FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Taneja, GS Brenner, RA Klinger, R Trumble, AC Qian, C Klebanoff, M AF Taneja, Gitanjali S. Brenner, Ruth A. Klinger, Ron Trumble, Ann C. Qian, Cong Klebanoff, Mark TI Participation of next of kin in research following sudden, unexpected death of a child SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID SLEEP POSITION; PARENTS; POPULATION; RISK AB Objective: To assess parents' perceptions of their experience being interviewed after the sudden, unexpected death of their child. Design: Case-control study in which cases were victims of unintentional drowning. Setting: Households of recent drowning victims in 6 states in the United States. Participants: Caregivers (primarily parents) of 87 cases and 491 matched controls were interviewed via telephone about their child. Main Exposure: Recent death of a child by unintentional drowning. Main Outcome Measures: Degree of stress related to interview, perception of interview length, and participants' views about their willingness to participate in this type of interview again, given their experience with the current interview. Results: Although case participants were more likely than controls to perceive the interview as somewhat or very stressful (odds ratio, 3.64; 95% confidence interval, 1.67-7.96), most of the case participants (87.2%) and controls (96.1%) perceived the interview to be not at all or a little stressful. A greater percentage of controls (31.8%) found the interview to be too long, compared with case participants (20.9%). Among case participants, perceived stress during the interview and the perceived length of the interview were not associated with willingness to participate again. Both of these associations were significant (P<.001) for controls. Conclusions: Caregivers who chose to participate in the study generally rated their experiences as not very stressful. Most of the caregivers indicated that they would be willing to participate again in a similar study. C1 WESTAT Corp, Rockville, MD 20850 USA. Allied Technol Grp Inc, Rockville, MD USA. NICHHD, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Taneja, GS (reprint author), WESTAT Corp, 1450 Res Blvd,TC Bldg,Room 3036, Rockville, MD 20850 USA. FU Intramural NIH HHS NR 9 TC 7 Z9 7 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAY PY 2007 VL 161 IS 5 BP 453 EP 456 DI 10.1001/archpedi.161.5.453 PG 4 WC Pediatrics SC Pediatrics GA 164VP UT WOS:000246263200004 PM 17485620 ER PT J AU Wagner, AK McElligott, J Chan, L Wagner, EP Segal, NA Gerber, LH AF Wagner, Amy K. McElligott, Jacinta Chan, Leighton Wagner, Eugene P., II Segal, Neil A. Gerber, Lynn H. TI How gender impacts career development and leadership in rehabilitation medicine: A report from the AAPM&R Research Committee SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE academic medical centers; career mobility; gender; leadership; rehabilitation; research ID ACADEMIC MEDICINE; WOMEN; SURGERY; HEALTH; GAP AB Objective: To examine the role that gender plays in meeting the medical academic mission by assessing career development, leadership, and research productivity among rehabilitation researchers. Design: Prospective, cross-sectional cohort study. Setting: National survey. Participants: Three hundred sixty rehabilitation professionals linked to the American Academy of Physical Medicine and Rehabilitation, Association of Academic Physiatrists, and/or the American Congress of Rehabilitation Medicine. Intervention: Online or paper survey. Main Outcome Measures: Research skills, resources and productivity, salary, leadership, and academic advancement. Results: Results suggested that women rated themselves as being less skilled and having, fewer resources for research compared with their male counterparts. Additionally, significantly fewer women applied for grant funding and had a lower publication rate compared with men. A proportionally larger number of women remained at lower academic ranks than men, and fewer women achieved senior academic ranks or positions of leadership. Even after adjusting for potential confounding factors, female sex remained a significant variable associated with lower salaries and lower manuscript production. Unlike men, female respondents tended to believe that being a woman was a negative factor with respect to academic advancement, leadership opportunities, salary, and resources. Conclusions: Female rehabilitation researchers were less developed professionally than their male counterparts and saw themselves as disadvantaged. These findings have potential implications for attracting women into rehabilitation research and the rehabilitation research community's efforts to sustain its academic mission, to improve research capacity, and to meet the needs of the 52 million people in the United States with disabilities. C1 Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15213 USA. Natl Rehabil Hosp, Dublin, Ireland. NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. Univ Iowa, Dept Orthoped, Iowa City, IA USA. George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. RP Wagner, AK (reprint author), Univ Pittsburgh, Dept Phys Med & Rehabil, 3471 5th Ave,Ste 202, Pittsburgh, PA 15213 USA. EM wagnerak@upmc.edu OI Segal, Neil/0000-0002-8294-080X NR 26 TC 8 Z9 8 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAY PY 2007 VL 88 IS 5 BP 560 EP 568 DI 10.1016/j.apmr.2007.01.014 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 164MN UT WOS:000246238200004 PM 17466723 ER PT J AU Hoffman, JM Shumway-Cook, A Yorkston, KM Ciol, MA Dudgeon, BJ Chan, L AF Hoffman, Jeanne M. Shumway-Cook, Anne Yorkston, Kathryn M. Ciol, Marcia A. Dudgeon, Brian J. Chan, Leighton TI Association of mobility limitations with health care satisfaction and use of preventive care: A survey of Medicare beneficiaries SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE disabled persons; Medicare; patient satisfaction; rehabilitation ID DISABILITY; SERVICES; POPULATION; PEOPLE; DIMENSIONS; QUALITY; WOMEN AB Objective: To examine the association between satisfaction with health care, the use of preventive health care, and mobility limitation. Design: Cross-sectional analysis of survey data. Setting: Community. Participants: A total of 12,769 people, age greater than 65, who participated in the 2001 Medicare Current Beneficiary Survey. Interventions: Not applicable. Main Outcome Measures: Self-report of mobility limitation, satisfaction, and use of preventive health care (immunizations, cancer screening). Sampling weights were used in all analyses, including logistic regression for survey data, to calculate estimates for a Medicare population of 31 million. Results: After controlling for sociodemographic characteristics, Medicare beneficiaries with mobility limitations were significantly more dissatisfied with their health care compared with beneficiaries without mobility limitations. Receipt of preventive care did not differ for those with and without mobility limitation on some preventive services. Conclusions: Mobility limitation is highly associated with dissatisfaction with health care among older adult beneficiaries. Although Medicare beneficiaries may receive similar rates of preventive care, those with mobility limitation may have more difficulty accessing services and be more dissatisfied with their health care in general. C1 Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. Natl Inst Med, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. RP Hoffman, JM (reprint author), Univ Washington, Dept Rehabil Med, Box 356490, Seattle, WA 98195 USA. EM jeanneh@u.washington.edu FU PHS HHS [MM-0625-04/04] NR 26 TC 11 Z9 11 U1 2 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAY PY 2007 VL 88 IS 5 BP 583 EP 588 DI 10.1016/j.apmr.2007.02.005 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 164MN UT WOS:000246238200007 PM 17466726 ER PT J AU Stoll, P Bassler, N Hagemeyer, CE Eisenhardt, SU Chen, YC Schmidt, R Schwarz, M Ahrens, I Katagiri, Y Pannen, B Bode, C Peter, K AF Stoll, Patrick Bassler, Nicole Hagemeyer, Christoph E. Eisenhardt, Steffen U. Chen, Yung Chih Schmidt, Rene Schwarz, Meike Ahrens, Ingo Katagiri, Yasuhiro Pannen, Benedikt Bode, Christoph Peter, Karlheinz TI Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE GPIIb/IIIa; anticoagulation; single-chain; fXa; thrombosis ID COAGULATION FACTOR-XA; PLASMINOGEN-ACTIVATOR; FUSION PROTEIN; UROKINASE-TYPE; ANTITHROMBOTIC POTENCY; PROCOAGULANT ACTIVITY; ARTERIAL THROMBOSIS; FIBRIN; INHIBITOR; CONSTRUCTION AB Objective - Therapeutic anticoagulation is widely used, but limitations in efficacy and bleeding complications cause an ongoing search for new agents. However, with new agents developed it seems to be an inherent problem that increased efficiency is accompanied by an increase in bleeding complications. We investigate whether targeting of anticoagulants to activated platelets provides a means to overcome this association of potency and bleeding. Methods and Results - Ligand-induced binding sites (LIBS) on fibrinogen/fibrin-binding GPIIb/IIIa represent an abundant clot-specific target. We cloned an anti-LIBS single-chain antibody (scFv(anti-LIBS)) and genetically fused it with a potent, direct factor Xa (fXa) inhibitor, tick anticoagulant peptide ( TAP). Specific antibody binding of fusion molecule scFv(anti-LIBS)-TAP was proven in flow cytometry; anti-fXa activity was demonstrated in chromogenic assays. In vivo anticoagulative efficiency was determined by Doppler-flow in a ferric chloride - induced carotid artery thrombosis model in mice. ScFv(anti-LIBS)-TAP prolonged occlusion time comparable to enoxaparine, recombinant TAP, and nontargeted mutant-scFv-TAP. ScFv(anti-LIBS)-TAP revealed antithrombotic effects at low doses at which the nontargeted mutant-scFv-TAP failed. In contrast to the other anticoagulants tested, bleeding times were not prolonged by scFv(anti-LIBS)-TAP. Conclusions - The novel clot-targeting approach of anticoagulants via single-chain antibody directed against a LIBS-epitope on GPIIb/IIIa promises effective anticoagulation with reduced bleeding risk. C1 Ctr Thrombosis & Myocardial Infarct, Baker Heart Res Inst, Melbourne, Vic 8008, Australia. Univ Freiburg, Dept Cardiol, Freiburg, Germany. Univ Freiburg, Dept Anaesthesiol, Freiburg, Germany. NIH, Bethesda, MD 20892 USA. Univ Hosp Dusseldorf, Dept Anaesthesia, Dusseldorf, Germany. RP Peter, K (reprint author), Ctr Thrombosis & Myocardial Infarct, Baker Heart Res Inst, POB 6492,St Kilda Rd Cent, Melbourne, Vic 8008, Australia. EM christoph.hagemeyer@baker.edu.au RI Peter, Karlheinz/E-8772-2010; Hagemeyer, Christoph/E-8958-2011 OI Peter, Karlheinz/0000-0002-8040-2258; Hagemeyer, Christoph/0000-0002-7114-4023 NR 42 TC 47 Z9 50 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAY PY 2007 VL 27 IS 5 BP 1206 EP 1212 DI 10.1161/ATVBAHA.106.138875 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 158RE UT WOS:000245810400035 PM 17322097 ER PT J AU Nevitt, MC Peterfy, C Guermazi, A Felson, DT Duryea, J Woodworth, T Chen, HP Kwoh, K Harris, TB AF Nevitt, Michael C. Peterfy, Charles Guermazi, Ali Felson, David T. Duryea, Jeff Woodworth, Thasia Chen, Hepei Kwoh, Kent Harris, Tamara B. TI Longitudinal performance evaluation and validation of fixed-flexion radiography of the knee for detection of joint space loss SO ARTHRITIS AND RHEUMATISM LA English DT Article ID AUTOMATED MEASUREMENTS; CLINICAL-TRIAL; OSTEOARTHRITIC KNEE; WIDTH MEASUREMENTS; SEMIFLEXED MTP; TIBIAL PLATEAU; CARTILAGE LOSS; SCHUSS VIEWS; FIELD-TEST; X-RAY AB Objective. The ability of nonfluoroscopically guided radiography of the knee to assess joint space loss is an important issue in studies of progression and treatment of knee osteoarthritis (OA), given the practical limitations of protocols involving fluoroscopically guided radiography of the knee. We evaluated the ability of the nonfluoroscopically guided fixed-flexion radiography protocol to detect knee joint space loss over 3 years. Methods. We assessed the same-day test-retest precision for measuring minimum joint space width (JSW), the sensitivity for detection of joint space loss using serial films obtained a median of 37 months (range 23-47 months) apart, and the relationship of joint space loss to radiographic and magnetic resonance imaging (MRI) measures of knee OA. Participants were men and women (ages 70-79 years) with knee pain who were participating in the Health, Aging, and Body Composition Study. We assessed baseline radiographic OA and measured JSW using a computerized algorithm. Serial knee MRIs obtained over the same interval were evaluated for cartilage lesions. Results. A total of 153 knees were studied, 35% of which had radiographic OA at baseline. The mean +/- SD joint space loss for all knees over 3 years was 0.24 +/- 0.59 mm (P < 0.001 for change). In knees with OA at baseline, the mean +/- SD joint space loss over 3 years was 0.43 +/- 0.66 nun (P < 0.001), and in knees with joint space narrowing at baseline, joint space loss was 0.50 +/- 0.67 mm (P < 0.001). Joint space loss and its standardized response mean increased with the severity of baseline joint space narrowing and with the presence of cartilage lesions at baseline and worsening during followup. Conclusion. Radiography of the knee in the fixed-flexion view provides a sensitive and valid measure of joint space loss in multiyear longitudinal studies of knee OA, without the use of fluoroscopy to aid knee positioning. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94102 USA. Synarc, San Francisco, CA USA. Boston Univ, Med Ctr, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Roche, Rheinfelden, Switzerland. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Pittsburgh Dept Vet Affairs Hlth Care Syst, Pittsburgh, PA USA. RP Nevitt, MC (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Lobby 4,Suite 5700, San Francisco, CA 94102 USA. EM mnevitt@psg.ucsf.edu FU Intramural NIH HHS NR 37 TC 69 Z9 69 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2007 VL 56 IS 5 BP 1512 EP 1520 DI 10.1002/art.22537 PG 9 WC Rheumatology SC Rheumatology GA 165SC UT WOS:000246324800018 PM 17469126 ER PT J AU Touitou, I Sarkisian, T Medlej-Hashim, M Tunca, M Livneh, A Cattan, D Yalcinkaya, F Ozen, S Majeed, H Ozdogan, H Kastner, D Booth, D Ben-Chetrit, E Pugnere, D Michelon, C Seguret, F Gershoni-Baruch, R AF Touitou, Isabelle Sarkisian, Tamara Medlej-Hashim, Myrna Tunca, Mehmet Livneh, Avi Cattan, Daniel Yalcinkaya, Fatos Ozen, Seza Majeed, Hassan Ozdogan, Huri Kastner, Daniel Booth, David Ben-Chetrit, Eldad Pugnere, Denis Michelon, Cecile Seguret, Fabienne Gershoni-Baruch, Ruth CA Internatl Study Grp Phenotype-Geno TI Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever SO ARTHRITIS AND RHEUMATISM LA English DT Article ID MEFV; MUTATIONS; GENE; FMF; SPECTRUM; CRITERIA; HEALTH AB Objective. Familial Mediterranean fever (FMF), the prototype of autoinflammatory disorders, is caused by recessive mutations in the MEFV gene. Some FMF patients develop renal amyloidosis, a potentially fatal condition. This complication has mainly been associated with the M694V mutation, although the different study designs, small numbers of patients, and/or evaluation of few or no covariables calls this association into question. The aim of this study was to examine the controversial issue of amyloidosis susceptibility in FMF by determining the relative contributions of MEFV and numerous epidemiologic factors to the risk of renal amyloidosis. Methods. Online questionnaires were completed at the MetaFMF database by patients at 35 centers in 14 countries. Using a standardized mode of data collection, we retrieved crude initial data from over half of the genetically confirmed FMF patients referred worldwide until May 2003 (2,482 cases, including 260 patients who developed renal amyloidosis). Results. Amyloid nephropathy was present in 11.4% of the cases. In the total study population, country of recruitment was the leading risk factor for this manifestation (odds ratio 3.2 [95% confidence interval 1.8-5.9]), followed by M694V homozygosity, proband status, and disease duration. Differing results were found when countries were stratified. Conclusion. Country of recruitment, rather than MEFV genotype, is the key risk factor for renal amyloidosis in FMF. This risk, which parallels infant mortality rates, indicates a possible environmental origin of amyloidosis susceptibility. The patient's country should be considered in addition to MEFV genotype as an indication for prophylactic colchicine, a treatment suggested for asymptomatic individuals who are incidentally discovered to be M694V homozygous. C1 CHU Montpellier, Hop Arnaud Villeneuve, Unite Med Malad Autoinflammatoires, Genet Lab, F-34295 Montpellier, France. Natl Acad Sci, Ctr Med Genet, Yerevan, Armenia. St Joseph Univ, Beirut, Lebanon. Dokuz Eylul Univ, Izmir, Turkey. Chaim Sheba Med Ctr, Ramat Gan, Israel. Ctr Hosp Villeneuve St Georges, Villeneuve St Georges, France. Ankara Univ, Sch Med, TR-06100 Ankara, Turkey. Univ Hacettepe, TR-06100 Ankara, Turkey. Jordan Univ Sci & Technol, Amman, Jordan. Istanbul Univ, Cerrahpasa Med Fac, Istanbul, Turkey. NIAMSD, NIH, Bethesda, MD 20892 USA. Westmead Millenium Inst, Sydney, NSW, Australia. Hadassah Hebrew Univ Hosp, Jerusalem, Israel. Rambam Med Ctr, Haifa, Israel. RP Touitou, I (reprint author), CHU Montpellier, Hop Arnaud Villeneuve, Unite Med Malad Autoinflammatoires, Genet Lab, 371 Ave Doyen Gaton Giraud, F-34295 Montpellier, France. EM isabelle.touitou@igh.cnrs.fr RI YILMAZ, ENGIN/I-8278-2013; Casademont, Jordi/A-6828-2010; OI Casademont, Jordi/0000-0002-8100-1827; Medlej-Hashim, Myrna/0000-0002-0295-345X FU Intramural NIH HHS NR 24 TC 134 Z9 137 U1 2 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2007 VL 56 IS 5 BP 1706 EP 1712 DI 10.1002/art.22507 PG 7 WC Rheumatology SC Rheumatology GA 165SC UT WOS:000246324800040 PM 17469185 ER PT J AU Finckh, A Cooper, GS Costenbader, KH Karlson, EW AF Finckh, Axel Cooper, Glinda S. Costenbader, Karen H. Karlson, Elizabeth W. TI Skin-lightening creams are a possible exposure risk for systemic lupus erythematosus: comment on the article by Finckh et al - Reply SO ARTHRITIS AND RHEUMATISM LA English DT Letter ID SENEGAL C1 Univ Hosp Geneva, Geneva, Switzerland. NIEHS, Durham, NC USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Finckh, A (reprint author), Univ Hosp Geneva, Geneva, Switzerland. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2007 VL 56 IS 5 BP 1721 EP 1722 DI 10.1002/art.22562 PG 2 WC Rheumatology SC Rheumatology GA 165SC UT WOS:000246324800045 ER PT J AU Hammonds, MD Shim, SS Feng, PF Calabrese, JR AF Hammonds, Michael D. Shim, Seong S. Feng, Pingfu Calabrese, Joseph R. TI Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus SO BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY LA English DT Article ID BIPOLAR DISORDER; DENTATE GYRUS; SYNAPTIC PLASTICITY; NEUROTROPHIC FACTOR; NEUROGENESIS; SCHIZOPHRENIA; DEPRESSION; PROTEIN; BRAIN; EXPRESSION AB Although it has been proposed that exposure to lithium up-regulates brain-derived neurotrophic factor (BDNF), B-cell leukaemia/lymphoma 2 protein (Bcl-2) and cyclic AMP-response element-binding protein (CREB), and these molecules are involved in the neuroplastic actions and clinical efficacy of the drug, the several lines of evidence suggest that the lithium-induced up-regulation of these molecules has not been consistently confirmed. Few studies have examined the effects of lithium exposure on the regulation of these molecules in the dentate gyrus (DG) and area CAI in the hippocampus. We examined the effects of subchronic lithium treatment on the levels of BDNF, Bcl-2 and phosphorylated CREB in the DG and area CAI. We administered LiCl intraperitoneally (1 mEq/kg per day) to adult rats for 14 days, killed animals in 24 hr after the last administration of the drug, and determined the tissue levels of BDNF, Bcl-2 and pCREB in the DG and area CAI. Subchronic lithium treatment for 14 days did not significantly alter the levels of BDNF, Bcl-2 or phosphorylated CREB in the DG and area CAI in the hippocampus. This study indicates that the lithium-induced up-regulation of these molecules may be various depending on the duration of lithium exposure and particular brain regions exposed to the drug. C1 Cleveland Dept Vet Affairs Med Ctr, Psychiat Serv 116 W A, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Ctr Biopolar Disorder, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. RP Shim, SS (reprint author), Cleveland Dept Vet Affairs Med Ctr, Psychiat Serv 116 W A, 10701 East Blvd, Cleveland, OH 44106 USA. EM seong.shim@med.va.gov NR 19 TC 11 Z9 13 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-7835 J9 BASIC CLIN PHARMACOL JI Basic Clin. Pharmacol. Toxicol. PD MAY PY 2007 VL 100 IS 5 BP 356 EP 359 DI 10.1111/j.1742-7843.2007.0058.x PG 4 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 167JZ UT WOS:000246449300012 PM 17448124 ER PT J AU Mori, T Ito, S Kita, T Narita, M Suzuki, T Matsubayashi, K Sawaguchi, T AF Mori, Tomohisa Ito, Shinobu Kita, Taizo Narita, Minoru Suzuki, Tsutomu Matsubayashi, Kenji Sawaguchi, Toshiko TI Oxidative stress in methamphetamine-induced self-injurious behavior in mice SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE apoptosis; free radial; mouse; methamphetamine; nitric oxide synthase; self-injurious behavior ID NITRIC-OXIDE SYNTHASE; STRIATAL DOPAMINE RELEASE; LESCH-NYHAN DISEASE; INDUCED NEUROTOXICITY; POLY(ADP-RIBOSE) POLYMERASE; IN-VIVO; NUCLEUS-ACCUMBENS; TOURETTE SYNDROME; FREE-RADICALS; C57BL/6 MICE AB Previous studies have shown that N-methyl-D-aspartate, the formation of free radicals and poly(ADP-ribose) polymerase are related to methamphetamine-induced neurotoxicity. This study was designed to investigate involvement of oxidative stress in methamphetamine-induced self-injurious behavior in mice. In this study, methamphetamine (20 mg/kg) induced continuous self-injurious behavior in six of seven mice. N-methyl-D-aspartate-receptor antagonists (MK801 and 3((R)-2carboxypiperazin-4-yl) propyl-1-phosphonic acid) significantly attenuated this methamphetamine-induced self-injurious behavior. These results suggest that the activation of N-methyl-D-aspartate receptors is involved in methamphetamine-induced self-injurious behavior. Furthermore, we found that the nonselective nitric oxide synthase inhibitor I-N-omega-nitro-L-arginine methyl ester hydrochloride and the neuronal nitric oxide synthase inhibitor 7-nitroindazole, but not the inducible nitric oxide synthase inhibitor aminoguanidine, the free-radical inhibitors fullerene and 3-methyl-1 -phenyl-2-pyrazolin-5one-186, or the poly(ADP-ribose) polymerase inhibitor benzamide, significantly attenuated methamphetamineinduced self-injurious behavior. The present results show that oxidative stress, which is mediated by the activation of neuronal nitric oxide synthase, is associated with methamphetamine-induced self-injurious behavior. These findings may help us to better understand the clinical phenomenon of self-injurious behavior. C1 Tokyo Womens Med Univ, Dept Legal Med, Shinjuku Ku, Tokyo, Japan. Mitsubishi Corp, Technol & Business Dev Dept, Tokyo, Japan. NIDA, DHHS, Cellular Pathobiol Unit, Dev & Plastic Sect,NIH,IRP, Baltimore, MD USA. RP Sawaguchi, T (reprint author), Tokyo Womens Med Univ, Dept Legal Med, Shinjuku Ku, 8-1 Kawada Cho, Tokyo, Japan. EM tsawagu@research.twmu.ac.jp NR 57 TC 12 Z9 14 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD MAY PY 2007 VL 18 IS 3 BP 239 EP 249 DI 10.1097/FBP.0b013e328153dae1 PG 11 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 165FA UT WOS:000246288200008 PM 17426488 ER PT J AU Sainz, E Cavenagh, MM Gutierrez, J Battey, JF Northup, JK Sullivan, SL AF Sainz, Eduardo Cavenagh, Margaret M. Gutierrez, Joanne Battey, James F. Northup, John K. Sullivan, Susan L. TI Functional characterization of human bitter taste receptors SO BIOCHEMICAL JOURNAL LA English DT Article DE bitter taste; G-protein-coupled receptor; in situ reconstitution G(alpha i) subunit; signal transduction; taste receptor cell ID G-PROTEIN; ALPHA-GUSTDUCIN; SIGNALING PATHWAYS; CELLS; IDENTIFICATION; TRANSDUCTION; EXPRESSION; RESPONSES; SWEET; RECONSTITUTION AB The T2Rs belong to a multi-gene family of G-protein-coupled receptors responsible for the detection of ingested bitter-tasting compounds. The T2Rs are conserved among mammals with the human and mouse gene families consisting of about 25 members. In the present study we address the signalling properties of human and mouse T2Rs using an in vitro reconstitution system in which both the ligands and G-proteins being assayed can be manipulated independently and quantitatively assessed. We confirm that the mT2R5, hT2R43 and hT2R47 receptors respond selectively to micromolar concentrations of cycloheximide, aristolochic acid and denatonium respectively. We also demonstrate that hT2R 14 is a receptor for aristolochic acid and report the first characterization of the ligand specificities of hT2R7, which is a broadly tuned receptor responding to strychnine, quinacrine, chloroquine and papaverine. Using these defined ligand-receptor interactions, we assayed the ability of the ligand-activated T2Rs to catalyse GTP binding on divergent members of the G(alpha) family including three members of the G(alpha i) subfamily (transducin, G(alpha i1) and G(alpha o))as well as G(alpha s) and G(alpha q). The T2Rs coupled with each of the three G(alpha i) members tested. However, none of the T2Rs coupled to either G(alpha s) or G(alpha q) suggesting the T2Rs signal primarily through G(alpha i) mediated signal transduction pathways. Furthermore, we observed different G-protein selectivities among the T2Rs with respect to both G(alpha i) subunits and G(beta y) dimers, suggesting that bitter taste is transduced by multiple G-proteins that may differ among the T2Rs. C1 Natl Inst Deafness & Other Commun Disorders, Mol Neurosci Sect, NIH, Rockville, MD 20850 USA. Natl Inst Neurol Disorders & Stroke, Sect G Prot Coupled Receptors, NIH, Rockville, MD 20850 USA. Natl Inst Deafness & Other Commun Disorders, Sect Signal Transduct, NIH, Rockville, MD 20850 USA. RP Sullivan, SL (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Neurosci Sect, NIH, 5 Res Court, Rockville, MD 20850 USA. EM sullivas@nidcd.nih.gov FU Intramural NIH HHS; NIDCD NIH HHS [Z01 DC000034-08, Z01 DC000034, Z01 DC000047, Z01 DC000047-08]; NINDS NIH HHS [Z01 NS003004, Z01 NS003004-02] NR 37 TC 68 Z9 69 U1 0 U2 9 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAY 1 PY 2007 VL 403 BP 537 EP 543 DI 10.1042/BJ20061744 PN 3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162ZF UT WOS:000246127300018 PM 17253962 ER PT J AU Filpula, D Yang, K Basu, A Hassan, R Xiang, LM Zhang, ZF Wang, ML Wang, QC Ho, M Beers, R Zhao, H Peng, P Zhou, J Li, XG Petti, G Janjua, A Liu, J Wu, DC Yu, DS Zhang, ZH Longley, C FitzGerald, D Kreitman, RJ Pastano, I AF Filpula, David Yang, Karen Basu, Amartya Hassan, Raffit Xiang, Laiman Zhang, Zhenfan Wang, Maoliang Wang, Qing-cheng Ho, Mitchell Beers, Richard Zhao, Hong Peng, Ping Zhou, John Li, Xiguang Petti, Gerald Janjua, Ahsen Liu, Jun Wu, Dechun Yu, Deshan Zhang, Zhihua Longley, Clifford FitzGerald, David Kreitman, Robert J. Pastano, Ira TI Releasable PEGylation of mesothelin targeted immunotoxin SS1P achieves single dosage complete regression of a human carcinoma in mice SO BIOCONJUGATE CHEMISTRY LA English DT Article ID MONOCLONAL-ANTIBODY K1; HAIRY-CELL LEUKEMIA; RECOMBINANT IMMUNOTOXIN; ANTITUMOR-ACTIVITY; POLYETHYLENE-GLYCOL; OVARIAN-CANCER; POLY(ETHYLENE GLYCOL); IN-VITRO; PSEUDOMONAS EXOTOXIN; PROTEIN PEGYLATION AB Recombinant immunotoxins exhibit targeting and cytotoxic functions needed for cell-specific destruction. However, antitumor efficacy, safety, and pharmacokinetics of these therapeutics might be improved by further macromolecular engineering. SS1P is a recombinant anti-mesothelin immunotoxin in clinical trials in patients with mesothelin-expressing tumors. We have modified this immunotoxin using several PEGylation strategies employing releasable linkages between the protein and the PEG polymers, and observed superior performance of these bioconjugates when compared to similar PEG derivatives bearing permanent linkages to the polymers. PEGylated derivatives displayed markedly diminished cytotoxicity on cultured mesothelin-overexpressing A431-K5 cells; however, the releasable PEGylated immunotoxins exhibited increased antitumor activity in A431-K5 xenografts in mice, with a diminished animal toxicity. Most significantly, complete tumor regressions were achievable with single dose administration of the bioconjugates but not the native immunotoxin. Pharmacokinetic analysis of the releasable PEGylated derivatives in mice demonstrated an over 80-fold expansion of the area under the curve exposure of bioactive protein when compared to native immunotoxin. A correlation in degree of derivatization, release kinetics, and polymer size with potency was observed in vivo, whereas in vitro cytotoxicity was not predictive of efficacy in animal models. The potent antitumor efficacy of the releasable PEGylated mesothelin-targeted immunotoxins was not exhibited by similar untargeted PEG immunotoxins in this model. Since the bioconjugates can also exhibit the attributes of passive targeting via enhanced permeability and retention, this is the first demonstration of a pivotal role of active targeting for immunotoxin bioconjugate efficacy. C1 Enzon Pharmaceut Incorp, Piscataway, NJ 08854 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Filpula, D (reprint author), Enzon Pharmaceut Incorp, 20 Kingsbridge Rd, Piscataway, NJ 08854 USA. EM david.filpula@enzon.com RI Ho, Mitchell/F-5059-2015 FU Intramural NIH HHS NR 51 TC 27 Z9 29 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY-JUN PY 2007 VL 18 IS 3 BP 773 EP 784 DI 10.1021/bc060314x PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 167XJ UT WOS:000246485500022 PM 17346030 ER PT J AU Boeggeman, E Ramakrishnan, B Kilgore, C Khidekel, N