-0403 Oslo, Norway. EM siri.haberg@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU Norwegian Ministry of Health; NIH/NIEHS [N01-ES-85433]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10]; Norwegian Association; Norwegian Foundation for Health and Rehabilitation; NIH; National Institute of Environmental Health Sciences FX We gratefully acknowledge Hein Stigum at the Norwegian Institute of Public Health in Oslo, Norway, for the advice in statistical analyses and comments given in the methods section. The donations of questionnaire data from MoBa participants are gratefully acknowledged. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, NIH/NIEHS (grant no N01-ES-85433), NIH/NINDS (grant no.1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). This study was supported by the Norwegian Association of Heart and Lung patients with EXTRA funds from the Norwegian Foundation for Health and Rehabilitation, and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 29 TC 23 Z9 24 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD JAN PY 2010 VL 99 IS 1 BP 99 EP 105 DI 10.1111/j.1651-2227.2009.01506.x PG 7 WC Pediatrics SC Pediatrics GA 530CF UT WOS:000272565800027 PM 19764924 ER PT J AU Barr, CS AF Barr, Christina S. TI CRHRI GENE VARIATION AND STRESS-INDUCED ALCOHOL DEPENDENCE - FROM EVALUTIONARY SELECTION TO SELECTION OF APPROPRIATE PATIENT POPULATIONS - Commentary on Nelson et al. (2010) SO ADDICTION BIOLOGY LA English DT Editorial Material ID CORTICOTROPIN-RELEASING HORMONE; OPIOID-RECEPTOR GENE; NALTREXONE RESPONSE; PRIMATES; BRAIN; POLYMORPHISM; TEMPERAMENT; SENSITIVITY; CONSUMPTION; EXPRESSION C1 NIAAA, NIH, LCTS, NIHAC, Poolesville, MD 20837 USA. RP Barr, CS (reprint author), NIAAA, NIH, LCTS, NIHAC, POB 529, Poolesville, MD 20837 USA. EM cbarr@mail.nih.gov NR 34 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JAN PY 2010 VL 15 IS 1 BP 12 EP 14 PG 3 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 530BY UT WOS:000272565100002 PM 20002019 ER PT J AU Panlilio, LV Schindler, CW Goldberg, SR AF Panlilio, Leigh V. Schindler, Charles W. Goldberg, Steven R. BE Miller, PG Strang, J Miller, PM TI ANIMAL MODELS SO ADDICTION RESEARCH METHODS LA English DT Article; Book Chapter ID CONDITIONED PLACE PREFERENCE; DRUG-DISCRIMINATION; RATS; MECHANISMS; HEROIN; SENSITIZATION; TRANSITION; ADDICTION; SCHEDULES; RELAPSE C1 [Panlilio, Leigh V.; Schindler, Charles W.; Goldberg, Steven R.] Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH DHHS, Baltimore, MD USA. RP Panlilio, LV (reprint author), Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH DHHS, Baltimore, MD USA. NR 26 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-1-405-17663-7 PY 2010 BP 269 EP 284 DI 10.1002/9781444318852.ch17 D2 10.1002/9781444318852 PG 16 WC Substance Abuse SC Substance Abuse GA BTV42 UT WOS:000288168100017 ER PT S AU Heidbreder, CA Newman, AH AF Heidbreder, Christian A. Newman, Amy H. BE Uhl, GR TI Current perspectives on selective dopamine D-3 receptor antagonists as pharmacotherapeutics for addictions and related disorders SO ADDICTION REVIEWS 2 SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE addiction; dopamine; D-3 receptor; impulse control disorder; polymorphisms; proof of concept; selective antagonists ID COCAINE-SEEKING BEHAVIOR; POTENTIAL ANTIPSYCHOTIC AGENT; FUNCTIONALIZED LINKING CHAINS; CONDITIONED PLACE PREFERENCE; ANTERIOR CINGULATE CORTEX; ABUSE THERAPEUTIC AGENTS; DRUG-ASSOCIATED STIMULI; ENHANCED BRAIN REWARD; IN-VIVO ACTIVITY; D3 RECEPTOR AB Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D-3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D-3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D-3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D-2/D-3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D-3 versus D-2 receptor, and their efficacy profile is related primarily to functional antagonism at D-2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D-3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed. C1 [Heidbreder, Christian A.] Reckitt Benckiser Pharmaceut, Global Res & Dev, Richmond, VA 23235 USA. [Newman, Amy H.] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, Baltimore, MD USA. RP Heidbreder, CA (reprint author), Reckitt Benckiser Pharmaceut, Global Res & Dev, 10710 Midlothian Turnpike,Ste 430, Richmond, VA 23235 USA. EM christian.heidbreder@reckittbenckiser.com FU Intramural NIH HHS [ZIA DA000424-11] NR 199 TC 144 Z9 148 U1 3 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN 02148, MA USA SN 0077-8923 BN 978-1-57331-767-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2010 VL 1187 BP 4 EP 34 DI 10.1111/j.1749-6632.2009.05149.x PG 31 WC Substance Abuse; Multidisciplinary Sciences SC Substance Abuse; Science & Technology - Other Topics GA BOV89 UT WOS:000277795700001 PM 20201845 ER PT S AU Sora, I Li, BJ Igari, M Hall, FS Ikeda, K AF Sora, Ichiro Li, BingJin Igari, Moe Hall, F. Scott Ikeda, Kazutaka BE Uhl, GR TI Transgenic mice in the study of drug addiction and the effects of psychostimulant drugs SO ADDICTION REVIEWS 2 SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE transgenic; knockout; psychostimulant; amphetamine; cocaine ID RECEPTOR MUTANT MICE; DOPAMINE-TRANSPORTER KNOCKOUT; CONDITIONED PLACE PREFERENCE; INDUCED LOCOMOTOR-ACTIVITY; GENOME-WIDE ASSOCIATION; METHAMPHETAMINE-INDUCED HYPERTHERMIA; INDUCED BEHAVIORAL SENSITIZATION; PREPULSE INHIBITION DEFICITS; BETA-HYDROXYLASE KNOCKOUT; WILD-TYPE MICE AB The first transgenic models used to study addiction were based upon a priori assumptions about the importance of particular genes in addiction, including the main target molecules of morphine, amphetamine, and cocaine. This consequently emphasized the importance of monoamine transporters, opioid receptors, and monoamine receptors in addiction. Although the effects of opiates were largely eliminated by p opioid receptor gene knockout, the case for psychostimulants was much more complex. Research using transgenic models supported the idea of a polygenic basis for psychostimulant effects and has associated particular genes with different behavioral consequences of psychostimulants. Phenotypic analysis of transgenic mice, especially gene knockout mice, has been instrumental in identifying the role of specific molecular targets of addictive drugs in their actions. In this article, we summarize studies that have provided insight into the polygenic determination of drug addiction phenotypes in ways that are not possible with other methods, emphasizing research into the effects of psychostimulant drugs in gene knockouts of the monoamine transporters and monoamine receptors. C1 [Sora, Ichiro; Li, BingJin; Igari, Moe] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. [Hall, F. Scott] Natl Inst Drug Abuse, Mol Neurobiol Branch, Baltimore, MD USA. [Ikeda, Kazutaka] Tokyo Inst Psychiat, Div Psychobiol, Tokyo, Japan. RP Sora, I (reprint author), Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 980, Japan. EM isora@mail.tains.tohoku.ac.jp RI Ikeda, Kazutaka/I-4694-2013; Hall, Frank/C-3036-2013 OI Ikeda, Kazutaka/0000-0001-8342-0278; Hall, Frank/0000-0002-0822-4063 FU Intramural NIH HHS NR 188 TC 25 Z9 25 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN 02148, MA USA SN 0077-8923 BN 978-1-57331-767-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2010 VL 1187 BP 218 EP 246 DI 10.1111/j.1749-6632.2009.05276.x PG 29 WC Substance Abuse; Multidisciplinary Sciences SC Substance Abuse; Science & Technology - Other Topics GA BOV89 UT WOS:000277795700012 PM 20201856 ER PT S AU Frascella, J Potenza, MN Brown, LL Childress, AR AF Frascella, Joseph Potenza, Marc N. Brown, Lucy L. Childress, Anna Rose BE Uhl, GR TI Shared brain vulnerabilities open the way for nonsubstance addictions: Carving addiction at a new joint? SO ADDICTION REVIEWS 2 SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE nonsubstance addiction; DSM-V; brain imaging; nosology ID BODY-MASS INDEX; HUMAN ORBITOFRONTAL CORTEX; INCREASE EXTRACELLULAR DOPAMINE; SUBSTANCE USE DISORDERS; VENTRAL TEGMENTAL AREA; POSITRON-EMISSION-TOMOGRAPHY; COCAINE-DEPENDENT SUBJECTS; IMPULSE CONTROL DISORDERS; GRAY-MATTER VOLUME; EVENT-RELATED FMRI AB For more than half a century, since the beginning of formal diagnostics, our psychiatric nosology has compartmentalized the compulsive pursuit of substance (e.g., alcohol, cocaine, heroin, nicotine) from nonsubstance (e.g., gambling, food, sex) rewards. Emerging brain, behavioral, and genetic findings challenge this diagnostic boundary, pointing to shared vulnerabilities underlying the pathological pursuit of substance and nonsubstance rewards. Working groups for the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V), are thus considering whether the nosologic boundaries of addiction should be redrawn to include nonsubstance disorders, such as gambling. This review discusses how neurobiological data from problem gambling, obesity, and "normal" states of attachment (romantic infatuation, sexual attraction, maternal bonds) may help us in the task of carving addictions "at a new joint." Diagnostic recarving may have a positive effect on addiction research, stimulating discovery of "crossover" pharmacotherapies with benefit for both substance and nonsubstance addictions. C1 [Childress, Anna Rose] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Frascella, Joseph] Natl Inst Drug Abuse, Div Clin Neurosci & Behav Res, Rockville, MD USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Brown, Lucy L.] Albert Einstein Coll Med, Saul R Korey Dept Neurol, New York, NY USA. [Brown, Lucy L.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, New York, NY USA. [Childress, Anna Rose] Dept Vet Affairs Med Ctr, VISN MIRECC 4, Philadelphia, PA 19104 USA. RP Childress, AR (reprint author), Univ Penn, Sch Med, Dept Psychiat, 3900 Chestnut St, Philadelphia, PA 19104 USA. EM childress_a@mail.trc.upenn.edu FU NIAAA NIH HHS [RL1 AA017539-01, RL1 AA017539]; NIDA NIH HHS [R01 DA019039, R01 DA019039-05] NR 254 TC 84 Z9 87 U1 10 U2 29 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN 02148, MA USA SN 0077-8923 BN 978-1-57331-767-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2010 VL 1187 BP 294 EP 315 DI 10.1111/j.1749-6632.2009.05420.x PG 22 WC Substance Abuse; Multidisciplinary Sciences SC Substance Abuse; Science & Technology - Other Topics GA BOV89 UT WOS:000277795700015 PM 20201859 ER PT J AU Song, YQ Zhang, CL Liu, SM AF Song, Yiqing Zhang, Cuilin Liu, Simin BE Preedy, VR TI Endothelial Adhesion Molecules in Diabetes SO ADHESION MOLECULES SE Modern Insights into Disease from Molecules to Man LA English DT Article; Book Chapter ID URINARY ALBUMIN EXCRETION; LOW-GRADE INFLAMMATION; INSULIN-RESISTANCE; E-SELECTIN; DYSFUNCTION; RISK; MELLITUS; WOMEN; RETINOPATHY; MARKERS AB A large body of evidence supports the contention that endothelial dysfunction is an important pathological basis for the metabolic or insulin resistance syndrome and may thus play a pivotal role in the pathogenesis of diabetes mellitus (type 1 and type 2) and related complications. Measurable levels of some soluble cellular adhesion molecules including E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) may reflect the degree of endothelial activation (i.e., released by activated endothelial cells to the general circulation, these molecules are considered useful indicators of endothelial dysfunction/activation). Elevated levels of soluble cellular adhesion molecules have been associated with insulin resistance and its associated metabolic abnormalities including diabetic complications. Recent evidence from several large prospective studies has shown that elevated levels of endothelial biomarkers, especially E-selectin, VCAM-1, and ICAM-1, were strong independent predictors of type 2 diabetes in populations with diverse ethnic backgrounds. This chapter aims to summarize both clinical and epidemiological studies relating plasma levels of endothelial adhesion molecules to diabetes mellitus and interpret these data in the context of emerging biological evidence. The available evidence indicates that elevated circulating levels of some, but not all, markers correlate not only with prediabetic insulin resistance and type 2 diabetes, but also with complications in both type 1 and type 2 diabetes. Future studies are warranted to evaluate the clinical utility of endothelial markers in comprehensively assessing and managing the development and prognosis of diabetes in the context of other diabetes biomarkers and traditional risk factors. C1 [Song, Yiqing] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02148 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Liu, Simin] Univ Calif Los Angeles, Program Genom & Nutr, Sch Publ Hlth, Los Angeles, CA 90095 USA. RP Song, YQ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02148 USA. EM ysong3@rics.bwh.harvard.edu; zhangcu@mail.nih.gov; siminliu@ucla.edu NR 23 TC 0 Z9 0 U1 0 U2 2 PU CRC PRESS-TAYLOR & FRANCIS GROUP PI BOCA RATON PA 6000 BROKEN SOUND PARKWAY NW, STE 300, BOCA RATON, FL 33487-2742 USA BN 978-1-4398-4060-3 J9 MOD INSIGHTS DIS MOL JI Mod. Insights Dis. Mol. Man PY 2010 BP 176 EP 190 D2 10.1201/b10167 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BTA34 UT WOS:000286193400013 ER PT S AU Rosenthal, L Schisterman, E AF Rosenthal, Leslie Schisterman, Enrique BE Armstrong, D TI Meta-Analysis: Drawing Conclusions When Study Results Vary SO ADVANCED PROTOCOLS IN OXIDATIVE STRESS II SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Meta-analysis; Low dose aspirin; Oxidative stress; Fixed-effects model; Random-effects model ID LOW-DOSE ASPIRIN; IN-VITRO FERTILIZATION; DOUBLE-BLIND; OVARIAN RESPONSIVENESS; THERAPY; DISEASE; UTERINE; TRIALS AB Low-dose aspirin has been suggested to positively impact a number of clinical outcomes associated with oxidative stress; however, results of clinical trials surrounding its effect on a woman's ability to achieve and sustain pregnancy have been inconclusive. A meta-analysis is an advantageous tool in this situation. Meta-analyses allow researchers to formally and systematically pool together all relevant research in order to clarify findings and form conclusions based on all currently available information. The purpose of this chapter is to describe how to perform a meta-analysis, clarify the impact of model selection, and provide examples of implementation. C1 [Rosenthal, Leslie; Schisterman, Enrique] Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. RP Rosenthal, L (reprint author), Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [ZIA HD008795-03] NR 19 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-60761-410-4 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2010 VL 594 BP 427 EP 434 DI 10.1007/978-1-60761-411-1_30 D2 10.1007/978-1-60761-411-1 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA BNM26 UT WOS:000274938200030 PM 20072935 ER PT S AU Walrath, JC Hawes, JJ Van Dyke, T Reilly, KM AF Walrath, Jessica C. Hawes, Jessica J. Van Dyke, Terry Reilly, Karlyne M. BE VandeWoude, GF Klein, G TI Genetically Engineered Mouse Models in Cancer Research SO ADVANCES IN CANCER RESEARCH, VOL 106 SE Advances in Cancer Research LA English DT Review; Book Chapter ID EMBRYONIC STEM-CELLS; RETROVIRAL INSERTIONAL MUTAGENESIS; MULTIPLE ENDOCRINE NEOPLASIA; REGULATED RNA INTERFERENCE; GENE TRAP RESOURCE; TRANSGENIC MICE; BREAST-CANCER; IN-VIVO; LENTIVIRAL VECTORS; MAMMALIAN-CELLS AB Mouse models of human cancer have played a vital role in understanding tumorigenesis and answering experimental questions that other systems cannot address. Advances continue to be made that allow better understanding of the mechanisms of tumor development, and therefore the identification of better therapeutic and diagnostic strategies. We review major advances that have been made in modeling cancer in the mouse and specific areas of research that have been explored with mouse models. For example, although there are differences between mice and humans, new models are able to more accurately model sporadic human cancers by specifically controlling timing and location of mutations, even within single cells. As hypotheses are developed in human and cell culture systems, engineered mice provide the most tractable and accurate test of their validity in vivo. For example, largely through the use of these models, the microenvironment has been established to play a critical role in tumorigenesis, since tumor development and the interaction with surrounding stroma can be studied as both evolve. These mouse models have specifically fueled our understanding of cancer initiation, immune system roles, tumor angiogenesis, invasion, and metastasis, and the relevance of molecular diversity observed among human cancers. Currently, these models are being designed to facilitate in vivo imaging to track both primary and metastatic tumor development from much earlier stages than previously possible. Finally, the approaches developed in this field to achieve basic understanding are emerging as effective tools to guide much needed development of treatment strategies, diagnostic strategies, and patient stratification strategies in clinical research. C1 [Walrath, Jessica C.; Hawes, Jessica J.; Van Dyke, Terry; Reilly, Karlyne M.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Walrath, JC (reprint author), NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. FU Intramural NIH HHS [Z99 CA999999] NR 262 TC 36 Z9 38 U1 4 U2 15 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 978-0-12-374771-6 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2010 VL 106 BP 113 EP 164 DI 10.1016/S0065-230X(10)06004-5 PG 52 WC Oncology SC Oncology GA BBJ05 UT WOS:000307009900004 PM 20399958 ER PT J AU Rachakonda, AK Kimmel, PL AF Rachakonda, Ajay K. Kimmel, Paul L. TI CKD in HIV-Infected Patients Other Than HIV-Associated Nephropathy SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Glomerulonephritis; Thrombotic microangiopathy; Lupus; Cryoglobulinemia; Immunotactoid; Fibrillary AB A spectrum of kidney diseases in HIV-infected patients has been reported both before and after the introduction of highly active antiretroviral therapy (HAART). Kidney syndromes affecting HIV-infected patients include CKD as well as proteinuria, nephrotic syndrome, and acute nephritic syndrome. Thrombotic microangiopathy should be considered in patients with kidney disease and typical clinical characteristics. As the HIV-infected population ages, there is increased concern regarding the incidence of vascular and metabolic disease, leading to an increased burden of CKD. Although HIV-associated nephropathy is still the major cause of nephrotic syndrome in HIV-infected patients, immune complex glomerulonephritis (ICGN) still comprises a substantial proportion of the disease burden, especially in people of European origin. Genetic investigations into the underpinnings of the various histologic expressions of HIV-associated kidney disease hold great promise. The single most important diagnostic test to differentiate various forms of kidney disease in HIV-infected patients is a kidney biopsy. The results of treating kidney disease in HIV-infected patients remain unclear, and properly designed randomized controlled trials of the treatment of ICGN with HAART and other approaches are desperately needed. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved. C1 [Kimmel, Paul L.] Natl Inst Diabet Digest & Kidney Dis, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. George Washington Univ, Dept Med, Washington, DC USA. RP Kimmel, PL (reprint author), Natl Inst Diabet Digest & Kidney Dis, Div Kidney Urol & Hematol Dis, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM kimmelp@extra.niddk.nih.gov NR 112 TC 12 Z9 13 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JAN PY 2010 VL 17 IS 1 BP 83 EP 93 DI 10.1053/j.ackd.2009.09.001 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA V24KD UT WOS:000208408400011 PM 20005492 ER PT S AU Maul, RW Gearhart, PJ AF Maul, Robert W. Gearhart, Patricia J. BE Alt, FW Austen, KF Honjo, T Melchers, F Uhr, JW Unanue, ER TI AID and Somatic Hypermutation SO ADVANCES IN IMMUNOLOGY, VOL 105 SE Advances in Immunology LA English DT Review; Book Chapter ID CLASS-SWITCH RECOMBINATION; INDUCED-CYTIDINE-DEAMINASE; ACTIVATION-INDUCED DEAMINASE; HEAVY-CHAIN LOCUS; DNA-POLYMERASE-ETA; MISMATCH REPAIR PROTEIN; SINGLE-STRANDED-DNA; IMMUNOGLOBULIN VARIABLE GENES; ANTIBODY DIVERSIFICATION ENZYME; KINASE-A PHOSPHORYLATION AB In response to an assault by foreign organisms, peripheral B cells can change their antibody affinity and isotype by somatically mutating their genomic DNA. The ability of a cell to modify its DNA is exceptional in light of the potential consequences of genetic alterations to cause human disease and cancer. Thus, as expected. this mechanism of antibody diversity is tightly regulated and coordinated through one protein, activation-induced deaminase (AID). AID produces diversity by converting cytosine to uracil within the immunoglobulin loci. The deoxyuracil residue is mutagenic when paired with deoxyguanosine, since it mimics thymidine during DNA replication. Additionally, B cells can manipulate the DNA repair pathways so that deoxyuracils are not faithfully repaired. Therefore, an intricate balance exists which is regulated at multiple stages to promote mutation of immunoglobulin genes, while retaining integrity of the rest of the genome. Here we discuss and summarize the current understanding of how AID functions to cause somatic hypermutation. C1 [Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Maul, RW (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. OI Maul, Robert/0000-0002-6958-8514 FU Intramural NIH HHS [Z01 AG000732-13] NR 203 TC 91 Z9 93 U1 2 U2 22 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2776 BN 978-0-12-381302-2 J9 ADV IMMUNOL JI Adv.Immunol. PY 2010 VL 105 BP 159 EP 191 DI 10.1016/S0065-2776(10)05006-6 PG 33 WC Immunology SC Immunology GA BPJ96 UT WOS:000279019700006 PM 20510733 ER PT S AU Cheng, R Glynn, S Flores-Santana, W Switzer, C Ridnour, L Wink, DA AF Cheng, Robert Glynn, Sharon Flores-Santana, Wilmarie Switzer, Christopher Ridnour, Lisa Wink, David A. BE Fishbein, JC TI NITRIC OXIDE AND REDOX INFLAMMATION IN CANCER SO ADVANCES IN MOLECULAR TOXICOLOGY, VOL 4 SE Advances in Molecular Toxicology LA English DT Article; Book Chapter ID MATRIX-METALLOPROTEINASE ACTIVITY; SIGNAL-REGULATED KINASE; HUMAN BREAST-CANCER; SYNTHASE EXPRESSION; POOR SURVIVAL; HYDROGEN-SULFIDE; CHEMICAL BIOLOGY; IN-VIVO; OXIDATIVE MECHANISM; NITROSATING AGENTS C1 [Cheng, Robert; Glynn, Sharon; Flores-Santana, Wilmarie; Switzer, Christopher; Ridnour, Lisa; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM wink@mail.nih.gov RI Glynn, Sharon/D-7136-2013; OI Glynn, Sharon/0000-0003-1459-2580; Cheng, Robert/0000-0003-0287-6439 NR 127 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1872-0854 BN 978-0-44-453585-6 J9 ADV MOLEC TOXICOL PY 2010 VL 4 BP 157 EP 182 DI 10.1016/S1872-0854(10)04005-1 PG 26 WC Biochemistry & Molecular Biology; Toxicology SC Biochemistry & Molecular Biology; Toxicology GA BCQ17 UT WOS:000310992000006 ER PT B AU Simone, CB AF Simone, Charles B., II BE Columbus, AM TI THE UTILIZATION OF PAIN MEDICATIONS AND THE ATTITUDES OF CANCER PATIENTS TOWARDS PAIN INTERVENTION SO ADVANCES IN PSYCHOLOGY RESEARCH, VOL 61 SE Advances in Psychology Research LA English DT Article; Book Chapter ID RADIATION ONCOLOGY; HEALTH-CARE; MANAGEMENT; INFORMATION; INTERNET; BARRIERS; PHYSICIANS; THERAPIES; ANXIETY; COMPLEMENTARY AB Introduction: Although pain is commonly reported by cancer patients, many of these patients experience inadequate medical management for their pain. There is currently little data quantifying the reasons that oncology patients fail to receive optimal analgesic therapy. This study evaluated those reasons and examined the perceived causes of pain among cancer patients. Methods: An IRB-approved Internet-based questionnaire assessing patient demographics and pain symptoms was piloted with both healthcare providers and oncology patients and posted on the OncoLink website (http://www.oncolink.org). The questionnaire was held on a secure server and included 22 queries that evaluated medication utilization, pain control, and attitudes towards pain medications. Results: From 11/2005 to 4/2006, 243 patients responded to the questionnaire. Respondents were predominantly female (73%), Caucasian (71%), and pursued education beyond high school (67%). The most commonly reported diseases included cancers of the breast (38%), lung (6%), and ovary (6%). Patients underwent surgery (68%), chemotherapy (65%), and radiation therapy (44%) to treat their cancer. Nearly half (47%) of the respondents reported pain directly from their cancer, while 44% reported pain from their cancer treatment. Patients described their pain as primarily intermittent (45%) or chronic (39%). Most (74%) patients did not use medication specifically to help manage their pain. Analgesic usage was significantly less in patients with higher education levels (18% vs. 38%, p=0.0005) and in patients with a diagnosis of breast cancer (18% vs. 31%, p=0.032). Analgesic usage also trended less in women (23% vs. 35%, p=0.053) and Caucasians (23% vs. 33%, p=0.106). The reasons most commonly cited for not taking analgesics included healthcare providers not recommending medications (84%), fear of becoming dependent or addicted (79%), and an inability to pay for medication (79%). Respondents experiencing pain, but not taking analgesic medications, sought alternative measures for pain control, including physical therapy (87%), massage (5%), and acupuncture (2%). Conclusion: Many cancer patients experience pain regularly from both their disease and their cancer treatment. However, most patients in this study did not consume analgesic medications due to concerns of addiction, cost, or the healthcare provider not discussing pain medications. Some patients pursue complementary therapies for pain control. Healthcare providers should regularly have open discussions with patients regarding pain symptoms and treatment. Further studies are needed to evaluate attitudes of patients towards pain and analgesic usage based on primary cancer diagnosis and by stage of disease. C1 NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Simone, CB (reprint author), NCI, NIH, Radiat Oncol Branch, Bldg 10-CRC,Room B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM simonec@mail.nih.gov NR 54 TC 0 Z9 0 U1 0 U2 0 PU NOVA SCIENCE PUBLISHERS, INC PI HAUPPAUGE PA 400 OSER AVE, STE 1600, HAUPPAUGE, NY 11788-3635 USA BN 978-1-60741-551-0 J9 ADV PSYCHOL RES PY 2010 VL 61 BP 69 EP 79 PG 11 WC Psychology; Psychology, Multidisciplinary SC Psychology GA BPC48 UT WOS:000278514600005 ER PT B AU Schooler, C Caplan, LJ Goren, A Mounkoro, PP Diakite, C AF Schooler, Carmi Caplan, Leslie J. Goren, Amir Mounkoro, Pakuy Pierre Diakite, Chiaka BE Avison, WR Anashensel, CS Schieman, S Wheaton, B TI It's Tough to Cope in Rural Mali: Financial Coping Style, Mastery, Self Confidence, and Anxiety in a Bad and Worsening Socioeconomic Environment SO ADVANCES IN THE CONCEPTUALIZATION OF THE STRESS PROCESS: ESSAYS IN HONOR OF LEONARD I. PEARLIN LA English DT Article; Book Chapter ID OLDER WORKERS; STRESS C1 [Schooler, Carmi; Caplan, Leslie J.; Goren, Amir] NIMH, Sect Socioenvironm Studies, Bethesda, MD 20892 USA. [Diakite, Chiaka] Inst Natl Rech Sante Publ, Dept Med Tradit, Bamako, Mali. [Mounkoro, Pakuy Pierre] Inst Natl Rech Sante Publ, Ctr Reg Med Tradit, Bandiagara, Mali. RP Schooler, C (reprint author), NIMH, Sect Socioenvironm Studies, Bethesda, MD 20892 USA. EM carmi.schooler@nih.gov NR 17 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4419-1020-2 PY 2010 BP 177 EP 188 DI 10.1007/978-1-4419-1021-9_10 D2 10.1007/978-1-4419-1021-9 PG 12 WC Public, Environmental & Occupational Health; Psychology, Social; Sociology SC Public, Environmental & Occupational Health; Psychology; Sociology GA BMR42 UT WOS:000273393500010 ER PT S AU Rahman, MM Antani, SK Thoma, GR AF Rahman, Md Mahmudur Antani, Sameer K. Thoma, George R. BA Hussain, M KarHan, T Crawfis, R Thalmann, D Kao, D Avila, L BF Hussain, M KarHan, T Crawfis, R Thalmann, D Kao, D Avila, L BE Bebis, G Boyle, R Parvin, B Koracin, D Chung, R Hammound, R TI Biomedical Image Retrieval in a Fuzzy Feature Space with Affine Region Detection and Vector Quantization of a Scale-Invariant Descriptor SO ADVANCES IN VISUAL COMPUTING, PT III SE Lecture Notes in Computer Science LA English DT Proceedings Paper CT 6th International Symposium on Visual Computing CY NOV 29-DEC 01, 2010 CL Las Vegas, NV SP UNR, DRI, LBNL, NASA Ames, Air Force Res Lab, Intel, DigitalPersona, Equinox, Ford, Hewlett Packard, Mitsubishi Elect Res Lab, iCore, Toyota, Delphi, Gen Elec6t, Microsoft MSDN, Volt AB This paper presents an approach to biomedical image retrieval by detecting affine covariant regions and representing them with an invariant fuzzy feature space. These regions refer to a set of pixels or interest points which change covariantly with a class of transformations, such as affinity. A vector descriptor based on Scale-Invariant Feature Transform (SIFT) computed from the intensity pattern within the region. These features are then vector quantized to build a codebbok of keypoints. By mapping the interest points extracted from one image to the keypoints in the codebook, their occurrences are counted and the resulting histogram is called the "bag of keypoints" for that image. Images are finally represented in fuzzy feature space by spreading each region's membership values through a global fuzzy membership function to all the keypoints in the codebook. The proposed feature extraction and representation scheme is not only invariant to affine transformations but also robust against quantization errors. A systematic evaluation of retrieval results on a heterogeneous medical image collection has shown around 15-20% improvement in precision at different recall levels for the proposed fuzzy feature-based representation when compared to individual color, texture, edge, and keypoint-based features. C1 [Rahman, Md Mahmudur; Antani, Sameer K.; Thoma, George R.] NIH, US Natl Lib Med, Bethesda, MD 20892 USA. RP Rahman, MM (reprint author), NIH, US Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM rahmanmm@mail.nih.gov; santani@mail.nih.gov; gthoma@mail.nih.gov OI Antani, Sameer/0000-0002-0040-1387 NR 17 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-642-17276-2 J9 LECT NOTES COMPUT SC PY 2010 VL 6455 BP 261 EP 270 PG 10 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods SC Computer Science GA BUU22 UT WOS:000290358400027 ER PT J AU Balzi, D Lauretani, F Barchielli, A Ferrucci, L Bandinelli, S Buiatti, E Milaneschi, Y Guralnik, JM AF Balzi, Daniela Lauretani, Fulvio Barchielli, Alessandro Ferrucci, Luigi Bandinelli, Stefania Buiatti, Eva Milaneschi, Yuri Guralnik, Jack M. TI Risk factors for disability in older persons over 3-year follow-up SO AGE AND AGEING LA English DT Article DE prevention; disability; physical activity; energy; ageing; elderly ID LOWER-EXTREMITY FUNCTION; RESTING METABOLIC-RATE; PHYSICAL-ACTIVITY; PERFORMANCE; MORTALITY; INCHIANTI; DECLINE; PEOPLE; RESTRICTION; LONGEVITY AB Purpose: to identify cross-sectional correlates of disability and risk factors for the development activities of daily living (ADL) and instrumental ADL (IADL) disability in community-dwelling older adults. Methods: the study population consisted of 897 subjects aged 65-102 years from the InCHIANTI study, a population-based cohort in Tuscany (Italy). Factors potentially associated with high risk of disability were measured at baseline (1998-2000), and disability in ADLs and IADLs were assessed both at baseline and at the 3-year follow-up (2001-03). Results: the baseline prevalence of ADL disability and IADL disability were, respectively, 5.5% (49/897) and 22.2% (199/897). Of 848 participants free of ADL disability at baseline, 72 developed ADL disability and 25 of the 49 who were already disabled had a worsening in ADL disability over a 3-year follow-up. Of 698 participants without IADL disability at baseline, 100 developed IADL disability and 104 of the 199 who already had IADL disability had a worsening disability in IADL over 3 years. In a fully adjusted model, high level of physical activity compared to sedentary state was significantly associated with lower incidence rates of both ADL and IADL disability at the 3-year follow-up visit (odds ratio (OR): 0.30; 95% confidence intervals (CI) 0.12-0.76 for ADL disability and OR: 0.18; 95% CI 0.09-0.36 for IADL disability). After adjusting for multiple confounders, higher energy intake (OR for difference in 100 kcal/day: 1.09; 95% CI 1.02-1.15) and hypertension (OR: 1.91; 95% CI 1.06-3.43) were significant risk factors for incident or worsening ADL disability. Conclusions: higher level of physical activity and lower energy intake may be protective against the development in ADL and IADL disability in older persons. C1 [Balzi, Daniela; Barchielli, Alessandro] Azienda Sanit Firenze, Epidemiol Unit, Florence, Italy. [Lauretani, Fulvio; Buiatti, Eva; Milaneschi, Yuri] Tuscany Reg Hlth Agcy, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Balzi, D (reprint author), Azienda Sanit Firenze, Epidemiol Unit, Florence, Italy. EM daniela.balzi@asf.toscana.it RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU 'targeted project' [ICS110.1/RF97.71]; Italian Ministry of Health; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111] FX Declaration of sources of funding: The InCHIANTI study baseline (1998-2000) was supported as a 'targeted project' (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Followup 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111). NR 26 TC 47 Z9 48 U1 5 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD JAN PY 2010 VL 39 IS 1 BP 92 EP 98 DI 10.1093/ageing/afp209 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 534UL UT WOS:000272922800017 PM 19933449 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Perspective: Does brown fat protect against diseases of aging? SO AGEING RESEARCH REVIEWS LA English DT Review DE Mitochondrial uncoupling; UCP; Alzheimer's disease diabetes; Insulin resistance ID ACTIVATED RECEPTOR-GAMMA; ENDOTHELIAL GROWTH-FACTOR; HUMAN SKELETAL-MUSCLE; DIET-INDUCED OBESITY; ADIPOSE-TISSUE; UNCOUPLING PROTEINS; CALORIC RESTRICTION; ADAPTIVE THERMOGENESIS; NERVOUS-SYSTEM; ADULT HUMANS AB The most commonly studied laboratory rodents possess a specialized form of fat called brown adipose tissue (BAT) that generates heat to help maintain body temperature in cold environments. In humans, BAT is abundant during embryonic and early postnatal development, but is absent or present in relatively small amounts in adults where it is located in paracervical and supraclavicular regions. BAT cells can 'burn' fatty acid energy substrates to generate heat because they possess large numbers of mitochondria in which oxidative phosphorylation is uncoupled from ATP production as a result of a transmembrane proton leak mediated by uncoupling protein 1 (UCP1). Studies of rodents in which BAT levels are either increased or decreased have revealed a role for BAT in protection against diet-induced obesity. Data suggest that individuals with low levels of BAT are prone to obesity, insulin resistance and cardiovascular disease, whereas those with higher levels of BAT maintain lower body weights and exhibit superior health as they age. BAT levels decrease during aging, and dietary energy restriction increases BAT activity and protects multiple organ systems including the nervous system against age-related dysfunction and degeneration. Future studies in which the effects of specific manipulations of BAT levels and thermogenic activity on disease processes in animal models (diabetes, cardiovascular disease, cancers, neurodegenerative diseases) are determined will establish if and how BAT affects the development and progression of age-related diseases. Data from animal studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity and age-related diseases. Examples include: diet and lifestyle changes; specific regimens of mild intermittent stress; drugs that stimulate BAT formation and activity; induction of brown adipose cell progenitors in muscle and other tissues: and transplantation of brown adipose cells. (C) 2009 Published by Elsevier Ireland Ltd. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 92 TC 52 Z9 55 U1 2 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD JAN PY 2010 VL 9 IS 1 SI SI BP 69 EP 76 DI 10.1016/j.arr.2009.11.004 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 556TT UT WOS:000274616100007 PM 19969105 ER PT B AU Lahiri, DK Ghosh, C Rogers, JT Bondy, S Greig, NH AF Lahiri, Debomoy K. Ghosh, Chandramallika Rogers, Jack T. Bondy, Stephen Greig, Nigel H. BE Bondy, S Maiese, K TI Role of Nitric Oxide in Neurodegeneration and Vulnerability of Neuronal Cells to Nitric Oxide Metabolites and Reactive Oxygen Species SO AGING AND AGE-RELATED DISORDERS SE Oxidative Stress in Applied Basic Research and Clinical Practice LA English DT Article; Book Chapter DE Alzheimer; Antioxidants; Chemical insults; Melatonin; Oxidative damage; Neuronal culture; Pineal hormone; Reactive nitrogen species; RNS; Tissue culture ID AMYLOID PRECURSOR PROTEIN; VASCULAR SMOOTH-MUSCLE; AGE-RELATED-CHANGES; ALZHEIMERS-DISEASE; SODIUM-NITROPRUSSIDE; MEDIATED TOXICITY; OXIDATIVE STRESS; GENE-EXPRESSION; GLIAL-CELLS; MELATONIN AB Nitric oxide (NO) is produced during the oxidative deamination catalyzed by nitric oxide synthase (NOS) that converts L-arginine to L-citrulline. NO can also be released chemically from a group of compounds called NO donors, such as sodium nitroprusside (SNP). NO directly or through its metabolites is believed to be involved in several disorders, including Alzheimer's disease (AD). This chapter summarizes the role of NO and oxidative stress in neurodegeneration and describes the experimental evidence of increased vulnerability of neuronal cells to NO metabolites and other reactive oxygen species (ROS). As NO is a highly labile, unstable free gas, levels of the stable end products, such as nitrite and nitrate (NOx), were measured. When different cell types were treated with SNP, a significant level of NOx was detected in a time- and dose-dependent manner, which was more than the spontaneous release by SNP. Astrocytic, glial, and epithelial cell lines released significantly higher levels of NOx compared with neuronal cell lines after SNP treatment. Neuronal cells were more sensitive to SNP-induced cytotoxicity, as determined by lactate dehydrogenase assay. SNP-mediated toxicity is known to be due, in large part, to the accumulation of cyanide ions, and the ability of cells to protect themselves against this toxicity depends upon their levels of NO metabolites. Cell lines that generate more NOx, such as astrocytic and epithelial, are better protected against the SNP-induced toxicity than are less NOx-protecting neuronal cell lines. Our results suggest that various cell types metabolize SNP differently and that neuronal cell lines are more vulnerable than other cell types to SNP treatment. As neuronal cell lines lack an NO-generated protective mechanism, these cells are potentially primary targets for neurodegeneration by toxic agents including the free radicals and peroxynitrites. C1 [Lahiri, Debomoy K.] Inst Psychiat Res, Mol Neurogenet Lab, Dept Psychiat, Indianapolis, IN USA. [Lahiri, Debomoy K.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Bondy, Stephen] Univ Calif Irvine, Dept Med Community & Environm Med, Ctr Occupat & Environm Hlth, Irvine, CA 92697 USA. [Ghosh, Chandramallika] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Greig, Nigel H.] NIA, Intramural Res Program, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Rogers, Jack T.] Harvard Univ, Sch Med, Dept Psychiat Neurosci, Massachusetts Gen Hosp E, Charlestown, MA USA. RP Lahiri, DK (reprint author), Inst Psychiat Res, Mol Neurogenet Lab, Dept Psychiat, Indianapolis, IN USA. EM dlahiri@iupui.edu NR 44 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-60761-601-6 J9 OXID STRESS APPL BAS JI Oxid. Stress Appl. Basic Res. Clin. Pract. PY 2010 BP 399 EP 415 DI 10.1007/978-1-60761-602-3_20 D2 10.1007/978-1-60761-602-3 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA BQX53 UT WOS:000282063600020 ER PT J AU de Cabo, R Siendones, E Minor, R Navas, P AF de Cabo, Rafael Siendones, Emilio Minor, Robin Navas, Placido TI CYB5R3: a key player in aerobic metabolism and aging? SO AGING-US LA English DT Article DE cytochrome b(5) reductase; NAD(+)/NADH; NQR1; lifespan; respiration ID LIFE-SPAN EXTENSION; CALORIE RESTRICTION EXTENDS; MEMBRANE REDOX SYSTEM; PLASMA-MEMBRANE; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL BIOGENESIS; DIETARY RESTRICTION; ANTIOXIDANT SYSTEM; NONHUMAN-PRIMATES; GENE-EXPRESSION AB Aging results from a complex and not completely understood chain of processes that are associated with various negative metabolic consequences and ultimately leads to senescence and death. The intracellular ratio of pyridine nucleotides (NAD(+)/NADH), has been proposed to be at the center stage of age-related biochemical changes in organisms, and may help to explain the observed influence of calorie restriction and energy-sensitive proteins on lifespan in model organisms. Indeed, the NAD(+)/NADH ratios affect the activity of a number of proteins, including sirtuins, which have gained prominence in the aging field as potential mediators of the beneficial effects of calorie restriction and mediating lifespan. Here we review the activities of a redox enzyme (NQR1 in yeast and CYB5R3 in mammals) that also influences the NAD(+)/NADH ratio and may play a regulatory role that connects aerobic metabolism with aging. C1 [Siendones, Emilio; Navas, Placido] Univ Pablo Olavide, CSIC, Ctr Andaluz Biol Desarrollo, E-41013 Seville, Spain. [Siendones, Emilio; Navas, Placido] ISCIII, Ctr Biomed Res Rare Dis CIBERER, E-41013 Seville, Spain. [de Cabo, Rafael; Minor, Robin] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Navas, P (reprint author), Univ Pablo Olavide, CSIC, Ctr Andaluz Biol Desarrollo, E-41013 Seville, Spain. EM pnavas@upo.es RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Spanish FIS [PI080500]; NIH [1R01AG028125-01A1] FX This paper has been partially supported by Spanish FIS Grant PI080500, NIH Grant 1R01AG028125-01A1, and the Intramural Research Program of the NIH, National Institute on Aging. NR 41 TC 7 Z9 7 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD JAN PY 2010 VL 2 IS 1 BP 63 EP 68 PG 6 WC Cell Biology SC Cell Biology GA 579VC UT WOS:000276403300006 ER PT J AU Reddy, K Winkler, CA Werner, L Mlisana, K Karim, SSA Ndung'u, T AF Reddy, Kavidha Winkler, Cheryl A. Werner, Lise Mlisana, Koleka Karim, Salim S. Abdool Ndung'u, Thumbi CA CAPRISA 002 Acute Infection Study Team TI APOBEC3G expression is dysregulated in primary HIV-1 infection and polymorphic variants influence CD4+ T-cell counts and plasma viral load SO AIDS LA English DT Article DE apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like; 3G; HIV-1 subtype C; host proteins; mRNA expression; polymorphisms; primary infection ID IMMUNODEFICIENCY-VIRUS TYPE-1; LONGITUDINAL DATA-ANALYSIS; MESSENGER-RNA LEVELS; E3 UBIQUITIN LIGASE; VIF PROTEIN; EDITING ENZYME; REVERSE TRANSCRIPTION; CYTIDINE DEAMINATION; HYPERMUTATION; DNA AB Objectives: In the absence of HIV-1 virion infectivity factor (Vif), cellular cytosine deaminases such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4(+) T-cell counts as outcomes. Methods: Study participants were 250 South African women at high risk for HIV-1 subtype C infection. We used real-time PCR to measure the expression of APOBEC3C in HIV-negative and HIV-positive primary infection samples. APOBEC3C variants were identified by DNA re-sequencing and TaqMan genotyping. Results: We found no correlation between APOBEC3C expression levels and plasma viral loads (r=0.053, P=0.596) or CD4(+) T-cell counts (r=0.030, P=0.762) in 32 seroconverters. APOBEC3C expression levels were higher in HIV-negative individuals as compared with HIV-positive individuals (P<0.0001), including matched pre and postinfection samples from the same individuals (n=13, P<0.0001). Twenty-four single nucleotide polymorphisms, including eight novel, were identified within APOBEC3C by re-sequencing and genotyping. The H186R mutation, a codon-changing variant in exon 4, and a 3' extragenic Mutation (rs35228531) were associated with high viral loads (P=0.0097 and P < 0.0001) and decreased CD4(+) T-cell levels (P=0.0081 and P < 0.0001), respectively. Conclusion: These data suggest that APOBEC3C transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3C expression levels in peripheral blood mononuclear cells do not correlate with viral loads or CD4(+) T-cell counts. Genetic variation of APOBEC3G may significantly affect early HIV-11 pathogenesis, although the mechanism remains unclear and warrants further investigation. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Reddy, Kavidha; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4013 Durban, South Africa. [Winkler, Cheryl A.] NCI, Sci Applicat Int Corp, Lab Genom Div, Frederick, MD 21701 USA. [Werner, Lise; Mlisana, Koleka; Karim, Salim S. Abdool; Ndung'u, Thumbi] Univ KwaZulu Natal, CAPRISA, ZA-4013 Durban, South Africa. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Private Bag X7, ZA-4013 Durban, South Africa. EM ndungu@ukzn.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Mlisana, Koleka/0000-0002-8436-3268; Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institute of Allergy an Infectious Diseases, National Institutes of Health (NIH); U.S. Department of Health and Human Services [U19 AI 51794]; Columbia University-Southern African Fogarty AIDS International Training; Fogarty International Center, NIH [D43TW00231]; South African Department of Science and Technology; Hasso Plattner Foundation; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX We thank Beth Binns-Roemer and Yuchun Zhou for excellent technical assistance. We thank the study participants, CAPRISA clinical and laboratory staff for providing specimens. The CAPRISA acute infection study was supported by the National Institute of Allergy an Infectious Diseases, National Institutes of Health (NIH) and U.S. Department of Health and Human Services (grant #U19 AI 51794). K.R. was supported by the Columbia University-Southern African Fogarty AIDS International Training and Research Programme funded by the Fogarty International Center, NIH (grant #D43TW00231) and by a training grant from the East Coast Biotechnology Research Innovation Centre (LifeLab), funded by the South African Department of Science and Technology. TN. is Supported by the Hasso Plattner Foundation and holds the South African DST/NRF Research Chair in Systems Biology of HIV/AIDS. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercia products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 39 TC 44 Z9 45 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN PY 2010 VL 24 IS 2 BP 195 EP 204 DI 10.1097/QAD.0b013e3283353bba PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 544SR UT WOS:000273680100003 PM 19996938 ER PT J AU Woelk, CH Beliakova-Bethell, N Goicoechea, M Zhao, YD Du, PY Rought, SE Lozach, J Perez-Santiago, J Richman, DD Smith, DM Little, SJ AF Woelk, Christopher H. Beliakova-Bethell, Nadejda Goicoechea, Miguel Zhao, Yingdong Du, Pinyi Rought, Steffney E. Lozach, Jean Perez-Santiago, Josue Richman, Douglas D. Smith, Davey M. Little, Susan J. TI Gene expression before HAART initiation predicts HIV-infected individuals at risk of poor CD4(+) T-cell recovery SO AIDS LA English DT Article DE CD4; gene expression; HIV; immune reconstitution; pathogenesis; prognosis ID BLOOD MONONUCLEAR-CELLS; ANTIRETROVIRAL THERAPY; VIROLOGICAL RESPONSES; COUNT RECOVERY; PROFILES; IDENTIFICATION; INTERRUPTION; MICROARRAY; CARCINOMA AB Objective: To identify a pre-HAART gene expression signature in peripheral blood mononuclear cells (PBMCs) predictive of CD4(+) T-cell recovery during HAART in HIV-infected individuals. Design: This retrospective study evaluated PBMC gene expression in 24 recently HIV-infected individuals before the initiation of HAART to identify genes whose expression is predictive of CD4(+) T-cell recovery after 48 weeks of HAART. Methods: The change in CD4(+) T-cell count (Delta CD4) over the 48-week study period was calculated for each of the 24 participants. Twelve participants were assigned to the 'good' (Delta CD4 >= 200 cells/mu l) and 12 to the 'poor' (Delta CD4 < 200 cells/mu l) CD4(+) T-cell recovery group. Gene expression profiling of the entire transcriptome using Illumina BeadChips was performed with PBMC samples obtained before HAART. Gene expression classifiers capable of predicting CD4(+) T-cell recovery group (good vs. poor), as well as the specific Delta CD4 value, at week 48 were constructed using methods of Class Prediction. Results: The expression of 40 genes in PBMC samples taken before HAART predicted CD4(+) T-cell recovery group (good vs. poor) at week 48 with 100% accuracy. The expression of 22 genes predicted a specific Delta CD4 value for each HIV-infected individual that correlated well with actual values (R=0.82). Predicted Delta CD4 values were also used to assign individuals to good vs. poor CD4(+) T-cell recovery groups with 79% accuracy. Conclusion: Gene expression in PBMCs can be used as biomarkers to successfully predict disease outcomes among HIV-infected individuals treated with HAART. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Woelk, Christopher H.; Goicoechea, Miguel; Du, Pinyi; Rought, Steffney E.; Perez-Santiago, Josue; Richman, Douglas D.; Smith, Davey M.; Little, Susan J.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Woelk, Christopher H.; Richman, Douglas D.; Smith, Davey M.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Beliakova-Bethell, Nadejda; Richman, Douglas D.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Rockville, MD USA. [Lozach, Jean] Illumina Inc, San Diego, CA USA. RP Woelk, CH (reprint author), Univ Calif San Diego, Dept Med, Stein Clin Res Bldg,Room 326,9500 Gilman Dr 0679, La Jolla, CA 92093 USA. EM cwoelk@ucsd.edu FU Developmental Grant from the Center for AIDS Research (CFAR) at the University of California San Diego (UCSD); Genomics Core at the UCSD CFAR; San Diego Veterans Medical Research Foundation, National Institutes of Health [AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI0477455, AI007384, AI74621]; California HIV/AIDS Research Program [RN07-SD-702]; Pfizer Inc; Merck Laboratories FX Gene expression data were generated via funding through a Developmental Grant from the Center for AIDS Research (CFAR) at the University of California San Diego (UCSD). This work was performed with the support of the Genomics Core at the UCSD CFAR, the San Diego Veterans Medical Research Foundation, National Institutes of Health research grants (AI69432, AI043638, MH62512, MH083552, AI077304, AI36214, AI0477455, AI007384 and AI74621), and a research grant from the California HIV/AIDS Research Program (RN07-SD-702). Microarray hybridization and scanning was performed at the UCSD Biomedical Genomics (BIOGEM) core facility with the help of Dr Gary Hardiman (Director) and James Sprague. Class Prediction analysis was performed using BRB-Array Tools developed by Dr Richard Simon and the BR-B-ArrayTools Development Team. We would like to thank the reviewers of this manuscript and Dr Sanjay Mehta whose comments resulted in a more coherent presentation of our results.; C.H.W conceived the study, analyzed patient and microarray data, wrote the original manuscript, and addressed the reviewers' comments. N.B.B. analyzed microarray data and generated the figures presented in the manuscript. P.D. and S.E.R. extracted and assessed the quality of RNA from PBMC samples. Y.Z. implemented the LASSO algorithm for the prediction of Delta CD4 from gene expression data. M.G. and J.L. advised on experimental design. J.P. performed statistical analyses. M.G., D.D.R., D.S., and S.J.L. provided access to blinded patient clinical data and aided in the interpretation of gene expression data.; Although not a direct conflict of interest, C.H.W, M.G., D.D.R., D.S., and S.J.L. have received research support from Pfizer Inc. In addition, S.J.L. has served on the clinical advisory board for Monogram Biosciences Inc. and received research support from Merck Laboratories. D.D.R. is also a consultant for Theraclone, Myriad, Bristol-Myers Squibb, Anadys Pharmaceuticals Inc., Gilead Sciences, Hoffman-La Roche Inc., Merck and Co. Inc., Monogram Biosciences, Biota, Chimerx, Idenix and Gen-Probe. J.L. is employed by Illumina Inc., manufacturer of the microarray platform used in this study, but this does not represent a conflict of interest, as this platform was selected prior to his inclusion on the project and he did not perform any data analysis. NR 27 TC 10 Z9 10 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN PY 2010 VL 24 IS 2 BP 217 EP 222 DI 10.1097/QAD.0b013e328334f1f0 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 544SR UT WOS:000273680100006 PM 19952713 ER PT J AU Henderson, WA Schlenk, EA Kim, KH Hadigan, CM Martino, AC Sereika, SM Erlen, JA AF Henderson, Wendy A. Schlenk, Elizabeth A. Kim, Kevin H. Hadigan, Colleen M. Martino, Angela C. Sereika, Susan M. Erlen, Judith A. TI Validation of the MOS-HIV as a measure of health-related quality of life in persons living with HIV and liver disease SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE health-related quality of life; HIV; liver disease; MOS-HIV; clinical research ID HEPATITIS-C VIRUS; MEDICAL OUTCOMES; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; COINFECTION; RELIABILITY; POPULATION; HIV/AIDS; VALIDITY; MORTALITY AB Background. Management of human immunodeficiency virus (HIV) infection with potent antiretroviral medication has transformed HIV into a chronic condition and has shifted much of the burden of disease to co-morbid conditions such as liver disease (LD). LD alone has been shown to have a significant effect on one's health-related quality of life (HRQOL). Clinical evidence suggests that the growing number of persons living with HIV + LD may have a poorer HRQOL than persons with HIV without LD. To date, the widely accepted instrument to assess HRQOL, Medical Outcomes Study-HIV Health Survey (MOS-HIV), has not been evaluated for reliability and validity in a population of HIV-infected persons with LD. Methods. HRQOL was prospectively assessed using the MOS-HIV in a sample of 532 HIV-infected adults on antiretroviral therapy (n = 305 HIV and n = 227 HIV + LD). In addition, participants completed standardized questionnaires of sociodemographics and co-morbid conditions. Results. The psychometric properties of the MOS-HIV were supported by testing reliability and construct, convergent, discriminative, and predictive validity. The MOS-HIV discriminated between those persons living with HIV with and without LD on the basis of the physical function subscale scores (p = 0.018). Conclusion. This study found the MOS-HIV valid and reliable instrument in persons with HIV + LD. C1 [Henderson, Wendy A.; Martino, Angela C.] NINR, Biobehav Unit, Symptom Management Branch, NIH, Bethesda, MD 20892 USA. [Schlenk, Elizabeth A.; Sereika, Susan M.; Erlen, Judith A.] Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA 15261 USA. [Kim, Kevin H.] Univ Pittsburgh, Sch Educ, Pittsburgh, PA 15261 USA. [Hadigan, Colleen M.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Henderson, WA (reprint author), NINR, Biobehav Unit, Symptom Management Branch, NIH, Bethesda, MD 20892 USA. EM hendersw@mail.nih.gov OI Schlenk, Elizabeth/0000-0001-7361-1951; Henderson, Wendy/0000-0003-3924-7118 FU Intramural NIH HHS [Z99 NR999999, ZIA NR000018-01, ZIA NR000018-02]; NCRR NIH HHS [1TL1 RR024155]; NINR NIH HHS [P30 NR003924, R01 NR004749, R01 NR04749, R01 NR004749-10] NR 33 TC 1 Z9 2 U1 1 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2010 VL 22 IS 4 BP 483 EP 490 DI 10.1080/09540120903207292 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 591PJ UT WOS:000277313800010 PM 20140792 ER PT J AU Serchuck, LK Williams, PL Nachman, S Gadow, KD Chernoff, M Schwartz, L AF Serchuck, Leslie K. Williams, Paige L. Nachman, Sharon Gadow, Kenneth D. Chernoff, Miriam Schwartz, Lynnae CA IMPAACT 1055 Team TI Prevalence of pain and association with psychiatric symptom severity in perinatally HIV-infected children as compared to controls living in HIV-affected households SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE pain; HIV; children ID IMMUNODEFICIENCY-VIRUS-INFECTION; PRIMARY FIBROMYALGIA SYNDROME; CATASTROPHIC THINKING; SEX-DIFFERENCES; AGE; DISABILITY; ADJUSTMENT; DEPRESSION; COMPLAINTS; CYTOKINES AB This cross-sectional study evaluated the prevalence of pain and psychiatric symptoms in perinatally HIV-infected children at entry into P1055, a multicenter investigation of the prevalence and severity of psychiatric symptoms in HIV-infected children. Subjects 6-17 years of age and their primary caregivers were recruited from 29 International Maternal Pediatric Adolescent AIDS Clinical Trials sites in the USA and Puerto Rico. A total of 576 children (320 HIV+ and 256 HIV- children) were enrolled from June 2005 to September 2006. Subject self-reports of pain were measured by the Wong-Baker visual analog scale and Short-Form McGill Pain Questionnaire. Symptomatology for anxiety, depression, and dysthymia was assessed through Symptom Inventory instruments. Caregiver's assessment of their child's pain and psychiatric symptomatology was similarly measured. Logistic regression models were used to evaluate predictors of pain. We found that a higher proportion of HIV-infected than uninfected subjects reported pain in the last two months (41% vs 32%, p=0.04), last two weeks (28% vs 19%, p=0.02), and lasting more than one week (20% vs 11%, p=0.03). Among HIV-infected youth, females (OR = 1.53, p=0.09), White race (OR = 2.15, p=0.04), and Centers for Disease Control (CDC) class C (OR = 1.83, p = 0.04) were significantly more likely to report pain. For all subjects, only 52% of caregivers recognized their child's pain and just 22% were aware that pain affected their child's daily activities. The odds of reported pain in HIV+ increased with higher symptom severity for generalized anxiety (OR = 1.14, p = 0.03), major depression (OR = 1.15, p=0.03), and dysthymia (OR = 1.18, p=0.01). This study underscores the importance of queries concerning pain and emotional stressors in the care of HIV+ and uninfected children exposed to HIV+ individuals. The discordance between patient and caregiver reports of pain and its impact on activities of daily living highlights that pain in children is under-recognized and therefore potentially under-treated. C1 [Schwartz, Lynnae] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. [Serchuck, Leslie K.] NIH, Pediat Adolescent & Maternal AIDS Branch, Eunice Shriver Inst Child Hlth & Human Dev, Rockville, MD 20892 USA. [Williams, Paige L.; Chernoff, Miriam] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Nachman, Sharon] SUNY Stony Brook, Dept Pediat, Stony Brook, NY 11794 USA. [Gadow, Kenneth D.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. RP Schwartz, L (reprint author), Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. EM schwartzl1@email.chop.edu FU NIAID NIH HHS [AI-41110, U01 AI068632-03, U01 AI041110] NR 29 TC 6 Z9 6 U1 0 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2010 VL 22 IS 5 BP 640 EP 648 AR PII 922244613 DI 10.1080/09540120903280919 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 597PG UT WOS:000277770000014 PM 20401767 ER PT J AU Ferrer, RA Morrow, KM Fisher, WA Fisher, JD AF Ferrer, Rebecca A. Morrow, Kathleen M. Fisher, William A. Fisher, Jeffrey D. TI Toward an information-motivation-behavioral skills model of microbicide adherence in clinical trials SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE microbicides; adherence; clinical trials; HIV prevention; health behavior change models ID RANDOMIZED CONTROLLED-TRIAL; PHASE-I TRIAL; VAGINAL MICROBICIDE; ANTIRETROVIRAL THERAPY; RISK BEHAVIOR; CONDOM USE; TOPICAL MICROBICIDES; HEALTH BEHAVIOR; INFECTED WOMEN; TENOFOVIR GEL AB Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising microbicide may be stopped, because low adherence rates create the illusion of poor efficacy. We provide a framework with which to conceptualize and improve microbicide adherence in clinical trials, supported by a critical review of the empirical literature. The information-motivation-behavioral skills (IMB) model of microbicide adherence conceptualizes microbicide adherence in clinical trials and highlights factors that can be addressed in behavioral interventions to increase adherence in such trials. This model asserts that microbicide adherence-related information, motivation, and behavioral skills are fundamental determinants of adherent microbicide utilization. Specifically, information consists of objective facts about microbicide use (e.g., administration and dosage) as well as heuristics that facilitate use (e.g., microbicides must be used with all partners). Motivation to adhere consists of attitudes toward personal use of microbicides (e.g., evaluating the consequences of using microbicides as good or pleasant) as well as social norms that support their use (e.g., beliefs that a sexual partner approves use of microbicides). Behavioral skills consist of objective skills necessary for microbicide adherence (e.g., the ability to apply the microbicide correctly and consistently). Empirical evidence concerning microbicide acceptability and adherence to spermicides, medication, and condom use regimens support the utility of this model for understanding and promoting microbicide adherence in clinical trials. C1 [Ferrer, Rebecca A.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Ferrer, Rebecca A.; Fisher, Jeffrey D.] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT USA. [Morrow, Kathleen M.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. [Morrow, Kathleen M.] Ctr Behav, Providence, RI USA. [Morrow, Kathleen M.] Ctr Prevent Med, Providence, RI USA. [Fisher, William A.] Univ Western Ontario, Dept Psychol, London, ON, Canada. [Fisher, William A.] Univ Western Ontario, Dept Obstet & Gynecol, London, ON, Canada. [Fisher, Jeffrey D.] Univ Connecticut, Dept Psychol, Storrs, CT USA. RP Ferrer, RA (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM ferrerra@mail.nih.gov NR 75 TC 17 Z9 17 U1 3 U2 14 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2010 VL 22 IS 8 BP 997 EP 1005 AR PII 923038441 DI 10.1080/09540121003623719 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 633ZF UT WOS:000280546100011 PM 20552466 ER PT J AU Weinberg, A Song, LY Fenton, T Nachman, SA Read, JS Patterson-Bartlett, J Levin, MJ AF Weinberg, Adriana Song, Lin-Ye Fenton, Terence Nachman, Sharon A. Read, Jennifer S. Patterson-Bartlett, Julie Levin, Myron J. TI T Cell Responses of HIV-Infected Children after Administration of Inactivated or Live Attenuated Influenza Vaccines SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; IMMUNE-RESPONSES; DENDRITIC CELLS; ANTIBODY-RESPONSES; YOUNG-CHILDREN; DOUBLE-BLIND; VACCINATION; TRIVALENT; IMMUNIZATION AB Live-attenuated influenza vaccine (LAIV) prevents significantly more cases of influenza in immune-competent children than the trivalent inactivated vaccine (TIV). We compared the T cell responses to LAIV or TIV in HIV-infected children. IFN-gamma-ELISPOT for the three vaccine-contained influenza strains, two mismatched strains, and phytohemagglutinin (PHA), was performed at 0, 4, and 24 weeks postimmunization in 175 HIV-infected children randomly assigned to LAIV or TIV. The contribution of CD8 T cells to the influenza-specific response (CD8-ELISPOT) was evaluated by CD8-cell depletion. CD8 T cells accounted for >= 87% of the total influenza-ELISPOT. At baseline, total influenza-ELISPOT and CD8-ELISPOT values were similar or higher in TIV compared with LAIV recipients. Four and 24 weeks after TIV, total influenza-ELISPOT and CD8-ELISPOT results were significantly lower than baseline results (p <= 0.001). Responses to PHA also tended to decrease at 4 weeks after TIV (p=0.06), but rebounded to baseline levels at 24 weeks. Four weeks after LAIV, total influenza-ELISPOT responses to vaccine-contained strains A H3N2 and B significantly decreased. Other ELISPOT values at 4 weeks and all values at 24 weeks were similar to the baseline values. At 4 and 24 weeks, TIV compared to LAIV administration resulted in a significantly greater decrease in influenza-specific ELISPOT values for vaccine-contained influenza A strains (p <= 0.02). Responses to PHA also tended to decrease more in TIV recipients (p=0.07). HIV-infected children immunized with TIV had significant and persistent decreases in ELISPOT responses to influenza. LAIV administration suppressed ELISPOT responses less. The clinical significance of these findings deserves further study. C1 [Weinberg, Adriana; Patterson-Bartlett, Julie; Levin, Myron J.] Univ Colorado Denver, Aurora, CO 80045 USA. [Song, Lin-Ye; Fenton, Terence] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Nachman, Sharon A.] SUNY Stony Brook, Stony Brook, NY 11790 USA. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Weinberg, A (reprint author), Mail Stop 8604,12700 E 19th Ave, Aurora, CO 80045 USA. EM Adriana.Weinberg@ucdenver.edu FU National Center for Research Resources, NIH [N01-HD-3-3162]; National Institute of Allergy and Infectious Diseases [U01AI068632, U01 AI068616]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3345, N01-HD-33162]; MedImmune LLC; [5 MO1-RR00069] FX This research was supported by Grant 5 MO1-RR00069, General Clinical Research Centers Program, National Center for Research Resources, NIH; N01-HD-3-3162 and by Grants U01AI068632 and U01 AI068616 from the National Institute of Allergy and Infectious Diseases; N01-HD-3-3345 and contract N01-HD-33162 ( A. W.) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and by MedImmune LLC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, or the National Institutes of Health. We thank Drs. Robert Walker and Maria Allende for their participation in this study and their critical review of this article. NR 49 TC 6 Z9 7 U1 1 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN PY 2010 VL 26 IS 1 BP 51 EP 59 DI 10.1089/aid.2009.0163 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 551EY UT WOS:000274190700007 PM 20059397 ER PT J AU Valentin, A Morrow, M Poirier, RH Aleman, K Little, R Yarchoan, R Pavlakis, GN AF Valentin, Antonio Morrow, Matthew Poirier, Richard H. Aleman, Karen Little, Richard Yarchoan, Robert Pavlakis, George N. TI Identification of a Potential Pharmacological Sanctuary for HIV Type 1 in a Fraction of CD4(+) Primary Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; PERIPHERAL-BLOOD LYMPHOCYTES; P-GLYCOPROTEIN FUNCTION; NATURAL-KILLER-CELLS; PROTEASE INHIBITORS; MULTIDRUG-RESISTANCE; T-CELLS; COMBINATION THERAPY; INTRACELLULAR CONCENTRATION AB We have identified a subset of HIV-susceptible CD4'CCR5' cells in human PBMCs that can efficiently exclude protease inhibitors (PI) due to high P-glycoprotein (P-gp) efflux activity. Phenotypically these cells are heterogeneous, include both T and non-T cells, and some display markers of memory cells. Cells with high P-gp represent 16-56% (median=37.3) of all CD4'CCR5' cells in healthy donors, and are selectively depleted in HIV-1-infected individuals (4.1-33%, median 10.1). A fraction of primary cells productively infected by HIV-1, in vitro, have high P-gp pump activity, demonstrating that infection does not inhibit P-gp function. In agreement with these data, HIV-susceptible cells expressing high levels of P-gp require higher levels of PI for complete inhibition of virus spread. We conclude that the PI concentrations achieved in plasma could be suboptimal for full inhibition of virus spread in high P-gp cells, indicating that they may represent a pharmacological sanctuary for HIV-1. C1 [Valentin, Antonio; Morrow, Matthew; Poirier, Richard H.; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Aleman, Karen; Little, Richard; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20895 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, POB B,Bldg 535,Room 210, Frederick, MD 21702 USA. EM pavlakig@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 71 TC 7 Z9 7 U1 2 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN PY 2010 VL 26 IS 1 BP 79 EP 88 DI 10.1089/aid.2009.0044 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 551EY UT WOS:000274190700010 PM 20059395 ER PT J AU Willey, R Nason, MC Nishimura, Y Follmann, DA Martin, MA AF Willey, Ronald Nason, Martha C. Nishimura, Yoshiaki Follmann, Dean A. Martin, Malcolm A. TI Neutralizing Antibody Titers Conferring Protection to Macaques from a Simian/Human Immunodeficiency Virus Challenge Using the TZM-bl Assay SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HIV-1/SIV CHIMERIC VIRUS; ENVELOPE GLYCOPROTEIN; PASSIVE TRANSFER; TYPE-1 ENVELOPE; RHESUS-MONKEYS; HIV-INFECTION; IN-VITRO; VACCINE; CELLS; SENSITIVITY AB We previously reported that passive transfer of polyclonal neutralizing antibodies (NAbs) sufficient to generate a titer of 1: 38 in the plasma would confer sterilizing protection to 99% of macaques challenged intravenously with 75 TCID(50) of SHIV(DH12). Neutralizing activity in that study was measured in an MT4 cell assay in which infection was completely blocked (EC(100)). In the current study, the TZM-bl system was used to measure EC(50) neutralizing titers in several of the same macaque plasma samples and the relationship between these titers and in vivo protection was determined. The antiviral EC(50) NAb titers measured in individual plasma samples were higher than those previously obtained in the MT4 system. Furthermore, the geometric mean EC(50) NAb titers against pseudotyped SHIV(DH12) were 33-fold greater than the EC(100) titers measured in the MT4 cell assay against the replication-competent SHIV(DH12) inoculated into animals. An augmented probit regression model was used to generate curves relating TZM-bl EC(50) NAb titers and protection from a virus challenge; estimated titers conferring various levels of protection were then determined. In TZM-bl assays using pseudotyped SHIV(DH12), representative percent in vivo protection/estimated EC(50) titers were 99%/1:4467, 90%/1:1175, 80%/1:676, 50%/1:234, and 33%/1:141. Because it is likely that contributions from other arms of the immune system will contribute to vaccine-induced control, the range of EC(50) NAb titers we have derived may be more informative for evaluating the protective value of NAb activity from TZM-bl assays. C1 [Willey, Ronald; Nishimura, Yoshiaki; Martin, Malcolm A.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.; Follmann, Dean A.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 315A,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM malm@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors acknowledge the John Mascola Laboratory and Tatsuhiko Igarashi for help in establishing the TZM-bl neutralization assay. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 29 Z9 29 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN PY 2010 VL 26 IS 1 BP 89 EP 98 DI 10.1089/aid.2009.0144 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 551EY UT WOS:000274190700011 PM 20059398 ER PT J AU Althoff, KN Gebo, KA Gange, SJ Klein, MB Brooks, JT Hogg, RS Bosch, RJ Horberg, MA Saag, MS Kitahata, MM Eron, JJ Napravnik, S Rourke, SB Gill, MJ Rodriguez, B Sterling, TR Deeks, SG Martin, JN Jacobson, LP Kirk, GD Collier, AC Benson, CA Silverberg, MJ Goedert, JJ McKaig, RG Thorne, J Rachlis, A Moore, RD Justice, AC AF Althoff, Keri N. Gebo, Kelly A. Gange, Stephen J. Klein, Marina B. Brooks, John T. Hogg, Robert S. Bosch, Ronald J. Horberg, Michael A. Saag, Michael S. Kitahata, Mari M. Eron, Joseph J. Napravnik, Sonia Rourke, Sean B. Gill, M. John Rodriguez, Benigno Sterling, Timothy R. Deeks, Steven G. Martin, Jeffrey N. Jacobson, Lisa P. Kirk, Gregory D. Collier, Ann C. Benson, Constance A. Silverberg, Michael J. Goedert, James J. McKaig, Rosemary G. Thorne, Jennifer Rachlis, Anita Moore, Richard D. Justice, Amy C. CA North Amer AIDS Cohort TI CD4 count at presentation for HIV care in the United States and Canada: Are those over 50 years more likely to have a delayed presentation? SO AIDS RESEARCH AND THERAPY LA English DT Article AB We assessed CD4 count at initial presentation for HIV care among >= 50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to <50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were >= 50-years-old increased from 17% to 27% (p-value < 0.01). The median CD4 count among >= 50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value < 0.01) with both age groups experiencing modest annual improvements over time (< 50-year-olds: 5[4, 6] cells/mm(3); >= 50-year-olds: 7[5, 9] cells/mm(3)), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13% vs. 10%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults >= 50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed. C1 [Althoff, Keri N.; Gange, Stephen J.; Jacobson, Lisa P.; Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Gebo, Kelly A.; Moore, Richard D.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Klein, Marina B.] McGill Univ, Dept Med, Montreal, PQ H2X 2P4, Canada. [Brooks, John T.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Hogg, Robert S.] British Columbia Ctr Excellence & HIV AIDS, Vancouver, BC V6Z 1Y6, Canada. [Hogg, Robert S.] Simon Fraser Univ, Vancouver, BC V6Z 1Y6, Canada. [Bosch, Ronald J.] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Horberg, Michael A.; Silverberg, Michael J.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Saag, Michael S.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kitahata, Mari M.; Collier, Ann C.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Eron, Joseph J.; Napravnik, Sonia] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Rourke, Sean B.] Univ Toronto, Dept Psychiat, Toronto, ON M5B 1W8, Canada. [Rourke, Sean B.] Univ Toronto, Dept Neurosci, Toronto, ON M5B 1W8, Canada. [Gill, M. John] Univ Calgary, South Alberta HIV Clin, Calgary, AB T2R 0X7, Canada. [Rodriguez, Benigno] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Sterling, Timothy R.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94105 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [Benson, Constance A.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [McKaig, Rosemary G.] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Thorne, Jennifer] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Rachlis, Anita] Univ Toronto, Dept Med, Toronto, ON M4N 3M5, Canada. [Justice, Amy C.] Yale Univ, Dept Med, Sch Med, West Haven, CT 06516 USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. RP Althoff, KN (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM kalthoff@jhsph.edu RI Rodriguez, Benigno/C-3365-2009; Gill, John/G-7083-2016; OI Rodriguez, Benigno/0000-0001-9736-7957; Gill, John/0000-0002-8546-8790; Gange, Stephen/0000-0001-7842-512X; Hogg, Robert/0000-0003-3463-5488 FU National Institutes of Health [U01-AI069918, U01-AA013566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634]; Centers for Disease Control [CDC200-2006-18797]; Canadian Institutes for Health Research [CIHR: TGF-96118, HCP-97105, CBR-86906, CBR-94036, KRS-86251, 169621]; Canadian Trials Network [242]; NIH [U01-AI68636, U01-HD32632, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, P30-AI27757, P30-AI27767, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-MH54907, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504]; N.I.H. [R01-DA11602, AI-69432, K01-AI071754, R01-AA16893, K24-00432, K23-AI-61-0320] FX We are grateful to all patients, physicians, investigators, and staff involved in the NA-ACCORD. This work was supported by grants from the National Institutes of Health: U01-AI069918, U01-AA013566, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-HD32632, M01-RR00071, M01-RR00079, M01-RR00083, M01-RR00722, P30-AI27757, P30-AI27767, P30-AI50410, P30-AI54999, R01-DA04334, R01-DA12568, R01-MH54907, R24-AI067039, Z01-CP010176, AHQ290-01-0012, N02-CP55504, R01-DA11602, AI-69432, K01-AI071754, R01-AA16893, K24-00432, K23-AI-61-0320. This work was also supported by the Centers for Disease Control (CDC200-2006-18797), the Canadian Institutes for Health Research (CIHR: TGF-96118; HCP-97105; CBR-86906; CBR-94036; KRS-86251; 169621) and the Canadian Trials Network (project number 242). NR 28 TC 29 Z9 30 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 45 DI 10.1186/1742-6405-7-45 PG 6 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700045 PM 21159161 ER PT J AU Bosch, RJ Pollard, RB Landay, A Aga, E Fox, L Mitsuyasu, R AF Bosch, Ronald J. Pollard, Richard B. Landay, Alan Aga, Evgenia Fox, Lawrence Mitsuyasu, Ronald TI Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328) SO AIDS RESEARCH AND THERAPY LA English DT Article AB Background: Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks. Results: The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm(3) at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed. Conclusions: Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease. C1 [Bosch, Ronald J.; Aga, Evgenia] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Pollard, Richard B.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Landay, Alan] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Fox, Lawrence] NIAID, Bethesda, MD 20892 USA. [Mitsuyasu, Ronald] Univ Calif Los Angeles, Los Angeles, CA USA. RP Bosch, RJ (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM rbosch@hsph.harvard.edu FU National Institute of Allergy and Infectious Diseases [AI 38858, AI 68636, AI 38855, AI 68634]; Chiron; Merck; Bristol-Myers Squibb; Glaxo Wellcome; NIH FX We wish to thank Anne Sevin, Deborah Cherng and Rui Wang, the participating ACTG sites and especially the study participants. This study was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI 38858, AI 68636, AI 38855, AI 68634). We also thank and acknowledge the support of Chiron, Merck, Bristol-Myers Squibb and Glaxo Wellcome. The following investigators and institutions participated in the study: T. Spitz and J. Frain (Washington University, AI 69495), W.A. O'Brien and G. Casey (University of Texas, Galveston, AI 32782), S.L. Koletar and C. Mills (Ohio State University, AI 69474), A. Conrad and B. Gripshover (Case Western Reserve, AI 69501), C. van der Horst and L. Frarey (University of North Carolina, AI 69423, RR 000046-48, AI 50410), C.D. Hamilton and S. Tedder (Duke University, AI 69484), A.C. Collier and S.S. Storey (University of Washington, AI 69434), J. Meier and J.T. Stapleton (University of Iowa, AI 27661, AI 58740), N. Hanks and S. Souza (University of Hawaii, AI 32853), B. Lambert and M. Saag (University of Alabama at Birmingham, AI 69452), M. Witt and R.Lopez (Harbor-UCLA Medical Center, AI 69424), J. Reid and C. Greisberger (University of Rochester, AI 69511, RR 024160), M.P. Dube and H. Edmondson (University of Southern California, AI 69428), Tulane University, Mt. Sinai Medical Center, M. Albrecht and N. Kim (Beth Israel Deaconess Medical Center AI 69472), D. Slamowitz and P. Cain (Stanford University, AI 69556), D. Mildvan (Beth Israel Medical Center AI 46370), B. Putnam and J. Koeppe (University of Colorado Hospital, RR 25780, AI 69450, AI 54907), V. Hughes and R. Emert (Cornell, AI 69419, RR 24996), J. Forcht and M. Vasquez (New York University, Bellevue Hospital Center AI 27665, AI 69532).; Funded by NIH. Presented at the 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, Brazil 24-27 July 2005. NR 6 TC 3 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 30 DI 10.1186/1742-6405-7-30 PG 5 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700030 PM 20687947 ER PT J AU Brown, J Magnus, M Czarnogosrki, M Lee, V AF Brown, Jeremy Magnus, Manya Czarnogosrki, Maggie Lee, Vanessa TI Another look at Emergency Department HIV screening in practice: no need to revise expectations SO AIDS RESEARCH AND THERAPY LA English DT Article AB Background: A recent study reported a lower than expected specificity and positive predictive value of the rapid oral HIV test in the setting of routine emergency department (ED) screening. These results appeared inconsistent with the findings in another urban Emergency Department during the same time period. Objective: To compare the specificity and positive predictive vale (PPV) of an oral rapid HIV test used in an ED screening program in Washington DC with that performed in the USHER clinical trial. Design: Period cross-sectional analysis of rapid oral HIV testing conducted in an ongoing HIV screening program emergency department patients. Setting: The George Washington University Emergency Department (Washington DC) from 7 February to 1 October 2007. Patients: 1,560 adults seen in the ED for non-HIV-related presenting complaints, who participated in the HIV screening program. Intervention: Rapid HIV testing with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania). Patients with reactive rapid test results were offered Western blot testing for confirmation. Measurements: Specificity and positive predictive value for the program were determined. Findings were compared to those found in the USHER trial. Results: Of 1,560 patients screened for HIV, 13 [0.8%, 95% CI 0.38% to 1.28%] had a reactive HIV screening test, and all were confirmed to be positive by Western Blot. The specificity was 100% (95% CI 99.6%-100%). Limitation: Since non-reactive tests were not confirmed, the test sensitivity cannot be determined. Conclusion: Review of our data conflict with findings from the USHER study surrounding false positive OraQuick HIV screening. Our data suggest that rapid HIV screening protocols implemented in EDs outside of the clinical trial paradigm perform effectively without an excess of false positive results. Compared with other screening tests, HIV rapid screening should remain an essential component of ED practice. C1 [Brown, Jeremy; Lee, Vanessa] George Washington Univ, Med Ctr, Dept Emergency Med, Washington, DC 20037 USA. [Magnus, Manya] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC USA. [Czarnogosrki, Maggie] NIAID, Bethesda, MD 20892 USA. RP Brown, J (reprint author), George Washington Univ, Med Ctr, Dept Emergency Med, Washington, DC 20037 USA. EM jbrown@mfa.gwu.edu FU OraSure FX JB has received lecture fees from OraSure. NR 15 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 1 DI 10.1186/1742-6405-7-1 PG 6 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700001 PM 20051116 ER PT J AU Lackman-Smith, CS Snyder, BA Marotte, KM Osterling, MC Mankowski, MK Jones, M Nieves-Duran, L Richardson-Harman, N Cummins, JE Sanders-Beer, BE AF Lackman-Smith, Carol S. Snyder, Beth A. Marotte, Katherine M. Osterling, Mark C. Mankowski, Marie K. Jones, Maureen Nieves-Duran, Lourdes Richardson-Harman, Nicola Cummins, James E., Jr. Sanders-Beer, Brigitte E. TI Safety and anti-HIV assessments of natural vaginal cleansing products in an established topical microbicides in vitro testing algorithm SO AIDS RESEARCH AND THERAPY LA English DT Article AB Background: At present, there is no effective vaccine or other approved product for the prevention of sexually transmitted human immunodeficiency virus type 1 (HIV-1) infection. It has been reported that women in resource-poor communities use vaginally applied citrus juices as topical microbicides. These easily accessible food products have historically been applied to prevent pregnancy and sexually transmitted diseases. The aim of this study was to evaluate the efficacy and cytotoxicity of these substances using an established topical microbicide testing algorithm. Freshly squeezed lemon and lime juice and household vinegar were tested in their original state or in pH neutralized form for efficacy and cytotoxicity in the CCR5-tropic cell-free entry and cell-associated transmission assays, CXCR4-tropic entry and fusion assays, and in a human PBMC-based anti-HIV-1 assay. These products were also tested for their effect on viability of cervico-vaginal cell lines, human cervical explant tissues, and beneficial Lactobacillus species. Results: Natural lime and lemon juice and household vinegar demonstrated anti-HIV-1 activity and cytotoxicity in transformed cell lines. Neutralization of the products reduced both anti-HIV-1 activity and cytotoxicity, resulting in a low therapeutic window for both acidic and neutralized formulations. For the natural juices and vinegar, the IC50 was <= 3.5 (0.8-3.5)% and the TC50 <= 6.3 (1.0-6.3)%. All three liquid products inhibited viability of beneficial Lactobacillus species associated with vaginal health. Comparison of three different toxicity endpoints in the cervical HeLa cell line revealed that all three products affected membrane integrity, cytosolic enzyme release, and dehydrogenase enzyme activity in living cells. The juices and vinegar also exerted strong cytotoxicity in cervico-vaginal cell lines, mainly due to their acidic pH. In human cervical explant tissues, treatment with 5% lemon or lime juice or 6% vinegar induced toxicity similar to application of 100 mu g/ml nonoxynol-9, and exposure to 10% lime juice caused tissue damage comparable to treatment with 5% Triton-X-100. Conclusions: Lemon and lime juice and household vinegar do not fulfill the safety criteria mandated for a topical microbicide. As a result of their unphysiological formulation for the vaginal tract, they exhibit cytotoxicity to human cell lines, human vaginal tissues, and beneficial vaginal Lactobacillus species. C1 [Lackman-Smith, Carol S.; Snyder, Beth A.; Marotte, Katherine M.; Osterling, Mark C.; Mankowski, Marie K.; Jones, Maureen; Nieves-Duran, Lourdes; Cummins, James E., Jr.; Sanders-Beer, Brigitte E.] So Res Inst, Frederick, MD USA. [Richardson-Harman, Nicola] Alpha StatConsult LLC, Damascus, MD USA. [Cummins, James E., Jr.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Sanders-Beer, Brigitte E.] BIOQUAL Inc, Rockville, MD USA. RP Lackman-Smith, CS (reprint author), So Res Inst, Frederick, MD USA. EM lackmansmith@southernresearch.org FU National Institute of Health, NICHD [N01-HD-3-3350]; NIAID [N01-AI-05415, N01-AI-70042]; National Institute of Health, NIAID [N01-AI-33350] FX This project has been funded in whole with Federal funds from the following National Institute of Health contracts: NICHD Contract N01-HD-3-3350 (Dr. Patricia Reichelderfer, Project Officer) and NIAID Contract N01-AI-33350 (Dr. Kailash Gupta, Project Officer). We also gratefully acknowledge NIAID Contract N01-AI-05415 and N01-AI-70042 (Dr. Roger Miller, Project Officer). We would like to thank Dr. Gustavo Doncel for providing nonoxynol-9. We would also like to thank Dr. Jim Turpin (NIAID) for his excellent scientific advice and leadership, and Drs. Jeff Spieler, Anke Hemmerling, Patricia Fletcher, Christine Mauck, Lut Van Damme, and Robin Shattock for excellent scientific discussions on the use of lemon and lime juice as topical microbicides. NR 39 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 22 DI 10.1186/1742-6405-7-22 PG 13 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700022 PM 20618951 ER PT J AU Sun, K Zhou, ST Chen, RY Cohen, MS Zhang, FJ AF Sun, Kai Zhou, Shuntai Chen, Ray Y. Cohen, Myron S. Zhang, Fujie TI Recent key advances in human immunodeficiency virus medicine and implications for China SO AIDS RESEARCH AND THERAPY LA English DT Review AB In this article we summarize several recent major developments in human immunodeficiency virus treatment, prevention, outcome, and social policy change. Updated international guidelines endorse more aggressive treatment strategies and safer antiretroviral drugs. New antiretroviral options are being tested. Important lessons were learned in the areas of human immunodeficiency virus vaccines and microbicide gels from clinical studies, and additional trials in prevention, especially pre-exposure prophylaxis, are nearing completion. Insight into the role of the virus in the pathogenesis of diseases traditionally thought to be unrelated to acquired immunodeficiency syndrome has become a driving force for earlier and universal therapy. Lastly, we review important achievements of and future challenges facing China as she steps into her eighth year of the National Free Antiretroviral Treatment Program. C1 [Sun, Kai] Washington Univ, St Louis, MO USA. [Zhou, Shuntai; Zhang, Fujie] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Div Treatment & Care, Beijing 100050, Peoples R China. [Chen, Ray Y.] Natl Inst Hlth, NIAID, Beijing 100600, Peoples R China. [Zhang, Fujie] China Med Univ, Shenyang, Liaoning, Peoples R China. RP Cohen, MS (reprint author), Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. EM mscohen@med.unc.edu; treatment@chinaaids.cn RI Zhou, Shuntai/R-4367-2016; OI Chen, Ray/0000-0001-6344-1442 FU Doris Duke Fellowship through the University of North Carolina at Chapel Hill School of Medicine; University of North Carolina Center for AIDS Research [P30AI50410]; NIH Fogarty AITRP [5-D43-TW001039-11-12]; Eleventh Key Science and Technology Five Year Plan of China [2008ZX10001-007] FX We acknowledge the support of the Doris Duke Fellowship through the University of North Carolina at Chapel Hill School of Medicine. This work was also supported by the University of North Carolina Center for AIDS Research (P30AI50410), NIH Fogarty AITRP (5-D43-TW001039-11-12), and the Eleventh Key Science and Technology Five Year Plan of China (2008ZX10001-007). NR 79 TC 2 Z9 2 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 12 DI 10.1186/1742-6405-7-12 PG 8 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700012 PM 20500898 ER PT J AU Van Duyne, R Guendel, I Kehn-Hall, K Easley, R Klase, Z Liu, CL Young, M Kashanchi, F AF Van Duyne, Rachel Guendel, Irene Kehn-Hall, Kylene Easley, Rebecca Klase, Zachary Liu, Chenglong Young, Mary Kashanchi, Fatah TI The identification of unique serum proteins of HIV-1 latently infected long-term non-progressor patients SO AIDS RESEARCH AND THERAPY LA English DT Article AB Background: The search for disease biomarkers within human peripheral fluids has become a favorable approach to preventative therapeutics throughout the past few years. The comparison of normal versus disease states can identify an overexpression or a suppression of critical proteins where illness has directly altered a patient's cellular homeostasis. In particular, the analysis of HIV-1 infected serum is an attractive medium with which to identify altered protein expression due to the ease and non-invasive methods of collecting samples as well as the corresponding insight into the in vivo interaction of the virus with infected cells/tissue. The utilization of proteomic techniques to globally identify differentially expressed serum proteins in response to HIV-1 infection is a significant undertaking that is complicated due to the innate protein profile of human serum. Results: Here, the depletion of 12 of the most abundant serum proteins, followed by two-dimensional gel electrophoresis coupled with identification of these proteins using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, has allowed for the identification of differentially expressed, low abundant serum proteins. We have analyzed and compared serum samples from HIV-1 infected subjects who are being treated using highly active antiretroviral therapy (HAART) to those who are latently infected but have not progressed to AIDS despite the absence of treatment, i.e. long term non-progressors (LTNPs). Here we have identified unique serum proteins that are differentially expressed in LTNP HIV-1 patients and may contribute to the ability of these patients to combat HIV-1 infection in the absence of HAART. We focused on the cdk4/6 cell cycle inhibitor p16(INK4A) and found that the treatment of HIV-1 latently infected cell lines with p16INK4A decreases viral production despite it not being expressed endogenously in these cells. Conclusions: Identification of these unique proteins may serve as an indication of altered viral states in response to infection as well as a natural phenotypic variability in response to HIV-1 infection in a given population. C1 [Van Duyne, Rachel] George Washington Univ, Med Ctr, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Van Duyne, Rachel; Guendel, Irene; Kehn-Hall, Kylene; Easley, Rebecca; Kashanchi, Fatah] George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. [Klase, Zachary] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Chenglong; Young, Mary] Georgetown Univ, Med Ctr, Div Infect Dis, Washington Metropolitan Womens Interagency HIV St, Washington, DC 20007 USA. [Kashanchi, Fatah] George Mason Univ, Natl Ctr Biodef & Infect Dis Prof Microbiol, Manassas, VA 20110 USA. RP Kashanchi, F (reprint author), George Mason Univ, Dept Mol & Microbiol, Natl Ctr Biodef & Infect Dis, Manassas, VA 20110 USA. EM bcmfxk@gwumc.edu RI Kehn-Hall, Kylene/I-5752-2013 FU NIH [AI078859, AI074410, AI043894]; National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders FX We would like to thank the members of the Kashanchi lab for experiments and assistance with the manuscript. We thank Dr. Ming-Daw Tsai (Institute of Biological Chemistry, Academia Sinica) for the GST-p16INK4A plasmid constructs. Most of the data on the current manuscript was generated using funds from NIH grants AI078859, AI074410 and AI043894. Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Rachel Van Duyne is a predoctoral student in the Microbiology and Immunology Program of the Institute for Biomedical Sciences at The George Washington University. NR 62 TC 6 Z9 6 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PY 2010 VL 7 AR 21 DI 10.1186/1742-6405-7-21 PG 17 WC Infectious Diseases SC Infectious Diseases GA V29JM UT WOS:000208744700021 PM 20604950 ER PT J AU Warren, KR Hewitt, BG AF Warren, Kenneth R. Hewitt, Brenda G. TI NIAAA: Advancing Alcohol Research for 40 Years SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcoholism; alcohol and other drug use, abuse, and dependence; National Institute on Alcohol Abuse and Alcoholism; National Epidemiologic Survey on Alcohol and Related Conditions; Collaborative Studies on Genetics of Alcoholism; research; health services research; treatment research; prevention research; research in practice ID NATIONAL EPIDEMIOLOGIC SURVEY; DSM-IV ALCOHOL; DRUG-USE DISORDERS; 3-YEAR FOLLOW-UP; UNITED-STATES; DEPENDENCE; PREVALENCE; NALTREXONE; COOCCURRENCE; COMORBIDITY AB The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has been the lead Federal agency responsible for scientific research on alcohol and its effects for 40 years. During that time, NIAAA has conducted and funded groundbreaking research, distilled and disseminated those research findings to a broad audience, and ultimately improved public health. Among NIAAA's many significant contributions are the National Epidemiologic Survey on Alcohol and Related Conditions, the largest survey ever conducted on alcohol and associated psychiatric and medical conditions; investment in research to identify the genes underlying vulnerability to alcoholism; creation of the Collaborative Studies on Genetics of Alcoholism, a study of the genetics of alcoholism in a human population; leadership in exploring the effects of alcohol on fetal development and on a variety of diseases and organ systems; fostering alcoholism treatment, including supporting a medications development program that has funded more than 30 Phase 2 trials and 15 human laboratory studies; international collaborations and work across the National Institutes of Health; influential research on preventing alcohol problems through community programs as well as policy changes; and the translation of research findings to everyday practice, including the production of award-winning clinician training materials. C1 [Warren, Kenneth R.; Hewitt, Brenda G.] NIAAA, Bethesda, MD USA. RP Warren, KR (reprint author), NIAAA, Bethesda, MD USA. NR 29 TC 6 Z9 6 U1 0 U2 2 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 1-2 BP 5 EP 17 PG 13 WC Substance Abuse SC Substance Abuse GA 624VK UT WOS:000279849800001 PM 23579932 ER PT J AU Hingson, RW AF Hingson, Ralph W. TI FOCUS ON: COLLEGE DRINKING AND RELATED PROBLEMS MAGNITUDE AND PREVENTION OF COLLEGE DRINKING AND RELATED PROBLEMS SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Underage drinking; college student; undergraduate student; problematic alcohol and other drug (AOD) use; AOD use (AODU) patterns; heavy episodic drinking; binge drinking; AOD-related (AODR) consequences; AODR injury; interventions; policy ID EXCESSIVE ALCOHOL-CONSUMPTION; RANDOMIZED CONTROLLED-TRIAL; FATAL CRASHES; STUDENT DRINKING; HEAVY DRINKING; OUTLET DENSITY; YOUNG DRIVERS; INTERVENTIONS; AGE; FEEDBACK AB In 2002, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) issued a report entitled A Call to Action: Changing the Culture of Drinking at U.S. Colleges. Data on the magnitude of college drinking problems in 1998 to 1999 were reported. From 1999 to 2005, the proportion of college students aged 18-24 who drank five or more drinks on a single occasion in the past month increased from 41.7 percent to 45.2 percent. The proportion who drove under the influence of alcohol increased from 26.1 percent to 29.2 percent. Higher percentages of 21- to 24-year-olds engaged in those behaviors than 18- to 20-year-olds, and between 1999 and 2005 the percentage increased among 21- to 24-year-olds but not among those aged 18-20. From 1998 to 2005, unintentional alcohol-related injury deaths increased 3 percent (from 1,442 to 1,825) per 100,000 college students aged 18-24. Alcohol misuse by college students often harms other people through traffic crashes and sexual/other assaults. Research regarding ways to reduce college drinking problems has shown that individual-oriented interventions, particularly screening and brief motivational counseling interventions, social norms interventions, environmental policy changes such as the minimum legal drinking age of 21 and drinking-and-driving laws, and comprehensive college community programs, can reduce college drinking and related morbidity and mortality. There is a growing need for colleges and surrounding communities to implement interventions shown through research to reduce alcohol misuse among college-aged people. C1 NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. RP Hingson, RW (reprint author), NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. NR 53 TC 48 Z9 48 U1 3 U2 24 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 1-2 BP 45 EP 54 PG 10 WC Substance Abuse SC Substance Abuse GA 624VK UT WOS:000279849800004 PM 23579935 ER PT J AU Mochly-Rosen, D Zakhari, S AF Mochly-Rosen, Dana Zakhari, Samir TI FOCUS ON: THE CARDIOVASCULAR SYSTEM WHAT DID WE LEARN FROM THE FRENCH (PARADOX)? SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcohol consumption; light drinking; moderate drinking; effects and consequences of alcohol and other drug use; beneficial moderate alcohol consumption; risk and protective factors; risk-benefit; cardiovascular system; cardioprotection; wine; red wine; French Paradox; cholesterol; resveratrol; aldehyde dehydrogenase 2 ID CORONARY-HEART-DISEASE; MODERATE ALCOHOL-CONSUMPTION; PROTEIN-KINASE-C; HIGH-DENSITY-LIPOPROTEIN; MIDDLE-AGED MEN; MITOCHONDRIAL PERMEABILITY TRANSITION; PRECONDITIONING-LIKE PROTECTION; ISCHEMIA-REPERFUSION INJURY; ALDEHYDE DEHYDROGENASE ALDH; INDUCED CARDIAC PROTECTION AB Although heavy alcohol consumption has deleterious effects on heart health, moderate drinking is thought to have cardioprotective effects, reducing the risk of coronary artery disease and improving prognosis after a myocardial infarction. It still is unclear, however, if this effect can be achieved with all types of alcoholic beverages and results from the alcohol itself from other compounds found in alcoholic beverages, or both. For example, the polyphenolic compound resveratrol, which is found particularly in red wine, can reduce the risk of atherosclerosis; however, it is not clear if the resveratrol levels present in wine are sufficient to achieve this result. Alcohol itself contributes to cardioprotection through several mechanisms. For example, it can improve the cholesterol profile, increasing the levels of "good" cholesterol and reducing the levels of "bad" cholesterol Alcohol also may contribute to blood clot dissolution and may induce a phenomenon called pre-conditioning, whereby exposure to moderate alcohol levels (like short bouts of blood supply disruption [i.e., ischemia]), and result in reduced damage to the heart tissue after subsequent prolonged ischemia. Finally, the enzyme aldehyde dehydrogenase (ALDH) 2, which is involved in alcohol metabolism, also may contribute to alcohol-related cardioprotection by metabolizing other harmful aldehydes that could damage the heart muscle. C1 [Mochly-Rosen, Dana] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 USA. [Zakhari, Samir] NIAAA, Div Metab & Hlth Effects, Bethesda, MD USA. RP Mochly-Rosen, D (reprint author), Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 USA. FU NIAAA NIH HHS [R01 AA011147]; PHS HHS [NIAAA-11147] NR 112 TC 1 Z9 1 U1 0 U2 3 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 1-2 BP 76 EP 86 PG 11 WC Substance Abuse SC Substance Abuse GA 624VK UT WOS:000279849800007 PM 23579938 ER PT J AU Thomas, JD Warren, KR Hewitt, BG AF Thomas, Jennifer D. Warren, Kenneth R. Hewitt, Brenda G. TI Fetal Alcohol Spectrum Disorders From Research to Policy SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcohol consumption; fetal alcohol spectrum disorders; fetal alcohol syndrome; prenatal alcohol exposure; fetus; teratogenesis; human studies; animal studies; prevention research; treatment research ID IDENTIFICATION TEST AUDIT; MATERNAL RISK-FACTORS; BEHAVIORAL ALTERATIONS; BRIEF INTERVENTION; ANIMAL-MODELS; EXPOSURE; DRINKING; ETHANOL; BRAIN; RATS AB Forty years ago, alcohol was not commonly recognized as a teratogen, an agent that can disrupt the development of a fetus. Today, we understand that prenatal alcohol exposure induces a variety of adverse effects on physical, neurological, and behavioral development. Research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has contributed to the identification of the range and prevalence of fetal alcohol spectrum disorders (FASD), as well as methods for prevention and treatment of FASD. The worldwide prevalence and high personal and societal costs of FASD speak to the importance of this research. This article briefly examines some of the ways that NIAAA has contributed to our understanding of FASD, the challenges that we still face, and how this research is translated into changes in public policy. C1 [Thomas, Jennifer D.