Hsieh-Wilson, LC Simpson, JT Qasba, PK AF Boeggeman, Elizabeth Ramakrishnan, Boopathy Kilgore, Charlton Khidekel, Nelly Hsieh-Wilson, Linda C. Simpson, John T. Qasba, Pradman K. TI Direct identification of nonreducing GlcNAc residues on N-glycans of glycoproteins using a novel chemoenzymatic method SO BIOCONJUGATE CHEMISTRY LA English DT Article ID HUMAN BETA-1,4-GALACTOSYLTRANSFERASE-I; CARBOHYDRATE INTERACTION; DONOR SPECIFICITY; ALPHA-LACTALBUMIN; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; CELL RECOGNITION; GALACTOSYLTRANSFERASE; GLYCOSYLTRANSFERASES; MUTATION AB The mutant beta 1,4-galactosyltransferase (beta 4Gal-T1), beta 4Gal-T1-Y289L, in contrast to wild-type beta 4Gal-T1, can transfer GalNAc from the sugar donor UDP-GalNAc to the acceptor, GlcNAc, with efficiency as good as that of galactose from UDP-Gal. Furthermore, the mutant can also transfer a modified sugar, C2 keto galactose, from its UDP derivative to O-GlcNAc modification on proteins that provided a functional handle for developing a highly sensitive chemoenzymatic method for detecting O-GlcNAc post-translational modification on proteins. We report herein that the modified sugar, C2 keto galactose, can be transferred to free GlcNAc residues on N-linked glycoproteins, such as ovalbumin or asialo-agalacto IgG1. The transfer is strictly dependent on the presence of both the mutant enzyme and the ketone derivative of the galactose. Moreover, the PNGase F treatment of the glycoproteins, which cleaves the N-linked oligosaccharide chain, shows that the modified sugar has been transferred to the N-glycan chains of the glycoproteins and not to the protein portion. The application of the mutant galactosyltransferase, beta 4Gal-T1-Y289L, to produce glycoconjugates carrying sugar moieties with reactive groups, is demonstrated. We envision a broad potential for this technology such as the possibilities to link cargo molecules to glycoproteins, such as monoclonal antibodies, via glycan chains, thereby assisting in the glycotargeting of drugs to the site of action or used as biological probes. C1 NCI, Struct Glycobiol Sect, CCR, Nanobiol Program,Ctr Canc Res, Frederick, MD 21702 USA. NCI, Prot Chem Lab, SAIC Inc, Frederick, MD 21702 USA. CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA. CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, CCR, Nanobiol Program,Ctr Canc Res, Bldg 469,Room 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIGMS NIH HHS [R01 GM084724] NR 36 TC 37 Z9 38 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY-JUN PY 2007 VL 18 IS 3 BP 806 EP 814 DI 10.1021/bc060341n PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 167XJ UT WOS:000246485500026 PM 17370997 ER PT J AU Shin, IS Jang, BS Danthi, SN Xie, J Yu, S Le, N Maeng, JS Hwang, IS Li, KCP Carrasquillo, JA Paik, CH AF Shin, In Soo Jang, Beom-Su Danthi, S. Narasimhan Xie, Jianwu Yu, Sarah Le, Nhat Maeng, Jin-Soo Hwang, In Sook Li, King C. P. Carrasquillo, Jorge A. Paik, Chang H. TI Use of antibody as carrier of oligomers of peptidomimetic alpha(v)beta(3) antagonist to target tumor-induced neovasculature SO BIOCONJUGATE CHEMISTRY LA English DT Article ID ARG-GLY-ASP; CANCER ALPHA(V)-INTEGRIN EXPRESSION; RGD PEPTIDE; RADIONUCLIDE THERAPY; BISPECIFIC ANTIBODY; MONOCLONAL-ANTIBODY; FUSION PROTEIN; RADIOIMMUNOTHERAPY; ANGIOGENESIS; MICROPET AB Sulfhydryl selective reactions were explored to conjugate oligomers of a peptidomimetic integrin alpha(v)beta(3) antagonist, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonylamino-beta-alanine (IA) to monoclonal antibody (MoAb) to increase integrin alpha(v)beta(3) receptor-binding avidity. To generate sulfhydryl groups, N-succinimidyl-S-acetylthioacetate (SATA) was conjugated to both MoAb and IA. Sulfhydryl groups were then generated upon the deacetylation of the protecting acetyl group from the S-acetylthioacetato (ATA) moiety of MoAb-(ATA)(n) or IA-ATA with 0.02 M hydroxylamine in the presence of 1 mM EDTA at pH 7.2. The major focus was on optimizing the reaction concentrations, molar ratios, and reaction pH to conjugate high levels of IA-(A-SH) to MoAb-(A-SH)(n) without causing the inter- and intramolecular cross-linking of MoAb. Stepwise reactions of MoAb-(A-SH)(n) (15 mu M MoAb) with a homobifunctional cross-linker, 1,8-bis(maleimido)diethylene glycol (BM[PEO](2)) at a > 50x molar excess to the -SH, followed by the reaction of the purified product MoAb-(A-S-succinimidomaleimido-[PEO](2))(n) with IA-(A-SH) at pH 7.2 afforded monomeric MoAb-(A-S-succinimido-[PEO](2)-succinimido-S-A-IA)(n) with < 10% high molecular weight oligomeric MoAb. Monomeric MoAb-(A-S-S-[PEO](2)-S-S-A-IA)(10) (MoAb-IA(10)) radiolabeled with In-111 using 2-(p-isothiocyanatobenzyl)cyclohexyl-DTPA and with I-125 using the Iodogen method showed > 70% bindability to 0.4 mu M alpha(v)beta(3). When injected iv to nude mice with the receptor-positive M21 tumor, MoAb-IA(10) radiolabeled with both In-111 and I-125 accumulated rapidly and was retained in the tumor for a 44 h period while the radioactivity cleared rapidly from the blood, thereby resulting in increasing tumor-to-blood ratios over time. The tumor uptake was similar between the I-125 label and the In-111 label for a 44 h period. In contrast, the blood radioactivity was lower, but liver and other organ uptakes were much higher for the In-111 label than for the I-125. The In-111 label produced higher tumor-to-blood ratios but much lower tumor-to-organ ratios than the I-125. The rapid blood clearance, a short peak tumor uptake time, and a low peak tumor uptake value with prolonged tumor retention of this macromolecule appear to support a hypothesis that MoAb-IA(10) primarily binds to alpha(v)beta(3) receptors on angiogenic vessels, but not on the tumor. This hypothesis was substantiated by the fluorescence microscopic analysis of FITC-MoAb-IA(10), which showed that FITC-MoAb-IA(10) outlined neovasculatures but not tumor cells at 4 and 21 h ex vivo. Additional proof was observed when blood vessels outlined with rhodamine-lectin, which specifically binds to blood vessels, were superimposable on neovasculatures outlined with FITC-MoAb-IA(10). C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. EM cpaik@mail.nih.gov RI Carrasquillo, Jorge/E-7120-2010; Danthi, Simhan/B-7639-2014 NR 45 TC 10 Z9 10 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY-JUN PY 2007 VL 18 IS 3 BP 821 EP 828 DI 10.1021/bc0603485 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 167XJ UT WOS:000246485500028 PM 17375899 ER PT J AU Wang, ZR Kim, GB Woo, JH Liu, YY Mathias, A Stavrou, S Neville, DM AF Wang, Zhirui Kim, Geun-Bae Woo, Jung-Hee Liu, Yuan Yi Mathias, Askale Stavrou, Scott Neville, David M., Jr. TI Improvement of a recombinant anti-monkey anti-CD3 diphtheria toxin based immunotoxin by yeast display affinity maturation of the scFv SO BIOCONJUGATE CHEMISTRY LA English DT Article ID T-CELL IMMUNOTOXIN; SINGLE-CHAIN IMMUNOTOXIN; PICHIA-PASTORIS; SURFACE DISPLAY; CRYSTAL-STRUCTURE; BIVALENT; PROTEIN; CD3; DEPLETION; EFFICACY AB Recently, a bivalent recombinant anti-human CD3 diphtheria toxin (DT) based immunotoxin derived from the scFv of UCHT1 antibody has been made that shows enhanced bioactivity and is free from the side effects of Fc receptor interaction. In this case, the diminution of CD3 binding due to the placement of the scFv domain at the C-terminus of the truncated DT in single scFv immunotoxins was compensated by adding an additional scFv domain. However, this strategy was less successful for constructing an anti-rhesus recombinant immunotoxin derived from the scFv of FN18 antibody due to poor binding of the anti-rhesus bivalent immunotoxin. We report here that, by increasing the FN18 scFv affinity through random mutagenesis and selection with a dye-labeled monkey CD3 epsilon gamma recombinant heterodimer, we greatly improved the bioactivity of FN18 derived immunotoxin. The best mutant, C207, contained nine mutations, two of which were located in CDRs that changed the charge from negative to positive. Binding affinity of the C207 scFv to the monkey T cell line HSC-F increased 9.8-fold. The potency of the C207 bivalent immunotoxin assayed by inhibition of protein synthesis increased by 238-fold. C1 NIMH, Sect Biophys Chem, Mol Biol Lab, Bethesda, MD 20892 USA. RP Neville, DM (reprint author), NIMH, Sect Biophys Chem, Mol Biol Lab, Bldg 10,Rm 3D46,10 Ctr Dr, Bethesda, MD 20892 USA. EM davidn@mail.nih.gov FU Intramural NIH HHS NR 38 TC 14 Z9 14 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAY-JUN PY 2007 VL 18 IS 3 BP 947 EP 955 DI 10.1021/bc0603438 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 167XJ UT WOS:000246485500043 PM 17352456 ER PT J AU Resnik, DB Roman, G AF Resnik, David B. Roman, Gerard TI Health, justice, and the environment SO BIOETHICS LA English DT Article DE health inequalities; health disparities; justice; environment; access to care; utilitarianism; contractarianism; international justice AB In this article, we argue that the scope of bioethical debate concerning justice in health should expand beyond the topic of access to health care and cover such issues as occupational hazards, safe housing, air pollution, water quality, food and drug safety, pest control, public health, childhood nutrition, disaster preparedness, literacy, and many other environmental factors that can cause differences in health. Since society does not have sufficient resources to address all of these environmental factors at one time, it is important to set priorities for bioethical theorizing and policy formation. Two considerations should be used to set these priorities: (1) the impact of the environmental factor on health inequality, and (2) the practicality of addressing the factor. C1 NIEHS, Off Equal Opportun & Divers Management, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, Off Equal Opportun & Divers Management, NIH, POB 12233,Mail Drop NH 06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-02, ZIA ES102646-01] NR 52 TC 13 Z9 14 U1 2 U2 13 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-9702 J9 BIOETHICS JI Bioethics PD MAY PY 2007 VL 21 IS 4 BP 230 EP 241 DI 10.1111/j.1467-8519.2007.00547.x PG 12 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 145RE UT WOS:000244881400007 PM 17845481 ER PT J AU Papadopoulos, JS Agarwala, R AF Papadopoulos, Jason S. Agarwala, Richa TI COBALT: constraint-based alignment tool for multiple protein sequences SO BIOINFORMATICS LA English DT Article ID PHYLOGENY RECONSTRUCTION; DATABASE; ALGORITHMS; PROFILES; TREES; IDENTIFICATION; CONSISTENCY; BENCHMARK; ACCURACY; SEARCHES AB Motivation: A tool that simultaneously aligns multiple protein sequences, automatically utilizes information about protein domains, and has a good compromise between speed and accuracy will have practical advantages over current tools. Results: We describe COBALT, a constraint based alignment tool that implements a general framework for multiple alignment of protein sequences. COBALT finds a collection of pairwise constraints derived from database searches, sequence similarity and user input, combines these pairwise constraints, and then incorporates them into a progressive multiple alignment. We show that using constraints derived from the conserved domain database (CDD) and PROSITE protein-motif database improves COBALT's alignment quality. We also show that COBALT has reasonable runtime performance and alignment accuracy comparable to or exceeding that of other tools for a broad range of problems. C1 NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Agarwala, R (reprint author), NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bldg 38A,Room 10-03N,8600 Rockville Pike, Bethesda, MD 20894 USA. EM richa@helix.nih.gov FU Intramural NIH HHS NR 55 TC 313 Z9 317 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 1 PY 2007 VL 23 IS 9 BP 1073 EP 1079 DI 10.1093/bioinformatics/btm076 PG 7 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 171ZG UT WOS:000246773300005 PM 17332019 ER PT J AU Schaffer, AA Rice, ES Cook, W Agarwala, R AF Schaffer, Alejandro A. Rice, Edward Stallknecht Cook, William Agarwala, Richa TI rh_tsp_map 3.0: end-to-end radiation hybrid mapping with improved speed and quality control SO BIOINFORMATICS LA English DT Article ID STATISTICAL-METHODS; HUMAN GENOME; MAP; EVOLUTION; CANINE AB rh_tsp_map is a software package for computing radiation hybrid (RH) maps and for integrating physical and genetic maps. It solves the central mapping instances by reducing them to the traveling salesman problem (TSP) and using a modification of the CONCORDE package to solve the TSP instances. We present some of the features added between the initial rh_tsp_map version 1.0 and the current version 3.0, emphasizing the automation of many steps and addition of various checks designed to find problems with the input data. Iterations of improved input data followed by fast re-computation of the maps improves the quality of the final maps. C1 NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. Thomas Jefferson High Sch Sci & Technol, Alexandria, VA 22312 USA. Georgia Tech, Atlanta, GA 30332 USA. RP Agarwala, R (reprint author), NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bldg 38A,Room 10-03N,8600 Rockville Pike, Bethesda, MD 20894 USA. EM richa@helix.nih.gov RI Schaffer, Alejandro/F-2902-2012 FU Intramural NIH HHS [Z01 LM000097-06, Z99 LM999999] NR 15 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 1 PY 2007 VL 23 IS 9 BP 1156 EP 1158 DI 10.1093/bioinformatics/btm077 PG 3 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 171ZG UT WOS:000246773300015 PM 17332018 ER PT J AU Insel, TR Lehner, T AF Insel, Thomas R. Lehner, Thomas TI A new era in psychiatric genetics? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; INCREASES; VARIANT C1 NIMH, Off Director, Bethesda, MD 20892 USA. NIMH, Div Neurosci & Basic Behav Sci, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Off Director, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 MH999999] NR 13 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2007 VL 61 IS 9 BP 1017 EP 1018 DI 10.1016/j.biopsych.2007.01.016 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 160VK UT WOS:000245970200001 PM 17434010 ER PT J AU Kalueff, AV Wheaton, M Ren-Patterson, R Murphy, DL AF Kalueff, Allan V. Wheaton, M. Ren-Patterson, R. Murphy, D. L. TI Brain-derived neurotrophic factor, serotonin transporter, and depression: Comment on Kaufman et al. SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID KNOCKOUT MICE; GENE; BDNF; ANXIETY; STRESS; POLYMORPHISM; ASSOCIATION; CHILDREN; PATHWAY; TRAITS C1 NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Kalueff, AV (reprint author), NIMH, Clin Sci Lab, NIH, Bldg 10,Room 3D41,10 Ctr Dr, Bethesda, MD 20892 USA. EM kalueva@mail.nih.gov NR 19 TC 3 Z9 4 U1 0 U2 2 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 MAY 1 PY 2007 VL 61 IS 9 BP 1112 EP 1113 DI 10.1016/j.biopsych.2006.07.001 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 160VK UT WOS:000245970200013 PM 16952335 ER PT J AU Savani, BN Donohue, T Kozanas, E Shenoy, A Singh, AK Childs, RW Barett, AJ AF Savani, Bipin N. Donohue, Theresa Kozanas, Eleftheria Shenoy, Aarthi Singh, Anurag K. Childs, Richard W. Barett, A. John TI Increased risk of bone loss without fracture risk in long-term survivors after allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE bone loss; myeloablative; nonmyeloablative; stem cell transplantation ID MINERAL DENSITY; MARROW-TRANSPLANTATION; FOLLOW-UP; OSTEONECROSIS; OSTEOPOROSIS; PAMIDRONATE; DIAGNOSIS; CHILDREN; WOMEN AB We studied bone mineral density (BMD) in 79 long-term survivors of allogeneic stem cell transplantation (SCT) (median follow-up: 78 months; range: 38-160). Seventy patients received a total body irradiation (TBI)-based myeloablative SCT and 9 patients received a non-TBI, reduced-intensity SCT. Fourteen (18%) patients were receiving immunosuppressive therapy (IST) for chronic graft-versus-host disease (cGVHD) beyond 3 years from SCT. Fifty-eight (73.4%) of patients had bone loss (BL): 33 (41.8%) with osteopenia and 25 (31.6%) with osteoporosis. Factors associated with a significantly increased risk of osteoporosis were age and prolonged IST and for overall BL prolonged IST. However, BL was not associated with an increased fracture risk, despite the fact that most patients had not received prophylactic biphosphonates. Our data shows that BL is a long-term posttransplant complication, and emphasize the importance of serial BMD scans, and the treatment of BL with biphosphonates reserved for worsening BL or additional risk factors. (c) 2007 American Society for Blood and Marrow Transplantation. C1 NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barett, AJ (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10,Hatfield CRC,room 3-5330,10 Ctr Dr MSC 12, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 14 TC 30 Z9 31 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2007 VL 13 IS 5 BP 517 EP 520 DI 10.1016/j.bbmt.2007.01.085 PG 4 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 164RV UT WOS:000246252600002 PM 17448910 ER PT J AU Shenoy, A Savani, BN Barrett, AJ AF Shenoy, Aarthi Savani, Bipin N. Barrett, A. John TI Recombinant factor VIIa to treat diffuse alveolar hemorrhage following allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Letter C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Shenoy, A (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 10 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2007 VL 13 IS 5 BP 622 EP 623 DI 10.1016/j.bbmt.2007.01.070 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 164RV UT WOS:000246252600015 PM 17448923 ER PT J AU Dreger, P Schmitz, N AF Dreger, Peter Schmitz, Norbert TI Autologous stem cell transplantation as part of first-line treatment of Waldenstrom's macroglobulinemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Letter C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Dreger, P (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 5 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAY PY 2007 VL 13 IS 5 BP 623 EP 624 DI 10.1016/j.bbmt.2007.01.083 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 164RV UT WOS:000246252600016 PM 17448924 ER PT J AU Michelman-Ribeiro, A Horkay, F Nossal, R Boukari, H AF Michelman-Ribeiro, Ariel Horkay, Ferenc Nossal, Ralph Boukari, Hacene TI Probe diffusion in aqueous poly(vinyl alcohol) solutions studied by fluorescence correlation spectroscopy SO BIOMACROMOLECULES LA English DT Article ID ENTANGLED POLYMER-SOLUTIONS; SELF-DIFFUSION; TRANSLATIONAL DIFFUSION; DELIVERY-SYSTEMS; DYNAMICS; GELS; PARTICLES; CELLS; SCATTERING; CYTOPLASM AB We report fluorescence correlation spectroscopy measurements of the translational diffusion coefficient of various probe particles in dilute and semidilute aqueous poly(vinyl alcohol) solutions. The range of sizes of the particles (fluorescent molecules, proteins, and polymers) was chosen to explore various length scales of the polymer solutions as defined by the polymer-polymer correlation length. For particles larger than the correlation length, we find that the diffusion coefficient, D, decreases exponentially with the polymer concentration. This can be explained by an exponential increase in the solution viscosity, consistent with the Stokes-Einstein equation. For probes on the order of the correlation length, the decrease of the diffusion coefficient cannot be accounted for by the Stokes-Einstein equation, but can be fit by a stretched exponential, D similar to exp(-alpha c(n)), where we find n = 0.73-0.84 and alpha is related to the probe size. These results are in accord with a diffusion model of Langevin and Rondelez (Polymer 1978, 19, 1875), where these values of n indicate a good solvent quality. C1 NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Boukari, H (reprint author), NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM boukarih@mail.nih.gov NR 59 TC 43 Z9 43 U1 1 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD MAY PY 2007 VL 8 IS 5 BP 1595 EP 1600 DI 10.1021/bm061195r PG 6 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 166XH UT WOS:000246413600029 PM 17441767 ER PT J AU Balboni, G Onnis, V Congiu, C Zotti, M Sasaki, Y Ambo, A Bryant, SD Jinsmaa, Y Lazarus, LH Lazzari, I Trapella, C Salvadori, S AF Balboni, Gianfranco Onnis, Valentina Congiu, Cenzo Zotti, Margherita Sasaki, Yusuke Ambo, Akihiro Bryant, Sharon D. Jinsmaa, Yunden Lazarus, Lawrence H. Lazzari, Ilaria Trapella, Claudio Salvadori, Severo TI Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE delta-opioid receptors; Dmt-Tic pharmacophore; designed multiple ligands; opioid peptides ID IN-VITRO; RECEPTOR ANTAGONIST; POTENT; SELECTIVITY; PEPTIDES; AFFINITY; AGONISTS; LIGANDS; DERIVATIVES; ANALOGS AB A wide range of activities are induced by Lys when introduced at C-terminus of the delta-opioid Dmt-Tic pharmacophore through the alpha-amine group, including: improved delta-antagonism, mu-agonism and p-antagonism. Here we report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH2)(4)-CH(R)-R' (R = -NH2, -NH-Ac, -NH-Z; R'= CO-NH-Ph, -CO-NH-CH2-Ph, -Bid) in which Lys is linked to Dint-Tic through its side-chain amine group. All new compounds (1-9) displayed potent and selective delta-antagonism (MVD, pA(2) = 7.81-8.27), which was independent of the functionalized alpha-amine and carboxylic groups of C-terminal Lys. This behaviour suggests a direct application as a prototype intermediate, such as Boc-Dmt-Tic-epsilon-Lys(Z)OMe, which could be successfully applied in the synthesis (after Z or methyl ester removal) of unique designed multiple ligands containing the pharmacophore of the quintessential delta-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Tohoku Pharmaceut Univ, Aoba Ku, Sendai, Miyagi 9818588, Japan. Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Med Chem Grp, Res Triangle Pk, NC 27709 USA. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM gbalboni@unica.it RI Onnis, Valentina/B-1649-2008; Trapella, Claudio/I-2128-2012; OI Onnis, Valentina/0000-0002-2438-725X; Trapella, Claudio/0000-0002-6666-143X; Congiu, Cenzo/0000-0003-2600-4221; SALVADORI, Severo/0000-0002-8224-2358 FU Intramural NIH HHS [Z01 ES100472-07, Z01 ES090053-20, Z01 ES090053-21, Z01 ES100472-06, Z99 ES999999, ZIA ES090053-23, ZIA ES100472-09] NR 32 TC 6 Z9 6 U1 0 U2 2 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 MAY 1 PY 2007 VL 15 IS 9 BP 3143 EP 3151 DI 10.1016/j.bmc.2007.02.039 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 161GO UT WOS:000246002800005 PM 17339114 ER PT J AU Kerr, DJ Hamel, E Jung, MK Flynn, BL AF Kerr, Daniel J. Hamel, Ernest Jung, M. Katherine Flynn, Bernard L. TI The concise synthesis of chalcone, indanone and indenone analogues of combretastatin A4 SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE tubulin polymerisation inhibitor; chalcone; indanone; indenone ID INHIBIT TUBULIN POLYMERIZATION; ANTIMITOTIC AGENTS; NATURAL-PRODUCTS; COLCHICINE; A-4; CYCLIZATION; DISCOVERY; BINDING; GROWTH; CANCER AB A series of aryl- and aroyl-substituted chalcone analogues of the tubulin binding agent combretastatin A4 (1) were prepared, using a recently introduced one-pot palladium-mediated hydrostannylation-coupling reaction sequence. These chalcones were converted to indanones by Nazarov cyclisation, followed by oxidation to give the corresponding indenones. Indenones were also prepared using a palladium-mediated formal [3+2]-cycloaddition process between ortho-halobenzaldehydes and diarylpropynones. All compounds were assessed as inhibitors of tubulin polymerisation, but only E-31 had activity similar to that of 1. However, compound E-31 did not exhibit antiproliferative activity against the MCF-7 cell line. (c) 2007 Elsevier Ltd. All rights reserved. C1 Monash Univ, Fac Pharm, Dept Med Chem, Parkville, Vic 3052, Australia. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Ft Detrick, MD 21702 USA. NCI, SAIC Frederick, NIH, Frederick, MD 21702 USA. RP Flynn, BL (reprint author), Monash Univ, Fac Pharm, Dept Med Chem, 381 Royal Pde, Parkville, Vic 3052, Australia. EM b.flynn@iliad.com.au FU NCI NIH HHS [N0-CO-12400] NR 34 TC 62 Z9 63 U1 1 U2 9 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 MAY 1 PY 2007 VL 15 IS 9 BP 3290 EP 3298 DI 10.1016/j.bmc.2007.02.006 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 161GO UT WOS:000246002800020 PM 17360188 ER PT J AU Buchete, NV Hummer, G AF Buchete, Nicolae-Viorel Hummer, Gerhard TI Structure and dynamics of parallel beta-sheets, hydrophobic core, and loops in Alzheimer's A beta fibrils SO BIOPHYSICAL JOURNAL LA English DT Article ID MOLECULAR-DYNAMICS; AMYLOID FIBRILS; PROTEIN AGGREGATION; EXPERIMENTAL CONSTRAINTS; DIMER FORMATION; WILD-TYPE; PEPTIDE; DISEASE; SIMULATIONS; NUCLEATION AB We explore the relative contributions of different structural elements to the stability of A beta fibrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our fibril structures are based on solid-state nuclear magnetic resonance experiments of A beta(1-40) peptides, with sheets of parallel beta-strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal beta-strands along the fibril axis. Multiple 10-20 ns molecular-dynamics simulations show that fibril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of fibril dissociation as a loss of order in the hydrophilic loops connecting the two beta-strands, and in the solvent-exposed N-terminal beta-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal beta-sheets on top of each other. The interior C-terminal beta-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of A beta fibrils. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Hummer, Gerhard/A-2546-2013; Buchete, Nicolae-Viorel/C-6200-2015 OI Hummer, Gerhard/0000-0001-7768-746X; Buchete, Nicolae-Viorel/0000-0001-9861-1157 FU Intramural NIH HHS NR 60 TC 96 Z9 96 U1 2 U2 25 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 1 PY 2007 VL 92 IS 9 BP 3032 EP 3039 DI 10.1529/biophysj.106.100404 PG 8 WC Biophysics SC Biophysics GA 154YI UT WOS:000245544100012 PM 17293399 ER PT J AU Wang, YL Reddy, S Beard, WA Wilson, SH Schlick, T AF Wang, Yanli Reddy, Sujatha Beard, William A. Wilson, Samuel H. Schlick, Tamar TI Differing conformational pathways before and after chemistry for insertion of dATP versus dCTP opposite 8-OxoG in DNA polymerase beta SO BIOPHYSICAL JOURNAL LA English DT Article ID INDUCED-FIT MECHANISM; ACTIVE-SITE; DYNAMICS SIMULATIONS; NUCLEOTIDE INCORPORATION; BIOMOLECULAR DYNAMICS; STRUCTURAL INSIGHTS; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURES; FINGERS SUBDOMAIN; LANGEVIN DYNAMICS AB To elucidate how human DNA polymerase beta (pol beta) discriminates dATP from dCTP when processing 8-oxoguanine (8-oxoG), we analyze a series of dynamics simulations before and after the chemical step with dATP and dCTP opposite an 8-oxoG template started from partially open complexes of pol beta. Analyses reveal that the thumb closing of pol beta before chemistry is hampered when the incorrect nucleotide dATP is bound opposite 8-oxoG; the unfavorable interaction between active-site residue Tyr(271) and dATP that causes an anti to syn change in the 8-oxoG (syn):dATP complex explains this slow motion, in contrast to the 8-oxoG (anti): dCTP system. Such differences in conformational pathways before chemistry for mismatched versus matched complexes help explain the preference for correct insertion across 8-oxoG by pol beta. Together with reference studies with a nonlesioned G template, we propose that 8-oxoG leads to lower efficiency in pol beta's incorporation of dCTP compared with G by affecting the requisite active-site geometry for the chemical reaction before chemistry. Furthermore, because the active site is far from ready for the chemical reaction after partial closing or even full thumb closing, we suggest that pol b is tightly controlled not only by the chemical step but also by a closely related requirement for subtle active-site rearrangements after thumb movement but before chemistry. C1 NYU, Dept Chem, New York, NY 10012 USA. NYU, Courant Inst Math Sci, New York, NY 10012 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. RP Schlick, T (reprint author), NYU, Dept Chem, 550 1St Ave, New York, NY 10012 USA. EM schlick@nyu.edu FU Intramural NIH HHS; NIEHS NIH HHS [R01 ES012692] NR 56 TC 18 Z9 18 U1 0 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 1 PY 2007 VL 92 IS 9 BP 3063 EP 3070 DI 10.1529/biophysj.106.092106 PG 8 WC Biophysics SC Biophysics GA 154YI UT WOS:000245544100015 PM 17293403 ER PT J AU Yamada, S Anderson, SA Lockett, E Uwabe, C Shiota, K Lo, CW AF Yamada, S. Anderson, S. A. Lockett, E. Uwabe, C. Shiota, K. Lo, C. W. TI Human embryo atlas constructed by magnetic resonance (MR) imaging and episcopic fluorescence image capture (EFIC) from the Kyoto collection of human embryos SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NHLBI, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Congenital Anomaly Res Ctr, Kyoto, Japan. Human Dev Anat Ctr, Natl Museum Hlth & Med, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA 6 BP 354 EP 354 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800007 ER PT J AU States, JC Singh, AV Miller, HL Piao, Y Ko, MSH Srivastava, S Knudsen, TB AF States, J. C. Singh, A., V Miller, H. L. Piao, Y. Ko, M. S. H. Srivastava, S. Knudsen, T. B. TI Developmental programming of fetal liver by prenatal arsenic exposure associated with accelerated atherogenesis in ApoE-knockout mice SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 Univ Louisville, Louisville, KY 40292 USA. NIA, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009; Singh, Amar/K-4400-2013 OI Ko, Minoru/0000-0002-3530-3015; Singh, Amar/0000-0003-3780-8233 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA 50 BP 378 EP 378 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800051 ER PT J AU Cho, EL Li, WJ Tuan, RS AF Cho, E. L. Li, W. J. Tuan, R. S. TI Chromatin, human stem cells, and tissue engineering: Shifting paradigms to improve relevancy in development toxicology research SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 Sci Int, Alexandria, VA USA. NIAMSD, CBOB, NIH, Bethesda, MD 20892 USA. RI Li, Wan-Ju/A-7002-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA 54 BP 380 EP 380 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800055 ER PT J AU Biesecker, L AF Biesecker, L. TI Polydactyly SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA S19 BP 391 EP 391 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800074 ER PT J AU Gohlke, JM AF Gohlke, J. M. TI Systems biology approaches in normal and abnormal development SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA W4 BP 397 EP 397 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800084 ER PT J AU Korach, KS Couse, JF Hewitt, S Walker, V Emmen, J Deroo, B Rodriguez, K Hansen, K AF Korach, K. S. Couse, J. F. Hewitt, S. Walker, V Emmen, J. Deroo, B. Rodriguez, K. Hansen, K. TI Physiological consequences from loss of estrogen receptor activity SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA W10 BP 401 EP 401 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800090 ER PT J AU Delclos, KB Weis, CC Newbold, RR AF Delclos, K. B. Weis, C. C. Newbold, R. R. TI Reproductive and developmental toxicity of phytoestrogens SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA W12 BP 402 EP 402 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800092 ER PT J AU Mattison, DR AF Mattison, D. R. TI Obstetric and pediatric drug development: Opportunities and challenges facing therapeutic advances in neglected populations. SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NICHD, CRMC, Obstetr & Pediat Pharmacol Branch, NIH, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA L1 BP 404 EP 404 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800093 ER PT J AU Gohlke, JM Griffith, WC Faustman, EM AF Gohlke, J. M. Griffith, W. C. Faustman, E. M. TI Computational modeling of ethanol-induced neurodevelopmental toxicity across species: Implications for risk assessment SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2007 VL 79 IS 5 MA P4 BP 407 EP 407 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 167BO UT WOS:000246425800097 ER PT J AU Lattouf, JB Grubb, RL Lee, SJ Bjurlin, MA Albert, P Singh, AK Ocak, I Choyke, P Coleman, JA AF Lattouf, Jean-Baptiste Grubb, Robert L., III Lee, S. Justin Bjurlin, Marc A. Albert, Paul Singh, Anurag K. Ocak, Iclal Choyke, Peter Coleman, Jonathan A. TI Magnetic resonance imaging-directed transrectal ultrasonography-guided biopsies in patients at risk of prostate cancer SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; prostate biopsy; MRI; ultrasonography; cancer ID CONTRAST-ENHANCED MRI; MICROVESSEL DENSITY; SEXTANT BIOPSY; TUMOR FOCI; LOCALIZATION; SPECTROSCOPY; CARCINOMA; ACCURACY; ANTIGEN; MRSI AB OBJECTIVE To evaluate whether using endorectal-coil magnetic resonance imaging (erMRI) before transrectal ultrasonography (TRUS)-guided biopsies of the prostate increases the yield of cancer in a high-risk population, and in a subset analysis to compare the yield with high-field (3 T) vs lower field (1.5 T) MRI. PATIENTS AND METHODS Between March 2003 and November 2005, 26 consecutive patients had erMRI before their TRUS biopsy of the prostate (median age 62 years, range 32-76). The median prostate-specific antigen (PSA) level was 8.40 (2.1-85.9) ng/mL. All patients had at least one previous negative prostate biopsy (median 3, range 1-12). Twenty-three patients had at least one risk factor for prostate cancer (family history, high PSA velocity, low percentage of free PSA, prostatic intraepithelial neoplasia or atypical small acinar proliferation on previous biopsy). MRI studies consisted of T2-weighted and dynamic contrast-enhanced (DCE) imaging studies. RESULTS There was a close correlation between T2-weighted and DCE images (85% agreement, P < 0.001). Neither T2-weighted nor DCE imaging correlated with a higher yield for cancer on final biopsy (T2, positive predictive value, PPV, 20%, negative PV, NPV, 14%, P = 0.21; DCE, PPV 21%, NPV 15%, P = 0.26). Combining the two methods did not improve the cancer yield. There was no significant difference in the probability of cancer based on 1.5 T or 3 T imaging (17% vs 16%, P = 0.88). CONCLUSION Although erMRI before TRUS-guided biopsies tended to give higher cancer yields the difference was not statistically significant. Reasons for this might include suboptimal localisation of the MRI findings and the biopsy location. Better methods for fusing MRI and TRUS images are presently being developed at our institution to allow more accurate targeting. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, DCTD, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Coleman, JA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,CRC Rm 2-5940,MSC 1210, Bethesda, MD 20892 USA. EM colemanj@mail.nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 NR 20 TC 34 Z9 37 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD MAY PY 2007 VL 99 IS 5 BP 1041 EP 1046 DI 10.1111/j.1464-410X.2006.06690.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 155UF UT WOS:000245603200021 PM 17437438 ER PT J AU Figg, WD Li, HQ Sissung, T Retter, A Wu, SH Gulley, JL Arlen, P Wright, JJ Parnes, H Fedenko, K Latham, L Steinberg, SM Jones, E Chen, C Dahut, W AF Figg, William D. Li, Haiqing Sissung, Tristan Retter, Avi Wu, Shenhong Gulley, James L. Arlen, Phil Wright, John J. Parnes, Howard Fedenko, Kathy Latham, Lea Steinberg, Seth M. Jones, Elizabeth Chen, Clara Dahut, William TI Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer SO BJU INTERNATIONAL LA English DT Article DE cancer; oncology; taxanes; drug development; clinical; phase II; xenografts; PC3 cells; pharmacogenetics; cytochrome P450; CYP1B1 ID PHASE-II TRIAL; ANGIOGENESIS INHIBITOR; PLUS THALIDOMIDE; HUMAN CYP1B1; PREDNISONE; MEN; MITOXANTRONE; ATRASENTAN; METABOLITE; PACLITAXEL AB OBJECTIVE To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AMD METHODS In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm(3). We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m(2)) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p = 0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P = 0.013). CONCLUSIONS Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC. C1 NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Canc Therapy & Evaluat Program, NIH, Bethesda, MD 20892 USA. NCI, Ctr Clin, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, NIH, Bldg 10-Rm 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; FU Intramural NIH HHS NR 44 TC 29 Z9 30 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD MAY PY 2007 VL 99 IS 5 BP 1047 EP 1055 DI 10.1111/j.1464-410X.2007.06763.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 155UF UT WOS:000245603200022 PM 17437439 ER PT J AU Vira, MA Novakovic, KR Pinto, PA Linehan, WM AF Vira, Manish A. Novakovic, Kristian R. Pinto, Peter A. Linehan, W. Marston TI Genetic basis of kidney cancer: a model for developing molecular-targeted therapies SO BJU INTERNATIONAL LA English DT Article DE von Hippel-Lindau; hereditary papillary renal carcinoma; Birt-Hogg-Dube; hereditary leiomyomatosis renal cell carcinoma ID RENAL-CELL CARCINOMA; HOGG-DUBE-SYNDROME; TUMOR-SUPPRESSOR GENE; HIPPEL-LINDAU-DISEASE; PARENCHYMAL SPARING SURGERY; TYROSINE KINASE DOMAIN; GERMLINE MUTATIONS; FUMARATE-HYDRATASE; MET PROTOONCOGENE; HEREDITARY LEIOMYOMATOSIS C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10,CRC,Room 1-5940, Bethesda, MD 20892 USA. EM wml@nih.gov FU Intramural NIH HHS NR 55 TC 12 Z9 13 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD MAY PY 2007 VL 99 IS 5 BP 1223 EP 1229 DI 10.1111/j.1464-410X.2007.06814.x PN B PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 157AZ UT WOS:000245692300006 PM 17441915 ER PT J AU Srinivasan, R Armstrong, AJ Dahut, W George, DJ AF Srinivasan, Ramaprasad Armstrong, Andrew J. Dahut, William George, Daniel J. TI Anti-angiogenic therapy in renal cell cancer SO BJU INTERNATIONAL LA English DT Article DE tyrosine kinase inhibitor; antibodies; receptor kinase inhibitors; vascular endothelial growth factor; time to progression ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR GENE; VONHIPPEL-LINDAU DISEASE; INTERFERON-ALPHA; MONOCLONAL-ANTIBODY; CARCINOMA; SAFETY; TRIAL; BEVACIZUMAB; COMBINATION C1 Duke Univ, Med Ctr, Dept Med, Div Med Oncol, Durham, NC 27706 USA. Duke Univ, Med Ctr, Dept Med, Div Urol, Durham, NC 27706 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. NCI, Urol Oncol Branch, Ctr Canc Res, Div Canc Prevent,Canc Therapy Program, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Div Canc Prevent,Canc Therapy Program, Bethesda, MD 20892 USA. RP George, DJ (reprint author), Duke Univ, Med Ctr, Dept Med, Div Med Oncol, Durham, NC 27706 USA. EM daniel.george@duke.edu NR 31 TC 9 Z9 12 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD MAY PY 2007 VL 99 IS 5 BP 1296 EP 1300 DI 10.1111/j.1464-410X.2007.06834.x PN B PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 157AZ UT WOS:000245692300018 PM 17441927 ER PT J AU Chu, YW Hakim, FT AF Chu, Yu-Waye Hakim, Frances T. TI KGF boosts thymic archiTECture SO BLOOD LA English DT Editorial Material ID PROGENITORS C1 NCI, Bethesda, MD 20892 USA. RP Chu, YW (reprint author), NCI, Bethesda, MD 20892 USA. NR 7 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2007 VL 109 IS 9 BP 3613 EP 3614 DI 10.1182/blood-2007-02-072637 PG 2 WC Hematology SC Hematology GA 162MJ UT WOS:000246091400001 ER PT J AU Rosenberg, PS AF Rosenberg, Philip S. TI Gene expression levels in lymphoma SO BLOOD LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Rosenberg, PS (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2007 VL 109 IS 9 BP 3621 EP 3621 PG 1 WC Hematology SC Hematology GA 162MJ UT WOS:000246091400009 ER PT J AU Cain, JA Xiang, ZF O'Neal, J Kreisel, F Colson, A Luo, H Hennighausen, L Tomasson, MH AF Cain, Jennifer A. Xiang, Zhifu O'Neal, Julie Kreisel, Friederike Colson, AnnaLynn Luo, Hui Hennighausen, Lothar Tomasson, Michael H. TI Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage SO BLOOD LA English DT Article ID CHRONIC MYELOMONOCYTIC LEUKEMIA; BETA-R FUSION; FAMILY TYROSINE KINASES; SIGNAL-TRANSDUCTION; PHOSPHORYLATION SITES; LYMPHOID DEVELOPMENT; CELL-PROLIFERATION; MYELOID-LEUKEMIA; RECEPTOR-BETA; PROTEINS AB Expression of the constitutively activated TEL/PDGF beta R fusion protein is associated with the t(5;12)(q33;pl3) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGF beta R activates multiple signal transduction pathways in cell-culture systems, and expression of the TEL-PDGFRB fusion gene induces myeloproliferative disease (MPD) in mice. We used gene-targeted mice to characterize the contribution of signal transducer and activator of transcription (Stat) and Src family genes to TEL-PDGFRB-mediated transformation in methylcellulose colony and murine bone marrow transduction/ transplantation assays. Fetal liver hematopoietic stem and progenitor cells harboring targeted deletion of both Stat5a and Stat5b (Staffab(null/null)) genes were refractory to transformation by TELPDGFRB in methylcellulose colony assays. Notably, these cell populations were maintained in Stat5ab(null/null) fetal livers and succumbed to transformation by c-Myc. Surprisingly, targeted disruption of either Stat5a or Stat5b alone also impaired TEL-PDGFRB-mediated transformation. Survival of TFIGFP -> Stat5a(-/-) and TPIGFP -> Stat5a(+/-) mice was significantly prolonged, demonstrating significant sensitivity of TEL-PDGFRB-induced MPD to the dosage of Stat5a. TEL-PDGFRB-mediated MPD was incompletely penetrant in TFIGFP -> Stat5b(-/-) mice. In contrast, Src family kinases Lyn, Hck, and Fgr and the Stat family member Stat1 were dispensable for TEL-PDGFRB disease. Together, these data demonstrate that Stat5a and Stat5b are dose-limiting mediators of TEL-PDGFRB-induced myeloproliferation. C1 Washington Univ, Siteman Canc Ctr, Dept Internal Med, Div Oncol, St Louis, MO USA. Washington Univ, Sch Med, Dept Pathol, St Louis, MO USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD USA. RP Tomasson, MH (reprint author), Dept Med, Div Oncol, 660 S Euclid Ave,Campus Box 8007, St Louis, MO 63110 USA. EM tomasson@im.wustl.edu OI xiang, Zhifu/0000-0003-0602-9827 FU Intramural NIH HHS; NCI NIH HHS [P01 CA 101937, P01 CA101937]; NHLBI NIH HHS [T32 HL 07088-31A1, T32 HL007088] NR 36 TC 36 Z9 36 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2007 VL 109 IS 9 BP 3906 EP 3914 DI 10.1182/blood-2006-07-036335 PG 9 WC Hematology SC Hematology GA 162MJ UT WOS:000246091400047 PM 17218386 ER PT J AU Hurt, EM Thomas, SB Peng, BJ Farrar, WL AF Hurt, Elaine M. Thomas, Suneetha B. Peng, Benjamin Farrar, William L. TI Integrated molecular profiling of SOD2 expression in multiple myeloma SO BLOOD LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; SIGNALING PATHWAYS; GENE-EXPRESSION; FREE-RADICALS; CELLS; CANCER; ACTIVATION; 2-METHOXYESTRADIOL; DIFFERENTIATION AB Reactive oxygen species are known to be involved in several cellular processes, including cell signaling. SOD2 is a key enzyme in the conversion of reactive oxygen species and has been implicated in a host of disease states, including cancer. Using an integrated, whole-cell approach encompassing epigenetics, genomics, and proteomics, we have defined the role of SOD2 in multiple myeloma. We show that the SOD2 promoter is methylated in several cell lines and there is a correlative decrease in expression. Furthermore, myeloma patient samples have decreased SOD2 expression compared with healthy donors. Overexpression of SOD2 results in decreased proliferation and altered sensitivity to 2-methoxyestradiol-induced DNA damage and apoptosis. Genomic profiling revealed regulation of 65 genes, including genes involved in tumorigenesis, and proteomic analysis identified activation of the JAK/STAT pathway. Analysis of nearly 400 activated transcription factors identified 31 transcription factors with altered DNA binding activity, including XBP1, NFAT, forkhead, and GAS binding sites. Integration of data from our gestalt molecular analysis has defined a role for SOD2 in cellular proliferation, JAK/STAT signaling, and regulation of several transcription factors. C1 NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Univ Melbourne, Sch Dent Sci, Melbourne, Vic 3000, Australia. RP Hurt, EM (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 1050 Boyles St,Bldg 560,Rm 21-81, Frederick, MD 21702 USA. EM hurte@ncifcrf.gov; farrar@mail.ncifcrf.gov FU NCI NIH HHS [N01CO12400] NR 47 TC 27 Z9 27 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2007 VL 109 IS 9 BP 3953 EP 3962 DI 10.1182/blood-2006-07-035162 PG 10 WC Hematology SC Hematology GA 162MJ UT WOS:000246091400053 PM 17192397 ER PT J AU Andrade, AC Nilsson, O Barnes, KM Baron, J AF Andrade, Anenisla C. Nilsson, Ola Barnes, Kevin M. Baron, Jeffrey TI Wnt gene expression in the post-natal growth plate: Regulation with chondrocyte differentiation SO BONE LA English DT Article DE Wnt; growth plate; chondrocyte; cartilage ID LONGITUDINAL BONE-GROWTH; BETA-CATENIN; ENDOCHONDRAL OSSIFICATION; SKELETAL DEVELOPMENT; EPIPHYSEAL FUSION; INDIAN HEDGEHOG; MESSENGER-RNA; RESTING ZONE; SENESCENCE; CHONDROGENESIS AB Longitudinal growth of long bones occurs at the growth plate by endochondral ossification. In the embryonic mouse, this process is regulated by Writ signaling. Little is known about which members of the Writ family of secreted signaling proteins might be involved in the regulation of the postnatal growth plate. We used microdissection and real-time PCR to study mRNA expression of Writ genes in the mouse growth plate. Of the 19 known members of the Writ family, only six were expressed in postnatal growth plate. Of these, Writs -2b, -4, and -10b signal through the canonical beta-catenin pathway and Writs -5a, -5b, and -11 signal through the noncanonical calcium pathway. The spatial expression for these six Writs was remarkably similar, showing low mRNA expression in the testing zone, increasing expression as the chondrocytes differentiated into the proliferative and prehypertrophic state and then (except Wnt-2b) decreasing expression as the chondrocytes underwent hypertrophic differentiation. This overall pattern is broadly consistent with previous studies of embryonic mouse growth cartilage Suggesting that Writ signaling modulates chondrocyte proliferation and hypertrophic differentiation. We also found that mRNA expression of these Writ genes persisted at similar levels at 4 weeks, when longitudinal bone growth is waning. In conclusion, we have identified for the first time the specific Writ genes that are expressed in the postnatal mammalian growth plate. The six identified Writ genes showed a similar pattern of expression during chondrocyte differentiation, suggesting overlapping or interacting roles in postnatal endochondral bone formation. (c) 2007 Elsevier Inc. All rights reserved. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Andrade, AC (reprint author), Rua Castro Alves 279,Apto 133, BR-01532001 Sao Paulo, Brazil. EM anenisia@gmail.com OI Nilsson, Ola/0000-0002-9986-8138 FU Intramural NIH HHS [Z01 HD000640-10] NR 56 TC 66 Z9 69 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAY PY 2007 VL 40 IS 5 BP 1361 EP 1369 DI 10.1016/j.bone.2007.01.005 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 162ZS UT WOS:000246128700023 PM 17337262 ER PT J AU Defazio, G Berardelli, A Hallett, M AF Defazio, Giovanni Berardelli, Alfredo Hallett, Mark TI Do primary adult-onset focal dystonias share aetiological factors? SO BRAIN LA English DT Review DE focal dystonia; complex disease; genetics; brain imaging; clinical neurophysiology ID TRANSCRANIAL MAGNETIC STIMULATION; BENIGN ESSENTIAL BLEPHAROSPASM; IDIOPATHIC CERVICAL DYSTONIA; PRIMARY TORSION DYSTONIA; DISORDERS STUDY-GROUP; HUMAN MOTOR CORTEX; WRITERS CRAMP; HAND DYSTONIA; MOVEMENT-DISORDERS; DRY EYE AB To consider whether the various clinical types of primary late-onset dystonia have a common aetiological background, or are each distinct and separate entities, sharing only the clinical appearance of dystonia, we reviewed epidemiological, clinical, neurophysiological and imaging data reported in patients with different forms of primary late-onset dystonia. The epidemiological and clinical features that distinguished the various clinical types and suggest aetiological differences were prevalence, age of onset, sex preference, sensory tricks, and tendency to spread. Likewise, aetiological differences were also supported by the observation that environmental risk factors possibly triggering focal dystonias in predisposed subjects can differ from one form to the other. The fact that different forms of focal dystonia may coexist in the same individual as the result of spread nevertheless suggests that the various focal dystonias are related. Detailed examination of available familial and genetic data indicates that the different forms of primary late-onset dystonia share aetiological factors, most probably genetic. Neurophysiological and imaging studies have demonstrated a number of abnormalities in focal dystonias and some of these are shared by the different clinical types. The shared abnormality of sensorimotor integration (and cortical excitability) beyond the symptomatic body part identified in various clinical types and in unaffected relatives might reflect the genetic abnormality indicating the substrate on which the dystonia develops. C1 Univ Roma La Sapienza, Dept Neurol Sci, I-00185 Rome, Italy. Univ Roma La Sapienza, NEUROMED Inst, I-00185 Rome, Italy. Univ Bari, Dept Neurol & Psychiat Sci, Bari, Italy. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Berardelli, A (reprint author), Univ Roma La Sapienza, Dept Neurol Sci, Viale Univ 30, I-00185 Rome, Italy. EM alfredo.berardelli@uniroma1.it NR 106 TC 135 Z9 140 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2007 VL 130 BP 1183 EP 1193 DI 10.1093/brain/aw1355 PN 5 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 165GW UT WOS:000246293400004 PM 17242025 ER PT J AU Roemer, SF Parisi, JE Lennon, VA Benarroch, EE Lassmann, H Bruck, W Mandler, RN Weinshenker, BG Pittock, SJ Wingerchuk, DM Lucchinetti, CF AF Roemer, Shanu F. Parisi, Joseph E. Lennon, Vanda A. Benarroch, Eduardo E. Lassmann, Hans Bruck, Wolfgang Mandler, Raul N. Weinshenker, Brian G. Pittock, Sean J. Wingerchuk, Dean M. Lucchinetti, Claudia F. TI Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis SO BRAIN LA English DT Article DE neuromyelitis optica; aquaporin-4; multiple sclerosis; demyelination; astrocyte; blood-brain barrier ID HUMAN BRAIN-TUMORS; WATER CHANNEL; ENHANCED EXPRESSION; LESIONS; RAT; DEMYELINATION; PATHOGENESIS; TRANSPORT; DOMAINS; PROTEIN AB Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS. C1 Mayo Clin & Mayo Fdn, Coll Med, Dept Neurol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Coll Med, Dept Immunol, Rochester, MN 55905 USA. NIH, Ctr Clin Trials Network, Bethesda, MD 20892 USA. Mayo Clin, Coll Med, Dept Neurol, Scottsdale, AZ USA. Med Univ Vienna, Ctr Brain Res, Vienna, Austria. Univ Gottingen, Dept Neuropathol, Inst Multiple Sclerosis Res, D-3400 Gottingen, Germany. RP Lucchinetti, CF (reprint author), Mayo Clin & Mayo Fdn, Coll Med, Dept Neurol, 200 1st St SW, Rochester, MN 55905 USA. EM lucchinetti.claudia@mayo.edu FU NINDS NIH HHS [R01-NS049577-01-A2] NR 37 TC 368 Z9 394 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2007 VL 130 BP 1194 EP 1205 DI 10.1093/brain/aw1371 PN 5 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 165GW UT WOS:000246293400005 PM 17282996 ER PT J AU Kopnisky, KL Bao, J Lin, YW AF Kopnisky, Kathy L. Bao, Jing Lin, Yu Woody TI Neurobiology of HIV, psychiatric and substance abuse comorbidity research: Workshop report SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Review DE brain; neuroAIDS; HIV; drugs; comorbidity; opioids; neuroassessment; depression; substance of abuse ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; HUMAN IMMUNE CELLS; NF-KAPPA-B; ACTIVE ANTIRETROVIRAL THERAPY; INDUCED SICKNESS BEHAVIOR; MU-OPIOID RECEPTOR; CEREBROSPINAL-FLUID; TAT PROTEIN; METHAMPHETAMINE USERS AB Viral infections can cause persistent and progressive changes in emotional and cognitive functions. The viral-induced imbalances in neuronal network functioning may precipitate or accentuate psychiatric conditions in vulnerable individuals, in part, as a function of the host response to proinflammatory cytokines resulting from infection or brain injury. Research indicates that the mediators of psychiatric illnesses and HIV-neuropathogenesis utilize similar brain structures, neurocircuitry and receptor systems. The genetic, cellular and molecular mechanisms contributing to HIV neuropathogenesis and its late stage clinical correlate, HIV-associated-dementia (HAD), are active areas of neuroAIDS research. The study of HIV in the context of psychiatric comorbidities and comorbid pathogenesis is in a fledgling stage despite epidemiological studies suggesting that > 60% of HIV infected individuals will suffer from at least one major psychiatric disorder during the course of infection. Depression is the primary comorbid disorder but anxiety and substance abuse disorders are also considerable in certain HIV+ populations. Certain substances of abuse and the biological mediators of psychiatric illnesses reportedly interact in the brain and presumptively worsen HIV-related neuropathogenesis and survival measures. A panel of experts discussed approaches for studying the neuroscience of HIV and psychiatric comorbidity at a basic, mechanistic level since they co-exist in high proportion in the human population. Recommended approaches ranged from improving human consent forms and maximizing the value of repository resources to novel research designs and identifying human and animal endophenotypes. Published by Elsevier Inc. C1 NIMH, HIV Therapeut Clin Trials & Psychiat Pathogenesis, Ctr Mental Hlth Res AIDS, NIH, Rockville, MD 20852 USA. NIMH, Preclin Therapeut Dev Program, Ctr Mental Hlth Res AIDS, NIH, Rockville, MD 20852 USA. NIDA, Div Clin Neurosci & Behav Res, NIH, Rockville, MD 20852 USA. RP Kopnisky, KL (reprint author), NIMH, HIV Therapeut Clin Trials & Psychiat Pathogenesis, Ctr Mental Hlth Res AIDS, NIH, 6001 Execut Blvd,Room 6205 MSC 9619, Rockville, MD 20852 USA. EM kkopnisk@mail.nih.gov NR 152 TC 21 Z9 25 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAY PY 2007 VL 21 IS 4 BP 428 EP 441 DI 10.1016/j.bbi.2007.01.011 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 163LM UT WOS:000246161300008 PM 17346925 ER PT J AU Hama, Y Koyama, Y Urano, Y Choyke, PL Kobayashi, H AF Hama, Yukihiro Koyama, Yoshinori Urano, Yasuteru Choyke, Peter L. Kobayashi, Hisataka TI Simultaneous two-color spectral fluorescence lymphangiography with near infrared quantum dots to map two lymphatic flows from the breast and the upper extremity SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE lymphatic drainage; imaging; breast cancer; lymph node; lymphedema; nanotechnology; quantum dots; spectral fluorescence imaging; near infrared ID MAGNETIC RESONANCE LYMPHANGIOGRAPHY; NODE BIOPSY; AXILLARY DISSECTION; CONTRAST AGENTS; CANCER; LYMPHEDEMA AB Due to their small size and poor access, the lymphatic function has been difficult to study in vivo. Especially difficult is the mapping of lymphatic drainage from two basins into the same node. Quantum dots can be used to perform multicolor images with high fluorescent intensity and are of a nano-size size suitable for lymphatic imaging via direct interstitial injection. Here we show simultaneous two-color in vivo wavelength-resolved spectral fluorescence lymphangiography using two near infrared quantum dots with different emission spectra, which allow non-invasive and simultaneous visualization of two separate lymphatic flows draining the breast and the upper extremity and variations in the drainage patterns and the water sheds within the axillary node. Two-color spectral fluorescence lymphangiography can provide insight into mechanisms of drainage from different lymphatic basins that may lead to sentinel lymph nodes detection of the breast cancer as well as prevention of complications such as lymphedema of the arm. C1 NCI, Ctr Canc Canc Res, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. RP Kobayashi, H (reprint author), NCI, Ctr Canc Canc Res, Mol Imaging Program, NIH, Bldg 10,Room 1B40,MSC 1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Intramural NIH HHS NR 14 TC 83 Z9 90 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 2007 VL 103 IS 1 BP 23 EP 28 DI 10.1007/s10549-006-9347-0 PG 6 WC Oncology SC Oncology GA 160TX UT WOS:000245966300003 PM 17028977 ER PT J AU Lee, SA Lee, KM Park, SK Choi, JY Kim, B Nam, J Yoo, KY Noh, DY Ahn, SH Kang, D AF Lee, Sang-Ah Lee, Kyoung-Mu Park, Sue Kyung Choi, Ji-Yeob Kim, Bongcheol Nam, Jinwu Yoo, Keun-Young Noh, Dong-Young Ahn, Sei-Hyun Kang, Daehee TI Genetic polymorphism of XRCC3 Thr(241)Met and breast cancer risk: case-control study in Korean women and meta-analysis of 12 studies SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE the genetic polymorphism of XRCC3 Thr(241)Met; breast cancer risk; case-control study in Korean women; meta-analysis ID DNA-REPAIR GENES; SINGLE NUCLEOTIDE POLYMORPHISMS; CHINESE POPULATION; COLORECTAL-CANCER; CLINICAL-TRIALS; RADIATION; SUSCEPTIBILITY; VARIANTS; ASSOCIATION; THR241MET AB To evaluate the relationship of genetic polymorphism in XRCC3 Thr(241)Met and the risk of breast cancer, a hospital-based case-control study was conducted in Korea. Histologically confirmed breast cancer cases (n = 574) and controls (n = 502) with no present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2001. Information on demographic characteristics and other information were collected by interviewed questionnaire. Genetic polymorphisms of XRCC3 Thr(241)Met (C > T) was determined by single base extention assay. The frequency of Thr/Thr, Thr/Met, and Met/Met genotype were 89.4, 10.4, 0.2% in cases and 92.3, 7.7, 0.0% in controls, respectively. Genotype distribution in controls fit well to the Hardy-Weinberg equilibrium (P = 0.74). XRCC3 codon 241 Thr/Met or Met/Met genotype moderately increased the risk of breast cancer (OR = 1.4, 95% CI: 0.87-2.33), but not significant in this study. In the results of meta-analysis using twelve reports, however, Thr/Met or Met/Met genotype increased the risk of breast cancer (OR = 1.08, 95%CI: 1.00-1.17). In conclusion, although the genetic polymorphism of XRCC3 Thr(241)Met was unlikely to have a substantial overall association in Korean women, the meta-analysis of studies, including ours, provided that Thr/Met and Met/Met was weakly increased the risk of breast cancer compare to Thr/Thr genotype. C1 Seoul Natl Univ, Coll Med, Inst Canc Res, Dept Prevent Med, Seoul 110799, South Korea. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Dept Epidemiol, Buffalo, NY 14263 USA. Pan Genom Co Ltd, Seoul, South Korea. Seoul Natl Univ, Coll Med, Dept Surg, Seoul 151, South Korea. Univ Ulsan, Coll Med, Dept Surg, Seoul, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Inst Canc Res, Dept Prevent Med, 28 Yongon Dong, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Choi, Ji-Yeob/J-2796-2012; Yoo, Keun-Young/J-5548-2012; Park, Sue Kyung/J-2757-2012 NR 32 TC 31 Z9 32 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 2007 VL 103 IS 1 BP 71 EP 76 DI 10.1007/s10549-006-9348-z PG 6 WC Oncology SC Oncology GA 160TX UT WOS:000245966300009 PM 17063279 ER PT J AU Trivers, KF Gammon, MD Abrahamson, PE Lund, MJ Flagg, EW Kaufman, JS Moorman, PG Cai, JW Olshan, AF Porter, PL Brinton, LA Eley, JW Coates, RJ AF Trivers, Katrina F. Gammon, Marilie D. Abrahamson, Page E. Lund, Mary Jo Flagg, Elaine W. Kaufman, Jay S. Moorman, Patricia G. Cai, Jianwen Olshan, Andrew F. Porter, Peggy L. Brinton, Louise A. Eley, J. William Coates, Ralph J. TI Association between reproductive factors and breast cancer survival in younger women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; reproductive factors; reproductive history; survival ID RISK-FACTORS; BODY-SIZE; PROGNOSIS; RECALL; CHILDBIRTH; PREGNANCY; DIAGNOSIS; ABORTION; HISTORY; PARITY AB This analysis investigated whether reproductive factors such as age at menarche, parity, and timing and outcomes of pregnancies were associated with survival among women with breast cancer younger than 55 years. Female residents of Atlanta, Georgia, and central New Jersey who were diagnosed with a primary, incident invasive breast cancer between 1990 and 1992 and enrolled in a population-based study (n = 1,264) were followed for 8-10 years. Detailed exposure and covariate information was collected via in-person interviews administered shortly after diagnosis. Vital status as of January 1, 2000 was ascertained through the National Death Index via the state cancer registries (n = 292 deaths). Cox regression methods were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for confounders. Parity of 4 or more births, as compared with nulliparity, was positively associated with all-cause mortality, [HR (95% CI) = 1.71 (1.09-2.67)]. Increased mortality was associated with having given birth within 5 years prior to diagnosis (<= 5 vs. > 5 years) [1.78 (1.28-2.47)], and was more pronounced among women with a pre-diagnostic body mass index of < 25 kg/m(2) [2.54 (1.61-4.00)]. Early age at menarche and early age at first birth also modestly increased mortality; history of miscarriage, induced abortion, and ever breastfeeding were not related to survival. These results may help elucidate breast cancer progression mechanisms and enable a better understanding of how reproductive characteristics influence breast cancer survival. C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent, Surveillance & Epidemiol Branch, Div Global Migrat & Quarantine, Natl Ctr Infect Dis, Atlanta, GA USA. Duke Univ, Med Ctr, Canc Prevent & Control Res Program, Dept Community & Family Med, Durham, NC 27706 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98104 USA. NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Winship Canc Ctr, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Trivers, KF (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM trivers@unc.edu RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NCI NIH HHS [R25 CA57726, T32 CA09330]; NIEHS NIH HHS [P30ES10126] NR 54 TC 27 Z9 27 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 2007 VL 103 IS 1 BP 93 EP 102 DI 10.1007/s10549-006-9346-1 PG 10 WC Oncology SC Oncology GA 160TX UT WOS:000245966300012 PM 17004111 ER PT J AU Korde, L Zujewski, J McShane, L Lukes, L Lebowitz, P Swain, S Finney, R Hunter, K AF Korde, L. Zujewski, J. McShane, L. Lukes, L. Lebowitz, P. Swain, S. Finney, R. Hunter, K. TI Gene expression profiling to predict response to neoadjuvant docetaxel and capecitabine for breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Meeting Abstract CT 29th Annual San Antonio Breast Cancer Symposium CY DEC 14-17, 2006 CL San Antonio, TX SP San Antonio Canc Inst, Baylor Coll Med, Canc Therapy & Res Ctr, Univ Texas, Hlth Sci Ctr C1 Natl Canc Inst, Bethesda, MD USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 2007 VL 103 IS 1 BP 119 EP 119 PG 1 WC Oncology SC Oncology GA 160TX UT WOS:000245966300022 ER PT J AU Bhanu, NV Aerbajinai, W Gantt, NM Jackson, EK Goh, SH Lee, YT Miller, JL AF Bhanu, Natarajan V. Aerbajinai, Wulin Gantt, Nicole M. Jackson, Edwin K. Goh, Sung-Ho Lee, Y. Terry Miller, Jeffery L. TI Cl-IB-MECA inhibits human erythropoiesis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Cl-IB-MECA; human; erythropoietin; erythropoiesis; cell cycle ID A3 ADENOSINE RECEPTOR; CELL-PROLIFERATION AB Candidate drugs are being sought for the suppression of human erythropoiesis. Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide] is a derivative of adenosine that inhibits the growth of leukaemic cell lines. To determine the effects of Cl-IB-MECA upon erythropoiesis, studies were performed by using an ex vivo culture system of primary human CD34+ cells. Cl-IB-MECA suppressed erythroblast growth and maturation at doses >= 50 mu mol/l through a mechanism of cell cycle inhibition and accumulation of cells in the G1/G0 phase. These findings demonstrate that Cl-IB-MECA inhibits human erythropoiesis, and suggest that further consideration of this drug is warranted for patients with erythrocytosis or polycythemia syndromes. C1 NIH, Mol Med Branch, NIDDK, Bethesda, MD 20892 USA. NIH, Mol & Clin Hematol Branch, NIDDK, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Ctr Clin Pharmacol, Pittsburgh, PA USA. RP Miller, JL (reprint author), NIH, Mol Med Branch, NIDDK, Bldg 10,Room 9B17, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 11 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2007 VL 137 IS 3 BP 233 EP 236 DI 10.1111/j.1365-2141.2007.06540.x PG 4 WC Hematology SC Hematology GA 152WR UT WOS:000245393400006 PM 17408462 ER PT J AU Isenberg, JS Jia, Y Field, L Ridnour, LA Sparatore, A Del Soldato, P Sowers, AL Yeh, GC Moody, TW Wink, DA Ramchandran, R Roberts, DD AF Isenberg, J. S. Jia, Y. Field, L. Ridnour, L. A. Sparatore, A. Del Soldato, P. Sowers, A. L. Yeh, G. C. Moody, T. W. Wink, D. A. Ramchandran, R. Roberts, D. D. TI Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE angiogenesis inhibitors; hsp27 phosphorylation; dithioles; nonsteroidal anti-inflammatory drugs ID IN-VIVO; TUMOR ANGIOGENESIS; NITRIC-OXIDE; TARGET; INDUCTION; SULINDAC; HSP27; HEAT-SHOCK-PROTEIN-27; CHEMOPREVENTION; CYTOSKELETON AB Background and purpose: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated antiangiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Experimental approach: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli: EGFP transgenic zebrafish embryos. Key results: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser 78 phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H2S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. Conclusions and implication: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD USA. Univ Milan, Ist Chim Farmaceut, Milan, Italy. CTG Pharma, Milan, Italy. NCI, Lab Metab, Frederick, MD 21701 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A33,10 Ctr Dr, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Sparatore, Anna/J-8634-2015; Wink, Michael/E-3803-2012 OI Roberts, David/0000-0002-2481-2981; Sparatore, Anna/0000-0003-2135-2649; Wink, Michael/0000-0002-7875-4510 NR 36 TC 11 Z9 11 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2007 VL 151 IS 1 BP 142 EP 151 DI 10.1038/sj.bjp.0707198 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 164JN UT WOS:000246230100014 ER PT J AU Cepollaro, C Lauretani, F Gozzini, A Masi, L Falchetti, A Monte, F Carbonell-Sala, S Tanini, A Corsi, AM Bandinelli, S Ferrucci, L Brandi, ML AF Cepollaro, C. Lauretani, F. Gozzini, A. Masi, L. Falchetti, A. Monte, F. Carbonell-Sala, S. Tanini, A. Corsi, A. M. Bandinelli, S. Ferrucci, L. Brandi, M. L. TI Relationship of volumetric bone mineral density and structural parameters with ER alpha gene polymorphisms SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE cortical thickness; ER alpha gene polymorphism; peripheral bone; quantitative computed tomography; volumetric bone mineral density ID ESTROGEN-RECEPTOR-ALPHA; VITAMIN-D-RECEPTOR; POSTMENOPAUSAL WOMEN; FRACTURE RISK; VERTEBRAL FRACTURES; ANDROGEN RECEPTOR; MUSCLE STRENGTH; FEMORAL-NECK; ASSOCIATION; MEN AB Bone mineral density (BMD) contributes to bone strength, and methods for clinical assessment of bone quality characteristics beyond what can be gathered by BMD are awaited. Peripheral quantitative computed tomography (pQCT) allows for separate assessments of cortical and trabecular bone, providing information on bone geometry. Previous studies examining the relationship between estrogen receptor alpha (ER alpha) gene polymorphisms and BMD have been performed in large populations. However, only limited information is available on the possible segregation of ER alpha gene polymorphisms with bone structural properties. The aim of our study was to evaluate the association of XbaI and PvuII ER alpha gene polymorphisms with QCT parameters. We studied 900 subjects (541 women, 449 men) participating to the InCHIANTI study. By tibial pQCT we evaluated trabecular volumetric BMD, cortical volumetric BMD, cortical bone area, and cortical thickness (CtTh). Subjects were genotyped for ER alpha gene PvuII and XbaI polymorphisms. Analysis of variance was used for statistical analysis. Male subjects with PP and XX genotypes had higher geometric parameters, and female subjects with XX and PP genotypes showed higher densitometric parameters than other genotypes; however, the differences did not reach statistical significance. After adjustment for potential confounders, we found a significant (P = 0.002) CtTh difference across PvuII polymorphism in male subjects, with higher CtTh values in PP genotypes with respect to Pp and pp genotypes. These results show a relationship between the presence of the P allele and higher values of CtTh in male subjects, indicating for ER alpha a role in the control of tibial bone geometry. C1 Univ Florence, Dept Internal Med, I-50139 Florence, Italy. Tuscany Hlth Reg Agcy, Florence, Italy. Univ Florence, Spin Off DeGene, Florence, Italy. Azienda Sanitaria Firenze, Florence, Italy. NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. RP Brandi, ML (reprint author), Univ Florence, Dept Internal Med, Viale Pieraccini 6, I-50139 Florence, Italy. EM mbrandi@dmi.unifi.it RI FALCHETTI, ALBERTO/Q-1787-2016; Lauretani, Fulvio/K-5115-2016 OI FALCHETTI, ALBERTO/0000-0002-6739-4417; Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [N01-AG-821336, N01-AG-916413]; NIMHD NIH HHS [263 MD 9164 13, R01 MD009164, 263 MD 821336] NR 50 TC 3 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD MAY PY 2007 VL 80 IS 5 BP 307 EP 315 DI 10.1007/s00223-007-9008-2 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 178AG UT WOS:000247193000002 PM 17505773 ER PT J AU Mariotto, AB Etzioni, R Krapcho, M Feuer, EJ AF Mariotto, Angela B. Etzioni, Ruth Krapcho, Martin Feuer, Eric J. TI Reconstructing PSA testing patterns between black and white men in the US from Medicare claims and the National Health Interview Survey SO CANCER LA English DT Article DE black men; white men; prostate-specific antigen; PSA testing patterns; Medicare; National Health Interview Survey ID PROSTATE-CANCER; UNITED-STATES; DECLINE; TRENDS; TRIAL; LUNG AB BACKGROUND. Frequencies of prostate-specific antigen (PSA) test administration were not actively monitored on a national level during the first decade of PSA testing. The objectives of this article were to reconstruct patterns of PSA testing between black and white men in the US and to determine the extent of any racial disparity in PSA use. METHODS. Data from the 2000 National Health Interview Survey were used to model the adoption of PSA and to estimate the distribution of age at first test. Longitudinal Medicare claims data were used to estimate the distribution of intervals between tests. The rates of initial and subsequent tests were then combined by simulation to reconstruct individual screening histories. Results are from the reconstructed model. RESULTS. Overall, 45% of white men and 43% of black men within ages 40-84 years had at least 1 PSA test by the year 2000. The authors found that among older men, whites adopted PSA screening earlier than blacks, whereas among younger men, this trend was reversed, with blacks adopting screening earlier than whites. Annual testing frequencies generated by the simulation model were higher for white men aged >= 60 years and higher for black men aged <60 years. CONCLUSIONS. Findings indicated fairly similar patterns overall of PSA testing for blacks and whites. These similarities indicated that racial disparity in PSA testing is probably not a major factor behind current racial differences in prostate cancer mortality rates and declines. Knowledge of patterns of screening is important to an understanding of the impact of population screening on cancer incidence and mortality, but retrospective data sources have significant limitations when used to estimate these patterns of care. C1 NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Infromat Management Serv Inc, Silver Spring, MD USA. RP Mariotto, AB (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd, Bethesda, MD 20892 USA. EM mariotta@mail.nih.gov NR 16 TC 49 Z9 50 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 1 PY 2007 VL 109 IS 9 BP 1877 EP 1886 DI 10.1002/cncr.22607 PG 10 WC Oncology SC Oncology GA 160JP UT WOS:000245937000026 PM 17372918 ER PT J AU Zhang, YW Wang, R Holford, TR Leaderer, B Zahm, SH Boyle, P Zhu, Y Qin, Q Zheng, TZ AF Zhang, Yawei Wang, Rong Holford, Theodore R. Leaderer, Brian Zahm, Shelia Hoar Boyle, Peter Zhu, Yong Qin, Qin Zheng, Tongzhang TI Family history of hematopoietic and non-hematopoietic malignancies and risk of non-Hodgkin lymphoma SO CANCER CAUSES & CONTROL LA English DT Article DE case-control study; lymphoma; non-Hodgkin; family history ID BREAST-CANCER RISK; C VIRUS-INFECTION; UNITED-STATES; CONNECTICUT WOMEN; POLYCHLORINATED-BIPHENYLS; ULTRAVIOLET-RADIATION; 1ST-DEGREE RELATIVES; EXPOSURE; EPIDEMIOLOGY; TRENDS AB Background Family history of hematopoietic malignancies has been linked to the risk of non-Hodgkin lymphoma (NHL). The relationship between family history of specific hematopoietic and non-hematopoietic malignancies and the risk of NHL and by NHL subtypes are unclear. Methods We analyzed data from a population-based case-control study in Connecticut women. A total of 601 histologically confirmed NHL incident cases and 717 randomly selected controls were included in the study. Unconditional logistic regression was used to estimate the association between family cancer history and risk of NHL overall and by NHL subtypes. Results Compared to women who reported to have no family history of any malignancies in first-degree relatives, those who reported to have a family history of lymphoma (OR = 2.2, 95%CI: 1.1-4.5) or leukemia (OR = 2.5, 95%CI: 1.2-5.2) had an increased risk of NHL. The risk was higher among women who had a sibling with lymphoma or leukemia than those who had parents with lymphoma or leukemia. Several non-hematopoietic malignancies in first-degree relatives, including cancer of the lung (OR = 1.7, 95%CI: 1.1-2.6) in first-degree relatives, stomach (OR = 2.2, 95%CI: 0.8-5.9) and pancreas (OR = 2.6, 95%CI: 0.9-7.1) in parents, as well as liver (OR = 5.0, 95%CI: 1.0-24.6), breast (OR = 2.2, 95%CI: 1.3-3.9), cervix (OR = 7.5, 95%CI: 0.9-64.9), and ovary (OR = 3.5, 95%CI: 1.1-11.5) in siblings were also associated with an increased risk of NHL. Conclusions The risk associated with a family history of malignancies in first degree-relatives appears to vary by type of first-degree relatives. C1 Yale Univ, Sch Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Int Agcy Res Canc, F-69372 Lyon, France. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Zhang, YW (reprint author), Yale Univ, Sch Epidemiol & Publ Hlth, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Wang, Rong/H-3112-2011; Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Wang, Rong/0000-0002-2169-4174; Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA62006] NR 48 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2007 VL 18 IS 4 BP 351 EP 359 DI 10.1007/s10552-006-0088-5 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 147HL UT WOS:000244993900002 PM 17206533 ER PT J AU Colt, JS Hartge, P Davis, S Cerhan, JR Cozen, W Severson, RK AF Colt, Joanne S. Hartge, Patricia Davis, Scott Cerhan, James R. Cozen, Wendy Severson, Richard K. TI Hobbies with solvent exposure and risk of non-Hodgkin lymphoma SO CANCER CAUSES & CONTROL LA English DT Article DE non-Hodgkin lymphoma; hobbies; solvents; epidemiology; exposure assessment ID OCCUPATIONAL EXPOSURES; ORGANIC-SOLVENTS; MALIGNANT-LYMPHOMAS; CHLOROPHENOLS; ACIDS AB Occupational exposure to solvents has been reported to increase non-Hodgkin lymphoma (NHL) risk in some, but not all, studies. In a population-based case-control study, we examined whether participation in selected hobbies involving solvent exposure increases NHL risk. We identified NHL cases diagnosed at ages 20-74 years between 1998 and 2000 in Iowa or metropolitan Los Angeles, Detroit, and Seattle. Controls were selected using random digit dialing or Medicare files. Computer-assisted personal interviews (551 cases, 462 controls) elicited data on model building, painting/silkscreening/artwork, furniture refinishing, and woodworking/home carpentry. Hobby participation (68% of cases, 69% of controls) was not associated with NHL risk (OR = 0.9, 95% CI = 0.7-1.2). Compared to people with none of the hobbies evaluated, those who built models had significantly lower risk (OR = 0.7, CI = 0.5-1.0), but risk did not vary with the number of years or lifetime hours. Risk estimates for the other hobbies were generally less than one, but the associations were not significant and there were no notable patterns with duration of exposure. Use of oil-based, acrylic, or water-based paints; paint strippers; polyurethane; or varnishes was not associated with NHL risk. We conclude that participation in hobbies involving exposure to organic solvents is unlikely to increase NHL risk. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Mayo Clin, Coll Med, Rochester, MN USA. Univ So Calif, Los Angeles, CA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Wayne State Univ, Dept Family Med, Detroit, MI USA. RP Colt, JS (reprint author), NCI, Epidemiol & Biostat Program, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,Suite 8112, Rockville, MD 20852 USA. EM coltj@mail.nih.gov OI Cerhan, James/0000-0002-7482-178X FU Intramural NIH HHS; NCI NIH HHS [N01-CN-67010-CP19114, N01-PC-65064, M01-PC-67009, N01-CN-67008] NR 17 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2007 VL 18 IS 4 BP 385 EP 390 DI 10.1007/s10552-006-0108-5 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 147HL UT WOS:000244993900005 PM 17262168 ER PT J AU Anderson, WF Matsuno, RK Sherman, ME Lissowska, J Gail, MH Brinton, LA Yang, XH Peplonska, B Chen, BE Rosenberg, PS Chatterjee, N Szeszenia-Dabrowska, N Bardin-Mikolajczak, A Zatonski, W Devesa, SS Garcia-Closas, M AF Anderson, William F. Matsuno, Rayna K. Sherman, Mark E. Lissowska, Jolanta Gail, Mitchell H. Brinton, Louise A. Yang, Xiaohong (Rose) Peplonska, Beata Chen, Bingshu E. Rosenberg, Philip S. Chatterjee, Nilanjan Szeszenia-Dabrowska, Neonila Bardin-Mikolajczak, Alicja Zatonski, Witold Devesa, Susan S. Garcia-Closas, Montserrat TI Estimating age-specific breast cancer risks: a descriptive tool to identify age interactions SO CANCER CAUSES & CONTROL LA English DT Article DE population-based case-control study; absolute risks; relative risks; odds ratio; rate ratios ID END RESULTS DATABASE; COLLABORATIVE REANALYSIS; FEMALE BREAST; WOMEN; EPIDEMIOLOGY; SURVEILLANCE; PREGNANCY; DIAGNOSIS; BIRTH C1 NCI, DHHS, DCEG, Biostat Branch,EPS,NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Ctr Canc, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. Marie Sklodowska Curie Inst Oncol, PL-02781 Warsaw, Poland. Nofer Inst Occupat Med, Lodz, Poland. RP Anderson, WF (reprint author), NCI, DHHS, DCEG, Biostat Branch,EPS,NIH, Room 8036,6120 Execut Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015 OI Lissowska, Jolanta/0000-0003-2695-5799; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562 NR 38 TC 37 Z9 40 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2007 VL 18 IS 4 BP 439 EP 447 DI 10.1007/s10552-006-0092-9 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 147HL UT WOS:000244993900011 PM 17216325 ER PT J AU Peters, U Leitzmann, MF Chatterjee, N Wang, YH Albanes, D Gelmann, EP Friesen, MD Riboli, E Hayes, RB AF Peters, Ulrike Leitzmann, Michael F. Chatterjee, Nilanjan Wang, Yinghui Albanes, Demetrius Gelmann, Edward P. Friesen, Marlin D. Riboli, Elio Hayes, Richard B. TI Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BASE-LINE CHARACTERISTICS; RETINOL EFFICACY TRIAL; DIETARY BETA-CAROTENE; ALPHA-TOCOPHEROL; PLASMA LYCOPENE; VITAMIN-C; TOMATO PRODUCTS; FOLLOW-UP; ANTIOXIDANT; MEN AB Background: Reports from several studies have suggested that carotenoids, and in particular lycopene, could be prostate cancer-preventive agents. This has stimulated extensive laboratory and clinical research, as well as much commercial and public enthusiasm. However, the epidemiologic evidence remains inconclusive. Materials and Methods: We investigated the association between prediagnostic serum carotenoids (lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin) and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to examine methods of early detection and risk factors for cancer. The study included 692 incident prostate cancer cases, diagnosed 1 to 8 years after study entry, including 270 aggressive cases, with regional or distant stage (n = 90) or Gleason score >= 7 (n = 235), and 844 randomly selected, matched controls. As study participants were selected from those who were assigned to annual standardized screening for prostate cancer, results are unlikely to be biased by differential screening, a circumstance that is difficult to attain under non-trial conditions. Results: No association was observed between serum lycopene and total prostate cancer [odds ratios (OR), 1.14; 95% confidence intervals (95% CI), 0.82-1.58 for highest versus lowest quintile; P for trend, 0.281 or aggressive prostate cancer (OR, 0.99; 95% CI, 0.62-1.57 for highest versus lowest quintile; P for trend, 0.433). beta-Carotene was associated with an increased risk of aggressive prostate cancer (OR, 1.67; 95% CI, 1.03-2.72 for highest versus lowest quintile; P for trend, 0.13); in particular, regional or distant stage disease (OR, 3.16; 95% CI, 1.37-7.31 for highest versus lowest quintile; P for trend, 0.02); other carotenoids were not associated with risk. Conclusion: In this large prospective study, high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer. Lycopene and other carotenoids were unrelated to prostate cancer. Consistent with other recent publications, these results suggest that lycopene or tomato-based regimens will not be effective for prostate cancer prevention. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. Univ Washington, Seattle, WA 98195 USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20057 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Int Agcy Res Canc, Nutr & Canc Unit, F-69372 Lyon, France. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, POB 19024,1100 Fairview Ave N,MB-B402, Seattle, WA 98109 USA. EM upeters@fhcrc.org RI Friesen, Marlin/D-7328-2012; Albanes, Demetrius/B-9749-2015 NR 75 TC 89 Z9 93 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2007 VL 16 IS 5 BP 962 EP 968 DI 10.1158/1055-9965.EPI-06-0861 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 170FX UT WOS:000246649200020 PM 17507623 ER PT J AU Hsing, AW Stanczyk, FZ Belanger, A Schroeder, P Chang, L Falk, RT Fears, TR AF Hsing, Ann W. Stanczyk, Frank Z. Belanger, Alain Schroeder, Paul Chang, Lilly Falk, Roni T. Fears, Thomas R. TI Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROSTATE-CANCER; POSTMENOPAUSAL WOMEN; HORMONE LEVELS; INTERLABORATORY CONCORDANCE; RELIABILITY; VALIDITY; RADIOIMMUNOASSAYS; EPIDEMIOLOGY; ESTROGENS; ANDROGENS AB There is an increasing trend to apply gas chromatography combined with mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry (LC-MS/MS) assay methods to large-scale epidemiologic studies for the measurement of serum sex steroids. These methods are generally considered the gold standard for sex steroid measurements because of their accuracy, sensitivity, turnaround time, and ability to assess a more complete panel of steroid metabolites in the same run. In this report, we evaluated the precision, including within-batch (intra) and between-batch (inter) reproducibility, of steroid hormone measurements determined by GC-MS and LC-MS/MS assays and RIA and compared measurements among these methods. Specifically, 282 overnight fasting serum samples from 20 male volunteers were analyzed for 12 steroid metabolites by GC-MS or LC-MS/MS in one lab over a 4-month period. Six of the analytes were also measured by RIA in another lab. Unconjugated hormones, including testosterone, dihydrotestosterone, dehydroepiandrosterone, androstenedione, androst-5-ene-3 beta,17 beta-diol, estrone, and estradiol, were measured by GC-MS, whereas conjugated hormones, including DHEA sulfate, androsterone glucuronide, 5 alpha.-androstane-3 alpha,17 beta-diol 3-glucuronide, 5 alpha-androstane-3 alpha,17 beta-diol 17-glucuronide,and estrone sulfate, were measured by LC-MS/MS. A subset of these hormones, including testosterone, dihydrotestosterone, androstenedione, 5 alpha-androstane-3 alpha,17 beta-diol 17-glucuronide, estrone, and estradiol, were also measured by RIA following extraction and chromatography. We used the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) to assess within- and between-batch assay variations. For the 12 analytes measured by GC-MS or LC-MS/MS, CVs and ICCs for within- and between-batch measurements were similar, with CVs ranging from 6.1% to 21.4% and ICCs ranging from 87.6% to 99.2%. The six analytes measured by RIA had good CVs and ICCs, with CVs < 10% and ICCs > 70% (range, 71.7-99.7%). For the six metabolites that were measured by both methods, the CVs were similar, whereas the ICCs were generally higher with the GC-MS method. The absolute values for each analyte measured by RIA and GC-MS differed, with RIAs usually yielding markedly higher levels than GC-MS, although the Pearson and Spearman correlation coefficients for these six analytes were near one and all were significant (P < 0.001). Our results show that RIA, GC-MS, and LC-MS/MS assays for androgens and estrogens in the two labs included in the study have good reproducibility, as measured by small CVs (< 15%) and high ICCs (> 80%), with the exception of estradiol (71.7%) when measured by RIA. Despite substantial differences in absolute measurements of sex steroid hormones by RIA and MS methods, correlations between the two assays for the six sex steroids measured in the two labs were high (> 0.9). However, it is important for future large epidemiologic studies to incorporate MS with high reproducibility and specificity to measure a more complete profile of androgen and estrogen metabolites to clarify the role of sex steroids in prostate cancer. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ So Calif, Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ Quebec, Ctr Hosp, Oncol & Mol Endocrinol Res Ctr, Ste Foy, PQ G1V 2M3, Canada. Univ Laval, Quebec City, PQ G1K 7P4, Canada. Westat Corp, Rockville, MD USA. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, MSC 7234,6120 Execut Blvd, Rockville, MD 20852 USA. EM hsinga@mail.nih.gov FU Intramural NIH HHS NR 23 TC 104 Z9 109 U1 2 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2007 VL 16 IS 5 BP 1004 EP 1008 DI 10.1158/1055-9965.EPI-06-0792 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 170FX UT WOS:000246649200026 PM 17507629 ER PT J AU Berrigan, D Potischman, N Dodd, KW Nicar, M McQuillan, G Lavigne, JA Barrett, JC Ballard-Barbash, R AF Berrigan, David Potischman, Nancy Dodd, Kevin W. Nicar, Michael McQuillan, Geraldine Lavigne, Jackie A. Barrett, J. Carl Ballard-Barbash, Rachel TI Serum levels of insulin-like growth factor-I and insulin-like growth factor-I binding protein-3: Quality control for studies of stored serum SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FACTOR BINDING-PROTEIN-3 CONCENTRATIONS; IGF-I; BREAST-CANCER; RISK; PLASMA; DISEASE; WOMEN; NEOPLASIA; HORMONES; ALCOHOL AB The insulin-like growth factor (IGF) axis, particularly IGF-I and IGF binding protein-3 (IGFBP-3), has been the subject of much attention because of its role in juvenile growth and their association with cancers at several sites. However, epidemiologic studies of IGF-I and IGFBP-3 have had mixed results and several authors have speculated that quality control (QC), sample storage history, and other methodologic concerns could play a role in this heterogeneity. This article documents the results of storage history and QC efforts for a study of IGF-I and IGFBP-3 in 6,226 serum samples from the National Health and Nutrition Examination Survey III (NHANES III). The study was carried out on site at Diagnostic Systems Laboratories in Webster, Texas, using the IGF-I ELISA (DSL 10-5600) and the IGFBP-3 immunoradiometric assay (DSL 6600). A run-in study of assay performance suggested that plates, days, and weeks significantly affected the variance of both assays. Analysis of samples with different storage histories also indicated strong effects of storage history. Serum samples disbursed to laboratories for measurement of diverse analytes and then returned for storage showed reductions in serum IGF-I level averaging 43% and reductions in IGFBP-3 of 25% compared with samples shipped immediately to the repository for long-term storage at -80 degrees C. Therefore, the main study was carried out using samples that had been shipped directly to the National Center for Health Statistics/NHANES collection center for storage. Laboratory analyses of NHANES III and QC samples were carried out over similar to 10 months. QC was monitored through repeated testing of blood samples from six individuals, with two individuals tested twice on each plate. Assay performance was stable over the entire study and coefficients of variation averaged 2% to 3% within plates and similar to 14% for IGF-I and similar to 11.5% for IGFBP-3 over the entire study. Coefficients of variation varied significantly among individual QC subjects, ranging from 12.3% to 17.6% for IGF-I and 8.9% to 12.8% for IGFBP-3. Based on Levy-Jennings plots, similar to 5% of the plates used for IGF-I in the main study were out of compliance. Finally, location on a plate had small but significant effects on IGF-I level. Together, these results highlight the need for care in large studies of putative biomarkers for cancer risk and illustrate some probable sources of heterogeneity in past epidemiologic studies of the IGF axis and cancer. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX USA. Natl Ctr Hlth Stat, Ctr Dis Control, Hyattsville, MD 20782 USA. RP Berrigan, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Room 4095B,Execut Plaza N,MSC 7344, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov NR 30 TC 21 Z9 21 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2007 VL 16 IS 5 BP 1017 EP 1022 DI 10.1158/1055-9965.EPI-07-0044 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 170FX UT WOS:000246649200028 PM 17507631 ER PT J AU Feigelson, HS Rodriguez, C Welch, R Hutchinson, A Shao, W Jacobs, K Diver, WR Calle, EF Thun, MJ Hunter, DJ Thomas, G Chanock, SJ AF Feigelson, Heather Spencer Rodriguez, Carmen Welch, Robert Hutchinson, Amy Shao, Wen Jacobs, Kevin Diver, W. Ryan Calle, Eugenia F. Thun, Michael J. Hunter, David J. Thomas, Gilles Chanock, Stephen J. TI Successful genome-wide scan in paired blood and buccal samples SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MULTIPLE DISPLACEMENT AMPLIFICATION; SINGLE NUCLEOTIDE POLYMORPHISM; AMPLIFIED DNA; WHOLE; ASSOCIATION; MOUTHWASH; COLLECTION; COHORT; YIELD AB Interest in genome-wide association studies to identify susceptibility alleles for cancer is growing, and several are currently planned or under way. Although the feasibility of collecting buccal cell samples as an alternative to venous blood samples as a source of genomic DNA has been shown, the validity of using DNA from buccal cells for genome-wide scans has not been assessed. We used 46 paired buffy coat and buccal cell samples to test the feasibility of using DNA from buccal cells for genotyping with the HumanHap300 Bead Chip (v.1.0.0) on the Illumina Infinium II platform. Genotyping was successful in every sample, regardless of DNA yield or sample type. Of the 317,502 genotypes attempted, 315,314 (99.3%) were successfully called. Completion rates were similar for buffy coat and buccal cell samples (99.63% and 99.44%, respectively; P = 0.15). Completion rates < 99% were observed in only four samples and did not differ by specimen type. The paired samples showed exceptionally high concordance (99.96%). These results show that buccal cell samples collected and processed under optimal conditions can be used for genome-wide association studies with results comparable to those obtained from DNA extracted from buffy coat. C1 Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. NCI, Intramural Res Support Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. NCI, Core Genotyping Facil, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Sect Genom Variat, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. RP Feigelson, HS (reprint author), Amer Canc Soc, Dept Epidemiol & Surveillance Res, 1599 Clifton Rd NE, Atlanta, GA 30329 USA. EM heather.feigelson@cancer.org NR 20 TC 15 Z9 15 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2007 VL 16 IS 5 BP 1023 EP 1025 DI 10.1158/1055-9965.EPI-06-0859 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 170FX UT WOS:000246649200029 PM 17507632 ER PT J AU Eriksson, F Culp, WD Massey, R Egevad, L Garland, D Persson, MAA Pisa, P AF Eriksson, Fredrik Culp, W. David Massey, Robert Egevad, Lars Garland, Donita Persson, Mats A. A. Pisa, Pavel TI Tumor specific phage particles promote tumor regression in a mouse melanoma model SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE phage display; cancer immunotherapy; targeting; innate immunity ID PEPTIDE LIBRARIES; IN-VIVO; DISPLAY; ANTIBODIES; ANTIGENS; PROSTATE; CANCER; VIRUS; CELLS; BACTERIOPHAGE AB Within cancer research, phage display libraries have been widely used for the identification of tumor targeting peptides and antibodies. Additionally, phages are known to be highly immunogenic; therefore we evaluated the immunotherapeutic potential of tumor specific phages to treat established solid tumors in a mouse model of melanoma. We developed two tumor specific phages, one derived from a peptide phage display library and one Fab expressing phage with known specificity, for the treatment of mice bearing palpable B16-F10 or B16/A2K(b) tumors. Therapy in B16-F10 tumor bearing mice with tumor specific phages was superior to treatment with non-tumor specific phages and lead to delayed tumor growth and increased survival. In B16/A2K(b) tumor bearing mice, therapy with tumor specific phages resulted in complete tumor regression and long-term survival in 50% of the mice. Histological analysis of tumors undergoing treatment with tumor specific phages revealed that phage administration induced a massive infiltration of polymorphonuclear neutrophils. Furthermore, phages induced secretion of IL-12 (p70) and IFN-gamma as measured in mouse splenocyte culture supernatants. These results demonstrate a novel, immunotherapeutic cancer treatment showing that tumor specific phages can promote regression of established tumors by recruitment of inflammatory cells and induction of Th1 cytokines. C1 Karolinska Univ Hosp, CCK, S-17176 Stockholm, Sweden. Karolinska Inst, Canc Ctr Karolinska, Immune & Gene Therapy Lab, Dept Oncol & Pathol, S-17176 Stockholm, Sweden. NEI, Prot Biochem Sect, NIH, Bethesda, MD 20892 USA. Tumor Res Inst, Washington, DC USA. Karolinska Univ Hosp, Ctr Mol Med, Dept Med, S-17176 Stockholm, Sweden. RP Eriksson, F (reprint author), Karolinska Univ Hosp, CCK, R8-01, S-17176 Stockholm, Sweden. EM fredrik.eriksson@ki.se OI Eriksson, Fredrik/0000-0001-9548-3276; Egevad, Lars/0000-0001-8531-222X NR 39 TC 31 Z9 33 U1 4 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2007 VL 56 IS 5 BP 677 EP 687 DI 10.1007/s00262-006-0227-6 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA 142UX UT WOS:000244677000008 PM 16967280 ER PT J AU Erez, A Castiel, A Trakhtenbrot, L Perelman, M Rosenthal, E Goldstein, I Stettner, N Harmelin, A Eldar-Finkelman, H Campaner, S Kirsch, I Izraeli, S AF Erez, Ayelet Castiel, Asher Trakhtenbrot, Luba Perelman, Marina Rosenthal, Esther Goldstein, Itamar Stettner, Noa Harmelin, Alon Eldar-Finkelman, Hagit Campaner, Stefano Kirsch, Ilan Izraeli, Shai TI The SIL gene is essential for mitotic entry and survival of cancer cells SO CANCER RESEARCH LA English DT Article ID MAMMALIAN-CELLS; EXPRESSION; MITOSIS; CHECKPOINT; PROTEIN; TUMORS AB Although mitosis is a general physiologic process, cancer cells are unusually sensitive to mitotic inhibitors. Therefore, there is an interest in the identification of novel mitotic inhibitors. Here, we report the novel discovery of the SIL gene as a regulator of mitotic entry and cell survival. The SLE gene was cloned from leukemia-associated chromosomal translocation. It encodes a cytosolic protein with an unknown function and no homology to known proteins. Previously, we observed an increased expression of SIL in multiple cancers that correlated with the expression of mitotic spindle checkpoint genes and with increased metastatic potential. Here, we show that SIL is important for the transition from the G(2) to the M phases of the cell cycle. Inducible knockdown of SIL in cancer cells in vitro delayed entrance into mitosis, decreased activation of the CDK1 (CDC2)-cyclin B complex, and induced apoptosis in a p530-independent manner. SIL is also essential for the growth of tumor explants in mice. Thus, SIL is required for mitotic entry and cancer cell survival. Because increased expression of SIL has been noted in multiple types of cancers and correlates with metastatic spread, it may be a suitable target for novel anticancer therapy. C1 Chaim Sheba Med Ctr, Dept Pediat Hemato Oncol, IL-52621 Tel Hashomer, Israel. Sheba Med Ctr, Inst Hematol, Tel Hashomer, Israel. Sheba Med Ctr, Dept Pathol, Tel Hashomer, Israel. Sheba Med Ctr, Dept Pediat Hematooncol, Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. Weizmann Inst Sci, Rehovot, Israel. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Izraeli, S (reprint author), Chaim Sheba Med Ctr, Dept Pediat Hemato Oncol, IL-52621 Tel Hashomer, Israel. EM sizraeli@sheba.health.gov.il NR 16 TC 23 Z9 24 U1 0 U2 1 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 MAY 1 PY 2007 VL 67 IS 9 BP 4022 EP 4027 DI 10.1158/0008-5472.CAN-07-0064 PG 6 WC Oncology SC Oncology GA 165UC UT WOS:000246330300007 PM 17456584 ER PT J AU Boylan, KLM Gosse, MA Staggs, SE Janz, S Grindle, S Kansas, GS Van Ness, BG AF Boylan, Kristin L. M. Gosse, Mary A. Staggs, Sarah E. Janz, Siegfried Grindle, Suzanne Kansas, Geoffrey S. Van Ness, Brian G. TI A Transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma SO CANCER RESEARCH LA English DT Article ID BCL-X-L; PRINCIPAL COMPONENT ANALYSIS; PLASMABLASTIC MORPHOLOGY; MOLECULAR CLASSIFICATION; PROSTATE-CANCER; BINDING-PROTEIN; B-CELLS; DIFFERENTIATION; REVEALS; GROWTH AB Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X-L in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 41), 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease. C1 Univ Minnesota, Minneapolis, MN 55455 USA. Northwestern Univ, Chicago, IL 60611 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Van Ness, BG (reprint author), Univ Minnesota, MMC 806,420 Delaware St SE, Minneapolis, MN 55455 USA. EM vanne001@tc.umn.edu FU NCI NIH HHS [P30 CA077598-09, R01 CA151354]; NHLBI NIH HHS [T32 HL007062-30]; NIAID NIH HHS [T32-AI007313, T32-AI007476] NR 59 TC 24 Z9 25 U1 0 U2 0 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 MAY 1 PY 2007 VL 67 IS 9 BP 4069 EP 4078 DI 10.1158/0008-5472.CAN-06-3699 PG 10 WC Oncology SC Oncology GA 165UC UT WOS:000246330300012 PM 17483317 ER PT J AU Trempus, CS Morris, RJ Ehinger, M Elmore, A Bortner, CD Ito, M Cotsarelis, G Nijhof, JGW Peckham, J Flagler, N Kissling, G Humble, MM King, LC Adams, LD Desai, D Amin, S Tennant, RW AF Trempus, Carol S. Morris, Rebecca J. Ehinger, Matthew Elmore, Amy Bortner, Carl D. Ito, Mayumi Cotsarelis, George Nijhof, Joanne G. W. Peckham, John Flagler, Norris Kissling, Grace Humble, Margaret M. King, Leon C. Adams, Linda D. Desai, Dhimant Amin, Shantu Tennant, Raymond W. TI CD34 expression by hair follicle stem cells is required for skin tumor development in mice SO CANCER RESEARCH LA English DT Article ID LABEL-RETAINING CELLS; PROGENITOR CELLS; DNA-ADDUCTS; INTERFOLLICULAR EPIDERMIS; BIOCHEMICALLY DISTINCT; BULGE CELLS; L-SELECTIN; CARCINOGENESIS; IDENTIFICATION; MARKER AB The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice. C1 NIEHS, Canc Biol Grp, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Columbia Univ, Med Ctr, Dept Dermatol, New York, NY USA. Integrated Lab Syst Inc, Durham, NC USA. Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. Penn State Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA USA. RP Trempus, CS (reprint author), NIEHS, Canc Biol Grp, Mol Toxicol Lab, 111 TW Alexander Dr,Mail Drop F1-05, Res Triangle Pk, NC 27709 USA. EM trempus@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999]; NCI NIH HHS [R01 CA097957-05, CA97957, R01 CA097957] NR 57 TC 77 Z9 83 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2007 VL 67 IS 9 BP 4173 EP 4181 DI 10.1158/0008-5472.CAN-06-3128 PG 9 WC Oncology SC Oncology GA 165UC UT WOS:000246330300024 PM 17483328 ER PT J AU Palmieri, D Bronder, JL Herring, JM Yoneda, T Weil, RJ Stark, AM Kurek, R Vega-Valle, E Feigenbaum, L Halverson, D Vortmeyer, AO Steinberg, SM Aldape, K Steeg, PS AF Palmieri, Diane Bronder, Julie L. Herring, Jeanne M. Yoneda, Toshiyuki Weil, Robert J. Stark, Andreas M. Kurek, Raffael Vega-Valle, Eleazar Feigenbaum, Lionel Halverson, Douglas Vortmeyer, Alexander O. Steinberg, Seth M. Aldape, Kenneth Steeg, Patricia S. TI Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain SO CANCER RESEARCH LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR RECEPTOR; TRASTUZUMAB-BASED THERAPY; ADJUVANT CHEMOTHERAPY; MONOCLONAL-ANTIBODY; CNS METASTASES; IN-VITRO; RISK; ACTIVATION; EXPRESSION AB Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2-amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2-overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 mu m(2); P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. C1 NCI, Mol Pharmacol Lab, Womens Canc Sect, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Lab Anim Sci Program, Sci Applicat Int Corp, NIH, Frederick, MD 21701 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. Brain Tumor Inst, Cleveland, OH USA. Univ Schleswig Holstein, Med Ctr, Kiel, Germany. Univ Tubingen, Dept Obstet & Gynecol, D-7400 Tubingen, Germany. Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. RP Palmieri, D (reprint author), NCI, Mol Pharmacol Lab, Womens Canc Sect, NIH, Bldg 37,MSC 4254, Bethesda, MD 20892 USA. EM palmierd@mail.nih.gov RI Palmieri, Diane/B-4258-2015; OI Mason, Julie/0000-0002-5144-175X NR 49 TC 150 Z9 151 U1 1 U2 7 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 MAY 1 PY 2007 VL 67 IS 9 BP 4190 EP 4198 DI 10.1158/0008-5472.CAN-06-3316 PG 9 WC Oncology SC Oncology GA 165UC UT WOS:000246330300026 PM 17483330 ER PT J AU Sedelnikova, OA Nakamura, A Kovalchuk, O Koturbash, I Mitchell, SA Marino, SA Brenner, DJ Bonner, WM AF Sedelnikova, Olga A. Nakamura, Asako Kovalchuk, Olga Koturbash, Igor Mitchell, Stephen A. Marino, Stephen A. Brenner, David J. Bonner, William M. TI DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models SO CANCER RESEARCH LA English DT Article ID INDUCED GENOMIC INSTABILITY; IN-VIVO; IONIZING-RADIATION; TARGETED IRRADIATION; UROTHELIAL EXPLANTS; METHYLATION CHANGES; HUMAN FIBROBLASTS; GAMMA-H2AX FOCI; HISTONE H2AX; SENESCENCE AB The "radiation-induced bystander effect;" in which irradiated cells can induce genomic instability in unirradiated neighboring cells, has important implications for cancer radiotherapy and diagnostic radiology as well as for human health in general. Although the mechanisms of this effect remain to be elucidated, we reported previously that DNA double-strand breaks (DSBs), directly measured by gamma-H2AX focus formation assay, are induced in bystander cultured cells. To overcome the deficiencies of cultured cell studies, we examined alpha-particle microbeam irradiation-induced bystander effects in human tissue models, which preserve the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. In marked contrast to DNA DSB dynamics in irradiated cells, in which maximal DSB formation is seen 30 min after irradiation, the incidence of DSBs in bystander cells reached a maximum by 12 to 48 h after irradiation, gradually decreasing over the 7-day time course. At the maxima, 40% to 60% of bystander cells were affected, a 4- to 6-fold increase over controls. These increases in bystander DSB formation were followed by increased levels of apoptosis and micronucleus formation, by loss of nuclear DNA methylation, and by an increased fraction of senescent cells. These findings show the involvement of DNA DSBs in tissue bystander responses and support the notion that bystander DNA DSBs are precursors to widespread downstream effects in human tissues. Bystander cells exhibiting postirradiation signs of genomic instability may be more prone than unaffected cells to become cancerous. Thus, this study points to the importance of considering the indirect biological effects of radiation in cancer risk assessment. C1 NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. Columbia Univ, Coll Phys & Surg, Ctr Radiol Res, Radiol Res Accelerator Facil, New York, NY USA. RP Sedelnikova, OA (reprint author), NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Room 5050,Bldg 37,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sedelnio@mail.nih.gov FU NCI NIH HHS [P01 CA49062]; NIBIB NIH HHS [P41 EB002033-09] NR 50 TC 124 Z9 132 U1 1 U2 17 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 MAY 1 PY 2007 VL 67 IS 9 BP 4295 EP 4302 DI 10.1158/0008-5472.CAN-06-4442 PG 8 WC Oncology SC Oncology GA 165UC UT WOS:000246330300038 PM 17483342 ER PT J AU Kim, CS Ying, H Willingham, MC Cheng, SY AF Kim, Caroline S. Ying, Hao Willingham, Mark C. Cheng, Sheue-Yann TI The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer SO CARCINOGENESIS LA English DT Article ID IODOTHYRONINE DEIODINASE; TARGETED MUTATION; BETA GENE; MICE; HORMONE; CARCINOMA; TUMORIGENESIS; EXPRESSION; PTTG; OVEREXPRESSION AB Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TR beta PV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TR beta PV mice with mice lacking PTTG (PTTG(-/-) mice). The thyroids of TR beta(PV/PV) PTTG(-/-) mice were significantly smaller than TR beta(PV/PV) mice. Ki-67 staining showed a decrease in thyroid proliferation in TR beta(PV/PV) PTTG(-/-) mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TR beta(PV/PV) PTTG(-/-) mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TR beta(PV/PV) and TR beta(PV/PV) PTTG(-/-) mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TR beta(PV/PV) PTTG(-/-) mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TR beta(PV/PV) PTTG(-/-) versus TR beta(PV/PV) thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription-polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options. C1 NCI, Canc Res Ctr, Mol Biol Lab, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Pathol, Winston Salem, NC 27157 USA. RP Cheng, SY (reprint author), NCI, Canc Res Ctr, Mol Biol Lab, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural NIH HHS NR 32 TC 35 Z9 36 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2007 VL 28 IS 5 BP 932 EP 939 DI 10.1093/carcin/bgl231 PG 8 WC Oncology SC Oncology GA 162WX UT WOS:000246121300005 PM 17127711 ER PT J AU Kim, I Morimura, K Shah, Y Yang, Q Ward, JM Gonzalez, FJ AF Kim, Insook Morimura, Keiichirou Shah, Yatrik Yang, Qian Ward, Jerrold M. Gonzalez, Frank J. TI Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice SO CARCINOGENESIS LA English DT Article ID HEPATIC STELLATE CELLS; MDR2 P-GLYCOPROTEIN; BILE-ACID; MOUSE HEPATOCARCINOGENESIS; LIVER FIBROSIS; ACTIVATION; EXPRESSION; GROWTH; PROLIFERATION; APOPTOSIS AB The farnesoid X receptor (FXR) controls the synthesis and transport of bile acids (BAs). Mice lacking expression of FXR, designated Fxr-null, have elevated levels of serum and hepatic BAs and an increase in BA pool size. Surprisingly, at 12 months of age, male and female Fxr-null mice had a high incidence of degenerative hepatic lesions, altered cell foci and liver tumors including hepatocellular adenoma, carcinoma and hepatocholangiocellular carcinoma, the latter of which is rarely observed in mice. At 3 months, Fxr-null mice had increased expression of the proinflammatory cytokine IL-1 beta mRNA and elevated beta-catenin and its target gene c-myc. They also had increased cell proliferation as revealed by increased PCNA mRNA and BrdU incorporation. These studies reveal a potential role for FXR and BAs in hepatocarcinogenesis. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005708-14] NR 37 TC 161 Z9 169 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2007 VL 28 IS 5 BP 940 EP 946 DI 10.1093/carcin/bgl249 PG 7 WC Oncology SC Oncology GA 162WX UT WOS:000246121300006 PM 17183066 ER PT J AU Sienkiewicz, P Ciolino, HP Leslie, BJ Hergenrother, PJ Singletary, K Yeh, GC AF Sienkiewicz, Pawel Ciolino, Henry P. Leslie, Benjamin J. Hergenrother, Paul J. Singletary, Keith Yeh, Grace Chao TI A novel synthetic analogue of a constituent of Isodon excisus inhibits transcription of CYP1A1,-1A2 and-1B1 by preventing activation of the aryl hydrocarbon receptor SO CARCINOGENESIS LA English DT Article ID CELL-CYCLE PROGRESSION; CYTOCHROME-P450 1A1; CANCER-CELLS; IDENTIFICATION; APOPTOSIS; EXPRESSION; TOXICITY; LIVER; HEPG2; GENE AB We investigated the effect of a novel synthetic analogue of a constituent from the Chinese medicinal herb Isodon excisus, 3-(3-methoxy-phenyl)-N-(3, 4, 5-trimethoxy-phenyl)-acrylamide (compound 343), on the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in human hepatoma HepG2 cells. We found that compound 343 inhibited the upregulation of cytochrome P-450 (CYP) enzyme activity in cells treated with the AhR ligands and potent carcinogens, dimethylbenz[a]anthracene (DMBA) or 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Compound 343 also inhibited the DMBA- or TCDD-induced increase in CYP1A1, -1A2 and -1B1 mRNA levels. Carcinogen-induced transcription of CYP genes was also suppressed by compound 343, as measured by a reporter gene controlled by the xenobiotic-responsive element (XRE). This was confirmed by measuring the amount of carcinogen-induced CYP1A1 heterogeneous nuclear RNA. Compound 343 blocked the DMBA- or TCDD-induced activation of the AhR DNA-binding capacity for the XRE, as measured by a chromatin immunoprecipitation assay. Compound 343 also inhibited CYP enzyme activity in microsomes isolated from DMBA- or TCDD-treated cells, as well as the activity of recombinant CYP1A1, -1A2 and -1B1, indicating that compound 343 directly inhibits CYP enzymes. These results indicate that compound 343 is both a potent inhibitor of carcinogen-induced CYP enzyme expression, as well as a direct inhibitor of CYP enzymes. C1 Natl Canc Inst, Ctr Canc Res, Cellular Def & Carcinogenesis Sect, Lab Metab,NIH, Frederick, MD 21702 USA. Univ Illinois, Dept Chem, Urbana, IL 61801 USA. Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. RP Yeh, GC (reprint author), Natl Canc Inst, Ctr Canc Res, Cellular Def & Carcinogenesis Sect, Lab Metab,NIH, Frederick, MD 21702 USA. EM yeh@ncifcrf.gov FU Intramural NIH HHS NR 29 TC 6 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2007 VL 28 IS 5 BP 1052 EP 1057 DI 10.1093/carcin/bgl248 PG 6 WC Oncology SC Oncology GA 162WX UT WOS:000246121300020 PM 17183067 ER PT J AU Wang, X Liu, L Montagna, C Ried, T Deng, CX AF Wang, X. Liu, L. Montagna, C. Ried, T. Deng, C-X TI Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE Brca1; Parp1; Ku70; genetic instability; cell death ID CELL-CYCLE CHECKPOINT; POLY(ADP-RIBOSE) POLYMERASE; BREAST-CANCER; DNA-REPAIR; CHROMOSOME STABILITY; GENOMIC STABILITY; TUMOR-FORMATION; IN-VIVO; BRCA1; MICE AB The breast tumor associated gene-1 ( BRCA1) and poly(ADP-ribose) polymerase-1 (PARP1) are both involved in DNA-damage response and DNA- damage repair. Recent investigations have suggested that inhibition of PARP1 represents a promising chemopreventive/therapeutic approach for specifically treating BRCA1- and BRCA2- associated breast cancer. However, studies in mouse models reveal that Parp1- null mutation results in genetic instability and mammary tumor formation, casting significant doubt on the safety of PARP1 inhibition as a therapy for the breast cancer. To study the genetic interactions between Brca1 and Parp1, we interbred mice carrying a heterozygous deletion of full- length Brca1 ( Brca1(+/Delta 11)) with Parp1- null mice. We show that Brca1(Delta 11/Delta 11); Parp1(-/-) embryos die before embryonic ( E) day 6.5, whereas Brca1(Delta 11/Delta 11) embryos die after E12.5, indicating that absence of Parp1 dramatically accelerates lethality caused by Brca1 deficiency. Surprisingly, haploinsufficiency of Parp1 in Brca1(Delta 11/ Delta 11) embryos induces a severe chromosome aberrations, centrosome amplification, and telomere dysfunction, leading to apoptosis and accelerated embryonic lethality. Notably, telomere shortening in Brca1(Delta 11/Delta 11); Parp1(+/-) MEFs was correlated with decreased expression of Ku70, which plays an important role in telomere maintenance. Thus, haploid loss of Parp1 is sufficient to induce lethality of Brca1-deficient cells, suggesting that partial inhibition of PARP1 may represent a practical chemopreventive/ therapeutic approach for BRCA1- associated breast cancer. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Univ S Florida, Coll Med, Lab Reprod Med, Dept Obstet & Gynecol, Tampa, FL USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 40 TC 13 Z9 15 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2007 VL 14 IS 5 BP 924 EP 931 DI 10.1038/sj.cdd.4402105 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FR UT WOS:000245851300005 PM 17318223 ER PT J AU Zhang, S Lin, Y Kim, YS Hande, MP Liu, ZG Shen, HM AF Zhang, S. Lin, Y. Kim, Y-S Hande, M. P. Liu, Z-G Shen, H-M TI c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE hydrogen peroxide; JNK1; PARP-1; non-apoptotic cell death; DNA damage ID RECEPTOR-INTERACTING PROTEIN; OXIDATIVE STRESS; REDOX REGULATION; IN-VITRO; APOPTOSIS; JNK; PHOSPHORYLATION; SIGNAL; INDUCTION; NECROSIS AB Reactive oxygen species ( ROS) have been closely associated with both apoptotic and non- apoptotic/ necrotic cell death. Our previous study has illustrated that c- Jun- N- terminal kinase 1 ( JNK1) is the main executor in hydrogen peroxide ( H2O2)- induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H2O2- induced cell death. In this study, poly( ADP- ribose) polymerase- 1 ( PARP- 1), a key DNA repair protein, was readily activated by H2O2 and inhibition of PARP- 1 activation by either a pharmacological or genetic approach offered significant protection against H2O2- induced cell death. More importantly, H2O2- mediated PARP- 1 activation is subject to regulation by JNK1. Suppression of JNK1 activation by a chemical inhibitor or genetic deletion markedly suppressed the late- phase PARP- 1 activation induced by H2O2, suggesting that JNK1 contributes to the sustained activation of PARP- 1. Such findings were supported by the temporal pattern of nuclear translocation of activated JNK and a direct protein - protein interaction between JNK1 and PARP- 1 in H2O2- treated cells. Finally, in vitro kinase assay suggests that PARP- 1 may serve as the direct phosphorylation target for JNK1. Taken together, data from our study reveal a novel underlying mechanism in H2O2- induced nonapoptotic cell death: JNK1 promotes a sustained PARP- 1 activation via nuclear translocation, protein - protein interaction and PARP- 1 phosphorylation. C1 Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, Singapore 117579, Singapore. Lovelace Resp Res Inst, Mol Biol & Lung Canc Program, Albuquerque, NM USA. NCI, Cell & Canc Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117548, Singapore. RP Shen, HM (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, Singapore 117579, Singapore. EM cofshm@nus.edu.sg RI SHEN, Han-Ming/B-5942-2011; Hande, M. Prakash/B-1645-2008; Zhang, Siyuan/A-1276-2014 OI SHEN, Han-Ming/0000-0001-7369-5227; Hande, M. Prakash/0000-0002-4511-6256; Zhang, Siyuan/0000-0003-0910-3666 NR 39 TC 60 Z9 63 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2007 VL 14 IS 5 BP 1001 EP 1010 DI 10.1038/sj.cdd.4402088 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FR UT WOS:000245851300013 PM 17218956 ER PT J AU Mandard, S Stienstra, R Escher, P Tan, NS Kim, I Gonzalez, FJ Wahli, W Desvergne, B Muller, M Kersten, S AF Mandard, S. Stienstra, R. Escher, P. Tan, N. S. Kim, I. Gonzalez, F. J. Wahli, W. Desvergne, B. Muller, M. Kersten, S. TI Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE PPAR; HNF4 alpha; liver; adipose tissue; microarray; glycogen synthase 2; gene transcription; PPRE ID ALPHA PPAR-ALPHA; FATTY-ACID OXIDATION; GLYCOGEN-SYNTHASE; SKELETAL-MUSCLE; RESPONSE ELEMENTS; ADIPOSE-TISSUE; IN-VIVO; BETA/DELTA; METABOLISM; GAMMA AB Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPAR alpha, PPAR beta/delta and PPAR gamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPAR alpha-/-, PPAR beta/delta-/- and PPAR gamma+/- mice. Furthermore, synthetic PPAR beta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPAR alpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4 alpha). In adipose tissue, which does not express HNF4 alpha, DR-1prom is occupied by PPAR beta/delta and PPAR gamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4 alpha is mediated by two distinct response elements. C1 Univ Wageningen & Res Ctr, Nutr Metab & Genom Grp, NL-6700 EV Wageningen, Netherlands. Univ Wageningen & Res Ctr, Nutrigenom Consortium, Div Human Nutr, NL-6700 EV Wageningen, Netherlands. Univ Basel, Inst Physiol, Pharmazentrum, Basel, Switzerland. Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland. NCI, Div Basic Sci, Lab Metab, Bethesda, MD 20892 USA. RP Kersten, S (reprint author), Univ Wageningen & Res Ctr, Nutr Metab & Genom Grp, POB 8129, NL-6700 EV Wageningen, Netherlands. EM sander.kersten@wur.nl RI Kersten, Sander/A-1116-2011; Muller, Michael/B-5795-2008; Stienstra, Rinke/A-4763-2015; Wahli, Walter/B-1398-2009; Desvergne, Beatrice/C-8892-2016; OI Kersten, Sander/0000-0003-4488-7734; Muller, Michael/0000-0002-5930-9905; Stienstra, Rinke/0000-0001-6729-7193; Wahli, Walter/0000-0002-5966-9089; Desvergne, Beatrice/0000-0001-5483-288X; MANDARD, Stephane/0000-0002-7298-821X NR 45 TC 38 Z9 39 U1 0 U2 1 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAY PY 2007 VL 64 IS 9 BP 1145 EP 1157 DI 10.1007/s00018-007-7006-1 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163QX UT WOS:000246178700009 PM 17437057 ER PT J AU Burlak, C Hammer, CH Robinson, MA Whitney, AR McGavin, MJ Kreiswirth, BN Deleo, FR AF Burlak, Christopher Hammer, Carl H. Robinson, Mary-Ann Whitney, Adeline R. McGavin, Martin J. Kreiswirth, Barry N. DeLeo, Frank R. TI Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection SO CELLULAR MICROBIOLOGY LA English DT Article ID FIBRONECTIN-BINDING PROTEINS; PANTON-VALENTINE LEUKOCIDIN; BACTERIAL SUPERANTIGENS; HUMAN NEUTROPHILS; PROTEOME ANALYSIS; EPITHELIAL-CELLS; PHOSPHOLIPASE-C; UNITED-STATES; IDENTIFICATION; EXPRESSION AB Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a threat to human health worldwide. Although progress has been made, mechanisms of CA-MRSA pathogenesis are poorly understood and a comprehensive analysis of CA-MRSA exoproteins has not been conducted. To address that deficiency, we used proteomics to identify exoproteins made by MW2 (USA400) and LAC (USA300) during growth in vitro. Two hundred and fifty unique exoproteins were identified by 2-dimensional gel electrophoresis coupled with automated direct infusion-tandem mass spectrometry (ADI-MS/MS) analysis. Eleven known virulence-related exoproteins differed in abundance between the strains, including alpha-haemolysin (Hla), collagen adhesin (Cna), staphylokinase (Sak), coagulase (Coa), lipase (Lip), enterotoxin C3 (Sec3), enterotoxin Q (Seq), V8 protease (SspA) and cysteine protease (SspB). Mice infected with MW2 or LAC produced antibodies specific for known or putative virulence factors, such as autolysin (Atl), Cna, Ear, ferritin (Ftn), Lip, 1-phosphatidylinositol phosphodiesterase (Plc), Sak, Sec3 and SspB, indicating the exoproteins are made during infection in vivo. We used confocal microscopy to demonstrate aureolysin (Aur), Hla, SspA and SspB are produced following phagocytosis by human neutrophils, thereby linking exoprotein production in vitro with that during host-pathogen interaction. We conclude that the exoproteins identified herein likely account in part for the success of CA-MRSA as a human pathogen. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Res Technol Branch, Mass Spectrometry Lab, NIH, Rockville, MD 20852 USA. Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M4N 3M5, Canada. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. Int Ctr Publ Hlth, Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. RP Deleo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural NIH HHS NR 56 TC 101 Z9 104 U1 2 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD MAY PY 2007 VL 9 IS 5 BP 1172 EP 1190 DI 10.1111/j.1462-5822.2006.00858.x PG 19 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 154KO UT WOS:000245506100009 PM 17217429 ER PT J AU Kocabas, C Katsenelson, N Kanswal, S Kennedy, MN Cui, XL Blake, MS Segal, DM Akkoyunlu, M AF Kocabas, Can Katsenelson, Nora Kanswal, Sunita Kennedy, Margaret N. Cui, Xinle Blake, Milan S. Segal, David M. Akkoyunlu, Mustafa TI Neisseria meningitidis type C capsular polysaccharide inhibits lipooligosaccharide-induced cell activation by binding to CD14 SO CELLULAR MICROBIOLOGY LA English DT Article ID HUMAN DENDRITIC CELLS; TOLL-LIKE RECEPTOR-4; BACTERIAL LIPOPOLYSACCHARIDE; IMMUNE-RESPONSES; ENDOTOXIN; PROTEIN; MACROPHAGES; EXPRESSION; LIGAND; LPS AB Encapsulated Neisseria meningitidis can invade mucosal barriers and cause systemic diseases. Activation of the innate immune system by conserved meningococcal molecules such as lipooligosaccharides (LOS) is essential for the generation of an effective host immune response. Here we show that the type C capsular polysaccharide of N. meningitidis (MCPS) inhibited LOS-induced interleukin-6 and TNF-alpha secretion from monocytes, and blocked the maturation of dendritic cells induced by LOS, while the capsular polysaccharide from group B streptococcus type III and t(4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll had no such effect. MCPS also inhibited the LOS-induced NF-kappa B activation and phosphorylation of signalling molecules such as ERK1/2, p38 and Jun N-terminal kinase. In a direct binding assay, MCPS manifested a concentration-dependent binding to recombinant lipoprotein binding protein and CD14, the two members of the LOS receptor complex. In addition, the binding of LOS to CD14 and lipopolysaccharide binding protein was inhibited by MCPS. We established that MCPS binding to CD14 is responsible for the inhibition of LOS-mediated cell activation because MCPS inhibition of LOS was reversed when access amounts of CD14 were added to culture media of HEK293 cells expressing TLR4 and MD-2, and the magnitude of recovery in LOS stimulation correlated with the increase in CD14 concentration. These results suggest a new virulence property of meningococcal capsular polysaccharides. C1 US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Rockville, MD 20852 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Akkoyunlu, M (reprint author), US FDA, Ctr Biol Evaluat & Res, Lab Bacterial Polysaccharides, Rockville, MD 20852 USA. EM Mustafa.Akkoyunlu@fda.hhs.gov RI Akkoyunlu, Mustafa/I-5712-2012 NR 38 TC 15 Z9 15 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD MAY PY 2007 VL 9 IS 5 BP 1297 EP 1310 DI 10.1111/j.1462-5822.2006.00872.x PG 14 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 154KO UT WOS:000245506100019 PM 17250593 ER PT J AU Sabatinelli, D Lang, PJ Keil, A Bradley, MM AF Sabatinelli, Dean Lang, Peter J. Keil, Andreas Bradley, Margaret M. TI Emotional perception: Correlation of functional MRI and event-related potentials SO CEREBRAL CORTEX LA English DT Article DE attention; emotion; ERP; fMRI; human; vision ID HUMAN SOMATOSENSORY CORTEX; AUDITORY-CORTEX; VISUAL-CORTEX; MOTIVATED ATTENTION; SIMULTANEOUS EEG; BRAIN ACTIVITY; BOLD SIGNAL; FMRI BOLD; ACTIVATION; AMYGDALA AB Dense-array electrocortical and functional hemodynamic measures of human brain activity were collected to assess the relationship between 2 established neural measures of emotional reactivity. Recorded in parallel sessions, the slow-wave late positive potential (LPP) and visual cortical blood oxygen level-dependent (BOLD) signals were both modulated by the rated intensity of picture arousal. The amplitude of the LPP correlated significantly with BOLD intensity in lateral occipital, inferotemporal, and parietal visual areas across picture contents. Estimated strength of modeled regional sources did not correlate significantly with regional BOLD intensity. These data suggest that the enhanced positive slow wave seen over posterior sites during emotional picture processing represents activity in a circuit of visual cortical structures, reflecting a perceptual sensitivity to the motivational relevance of visual scenes. C1 Univ Florida, CSEA, NIMH, Gainesville, FL 32610 USA. Univ Konstanz, Dept Psychol, D-7750 Constance, Germany. RP Sabatinelli, D (reprint author), Univ Florida, CSEA, NIMH, POB 100165, Gainesville, FL 32610 USA. EM sabat@ufl.edu RI Frank, David/E-8213-2012; Keil, Andreas/F-9427-2011; OI Keil, Andreas/0000-0002-4064-1924; sabatinelli, dean/0000-0001-7409-8504 FU NIDCR NIH HHS [DE13956]; NIMH NIH HHS [P50-MH072850] NR 50 TC 194 Z9 198 U1 5 U2 28 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD MAY PY 2007 VL 17 IS 5 BP 1085 EP 1091 DI 10.1093/cercor/bhl017 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 156VI UT WOS:000245677600009 PM 16769742 ER PT J AU Chudasama, Y Kralik, JD Murray, EA AF Chudasama, Y. Kralik, J. D. Murray, E. A. TI Rhesus monkeys with orbital prefrontal cortex lesions can learn to inhibit prepotent responses in the reversed reward contingency task SO CEREBRAL CORTEX LA English DT Article DE affective inhibition; response control; reward magnitude ID ANTERIOR CINGULATE CORTEX; ORBITOFRONTAL CORTEX; DECISION-MAKING; FRONTAL-CORTEX; MACACA-MULATTA; DISSOCIABLE CONTRIBUTIONS; MACAQUE MONKEYS; SELECTION; FOOD; PERFORMANCE AB Monkeys with lesions of the orbital prefrontal cortex (PFo) are impaired on behavioral tasks that require the ability to respond flexibly to changes in reward contingency (e.g., object reversal learning and extinction). These and related findings in rodents and humans have led to the suggestion that PFo is critical for the inhibitory control needed to overcome prepotent responses. To test this idea, we trained rhesus monkeys with PFo lesions and unoperated controls on acquisition of the reversed reward contingency task. In this task, selecting the smaller of 2 food quantities (1 half peanut [1P]) leads to receipt of the larger quantity (4 half peanuts [4P]) and vice versa. Choice of a larger quantity of food is a reliable prepotent response, and, accordingly, all monkeys initially selected 4P rather than one. With experience, however, all monkeys learned to select 1P in order to receive 4. Surprisingly, monkeys with PFo lesions learned as quickly as unoperated controls. Thus, PFo lesions do not yield a deficit in all tests that require the inhibition of a prepotent response. C1 NIMH, Lab Neuropsychol, Bethesda, MD 20892 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Chudasama, Y (reprint author), NIMH, Lab Neuropsychol, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM Yogita@ln.nimh.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 FU Intramural NIH HHS NR 50 TC 28 Z9 28 U1 3 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD MAY PY 2007 VL 17 IS 5 BP 1154 EP 1159 DI 10.1093/cercor/bhl025 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 156VI UT WOS:000245677600016 PM 16774961 ER PT J AU Tunbridge, EM Weickert, CS Kleinman, JE Herman, MM Chen, J Kolachana, BS Harrison, PJ Weinberger, DR AF Tunbridge, E. M. Weickert, C. S. Kleinman, J. E. Herman, M. M. Chen, J. Kolachana, B. S. Harrison, P. J. Weinberger, D. R. TI Catechol-o-methyltransferase enzyme activity and protein expression in human prefrontal cortex across the postnatal lifespan SO CEREBRAL CORTEX LA English DT Article DE COMT; development; dopamine; schizophrenia ID 22Q11.2 DELETION SYNDROME; FRONTAL-CORTEX; HUMAN-BRAIN; COGNITIVE FUNCTION; GENETIC-VARIATION; DOPAMINE RELEASE; COMT; SCHIZOPHRENIA; POLYMORPHISM; PERFORMANCE AB The prefrontal cortex (PFC) dopamine system, which is critical for modulating PFC function, undergoes remodeling until at least young adulthood in primates. Catechol-o-methyltransferase (COMT) alters extracellular dopamine levels in PFC, and its gene contains a functional polymorphism (Val(158)Met) that has been associated with variation in PFC function. We examined COMT enzyme activity and protein immunoreactivity in the PFC during human postnatal development. Protein was extracted from PFC of normal individuals from 6 age groups: neonates (1-4 months), infants (5-11 months), teens (14-18 years), young adults (20-24 years), adults (31-43 years), and aged individuals (68-86 years; n = 5-8 per group). There was a significant 2-fold increase in COMT enzyme activity from neonate to adulthood, paralleled by increases in COMT protein immunoreactivity. Furthermore, COMT protein immunoreactivity was related to Val(158)Met genotype, as has been previously demonstrated. The significant increase in COMT activity from neonate to adulthood complements previous findings of protracted postnatal changes in the PFC dopamine system and may reflect an increasing importance of COMT for PFC dopamine regulation during maturation. C1 Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England. NIMH, Gene Cognit & Psychosis Program, Intramural Res Program, NIHUS Dept Human & Human Serv, Bethesda, MD 20892 USA. RP Tunbridge, EM (reprint author), Univ Oxford, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, England. EM elizabeth.tunbridge@psych.ox.ac.uk RI Shannon Weickert, Cynthia/G-3171-2011; OI Tunbridge, Elizabeth/0000-0002-2966-2281 NR 41 TC 78 Z9 79 U1 3 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD MAY PY 2007 VL 17 IS 5 BP 1206 EP 1212 DI 10.1093/cercor/bhl032 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 156VI UT WOS:000245677600023 PM 16835293 ER PT J AU Kato, N Akai, M Zulkifli, L Matsuda, N Kato, Y Goshima, S Hazama, A Yamagami, M Guy, HR Uozumi, N AF Kato, Naoki Akai, Masaro Zulkifli, Lalu Matsuda, Nobuyuki Kato, Yasuhiro Goshima, Shinobu Hazama, Akihiro Yamagami, Mutsumi Guy, H. Robert Uozumi, Nobuyuki TI Role of positively charged amino acids in the M2(D) transmembrane helix of Ktr/Trk/HKT type cation transporters SO CHANNELS LA English DT Article DE positive charge; transporter; Ktr; HKT; salt bridge; channel ID K+-UPTAKE SYSTEMS; SACCHAROMYCES-CEREVISIAE; POTASSIUM CHANNEL; CRYSTAL-STRUCTURE; HIGH-AFFINITY; VIBRIO-ALGINOLYTICUS; ESCHERICHIA-COLI; HKT TRANSPORTERS; GATING MECHANISM; CALCIUM-PUMP AB Studies suggest that Ktr/Trk/HKT-type transporters have evolved from multiple gene fusions of simple K+ channels of the KcsA type into proteins that span the membrane at least eight times. Several positively charged residues are present in the eighth transmembrane segment, M2(D), in the transporters but not K+ channels. Some models of ion transporters require a barrier to prevent free diffusion of ions down their electrochemical gradient, and it is possible that the positively charged residues within the transporter pore may prevent transporters from being channels. Here we studied the functional role of these positive residues in three Ktr/Trk/HKT-type transporters (Synechocystis KtrB-mediated K+ uniporter, Arabidopsis AtHKT1-mediated Na+ uniporter and wheat TaHKT1-mediated K+/Na+ symporter) by examining K+ uptake rates in E. coli, electrophysiological measurements in oocytes and growth rates of E. coli and yeast. The conserved Arg near the middle of the M2(D) segment was essential for the K+ transport activity of KtrB and plant HKTs. Combined replacement of several positive residues in TaHKT1 showed that the positive residue at the beginning of the M2(D), which is conserved in many K+ channels, also contributed to cation transport activity. This positive residue and the conserved Arg both face towards the ion conducting pore side. We introduced an atomic-scale homology model for predicting amino acid interactions. Based on the experimental results and the model, we propose that a salt bridge(s) exists between positive residues in the M2D and conserved negative residues in the pore region to reduce electrostatic repulsion against cation permeation caused by the positive residue(s). This salt bridge may help stabilize the transporter configuration, and may also prevent the conformational change that occurs in channels. C1 [Uozumi, Nobuyuki] Tohoku Univ, Dept Biomol Engn, Grad Sch Engn, Sendai, Miyagi 9808579, Japan. [Kato, Naoki; Akai, Masaro; Zulkifli, Lalu; Matsuda, Nobuyuki; Kato, Yasuhiro; Goshima, Shinobu; Uozumi, Nobuyuki] Nagoya Univ, Biosci & Biotechnol Ctr, Nagoya, Aichi 4648601, Japan. [Hazama, Akihiro] Fukushima Med Univ, Dept Physiol, Sch Med, Fukushima, Japan. [Yamagami, Mutsumi] Inst Environm Sci, Aomori, Japan. [Guy, H. Robert] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Uozumi, N (reprint author), Tohoku Univ, Dept Biomol Engn, Grad Sch Engn, Aobayama 6 6 07, Sendai, Miyagi 9808579, Japan. EM uozumi@biophy.che.tohoku.ac.jp RI Kato, Yasuhiro/L-4328-2013; Kato, Naoki/D-4018-2017 OI Kato, Yasuhiro/0000-0002-7835-1754; Kato, Naoki/0000-0003-4410-4090 FU MEXT [19380058, 17078005]; JSPS FX This work was supported by a grants in aid for scientific research (19380058 and 17078005 to Nobuyuki Uozumi) from MEXT and JSPS. NR 46 TC 27 Z9 29 U1 0 U2 14 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6950 J9 CHANNELS JI Channels PD MAY-JUN PY 2007 VL 1 IS 3 BP 161 EP 171 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 344SP UT WOS:000258947900006 PM 18690031 ER PT J AU Henrich, CJ Goncharova, EI Wilson, JA Gardella, RS Johnson, TR McMahon, JB Takada, K Bokesch, HR Gustafson, KR AF Henrich, Curtis J. Goncharova, Ekaterina I. Wilson, Jennifer A. Gardella, Roberta S. Johnson, Tanya R. McMahon, James B. Takada, Kentaro Bokesch, Heidi R. Gustafson, Kirk R. TI Natural products active in aberrant c-Kit signaling SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE chemical biology; c-Kit; high-throughput screening; natural products ID TYROSINE KINASE INHIBITORS; FACTOR RECEPTOR/C-KIT; CELL FACTOR-RECEPTOR; HUMAN MAST-CELLS; CATALYTIC DOMAIN; CONSTITUTIVE ACTIVATION; ANNONACEOUS ACETOGENINS; CANCER-CELLS; WILD-TYPE; IN-VITRO AB Development of modulators of constitutively active, kinase domain mutants of c-Kit has proved to be very difficult. Therefore, a high-throughput differential cytotoxicity assay was developed to screen for compounds that preferentially kill cells expressing constitutively active c-Kit. The cells used in the assay, murine IC2 mast cells, express either the D814Y activating mutation (functionally equivalent to human D816Y) or wild type protein. This assay is robust and highly reproducible. When applied to libraries of natural product extracts (followed by assay-guided fractionation), two differentially active compounds were identified. To assess possible mechanisms of action, the active compounds were tested for inhibitory activity against a panel of signaling enzymes (including wild type and mutant c-Kit). Neither of the compounds significantly affected any of the 73 enzymes tested. The effects of commercially available modulators of known signaling components were also assessed using the screening assay. None of these inhibitors reproduced the differential activity seen with the natural products. Finally, both compounds were found to affect mitochondrial potential in cells expressing c-Kit(D814Y). These results suggest that the newly identified natural products may provide new avenues for intervention in aberrant c-Kit signaling pathways. C1 NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. SAIC, NCI, Basic Res Program, Frederick, MD 21702 USA. NCI, Data Mangagement Serv Inc, Frederick, MD USA. RP Henrich, CJ (reprint author), NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. EM henrichc@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 47 TC 7 Z9 7 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD MAY PY 2007 VL 69 IS 5 BP 321 EP 330 DI 10.1111/j.1747-0285.2007.00508.x PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 172HM UT WOS:000246794800004 PM 17539824 ER PT J AU Yee, SB Bourdi, M Masson, MJ Pohl, LR AF Yee, Steven B. Bourdi, Mohammed Masson, Mary Jane Pohl, Lance R. TI Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID INDUCED HEPATIC-NECROSIS; NITRIC-OXIDE; INDUCED HEPATOTOXICITY; INFLAMMATORY RESPONSE; OXIDATIVE STRESS; PROTECTIVE ROLE; T-CELLS; GM-CSF; INJURY; MICE AB Recent evidence suggests that a deficiency in one or more hepatoprotective regulatory mechanisms may contribute to determining susceptibility in drug-induced liver disease. In the present study, we investigated the role of interleukin (IL)-13 in acetaminophen (APAP)-induced liver disease (AILD). Following APAP (200 mg/kg) administration to male C57BL/6 wild-type (WT) mice, hepatotoxicity developed up to 24 h post-APAP, with a concomitant increase in serum IL-13 concentration. Pretreatment of these mice with an IL-13-neutralizing antibody exacerbated liver injury, as did APAP administration to IL-13 knockout (KO) mice in comparison to WT mice. No difference was observed in either overall APAP-protein adduct formation or liver glutathione levels between KO and WT mice following APAP administration, suggesting that the increased susceptibility of IL-13 KO mice to AILD was not due to enhanced APAP bioactivation but rather injurious downstream events. In this regard, multiplex antibody arrays were used to identify potential IL-13-regulated biomarkers, including various cytokines and chemokines, as well as nitric oxide (NO), associated with AILD that were present at higher concentrations in the sera of APAP-treated IL-13 KO mice than in WT mice. Subsequent inhibition studies determined interferon-gamma, NO, neutrophils, natural killer cells, and natural killer cells with T-cell receptors had pathologic roles in AILD in IL-13 KO mice. Taken together, these results suggest that IL-13 is a critical hepatoprotective factor modulating the susceptibility to AILD and may provide hepatoprotection, in part, by down-regulating protoxicant factors and cells associated with the innate immune system. C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Yee, SB (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH,Dept Hlth & Human Serv, 9000 Rockville Pike,Bldg 10,Room 8N110, Bethesda, MD 20892 USA. EM yees@mail.nih.gov FU Intramural NIH HHS NR 63 TC 35 Z9 36 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2007 VL 20 IS 5 BP 734 EP 744 DI 10.1021/TX600349f PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 169GT UT WOS:000246581400004 PM 17439248 ER PT J AU Sadaghiani, AM Verhelst, SHL Gocheva, V Hill, K Majerova, E Stinson, S Joyce, JA Bogyo, M AF Sadaghiani, Amir Masoud Verhelst, Steven H. L. Gocheva, Vasilena Hill, Kimberly Majerova, Eva Stinson, Sherman Joyce, Johanna A. Bogyo, Matthew TI Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases SO CHEMISTRY & BIOLOGY LA English DT Article ID CATHEPSIN-K INHIBITORS; CRYSTAL-STRUCTURE; PEPTIDES; PHASE; OSTEOPOROSIS; ANALOGS; COMPLEX; PROBE; VITRO AB The papain-family cathepsins are cysteine proteases that are emerging as promising therapeutic targets for a number of human disease conditions ranging from osteoporosis to cancer. Relatively few selective inhibitors for this family exist, and the in vivo selectivity of most existing compounds is unclear. We present here the synthesis of focused libraries of epoxysuccinyl-based inhibitors and their screening in crude tissue extracts. We identified a number of potent inhibitors that display selectivity for endogenous cathepsin targets both in vitro and in vivo. Importantly, the selectivity patterns observed in crude extracts were generally retained in vivo, as assessed by active-site labeling of tissues from treated animals. Overall, this study identifies several important compound classes and highlights the use of activity-based probes to assess pharmacodynamic properties of small-molecule inhibitors in vivo. C1 Stanford Sch Med, Dept Pathol, Stanford, CA 94305 USA. Stanford Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA. SAIC Frederick, Frederick, MD USA. Natl Canc Inst, Dev Therapeut Program, Frederick, MD 21702 USA. RP Bogyo, M (reprint author), Stanford Sch Med, Dept Pathol, 300 Pasteur Dr, Stanford, CA 94305 USA. EM mbogyo@stanford.edu OI Verhelst, Steven/0000-0002-7400-1319 FU NCI NIH HHS [N01-CO-12400, P01 CA072006]; NCRR NIH HHS [U54 RR020843]; NIBIB NIH HHS [R01 EB005011] NR 30 TC 46 Z9 47 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD MAY PY 2007 VL 14 IS 5 BP 499 EP 511 DI 10.1016/j.chembiol.2007.03.010 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 174MI UT WOS:000246946000005 PM 17524981 ER PT J AU Hegewald, MJ Lefor, MJ Jensen, RL Crapo, RO Kritchevsky, SB Haggerty, CL Bauer, DC Satterfield, S Harris, T AF Hegewald, Matthew J. Lefor, Michael J. Jensen, Robert L. Crapo, Robert O. Kritchevsky, Stephen B. Haggerty, Catherine L. Bauer, Douglas C. Satterfield, Suzanne Harris, Tamara CA Hlth Aging Body Composition Study TI Peak expiratory flow is not a quality indicator for spirometry - Peak expiratory flow variability and FEV1 are poorly correlated in an elderly population SO CHEST LA English DT Article DE forced expiratory flow rate; forced expiratory volume; peak expiratory flow; respiratory function tests; spirometry ID OCCUPATIONAL ASTHMA; TRACHEAL SIZE; VOLUME; STANDARDIZATION AB Background: Peak forced expiratory flow (PEF) and FEV1 are spirometry measures used in diagnosing and monitoring lung diseases. We tested the premise that within-test variability in PEF is associated with corresponding variability in FEV1 during a single test session. Methods: A total of 2,464 healthy adults from the Health, Aging, and Body Composition Study whose spirometry results met American Thoracic Society acceptability criteria were screened and analyzed. The three "best" test results (highest sum of FVC and FEV1) were selected for each subject. For those with acceptable spirometry results, two groups were created: group 1, normal FEV1/FVC ratio; group 2, reduced FEV1/FVC ratio. For each subject, the difference between the highest and lowest PEF (Delta PEF) and the associated difference between the highest and lowest FEV1 (Delta FEV1) were calculated. Regression analysis was performed using the largest PEF and best FEV1,and the percentage of Delta PEF (%Delta PEF) and percentage of Delta FEV1 (%Delta FEV1) were calculated in both groups. Results: Regression analysis for group I and group 2 showed an insignificant association between %Delta PEF and %Delta FEV1 (r(2) = 0.0001, p = 0.59, and r(2) = 0.040, p = 0.15, respectively). For both groups, a 29% Delta PEF was associated with a 1% Delta FEV1. Conclusion: Within a single spirometry test session, %Delta PEF and %Delta FEV1 contain independent information. PEF has a higher degree of intrinsic variability than FEV1. Changes in PEF do not have a significant effect on FEV1. Spirometry maneuvers should not be excluded based on peak flow variability. C1 Latter Day St Hosp, Div Pulm & Crit Care Med, Salt Lake City, UT 84143 USA. Univ Utah, Salt Lake City, UT USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Tennessee, Memphis, TN USA. NIH, Bethesda, MD 20892 USA. RP Hegewald, MJ (reprint author), Latter Day St Hosp, Div Pulm, 8th Ave & C St, Salt Lake City, UT 84143 USA. EM matt.hegewald@intermountainmail.org OI Kritchevsky, Stephen/0000-0003-3336-6781; Haggerty, Catherine/0000-0002-9849-7865 FU Intramural NIH HHS; NIA NIH HHS [N01 AG 62106, N01 AG 62103, N01 AG 62101] NR 24 TC 16 Z9 16 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAY PY 2007 VL 131 IS 5 BP 1494 EP 1499 DI 10.1378/chest.06-2707 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 168SQ UT WOS:000246544700035 PM 17400677 ER PT J AU Barrett, AJ Rezvani, K AF Barrett, A. J. Rezvani, K. TI Translational mini-review series on vaccines: Peptide vaccines for myeloid leukaemias SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Review DE clinical trials; myeloid leukaemia; peptide; vaccines ID CYTOTOXIC T-LYMPHOCYTES; CHRONIC MYELOGENOUS LEUKEMIA; TUMOR GENE WT1; ALLOGENEIC BONE-MARROW; GRAFT-VERSUS-LEUKEMIA; MINOR HISTOCOMPATIBILITY ANTIGENS; HEMATOPOIETIC PROGENITOR CELLS; ACUTE PROMYELOCYTIC LEUKEMIA; WEGENERS-GRANULOMATOSIS WG; HUMORAL IMMUNE-RESPONSES AB The graft-versus-leukaemia (GVL) effect following allogeneic stem cell transplantation is clear evidence that T lymphocytes can control and eliminate myeloid leukaemias. The successful identification of a range of leukaemia specific antigens (LSA) in recent years has stimulated efforts to induce leukaemia specific T cell responses to these antigens with peptide vaccines. An ideal LSA should be restricted in its expression to leukaemia including progenitor cells, intrinsically connected with the leukaemic phenotype, and capable of inducing strong cytotoxic T cell responses to the leukaemia. Peptides from three well-characterized LSA, the breakpoint cluster region-abelson (BCR-ABL) fusion protein of chronic myelogenous leukaemia, proteinase-3 and Wilms tumour 1 protein, serve as the basis for several clinical trials using peptide and adjuvants to treat patients with a variety of myeloid malignancies. Preliminary results from these studies indicate that these peptides induce immune responses which can translate into clinical responses which include complete remissions from leukaemia. These promising early results point the way to optimizing the administration of peptide vaccines and suggest ways of combining vaccination with allogeneic stem cell transplantation to boost GVL effects. C1 NHLBI, Hematol Branch, Stem Cell Allotransplantat Sect, Clin Res Ctr,NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Hematol Branch, Stem Cell Allotransplantat Sect, Clin Res Ctr,NIH, Room 3-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 113 TC 27 Z9 28 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD MAY PY 2007 VL 148 IS 2 BP 189 EP 198 DI 10.1111/j.1365-2249.2007.03383.x PG 10 WC Immunology SC Immunology GA 155UL UT WOS:000245603800001 PM 17437417 ER PT J AU De Jesus, M Hackett, E Durkin, M Connolly, P Casadevall, A Petraitiene, R Walsh, TJ Wheat, LJ AF De Jesus, Magdia Hackett, Emily Durkin, Michelle Connolly, Patricia Casadevall, Arturo Petraitiene, Ruta Walsh, Thomas J. Wheat, L. Joseph TI Galactoxylomannan does not exhibit cross-reactivity in the Platelia Aspergillus enzyme immunoassay SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CRYPTOCOCCUS-NEOFORMANS; MONOCLONAL-ANTIBODIES; GALACTOMANNAN; CAPSULE AB Given the recent report of a false-positive result in the Platelia Aspergillus enzyme immunoassay in a patient with cryptococcosis and in yeast extracts and purified galactoxylomannan of Cryptococcus neoformans, we evaluated culture extracts, purified polysaccharides, clinical specimens, and specimens from animals following experimental infection. Our results revealed no cross-reactions. C1 MiraVista Diagnost, Indianapolis, IN 46241 USA. Yeshiva Univ Albert Einstein Coll Med, Bronx, NY 10461 USA. NCI, CRC, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD 21702 USA. RP Wheat, LJ (reprint author), MiraVista Diagnost, 4444 Decatur Blvd,Suite 300, Indianapolis, IN 46241 USA. EM jwheat@miravistalabs.com FU Intramural NIH HHS; NCI NIH HHS [T32 CA009173, 2T32CA009173-31]; NHLBI NIH HHS [R01 HL059842, HL59842-01]; NIAID NIH HHS [R01 AI033142, R01 AI033774, AI33142, R37 AI033142, AI33774] NR 13 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2007 VL 14 IS 5 BP 624 EP 627 DI 10.1128/CVI.00368-06 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 170RN UT WOS:000246681800019 PM 17360857 ER PT J AU Wheat, LJ Hackett, E Durkin, M Connolly, P Petraitiene, R Walsh, TJ Knox, K Hage, C AF Wheat, L. Joseph Hackett, Emily Durkin, Michelle Connolly, Patricia Petraitiene, Ruta Walsh, Thomas J. Knox, Kenneth Hage, Chadi TI Histoplasmosis-associated cross-reactivity in the BioRad Platelia Aspergillus enzyme immunoassay SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID TRIAZOLE AB We observed false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA) for specimens from patients with histoplasmosis and mice with experimental infection. Platelia Aspergillus EIA-positive specimens were negative in the second-generation Histoplasma antigen EIA. Care must be taken to exclude histoplasmosis for patients with positive Platelia Aspergillus EIA results. C1 MiraVista Diagnost, Indianapolis, IN 46241 USA. NCI, CRC, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD 21702 USA. Indiana Univ, Sch Med, Dept Pulm Med, Roudebush Vet Adm Hosp, Indianapolis, IN 46202 USA. RP Wheat, LJ (reprint author), MiraVista Diagnost, 4444 Decatur Blvd,Suite 300, Indianapolis, IN 46241 USA. EM jwheat@miravistalabs.com FU Intramural NIH HHS NR 6 TC 66 Z9 71 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2007 VL 14 IS 5 BP 638 EP 640 DI 10.1128/CVI.00479-06 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 170RN UT WOS:000246681800022 PM 17344352 ER PT J AU Castle, PE Dockter, J Giachetti, C Garcia, FAR McCormick, MK Mitchell, AL Holladay, EB Kolk, DP AF Castle, Philip E. Dockter, Janel Giachetti, Cristina Garcia, Francisco A. R. McCormick, Mary Kay Mitchell, Amy L. Holladay, E. Blair Kolk, Daniel P. TI A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID 2-YEAR FOLLOW-UP; CONSENSUS PCR; WOMEN; DNA; CYTOLOGY; RISK; NEOPLASIA; ABNORMALITIES; EXPRESSION; INFECTION AB Purpose: To evaluate carcinogenic human papillomavirus (HPV) mRNA for E6 and E7 mRNA detection on clinical specimens to identify women with cervical precancer and cancer. Experimental Design: We evaluated a prototype assay that collectively detects oncogenes E6/ E7 mRNA for 14 carcinogenic HPV genotypes on a sample of liquid cytology specimens (n = 531), masked to clinical data and to the presence of HPV genotypes detected by PGMY09/ 11 L1 consensus primer PCR assay. Results: We found an increasing likelihood of testing positive for carcinogenic HPV E6/E7 mRNA with increasing severity of cytology (P-Trend < 0.0001) and histology (P-Trend < 0.0001), with 94% of cervical intraepithelial neoplasia grade 3 (CIN3) histology cases (46 of 49) and all five cancer cases testing positive for carcinogenic HPV E6/E7 mRNA. Overall, fewer specimens tested positive for carcinogenic HPV E6/E7 mRNA than for carcinogenic HPV DNA (P < 0.0001, McNemar's chi(2) test), especially in women with < CIN1 (P < 0.0001). We also found that using a higher positive cutpoint for detection of carcinogenic HPV E6/E7 mRNA improved the association of positive test results with cervical precancer and cancer by reducing the number of test positives in women without precancer without reducing clinical sensitivity for cervical precancer and cancer compared with detection of carcinogenic HPV E6/E7 mRNA using a lower positive cutpoint by the same assay and with detection of carcinogenic HPV DNA. Conclusions: We found that carcinogenic HPV E6/E7 mRNA is a potentially useful biomarker for detection of cervical precancer and cancer and warrants further evaluation. C1 NCI, Div Canc Epidemiol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Genprobe Inc, San Diego, CA USA. Univ Arizona, Natl Ctr Excellence Womens Hlth, Tucson, AZ USA. Arizona Hispan Ctr Excellence, Tucson, AZ USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS NR 29 TC 67 Z9 76 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 MAY 1 PY 2007 VL 13 IS 9 BP 2599 EP 2605 DI 10.1158/1078-0432.CCR-06-2881 PG 7 WC Oncology SC Oncology GA 162ZW UT WOS:000246129100011 PM 17473189 ER PT J AU Edelman, MJ Bauer, KS Smith, R Bisacia, S Dancey, J AF Edelman, Martin J. Bauer, Kenneth S., Jr. Smith, Ruth Bisacia, Sonia Dancey, Janet TI Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID DEPENDENT KINASE INHIBITOR; CELL LUNG-CARCINOMA; PROTEIN-KINASE; UCN-01 7-HYDROXYSTAUROSPORINE; ALPHA(1)-ACID GLYCOPROTEIN; CANCER-CELLS; TRIAL; COMBINATION; CHECKPOINT; CISPLATIN AB Purpose: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m(2). Results: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 go mg/m(2) in cycle 1, 45 mg/m(2) in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables C-max and t(1/2) Of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t(1/2) for cycle 1 was 506 +/- 301 h, and the mean C-max for all dose levels was > 30 mu mol/L. The mean AUC over the dosing interval for each dose level ranged from similar to 6,000 to 9,000 mu mol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion. Conclusion: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted. C1 Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Edelman, MJ (reprint author), Univ Maryland, Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. EM medelman@umm.edu NR 22 TC 29 Z9 30 U1 0 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 MAY 1 PY 2007 VL 13 IS 9 BP 2667 EP 2674 DI 10.1158/1078-0432.CCR-06-1832 PG 8 WC Oncology SC Oncology GA 162ZW UT WOS:000246129100020 PM 17473198 ER PT J AU Dromi, S Frenkel, V Luk, A Traughber, B Angstadt, M Bur, M Poff, J Xie, JW Libutti, SK Li, KCP Wood, BJ AF Dromi, Sergio Frenkel, Victor Luk, Alfred Traughber, Bryan Angstadt, Mary Bur, Monica Poff, Jason Xie, Jianwu Libutti, Steven K. Li, King C. P. Wood, Bradford J. TI Pulsed-high intensity focused ultrasound and low temperature sensitive liposomes for enhanced targeted drug delivery and antitumor effect SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN TUMOR XENOGRAFT; MR CONTRAST AGENT; IN-VIVO; THERMOSENSITIVE LIPOSOMES; LOCAL HYPERTHERMIA; DOXORUBICIN DOXIL; CANCER-THERAPY; BREAST-CANCER; MODEL; EFFICACY AB Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between non thermosensitive liposomes (NTSL) and low temperature - Sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42 degrees C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and non-destructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases. C1 NIH, Dept Diagnost Radiol, Mol Imaging Lab, Ctr Clin, Bethesda, MD 20892 USA. NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Frenkel, V (reprint author), NIH, Dept Diagnost Radiol, Mol Imaging Lab, Ctr Clin, Room 1N306A,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM vfrenkel@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 32 TC 250 Z9 258 U1 7 U2 74 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 MAY 1 PY 2007 VL 13 IS 9 BP 2722 EP 2727 DI 10.1158/1078-0432.CCR-06-2443 PG 6 WC Oncology SC Oncology GA 162ZW UT WOS:000246129100027 PM 17473205 ER PT J AU Hsiao, HP Iglesias, ML Keil, MF Boikos, S Robinson-White, A Stratakis, CA AF Hsiao, Hui-Pin Iglesias, Maria Lopez Keil, Margaret F. Boikos, Sosipatros Robinson-White, Audrey Stratakis, Constantine A. TI Differences in cortisol levels and body mass index between East Asians and Caucasians with Cushing's syndrome: an 'East Asian' phenotype for Cushing syndrome SO CLINICAL ENDOCRINOLOGY LA English DT Letter ID MEN; METABOLISM; WOMEN C1 NICHHD, SEGEN, DEB, US Natl Inst Hlth,NIH, Bethesda, MD 20892 USA. Kaohsiung Med Univ, Kaohsiung Municipal HsiaoKang Hosp, Dept Pediat, Kaohsiung, Taiwan. RP Hsiao, HP (reprint author), NICHHD, SEGEN, DEB, US Natl Inst Hlth,NIH, Bldg 10,Clin Res Ctr,Room 1-3330,10 Ctr Dr,MSC110, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Hsiao, Hui-Pin/B-3892-2010 NR 5 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD MAY PY 2007 VL 66 IS 5 BP 753 EP 755 DI 10.1111/j.1365-2265.2007.02793.x PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 163YK UT WOS:000246199100026 PM 17381493 ER PT J AU Graf, SA Calado, RT Kajigaya, S Young, NS AF Graf, S. A. Calado, R. T. Kajigaya, S. Young, N. S. TI RMRP mutations in hematological disorders SO CLINICAL GENETICS LA English DT Letter ID CARTILAGE-HAIR HYPOPLASIA; RNA C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC,Room 3E-5140, Bethesda, MD 20892 USA. EM youngns@mail.nih.gov RI Calado, Rodrigo/G-2619-2011 NR 14 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD MAY PY 2007 VL 71 IS 5 BP 468 EP 470 DI 10.1111/j.1399-0004.2007.00776.x PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 163TU UT WOS:000246186900012 PM 17489853 ER PT J AU Herbeuval, JP Shearer, GM AF Herbeuval, Jean-Philippe Shearer, Gene M. TI HIV-1 immunopathogenesis: How good interferon turns bad SO CLINICAL IMMUNOLOGY LA English DT Review DE HIV; interferon; dendritic cells; apoptosis; TRAIL; T cells; lymphoid tissue; DR5; nonprogressor ID IMMUNODEFICIENCY-VIRUS TYPE-1; APOPTOSIS-INDUCING LIGAND; CD4(+) T-CELLS; PLASMACYTOID DENDRITIC CELLS; PHASE-I TRIAL; ANTIRETROVIRAL THERAPY; HIV-1-INFECTED PATIENTS; IFN-ALPHA; GASTROINTESTINAL-TRACT; PERIPHERAL-BLOOD AB The hallmark of acquired immunodeficiency syndrome (AIDS) is the progressive loss of CD4(+) T cells that results from infection with human immunodeficiency virus type-1 (HIV-1). Despite 25 years of AIDS research, questions remain concerning the mechanisms responsible for HIV-induced CD4(+) T cell depletion. Here we briefly review the in vitro and in vivo literature concerning the protective rote of interferon -alpha (IFN-alpha) in HIV/AIDS. We then develop a laboratory- and clinically supported model of CD4(+) T cell apoptosis in which either infectious or noninfectious HIV-1 induces the production of type I interferon by plasmacytoid dendritic cells (pDC). The interferon produced binds to its receptor on primary CD4(+) T cells resulting in membrane expression of the TNF-retated apoptosis-inducing ligand (TRAIL) death molecule. The binding of infectious or noninfectious HIV-1 to CD4 on these T cells results in expression of the TRAIL death receptor 5 (DR5), leading to the selective death of HIV-exposed CD4(+) T cells. Published by Elsevier Inc. C1 NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Paris 05, Hop Necker Enfants Malad, UMR 8147, CNRS, Paris, France. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM shearerg@mail.nih.gov FU NCI NIH HHS [Z01 BC009267-23] NR 67 TC 131 Z9 136 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAY PY 2007 VL 123 IS 2 BP 121 EP 128 DI 10.1016/j.clim.2006.09.016 PG 8 WC Immunology SC Immunology GA 164QN UT WOS:000246249000001 PM 17112786 ER PT J AU Zaoutis, TE Heydon, K Localio, R Walsh, TJ Feudtner, C AF Zaoutis, Theoklis E. Heydon, Kateri Localio, Russell Walsh, Thomas J. Feudtner, Chris TI Outcomes attributable to neonatal candidiasis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BIRTH-WEIGHT INFANTS; INTENSIVE-CARE-UNIT; FUNGAL COLONIZATION; PROPENSITY SCORE; RISK-FACTORS; CANDIDEMIA; HOSPITALIZATIONS; FLUCONAZOLE; SENSITIVITY; INFECTIONS AB Background. The incidence of candidiasis has increased in neonatal intensive care units, and invasive candidiasis is associated with significant morbidity and mortality. However, few data exist on outcomes directly attributable to neonatal candidiasis. Methods. We estimated the incidence of systemic candidiasis in hospitalized neonates within the United States and determined the attributable mortality, length of hospital stay, and associated costs. We used the 2003 Kid's Inpatient Database from the Healthcare Cost and Utilization Project. Systemic candidiasis and comorbidities were defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Neonates with uncomplicated births and neonates who died within the first 3 days of life were excluded. We used propensity score methods to balance covariates between the neonates with and neonates without candidiasis. Attributable outcomes were calculated between propensity score - matched neonates with and neonates without candidiasis. Because of the known confounding effect of birth weight, we performed separate propensity score analyses for extremely low birth weight (ELBW) neonates (i.e., neonates weighing < 1000 g). Results. The overall incidence of invasive candidiasis in neonates is 15 cases per 10,000 neonatal admissions ( 95% confidence interval [CI], 13 - 16 cases per 10,000 neonatal admissions). ELBW neonates with invasive candidiasis were 2 times more likely to die ( odds ratio, 2.2; 95% CI, 1.4-3.5) than propensity-matched ELBW neonates without candidiasis. The propensity score - adjusted mortality rate attributable to candidiasis among ELBW neonates was 11.9%. Candidiasis in ELBW infants was not associated with an increase in length of hospital stay but was associated with a mean increase in total charges of $39,045 ( 95% CI, $1374-$76,715). Among infants with a birth weight >= 1000 g, those who had candidiasis did not experience a significant increase in mortality, compared with infants without candidiasis. However, the propensity score - adjusted length of stay and charges attributable to candidiasis among neonates with a birth weight >= 1000 g were 16 days ( 95% CI, 8 - 24 days) and $122,302 ( 95% CI, $80,457-$164,148), respectively. Conclusions. Invasive candidiasis is associated with a significantly increased risk of death and excess hospital charges in ELBW neonates and with excess hospital stay and excess hospital charges in neonates with a birth weight >= 1000 g. C1 Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Div Gen Pediat, Pediat Genb Res Grp, Philadelphia, PA 19104 USA. Univ Penn, Dept Pediat, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Epidemiol, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Ctr Epidemiol & Biostat, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Leonard Davis Inst Hlth Econ, Sch Med, Philadelphia, PA 19104 USA. NCI, Pediat Oncol Branch, Immunocompromised Hot Sect, Bethesda, MD 20892 USA. RP Zaoutis, TE (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, CHOP N,3535 Market St,Ste 1527, Philadelphia, PA 19104 USA. EM zaoutis@email.chop.edu FU NIAID NIH HHS [1K23 AI0629753-01] NR 22 TC 44 Z9 49 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2007 VL 44 IS 9 BP 1187 EP 1193 DI 10.1086/513196 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 153AZ UT WOS:000245405400009 PM 17407037 ER PT J AU Waldman, M Crew, RJ Valeri, A Busch, J Stokes, B Markowitz, G D'Agati, V Appel, G AF Waldman, Meryl Crew, R. John Valeri, Anthony Busch, Joshua Stokes, Barry Markowitz, Glen D'Agati, Vivette Appel, Gerald TI Adult minimal-change disease: Clinical characteristics, treatment, and outcomes SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHANGE NEPHROTIC SYNDROME; MYCOPHENOLATE-MOFETIL; RENAL-FAILURE; CORTICOSTEROID-THERAPY; STEROID RESPONSIVENESS; CHANGE GLOMERULOPATHY; PROTEIN-OVERLOAD; RANDOMIZED TRIAL; FOLLOW-UP; CYCLOSPORINE AB Minimal-change disease (MCD) counts for 10 to 15% of cases of primary nephrotic syndrome in adults. Few series have examined this disease in adults. A retrospective review was performed of 95 adults who had MCD and were seen at a single referral center. Examined were presenting features, response to daily versus alternate-day steroids, response to second-line agents, relapse patterns, complications of the disease and therapy, presence of acute renal failure (ARF), and outcome data. Sixty-five patients received daily and 23 received alternate-day steroids initially. There were no differences in remissions, time to remission, relapse rate, or time to relapse between daily- and altemate-day treated patients. More than one quarter of patients were steroid resistant. At least one relapse occurred in 73% of patients; 28% were frequently relapsing. A significant proportion of frequently relapsing patients became steroid dependent. Second-line agents were used for steroid dependence, steroid resistance, or frequent relapses. No single agent proved superior. There were more remissions with second-line agents in steroid-dependent patients compared with steroid-resistant patients, and remissions were more likely to be complete in steroid-dependent patients. ARF occurred in 24 patients; they tended to be older and hypertensive with lower serum albumin and more proteinuria than those without ARF. At follow up, patients with an episode of ARF had higher serum creatinine than those without ARF. Four patients progressed to ESRD. These patients were less likely to have responded to steroids and more likely to have FSGS on repeat renal biopsy. In this referral MCD population, response to daily and alternate-day steroids is similar. Second-line agents give greater response in patients who are steroid dependent. ARF occurs in a significant number of adult MCD patients and may leave residual renal dysfunction. Few patients progress to ESRD. C1 NIDDK, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. Columbia Presbyterian, Dept Nephrol, New York, NY USA. Columbia Presbyterian, Dept Pathol, New York, NY USA. Univ Washington, Dept Med, Seattle, WA USA. RP Waldman, M (reprint author), NIDDK, NIH, Clin Res Ctr, Bldg 10,Room 5225-1,10 Ctr Dr, Bethesda, MD 20892 USA. EM waldmanm@niddk.nih.gov OI Stokes, Michael/0000-0003-0958-7672 NR 42 TC 115 Z9 134 U1 0 U2 6 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2007 VL 2 IS 3 BP 445 EP 453 DI 10.2215/CJN.03531006 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 161XB UT WOS:000246049100009 PM 17699450 ER PT J AU Barisoni, L Schnaper, HW Kopp, JB AF Barisoni, Laura Schnaper, H. William Kopp, Jeffrey B. TI A proposed taxonomy for the podocytopathies: A reassessment of the primary nephrotic diseases SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR TIP LESION; HIV-ASSOCIATED NEPHROPATHY; MINIMAL CHANGE NEPHROPATHY; PODOCYTE SLIT DIAPHRAGM; COLLAPSING GLOMERULOPATHY; CLINICAL SPECTRUM; C1Q NEPHROPATHY; GENETIC-HETEROGENEITY; MESANGIAL SCLEROSIS AB A spectrum of proteinuric glomerular diseases results from podocyte abnormalities. The understanding of these podocytopathies has greatly expanded in recent years, particularly with the discovery of more than a dozen genetic mutations that are associated with loss of podocyte functional integrity. It is apparent that classification of the podocytopathies on the basis of morphology alone is inadequate to capture fully the complexity of these disorders. Herein is proposed a taxonomy for the podocytopathies that classifies along two dimensions: Histopathology, including podocyte phenotype and glomerular morphology (minimal-change nephropathy, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, and collapsing glomerulopathy), and etiology (idiopathic, genetic, and reactive forms). A more complete understanding of the similarities and differences among podocyte diseases will help the renal pathologist and the nephrologist communicate more effectively about the diagnosis; this in turn will help the nephrologist provide more accurate prognostic information and select the optimal therapy for these often problematic diseases. It is proposed that final diagnosis of the podocytopathies should result from close collaboration between renal pathologists and nephrologists and should whenever possible include three elements: Morphologic entity, etiologic form, and specific pathogenic mechanism or association. C1 NYU, Sch Med, Dept Pathol, New York, NY USA. Northwestern Univ, Sch Med, Feinberg Sch Med, Dept Pediat,Div Kidney Dis, Chicago, IL USA. NIDDKD, Kidney Dis Sect, NIH, US Dept HHS, Bethesda, MD USA. RP Schnaper, HW (reprint author), 303 E Chicago Ave, Chicago, IL 60611 USA. EM schnaper@northwestern.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU NIDDK NIH HHS [R01 DK049362] NR 88 TC 107 Z9 127 U1 0 U2 3 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2007 VL 2 IS 3 BP 529 EP 542 DI 10.2215/CJN.04121206 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 161XB UT WOS:000246049100020 PM 17699461 ER PT J AU Pritsch, T Bickels, J Wu, CC Squires, HM Malawer, MM AF Pritsch, Tamir Bickels, Jacob Wu, Chia-Chun Squires, Hart M. Malawer, Martin M. TI The risk for fractures after curettage and cryosurgery around the knee SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID GIANT-CELL TUMOR; ANEURYSMAL BONE-CYSTS; INTRALESIONAL EXCISION; PIN AUGMENTATION; FEMORAL DEFECTS; PROXIMAL TIBIA; LONG BONES; RECONSTRUCTION; CEMENT; FEMUR AB Curettage and cryosurgery have been used successfully for treatment of benign locally aggressive and some low-grade malignant bone tumors. After treating these lesions, we reconstruct residual bone defects around the knee with cement, intramedullary pins, and autogenous bone graft for subchondral augmentation and closure of cortical windows. We questioned the incidence of fractures and the rates of nonunion and malunion and asked whether patients at risk for fractures can be identified. We conducted chart and radiographic reviews of 60 consecutive patients who had curettage and cryosurgery of primary bone lesions in the distal femur or proximal tibia. Ten of the 60 patients (17%) sustained postoperative intraarticular fractures. Patients who sustained fractures had (1) more freeze-thaw cycles; (2) metaphyseal defect ratios greater than 0.6 and 0.8 on the anteroposterior and lateral projections, respectively; and (3) 4 mm or less proximity of the defect to the joint. Only one fracture united in good alignment. Radiographic measurements can assist in identifying patients at risk for fractures after curettage and cryosurgery around the knee. We expect the fracture rate to decline by reducing the number of freeze-thaw cycles and improving our reconstruction method. C1 Washington Hosp Ctr, Washington Canc Inst, Dept Orthopaed Oncol, Washington, DC 20010 USA. Tel Aviv Sourasky Med Ctr, Natl Unit Orthoped Oncol, Tel Aviv, Israel. Georgetown Univ, Washington, DC USA. NCI, Pediat & Surg Branch, Bethesda, MD 20892 USA. RP Pritsch, T (reprint author), Washington Hosp Ctr, Washington Canc Inst, Dept Orthopaed Oncol, C2173,110 Irving St NW, Washington, DC 20010 USA. EM Pritscht@yahoo.com NR 45 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAY PY 2007 IS 458 BP 159 EP 167 DI 10.1097/BLO.0b013e318038fc3d PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 164UE UT WOS:000246259200032 ER PT J AU Staten, MA AF Staten, M. A. TI Challenges in the discovery and development of new agents for the treatment of obesity SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID TERM WEIGHT CONTROL; FENFLURAMINE PLUS PHENTERMINE; BEHAVIOR-MODIFICATION; CALORIC RESTRICTION; UNITED-STATES; OPEN-LABEL; MEDICATION; EXERCISE; TRIAL AB New pharmacologic agents are being sought to help manage the epidemic of obesity and its consequences. Understanding the challenges of the history of obesity drugs is wise before investing in new obesity agents. Expectations of patients, physicians, and drug company executives are not consistent with characteristics of current agents or most potential new ones. Owing to the complex biology underlying body weight regulation, combinations of agents may be necessary to improve weight loss efficacy. C1 NIDDKD, Div Diabet & Kidney & Digest Dis, NIH, Bethesda, MD 20892 USA. RP Staten, MA (reprint author), NIDDKD, Div Diabet & Kidney & Digest Dis, NIH, Bethesda, MD 20892 USA. EM statenm@niddk.nih.gov NR 15 TC 6 Z9 6 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2007 VL 81 IS 5 BP 753 EP 755 DI 10.1038/sj.clpt.6100161 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160DT UT WOS:000245921500025 PM 17377527 ER PT J AU Skyler, JS AF Skyler, J. S. TI Prediction and prevention of type 1 diabetes: Progress, problems, and prospects SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ISLET-CELL ANTIBODIES; FIRST-DEGREE RELATIVES; NATURAL-HISTORY; RECENT-ONSET; DOUBLE-BLIND; INSULIN PROPHYLAXIS; CONTROLLED-TRIAL; HIGH-RISK; IDDM; AUTOANTIBODIES AB Type 1 diabetes mellitus ( T1D) arises from selective immunologically mediated destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans with consequent insulin deficiency.(1,2) This occurs in genetically susceptible individuals and is a cellular-mediated process, presumably a specific reaction to one or more beta-cell proteins ( autoantigens), although probably initiated by some environmental factor( s). There is consequent progressive impairment of beta-cell function and decline in beta-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to beta-cells.(3-5) This insidious T1D disease process evolves over a period of years.(6) The decline in beta-cell function and mass is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge,(7,8) and later by the appearance of impairment in glycemic regulation, manifested as dysglycemia-usually as impaired glucose tolerance, but occasionally as impaired fasting glucose.(9) Ultimately, the clinical syndrome of T1D becomes evident when the majority of beta-cells have been destroyed and frank hyperglycemia supervenes. Given this sequence of events, for which it is possible to envision intervention to interdict the process, it is not surprising that much research effort has been expended to identify individuals at risk of the disease. C1 Univ Miami, Miller Sch Med, Diabet Res Inst, NIDDK Type 1 Diabet TrialNet Clin Trials Network, Miami, FL 33152 USA. RP Skyler, JS (reprint author), Univ Miami, Miller Sch Med, Diabet Res Inst, NIDDK Type 1 Diabet TrialNet Clin Trials Network, Miami, FL 33152 USA. EM jskyler@miami.edu RI Skyler, Jay/F-4211-2016 NR 45 TC 49 Z9 50 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2007 VL 81 IS 5 BP 768 EP 771 DI 10.1038/sj.clpt.6100179 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160DT UT WOS:000245921500028 PM 17392722 ER PT J AU Dierker, LC Sledjeski, EM Botello-Harbaum, M Ramirez, RR Chavez, LM Canino, G AF Dierker, Lisa C. Sledjeski, Eve M. Botello-Harbaum, Maria Ramirez, Rafael R. Chavez, Ligia M. Canino, Glorisa TI Association between psychiatric disorders and smoking stages within a representative clinic sample of Puerto Rican adolescents SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID DIAGNOSTIC INTERVIEW SCHEDULE; TEST-RETEST RELIABILITY; CIGARETTE-SMOKING; SUBSTANCE USE; NICOTINE DEPENDENCE; ANXIETY DISORDERS; DEPRESSIVE SYMPTOMS; CHILDREN DISC-2.1; MAJOR DEPRESSION; MENTAL-ILLNESS AB Objective: We examined the prevalence of smoking behaviors and their association with specific psychiatric disorders in a representative sample of youth from behavioral health clinics in Puerto Rico. Method: A complex sampling design was used to select the sample, and analyses were conducted to account for the unequal selection probability, stratification, and clustering. All analyses were weighted back to the clinical population from which they were drawn. Psychiatric and substance use disorders were assessed using the parent and youth versions of the Diagnostic Interview Schedule for Children, Version 4.0. Results: More than one third of the sample reported experience with cigarette smoking, and approximately one quarter reported smoking at least once per week (23.4%). As expected, the alcohol and drug use disorders demonstrated some of the strongest associations with individual smoking stages. These were the only disorders that remained significantly associated with nicotine dependence after controlling for comorbidity. Conclusions: Our findings confirm the need for screening of smoking behavior and nicotine dependence in treatment settings and the integration of psychiatric/substance use treatments with smoking cessation. (c) 2007 Elsevier Inc. All rights reserved. C1 Wesleyan Univ, Dept Psychol, Middletown, CT 06549 USA. NICHD, DESPR, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. Univ Puerto Rico, Behav Sci Res Inst, San Juan, PR 00936 USA. RP Dierker, LC (reprint author), Wesleyan Univ, Dept Psychol, Middletown, CT 06549 USA. EM ldierker@wesleyan.edu RI Sledjeski, Eve/L-9004-2015; OI Sledjeski, Eve/0000-0002-7046-7584; ramirez, rafael/0000-0002-9504-7260 FU Intramural NIH HHS; NIDA NIH HHS [K01 DA015454, K01-DA15454]; NIMH NIH HHS [P01 MH059876, P01-MH 59876-02, U01-MH54827]; NIMHD NIH HHS [P20 MD000537, P20 MD000537-01] NR 61 TC 7 Z9 7 U1 16 U2 18 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAY-JUN PY 2007 VL 48 IS 3 BP 237 EP 244 DI 10.1016/j.comppsych.2007.01.002 PG 8 WC Psychiatry SC Psychiatry GA 161ZO UT WOS:000246056000005 PM 17445517 ER PT J AU Shapiro, EM Medford-Davis, LN Fahmy, TM Dunbar, CE Koretsky, AP AF Shapiro, Erik M. Medford-Davis, Laura N. Fahmy, Tarek M. Dunbar, Cynthia E. Koretsky, Alan P. TI Antibody-mediated cell labeling of peripheral T cells with micron-sized iron oxide particles (MPIOs) allows single cell detection by MRI SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE MRI; iron oxide; T cells; contrast agents ID LYMPHOCYTE TRAFFICKING; MONOCLONAL-ANTIBODY; CONTRAST AGENTS; STEM-CELLS; PROGENITOR; REJECTION; TUMORS AB Labeling cells with iron oxide is a useful tool for MRI based cellular imaging. Here it is demonstrated that peripheral rat T cells can be labeled in whole blood, in vitro, with streptavidin-coated micron-sized iron oxide particles (MPIOs), achieving iron concentrations as high as 60 pg iron per cell. This is 30 times the amount of labeling reported with ultrasmall particles of iron oxide (USPIOs). Labeling was mediated by use of a biotinylated anti-CD5 antibody, which is specific for peripheral T cells. Such labeling allowed the in vitro detection of single lymphocytes by MRI, using conditions well suited for in vivo animal work. Electron microscopic analysis demonstrated that MPIOs remained largely extracellular after labeling, with some evidence of intracellular uptake. Cell viability and early and late cytokine release studies showed no significant differences between labeled and unlabeled cells. Therefore, the use of MPIOs for achieving high iron concentrations for cellular MRI is potentially an effective new modality for non-invasive imaging of lymphocytes. Published in 2007 by John Wiley & Sons, Ltd. C1 Yale Univ, Sch Med, Dept Diagnost Radiol, Mol & Cellular Imaging Lab, New Haven, CT 06510 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. Yale Univ, Dept Biomed Engn, New Haven, CT USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Shapiro, EM (reprint author), Yale Univ, Sch Med, Dept Diagnost Radiol, Mol & Cellular Imaging Lab, New Haven, CT 06510 USA. EM erik.shapiro@yale.edu RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01] NR 19 TC 50 Z9 51 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD MAY-JUN PY 2007 VL 2 IS 3 BP 147 EP 153 DI 10.1002/cmmi.134 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 194BQ UT WOS:000248319300005 PM 17541955 ER PT J AU Boller, F Bick, K Duyckaerts, C AF Boller, Francois Bick, Katherine Duyckaerts, Charles TI They have shaped Alzheimer disease the protagonists, well known and less well known SO CORTEX LA English DT Article DE Alzheimer's disease; dementia; history of neurology ID PAIRED HELICAL FILAMENTS; CEREBRAL GREY MATTER; PLAQUE CORE PROTEIN; ELDERLY SUBJECTS; DEMENTIA AB This paper discusses the history of dementia and Alzheimer's disease (AD) with emphasis on the individuals who have shaped its development. In addition to the best known protagonists recognized as founders of the field, it will mention other figures who have provided important contributions but are sometimes overlooked. Many of these have also become famous for work unrelated to AD. C1 INSERM, U 549, Ctr Paul Broca, Paris, France. Raymond Escourolle Lab Neuropathol, Paris, France. La Salpetriere Hosp, INSERM, U 106, Paris, France. RP Boller, F (reprint author), NIH, Ctr Sci Review, 6701 