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Thomas, Jennifer D.] San Diego State Univ, Ctr Behav Teratol, San Diego, CA 92182 USA. [Warren, Kenneth R.; Hewitt, Brenda G.] NIAAA, Bethesda, MD USA. RP Thomas, JD (reprint author), San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. NR 63 TC 6 Z9 6 U1 5 U2 10 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 1-2 BP 118 EP 126 PG 9 WC Substance Abuse SC Substance Abuse GA 624VK UT WOS:000279849800011 PM 23579942 ER PT J AU Bryant, KJ Nelson, S Braithwaite, RS Roach, D AF Bryant, Kendall J. Nelson, Steve Braithwaite, R. Scott Roach, Deidra TI Integrating HIV/AIDS and Alcohol Research SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcohol consumption; alcohol abuse; alcohol and other drug effects and consequences; risk factors; risky sexual behavior; human immunodeficiency virus; acquired immune deficiency syndrome ID HIV RISK BEHAVIORS; TOWN SOUTH-AFRICA; UNITED-STATES; INFECTION; CONSUMPTION; PREVENTION; ADHERENCE; DISEASE; WOMEN; CARE AB Many people at risk for or already infected with HIV abuse alcohol, contributing to the difficulties in preventing the spread of the infection and treating infected patients. Thus, alcohol-abusing patients may delay testing for HIV accessing appropriate medical care, and initiating anti retroviral therapy (ART), which may hasten disease progression to full-blown AIDS. Alcohol abuse also increases the risk of HIV infection by promoting risky behaviors and counteracting efforts to minimize the risk of infection, prevent transmission of the virus to others once exposure has occurred, and reduce the risk of progression and organ or tissue injury after infection. In HIV-infected people undergoing treatment, concurrent alcohol abuse often renders treatment ineffective because patients frequently fail to adhere to the strict treatment regimens necessary to achieve control of the infection. Moreover, alcohol may interact with ART medications and exacerbate adverse effects of these medications. Future research needs to better integrate behavioral and biological research to identify strategies to prevent the spread of HIV infection in alcohol-abusing populations as well as focus on translational research to effectively implement promising approaches on a large scale. C1 [Bryant, Kendall J.] NIAAA, Bethesda, MD USA. [Nelson, Steve] Louisiana State Univ, Hlth Sci Ctr, Sch Med, New Orleans, LA USA. [Braithwaite, R. Scott] NYU, Sch Med, Operat Res Collaborat Hlth TORCH, Div Gen Internal Med, New York, NY USA. [Roach, Deidra] NIAAA, Rockville, MD 20852 USA. RP Bryant, KJ (reprint author), NIAAA, Bethesda, MD USA. NR 37 TC 27 Z9 27 U1 2 U2 6 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 3 BP 167 EP 178 PG 12 WC Substance Abuse SC Substance Abuse GA 663BO UT WOS:000282858200001 PM 23584058 ER PT J AU Braithwaite, RS Bryant, K AF Braithwaite, R. Scott Bryant, Kendall TI Influence of Alcohol Consumption on Adherence to and Toxicity of Antiretroviral Therapy and Survival SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE Alcohol consumption; human immunodeficiency virus (HIV); HIV treatment; antiretroviral therapy; medication adherence; immunosuppression ID HIV-INFECTED PATIENTS; VIRUS TYPE-1 REPLICATION; BLOOD MONONUCLEAR-CELLS; MEDICATION ADHERENCE; PROTEASE INHIBITORS; VIROLOGICAL FAILURE; REPORTED ADHERENCE; IMMUNE-RESPONSES; DRUG-RESISTANCE; VIRAL LOAD AB Antiretroviral therapy (ART) has substantially altered the fate of HIV-infected people, transforming the infection from an invariably fatal disease to a chronic condition manageable by pharmacotherapy. However, in order for ART to be effective, patients must adhere strictly to an often-demanding treatment regimen. Alcohol consumption may impact survival of HIV-infected patients through a variety of pathways. Some of these are not related to the effectiveness of ART (e.g., alcohol-induced immunosuppression that exacerbates the HIV-related immunosuppression, increased hepatotoxicity, and increased mortality from non HIV-related causes). However, some pathways mediating alcohol's negative effect on survival are related to ART effectiveness. In particular, alcohol consumption may reduce adherence to ART leading to decreased ART effectiveness and ultimately, increased HIV-related mortality. Both clinical data and computer simulations have yielded information about the impact of alcohol consumption on medication adherence in both HIV-infected and noninfected patients. The findings suggest that alcohol-related nonadherence may account for a substantial amount of preventable mortality among HIV-infected patients. These findings may have clinical implications with respect to optimal treatment for HIV-infected patients who also consume alcohol. C1 [Braithwaite, R. Scott] NYU, Sch Med, Sect Value & Comparat Effectiveness, New York, NY 10012 USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. RP Braithwaite, RS (reprint author), NYU, Sch Med, Sect Value & Comparat Effectiveness, New York, NY 10012 USA. NR 44 TC 20 Z9 20 U1 2 U2 3 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2010 VL 33 IS 3 BP 280 EP 287 PG 8 WC Substance Abuse SC Substance Abuse GA 663BO UT WOS:000282858200012 PM 23584069 ER PT B AU Williams, KM Gress, RE AF Williams, Kirsten M. Gress, Ronald E. BE Lazarus, HM Laughlin, MJ TI Immune Reconstitution and Implications for Immunotherapy Following Hematopoeitic Stem Cell Transplantation SO ALLOGENEIC STEM CELL TRANSPLANTATION, SECOND EDITION SE Contemporary Hematology LA English DT Article; Book Chapter ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; REGULATORY T-CELLS; INTENSITY CONDITIONING REGIMEN; KIR LIGAND INCOMPATIBILITY; RECEPTOR EXCISION CIRCLE; PULSED DENDRITIC CELLS; ACUTE MYELOID-LEUKEMIA; STAGE-IV MELANOMA; B-CELL C1 [Williams, Kirsten M.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Williams, KM (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 137 TC 0 Z9 0 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND BN 978-1-934115-33-6 J9 CONTEMP HEMATOL PY 2010 BP 545 EP 564 DI 10.1007/978-1-59745-478-0_31 D2 10.1007/978-1-59745-478-0 PG 20 WC Hematology; Medicine, General & Internal SC Hematology; General & Internal Medicine GA BNS22 UT WOS:000275376700031 ER PT B AU Jagasia, M Pavletic, S AF Jagasia, Madan Pavletic, Steven BE Lazarus, HM Laughlin, MJ TI Chronic Graft-Versus-Host Disease SO ALLOGENEIC STEM CELL TRANSPLANTATION, SECOND EDITION SE Contemporary Hematology LA English DT Article; Book Chapter ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; TERM-FOLLOW-UP; REFRACTORY CHRONIC GVHD; RANDOMIZED-TRIAL; MYCOPHENOLATE-MOFETIL; DONOR TRANSPLANTATION; PREDICTIVE FACTORS; APLASTIC-ANEMIA; CLINICAL-TRIALS C1 [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol,Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. [Pavletic, Steven] NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Autoimmun Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Jagasia, M (reprint author), Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol,Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. NR 68 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND BN 978-1-934115-33-6 J9 CONTEMP HEMATOL PY 2010 BP 577 EP 595 DI 10.1007/978-1-59745-478-0_33 D2 10.1007/978-1-59745-478-0 PG 19 WC Hematology; Medicine, General & Internal SC Hematology; General & Internal Medicine GA BNS22 UT WOS:000275376700033 ER PT J AU Sprankle, C AF Sprankle, Catherine TI INT: Workshop on vaccine potency and safety testing SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT News Item C1 NIEHS, Integrated Lab Syst Inc, NTP Interagcy Ctr Evaluat Alternat Toxicol Method, Res Triangle Pk, NC 27709 USA. RP Sprankle, C (reprint author), NIEHS, Integrated Lab Syst Inc, NTP Interagcy Ctr Evaluat Alternat Toxicol Method, POB 12233, Res Triangle Pk, NC 27709 USA. EM niceatm@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPEKTRUM AKAD VERLAG PI HEIDELBERG PA SLEVOGTSTRASSE 3-5, D-69126 HEIDELBERG, GERMANY SN 1868-596X J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2010 VL 27 IS 2 BP 167 EP 167 PG 1 WC Instruments & Instrumentation; Medicine, Research & Experimental SC Instruments & Instrumentation; Research & Experimental Medicine GA 734DU UT WOS:000288314200016 ER PT J AU Stokes, WS Wind, M AF Stokes, William S. Wind, Marilyn TI Validation of Innovative Technologies and Strategies for Regulatory Safety Assessment Methods: Challenges and Opportunities SO ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION LA English DT Article DE validation; safety testing; integrated testing strategies; integrated decision strategies AB Advances in science and innovative technologies are providing new opportunities to develop test methods and strategies that may improve safety assessments and reduce animal use for safety testing. These include high throughput screening and other approaches that can rapidly measure or predict various molecular, genetic, and cellular perturbations caused by test substances. Integrated testing and decision strategies that consider multiple types of information and data are also being developed. Prior to their use for regulatory decision-making, new methods and strategies must undergo appropriate validation studies to determine the extent that their use can provide equivalent or improved protection compared to existing methods and to determine the extent that reproducible results can be obtained in different laboratories. Comprehensive and optimal validation study designs are expected to expedite the validation and regulatory acceptance of new test methods and strategies that will support improved safety assessments and reduced animal use for regulatory testing. C1 [Stokes, William S.] NIEHS, Dept Hlth & Human Serv, Natl Inst Hlth, Natl Toxicol Program,Interagcy Ctr Evaluat Altern, Res Triangle Pk, NC 27709 USA. [Wind, Marilyn] US Consumer Prod Safety Commiss, Bethesda, MD USA. RP Stokes, WS (reprint author), NIEHS, Dept Hlth & Human Serv, Natl Inst Hlth, Natl Toxicol Program,Interagcy Ctr Evaluat Altern, POB 12233,Mail Stop K2-16, Res Triangle Pk, NC 27709 USA. EM stokes@niehs.nih.gov FU National Institutes of Health FX The authors acknowledge the expert assistance of David Allen and Steven Morefield from ILS, Inc., the NICEATM Support Contractor, and Debbie McCarley, NICEATM/NIEHS, in the preparation of this manuscript. The content of this manuscript was supported by the Intramural Research Program of the National Institutes of Health. NR 22 TC 0 Z9 0 U1 0 U2 1 PU SPEKTRUM AKAD VERLAG PI HEIDELBERG PA SLEVOGTSTRASSE 3-5, D-69126 HEIDELBERG, GERMANY SN 1868-596X J9 ALTEX-ALTERN ANIM EX JI ALTEX-Altern. Anim. Exp. PY 2010 VL 27 IS 3 BP 198 EP 206 PG 9 WC Instruments & Instrumentation; Medicine, Research & Experimental SC Instruments & Instrumentation; Research & Experimental Medicine GA 734DT UT WOS:000288314100005 ER PT B AU Cooper, AR Covington, SN Nelson, LM AF Cooper, Amber R. Covington, Sharon N. Nelson, Lawrence M. BE Santoro, NF NealPerry, G TI Primary Ovarian Insufficiency SO AMENORRHEA: A CASE-BASED, CLINICAL GUIDE SE Contemporary Endocrinology LA English DT Article; Book Chapter ID GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE GENE; ADRENAL-CORTEX AUTOANTIBODIES; HYPOACTIVE SEXUAL DESIRE; FRAGILE-X PREMUTATION; DNA POLYMERASE-GAMMA; BONE-MINERAL DENSITY; PREMATURE MENOPAUSE; POSTMENOPAUSAL WOMEN; YOUNG-WOMEN; NATURAL MENOPAUSE C1 [Cooper, Amber R.] Washington Univ, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, St Louis, MO 63110 USA. [Covington, Sharon N.; Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, Bethesda, MD USA. RP Cooper, AR (reprint author), Washington Univ, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, St Louis, MO 63110 USA. EM coopera@wustl.edu NR 124 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-60327-863-8 J9 CONTEMP ENDOCRINOL S PY 2010 BP 55 EP 82 DI 10.1007/978-1-60327-864-5_5 D2 10.1007/978-1-60327-864-5 PG 28 WC Endocrinology & Metabolism; Obstetrics & Gynecology SC Endocrinology & Metabolism; Obstetrics & Gynecology GA BRH74 UT WOS:000282725300005 ER PT J AU Resnik, DB AF Resnik, David B. TI Public Trust as a Policy Goal for Research With Human Subjects SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Mail Drop NH 06,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-03, ZIA ES102646-02] NR 8 TC 3 Z9 3 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 6 BP 15 EP 17 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 606SJ UT WOS:000278447300006 PM 20526961 ER PT J AU Borgerson, K Millum, J AF Borgerson, Kirstin Millum, Joseph TI A Third Way: Ethics Guidance as Evidence-Informed Provisional Rules SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID TRIALS; POLICY C1 [Borgerson, Kirstin] Dalhousie Univ, Dept Philosophy, Halifax, NS B3H 4P9, Canada. [Millum, Joseph] NIH, Bethesda, MD USA. RP Borgerson, K (reprint author), Dalhousie Univ, Dept Philosophy, Halifax, NS B3H 4P9, Canada. EM kirstin.borgerson@dal.ca NR 12 TC 2 Z9 2 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 6 BP 20 EP 22 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 606SJ UT WOS:000278447300008 PM 20526963 ER PT J AU Resnik, D AF Resnik, David TI Trans Fat Bans and Human Freedom SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article DE ethics; freedom; policy; public health; slippery slope; trans fats ID PUBLIC-HEALTH; ACIDS; OBESITY; DISEASE; ETHICS; FOOD AB A growing body of evidence has linked consumption of trans fatty acids to cardiovascular disease. To promote public health, numerous state and local governments in the United States have banned the use of artificial trans fats in restaurant foods, and additional bans may follow. Although these policies may have a positive impact on human health, they open the door to excessive government control over food, which could restrict dietary choices, interfere with cultural, ethnic, and religious traditions, and exacerbate socioeconomic inequalities. These slippery slope concerns cannot be dismissed as far-fetched, because the social and political pressures are place to induce additional food regulations. To protect human freedom and other values, policies that significantly restrict food choices, such as bans on types of food, should be adopted only when they are supported by substantial scientific evidence, and when policies that impose fewer restrictions on freedom, such as educational campaigns and product labeling, are likely to be ineffective. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, D (reprint author), NIEHS, NIH, Mail Drop NH 06 Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported by the intramural program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). The views expressed in this article are solely the views of the author. They do not represent the opinions of the NIEHS, NIH, or the U.S. government. I am grateful to Chris Portier and Bill Schrader for helpful comments. NR 38 TC 26 Z9 26 U1 0 U2 17 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 3 BP 27 EP 32 DI 10.1080/15265160903585636 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 568PV UT WOS:000275535700010 PM 20229412 ER PT J AU Wertheimer, A Millum, J Schaefer, GO AF Wertheimer, Alan Millum, Joseph Schaefer, G. Owen TI Why Adopt a Maximin Theory of Exploitation? SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Wertheimer, Alan] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wertheimer, A (reprint author), NIH, Dept Bioeth, Ctr Clin, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov OI Schaefer, Gerald Owen/0000-0002-6915-6148 NR 5 TC 4 Z9 4 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 6 BP 38 EP 39 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 606SJ UT WOS:000278447300013 PM 20526968 ER PT J AU Resnik, DB AF Resnik, David B. TI Practical and Political Problems With a Global Research Tax SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Mail Drop NH 06,Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-03, ZIA ES102646-02] NR 1 TC 2 Z9 2 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 6 BP 44 EP 45 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 606SJ UT WOS:000278447300016 PM 20526971 ER PT J AU Persad, GC Wertheimer, A Emanuel, EJ AF Persad, Govind C. Wertheimer, Alan Emanuel, Ezekiel J. TI Standing By Our Principles: Meaningful Guidance, Moral Foundations, and Multi-Principle Methodology in Medical Scarcity SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 [Persad, Govind C.] Stanford Univ, Dept Philosophy, Stanford, CA 94305 USA. [Wertheimer, Alan; Emanuel, Ezekiel J.] Natl Inst Hlth, Bethesda, MD 20892 USA. RP Persad, GC (reprint author), Stanford Univ, Dept Philosophy, Bldg 90, Stanford, CA 94305 USA. EM gpersad@stanford.edu NR 8 TC 5 Z9 5 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 4 BP 46 EP 48 DI 10.1080/15265161003650528 PG 3 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 588DY UT WOS:000277048800011 PM 20379921 ER PT J AU Miller, FG AF Miller, Franklin G. TI Striking the Right Balance in Research Ethics and Regulation SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 8 BP 65 EP 65 AR PII 925253102 DI 10.1080/15265161.2010.481350 PG 1 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 635SC UT WOS:000280675500021 PM 20694916 ER PT J AU Resnik, D AF Resnik, David TI Response to Open Peer Commentaries on "Trans Fat Bans and Human Freedom" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, D (reprint author), Natl Inst Environm Hlth Sci, NIH, Mail Drop NH 06 Box 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-03, ZIA ES102646-02] NR 6 TC 1 Z9 1 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2010 VL 10 IS 3 BP W4 EP W5 DI 10.1080/15265161003708557 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 568PV UT WOS:000275535700033 PM 20229403 ER PT J AU Bailey, RL Dodd, KW Gahche, JJ Dwyer, JT McDowell, MA Yetley, EA Sempos, CA Burt, VL Radimer, KL Picciano, MF AF Bailey, Regan L. Dodd, Kevin W. Gahche, Jaime J. Dwyer, Johanna T. McDowell, Margaret A. Yetley, Elizabeth A. Sempos, Christopher A. Burt, Vicki L. Radimer, Kathy L. Picciano, Mary Frances TI Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NEURAL-TUBE DEFECTS; MULTIVITAMIN-MULTIMINERAL SUPPLEMENTS; CEREAL-GRAIN PRODUCTS; COMPLEX SURVEY DATA; NUTRIENT INTAKE; INTAKE DISTRIBUTIONS; FORTIFICATION; PREVENTION; ASSOCIATION; NUTRITION AB Background: The term total folate intake is used to represent folate that occurs naturally in food as well as folic acid from fortified foods and dietary supplements. Folic acid has been referred to as a double-edged sword because of its beneficial role in the prevention of neural tube defects and yet possible deleterious effects on certain cancers and cognitive function. Previous monitoring efforts did not include folic acid from dietary supplements and are therefore not complete. Objective: Our objective was to combine data on dietary folate (as measured by two 24-h recalls) and folic acid from dietary supplements (collected with a 30-d frequency questionnaire) with the use of the bias-corrected best power method to adjust for within-person variability. Design: The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey. Linear contrasts were constructed to determine differences in dietary and total folate intake for age and racial-ethnic groups by sex; prevalence of inadequate and excessive intakes is presented. Results: In 2003-2006, 53% of the US population used dietary supplements; 34.5% used dietary supplements that contained folic acid. Total folate intake (in dietary folate equivalents) was higher for men (813 +/- 14) than for women (724 +/- 16) and higher for non-Hispanic whites (827 +/- 19) than for Mexican Americans (615 +/- 11) and non-Hispanic blacks (597 +/- 12); 29% of non-Hispanic black women had inadequate intakes. Total folate and folic acid intakes are highest for those aged > 50 y, and 5% exceed the Tolerable Upper Intake Level. Conclusions: Improved total folate intake is warranted in targeted subgroups, which include women of childbearing age and non-Hispanic black women, whereas other population groups are at risk of excessive intake. Am J Clin Nutr 2010;91:231-7. C1 [Bailey, Regan L.; Dwyer, Johanna T.; Yetley, Elizabeth A.; Sempos, Christopher A.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Dodd, Kevin W.] NCI, NIH, Bethesda, MD 20892 USA. [Gahche, Jaime J.; McDowell, Margaret A.; Burt, Vicki L.; Radimer, Kathy L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Bailey, RL (reprint author), 6100 Execut Blvd,2B03, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 NR 42 TC 108 Z9 115 U1 3 U2 22 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2010 VL 91 IS 1 BP 231 EP 237 DI 10.3945/ajcn.2009.28427 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 534SM UT WOS:000272917600029 PM 19923379 ER PT J AU Bagnardi, V Randi, G Lubin, J Consonni, D Lam, TK Subar, AF Goldstein, AM Wacholder, S Bergen, AW Tucker, MA Decarli, A Caporaso, NE Bertazzi, PA Landi, MT AF Bagnardi, Vincenzo Randi, Giorgia Lubin, Jay Consonni, Dario Lam, Tram Kim Subar, Amy F. Goldstein, Alisa M. Wacholder, Sholom Bergen, Andrew W. Tucker, Margaret A. Decarli, Adriano Caporaso, Neil E. Bertazzi, Pier Alberto Landi, Maria Teresa TI Alcohol Consumption and Lung Cancer Risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; case-control studies; ethanol; lung neoplasms; risk factors; smoking ID METAANALYSIS; BEVERAGE; VALIDITY; SMOKING; COHORT; DIET AB The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (>= 60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1-4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures. C1 [Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bagnardi, Vincenzo] Univ Milano Bicocca, Dept Stat, Milan, Italy. [Bagnardi, Vincenzo] European Inst Oncol, Div Epidemiol & Biostat, Milan, Italy. [Randi, Giorgia; Decarli, Adriano] Univ Milan, Ist Stat Med & Biometria GA Maccacaro, Milan, Italy. [Decarli, Adriano] Fdn IRCSS, Ist Nazl Tumori, Milan, Italy. [Randi, Giorgia] Ist Ric Farmacol Mario Negri, Milan, Italy. [Lubin, Jay; Wacholder, Sholom] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. [Consonni, Dario; Bertazzi, Pier Alberto] Osped Maggiore Policlin Mangiagalli & Regina Elen, Fdn IRCCS, Milan, Italy. [Lam, Tram Kim] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Subar, Amy F.] NCI, Risk Factor Monitoring & Methods Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Decarli, Adriano/C-3129-2017; bertazzi, pietro alberto/D-5039-2017; OI Decarli, Adriano/0000-0003-1451-8292; bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644 FU National Institutes of Health, National Cancer Institute (Division of Cancer Epidemiology and Genetics); Region of Lombardy, Milan, Italy (Environmental Epidemiology Program); University of Milan-Bicocca, Milan, Italy FX Support for this study was provided by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (Division of Cancer Epidemiology and Genetics); by the Region of Lombardy, Milan, Italy (Environmental Epidemiology Program); and by the University of Milan-Bicocca, Milan, Italy ("Fondo Ateneo per la Ricerca" 2007). NR 26 TC 15 Z9 15 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2010 VL 171 IS 1 BP 36 EP 44 DI 10.1093/aje/kwp332 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 537KT UT WOS:000273112500005 PM 19933698 ER PT J AU Peralta, CA Adeney, KL Shlipak, MG Jacobs, D Duprez, D Bluemke, D Polak, J Psaty, B Kestenbaum, BR AF Peralta, Carmen A. Adeney, Kathryn L. Shlipak, Michael G. Jacobs, David, Jr. Duprez, Daniel Bluemke, David Polak, Joseph Psaty, Bruce Kestenbaum, Bryan R. TI Structural and Functional Vascular Alterations and Incident Hypertension in Normotensive Adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arteries; elasticity; hypertension ID INTIMA-MEDIA THICKNESS; PULSE CONTOUR ANALYSIS; ARTERIAL COMPLIANCE; BLOOD-PRESSURE; INDEPENDENT PREDICTOR; SERUM CREATININE; WAVE VELOCITY; NORMAL VALUES; ATHEROSCLEROSIS; DISEASE AB Vascular abnormalities may exist before clinical hypertension. Using Poisson regression, the authors studied the association of coronary artery calcium (CAC), common carotid intima-media thickness (CIMT), aortic distensibility, and large and small arterial elasticity with incident hypertension among 2,512 normotensive US adults free of cardiovascular disease. Incidence rate ratios for incident hypertension (blood pressure >= 140/90 mm Hg or new antihypertensive medication) were calculated. Increased CAC was associated with incident hypertension in demographics-adjusted models (incidence rate ratio (IRR) = 1.35, 95% confidence interval (CI): 1.04, 1.75; IRR = 1.35, 95% CI: 1.02, 1.78; and IRR = 1.59, 95% CI: 1.12, 2.25 for CAC scores of 30-99, 100-399, and >= 400, respectively) but was attenuated after further adjustment. Increased common CIMT was associated with incident hypertension (IRR = 1.77, 95% CI: 1.28, 2.46 for quintile 4; IRR = 1.80, 95% CI: 1.28, 2.53 for quintile 5). Participants with the lowest, compared with the highest, aortic distensibility had an increased risk of hypertension (IRR = 1.75, 95% CI: 1.10, 2.79), as did those with the lowest large arterial elasticity (IRR = 1.49, 95% CI: 1.11, 1.99). Lower small arterial elasticity was incrementally associated with incident hypertension starting at quintile 2 (IRR = 2.01, 95% CI: 1.39, 2.91; IRR = 2.47, 95% CI: 1.71, 3.57; IRR = 2.73, 95% CI: 1.88, 3.95; and IRR = 2.85, 95% CI: 1.95, 4.16). Structural and functional vascular abnormalities are independent predictors of incident hypertension. These findings are important for understanding the pathogenesis of hypertension. C1 [Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Peralta, Carmen A.; Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Adeney, Kathryn L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jacobs, David, Jr.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Duprez, Daniel] Univ Minnesota, Div Cardiovasc, Sch Med, Minneapolis, MN 55455 USA. [Bluemke, David] NIH, Bethesda, MD 20892 USA. [Polak, Joseph] Tufts Univ, Dept Radiol, Boston, MA 02111 USA. [Psaty, Bruce] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce] Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Kestenbaum, Bryan R.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. RP Peralta, CA (reprint author), VA Med Ctr, Gen Internal Med Sect 111A1, 4150 Clement St, San Francisco, CA 94124 USA. EM carmenalicia.peralta@ucsf.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; National Center for Research Resources [KL2 RR024130] FX This work was supported by contracts (N01-HC-95159 through N01-HC-95165 and N01-HC-95169) from the National Heart, Lung, and Blood Institute. This work was also funded by the National Center for Research Resources (KL2 RR024130 to C. A. P.). NR 28 TC 48 Z9 51 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2010 VL 171 IS 1 BP 63 EP 71 DI 10.1093/aje/kwp319 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 537KT UT WOS:000273112500008 PM 19951938 ER PT J AU Morgan, G Backinger, C Lerman, C Vocci, F AF Morgan, Glen Backinger, Cathy Lerman, Caryn Vocci, Francis TI Translational Medication Development for Nicotine Addiction SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE nicotine; tobacco; addiction; medication development ID PLACEBO-CONTROLLED TRIAL; SMOKING-CESSATION; RECEPTOR ANTAGONISTS; TOBACCO DEPENDENCE; CONJUGATE VACCINE; SMOKERS; RATS; WITHDRAWAL; BUPROPION; GENETICS AB Objective: To review the current state of the science in medication development for nicotine dependence and to identify important areas for future research. Methods: The National Cancer Institute and the National Institute on Drug Abuse convened a conference focused on translational approaches to the development, evaluation, and delivery of medications for the treatment of tobacco dependence. Results: Future research directions include investigations of the efficacy of novel compounds and new applications for existing medications; pharmacogenetic trials of nicotine dependence treatments; and studies of the molecular, neural, and behavioral mechanisms of action of efficacious medications. Conclusions: Medication development for the treatment of tobacco dependence remains a scientific and public health priority. C1 [Morgan, Glen; Backinger, Cathy] NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Lerman, Caryn] Univ Penn, Dept Psychiat, Annenberg Publ Policy Ctr, Philadelphia, PA 19104 USA. [Lerman, Caryn] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Vocci, Francis] Friends Res Inst Inc, Baltimore, MD USA. RP Morgan, G (reprint author), NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, 6130 Execut Blvd, Rockville, MD 20852 USA. EM gmorgan@nih.gov NR 42 TC 4 Z9 4 U1 3 U2 4 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PY 2010 VL 34 IS 3 BP 267 EP 274 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 781LE UT WOS:000291932900002 PM 20001184 ER PT J AU Nilsen, WJ Haverkos, L Nebeling, L Taylor, MV AF Nilsen, Wendy J. Haverkos, Lynne Nebeling, Linda Taylor, Martina Vogel TI Maintenance of Long-term Behavior Change SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE behavior change; behavior maintenance; health behavior; National Institutes of Health AB Objectives: To describe the formation and work of the Health Maintenance Consortium (HMC), a collaborative of researchers funded by the National Institutes of Health to study long-term behavior change across a variety of diseases and conditions. Methods: The historical development of the program, especially the focus on behavior change maintenance, is briefly described. Previous work on behavior change that paved the way for the HMC is also discussed. Results: Aiming to accelerate the pace of discovery and application, NIH funding to create the HMC has created a strong research base for making progress toward filling key knowledge and intervention gaps in long-term behavior change. Conclusions: Investments in behavior change and maintenance have yielded important information that can be used to guide the development of future programs to improve health. C1 [Nilsen, Wendy J.] NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. [Haverkos, Lynne] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Nebeling, Linda] NCI, NIH, Bethesda, MD 20892 USA. [Taylor, Martina Vogel] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Nilsen, WJ (reprint author), NIH, Off Behav & Social Sci Res, Off Director, 31 Ctr Dr,Bldg 31,B1C19, Bethesda, MD 20892 USA. EM nilsenwj@od.nih.gov NR 21 TC 6 Z9 6 U1 0 U2 4 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PY 2010 VL 34 IS 6 SI SI BP 643 EP 646 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 781ME UT WOS:000291935900001 PM 20604690 ER PT J AU Seymour, RB Hughes, SL Ory, MG Elliot, DL Kirby, KC Migneault, J Patrick, H Roll, JM Williams, G AF Seymour, Rachel B. Hughes, Susan L. Ory, Marcia G. Elliot, Diane L. Kirby, Kimberly C. Migneault, Jeffrey Patrick, Heather Roll, John M. Williams, Geoffrey TI A Lexicon for Measuring Maintenance of Behavior Change SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE multiple behavior change; long-term maintenance; measurement AB Objectives: To establish a workgroup within the NIH-funded Health Maintenance Consortium (HMC) to examine how "maintenance" of behavior change was conceptualized and measured across and within behaviors. Methods: Multiple meetings were held by the workgroup to reach consensus definitions of maintenance and maintenance-related constructs across diet/nutrition, tobacco, substance abuse, and physical activity. Once consensus was reached, a survey assessed how maintenance was operationalized across 16 HMC intervention studies. Results: Seventy-five percent of 16 studies assessed are using a criterion to assess maintenance and are tracking maintenance as a continuous measure. Eighty-one percent are assessing facilitators and barriers, and conceptualizing maintenance as both an intermediate and primary outcome measure. All 16 studies are assessing maintenance at the individual level with fewer at the organizational (N=3), environmental (N=3), and policy levels (N=1). Conclusions: This survey found similarities and differences in measurement across behaviors that have important implications for advancing the quality of transbehavioral research. C1 [Seymour, Rachel B.; Hughes, Susan L.] Univ Illinois, Ctr Res Hlth & Aging, Inst Hlth Res & Policy, Chicago, IL 60608 USA. [Ory, Marcia G.] Texas A&M Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX USA. [Elliot, Diane L.] Oregon Hlth & Sci Univ, Div Hlth Promot & Sports Med, Portland, OR 97201 USA. [Kirby, Kimberly C.] Treatment Res Inst Inc, Philadelphia, PA USA. [Migneault, Jeffrey] Boston Univ, Sch Med, Med Informat Syst Unit, Boston, MA 02118 USA. [Patrick, Heather] NCI, HPRB BPN DCCPS, Rockville, MD USA. [Roll, John M.] Friends Res Inst Inc, Mead, WA 99021 USA. [Williams, Geoffrey] Univ Rochester, Dept Med, Dept Clin & Social Psychol, Rochester, NY USA. RP Seymour, RB (reprint author), Univ Illinois, Ctr Res Hlth & Aging, Inst Hlth Res & Policy, 1747 W Roosevelt Rd,Room 558, Chicago, IL 60608 USA. EM rseymo1@uic.edu OI Kirby, Kimberly/0000-0001-6745-3854 FU NIA NIH HHS [R01 AG023424, R01 AG23424] NR 10 TC 10 Z9 11 U1 1 U2 3 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PY 2010 VL 34 IS 6 SI SI BP 660 EP 668 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 781ME UT WOS:000291935900003 PM 20604692 ER PT J AU Fitzhugh, CD Lauder, N Jonassaint, JC Telen, MJ Zhao, XC Wright, EC Gilliam, FR De Castro, LM AF Fitzhugh, Courtney D. Lauder, Naudia Jonassaint, Jude C. Telen, Marilyn J. Zhao, Xiongce Wright, Elizabeth C. Gilliam, Francis R. De Castro, Laura M. TI Cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID PULMONARY-HYPERTENSION; IRON OVERLOAD; MYOCARDIAL-PERFUSION; LUNG-DISEASE; RISK-FACTOR; MORTALITY; CHILDREN; ANEMIA; DEFIBRILLATOR; HYDROXYUREA AB Sickle cell disease (SCD) is associated with early mortality. We sought to determine the incidence, cause, and risk factors for death in an adult population of patients with SCD. All patients aged >= 18 years seen at the Adult Sickle Cell Center at Duke University Medical Center between January 2000 and April 2005 were enrolled. Forty-three patients (21 males and 22 females) died during the study period. The median age of survival was 39 years for females (95% CI: 34-56), 40 years for males (95% CI: 34-48), and 40 years overall (95% CI: 35-48). Cardiac causes of death accounted for 25.6% (11/43 patients); pulmonary, 14.0% (six patients); other SCD related, 32.6% (14 patients); unknown, 14.0% (six patients); and others, 14.0% (six patients). Pulseless electrical activity arrest, pulmonary emboli, multiorgan failure, and stroke were the most frequent causes of death. Among the deceased patients, the most common premorbid conditions were cardiopulmonary: acute chest syndrome/pneumonia (58.1%), Pulmonary hypertension (pHTN; 41.9%), systemic HTN (25.6%), congestive heart failure (25.6%), myocardial infarction (20.9%), and arrhythmias (14.0%). Tricuspid regurgitant jet velocity was significantly higher (3.1 m/sec vs. 2.6 misec, P < 0.001) and hemoglobin significantly lower (8.3 g/dL vs. 9.2 g/dL, P < 0.05) in deceased patients when compared with patients who lived, respectively. With improved preventive and therapeutic advances, including hydroxyurea therapy, acute complications such as infection are no longer the leading cause of death; instead, causes of death and premorbid conditions are shifting to chronic cardiopulmonary complications. Further, arrhythmia leading to premature death is under-recognized in SCD and warrants further investigation. Am. J. Hematol. 85:36-40, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Fitzhugh, Courtney D.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bethesda, MD 20892 USA. [Lauder, Naudia] Johns Hopkins Univ Hosp, Dept Internal Med, Baltimore, MD 21287 USA. [Jonassaint, Jude C.; Telen, Marilyn J.; De Castro, Laura M.] Duke Univ, Med Ctr, Div Hematol, Durham, NC USA. [Jonassaint, Jude C.; Telen, Marilyn J.; De Castro, Laura M.] Duke Univ, Med Ctr, Duke Comprehens Sickle Cell Ctr, Durham, NC USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD USA. [Gilliam, Francis R.] Cardiol Associates N Arkansas, Electrophysiol Div, Jonesboro, AR USA. RP Fitzhugh, CD (reprint author), NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, 9000 Rockville Pike,Bldg 10,Room 9N-116, Bethesda, MD 20892 USA. EM fitzhughc@nhlbi.nih.gov FU National Institutes of Health [R01HL68959, R01HL79915, U54HL070769]; Duke-UNC Comprehensive Sickle Cell Center [U54HL070769] FX Contract grant sponsor: National Institutes of Health (Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases and the National Heart, Lung, and Blood Institute); Contract grant numbers: R01HL68959, R01HL79915, U54HL070769. Contract grant sponsor: Duke-UNC Comprehensive Sickle Cell Center; Contract grant number: U54HL070769. NR 49 TC 58 Z9 59 U1 2 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JAN PY 2010 VL 85 IS 1 BP 36 EP 40 DI 10.1002/ajh.21569 PG 5 WC Hematology SC Hematology GA 542NO UT WOS:000273501200008 PM 20029950 ER PT J AU Han, XS Zheng, TZ Foss, FM Lan, Q Holford, TR Rothman, N Ma, SG Zhang, YW AF Han, Xuesong Zheng, Tongzhang Foss, Francine M. Lan, Qing Holford, Theodore R. Rothman, Nathaniel Ma, Shuangge Zhang, Yawei TI Genetic polymorphisms in the metabolic pathway and non-Hodgkin lymphoma survival SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID S-TRANSFERASE GENOTYPES; B-CELL LYMPHOMA; UNITED-STATES; BIOTRANSFORMATION ENZYMES; RISK; ASSOCIATION; POPULATION; N-ACETYLTRANSFERASE-1; CLASSIFICATION; CONNECTICUT AB Metabolic pathway enzymes, such as Cytochrome P450 (CYP), glutathione S-transferase (GST), and N-acetyltransferases (NAT) are involved in activation and detoxification of environmental carcinogens as well as drug metabolism. We hypothesized that the genetic variations in such metabolic pathways may affect NHL prognosis and survival. Follow-up information of 496 female NHL incident cases diagnosed during 1996-2000 in Connecticut were abstracted from the Connecticut Tumor Registry in 2008; survival analyses were conducted by comparing the Kaplan-Meier curves, and hazard ratios (HR) were computed from the Cox Proportional Hazard models adjusting for demographic and tumor characteristics which were suggested by previous studies to be determinants of NHL survival. We identified six SNPs from four metabolism genes (CYP2E1, GSTP1, GSTT1, and NAT1) that were associated with NHL survival. Specifically, polymorphisms in GSTT1 were associated with follicular lymphoma survival; and polymorphisms in CYP2E1, GSTP1, and NAT1 were associated with survival of chronic lymphocytic leukemia/small lymphocytic lymphoma. Our study suggests that genetic polymorphisms in metabolic pathways may help improve the prediction of NHL survival and prognosis. Am. J. Hematol. 85:51-56, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Han, Xuesong; Zheng, Tongzhang; Holford, Theodore R.; Ma, Shuangge; Zhang, Yawei] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Foss, Francine M.] Yale Canc Ctr, New Haven, CT USA. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St,LEPH 440,POB 208034, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu FU National Cancer Institute (NCI) [CA62006]; Yale Cancer Center [22067A]; National Institute of Health (NIH) [1 D43TW008323-01, 1 D43TW007864-01]; National Center for Research Resources (NCRR) [UL1 RR024139] FX Contract grant sponsor: National Cancer Institute (NCI); Contract grant number: CA62006. Contract grant sponsor: Yale Cancer Center (Hull Argall & Anna Grant); Contract grant number: 22067A. Contract grant sponsor: National Institute of Health (NIH; Fogarty training grants); Contract grant numbers: 1 D43TW008323-01, 1 D43TW007864-01. Contract grant sponsor: National Center for Research Resources (NCRR; CTSA; a component of the NIH and NHL roadmap for medical Research); Contract grant number: UL1 RR024139. NR 43 TC 11 Z9 12 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JAN PY 2010 VL 85 IS 1 BP 51 EP 56 DI 10.1002/ajh.21580 PG 6 WC Hematology SC Hematology GA 542NO UT WOS:000273501200011 PM 20029944 ER PT J AU Joy, MS Gipson, DS Powell, L MacHardy, J Jennette, JC Vento, S Pan, C Savin, V Eddy, A Fogo, AB Kopp, JB Cattran, D Trachtman, H AF Joy, Melanie S. Gipson, Debbie S. Powell, Leslie MacHardy, Jacqueline Jennette, J. Charles Vento, Suzanne Pan, Cynthia Savin, Virginia Eddy, Allison Fogo, Agnes B. Kopp, Jeffrey B. Cattran, Daniel Trachtman, Howard TI Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Focal segmental glomerulosclerosis (FSGS); pharmacokinetics; nephrotic syndrome; adalimumab; tumor necrosis factor alpha; antifibrotic ID NECROSIS-FACTOR-ALPHA; CHILDHOOD NEPHROTIC-SYNDROME; RHEUMATOID-ARTHRITIS; TNF-ALPHA; MEMBRANOUS NEPHROPATHY; ALBUMIN PERMEABILITY; ANTIBODY; DISEASE; METHOTREXATE; CYTOKINES AB Background: Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. Study Design: Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha. Setting & Participants: 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied. Intervention: Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses). Outcomes: Pharmacokinetic assessment, tolerability, and safety. Measurements: Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state. Results: Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by >= 50% in 4 of 10 treated patients. Limitations: Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS. Conclusions: Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials. Am J Kidney Dis 55: 50-60. (C) 2009 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Trachtman, Howard] Schneider Childrens Hosp, Div Nephrol, N Shore LIJ Hlth Syst, New Hyde Pk, NY 11040 USA. [Joy, Melanie S.; Gipson, Debbie S.; Powell, Leslie; MacHardy, Jacqueline] Univ N Carolina, UNC Kidney Ctr, Chapel Hill, NC USA. [Joy, Melanie S.; Gipson, Debbie S.; Powell, Leslie; MacHardy, Jacqueline] Univ N Carolina, Div Nephrol & Hypertens, Chapel Hill, NC USA. [Joy, Melanie S.] Univ N Carolina, Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Jennette, J. Charles] Univ N Carolina, Dept Pathol, Chapel Hill, NC USA. [Pan, Cynthia; Savin, Virginia] Med Coll Wisconsin, Dept Pediat, Div Nephrol, Milwaukee, WI 53226 USA. [Pan, Cynthia; Savin, Virginia] Med Coll Wisconsin, Dept Med, Div Nephrol, Milwaukee, WI 53226 USA. [Eddy, Allison] Seattle Childrens Hosp, Div Nephrol, Seattle, WA USA. [Fogo, Agnes B.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD USA. [Cattran, Daniel] Univ Hlth Network, Toronto Gen Res Inst, Toronto, ON, Canada. RP Trachtman, H (reprint author), Schneider Childrens Hosp, Div Nephrol, N Shore LIJ Hlth Syst, 269-01 76th Ave, New Hyde Pk, NY 11040 USA. EM trachtma@lij.edu OI Trachtman, Howard/0000-0001-7447-9489; Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [5R21-DK070341]; NIH National Center for Research Resources, University of North Carolina at Chapel Hill [RR00046]; NIH National Center for Research Resources, University of North Carolina at North Shore-LIJ [RR018535] FX This work was presented in abstract form at the 41st Annual Meeting of the American Society of Nephrology, November 4-9, 2008, Philadelphia, PA. We thank Raymond Pica, BS, for performing the serum TNF-alpha assay.; Support: This work was supported by the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant 5R21-DK070341, the NIDDK intramural research program, and the General Clinical Research Centers program of the NIH National Center for Research Resources, via RR00046 (University of North Carolina at Chapel Hill) and RR018535 (North Shore-LIJ). NR 34 TC 29 Z9 31 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JAN PY 2010 VL 55 IS 1 BP 50 EP 60 DI 10.1053/j.ajkd.2009.08.019 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 548JN UT WOS:000273958000009 PM 19932542 ER PT J AU Tierney, E Conley, SK Goodwin, H Porter, FD AF Tierney, Elaine Conley, Sandra K. Goodwin, Halima Porter, Forbes D. TI Analysis of Short-Term Behavioral Effects of Dietary Cholesterol Supplementation in Smith-Lemli-Opitz Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Opitz syndrome; SLOS; RSH syndrome; cholesterol; DHCR7; Aberrant Behavior Checklist; randomized-controlled clinical trial ID CHECKLIST; MUTATIONS; GENE AB Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis due to mutations of 7-dehydrocholesterol reductase (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to yield cholesterol in the final step of cholesterol biosynthesis. Phenotypically patients with SLOS have multiple malformations, cognitive deficits, and behavioral difficulties. Impaired DHCR7 activity results in the accumulation of 7DHC and frequently decreased cholesterol in blood and tissues. Dietary cholesterol supplementation has become standard therapy for SLOS, and anecdotal reports suggest rapid, marked clinical improvement of behavior problems. Although reported in the literature, beneficial behavioral effects of dietary cholesterol supplementation have not been formally documented through a randomized clinical trial. To address this we initiated a double-masked, placebo-controlled, cross-over trial to test the hypothesis that dietary cholesterol supplementation has rapid beneficial effects on behavior. Our primary outcome measure was the hyperactivity subscale of the Aberrant Behavior Checklist (ABC). Hyperactivity is a symptom that has been reported to respond rapidly to dietary cholesterol supplementation. Secondary outcome measures included the total ABC score and other ABC subscale scores. Ten subjects completed this study. Although the trial was done under conditions similar to those reported to induce marked behavioral changes in SLOS patients, we observed no differences between treatment and placebo phases. The results of this study call into question anecdotal reports supporting rapid behavioral benefits previously reported for dietary cholesterol supplementation in SLOS and underscore the need for a larger placebo-controlled trial. Published 2009 Wiley-Liss, Inc.dagger C1 [Conley, Sandra K.; Goodwin, Halima; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Tierney, Elaine] Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD USA. [Tierney, Elaine] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Porter, FD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, DHHS, Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Kennedy Krieger Institute FX This work was supported by both intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Kennedy Krieger Institute. The authors would especially like to thank the children and parents who participated in this study. NR 14 TC 23 Z9 24 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2010 VL 152A IS 1 BP 91 EP 95 DI 10.1002/ajmg.a.33148 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 544SV UT WOS:000273680500009 PM 20014133 ER PT J AU Chik, CL Rollag, MD Duncan, WC Smith, ACM AF Chik, Constance L. Rollag, Mark D. Duncan, Wallace C. Smith, Ann C. M. TI Diagnostic Utility of Daytime Salivary Melatonin Levels in Smith-Magenis Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE saliva; melatonin; Smith-Magenis syndrome ID CIRCADIAN-RHYTHM; SERUM MELATONIN; HUMAN-PLASMA; SLEEP; DELETION; DISTURBANCES; EXCRETION; SHIFTS; PHASE AB An inverted circadian rhythm of melatonin (MT) likely contributes to the sleep disturbance in patients with Smith-Magenis syndrome (SMS). Plasma NIT levels have documented this altered rhythm, but daytime levels of salivary MT has not been determined. Daytime measures of salivary MT might have utility in home/outpatient settings for assessing MT levels in undiagnosed patients with clinical features of SMS. The objective of this study was to determine the utility of daytime salivary MT as a diagnostic test in SMS. Thirty individuals with confirmed SMS [28 with del 17p11.2 and 2 with the retinoic acid induced I (RAI1) gene mutation] and five controls were studied. Single or serial daytime salivary NIT levels were measured. The mean midday salivary MT level was 79.0 pg/ml in SMS patients, compared with 16.3 pg/ml in controls, with nine patients having values similar to controls. The median NIT level in SMS patients was 49.0 pg/ml (first and third quartile values = 15.5 and 106.8 pg/ml). Twenty-six (90%) of 29 patients had at least one NIT value > 15.5 pg/ml, including 70 (78%) of 90 samples from patients with del 17p11.2 and one (20%) of five samples from the two patients with the RAII mutation. Neither the pattern of medication use nor age had an effect on daytime salivary NIT levels. Although most SMS patients had elevated daytime salivary MT levels, multiple sampling appears necessary to distinguish patients with SMS from other conditions. (C) 2009 Wiley-Liss, Inc. C1 [Chik, Constance L.] Univ Alberta, HMRC 362, Dept Med, Edmonton, AB T6G 2S2, Canada. [Rollag, Mark D.] Univ Virginia, Dept Biol, Charlottesville, VA USA. [Duncan, Wallace C.] NIMH, NIH, Bethesda, MD 20892 USA. [Smith, Ann C. M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Chik, CL (reprint author), Univ Alberta, HMRC 362, Dept Med, Edmonton, AB T6G 2S2, Canada. EM cchik@ualberta.ca FU National Human Genome Research Institute, National Institutes of Health; NTH FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health and a NTH Clinical Center Bench-to-Bedside award to ACMS. NR 33 TC 6 Z9 6 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2010 VL 152A IS 1 BP 96 EP 101 DI 10.1002/ajmg.a.33158 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 544SV UT WOS:000273680500010 PM 20034098 ER PT J AU Tsai, HT North, KE West, SL Poole, C AF Tsai, Huei-Ting North, Kari E. West, Suzanne L. Poole, Charles TI The DRD3 rs6280 Polymorphism and Prevalence of Tardive Dyskinesia: A Meta-Analysis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE tardive dyskinesia; dopamine receptor 3; rs6280; meta-analysis ID DOPAMINE D3 RECEPTOR; CHINESE SCHIZOPHRENIC-PATIENTS; SER9GLY POLYMORPHISM; GENE POLYMORPHISMS; PUBLICATION BIAS; D-3 RECEPTOR; RISK-FACTORS; ASSOCIATION; SUSCEPTIBILITY; EXPRESSION AB To elucidate a widely suspected but inconclusive association between rs6280 in the dopamine receptor 3 gene (DRD3) and prevalence of tardive dyskinesia (TD), we conducted a meta-analysis of studies obtained in a systematic search of several bibliographic systems. We conducted several analyses of funnel plot asymmetry, overall heterogeneity, and study characteristics in analyses analogous to general, dominant and recessive inheritance models with the prevalence odds ratio (POR) as the measure of association. Thirteen eligible studies were identified with publication dates between 1997 and 2008. Evidence of funnel plot asymmetry was discerned in the dominant and general model analyses, but not in the recessive model analysis. Stratified analyses indicated that publication year, TD assessment method (Schooler-Kane criteria or other) and TD assessment frequency (single or repeated) were important study characteristics associated with heterogeneous PORs across studies. Studies conducted among patients with older age, fewer women or European (compared with Asian) ancestry reported stronger average PORs. Summary POR estimates under the dominant and general inheritance models were not warranted due to funnel plot asymmetry and heterogeneity. Under the recessive model, the summary estimate was POR = 0.93 (95% confidence interval: 0.70-1.23). We conclude that there is no or little association between DRD3 rs6280 polymorphisms and prevalence of TD. (C) 2009 Wiley-Liss, Inc. C1 [Tsai, Huei-Ting] NCI, NIH, DHHS, Rockville, MD 20852 USA. [Tsai, Huei-Ting; North, Kari E.; West, Suzanne L.; Poole, Charles] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [West, Suzanne L.] RTI Int Hlth Social & Econ Res, Res Triangle Pk, NC USA. RP Tsai, HT (reprint author), NCI, NIH, DHHS, 6120 Execut Blvd,EPS 7016, Rockville, MD 20852 USA. EM tsaih2@mail.nih.gov NR 53 TC 20 Z9 22 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2010 VL 153B IS 1 BP 57 EP 66 DI 10.1002/ajmg.b.30946 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500007 PM 19358223 ER PT J AU Yanjanin, NM Velez, JI Gropman, A King, K Bianconi, SE Conley, SK Brewer, CC Solomon, B Pavan, WJ Arcos-Burgos, M Patterson, MC Porter, FD AF Yanjanin, Nicole M. Velez, Jorge I. Gropman, Andrea King, Kelly Bianconi, Simona E. Conley, Sandra K. Brewer, Carmen C. Solomon, Beth Pavan, William J. Arcos-Burgos, Mauricio Patterson, Marc C. Porter, Forbes D. TI Linear Clinical Progression, Independent of Age of Onset, in Niemann-Pick Disease, Type C SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE Niemann-Pick disease; type C; NPC1; neurodegenerative diseases; lysosomal storage disease; disease progression ID NPC1 MOUSE; CHOLESTEROL; ACTIVATION; STORAGE AB Niemann-Pick disease, type C is a neurodegenerative, lysosomal storage disorder with a broad clinical spectrum and a variable age of onset. The absence of a universally accepted clinical outcome measure is an impediment to the design of a therapeutic trial for NPC. Thus, we developed a clinical severity scale to characterize and quantify disease progression. Clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, and swallowing) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, and respiratory problems) domains were scored. Data were collected from 18 current NPC patients and were extracted from records of 19 patients. Both patient cohorts showed a linear increase in severity scores over time. Cross-sectional evaluation of current patients showed a linear increase in the severity score. Longitudinal chart review of historical data demonstrated that although age of onset varied significantly, the rate of progression appeared linear, independent of age of onset, and similar in all patients. Combining the data from both cohorts, disease progression could be modeled by the following equation: (S) over cap (t0+x) = (S) over cap (t0) + 1.87x; where (S) over cap (t0) is the initial score and (S) over cap (t0+x) is the predicted future score after x years. Our observation that disease progression is similar across patients and independent of age of onset is consistent with a biphasic pathological model for NPC. This scale may prove useful in the characterization of potential biomarkers, and as an outcome measure to monitor disease progression in NPC patients. (C) 2009 Wiley-Liss, Inc. C1 [Yanjanin, Nicole M.; Bianconi, Simona E.; Conley, Sandra K.; Porter, Forbes D.] NICHD, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Velez, Jorge I.] NHGRI, Human Dev Sect, Med Genet Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Div Neurol, Washington, DC 20010 USA. [King, Kelly; Brewer, Carmen C.] NIDCD, Otolaryngol Branch, NIH, DHHS, Bethesda, MD USA. [King, Kelly] Univ Maryland, Dept Hearing & Speech Sci, College Pk, MD 20742 USA. [Solomon, Beth] NIH, Speech & Language Pathol Sect, RMD, CC,DHHS, Bethesda, MD 20892 USA. [Pavan, William J.] NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Arcos-Burgos, Mauricio] Univ Miami, Leonard M Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. [Patterson, Marc C.] Mayo Clin, Dept Neurol, Rochester, MN USA. RP Porter, FD (reprint author), NICHD, PDGEN, NIH, DHHS, Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov OI Patterson, Marc/0000-0002-1116-126X FU NICHD; NHGRI; NIDCD; ORD; Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust FX Grant sponsor: NICHD; Grant sponsor: NHGRI; Grant sponsor: NIDCD; Grant sponsor: ORD; Grant sponsor: Ara Parseghian Medical Research Foundation; Grant sponsor: Dana's Angels Research Trust. NR 28 TC 65 Z9 66 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2010 VL 153B IS 1 BP 132 EP 140 DI 10.1002/ajmg.b.30969 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500015 PM 19415691 ER PT J AU Tsai, HT Caroff, SN Miller, DD McEvoy, J Lieberman, JA North, KE Stroup, TS Sullivan, PF AF Tsai, Huei-Ting Caroff, Stanley N. Miller, Del D. McEvoy, Joseph Lieberman, Jeffrey A. North, Kari E. Stroup, T. Scott Sullivan, Patrick F. TI A Candidate Gene Study of Tardive Dyskinesia in the CATIE Schizophrenia Trial SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; tardive dyskinesia; antipsychotic medication; adverse drug reaction; genetic; candidate gene association ID RECEPTOR GENE; GENOMEWIDE ASSOCIATION; METAANALYSIS; ANTIPSYCHOTICS; POLYMORPHISMS; METABOLISM; RISK; SET AB Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature. (C) 2009 Wiley-Liss, Inc. C1 [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Tsai, Huei-Ting; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Tsai, Huei-Ting] NCI, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Caroff, Stanley N.] Univ Penn, Dept Psychiat, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Miller, Del D.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [McEvoy, Joseph] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, New York, NY USA. [Stroup, T. Scott; Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. RP Sullivan, PF (reprint author), Univ N Carolina, Dept Genet, CB 7264,4109D Neurosci Res Bldg, Chapel Hill, NC 27599 USA. EM pfsulliv@med.unc.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH [N01 MH90001]; [R01s MH074027]; [R01s MH077139]; [R01s MH080403] FX Dr. Sullivan was supported by R01s MH074027, MH077139, and MH080403. The CATIE project was funded by NIMH contract N01 MH90001. We thank Dr. David Goldstein of Duke University for providing genotypes. NR 29 TC 27 Z9 30 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN PY 2010 VL 153B IS 1 BP 336 EP 340 DI 10.1002/ajmg.b.30981 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 541SM UT WOS:000273440500043 PM 19475583 ER PT J AU Freedman, BI Edberg, JC Comeau, ME Murea, M Bowden, DW Divers, J Alarcon, GS Brown, EE McGwin, G Kopp, JB Winkler, CA Nelson, GW Illei, G Petri, M Ramsey-Goldman, R Reveille, JD Vila, LM Langefeld, CD Kimberly, RP AF Freedman, Barry I. Edberg, Jeffrey C. Comeau, Mary E. Murea, Mariana Bowden, Donald W. Divers, Jasmin Alarcon, Graciela S. Brown, Elizabeth E. McGwin, Gerald, Jr. Kopp, Jeffrey B. Winkler, Cheryl A. Nelson, George W. Illei, Gabor Petri, Michelle Ramsey-Goldman, Rosalind Reveille, John D. Vila, Luis M. Langefeld, Carl D. Kimberly, Robert P. CA PROFILE Study Grp TI The Non-Muscle Myosin Heavy Chain 9 Gene (MYH9) Is Not Associated with Lupus Nephritis in African Americans SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE African Americans; Genetics; Lupus nephritis; Kidney; MYH9; Systemic lupus erythematosus ID STAGE RENAL-DISEASE; SUSCEPTIBILITY; ERYTHEMATOSUS; HYPERTENSION; WOMEN; MICE AB Background: African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN. Methods: Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA. Results: A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association. Conclusions: These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA. Copyright (C) 2010 S. Karger AG, Basel C1 [Freedman, Barry I.; Comeau, Mary E.; Murea, Mariana; Bowden, Donald W.; Divers, Jasmin; Langefeld, Carl D.] Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA. [Edberg, Jeffrey C.; Alarcon, Graciela S.; Brown, Elizabeth E.; McGwin, Gerald, Jr.; Kimberly, Robert P.] Univ Alabama, Birmingham, AL USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Winkler, Cheryl A.; Nelson, George W.] NCI, Lab Genom Div, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Illei, Gabor] Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. [Petri, Michelle] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinstein Sch Med, Chicago, IL 60611 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Vila, Luis M.] Univ Puerto Rico, San Juan, PR 00936 USA. RP Freedman, BI (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM bfreedma@wfubmc.edu OI Kimberly, Robert/0000-0002-5330-3086; Kopp, Jeffrey/0000-0001-9052-186X FU NIH [RO1 DK-070941, RO1 DK084149, RO1 DK53591, P01 AR49084, N01-CO-12400, HHSN261200800001E]; Program Project in the Genetics of Systemic Lupus Erythematosus [1RC2 AR058951-01]; National Consortia to Explore the Genotypic Basis for ESRD in Lupus; NIDDK; NIAMS; NCI; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported in part by NIH grants RO1 DK-070941 (B. I. F.), RO1 DK084149 (B. I. F.), RO1 DK53591 (D. W. B.), P01 AR49084 Program Project in the Genetics of Systemic Lupus Erythematosus, 1RC2 AR058951-01 National Consortia to Explore the Genotypic Basis for ESRD in Lupus and the NIDDK, NIAMS and NCI Intramural Research Programs. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Programs of the NIH, National Cancer Institute, Center for Cancer Research. The authors report no conflicts of interest in this work. The authors are indebted to the local nephrology community, including all physicians and their patients who participated, as well as to our study coordinators Joyce Byers, Carrie Smith, Mitzie Spainhour, Cassandra Bethea and Sharon Warren. NR 25 TC 12 Z9 13 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 32 IS 1 BP 66 EP 72 DI 10.1159/000314688 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 609VE UT WOS:000278684800009 PM 20523037 ER PT J AU Chen, LM Faulhaber-Walter, R Wen, YB Huang, YN Mizel, D Chen, M Lopez, MLS Weinstein, LS Gomez, RA Briggs, JP Schnermann, J AF Chen, Limeng Faulhaber-Walter, Robert Wen, Yubing Huang, Yuning Mizel, Diane Chen, Min Lopez, Maria Luisa Sequeira Weinstein, Lee S. Gomez, R. Ariel Briggs, Josephine P. Schnermann, Jurgen TI Renal Failure in Mice with Gs alpha Deletion in Juxtaglomerular Cells SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Renin-angiotension system; Renal failure; Pathology ID ANGIOTENSIN-CONVERTING ENZYME; DEFICIENT MICE; TRANSGENIC MICE; RENIN; INJURY; EXPRESSION; HYPERTENSION; OBSTRUCTION; INHIBITION; RECEPTORS AB Background: Mice with deletion of Gs alpha in renin-producing cells (RC/FF mice) have been shown to have greatly reduced renin production and lack of responsiveness of renin secretion to acute stimuli. In addition, young RC/FF mice are hypotensive and have a vasopressin-resistant concentrating defect. In the present study we have determined the long-term effect on renal function, blood pressure, and renal pathology in this low renin and diuretic mouse model. Methods and Results: Urine osmolarity of RC/FF mice was decreased in all age groups. GFR measured at 7, 14 and 20 weeks of age declined progressively. Single nephron GFR similarly declined while fractional proximal fluid absorption was maintained. Expression levels of extracellular matrix proteins (collagen I, IV and fibronectin) and alpha-smooth muscle actin were increased in kidneys of RC/FF mice at 20 weeks, and this was accompanied by focal segmental glomerulosclerosis and periglomerular interstitial fibrosis. RC/FF mice showed a progressive reduction of body weight, an increase in urine albumin excretion, and an increase of blood pressure with aging. Conclusion: A chronic reduction of renin production in mice may be a risk factor in its own right, and does not protect renal function against the profibrotic influence of a chronically elevated urine flow. Copyright (C) 2010 S. Karger AG, Basel C1 [Chen, Limeng] Chinese Acad Med Sci, Dept Nephrol, Beijing 100730, Peoples R China. [Chen, Limeng; Faulhaber-Walter, Robert; Huang, Yuning; Mizel, Diane; Chen, Min; Weinstein, Lee S.; Briggs, Josephine P.; Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD USA. [Chen, Limeng; Wen, Yubing] Beijing Union Med Coll Hosp, Beijing 100730, Peoples R China. [Lopez, Maria Luisa Sequeira; Gomez, R. Ariel] Univ Virginia, Charlottesville, VA USA. [Faulhaber-Walter, Robert] Hannover Med Sch, D-3000 Hannover, Germany. RP Chen, LM (reprint author), Chinese Acad Med Sci, Dept Nephrol, 1 Shuaifuyuan,Wangfujing St, Beijing 100730, Peoples R China. EM climeng2000@yahoo.com.cn RI Briggs, Josephine/B-9394-2009; OI Briggs, Josephine/0000-0003-0798-1190; Gomez, R. Ariel/0000-0002-5124-8255 FU National Institute of Diabetes and Digestive and Kidney Diseases; NIH [HL 66242]; National Natural Science Foundation of China [30770861, 30971369]; Scientific Research Foundation for Excellent Returned Scholars, Ministry of Human Resources of China FX This work was supported by intramural funds from the National Institute of Diabetes and Digestive and Kidney Diseases, and by NIH grant HL 66242 (R. A. G.), the National Natural Science Foundation of China (No. 30770861, 30971369), and Scientific Research Foundation for Excellent Returned Scholars, Ministry of Human Resources of China. NR 26 TC 9 Z9 10 U1 1 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 32 IS 1 BP 83 EP 94 DI 10.1159/000314635 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 609VE UT WOS:000278684800011 PM 20551626 ER PT J AU McCullough, PA Franklin, BA Leifer, E Fonarow, GC AF McCullough, Peter A. Franklin, Barry A. Leifer, Eric Fonarow, Gregg C. CA HF-Action Investigators TI Impact of Reduced Kidney Function on Cardiopulmonary Fitness in Patients with Systolic Heart Failure SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Heart failure; Chronic kidney disease; Cardiopulmonary fitness; Glomerular filtration rate; Renal insufficiency; Mortality risk ID TRIAL INVESTIGATING OUTCOMES; SURVEY NHANES 1999-2004; EVALUATION PROGRAM KEEP; ANAEROBIC THRESHOLD; CARDIOVASCULAR RISK; POSITION STATEMENT; NATIONAL-HEALTH; HF-ACTION; DISEASE; EXERCISE C1 [McCullough, Peter A.] William Beaumont Hosp, Div Cardiol, Beaumont Hlth Ctr, Royal Oak, MI 48073 USA. [Leifer, Eric] NHLBI, Bethesda, MD 20892 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. RP McCullough, PA (reprint author), William Beaumont Hosp, Div Cardiol, Beaumont Hlth Ctr, 4949 Coolidge, Royal Oak, MI 48073 USA. EM peteramccullough@gmail.com FU National Institutes of Health, National Heart, Lung and Blood Institute FX Gregg C. Fonarow is a consultant/honorarium recipient from Novartis (significant), and a honorarium recipient from Merck-Schering Plough (significant). The study was supported/funded by the National Institutes of Health, National Heart, Lung and Blood Institute. NR 30 TC 6 Z9 6 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 32 IS 3 BP 226 EP 233 DI 10.1159/000317544 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 650TV UT WOS:000281876400006 PM 20664198 ER PT J AU Murakami, T Abe, H Nagai, K Tominaga, T Takamatsu, N Araoka, T Kishi, S Takahashi, T Mima, A Takai, Y Kopp, JB Doi, T AF Murakami, Taichi Abe, Hideharu Nagai, Kojiro Tominaga, Tatsuya Takamatsu, Norimichi Araoka, Toshikazu Kishi, Seiji Takahashi, Toshikazu Mima, Akira Takai, Yoshimi Kopp, Jeffrey B. Doi, Toshio TI Trophoblast Glycoprotein: Possible Candidate Mediating Podocyte Injuries in Glomerulonephritis SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Trophoblast glycoprotein; Podocyte; Thy1 glomerulonephritis; Transforming growth factor-beta; Cell motility; Stress fiber ID STEM-CELL DIFFERENTIATION; 5T4 ONCOFETAL ANTIGEN; GROWTH-FACTOR-BETA; TGF-BETA; MESENCHYMAL TRANSITION; ACTIN CYTOSKELETON; NEPHROTIC SYNDROME; EPITHELIAL-CELLS; EXPRESSION; MOTILITY AB Background: Trophoblast glycoprotein (Tpbg), a 72-kDa transrnembrane glycoprotein, is known to regulate the phenotypes of epithelial cells by modifying actin organization and cell motility. Recently, a microarray study showed that Tpbg is upregulated in Thy1 glomerulonephritis (Thy1 GN). We hypothesized that Tpbg regulates cytoskeletal rearrangement and modulates phenotypic alteration in podocytes under pathological conditions. Methods: We examined Tpbg expression in Thy1 GN and Tpbg function in mouse podocytes. Results: We demonstrated that Tpbg is upregulated in the injured podocytes of Thy1 GN. In vitro, immunofluorescence studies revealed that Tpbg colocalized with the focal adhesion protein, vinculin, in parallel with stress fiber formation. This colocalization was observed even when actin filaments were depolymerized with cytochalasin D. Tpbg localization at focal adhesions was induced by dominant-active RhoA and suppressed by the ROCK1 inhibitor Y-26732. In addition, transforming growth factor-beta increased Tpbg expression at focal adhesions concurrently with rearrangement of stress fibers. Stress fiber formation was suppressed in differentiated podocytes transfected with full-length Tpbg. Furthermore, knockdown of Tpbg using small interfering RNA decreased podocyte motility. Conclusion: Our findings suggest a novel role of Tpbg in the phenotypic alteration of injured podocytes, and we accordingly propose a new mechanism of glomerular injury in glomerulonephritis. Copyright (C) 2010 S. Karger AG, Basel C1 [Murakami, Taichi; Abe, Hideharu; Nagai, Kojiro; Tominaga, Tatsuya; Araoka, Toshikazu; Kishi, Seiji; Takahashi, Toshikazu; Mima, Akira; Doi, Toshio] Univ Tokushima, Grad Sch Med, Inst Hlth Biosci, Dept Nephrol, Tokushima 770, Japan. [Takamatsu, Norimichi] Tokushima Univ Hosp, Tokushima, Japan. [Takai, Yoshimi] Kobe Univ, Grad Sch Med, Dept Biochem & Mol Biol, Div Mol & Cellular Biol, Kobe, Hyogo 657, Japan. [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Abe, H (reprint author), 3-18-15 Kuramoto Cho, Tokushima 7708503, Japan. EM abeabe@clin.med.tokushima-u.ac.jp OI Kopp, Jeffrey/0000-0001-9052-186X FU Kidney Foundation, Japan [JKFB09-41]; Mitsui Sumitomo Welfare Foundation [19590973]; NIDDK FX This study was supported by the Kidney Foundation, Japan (JKFB09-41), Mitsui Sumitomo Welfare Foundation and Grant-in-Aid for Scientific Research (19590973) and the NIDDK Intramural Research Program. NR 36 TC 2 Z9 2 U1 1 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 32 IS 6 BP 505 EP 521 DI 10.1159/000321366 PG 17 WC Urology & Nephrology SC Urology & Nephrology GA 699OU UT WOS:000285673500001 PM 20980737 ER PT J AU Joffe, M Hsu, CY Feldman, HI Weir, M Landis, JR Hamm, LL AF Joffe, Marshall Hsu, Chi-Yuan Feldman, Harold I. Weir, Matthew Landis, J. R. Hamm, L. Lee CA CRIC Study Grp TI Variability of Creatinine Measurements in Clinical Laboratories: Results from the CRIC Study SO AMERICAN JOURNAL OF NEPHROLOGY LA English DT Article DE Chronic renal disease; Creatinine measurements, variability; Chronic Renal Insufficiency Cohort (CRIC) Study; Glomerular filtration rate ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; NUTRITION EXAMINATION SURVEY; CHRONIC RENAL-INSUFFICIENCY; 3RD NATIONAL-HEALTH; SERUM CREATININE; PREVALENCE; CALIBRATION; EQUATION; AMERICAN C1 [Hamm, L. Lee] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Hamm, L. Lee] Tulane Univ, Sch Med, Dept Epidemiol & Hypertens, New Orleans, LA 70112 USA. [Hamm, L. Lee] Tulane Univ, Sch Med, Renal Ctr, New Orleans, LA 70112 USA. [Feldman, Harold I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Joffe, Marshall; Feldman, Harold I.; Landis, J. R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Joffe, Marshall; Feldman, Harold I.; Landis, J. R.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Hsu, Chi-Yuan] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Weir, Matthew] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Joffe, Marshall; Feldman, Harold I.; Landis, J. R.] NIDDK, NIH, Bethesda, MD USA. RP Hamm, LL (reprint author), Tulane Univ, Sch Med, Dept Med, SL-12,1430 Tulane Ave, New Orleans, LA 70112 USA. EM Lhamm@tulane.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, 5U01DK060902]; Johns Hopkins University [UL1 RR-025005]; University of Maryland [M01 RR-16500]; Case Western Reserve University Clinical and Translational Science Collaborative (University Hospitals of Cleveland, Cleveland Clinic Foundation, and MetroHealth) [UL1 RR-024989]; University of Michigan [M01 RR-000042]; CTSA [UL1 RR-024986]; University of Illinois at Chicago Clinical Research Center [M01RR-013987-06]; Tulane/LSU/Charity Hospital General Clinical Research Center [RR-05096]; Kaiser NIH/NCRR [UL1 RR-024131, 5K24DK002651]; National Center for Minority Health and Health Disparities; National Institutes of Health, and Department of Veterans Affairs FX In addition to funding under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902), this work was supported in part by the following institutional Clinical Translational Science Awards and other National Institutes of Health grants: Johns Hopkins University UL1 RR-025005, University of Maryland GRCR M01 RR-16500, Case Western Reserve University Clinical and Translational Science Collaborative (University Hospitals of Cleveland, Cleveland Clinic Foundation, and MetroHealth) UL1 RR-024989, University of Michigan GCRC M01 RR-000042 and CTSA UL1 RR-024986, University of Illinois at Chicago Clinical Research Center, M01RR-013987-06, Tulane/LSU/Charity Hospital General Clinical Research Center RR-05096, and Kaiser NIH/NCRR UCSF-CTSI UL1 RR-024131 and 5K24DK002651. Additional support provided by the National Center for Minority Health and Health Disparities, National Institutes of Health, and Department of Veterans Affairs. NR 19 TC 26 Z9 27 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0250-8095 J9 AM J NEPHROL JI Am. J. Nephrol. PY 2010 VL 31 IS 5 BP 426 EP 434 DI 10.1159/000296250 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 597KY UT WOS:000277757300007 PM 20389058 ER PT J AU Hassan, SS Romero, R Pineles, B Tarca, AL Montenegro, D Erez, O Mittal, P Kusanovic, JP Mazaki-Tovi, S Espinoza, J Nhan-Chang, CL Draghici, S Kim, CJ AF Hassan, Sonia S. Romero, Roberto Pineles, Beth Tarca, Adi L. Montenegro, Daniel Erez, Offer Mittal, Pooja Kusanovic, Juan Pedro Mazaki-Tovi, Shali Espinoza, Jimmy Nhan-Chang, Chia-Ling Draghici, Sorin Kim, Chong Jai TI MicroRNA expression profiling of the human uterine cervix after term labor and delivery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 14-17, 2007 CL Reno, NV SP Soc Gynecol Invest DE cervical dilation; cervical remodeling; cervix; labor; microarray; microRNA; parturition ID FETAL MEMBRANES; PRETERM LABOR; BREAST-CANCER; PARTURITION; INTERLEUKIN-8; FIBROBLASTS; MYOMETRIUM; PATTERNS; ADENOCARCINOMA; BIOSYNTHESIS AB OBJECTIVE: MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional regulation of target genes. The objective of this study was to determine the miRNA expression profile of the human uterine cervix after spontaneous term labor (TL). STUDY DESIGN: The miRNA expression pattern of cervical tissue was characterized using microarrays. Samples were collected at term from patients with (n = 8) and without (n = 9) TL. Moderated t tests and false discovery rate correction were applied. Results were confirmed using quantitative reverse transcriptase-polymerase chain reaction. RESULTS: A total of 226 miRNAs were expressed in human cervical tissue. miR-223, miR-34b, and miR-34c were overexpressed in cervical tissue of patients with TL compared to those without. Quantitative reverse transcriptase-polymerase chain reaction assays confirmed these findings (miR-223 [fold change {FC} = 5.7], miR-34b [FC = 4.5], miR-34c [FC = 6.2]; P < .001). CONCLUSION: This is the first report of miRNA expression in the human uterine cervix in pregnancy. Cervical remodeling after TL and delivery was associated with changes in miR-223, miR-34b, and miR-34c. C1 [Hassan, Sonia S.; Erez, Offer; Mittal, Pooja; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Espinoza, Jimmy; Nhan-Chang, Chia-Ling] Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Romero, Roberto; Tarca, Adi L.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Kim, Chong Jai] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. RP Hassan, SS (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 FU Intramural NIH HHS; NCI NIH HHS [U01CA117478]; NHGRI NIH HHS [R01 HG003491] NR 58 TC 5 Z9 5 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2010 VL 202 IS 1 AR 80.e1 DI 10.1016/j.ajog.2009.08.016 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 536EN UT WOS:000273026200024 PM 19889381 ER PT J AU Takahashi, S Ohshima, T Hirasawa, M Pareek, TK Bugge, TH Morozov, A Fujieda, K Brady, RO Kulkarni, AB AF Takahashi, Satoru Ohshima, Toshio Hirasawa, Motoyuki Pareek, Tej K. Bugge, Thomas H. Morozov, Alexei Fujieda, Kenji Brady, Roscoe O. Kulkarni, Ashok B. TI Conditional Deletion of Neuronal Cyclin-Dependent Kinase 5 in Developing Forebrain Results in Microglial Activation and Neurodegeneration SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; CEREBRAL-CORTEX; MOUSE HIPPOCAMPUS; CELL-CYCLE; EXCITOTOXIC INJURY; BRAIN; EXPRESSION; CDK5; DEGENERATION; ARREST AB Neuronal migration disorders are often identified in patients with epilepsy refractory to medical treatment. The prolonged or repeated seizures are known to cause neuronal death; however, the mechanism underlying seizure-induced neuronal death remains to be elucidated. An essential role of cyclin-dependent kinase 5 (Cdk5) in brain development has been demonstrated in Cdk5(-/-) mice, which show neuronal migration defects and perinatal lethality. Here, we show the consequences of Cdk5 deficiency in the postnatal brain by generating Cdk5 conditional knockout mice, in which Cdk5 is selectively eliminated from neurons in the developing forebrain. The conditional mutant mice were viable, but exhibited complex neurological deficits including seizures, tremors, and growth retardation. The forebrain not only showed disruption of layering, but also neurodegenerative changes accompanied by neuronal loss and microglial activation. The neurodegenerative changes progressed with age and were accompanied by up-regulation of the neuronal tissue-type plasminogen activator, a serine protease known to mediate microglial activation. Thus age-dependent neurodegeneration in the Cdk5 conditional knockout mouse brain invoked a massive inflammatory reaction. These findings indicate an important role of Cdk5 in inflammation, and also provide a mouse model to examine the possible involvement of inflammation in the pathogenesis of progressive cognitive decline in patients with neuronal migration disorders. (Am J Pathol 2010, 176:320-329; DOI: 10.2353/ajpath.2010.081158) C1 [Takahashi, Satoru; Hirasawa, Motoyuki; Pareek, Tej K.; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Takahashi, Satoru; Fujieda, Kenji] Asahikawa Med Coll, Dept Pediat, Asahikawa, Hokkaido 078, Japan. [Ohshima, Toshio] Waseda Univ, Dept Life Sci & Med Biosci, Tokyo, Japan. [Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Morozov, Alexei] NIMH, Unit Behav Genet, NIH, Bethesda, MD 20892 USA. [Brady, Roscoe O.] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Room 130, Bethesda, MD 20892 USA. EM ak40m@nih.gov OI Pareek, Tej/0000-0001-5134-1647 FU Division of Intramural Research of National Institute of Dental and Craniofacial Research, National Institutes of Health FX Supported by the Division of Intramural Research of National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 41 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JAN PY 2010 VL 176 IS 1 BP 320 EP 329 DI 10.2353/ajpath.2010.081158 PG 10 WC Pathology SC Pathology GA 550EN UT WOS:000274111200032 PM 19948833 ER PT J AU Sun, QF Tian, E Turner, RJ Ten Hagen, KG AF Sun, Qifei Tian, E. Turner, R. James Ten Hagen, Kelly G. TI Developmental and functional studies of the SLC12 gene family members from Drosophila melanogaster SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE Drosophila embryogenesis; in situ hybridization; Na(+)-K(+)-2Cl(-) cotransport; cation-chloride cotransport; chloride transport ID NA+-K+-2CL(-) COTRANSPORTER NKCC1; K-CL COTRANSPORTER; CHLORIDE COTRANSPORTERS; EXPRESSION AB Sun Q, Tian E, Turner RJ, Ten Hagen KG. Developmental and functional studies of the SLC12 gene family members from Drosophila melanogaster. Am J Physiol Cell Physiol 298: C26-C37, 2010. First published October 14, 2009; doi:10.1152/ajpcell.00376.2009.- The electroneutral cation-chloride cotransporter gene family, SLC12, contains nine members in vertebrates. These include seven sodium and/or potassium-coupled chloride transporters and two membrane proteins of unknown function. Although SLC12 family members have been identified in a number of lower species, the functional properties of these proteins are unknown. There are five SLC12 homologues in Drosophila melanogaster, including at least one member on each of the four main branches of the vertebrate phylogenetic tree. We have employed in situ hybridization to study the expression patterns of the Drosophila SLC12 proteins during embryonic development. Our studies indicate that all five members of this family are expressed during early embryogenesis (stages 1-6), but that spatial and temporal expression patterns become more refined as development proceeds. Expression during late embryogenesis was seen predominantly in the ventral nerve cord, salivary gland, gut, and anal pad. In parallel studies, we have carried out transport assays on each of the five Drosophila homologues, expressed as recombinant proteins in the cultured insect cell line High Five. Under our experimental conditions, we found that only one of these proteins, CG4357, transported the potassium congener (86)Rb. Additional experiments established that rubidium transport via CG4357 was saturable (K(m) = 0.29 +/- 0.05 mM), sodium-dependent (half-saturation constant = 53 +/- 11 mM), chloride-dependent (half-saturation constant = 48 +/- 5 mM), and potently inhibited by bumetanide (inhibitor constant = 1.17 +/- 0.08 mu M), a specific inhibitor of Na(+)-K(+)-2Cl(-) cotransporters. Taken together, our results provide strong evidence that CG4357 is an insect ortholog of the vertebrate Na(+)-K(+)-2Cl(-) cotransporters. C1 [Tian, E.; Ten Hagen, Kelly G.] Natl Inst Dent & Craniofacial Res, Dev Glycobiol Unit, Lab Cell & Dev Biol, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sun, Qifei; Turner, R. James] Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Mol Physiol & Therapeut Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), Natl Inst Dent & Craniofacial Res, Dev Glycobiol Unit, Lab Cell & Dev Biol, NIH,Dept Hlth & Human Serv, Bldg 30,Rm 426,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. EM tenhagen@mail.nih.gov FU National Institute of Dental and Craniofacial Research; National Institutes of Health, Bethesda MD FX This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda MD. NR 18 TC 9 Z9 9 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2010 VL 298 IS 1 BP C26 EP C37 DI 10.1152/ajpcell.00376.2009 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 533LO UT WOS:000272825500004 PM 19828839 ER PT J AU Zanou, N Shapovalov, G Louis, M Tajeddine, N Gallo, C Van Schoor, M Anguish, I Cao, ML Schakman, O Dietrich, A Lebacq, J Ruegg, U Roulet, E Birnbaumer, L Gailly, P AF Zanou, Nadege Shapovalov, Georges Louis, Magali Tajeddine, Nicolas Gallo, Chiara Van Schoor, Monique Anguish, Isabelle Cao, My Linh Schakman, Olivier Dietrich, Alexander Lebacq, Jean Ruegg, Urs Roulet, Emmanuelle Birnbaumer, Lutz Gailly, Philippe TI Role of TRPC1 channel in skeletal muscle function SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE calcium; canonical transient receptor potential 1; fatigue ID DUCHENNE MUSCULAR-DYSTROPHY; OPERATED CALCIUM-CHANNELS; MDX MICE; SARCOPLASMIC-RETICULUM; CA2+ ENTRY; CONTRACTILE PROPERTIES; CELLULAR MECHANISMS; ORAI PROTEINS; FIBERS; MOUSE AB Zanou N, Shapovalov G, Louis M, Tajeddine N, Gallo C, Van Schoor M, Anguish I, Cao ML, Schakman O, Dietrich A, Lebacq J, Ruegg U, Roulet E, Birnbaumer L, Gailly P. Role of TRPC1 channel in skeletal muscle function. Am J Physiol Cell Physiol 298: C149-C162, 2010. First published October 21, 2009; doi:10.1152/ajpcell.00241.2009.-Skeletal muscle contraction is reputed not to depend on extracellular Ca(2+). Indeed, stricto sensu, excitation-contraction coupling does not necessitate entry of Ca(2+). However, we previously observed that, during sustained activity (repeated contractions), entry of Ca(2+) is needed to maintain force production. In the present study, we evaluated the possible involvement of the canonical transient receptor potential (TRPC) 1 ion channel in this entry of Ca(2+) and investigated its possible role in muscle function. Patch-clamp experiments reveal the presence of a small-conductance channel (13 pS) that is completely lost in adult fibers from TRPC1(-/-) mice. The influx of Ca(2+) through TRPC1 channels represents a minor part of the entry of Ca(2+) into muscle fibers at rest, and the activity of the channel is not store dependent. The lack of TRPC1 does not affect intracellular Ca(2+) concentration ([Ca(2+)](i)) transients reached during a single isometric contraction. However, the involvement of TRPC1-related Ca(2+) entry is clearly emphasized in muscle fatigue. Indeed, muscles from TRPC1(-/-) mice stimulated repeatedly progressively display lower [Ca(2+)](i) transients than those observed in TRPC1(-/-) fibers, and they also present an accentuated progressive loss of force. Interestingly, muscles from TRPC1(-/-) mice display a smaller fiber cross-sectional area, generate less force per cross-sectional area, and contain less myofibrillar proteins than their controls. They do not present other signs of myopathy. In agreement with in vitro experiments, TRPC1(-/-) mice present an important decrease of endurance of physical activity. We conclude that TRPC1 ion channels modulate the entry of Ca(2+) during repeated contractions and help muscles to maintain their force during sustained repeated contractions. C1 [Zanou, Nadege; Louis, Magali; Tajeddine, Nicolas; Van Schoor, Monique; Cao, My Linh; Schakman, Olivier; Lebacq, Jean; Gailly, Philippe] Univ Catholique Louvain, Inst Neurosci, Lab Cell Physiol, B-1200 Brussels, Belgium. [Shapovalov, Georges; Gallo, Chiara; Anguish, Isabelle; Ruegg, Urs; Roulet, Emmanuelle] Univ Geneva, Pharmacol Lab, Geneva Lausanne Sch Pharmaceut Sci, Geneva, Switzerland. [Dietrich, Alexander] Univ Marburg, Sch Med, Inst Pharmacol & Toxicol, Marburg, Germany. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Res Triangle Pk, NC USA. RP Gailly, P (reprint author), Univ Catholique Louvain, Inst Neurosci, Lab Cell Physiol, 55-40 Av Hippocrate, B-1200 Brussels, Belgium. EM philippe.gailly@uclouvain.be RI Dietrich, Alexander/G-8619-2013; OI Dietrich, Alexander/0000-0002-1168-8707; RUEGG, Urs/0000-0001-6078-8280 FU "Association francaise contre les myopathies" (AFM; "Association belge contre les maladies neuro-musculaires" (ABMM); General Direction of Scientific Research of the French Community of Belgium [ARC 05/10-328]; Region Walonne; Swiss National Science Foundation (SNSF); Swiss Foundation for Research on Muscular Diseases; National Institutes of Health [Z01-ES-101684] FX This work was supported by the "Association francaise contre les myopathies" (AFM), the "Association belge contre les maladies neuro-musculaires" (ABMM), by grant ARC 05/10-328 from the General Direction of Scientific Research of the French Community of Belgium, the "Programme d'excellence Marshall" (DIANE convention) from the "Region Walonne," by grants of the Swiss National Science Foundation (SNSF), the Swiss Foundation for Research on Muscular Diseases, and in part by the Intramural Research Program of the National Institutes of Health (project Z01-ES-101684 to L. Birnbaumer). NR 76 TC 54 Z9 55 U1 0 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD JAN PY 2010 VL 298 IS 1 BP C149 EP C162 DI 10.1152/ajpcell.00241.2009 PG 14 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 533LO UT WOS:000272825500017 PM 19846750 ER PT J AU Wong, R Aponte, AM Steenbergen, C Murphy, E AF Wong, Renee Aponte, Angel M. Steenbergen, Charles Murphy, Elizabeth TI Cardioprotection leads to novel changes in the mitochondrial proteome SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE glycogen synthase kinase-3; preconditioning; electron transport chain; supercomplex ID GLYCOGEN-SYNTHASE KINASE-3-BETA; PERMEABILITY TRANSITION PORE; PHOSPHORYLATED IN-VIVO; OXIDASE SUBUNIT-IV; CYTOCHROME-C; KINASE-C; OXIDATIVE-PHOSPHORYLATION; ELECTRON-TRANSPORT; BETA-CATENIN; RAT-HEART AB Wong R, Aponte AM, Steenbergen C, Murphy E. Cardioprotection leads to novel changes in the mitochondrial proteome. Am J Physiol Heart Circ Physiol 298: H75-H91, 2010. First published October 23, 2009; doi:10.1152/ajpheart.00515.2009.-It is proposed that ischemic preconditioning (PC) initiates signaling that converges on mitochondria and results in cardioprotection. The outcome of this signaling on mitochondrial enzyme complexes is yet to be understood. We therefore used proteomic methods to test the hypothesis that PC and pharmacological preconditioning similarly alter mitochondrial signaling complexes. Langendorff-perfused murine hearts were treated with the specific GSK-3 inhibitor AR-A014418 (GSK Inhib VIII) for 10 min or subjected to four cycles of 5-min ischemia-reperfusion (PC) before 20-min global ischemia and 120-min reperfusion. PC and GSK Inhib VIII both improved recovery of postischemic left ventricular developed pressure, decreased infarct size, and reduced lactate production during ischemia compared with their time-matched controls. We used proteomics to examine mitochondrial protein levels/posttranslational modifications that were common between PC and GSK Inhib VIII. Levels of cytochrome-c oxidase subunits Va and VIb, ATP synthase-coupling factor 6, and cytochrome b-c1 complex subunit 6 were increased while cytochrome c was decreased with PC and GSK Inhib VIII. Furthermore, the amount of cytochrome-c oxidase subunit VIb was found to be increased in PC and GSK Inhib VIII mitochondrial supercomplexes, which are comprised of complexes I, III, and IV. This result would suggest that changes in complex subunits associated with cardioprotection may affect supercomplex composition. Thus the ability of PC and GSK inhibition to alter the expression levels of electron transport complexes will have important implications for mitochondrial function. C1 [Wong, Renee; Murphy, Elizabeth] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Wong, R (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Rm 7N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM wongr2@mail.nih.gov FU National Heart, Lung, and Blood Institute, NIH FX This work was supported by the National Heart, Lung, and Blood Institute, NIH intramural program. NR 44 TC 35 Z9 36 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JAN PY 2010 VL 298 IS 1 BP H75 EP H91 DI 10.1152/ajpheart.00515.2009 PG 17 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 533NT UT WOS:000272831600010 PM 19855063 ER PT J AU Atienza, AA Hesse, BW Gustafson, DH Croyle, RT AF Atienza, Audie A. Hesse, Bradford W. Gustafson, David H. Croyle, Robert T. TI e-Health Research and Patient-Centered Care Examining Theory, Methods, and Application SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID INTERNET; EHEALTH; INFORMATION; TRENDS; IMPACT C1 [Atienza, Audie A.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Hlth Promot Res Branch, Bethesda, MD 20892 USA. [Gustafson, David H.] Univ Wisconsin, Ctr Hlth Enhancement Syst Studies, Madison, WI USA. RP Atienza, AA (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Hlth Promot Res Branch, 6130 Execut Blvd,EPN 4082, Bethesda, MD 20892 USA. EM atienzaa@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 36 TC 12 Z9 13 U1 0 U2 3 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 JAN PY 2010 VL 38 IS 1 BP 85 EP 88 DI 10.1016/j.amepre.2009.10.027 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 541KL UT WOS:000273413800012 PM 20117562 ER PT J AU Taplin, SH Rollason, D Camp, A diDonato, K Maggenheimer, E AF Taplin, Stephen H. Rollason, David Camp, Anne diDonato, Kristen Maggenheimer, Elizabeth TI Imagining an Electronic Medical Record for Turning Cancer Screening Knowledge into Practice SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID COMMUNITY-HEALTH CENTERS; CHRONIC CARE MODEL; INCREASE MAMMOGRAPHY USE; IMPROVING DIABETES CARE; SHARED DECISION-MAKING; QUALITY; INTERVENTIONS; METAANALYSIS; DISPARITIES C1 [Taplin, Stephen H.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rollason, David] Prairie Community Hlth, Isabel, SD USA. [Camp, Anne; Maggenheimer, Elizabeth] Fairhaven Community Hlth Ctr Inc, New Haven, CT USA. [diDonato, Kristen] Community Hlth Ctr Assoc Connecticut, New Haven, CT USA. RP Taplin, SH (reprint author), 6130 Execut Blvd,MSC 7344,EPN 4005, Rockville, MD 20852 USA. EM TaplinS@mail.nih.gov NR 31 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2010 VL 38 IS 1 BP 89 EP 97 DI 10.1016/j.amepre.2009.09.037 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 541KL UT WOS:000273413800013 PM 20117563 ER PT J AU Resnicow, K Strecher, V Couper, M Chua, H Little, R Nair, V Polk, TA Atienza, AA AF Resnicow, Ken Strecher, Victor Couper, Mick Chua, Hannah Little, Roderick Nair, Vijay Polk, Thad A. Atienza, Audie A. TI Methodologic and Design Issues in Patient-Centered e-Health Research SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SMOKING-CESSATION PROGRAM; TAILORED INTERVENTIONS; VEGETABLE INTERVENTION; PHYSICAL-ACTIVITY; PUBLIC-HEALTH; ENGAGEMENT; EDUCATION; MESSAGES; IDENTIFY C1 [Resnicow, Ken; Strecher, Victor; Couper, Mick; Chua, Hannah; Little, Roderick; Nair, Vijay; Polk, Thad A.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Atienza, Audie A.] NCI, Bethesda, MD 20892 USA. RP Resnicow, K (reprint author), Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, 109 Observ St,Room 3867,SPH 1, Ann Arbor, MI 48109 USA. EM kresnic@umich.edu RI Little, Roderick/H-2440-2011 FU NCI NIH HHS [P50 CA101451]; NHLBI NIH HHS [R01 HL085400] NR 33 TC 16 Z9 16 U1 3 U2 14 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 JAN PY 2010 VL 38 IS 1 BP 98 EP 102 DI 10.1016/j.amepre.2009.09.034 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 541KL UT WOS:000273413800014 PM 20117564 ER PT J AU Baron, RC Melillo, S Rimer, BK Coates, RJ Kerner, J Habarta, N Chattopadhyay, S Sabatino, SA Elder, R Leeks, KJ AF Baron, Roy C. Melillo, Stephanie Rimer, Barbara K. Coates, Ralph J. Kerner, Jon Habarta, Nancy Chattopadhyay, Sajal Sabatino, Susan A. Elder, Randy Leeks, Kimberly Jackson CA Task Force Community Preventive Se TI Intervention to Increase Recommendation and Delivery of Screening for Breast, Cervical, and Colorectal Cancers by Healthcare Providers A Systematic Review of Provider Reminders SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COMMUNITY-PREVENTIVE-SERVICES; MAINTENANCE ORGANIZATION; COMPUTERIZED REMINDERS; IMPROVING ATTENDANCE; PHYSICIAN COMPLIANCE; REPEAT MAMMOGRAPHY; COST-EFFECTIVENESS; PATIENT REMINDERS; PRIVATE-PRACTICE AB Most major medical organizations recommend routine screening for breast, cervical, and colorectal cancers. Screening can lead to early detection of these cancers, resulting in reduced mortality. Yet, not all people who should be screened are screened regularly or, in some cases, ever. This report presents results of systematic reviews of effectiveness, applicability, economic efficiency, barriers to implementation, and other harms or benefits of provider reminder/recall interventions to increase screening for breast, cervical, and colorectal cancers. These interventions involve using systems to inform healthcare providers when individual clients are due (reminder) or overdue (recall) for specific cancer screening tests. Evidence in this review of studies published from 1986 through 2004 indicates that reminder/recall systems can effectively increase screening with mammography, Pap, fecal occult blood tests, and flexible sigmoidoscopy. Additional research is needed to determine if provider reminder/recall systems are effective in increasing colorectal cancer screening by colonoscopy. Specific areas for further research are also suggested. (Am J Prev Med 2010;38(1):110-117) (C) 2010 Published by Elsevier Inc. on behalf of American journal of Preventive Medicine. C1 [Baron, Roy C.; Melillo, Stephanie; Habarta, Nancy; Chattopadhyay, Sajal; Elder, Randy; Leeks, Kimberly Jackson] Ctr Dis Control & Prevent, Community Guide Branch, Natl Ctr Hlth Mkt, Atlanta, GA 30333 USA. [Coates, Ralph J.; Sabatino, Susan A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Kerner, Jon] NCI, NIH, Bethesda, MD 20892 USA. [Rimer, Barbara K.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. RP Elder, R (reprint author), Ctr Dis Control & Prevent, Community Guide Branch, Natl Ctr Hlth Mkt, 1600 Clifton Rd,MS E-69, Atlanta, GA 30333 USA. EM relder1@cdc.gov RI Stockwell, Tim/B-6662-2012; OI Kerner, Jon/0000-0002-8792-3830 FU PHS HHS [U50/CCU300860] NR 64 TC 66 Z9 66 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2010 VL 38 IS 1 BP 110 EP 117 DI 10.1016/j.amepre.2009.09.031 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 541KL UT WOS:000273413800016 PM 20117566 ER PT J AU Lissek, S Rabin, S Heller, RE Lukenbaugh, D Geraci, M Pine, DS Grillon, C AF Lissek, Shmuel Rabin, Stephanie Heller, Randi E. Lukenbaugh, David Geraci, Marilla Pine, Daniel S. Grillon, Christian TI Overgeneralization of Conditioned Fear as a Pathogenic Marker of Panic Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID LEARNING-THEORY PERSPECTIVE; D-CYCLOSERINE; STIMULUS-GENERALIZATION; POTENTIATED STARTLE; ANXIETY DISORDERS; AUDITORY-CORTEX; DISCRIMINATION; ETIOLOGY; HUMANS; MEMORY AB Objective: Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear. Method: Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG). Results: Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity. Conclusions: The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder. C1 [Lissek, Shmuel; Rabin, Stephanie; Heller, Randi E.; Lukenbaugh, David; Geraci, Marilla; Pine, Daniel S.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20892 USA. RP Lissek, S (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, 15K North Dr,Rm 200, Bethesda, MD 20892 USA. EM lisseks@mail.nih.gov OI Rabin, Stephanie/0000-0002-8282-0867 FU NIMH FX Supported by the NIMH Intramural Research Program. NR 27 TC 177 Z9 183 U1 6 U2 29 PU AMER PSYCHIATRIC PUBLISHING, 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 JAN PY 2010 VL 167 IS 1 BP 47 EP 55 DI 10.1176/appi.ajp.2009.09030410 PG 9 WC Psychiatry SC Psychiatry GA 543KL UT WOS:000273575900009 PM 19917595 ER PT J AU Brotman, MA Rich, BA Guyer, AE Lunsford, JR Horsey, SE Reising, MM Thomas, LA Fromm, SJ Towbin, K Pine, DS Leibenluft, E AF Brotman, Melissa A. Rich, Brendan A. Guyer, Amanda E. Lunsford, Jessica R. Horsey, Sarah E. Reising, Michelle M. Thomas, Laura A. Fromm, Stephen J. Towbin, Kenneth Pine, Daniel S. Leibenluft, Ellen TI Amygdala Activation During Emotion Processing of Neutral Faces in Children With Severe Mood Dysregulation Versus ADHD or Bipolar Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CALLOUS-UNEMOTIONAL TRAITS; FACIAL EXPRESSIONS; LABELING DEFICITS; CONDUCT PROBLEMS; FEARFUL FACES; YOUTH; ADOLESCENTS; BRAIN AB Objective: To understand disorder-unique and common pathophysiology, studies in multiple patient groups with overlapping symptoms are needed. Deficits in emotion processing and hyper-arousal symptoms are prominent features of bipolar disorder, attention deficit hyperactivity disorder (ADHD), and severe mood dysregulation. The authors compared amygdala response during emotional and nonemotional ratings of neutral faces in youths with these disorders as well as a group of healthy comparison youths. Method: Blood-oxygen-level-dependent (BOLD) signal in the amygdala was examined in children with bipolar disorder (N=43), ADHD (N=18), and severe mood dysregulation (N=29) and healthy comparison subjects (N=37). During functional magnetic resonance imaging (fMRI), participants attended to emotional and nonemotional aspects of neutral faces. Results: While rating subjective fear of neutral faces, youths with ADHD demonstrated left amygdala hyperactivity relative to the other three groups, whereas youths with severe mood dysregulation demonstrated hypoactivity. Conclusions: These findings support the role of unique neural correlates in face-emotion processing among youths with bipolar disorder, ADHD, and severe mood dysregulation. C1 NIMH, Emot & Dev Branch, Mood & Anxiety Disorders Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. RP Brotman, MA (reprint author), 15K North Dr,Rm 208, Bethesda, MD 20892 USA. EM brotmanm@mail.nih.gov RI Brotman, Melissa/H-7409-2013; OI Thomas, Laura/0000-0002-4106-1358 FU NIMH FX Supported by the NIMH Intramural Research Program. NR 51 TC 130 Z9 131 U1 1 U2 21 PU AMER PSYCHIATRIC PUBLISHING, 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 JAN PY 2010 VL 167 IS 1 BP 61 EP 69 DI 10.1176/appi.ajp.2009.09010043 PG 9 WC Psychiatry SC Psychiatry GA 543KL UT WOS:000273575900011 PM 19917597 ER PT J AU Brown, TM Fee, E AF Brown, Theodore M. Fee, Elizabeth TI Birth of the American Journal of Public Health SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Brown, Theodore M.] Univ Rochester, Dept Hist, Rochester, NY 14627 USA. [Brown, Theodore M.] Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. EM Theodore_Brown@urmc.rochester.edu NR 6 TC 2 Z9 2 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2010 VL 100 IS 1 BP 66 EP 67 DI 10.2105/AJPH.2009.181867 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 538EK UT WOS:000273166800015 PM 19965564 ER PT J AU Blum, N Lane, HJ Fee, E AF Blum, Nava Lane, Hilary J. Fee, Elizabeth TI Justina Siegemund and the Art of Midwifery SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Blum, Nava] Univ Haifa, Fac Social Welf & Hlth Sci, Sch Publ Hlth, IL-31905 Haifa, Israel. [Blum, Nava] Max Stern Acad Coll Emek Yezreel, Dept Hlth Syst Adm, Yezreel Valley, Israel. [Lane, Hilary J.] Mayo Med Lib, Hist Med Lib, Rochester, MN USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Blum, N (reprint author), Univ Haifa, Fac Social Welf & Hlth Sci, Sch Publ Hlth, IL-31905 Haifa, Israel. EM navablum@hotmail.com NR 6 TC 0 Z9 0 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2010 VL 100 IS 1 BP 68 EP 69 DI 10.2105/AJPH.2009.171371 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 538EK UT WOS:000273166800016 PM 19910341 ER PT J AU Arias, E Eschbach, K Schauman, WS Backlund, EL Sortie, PD AF Arias, Elizabeth Eschbach, Karl Schauman, William S. Backlund, Eric L. Sortie, Paul D. TI The Hispanic Mortality Advantage and Ethnic Misclassification on US Death Certificates SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID UNITED-STATES; PARADOX; HEALTH AB Objectives. We tested the data artifact hypothesis regarding the Hispanic mortality advantage by investigating whether and to what degree this advantage is explained by Hispanic origin misclassification on US death certificates. Methods. We used the National Longitudinal Mortality Study, which links Current Population Survey records to death certificates for 1979 through 1998, to estimate the sensitivity, specificity, and net ascertainment of Hispanic ethnicity on death certificates compared with survey classifications. Using national vital statistics mortality data, we estimated Hispanic age-specific and age-adjusted death rates, which were uncorrected and corrected for death certificate misclassification, and produced death rate ratios comparing the Hispanic with the non-Hispanic White population. Results. Hispanic origin reporting on death certificates in the United States is reasonably good. The net ascertainment of Hispanic origin is just 5% higher on survey records than on death certificates. Corrected age-adjusted death rates for Hispanics are lower than those for the non-Hispanic White population by close to 20%. Conclusions. The Hispanic mortality paradox is not explained by an incongruence between ethnic classification in vital registration and population data systems. (Am J Public Health. 2010;100:S171-S177. doi:10.2105/AJPH.2008.135863) C1 [Arias, Elizabeth] Ctr Dis Control & Prevent, Mortal Stat Branch, Div Vital Stat, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Eschbach, Karl] Univ Texas San Antonio, San Antonio, TX USA. [Schauman, William S.; Backlund, Eric L.] US Bur Census, Suitland, MD USA. [Sortie, Paul D.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Arias, E (reprint author), Ctr Dis Control & Prevent, Mortal Stat Branch, Div Vital Stat, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 7330, Hyattsville, MD 20782 USA. EM earias@cdc.gov FU University of Texas Medical Branch Center for Population Health and Health Disparity [P50CA105631-05] FX Karl Eschbach was supported by the University of Texas Medical Branch Center for Population Health and Health Disparity, P50CA105631-05. NR 27 TC 44 Z9 44 U1 1 U2 9 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S171 EP S177 DI 10.2105/AJPH.2008.135863 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600032 PM 19762677 ER PT J AU Dankwa-Mullan, I Rhee, KB Stoff, DM Pohlhaus, JR Sy, FS Stinson, N Ruffin, J AF Dankwa-Mullan, Irene Rhee, Kyu B. Stoff, David M. Pohlhaus, Jennifer Reineke Sy, Francisco S. Stinson, Nathaniel, Jr. Ruffin, John TI Moving Toward Paradigm-Shifting Research in Health Disparities Through Translational, Transformational, and Transdisciplinary Approaches SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID UNIDENTIFIED CURVED BACILLI; PUBLIC-HEALTH; OBESITY; ENVIRONMENT; GASTRITIS; DISEASE; STRESS; GENE AB Translational, transclisciplinary, and transformational research stands to become a paradigm-shifting mantra for research in health disparities. A windfall of research discoveries using these 3 approaches has increased our understanding of the health disparities in racial, ethnic, and low socioeconomic status groups. These distinct but related research spheres possess unique environments, which, when integrated, can lead to innovation in health disparities science. In this article, we review these approaches and propose integrating them to advance health disparities research through a change in philosophical position and an increased emphasis on community engagement. We argue that a balanced combination of these research approaches is needed to inform evidence-based practice, social action, and effective policy change to improve health in disparity communities. (Am J Public Health. 2010; 100: S19-S24. doi:10.2105/AJPH.2009.189167) C1 [Dankwa-Mullan, Irene; Sy, Francisco S.; Stinson, Nathaniel, Jr.; Ruffin, John] NIH, Natl Ctr Minor Hlth & Hlth Dispar, Bethesda, MD 20892 USA. [Rhee, Kyu B.] Hlth Resources & Serv Adm, Rockville, MD USA. [Stoff, David M.] NIMH, NIH, Bethesda, MD 20892 USA. [Pohlhaus, Jennifer Reineke] Ripple Effects Commun Inc, Rockville, MD USA. RP Dankwa-Mullan, I (reprint author), NIH, Natl Ctr Minor Hlth & Hlth Dispar, 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. EM dankwamullani@mail.nih.gov NR 38 TC 42 Z9 42 U1 2 U2 10 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S19 EP S24 DI 10.2105/AJPH.2009.189167 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600007 PM 20147662 ER PT J AU Dankwa-Mullan, I Rhee, KB Williams, K Sanchez, I Sy, FS Stinson, N Ruffin, J AF Dankwa-Mullan, Irene Rhee, Kyu B. Williams, Kester Sanchez, Idalia Sy, Francisco S. Stinson, Nathaniel, Jr. Ruffin, John TI The Science of Eliminating Health Disparities: Summary and Analysis of the NIH Summit Recommendations SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB In December 2008, the National Institutes of Health (NIH) sponsored the first NIH Summit showcasing its investment and contribution to health disparities research and unveiling a framework for moving this important field forward. The Summit, titled "The Science of Eliminating Health Disparities," drew on extensive experience of experts leading health disparities research transformation in diverse fields. The Summit also provided a historic educational opportunity to contribute to health care reform. The theme, addressing disparities through integration of science, practice, and policy, introduced a paradigm for advancing research through transformational, translational, and transdisciplinary research. Engaging active participation throughout the Summit generated recommendations bridging science, practice, and policy, including action on social determinants of health, community engagement, broad partnerships, capacity-building, and media outreach. (Am J Public Health. 2010; 100: S12-S18. doi:10.2105/AJPH.2010.191619) C1 [Dankwa-Mullan, Irene; Rhee, Kyu B.; Williams, Kester; Sanchez, Idalia; Sy, Francisco S.; Stinson, Nathaniel, Jr.; Ruffin, John] NIH, Natl Ctr Minor Hlth & Hlth Dispar, Bethesda, MD 20892 USA. RP Dankwa-Mullan, I (reprint author), NIH, Natl Ctr Minor Hlth & Hlth Dispar, 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. EM dankwamullani@mail.nih.gov FU National Institutes of Health FX The supplement was commissioned as part of the National Institutes of Health Summit, "The Science of Eliminating Health Disparities" convened in December 2008 in National Harbor, NR 5 TC 37 Z9 37 U1 0 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S12 EP S18 DI 10.2105/AJPH.2010.191619 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600006 PM 20147660 ER PT J AU Finlayson, TL Williams, DR Siefert, K Jackson, JS Nowjack-Raymer, R AF Finlayson, Tracy L. Williams, David R. Siefert, Kristine Jackson, James S. Nowjack-Raymer, Ruth TI Oral Health Disparities and Psychosocial Correlates of Self-Rated Oral Health in the National Survey of American Life SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SOCIOECONOMIC DISPARITIES; OLDER-ADULTS; SOCIAL DETERMINANTS; PERIODONTAL-DISEASE; COMORBIDITY SURVEY; AFRICAN-AMERICANS; GENERAL HEALTH; MENTAL-HEALTH; UNITED-STATES; EPIDEMIOLOGY AB Objectives. We sought to better understand the determinants of oral health disparities by examining individual-level psychosocial stressors and resources and self-rated oral health in nationally representative samples of Black American, Caribbean Black, and non-Hispanic White adults. Methods, We conducted logistic regression analyses on fair or poor versus better oral health using data from the National Survey of American Life (n=6082). Results. There were no significant racial differences. Overall, 28% of adults reported having fair or poor oral health. Adults with lower income and less than a high school education were each about 1.5 times as likely as other adults to report fair or poor oral health. Higher levels of chronic stress, depressive symptoms, and material hardship were associated with fair or poor oral health. Adults living near more neighborhood resources were less likely to report fair or poor oral health. Higher levels of self-esteem and mastery were protective, and more-religious adults were also less likely to report fair or poor oral health. Conclusions. Social gradients in self-rated oral health were found, and they have implications for developing interventions to address oral health disparities. (Am J Public Health. 2010;100:S246-S255. doi:10.2105/AJPH.2009.167783) C1 [Finlayson, Tracy L.] San Diego State Univ, Div Hlth Management & Policy, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Williams, David R.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Siefert, Kristine] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. [Jackson, James S.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Nowjack-Raymer, Ruth] Natl Inst Dental & Craniofacial Res, NIH, Bethesda, MD USA. RP Finlayson, TL (reprint author), San Diego State Univ, Div Hlth Management & Policy, Grad Sch Publ Hlth, 5500 Campanile Dr, San Diego, CA 92182 USA. EM tfinlays@mail.sdsu.edu FU National Institute of Mental Health [5T32MH16806] FX This work was supported by the National Institute of Mental Health (grant 5T32MH16806). NR 66 TC 22 Z9 22 U1 2 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S246 EP S255 DI 10.2105/AJPH.2009.167783 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600042 PM 20147685 ER PT J AU Morrison, SM Fee, E AF Morrison, Sheena M. Fee, Elizabeth TI The Journal of the National Medical Association: A Voice for Civil Rights and Social Justice SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Morrison, Sheena M.] Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, New York, NY USA. [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Morrison, SM (reprint author), 3805 Kansas Ave NW, Washington, DC 20011 USA. EM smm65@columbia.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S70 EP S71 DI 10.2105/AJPH.2009.175042 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600017 PM 20147673 ER PT J AU Morrison, SM Fee, E AF Morrison, Sheena M. Fee, Elizabeth TI Charles V. Roman: Physician, Writer, Educator, Historian (1864-1934) SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Morrison, Sheena M.] Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, New York, NY USA. [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Morrison, SM (reprint author), 3805 Kansas Ave NW, Washington, DC 20011 USA. EM smm65@columbia.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S69 EP S69 DI 10.2105/AJPH.2009.175562 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600016 ER PT J AU Ruffin, J AF Ruffin, John TI The Science of Eliminating Health Disparities: Embracing a New Paradigm SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 NIH, Natl Ctr Minor Hlth & Hlth Dispar, Bethesda, MD 20892 USA. RP Ruffin, J (reprint author), NIH, Natl Ctr Minor Hlth & Hlth Dispar, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM williake@mail.nih.gov NR 6 TC 15 Z9 15 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S8 EP S9 DI 10.2105/AJPH.2010.191957 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600004 PM 20147659 ER PT J AU Thomas, SB Sansing, VV Davis, A Magee, M Massaro, E Srinivas, VS Helmy, T Desvigne-Nickens, P Brooks, MM AF Thomas, Stephen B. Sansing, Veronica V. Davis, Andrew Magee, Michelle Massaro, Elaine Srinivas, V. S. Helmy, Tarek Desvigne-Nickens, Patrice Brooks, Maria Mori CA BARI 2D Study Grp TI Racial Differences in the Association Between Self-Rated Health Status and Objective Clinical Measures Among Participants in the BARI 2D Trial SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID QUALITY-OF-LIFE; FUNCTIONAL STATUS OUTCOMES; CARDIOVASCULAR-DISEASE; AFRICAN-AMERICANS; UNITED-STATES; DIABETES-MELLITUS; WHITE ADULTS; OLDER-ADULTS; DISPARITIES; MORTALITY AB Objectives. We explored whether and how race shapes perceived health status in patients with type 2 diabetes mellitus and coronary artery disease. Methods. We analyzed self-rated health (fair or poor versus good, very good, or excellent) and associated clinical risk factors among 866 White and 333 Black participants in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. Results. Michigan Neuropathy Screening Instrument scores, regular exercise, and employment were associated with higher self-rated health (P<.05). Blacks were more likely than were Whites to rate their health as fair or poor (adjusted odds ratio [OR]=1.88; 95% confidence interval [Cl]=1.38, 2.57; P<.001). Among Whites but not Blacks, a clinical history of myocardial infarction (OR=1.61; 95% CI=1.12, 2.31; P<.001) and insulin use (OR=1.62; 95% CI=1.10, 2.38; P=.01) was associated with a fair or poor rating. A post-high school education was related to poorer self-rated health among Blacks (OR=1.86; 95% CI=1.07, 3.24; P<.001). Conclusions. Symptomatic clinical factors played a proportionally larger role in self-assessment of health among Whites with diabetes and coronary artery disease than among Blacks with the same conditions. (Am J Public Health. 2010; 100:S269-S276. doi:10.2105/AJPH.2009.176180) C1 [Thomas, Stephen B.; Sansing, Veronica V.; Brooks, Maria Mori] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Davis, Andrew] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Magee, Michelle] Georgetown Univ, Sch Med, Washington, DC USA. [Massaro, Elaine] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Srinivas, V. S.] Albert Einstein Coll Med Montefiore, New York, NY USA. [Helmy, Tarek] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Desvigne-Nickens, Patrice] NHLBI, Bethesda, MD 20892 USA. RP Thomas, SB (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, 130 DeSoto St,A718 Crabtree Hall, Pittsburgh, PA 15261 USA. EM sbthomas@pitt.edu OI Brooks, Maria/0000-0002-2030-7873 FU NIMHD NIH HHS [5P60MD000207-07, P60 MD000207] NR 35 TC 8 Z9 8 U1 0 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PY 2010 VL 100 SU 1 BP S269 EP S276 DI 10.2105/AJPH.2009.176180 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573TK UT WOS:000275937600045 PM 20147671 ER PT J AU Madsen-Bouterse, SA Romero, R Tarca, AL Kusanovic, JP Espinoza, J Kim, CJ Kim, JS Edwin, SS Gomez, R Draghici, S AF Madsen-Bouterse, Sally A. Romero, Roberto Tarca, Adi L. Kusanovic, Juan Pedro Espinoza, Jimmy Kim, Chong Jai Kim, Jung-Sun Edwin, Samuel S. Gomez, Ricardo Draghici, Sorin TI The Transcriptome of the Fetal Inflammatory Response Syndrome SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE Chorioamnionitis; FIRS; microarray; prematurity; preterm birth; transcriptomics ID TUMOR-NECROSIS-FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; AMNIOTIC-FLUID INTERLEUKIN-6; PRETERM PREMATURE RUPTURE; GENE-EXPRESSION PROFILES; MESSENGER-RNA REDUCTION; INNATE IMMUNE-RESPONSE; UMBILICAL-CORD PLASMA; SEPTIC SHOCK PATIENTS; WHITE-MATTER LESIONS AB Problem The fetal inflammatory response syndrome (FIRS) is considered the counterpart of the systemic inflammatory response syndrome (SIRS), but similarities in their regulatory mechanisms are unclear. This study characterizes the fetal mRNA transcriptome of peripheral leukocytes to identify key biological processes and pathways involved in FIRS. Method of study Umbilical cord blood from preterm neonates with FIRS (funisitis, plasma IL-6 > 11 pg/mL; n = 10) and neonates with no evidence of inflammation (n = 10) was collected at birth. Results Microarray analysis of leukocyte RNA revealed differential expression of 541 unique genes, changes confirmed by qRT-PCR for 41 or 44 genes tested. Similar to SIRS and sepsis, ontological and pathway analyses yielded significant enrichment of biological processes including antigen processing and presentation, immune response, and processes critical to cellular metabolism. Results are comparable with microarray studies of endotoxin challenge models and pediatric sepsis, identifying 25 genes across all studies. Conclusion This study is the first to profile genome-wide expression in FIRS, which demonstrates a substantial degree of similarity with SIRS despite differences in fetal and adult immune systems. C1 [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, Detroit, MI 48201 USA. [Madsen-Bouterse, Sally A.; Romero, Roberto; Tarca, Adi L.; Kusanovic, Juan Pedro; Espinoza, Jimmy; Kim, Chong Jai; Kim, Jung-Sun; Edwin, Samuel S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Kusanovic, Juan Pedro; Espinoza, Jimmy] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Womens Hosp, Detroit, MI 48201 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Kim, Chong Jai; Kim, Jung-Sun] Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. [Gomez, Ricardo] Pontificia Univ Catolica Chile, Sotero Rio Hosp, Dept Obstet & Gynecol, CEDIP Ctr Perinatal Diag & Res, Santiago, Chile. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 FU Perinatology Research Branch, Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [1R21 CA10074001, 1R21 EB00990-01, 1R01 NS045207-01]; DHHS; NSF [DBI-0234806]; NIH(NCRR) [1S10 RR017857-01]; MLSC [MEDC-538]; MEDC [GR-352] FX The authors wish to thank the nursing staffs of the Perinatology Research Branch, the Detroit Medical Center, and Sotero del Rio Hospital for their contributions to this work. This research was supported (in part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, by NSF DBI-0234806, NIH(NCRR) 1S10 RR017857-01, MLSC MEDC-538 and MEDC GR-352, NIH 1R21 CA10074001, 1R21 EB00990-01, and 1R01 NS045207-01. NR 126 TC 62 Z9 65 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD JAN PY 2010 VL 63 IS 1 BP 73 EP 92 DI 10.1111/j.1600-0897.2009.00791.x PG 20 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 533ZC UT WOS:000272864100012 PM 20059468 ER PT J AU Aldrich, M Kritchevsky, S Meibohm, B Leak, T Harris, T Kumar, R Ziv, E Burchard, E AF Aldrich, M. Kritchevsky, S. Meibohm, B. Leak, T. Harris, T. Kumar, R. Ziv, E. Burchard, E. TI Lower Lung Function For African Americans With High African Genetic Ancestry And Tobacco Smoke Exposure: A Gene-Environment Interaction SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Aldrich, M.; Ziv, E.; Burchard, E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kritchevsky, S.] Wake Forest Sch Med, Winston Salem, NC USA. [Meibohm, B.] Univ Tennessee, Memphis, TN USA. [Leak, T.] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Kumar, R.] Childrens Mem Hosp, Chicago, IL 60614 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1263 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000264 ER PT J AU Calfee, CS Thompson, BT Parsons, PE Ware, LB Matthay, MA Wong, HR AF Calfee, C. S. Thompson, B. T. Parsons, P. E. Ware, L. B. Matthay, M. A. Wong, H. R. CA NIH NHLBI ARDS Network TI Plasma IL-8 As A Risk Stratification Tool For Adults With Septic Shock SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Calfee, C. S.; Matthay, M. A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Thompson, B. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Parsons, P. E.] Univ Vermont, Burlington, VT USA. [Ware, L. B.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Wong, H. R.] Univ Cincinnati, Cincinnati, OH USA. [NIH NHLBI ARDS Network] NHLBI, NIH, Bethesda, MD 20892 USA. EM carolyn.calfee@ucsf.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1652 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000652 ER PT J AU Cassano, PA Arnold, KB Guertin, KA Kristal, AR Crowley, JJ Hartline, J Goodman, PJ Tangen, CM Minasian, LM Lippman, SM Coltman, CA Klein, E AF Cassano, P. A. Arnold, K. B. Guertin, K. A. Kristal, A. R. Crowley, J. J. Hartline, J. Goodman, P. J. Tangen, C. M. Minasian, L. M. Lippman, S. M. Coltman, C. A. Klein, E. TI Effect Of Vitamin E And Selenium On Incidence Of Physician-Diagnosed COPD: The Selenium And Vitamin E Cancer Prevention Trial (SELECT) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Cassano, P. A.; Guertin, K. A.] Cornell Univ, Ithaca, NY USA. [Arnold, K. B.; Crowley, J. J.; Hartline, J.; Goodman, P. J.] SW Oncol Grp, Ctr Stat, Seattle, WA USA. [Kristal, A. R.] Univ Washington, Seattle, WA 98195 USA. [Tangen, C. M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Minasian, L. M.] NCI, Bethesda, MD 20892 USA. [Lippman, S. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Coltman, C. A.] SW Oncol Grp, San Antonio, TX USA. [Coltman, C. A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Klein, E.] Cleveland Clin, Cleveland, OH 44106 USA. EM pac6@cornell.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A6765 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771005384 ER PT J AU Eberlein, M Martinez, MA Kern, S Munson, P Barb, J Danner, RL Logun, C Shelhamer, JH AF Eberlein, M. Martinez, M. A. Kern, S. Munson, P. Barb, J. Danner, R. L. Logun, C. Shelhamer, J. H. TI The Effect Of Leukotriene E4 On MicroRNA Expression In Human Elutriated Monocytes SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Eberlein, M.; Martinez, M. A.; Kern, S.; Danner, R. L.; Logun, C.; Shelhamer, J. H.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Munson, P.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Barb, J.] Ctr Informat Technol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2041 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001248 ER PT J AU El-Chemaly, S Ziegler, SG Wilson, K Gahl, WA Moss, J Gochuico, BR AF El-Chemaly, S. Ziegler, S. G. Wilson, K. Gahl, W. A. Moss, J. Gochuico, B. R. TI Familial Pulmonary Fibrosis: Natural History Of Preclinical Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [El-Chemaly, S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ziegler, S. G.; Wilson, K.; Gahl, W. A.; Gochuico, B. R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Moss, J.] NIH, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2980 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771002091 ER PT J AU Garantziotis, S Heise, RL Potts, E Stober, V Fessler, MB Kraft, M Schwartz, DA Foster, WM Hollingsworth, JW AF Garantziotis, S. Heise, R. L. Potts, E. Stober, V. Fessler, M. B. Kraft, M. Schwartz, D. A. Foster, W. M. Hollingsworth, J. W. TI Blockade Of Hyaluronan Binding Abolishes Airway Hyperresponsiveness In Mouse Asthma Models SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Garantziotis, S.; Heise, R. L.; Stober, V.] NIEHS, Res Triangle Pk, NC 27709 USA. [Potts, E.; Kraft, M.; Foster, W. M.; Hollingsworth, J. W.] Duke Univ, Med Ctr, Durham, NC USA. [Fessler, M. B.] Natl Inst Environm Hlth, Res Triangle Pk, NC USA. [Schwartz, D. A.] Natl Jewish Hlth, Denver, CO USA. EM heiser@niehs.nih.gov RI Heise, Rebecca/N-7797-2016; Garantziotis, Stavros/A-6903-2009 OI Heise, Rebecca/0000-0002-6602-6700; Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2835 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001747 ER PT J AU Gladwell, W Middleton, L Kleeberger, SR Ciencewicki, J AF Gladwell, W. Middleton, L. Kleeberger, S. R. Ciencewicki, J. TI Exposure To Hyperoxic Conditions Enhances Susceptibility And Response To Respiratory Syncytial Virus Infection SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Gladwell, W.; Kleeberger, S. R.; Ciencewicki, J.] NIEHS, Durham, NC USA. [Middleton, L.] Louisiana State Univ, Baton Rouge, LA 70803 USA. EM gladwell@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2640 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001553 ER PT J AU Hamblin, MJ Eberlein, M Collins, SL Black, KE Wunderlich, T Chan-Li, Y Horton, MR AF Hamblin, M. J. Eberlein, M. Collins, S. L. Black, K. E. Wunderlich, T. Chan-Li, Y. Horton, M. R. TI RhoGTPase And LFA-1 Signaling Pathways Are Critical Components Of HA Fragment-induced TLR-2 Mediated Inflammatory Gene Expression And Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Hamblin, M. J.; Chan-Li, Y.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Eberlein, M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Collins, S. L.; Wunderlich, T.; Horton, M. R.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Black, K. E.] Johns Hopkins, Baltimore, MD USA. EM mhorton2@jhmi.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2779 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001692 ER PT J AU Hawkins, GA Moore, WC Robinson, MB Peters, SP Meyers, D Bleecker, ER AF Hawkins, G. A. Moore, W. C. Robinson, M. B. Peters, S. P. Meyers, D. Bleecker, E. R. CA SARP Investigators TI IL6R Polymorphisms Predict Measures Of Lung Function In Caucasian Asthmatics: Data From The Severe Asthma Research Program (SARP) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Hawkins, G. A.; Moore, W. C.; Robinson, M. B.; Meyers, D.; Bleecker, E. R.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Peters, S. P.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [SARP Investigators] NHLBI, NIH, Bethesda, MD USA. EM ghawkins@wfubmc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1298 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000299 ER PT J AU Heise, RL Li, M Stober, V Hollingsworth, JW Kraft, M Garantziotis, S AF Heise, R. L. Li, M. Stober, V. Hollingsworth, J. W. Kraft, M. Garantziotis, S. TI Hyaluronan Causes Sustained Human Airway Myocyte Contraction SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Heise, R. L.; Stober, V.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Li, M.] Duke Univ, Durham, NC USA. [Hollingsworth, J. W.; Kraft, M.] Duke Univ, Med Ctr, Durham, NC USA. EM heiser@niehs.nih.gov RI Heise, Rebecca/N-7797-2016; Garantziotis, Stavros/A-6903-2009 OI Heise, Rebecca/0000-0002-6602-6700; Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2077 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001284 ER PT J AU Heise, RL Stober, V Hollingsworth, JW Garantziotis, S AF Heise, R. L. Stober, V. Hollingsworth, J. W. Garantziotis, S. TI Mechanical Stretch Induces Epithelial To Mesenchymal Transition Of Alveolar Type II Epithelium Through Hyaluronan Expression And Innate Immune Activation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Heise, R. L.; Stober, V.; Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Hollingsworth, J. W.] Duke Univ, Med Ctr, Durham, NC USA. EM heiser@niehs.nih.gov RI Heise, Rebecca/N-7797-2016; Garantziotis, Stavros/A-6903-2009 OI Heise, Rebecca/0000-0002-6602-6700; Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1220 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000221 ER PT J AU Kelly, FL Kirby, PJ Price, HC Gage, PS Flake, GP Morgan, DL Palmer, SM AF Kelly, F. L. Kirby, P. J. Price, H. C. Gage, P. S. Flake, G. P. Morgan, D. L. Palmer, S. M. TI A Rodent Model Of Toxin Induced Bronchiolitis Obliterans SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Kelly, F. L.; Palmer, S. M.] Duke Univ, Med Ctr, Durham, NC USA. [Kirby, P. J.; Flake, G. P.; Morgan, D. L.] NIEHS, Res Triangle Pk, NC 27709 USA. [Price, H. C.; Gage, P. S.] Alion Inc, Res Triangle Pk, NC USA. EM kelly088@mc.duke.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1750 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000750 ER PT J AU Lam, J Bhakta, H Yao, X Fredriksson, K Zhang, J Yu, M Yu, Z Levine, SJ AF Lam, J. Bhakta, H. Yao, X. Fredriksson, K. Zhang, J. Yu, M. Yu, Z. Levine, S. J. TI The Multi-receptor Tryosine Kinase Inhibitor, Sunitinib, Selectively Attenuates Airway Hyperreactivity In A Murine Model Of Allergic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Lam, J.; Bhakta, H.] NIH, Bethesda, MD 20892 USA. [Yao, X.; Fredriksson, K.; Zhang, J.; Yu, M.; Yu, Z.; Levine, S. J.] NHLBI, NIH, Bethesda, MD 20892 USA. EM lamjk@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2823 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001735 ER PT J AU Li, Z Potts, EN Garantziotis, S Foster, WM Hollingsworth, JW AF Li, Z. Potts, E. N. Garantziotis, S. Foster, W. M. Hollingsworth, J. W. TI Hyaluronan Fragments Released By Ozone Exposure Contribute To Airway Hyperresponsiveness Via TLR4-MyD88-TIRAP SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Li, Z.; Potts, E. N.; Foster, W. M.; Hollingsworth, J. W.] Duke Univ, Med Ctr, Durham, NC USA. [Garantziotis, S.] NIEHS, Res Triangle Pk, NC 27709 USA. EM zhuowei.li@duke.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1166 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000167 ER PT J AU Machado, RF Barst, RJ Yovetich, NA Hassell, KL Goldsmith, JC Woolson, R Gordeuk, VR Gibbs, S Little, JA Kato, GJ Schraufnagel, DE Krishnamurti, L Girgis, R Morris, CR Berman-Rosenzweig, E Badesch, DB Waclawiw, MA Gladwin, MT AF Machado, R. F. Barst, R. J. Yovetich, N. A. Hassell, K. L. Goldsmith, J. C. Woolson, R. Gordeuk, V. R. Gibbs, S. Little, J. A. Kato, G. J. Schraufnagel, D. E. Krishnamurti, L. Girgis, R. Morris, C. R. Berman-Rosenzweig, E. Badesch, D. B. Waclawiw, M. A. Gladwin, M. T. TI Evaluation Of Sildenafil Therapy For Patients With Sickle Cell Disease And Increased Tricuspid Regurgitant Velocity: Preliminary Results Of The Walk-PHaSST Trial SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Machado, R. F.] Univ Chicago, Chicago, IL 60637 USA. [Barst, R. J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Yovetich, N. A.; Woolson, R.] Rho Inc, Chapel Hill, NC USA. [Hassell, K. L.] Univ Colorado HSC, Denver, CO USA. [Goldsmith, J. C.] NIH, NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. [Gordeuk, V. R.] Howard Univ, Washington, DC 20059 USA. [Gibbs, S.] Hammersmith Hosp, London, England. [Little, J. A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Kato, G. J.] NHLBI, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Schraufnagel, D. E.] Univ Illinois, Chicago, IL USA. [Krishnamurti, L.; Gladwin, M. T.] Univ Pittsburgh, Pittsburgh, PA USA. [Girgis, R.] Johns Hopkins Univ, Baltimore, MD USA. [Morris, C. R.] Childrens Hosp, Oakland, CA 94609 USA. [Morris, C. R.] Res Ctr Oakland, Oakland, CA USA. [Berman-Rosenzweig, E.] Columbia Univ, New York, NY USA. [Badesch, D. B.] Univ Colorado, Ctr Hlth Sci, Aurora, CO USA. [Waclawiw, M. A.] NIH, Bethesda, MD 20892 USA. EM rmachado@medicine.bsd.uchicago.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 1 Z9 2 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2514 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001428 ER PT J AU Mahavadi, P Korfei, M Henneke, I Liebisch, G Gerd, S Gochuico, BR Markart, P Seeger, W Guenther, A Ruppert, C AF Mahavadi, P. Korfei, M. Henneke, I. Liebisch, G. Gerd, S. Gochuico, B. R. Markart, P. Seeger, W. Guenther, A. Ruppert, C. TI Role Of Alveolar Epithelial Stress In A Murine Model Of Hermansky-Pudlak Syndrome Associated Interstitial Pneumonia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Mahavadi, P.; Korfei, M.; Henneke, I.; Markart, P.; Seeger, W.; Guenther, A.; Ruppert, C.] UGLC, Giessen, Germany. [Liebisch, G.; Gerd, S.] Univ Regensburg, D-93053 Regensburg, Germany. [Gochuico, B. R.] Natl Inst Hlth, NHGRI, Bethesda, MD USA. EM Poornima.Mahavadi@innere.med.uni-giessen.de NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2445 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001359 ER PT J AU Martinez, MA Eberlein, M Kern, S Barb, J Munson, P Danner, RL Logun, C Shelhamer, JH AF Martinez, M. A. Eberlein, M. Kern, S. Barb, J. Munson, P. Danner, R. L. Logun, C. Shelhamer, J. H. TI MIcroRNA Expression During Differentiation Of Normal Human Bronchial Epithelial (NHBECs) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Martinez, M. A.; Eberlein, M.; Kern, S.; Danner, R. L.; Logun, C.; Shelhamer, J. H.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Barb, J.; Munson, P.] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2034 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001241 ER PT J AU Olivier, KN O'Connell, ML Holland, SM Knowles, MR AF Olivier, K. N. O'Connell, M. L. Holland, S. M. Knowles, M. R. TI Mucosal Defense Abnormalities In Idiopathic Bronchiectasis Associated With Nontuberculous Mycobacteria SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Olivier, K. N.] NIAID, Bethesda, MD 20892 USA. [O'Connell, M. L.; Holland, S. M.] NIH, Bethesda, MD 20892 USA. [Knowles, M. R.] Univ N Carolina, Chapel Hill, NC USA. EM olivierk@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2616 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001529 ER PT J AU Ortega, VE Hawkins, GA Montealegre, F Chardon, D Sadeghnejad, A Moore, WC Peters, SP Meyers, D Bleecker, ER AF Ortega, V. E. Hawkins, G. A. Montealegre, F. Chardon, D. Sadeghnejad, A. Moore, W. C. Peters, S. P. Meyers, D. Bleecker, E. R. CA S Severe Asthma Research Progr TI Rare beta 2 Adrenergic Receptor Gene Polymorphisms In Asthma Cases And Controls From Different Ethnic Groups SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Ortega, V. E.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Hawkins, G. A.; Sadeghnejad, A.; Moore, W. C.; Peters, S. P.; Meyers, D.; Bleecker, E. R.] Wake Forest Univ, Sch Med, Winston Salem, NC USA. [S Severe Asthma Research Progr] NHLBI, NIH, Bethesda, MD USA. EM vortega@wfubmc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1316 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000317 ER PT J AU Ortega, VE Hawkins, GA Sadeghnejad, A Moore, WC Meyers, D Bleecker, ER AF Ortega, V. E. Hawkins, G. A. Sadeghnejad, A. Moore, W. C. Meyers, D. Bleecker, E. R. TI Characterization Of Asthma Cases And Controls With Rare ADAM33 Gene Polymorphisms In A Multi-Ethnic Population SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Ortega, V. E.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Hawkins, G. A.] Wake Forest Univ, Sch Med, Winston Salem, NC USA. NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1315 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000316 ER PT J AU Prevots, D Gardner, A Knowles, MR Olivier, KN AF Prevots, D. Gardner, A. Knowles, M. R. Olivier, K. N. TI Environmental Risks For Nontuberculous Mycobacterial Lung Disease Among Persons With Cystic Fibrosis: A Multisite Nested Case-Control Study. SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Prevots, D.; Gardner, A.] NIH, Bethesda, MD 20892 USA. [Knowles, M. R.] Univ N Carolina, Chapel Hill, NC USA. [Olivier, K. N.] NIAID, Bethesda, MD 20892 USA. EM rprevots@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2604 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001517 ER PT J AU Ptaschinski, C Phipps, S Hansbro, N Rosenberg, HF Mattes, J Foster, PS AF Ptaschinski, C. Phipps, S. Hansbro, N. Rosenberg, H. F. Mattes, J. Foster, P. S. TI MicroRNAs Are Involved In The Regulation Of Inflammatory Responses Characteristic Of Severe Respiratory Virus Infection SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Ptaschinski, C.; Phipps, S.; Hansbro, N.; Mattes, J.; Foster, P. S.] Univ Newcastle, Newcastle, NSW 2300, Australia. [Rosenberg, H. F.] Natl Inst Hlth, Bethesda, MD USA. [Mattes, J.] John Hunter Childrens Hosp, Newcastle, NSW, Australia. [Foster, P. S.] Hunter Med Res Inst, Newcastle, NSW, Australia. EM Catherine.Ptaschinski@newcastle.edu.au NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2037 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001244 ER PT J AU Rosas, IO Yao, J Avila, NA Chow, CK Gahl, WA Gochuico, BR AF Rosas, I. O. Yao, J. Avila, N. A. Chow, C. K. Gahl, W. A. Gochuico, B. R. TI Quantification Of HRCT Scan Findings In Populations At Risk For Pulmonary Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Rosas, I. O.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yao, J.; Gahl, W. A.; Gochuico, B. R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Avila, N. A.; Chow, C. K.] NIH CC, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1115 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000116 ER PT J AU Teodorescu, M Busse, WW Everett, D Jarjour, NN AF Teodorescu, M. Busse, W. W. Everett, D. Jarjour, N. N. CA S Severe Asthma Res Program SARP I TI Obstructive Sleep Apnea (OSA) Symptoms In Patients With Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Teodorescu, M.; Jarjour, N. N.] Univ Wisconsin, Madison, WI 53706 USA. [Busse, W. W.] Univ Wisconsin Hosp, Madison, WI USA. [Everett, D.] Natl Jewish, Denver, CO USA. [S Severe Asthma Res Program SARP I] NHLBI, NIH, Bethesda, MD USA. EM mt3@medicine.wisc.edu NR 0 TC 1 Z9 1 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2551 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001464 ER PT J AU Van Hee, VC Szpiro, AA Adar, SD Barr, RG Roux, AVD Bluemke, DA Sheppard, L Gill, EA Bahrami, H Wassel, C Sale, MM Arnett, D Rotter, JI Rich, SS Kaufman, JD AF Van Hee, V. C. Szpiro, A. A. Adar, S. D. Barr, R. G. Roux, A. V. Diez Bluemke, D. A. Sheppard, L. Gill, E. A. Bahrami, H. Wassel, C. Sale, M. M. Arnett, D. Rotter, J. I. Rich, S. S. Kaufman, J. D. TI Interactions Between Candidate Cardiovascular Disease Genes, Traffic Proximity, And Left Ventricular Mass: The Multi-Ethnic Study Of Atherosclerosis (MESA) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Van Hee, V. C.; Szpiro, A. A.; Adar, S. D.; Sheppard, L.; Gill, E. A.; Rich, S. S.; Kaufman, J. D.] Univ Washington, Seattle, WA 98195 USA. [Barr, R. G.] Columbia Univ, New York, NY USA. [Roux, A. V. Diez] Univ Michigan, Ann Arbor, MI 48109 USA. [Bluemke, D. A.] NIH, Bethesda, MD 20892 USA. [Bahrami, H.] Johns Hopkins, Baltimore, MD USA. [Wassel, C.] Univ Calif San Diego, San Diego, CA 92103 USA. [Sale, M. M.; Rich, S. S.] Univ Virginia, Charlottesville, VA USA. [Arnett, D.] Univ Alabama Birmingham, Birmingham, AL USA. [Rotter, J. I.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RI Adar, Sara/L-2278-2016 OI Adar, Sara/0000-0001-8383-485X NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1714 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000714 ER PT J AU Wang, PM MartinIi, WJ AF Wang, P. M. Martin, W. J., II TI Pulmonary Lymphangiogenesis Quantified Following Bleomycin Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Wang, P. M.; Martin, W. J., II] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2776 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001689 ER PT J AU Whitehead, G Wilson, RH Nakano, H Burch, LH Cook, DN AF Whitehead, G. Wilson, R. H. Nakano, H. Burch, L. H. Cook, D. N. TI Induction And Suppression Of IL-17-dependent Airway Neutrophilia And Hyperresponsiveness SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Whitehead, G.] NIEHS, Res Triangle Pk, NC 27709 USA. [Wilson, R. H.; Nakano, H.; Burch, L. H.; Cook, D. N.] NIEHS, NIH, RTP, Res Triangle Pk, NC 27709 USA. EM whiteheadg@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2801 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001713 ER PT J AU Yang, IV Warg, LA Davidson, EJ Kelada, SNP Kubalanza, K Collins, FS Chesler, EJ Churchill, G Miller, D Aylor, D de Villena, F Schwartz, DA AF Yang, I. V. Warg, L. A. Davidson, E. J. Kelada, S. N. P. Kubalanza, K. Collins, F. S. Chesler, E. J. Churchill, G. Miller, D. Aylor, D. de Villena, F. Schwartz, D. A. TI INNATE IMMUNE GENE DISCOVERY USING MACROPHAGE RESPONSE TO PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPS) SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yang, I. V.; Warg, L. A.; Davidson, E. J.; Schwartz, D. A.] Natl Jewish Hlth, Denver, CO USA. [Kelada, S. N. P.; Kubalanza, K.; Collins, F. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chesler, E. J.] Oak Ridge Natl Lab, Oak Ridge, TN USA. [Churchill, G.] Jackson Lab, Bar Harbor, ME 04609 USA. [Miller, D.; Aylor, D.; de Villena, F.] Univ N Carolina, Chapel Hill, NC USA. EM yangi@njhealth.org NR 0 TC 0 Z9 1 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1273 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000274 ER PT J AU Yao, J Taveira-DaSilva, AM Colby, TV Moss, J AF Yao, J. Taveira-DaSilva, A. M. Colby, T. V. Moss, J. TI Computer-aided Grading Of Lymphangioleiomyomatosis And Pathological Examination Detect Lung Tissue Abnormalities In Areas Adjacent To Cysts That Correlate With Lung Function SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yao, J.; Taveira-DaSilva, A. M.; Moss, J.] NIH, Bethesda, MD 20892 USA. [Colby, T. V.] Mayo Clin Scottsdale, Scottsdale, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1262 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000263 ER PT J AU Yao, X Fredriksson, K Amar, M Remaley, AT Levine, SJ AF Yao, X. Fredriksson, K. Amar, M. Remaley, A. T. Levine, S. J. TI An Apolipoprotein E Mimetic Peptide Inhibits Airway Hyperreactivity In A House Dust Mite Model Of Allergic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yao, X.; Fredriksson, K.; Amar, M.; Remaley, A. T.; Levine, S. J.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A2836 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771001748 ER PT J AU Yu, M Levine, SJ AF Yu, M. Levine, S. J. TI Poly (I:C) Induces Soluble TNFR1 Shedding From Human Airway Epithelial Cells Via TLR3-TRIF-RIP1-dependent Signaling: Roles For Duox2-And Caspase-dependent Pathways SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Meeting Abstract C1 [Yu, M.; Levine, S. J.] NHLBI, NIH, Bethesda, MD 20892 USA. EM yum2@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PY 2010 VL 181 MA A1414 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA V29TP UT WOS:000208771000415 ER PT J AU Fayad, LM Salibi, N Wang, X Machado, AJ Jacobs, MA Bluemke, DA Barker, PB AF Fayad, Laura M. Salibi, Nouha Wang, Xin Machado, Antonio J. Jacobs, Michael A. Bluemke, David A. Barker, Peter B. TI Quantification of Muscle Choline Concentrations by Proton MR Spectroscopy at 3 T: Technical Feasibility SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE choline; MRI; neoplasm; proton MR spectroscopy; skeletal muscle ID MAGNETIC-RESONANCE SPECTROSCOPY; HUMAN SKELETAL-MUSCLE; HUMAN-BRAIN; RELAXATION-TIMES; NMR-SPECTROSCOPY; INTERNAL REFERENCE; INVIVO; TUMORS; CREATINE; SIGNALS AB OBJECTIVE. The quantification of choline in musculoskeletal tissues has several potential uses, including characterizing malignancy, but has not been previously achievable. We present a method of measuring the absolute concentration of choline by proton MR spectroscopy (MRS) in skeletal muscle at 3 T. MATERIALS AND METHODS. At 3 T, choline measurements were performed in phantoms and healthy volunteers using proton MRS (point-resolved spectroscopy sequence [PRESS]; TR/TE, 2,000/135). In vitro choline concentrations were measured in three phantom solutions (10, 5, 1.25 mmol). Choline T1 and T2 relaxation times were measured in the muscles of five healthy subjects. In vivo choline concentrations were measured using water as an internal reference and average T1 and T2 relaxation times in 20 muscle locations (quadriceps, hamstring, adductor) of seven healthy subjects (four men, three women). Descriptive statistics are reported. RESULTS. In vitro, the average measured choline concentrations of the 10-, 5-, and 1.25-mmol solutions were 9.91, 5.03, and 1.22 mmol, respectively. In vivo, the average T1 and T2 relaxation times of choline were 1,372 +/- 57 (SD) and 134 +/- 11 milliseconds, respectively. The average choline concentrations in the quadriceps and hamstring muscles were 10.0 +/- 0.4 (SD) and 8.0 +/- 2.9 mmol/kg. Interindividual variation existed in the choline concentrations (quadriceps range, 6.7-13 mmol/kg), but there was little variation by patient sex. CONCLUSION. In the musculoskeletal system, the measurement of choline concentration by proton MRS at 3 T is feasible using water as an internal reference. These data provide a quantitative basis for future investigations of metabolite concentrations in normal and diseased musculoskeletal tissues. C1 [Fayad, Laura M.; Wang, Xin; Machado, Antonio J.; Barker, Peter B.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Fayad, Laura M.] Johns Hopkins Med Inst, Dept Orthopaed Surg, Baltimore, MD 21287 USA. [Salibi, Nouha] Siemens Med Solut USA Inc, Res Collaborat, MR Spect, MR Div, Earth City, MO USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Dept Radiol, Div MR Res, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Fayad, LM (reprint author), Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St,MRI 143C, Baltimore, MD 21287 USA. EM lfayad1@jhmi.edu RI Jacobs, Michael/G-2901-2010; wang, xin/I-3395-2013; OI wang, xin/0000-0002-9519-8413; Bluemke, David/0000-0002-8323-8086 FU Society of Body CT; GE Healthcare Association of University Radiologists Radiology Research Academic Fellowship (GERRAF); National Institutes of Health [1R01CA100184, P50CA103175] FX L. M. Fayad received support from the Society of Body CT (2004 Young Investigator's Award); the 2007 William M. G. Gatewood, MD, Fellowship; and the 2008 GE Healthcare Association of University Radiologists Radiology Research Academic Fellowship (GERRAF). M. A. Jacobs received support from the National Institutes of Health (grants 1R01CA100184 and P50CA103175). N. Salibi is an employee of Siemens Medical Solutions USA, Inc. NR 35 TC 22 Z9 22 U1 0 U2 3 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 JAN PY 2010 VL 194 IS 1 BP W73 EP W79 DI 10.2214/AJR.09.3125 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 535SH UT WOS:000272990500054 PM 20028894 ER PT J AU Zhang, LZ Smyrk, TC Young, WF Stratakis, CA Carney, JA AF Zhang, Lizhi Smyrk, Thomas C. Young, William F., Jr. Stratakis, Constantine A. Carney, J. Aidan TI Gastric Stromal Tumors in Carney Triad Are Different Clinically, Pathologically, and Behaviorally From Sporadic Gastric Gastrointestinal Stromal Tumors: Findings in 104 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Carney triad; nonfamilial syndrome; gastric gastrointestinal stromal tumor; pulmonary chondroma; paraganglioma ID LYMPH-NODE METASTASIS; OF-THE-LITERATURE; TERM-FOLLOW-UP; PULMONARY CHONDROMA; GERMLINE MUTATION; C-KIT; EXTRAADRENAL PARAGANGLIOMA; INTERSTITIAL-CELLS; MUSCLE TUMORS; SMOOTH-MUSCLE AB Carney triad, as originally described in 1977, was the association of 3 tumors: gastric epithelioid leiomyosarcoma [later renamed gastrointestinal stromal tumor (GIST)], extra-adrenal paraganglioma, and pulmonary chondroma. The disorder affected mostly young women and was not familial. We studied the clinical and pathologic features of the gastric neoplasm in 104 patients with the syndrome. Most (88%) were young women (mean age, 22 y), and the usual presentation was gastric bleeding. The tumors, commonly antral-based (61%), were multifocal, and ranged from 0.2 to 18.0cm in dimension. Most (86%) featured round and polygonal (epithelioid) cells. Metastasis occurred in 49 patients (47%): to gastric lymph nodes (29%), liver (25%), and peritoneum (13%). Immunopositivity was detected in the tumors tested as follows: KIT, 100%; CD34, 75%; PKCO, 21%; PDGFRA, 90%; and smooth muscle actin, 6%. Fourteen patients (13%) died of metastatic GIST at a mean age of 45 years (range, 30 to 69 y). Estimated 10 and 40-year survivals were 100% and 73%, respectively. Median survival time was 26.5 years (range, 16 to 60y). There was no correlation between the National Institutes of Health tumor risk classification and the tumor behavior. Compared with sporadic gastric GISTs, the gastric stromal tumor in Carney triad showed distinctive features: female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior. Thus, the Carney triad gastric stromal turner is different clinically, pathologically, and behaviorally from sporadic gastric GIST. C1 [Zhang, Lizhi; Smyrk, Thomas C.; Carney, J. Aidan] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN 55905 USA. [Young, William F., Jr.] Mayo Clin, Div Endocrinol Diabet Metab & Nutr, Rochester, MN 55905 USA. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD USA. RP Carney, JA (reprint author), Mayo Clin, Dept Pathol & Lab Med, 200 1st St SW, Rochester, MN 55905 USA. EM carney.aidan@mayo.edu FU Intramural NIH HHS [ZIA HD008920-01] NR 80 TC 82 Z9 92 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JAN PY 2010 VL 34 IS 1 BP 53 EP 64 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA 540UZ UT WOS:000273366800007 PM 19935059 ER PT J AU Duffy, A Kummar, S AF Duffy, Austin Kummar, Shivaani TI Metastatic Pancreatic Adenocarcinoma: Current Standards, Future Directions SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Review DE pancreatic cancer; metastatic ID PHASE-III TRIAL; GROWTH-FACTOR RECEPTOR; GEMCITABINE PLUS CAPECITABINE; COOPERATIVE-ONCOLOGY-GROUP; 2ND-LINE CHEMOTHERAPY; CLINICAL BENEFIT; DOSE-RATE; CANCER; MULTICENTER; FLUOROURACIL AB Pancreatic cancer is the fourth most common cause of cancer death in the United States. In the landmark study in 1997, which established the central although modest role of gemcitabine in this disease, progress has been incremental. Significant developments have been an increased acceptance for combination chemotherapy in patients with good performance status in addition to an increased understanding of tumorigenesis. The parallel technologic and engineering developments that have occurred hold the promise of exploiting this understanding. This review attempts to summarize the standard therapeutic approach to metastatic pancreatic cancer and point to areas that hold promise for the future. C1 [Duffy, Austin; Kummar, Shivaani] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,10-13N240G, Bethesda, MD 20892 USA. EM kummars@exchange.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 56 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD JAN-FEB PY 2010 VL 17 IS 1 BP 79 EP 85 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 546XR UT WOS:000273849000014 PM 19636248 ER PT J AU Burbelo, PD Ching, KH Han, BL Bush, ER Reeves, WH Iadarola, MJ AF Burbelo, Peter D. Ching, Kathryn H. Han, Brian L. Bush, Emily R. Reeves, Westley H. Iadarola, Michael J. TI Extraordinary antigenicity of the human Ro52 autoantigen SO AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH LA English DT Article DE Autoantibody; autoantigen; Sjogren's Syndrome; Luciferase Immunoprecipitation Systems (LIPS); and Ro52 AB Autoantibody levels to the SSA complex, composed of Ro52 and Ro60 proteins, are commonly measured in the diagnoses of Sjogren's Syndrome (SjS), as well as other rheumatological diseases. One of these proteins, Ro52, is an interferon-inducible member of the tripartite motif family bearing a RING motif functioning as an E3 ligase that ubiquitinates interferon regulatory factor 8 and other proteins. Using Luciferase Immunoprecipitation Systems (LIPS) we explored the antigenicity of Ro52 in detail. Analysis of antibody responses against Ro52 and 20 other established antigens revealed that Ro52 had the highest antibody titers and most likely represents one of the most immunogenic human proteins. While the antibody titers in many of the SjS patients were significantly and substantially higher than the controls, all healthy individuals had anti-Ro52 autoantibodies. N- and C-terminal fragments of Ro52 showed immunoreactivity in these serum samples, but the sums of these antibody titers were significantly lower than the antibody titers directed against the full-length Ro52. Antibody profiling of controls and SjS patients with three different N-terminal fragments of Ro52 revealed that the coiled-coil region was the most useful diagnostic (66% sensitivity), followed by the B-box (31% sensitivity), and then the RING-finger (24% sensitivity). The C-terminal region of Ro52, containing the B30.2 domain, showed higher antibody titers in SjS patients compared to controls and this region was responsible for the high level of Ro52 immunoreactivity in healthy individuals. Analysis of immunoreactivity to TRIM5, a Ro52-related protein, and the B30.2 domain from BTN1 and pyrin, failed to show significant antibody titers with the control or SjS patient serum. These results highlight the unusually high level of Ro52 antigenicity and demonstrate that autoantibodies are directed at both linear and conformational epitopes spanning the entire molecule. C1 [Burbelo, Peter D.; Ching, Kathryn H.; Han, Brian L.; Bush, Emily R.; Iadarola, Michael J.] Natl Inst Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Reeves, Westley H.] Univ Florida, Div Rheumatol & Clin Immunol, Gainesville, FL USA. [Reeves, Westley H.] Univ Florida, Ctr Autoimmune Dis, Gainesville, FL USA. RP Burbelo, PD (reprint author), Bldg 49,Room 1C36,49 Convent Dr, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU Division of Intramural Research, National Institute of Dental and Craniofacial Research FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research. We also thank the SjS patients that participated in this study. NR 42 TC 14 Z9 15 U1 0 U2 0 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1943-8141 J9 AM J TRANSL RES JI Am. J. Transl. Res. PY 2010 VL 2 IS 2 BP 145 EP 155 PG 11 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA V28QA UT WOS:000208694100004 PM 20407604 ER PT J AU Erickson, HS Josephson, JW Vira, M Albert, PS Gillespie, JW Rodriguez-Canales, J Pinto, PA Chuaqui, RF Emmert-Buck, MR Coleman, JA AF Erickson, Heidi S. Josephson, John W. Vira, Manish Albert, Paul S. Gillespie, John W. Rodriguez-Canales, Jaime Pinto, Peter A. Chuaqui, Rodrigo F. Emmert-Buck, Michael R. Coleman, Jonathan A. TI Influence of hypoxia induced by minimally invasive prostatectomy on gene expression: implications for biomarker analysis SO AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH LA English DT Article DE Laparoscopic surgery; prostatectomy; warm ischemia; hypoxia; tissue microdissection; gene expression analysis AB Handling and processing of clinical specimens during and after surgical resection may significantly skew the molecular data obtained from analysis of those samples. Minimally invasive prostatectomy was used as a model to specifically study effects of surgical ischemia on gene expression in human clinical samples. Normal prostatic urethra cup biopsies were procured from 12 patients at three time points during laparoscopic radical prostatectomy. Homogeneous cells (stroma and epithelium) were microdissected. Transcript analysis of 3 oxygen-dependent, 3 oxygen-independent, and 3 control class genes was performed using quantitative RT-PCR. Data were analyzed by relative quantitation and two-sided t-test. Patient demographic and time covariates were fit by a linear mixed model. VEGF, an oxygen-dependent gene, showed significant expression alterations across three time points in epithelium (p=0.008), but not in stroma (p=0.66). Expression levels of VHL, STAT5B, and CYPA showed significant changes at the p<0.05 level in the stroma only. Effects of age, PSA, prostate size, Gleason score, surgery type, total surgery time, total ischemia time, and estimated blood loss on VEGF expression over time were not significant at the p<0.01 level. Therefore, surgical manipulation and tissue processing methods need to be taken into account when assessing prostatic biomarkers; however, resection does not dramatically alter mRNA profiles in prostate specimens. C1 [Erickson, Heidi S.; Chuaqui, Rodrigo F.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Erickson, Heidi S.; Josephson, John W.; Rodriguez-Canales, Jaime; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Vira, Manish; Pinto, Peter A.; Coleman, Jonathan A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Vira, Manish] North Shore Long Isl Jewish Hlth Syst, Smith Inst Urol, New Hyde Pk, NY 11040 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. [Gillespie, John W.] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Coleman, Jonathan A.] Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. RP Erickson, HS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd,Unit 432, Houston, TX 77030 USA. EM HSErickson@mdanderson.org OI Coleman, Jonathan/0000-0002-6428-7835 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; NIH; Pfizer Pharmaceuticals Group FX We thank Inger Rosner for assistance in compiling patient demographics data, Stephen Hewitt for reviewing the manuscript, and Gallya Gannot, Michael Tangrea, and Annely Richardson for discussions about this study. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was also made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and a grant to the Foundation for the NIH from Pfizer Pharmaceuticals Group. NR 28 TC 8 Z9 8 U1 0 U2 0 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1943-8141 J9 AM J TRANSL RES JI Am. J. Transl. Res. PY 2010 VL 2 IS 3 BP 210 EP 222 PG 13 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA V28QC UT WOS:000208694300001 PM 20589162 ER PT J AU Burbelo, PD Ching, KH Han, BL Klimavicz, CM Iadarola, MJ AF Burbelo, Peter D. Ching, Kathryn H. Han, Brian L. Klimavicz, Caitlin M. Iadarola, Michael J. TI Synthetic biology for translational research SO AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH LA English DT Review DE Artificial gene synthesis; synthetic biology; drug discovery; genetically-modified organisms; translational research; vaccines ID MERKEL CELL-CARCINOMA; BACTERIOLYTIC THERAPY; EXPERIMENTAL-TUMORS; CHEMICAL-SYNTHESIS; GENOME; BACTERIOPHAGE; POLYOMAVIRUS; INFECTION; VIRUS; GENE AB Synthetic biology involves the engineering of proteins, signaling pathways and even whole organisms using modular designs and formats. A major tool of synthetic biology is artificial gene synthesis, which provides a direct means from a conceptualized DNA sequence to the corresponding physical DNA for the construction of a variety of biological components. To date, synthetic biology has often been used to answer fundamental questions in basic research, but now is poised to greatly enhance translational research. In this review, we discuss several translational applications of synthetic biology including the construction of novel diagnostics and vaccines, development of new synthetic pathways for drug screening and biosynthesis, and the creation of engineered viruses and microbes to fight human disease. Together these and other novel translational applications of artificial gene synthesis and synthetic biology have the opportunity to make major advances for improving human health. C1 [Burbelo, Peter D.; Ching, Kathryn H.; Han, Brian L.; Klimavicz, Caitlin M.; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD 20892 USA. RP Burbelo, PD (reprint author), Bldg 49,Room 1C36,49 Convent Dr, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU NIDCR, NIH. FX This research was supported by the Intramural Research Program of the NIDCR, NIH. NR 30 TC 7 Z9 8 U1 3 U2 17 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1943-8141 J9 AM J TRANSL RES JI Am. J. Transl. Res. PY 2010 VL 2 IS 4 BP 381 EP 389 PG 9 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA V28QD UT WOS:000208694400004 PM 20733948 ER PT J AU Singh, AK Seavey, CN Horvath, KA Mohiuddin, MM AF Singh, Avneesh K. Seavey, Caleb N. Horvath, Keith A. Mohiuddin, Muhammad M. TI Ex-Vivo Expanded CD4+CD25+Treg Cells Suppress T and B Immune Response SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT American-Society-of-Transplantation Annual Scientific Exchange CY DEC 03-06, 2009 CL Orlando, FL SP Amer Soc Transplatat, ASE C1 [Singh, Avneesh K.; Seavey, Caleb N.; Horvath, Keith A.; Mohiuddin, Muhammad M.] NHLBI, NIH, Cardiothorac Surg Res Program, Bethesda, MD 20892 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2010 VL 10 SU 2 MA 87 BP 21 EP 21 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 544KD UT WOS:000273654600079 ER PT J AU Benfield, MR Bartosh, S Ikle, D Warshaw, B Bridges, N Morrison, Y Harmon, W AF Benfield, M. R. Bartosh, S. Ikle, D. Warshaw, B. Bridges, N. Morrison, Y. Harmon, W. TI A Randomized Double-Blind, Placebo Controlled Trial of Steroid Withdrawal after Pediatric Renal Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Growth after transplant; kidney transplantation; pediatric kidney transplant; steroid withdrawal ID MYCOPHENOLATE-MOFETIL; CALCINEURIN INHIBITOR; KIDNEY-TRANSPLANT; RECIPIENTS; CYCLOSPORINE; TACROLIMUS; THERAPY; IMMUNOSUPPRESSION; METAANALYSIS; CHILDREN AB In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti-CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n = 73) versus continued low-dose steroids (n = 59). This study was stopped prior to target enrollment because of the incidence of post-transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p = 0.033). There were no differences in acute rejection episodes between treatment groups. The 3-year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p = 0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients. C1 [Benfield, M. R.] Univ Alabama, Dept Pediat, Div Pediat Nephrol, Birmingham, AL USA. [Bartosh, S.] Univ Wisconsin, Dept Pediat, Div Pediat Nephrol, Madison, WI USA. [Ikle, D.] PPD, Wilmington, NC USA. [Warshaw, B.] Emory Univ, Dept Pediat, Div Pediat Nephrol, Atlanta, GA 30322 USA. [Bridges, N.; Morrison, Y.] NIH, Bethesda, MD 20892 USA. [Harmon, W.] Harvard Univ, Dept Pediat, Boston, MA 02115 USA. RP Benfield, MR (reprint author), Univ Alabama, Dept Pediat, Div Pediat Nephrol, Birmingham, AL USA. EM Benfield@uab.edu FU National Institute of Allergy and Infectious Diseases, NIH; NIH [U01-A1-46135]; Wyeth Pharmaceuticals, Inc FX Results of a study conducted by the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT) of the National Institute of Allergy and Infectious Diseases, NIH. Support provided by NIH U01-A1-46135 and Wyeth Pharmaceuticals, Inc. NR 18 TC 24 Z9 25 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2010 VL 10 IS 1 BP 81 EP 88 DI 10.1111/j.1600-6143.2009.02767.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 534FP UT WOS:000272882000014 PM 19663893 ER PT J AU Mills, LA Kagaayi, J Nakigozi, G Galiwango, RM Ouma, J Shott, JP Ssempijja, V Gray, RH Wawer, MJ Serwadda, D Quinn, TC Reynolds, SJ AF Mills, Lisa A. Kagaayi, Joseph Nakigozi, Gertrude Galiwango, Ronald M. Ouma, Joseph Shott, Joseph P. Ssempijja, Victor Gray, Ronald H. Wawer, Maria J. Serwadda, David Quinn, Thomas C. Reynolds, Steven J. TI Short Report: Utility of a Point-of-Care Malaria Rapid Diagnostic Test for Excluding Malaria as the Cause of Fever among HIV-Positive Adults in Rural Rakai, Uganda SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article AB We compared results of a malaria rapid diagnostic test (Binax Now (R) Malaria, Binax-M, Inverness Medical Innovations, Inc., Waltham, MA) performed at rural mobile clinics in Uganda by clinicians evaluating febrile adult HIV patients to thick smear evaluated at a central laboratory by trained microscopists. Two hundred forty-six samples were analyzed, including 14 (5.7%) which were thick-smear positive for falciparum malaria. Sensitivity of Binax-M compared with thick smear was 85.7% (95% CI: 57.2-98.2), specificity 97.8% (95% CI: 94.9-99.3), positive and negative predictive values were 70.6% (95% CI: 44.0-89.7) and 99.1% (95% CI: 96.8-99.9), respectively. The rapid diagnostic test accurately ruled malaria "in or out" at the point-of-care, facilitating appropriate clinical management and averting unnecessary antimalarial therapy. C1 [Mills, Lisa A.] Johns Hopkins Med Inst, Div Infect Dis, Baltimore, MD 21287 USA. Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD USA. [Kagaayi, Joseph; Nakigozi, Gertrude; Galiwango, Ronald M.; Ouma, Joseph; Ssempijja, Victor] Rakai Hlth Sci Program, Kalisizo, Rakai District, Uganda. NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Shott, Joseph P.] NIAID, SAIC Frederick Inc, DIR, NIH, Bethesda, MD 20892 USA. [Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. RP Mills, LA (reprint author), Johns Hopkins Med Inst, Div Infect Dis, 1830 E Monument St,Room 401, Baltimore, MD 21287 USA. EM LMills@ke.cdc.gov; JKagayi@rhsp.org; FTrudie@yahoo.com; RMGaliwango@rhsp.org; Oumaotobi@yahoo.com; ShottJ@mail.nih.gov; VSsempijja@gmail.com; RGray@jhsph.edu; MWawer@jhsph.edu; DSerwada@infocom.co.ug; TQuinn@jhmi.edu; SJR@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and the National Cancer Institute, National Institutes of Health, under Contract Number HHSN261200800001E. NR 11 TC 13 Z9 13 U1 2 U2 2 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 JAN PY 2010 VL 82 IS 1 BP 145 EP 147 DI 10.4269/ajtmh.2010.09-0408 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 540VF UT WOS:000273367400027 PM 20065011 ER PT J AU Khalsa, JH Elkashef, A AF Khalsa, Jag H. Elkashef, Ahmed TI Drug Interactions between Antiretroviral Medications and Medications Used in the Treatment of Drug Addiction: Research Needs SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID OPIOID-DEPENDENT PATIENTS; ZIDOVUDINE DISPOSITION; HEPATITIS-C; METHADONE; BUPRENORPHINE; VIRUS; HIV AB Today substance dependence is one of the major public health problems in the world with millions of people abusing legal and illegal drugs. In addition, almost one-third of the world's population suffers with one or more infections. Both drugs of abuse and infections are associated with serious medical and health consequences, some of which may be exacerbated by the occurrence of pharmacokinetic and/or pharmacodynamic interactions between medications used in the treatment of these conditions when they co-occur. This review briefly discusses issues surrounding clinical management related to drug interactions experienced by substance abusing patients. The emphasis of this paper is on the research needed to further study the extent, nature, and underlying molecular/genetic mechanism(s) of interactions between drugs of abuse, medications used in the treatment of drug addiction, and co-occurring infections. (Am J Addict 2009;19:96-100). C1 NIDA, Med Consequences Div Pharmacotherapies & Med Cons, Bethesda, MD 20892 USA. RP Khalsa, JH (reprint author), NIDA, Med Consequences Div Pharmacotherapies & Med Cons, 6001 Execut Blvd,Room 4137, Bethesda, MD 20892 USA. EM jk98p@nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 31 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JAN-FEB PY 2010 VL 19 IS 1 BP 96 EP 100 PG 5 WC Substance Abuse SC Substance Abuse GA 533ZE UT WOS:000272864300012 PM 20132126 ER EF