Rockledge Dr,MSC 7808,Room 3206, Bethesda, MD 20892 USA. EM bollerf@csr.nih.gov NR 52 TC 5 Z9 5 U1 1 U2 3 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD MAY PY 2007 VL 43 IS 4 BP 565 EP 569 DI 10.1016/S0010-9452(08)70251-X PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 184AQ UT WOS:000247613900011 PM 17624003 ER PT J AU Ognibene, FP AF Ognibene, Frederick P. TI Mentoring and lifelong learning: A critical part of who we are and what we do SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE mentoring; teaching; critical care medicine C1 NIH, Off Clin Res Training & Med Educ, Ctr Clin, Clin Res Training Program,Off Intramural Res,Crit, Bethesda, MD 20892 USA. RP Ognibene, FP (reprint author), NIH, Off Clin Res Training & Med Educ, Ctr Clin, Clin Res Training Program,Off Intramural Res,Crit, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2007 VL 35 IS 5 BP 1227 EP 1229 DI 10.1097/01.CCM.0000262941.59652.57 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 159LR UT WOS:000245867800001 PM 17414733 ER PT J AU Montefiori, DC Morris, L Ferrari, G Mascola, JR AF Montefiori, David C. Morris, Lynn Ferrari, Guido Mascola, John R. TI Neutralizing and other antiviral antibodies in HIV-1 infection and vaccination SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE adjuvants; AIDS; antibodies; complement; Fc receptors; vaccines AB Purpose of review New findings continue to support the notion that broadly crossreactive neutralizing antibody induction is a worthwhile and achievable goal for HIV-1 vaccines. Immunogens are needed that can overcome the genetic variability and complex immune evasion tactics of the virus. Other antibodies might bridge innate and acquired immunity for possible beneficial vaccine effects. This review summarizes progress made over the past year that has enhanced our understanding of humoral immunity as it relates to HIV-1 vaccine development. Recent findings Although a clear path to designing an effective neutralizing antibody-based HIV-1 vaccine remains elusive, there is new information on how antibodies neutralize HIV-1, the epitopes involved, and clues to the possible nature of protective immunogens that keep this goal alive. Moreover, there is a greater understanding of HIV-1 diversity and its possible limits under immune pressure. Other antibodies might possess antiviral activity by mechanisms involving Fc receptor engagement or complement activation that would be of value for HIV-1 vaccines. Summary Recent developments strengthen the rationale for antibody-based HIV-1 vaccine immunogens and provide a stronger foundation for vaccine discovery. C1 [Montefiori, David C.; Ferrari, Guido] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Morris, Lynn] Natl Inst Communicable Dis, Johannesburg, South Africa. [Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Dept Surg, Box 2926, Durham, NC 27710 USA. EM monte@duke.edu RI Ferrari, Guido/A-6088-2015; OI , Lynn/0000-0003-3961-7828 FU NIAID NIH HHS [U19 AI067854, U19 AI067854-07] NR 79 TC 15 Z9 15 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2007 VL 2 IS 3 BP 169 EP 176 DI 10.1097/COH.0b013e3280ef691e PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NT UT WOS:000208417800002 PM 19372883 ER PT J AU Barzilay, JI Cutler, JA Davis, BR AF Barzilay, Joshua I. Cutler, Jeffrey A. Davis, Barry R. TI Antihypertensive medication and risk of diabetes mellitus SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; elevated glucose; hypertension; thiazide diuretic ID LIPID-LOWERING TREATMENT; ATTACK TRIAL ALLHAT; IMPAIRED FASTING GLUCOSE; HYPERTENSIVE PATIENTS; TYPE-2; POTASSIUM; OUTCOMES; DRUGS; PREVENTION; INHIBITOR AB Purpose of review Over the past decade post-hoc analyses of clinical trials and observational studies have tended to show that participants treated with thiazide diuretics are at greater risk for newly diagnosed diabetes mellitus than those treated with other medication classes. We review the results of several recent studies on the impact of thiazide-related hyperglycemia and diabetes mellitus on cardiovascular disease outcomes. We also examine the impact of the glucose-sparing effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on preventing cardiovascular disease. Recent findings No consistent or conclusive evidence has been found that hyperglycemia or diabetes mellitus in association with thiazide diuretic use is associated with increased cardiovascular disease outcomes. This benign outcome may be a consequence of the fact that only a segment of such diuretic-associated cases is induced by the usual etiologic mechanisms that are associated with classic 'diabetes mellitus'. Likewise, no evidence has been found that the glucose-lowering effect of angiotensin-converting enzyme inhibitors is associated with decreased cardiovascular disease risk. Summary We conclude that thiazide diuretics are safe to use, even in hypertensive individuals at risk for incident glucose disorders. The use of angiotensin-converting enzyme inhibitors for protection against glucose disorders and subsequent cardiovascular disease remains to be determined. C1 Kaiser Permanente Georgia, Atlanta, GA USA. Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA 30322 USA. NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. RP Barzilay, JI (reprint author), 200 Crescent Ctr Pkwy, Tucker, GA 30084 USA. EM joshua.barzilay@kp.org NR 27 TC 6 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAY PY 2007 VL 16 IS 3 BP 256 EP 260 DI 10.1097/MNH.0b013e328057dea2 PG 5 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 161FT UT WOS:000246000600012 PM 17420670 ER PT J AU Coleman, H Chew, E AF Coleman, Hanna Chew, Emily TI Nutritional supplementation in age-related macular degeneration SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE age-related macular degeneration; antioxidant vitamins; long-chain polyunsaturated fatty acids; lutein/zeaxanthin; macular edema; zinc ID MODIFIABLE RISK-FACTORS; EYE DISEASE; ZEAXANTHIN; LUTEIN; CAROTENOIDS; ASSOCIATIONS; MACULOPATHY; ANCILLARY; EFFICACY AB Purpose of review This review assesses the current status of the knowledge of the role of nutrition in age-related macular degeneration - a leading cause of vision loss in the persons with European ancestry. Recent findings We will evaluate the different nutritional factors and both observational and interventional studies used to assess the association of nutrition with age-related macular degeneration. Persons with intermediate risk of age-related macular degeneration or advanced age-related macular degeneration in one eye are recommended to take the formulation proven in the Age-Related Eye Disease Study (AREDS) to be successful in preventing the development of advanced age-related macular degeneration by 25%. The formulation consists of vitamins C, E, beta-carotene and zinc. In addition, observational data suggest that high dietary intake of macular xanthophylls lutein and zeaxanthin are associated with a lower risk of advanced age-related macular degeneration. Similarly, long-chain polyunsaturated fatty acids derived from fish consumption are also associated with a decreased risk of advanced age-related macular degeneration. Summary Persons with intermediate age-related macular degeneration or advanced age-related macular degeneration (neovascular or central geographic atrophy) in one eye should consider taking the AREDS-type supplements. Further evaluation of nutritional factors, specifically, lutein/zeaxanthin and omega-3 fatty acids will be tested in a multicenter controlled, randomized trial - the Age-Related Eye Disease Study 2 (AREDS2). C1 NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Chew, E (reprint author), NEI, Div Epidemiol & Clin Res, NIH, Bldg 10,CRC,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999, ZIA EY000489-01] NR 16 TC 54 Z9 61 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD MAY PY 2007 VL 18 IS 3 BP 220 EP 223 DI 10.1097/ICU.0b013e32814a586b PG 4 WC Ophthalmology SC Ophthalmology GA 162BL UT WOS:000246061200007 PM 17435429 ER PT J AU Gould, TD Manji, HK AF Gould, Todd D. Manji, Husseini K. TI Targeting neurotrophic signal transduction pathways in the treatment of mood disorders SO CURRENT SIGNAL TRANSDUCTION THERAPY LA English DT Review DE bipolar disorder; manic-depressive illness; depression; lithium; valproate; antidepressant; glycogen synthase kinase-3; treatment ID HISTONE DEACETYLASE INHIBITION; GLYCOGEN-SYNTHASE KINASE-3; MAJOR DEPRESSIVE DISORDER; EMERGING EXPERIMENTAL THERAPEUTICS; RESISTANT BIPOLAR DEPRESSION; CEREBRAL CORTICAL-NEURONS; LONG-TERM POTENTIATION; DI-N-PROPYLACETATE; OPEN-LABEL TRIAL; VALPROIC ACID AB Mood disorders such as bipolar disorder and unipolar depression are pervasive diseases associated with high rates of morbidity and mortality. There exists an urgent need for novel medications. Current compounds often do not bring about full remission, and if they do, it is only after a minimum of many weeks, if not months of treatment, Alterations in signaling pathways represent a likely source of pathogenesis. Dynamic regulation of complex signaling pathways plays a critical role in higher order brain functions, which include the regulation of mood, cognition, and sense of self and reality; thus implicating their involvement in mood disorder pathophysiology and pathogenesis. Impairments in neuroplasticity in the brains of patients suffering from mood disorders suggest that novel medications designed to attenuate impairments in these processes may have efficacy in their treatment. Further, since the onset of the vast majority of psychotrophic medications takes an extended period of treatment, it is a widely held belief that these drugs may act by modulation of critical neuronal signaling pathways and the resultant changes in gene expression and protein function. Preclinical, and some clinical, evidence implicates the action of specific neurotrophic signaling pathways in the downstream mechanism of action of medications useful for the treatment of mood disorders. We discuss specific signaling pathway and molecular treatment targets that are being considered for the development of novel treatments for mood disorders C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH,HHS, Bethesda, MD 20892 USA. RP Gould, TD (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH,HHS, Bldg 35,Room 1C-912, Bethesda, MD 20892 USA. EM gouldt@mail.nih.gov NR 142 TC 1 Z9 1 U1 2 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-3624 J9 CURR SIGNAL TRANSD T JI Curr. Signal Transduct. Ther. PD MAY PY 2007 VL 2 IS 2 BP 101 EP 110 DI 10.2174/157436207780619518 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 167YY UT WOS:000246490000001 ER PT J AU Nagpal, R Yadav, H Puniya, AK Singh, K Jain, S Marotta, F AF Nagpal, Ravinder Yadav, Hariom Puniya, Anil Kumar Singh, Kishan Jain, Shalini Marotta, Francsco TI Conjugated linoleic acid: Sources, synthesis and potential health benefits - An overview SO CURRENT TOPICS IN NUTRACEUTICAL RESEARCH LA English DT Review DE CLA; dairy; health benefits; milk ID UNSATURATED FATTY ACIDS; STEAROYL-COA DESATURASE; LACTATING DAIRY-COWS; REDUCES CANCER-RISK; FED FISH-OIL; MILK-FAT; BUTYRIVIBRIO-FIBRISOLVENS; BOVINE-MILK; LACTOBACILLUS-ACIDOPHILUS; BODY-COMPOSITION AB Conjugated linoleic acid is a group of positional and geometrical isomers of linoleic acid (08:2, cis-9, cis-12), an essential fatty acid for human and animals. It is produced in ruminants via biohydrogenation of poly-unsaturated fatty acids and during the mechanical processing of dairy products. Meat and dairy products from ruminant animals (such as milk, butter, yogurt and cheese) are the principal natural sources of CLA in the human diet. Because of its reported biological activities (i.e. anticarcinogenic, antiatherogenic, immune-enhancing and weight-reducing properties) in animal models, CLA has become a subject of interest as a supplement for human nutrition. However, further research is required to check the efficacy and role of CLA, the good fat, in cancer and other disease prevention; and to form the basis of evaluating its effect in humans by observational studies and clinical trials. C1 [Nagpal, Ravinder; Puniya, Anil Kumar] Natl Dairy Res Inst, Dairy Microbiol Div, Karnal 132001, Haryana, India. [Yadav, Hariom; Jain, Shalini] Natl Dairy Res Inst, Anim Biochem Div, Karnal 132001, Haryana, India. [Marotta, Francsco] S Giuseppe Hosp, Hepatogastroenterol Unit, Milan, Italy. [Marotta, Francsco] GAIA Age Management Fdn, Milan, Italy. RP Yadav, H (reprint author), NIDDKD, Regenerat Biol Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. EM yadavhariom@gmail.com NR 105 TC 9 Z9 10 U1 3 U2 20 PU NEW CENTURY HEALTH PUBLISHERS, LLC PI COPPELL PA PO BOX 175, COPPELL, TX 75019 USA SN 1540-7535 J9 CURR TOP NUTRACEUT R JI Curr. Top. Nutraceutical Res. PD MAY-AUG PY 2007 VL 5 IS 2-3 BP 55 EP 65 PG 11 WC Nutrition & Dietetics; Pharmacology & Pharmacy SC Nutrition & Dietetics; Pharmacology & Pharmacy GA 246TY UT WOS:000252031400002 ER PT J AU Brazhnik, O AF Brazhnik, Olga TI Databases and the geometry of knowledge SO DATA & KNOWLEDGE ENGINEERING LA English DT Article DE data models; knowledge acquisition; ontologies; concept mapping; data integration ID DATA VISUALIZATION; SYSTEMS; INFORMATION; DISCOVERY; PROTEGE; WEB AB Based on a geometrical interpretation of knowledge space, this work defines relationships between data, concepts and models, and establishes a framework for their integration. Concepts encapsulate our knowledge and provide a basis for data acquisition. They change as we learn more. Every discipline operates with a specific set of concepts organized in models. In order to co-process data collected against different concepts, we need to map the underlying concepts. Modal Intentional Actual (MIA) structure, derived from knowledge representation theory, enables the separation of data from hypotheses, and provides a consistent approach for building data models, concept mapping and defining complex relationships, which are represented by morphisms in category theory. Essential data elements from enterprise modeling techniques provide specifications for storing concepts and morphisms in a database. Published by Elsevier B.V. C1 NIH, Ctr Informat Technol, Bethesda, MD 20897 USA. RP Brazhnik, O (reprint author), NIH, Ctr Informat Technol, 10401 Fernwood Rd, Bethesda, MD 20897 USA. EM brazhnik@nih.gov NR 46 TC 10 Z9 13 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-023X EI 1872-6933 J9 DATA KNOWL ENG JI Data Knowl. Eng. PD MAY PY 2007 VL 61 IS 2 BP 207 EP 227 DI 10.1016/j.datak.2006.05.005 PG 21 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems SC Computer Science GA 158UM UT WOS:000245820400001 ER PT J AU Bok, J Dolson, DK Hill, P Ruther, U Epstein, DJ Wu, DK AF Bok, Jinwoong Dolson, Diane K. Hill, Patrick Ruether, Ulrich Epstein, Douglas J. Wu, Doris K. TI Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear SO DEVELOPMENT LA English DT Article DE inner ear; Gli; sonic hedgehog; Shh; activator; repressor; mouse ID PALLISTER-HALL SYNDROME; SONIC-HEDGEHOG; SPINAL-CORD; FLOOR PLATE; MOUSE; GENE; MICE; MUTATION; SPECIFICATION; INDUCTION AB Organization of the vertebrate inner ear is mainly dependent on localized signals from surrounding tissues. Previous studies demonstrated that sonic hedgehog (Shh) secreted from the floor plate and notochord is required for specification of ventral (auditory) and dorsal (vestibular) inner ear structures, yet it was not clear how this signaling activity is propagated. To elucidate the molecular mechanisms by which Shh regulates inner ear development, we examined embryos with various combinations of mutant alleles for Shh, Gli2 and Gli3. Our study shows that Gli3 repressor (R) is required for patterning dorsal inner ear structures, whereas Gli activator (A) proteins are essential for ventral inner ear structures. A proper balance of Gli3R and Gli2/3A is required along the length of the dorsoventral axis of the inner ear to mediate graded levels of Shh signaling, emanating from ventral midline tissues. Formation of the ventral-most otic region, the distal cochlear duct, requires robust Gli2/3A function. By contrast, the formation of the proximal cochlear duct and saccule, which requires less Shh signaling, is achieved by antagonizing Gli3R. The dorsal vestibular region requires the least amount of Shh signaling in order to generate the correct dose of Gli3R required for the development of this otic region. Taken together, our data suggest that reciprocal gradients of GliA and GliR mediate the responses to Shh signaling along the dorsoventral axis of the inner ear. C1 Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Univ Dusseldorf, Inst Anim Dev & Mol Biol, D-4000 Dusseldorf, Germany. RP Wu, DK (reprint author), Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov RI Bok, Jinwoong/B-8982-2016 OI Bok, Jinwoong/0000-0003-1958-1872 FU Intramural NIH HHS; NIDCD NIH HHS [R01 DC006254] NR 51 TC 50 Z9 55 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY 1 PY 2007 VL 134 IS 9 BP 1713 EP 1722 DI 10.1242/dev.000760 PG 10 WC Developmental Biology SC Developmental Biology GA 156ZB UT WOS:000245687300010 PM 17395647 ER PT J AU Iwamoto, M Tamamura, Y Koyama, E Komori, T Takeshita, N Williams, JA Nakamura, T Enomoto-Iwamoto, M Pacifici, M AF Iwamoto, Masahiro Tamamura, Yoshihiro Koyama, Eiki Komori, Toshihisa Takeshita, Nobuo Williams, Julie A. Nakamura, Takashi Enomoto-Iwamoto, Motomi Pacifici, Maurizio TI Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE ERG transcription factor; articular chondrocytes; limb and spine skeletogenesis; GDF-5; extracellular matrix ID ETS-RELATED GENE; HUMAN OSTEOARTHRITIC CARTILAGE; X COLLAGEN-SYNTHESIS; ENDOCHONDRAL OSSIFICATION; SYNOVIAL JOINT; BONE-FORMATION; GROWTH-PLATE; DEVELOPMENTAL REGULATION; FAMILY-MEMBER; EXPRESSION AB Articular cartilage and synovial joints are critical for skeletal function, but the mechanisms regulating their development are largely unknown. In previous studies we found that the ets transcription factor ERG and its alternatively-spliced variant C-1-1 have roles in joint formation in chick. Here, we extended our studies to mouse. We found that ERG is also expressed in developing mouse limb joints. To test regulation of ERG expression, beads coated with the joint master regulator protein GDF-5 were implanted close to incipient joints in mouse limb explants; this led to rapid and strong ectopic ERG expression. We cloned and characterized several mammalian ERG variants and expressed a human C-1-1 counterpart (hERG3 Delta 81) throughout the cartilaginous skeleton of transgenic mice, using Col2al gene promoter/enhancer sequences. The skeletal phenotype was severe and neonatal lethal, and the transgenic mice were smaller than wild type littermates and their skeletons were largely cartilaginous. Limb long bone anlagen were entirely composed of chondrocytes actively expressing collagen IX and aggrecan as well as articular markers such as tenascin-C. Typical growth plates were absent and there was very low expression of maturation and hypertrophy markers, including Indian hedgehog, collagen X and MMP-13. The results suggest that ERG is part of molecular mechanisms leading chondrocytes into a permanent developmental path and become joint forming cells, and may do so by acting downstream of GDF-5. (c) 2007 Elsevier Inc. All rights reserved. C1 Thomas Jefferson Univ, Coll Med, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. Nagasaki Univ, Grad Sch Biomed Sci, Dept Dev & Reconstruct Med, Nagasaki 8528588, Japan. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Iwamoto, M (reprint author), Thomas Jefferson Univ, Coll Med, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. EM masahiro.iwamoto@jefferson.edu RI Nakamura, Takashi/P-7796-2016 OI Nakamura, Takashi/0000-0001-9904-1037 FU NIA NIH HHS [R01 AG025868, AG025868, R01 AG025868-02]; NIAMS NIH HHS [AR046000, AR050507, AR051007, R01 AR046000, R01 AR046000-07, R01 AR050507, R01 AR050507-03, R01 AR051007, R01 AR051007-02, R01 AR056837] NR 55 TC 62 Z9 64 U1 3 U2 9 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 MAY 1 PY 2007 VL 305 IS 1 BP 40 EP 51 DI 10.1016/j.ydbio.2007.01.037 PG 12 WC Developmental Biology SC Developmental Biology GA 161QN UT WOS:000246030500004 PM 17336282 ER PT J AU Sapir, A Choi, J Leikina, E Avinoam, O Valansi, C Chernomordik, LV Newman, AP Podbilewicz, B AF Sapir, Amir Choi, Jaebok Leikina, Evgenia Avinoam, Ori Valansi, Clari Chernomordik, Leonid V. Newman, Anna P. Podbilewicz, Benjamin TI AFF-1, a FOS-1-regulated fusogen, mediates fusion of the anchor cell in C-elegans SO DEVELOPMENTAL CELL LA English DT Article ID DOMAIN TRANSCRIPTION FACTOR; CAENORHABDITIS-ELEGANS; EFF-1; PROTEIN; MORPHOGENESIS; ORGANOGENESIS; SUPERFAMILY; PARADIGM; INVASION; VULVA AB Cell fusion is fundamental for reproduction and organ formation. Fusion between most C. elegans epithelial cells is mediated by the EFF-1 fusogen. However, fusion between the anchor cell and the utse syncytium that establishes a continuous uterine-vulval tube proceeds normally in eff-1 mutants. By isolating mutants where the anchor-cell fails to fuse, we identified aff-1. AFF-1 ectopic expression results. infusion of cells that normally do not fuse in C. elegans. The fusogen activity of AFF-1 was further confirmed by its ability to fuse heterologous cells. AFF-1 and EFF-1 differ in their fusogenic activity and expression patterns but share eight conserved predicted disulfide bonds in their ectodomains, including a putative TGF-beta-type-I-Receptor domain. We found that FOS-1, the Fos transcription factor ortholog that controls anchor-cell invasion during nematode development, is a specific activator of aff-l-mediated anchor-cell fusion. Thus, FOS-1 links cell invasion and fusion in a developmental cascade. C1 Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. Baylor Coll Med, Verna & Mars McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. RP Podbilewicz, B (reprint author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. EM podbilew@tx.technion.ac.il RI Podbilewicz, Benjamin/N-4825-2014; Sapir, Amir/C-5758-2015; OI Sapir, Amir/0000-0001-9888-1800; Avinoam, Ori/0000-0003-3543-168X; Podbilewicz, Benjamin/0000-0002-0411-4182 FU Intramural NIH HHS [Z01 HD001501-14, Z01 HD001501-16] NR 32 TC 58 Z9 64 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2007 VL 12 IS 5 BP 683 EP 698 DI 10.1016/j.devcel.2007.03.003 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 167OF UT WOS:000246460300007 PM 17488621 ER PT J AU Goyal, G Fell, B Sarin, A Youle, RJ Sriram, V AF Goyal, Gaurav Fell, Brennan Sarin, Apurva Youle, Richard J. Sriram, V. TI Role of mitochondrial remodeling in programmed cell death in Drosophila melanogaster SO DEVELOPMENTAL CELL LA English DT Article ID CYTOCHROME-C; CASPASE ACTIVATION; ENDOPLASMIC-RETICULUM; APOPTOSIS; FISSION; FUSION; DIFFERENTIATION; DEPOLARIZATION; MORPHOLOGY; PROMOTES AB The role of mitochondria in Drosophila programmed cell death remains unclear, although certain gene products that regulate cell death seem to be evolutionarily conserved. We find that developmental programmed cell death stimuli in vivo and multiple apoptotic stimuli ex vivo induce dramatic mitochondrial fragmentation upstream of effector caspase activation, phosphatidylserine exposure, and nuclear condensation in Drosophila cells. Unlike genotoxic stress, a lipid cell death mediator induced an increase in mitochondrial contiguity prior to fragmentation of the mitochondria. Using genetic mutants and RNAi-mediated knockdown of drp-1, we find that Drp-1 not only regulates mitochondrial fission in normal cells, but mediates mitochondrial fragmentation during programmed cell death. Mitochondria in drp-1 mutants fail to fragment, resulting in hyperplasia of tissues in vivo and protection of cells from multiple apoptotic stimuli ex vivo. Thus, mitochondrial remodeling is capable of modifying the propensity of cells to undergo death in Drosophila. C1 Tate Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. Surg Neurol Branch, Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Sriram, V (reprint author), Tate Inst Fundamental Res, Natl Ctr Biol Sci, GKVK Campus,Bellary Rd, Bangalore 560065, Karnataka, India. EM sriram@ncbs.res.in FU Intramural NIH HHS NR 43 TC 97 Z9 98 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2007 VL 12 IS 5 BP 807 EP 816 DI 10.1016/j.devcel.2007.02.002 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 167OF UT WOS:000246460300016 PM 17488630 ER PT J AU Buchholz, DR Singamsetty, S Karadge, U Williamson, S Langer, CE Elinson, RP AF Buchholz, Daniel R. Singamsetty, Srikanth Karadge, Uma Williamson, Sean Langer, Carrie E. Elinson, Richard P. TI Nutritional endoderm in a direct developing frog: A potential parallel to the evolution of the amniote egg SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Eleutherodactylus coqui; direct development; endoderm; yolk; Sox17; lineage tracing; amniote egg; amniote evolution ID XENOPUS-LAEVIS OOCYTES; ELEUTHERODACTYLUS-COQUI; CYTOSTATIC FACTOR; AMPHIBIAN METAMORPHOSIS; EMBRYO RETENTION; THYROID-HORMONE; RANA-PIPIENS; YOLK; GASTRULATION; ORIGIN AB The egg of the direct-developing frog, Eleutherodactylus coqui, has 20x the volume as that of the model amphibian, Xenopus laevis. Increased egg size led to the origin of nutritional endoderm, a novel cell type that provides nutrition but does not differentiate into digestive tract tissues. As the E. coqui endoderm develops, a distinct boundary exists between differentiating intestinal cells and large yolky cells, which persists even when yolk platelets are depleted. The yolky cells do not become tissues of the digestive tract and are lost, as shown by histology and lineage tracing. EcSox17, an endodermal transcriptional factor, did not distinguish these two cell types, however. When cleavage of the yolky cells was inhibited, embryogenesis continued, indicating that some degree of incomplete cleavage can be tolerated. The presence of cellularized nutritional endoderm in E. coqui may parallel changes that occurred in the evolution of the amniote egg 360 million years ago. Developmental Dynamics 236.1259-1272, 2007. (C) 2007 Wiley-Liss, Inc. C1 Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA. NICHD, Sect Mol Morphogenesis, LGRD, NIH, Bethesda, MD USA. RP Elinson, RP (reprint author), Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA. EM elinson@duq.edu OI Williamson, Sean/0000-0002-3898-1460 NR 53 TC 24 Z9 24 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAY PY 2007 VL 236 IS 5 BP 1259 EP 1272 DI 10.1002/dvdy.21153 PG 14 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 166AK UT WOS:000246349000009 PM 17436277 ER PT J AU Fu, M Sabra, MM Damcott, C Pollin, TI Ma, LJ Ott, S Shelton, JC Shi, XL Reinhart, L O'Connell, J Mitchell, BD Baier, LJ Shuldiner, AR AF Fu, Mao Sabra, Mona M. Damcott, Coleen Pollin, Toni I. Ma, Lijun Ott, Sandra Shelton, John C. Shi, Xiaolian Reinhart, Laurie O'Connell, Jefrey Mitchell, Braxton D. Baier, Leslie J. Shuldiner, Alan R. TI Evidence that Rho guanine nucleotide exchange factor 11 (ARHGEF11) on 1q21 is a type 2 diabetes susceptibility gene in the old order Amish SO DIABETES LA English DT Article ID GENOME-WIDE SEARCH; CHROMOSOME 1Q21-Q24; INDEPENDENT REPLICATION; INSULIN; ACTIVATION; LOCUS; LINKAGE; KINASE; SCAN; CONFIRMATION AB Rho guanine nucleotide exchange factor 11 (ARHGEF11), located on chromosome 1q21, is involved in G protein signaling and is a pathway known to play a role in both insulin secretion and action. We genotyped 52 single nucleotide polymorphims (SNPs) in ARHGEF11 and compared the genotype frequencies of subjects with type 2 diabetes (n = 145) or type 2 diabetes/impaired glucose tolerance (IGT) (n = 293) with those of control subjects with normal glucose tolerance (NGT) (n = 358). Thirty SNPs, spanning the entire gene, were significantly associated with type 2 diabetes or type 2 diabetes/IGT. The most significantly associated SNP was rs6427340 (intron 2), in which the less common allele was the risk allele (odds ratio [OR] 1.82 [95% CI 1.20-2.70], P = 0.005 for type 2 diabetes vs. NGT and 1.79 [1.27-2.50], P = 0.0008 for type 2 diabetes/IGT vs. NGT). In an expanded set of nondiabetic subjects (n = 754), most of the type 2 diabetes- and IGT-associated SNPs were significantly associated with glucose levels during an oral glucose tolerance test, with the same SNP (rs6427340) showing the most significant associations (P = 0.007). All type 2 diabetes- and IGT-associated SNPs were in high linkage disequilibrium and constitute a single 133-kb haplotype block. These results, coupled with similar findings in Pima Indians, suggest that sequence variation in ARHGEF11 may influence risk of type 2 diabetes. C1 Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. GRECC, Vet Adm Med Ctr, Baltimore, MD USA. NIDDKD, Diabet Mol Genet Sect, Phoenix & Clin Res Branch, NIH, Phoenix, AZ USA. RP Shuldiner, AR (reprint author), Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, 660 W Redwood St,Room 494, Baltimore, MD 21201 USA. EM ashudin@medicine.umaryland.edu OI Mitchell, Braxton/0000-0003-4920-4744 FU NCRR NIH HHS [M01 RR 02719, M01 RR 16500]; NIA NIH HHS [T32 AG000219]; NIDDK NIH HHS [P30 DK072488, R01 DK073490, R01 DK54361] NR 25 TC 18 Z9 18 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2007 VL 56 IS 5 BP 1363 EP 1368 DI 10.2337/db06-1421 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 165GG UT WOS:000246291500020 PM 17369523 ER PT J AU Ma, LJ Hanson, RL Que, LN Cali, AMG Fu, M Mack, JL Infante, AM Kobes, S Bogardus, C Shuldiner, AR Baier, LJ AF Ma, Lijun Hanson, Robert L. Que, Lorem N. Cali, Anna M. G. Fu, Mao Mack, Janel L. Infante, Aniello M. Kobes, Sayuko Bogardus, Clifton Shuldiner, Alan R. Baier, Leslie J. CA Int Type 2 Diabet 1q Consortium TI Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in pima Indians SO DIABETES LA English DT Article ID AUTOSOMAL GENOMIC SCAN; SUSCEPTIBILITY GENES; INDEPENDENT REPLICATION; QUANTITATIVE TRAITS; GENOMEWIDE SEARCH; WIDE SEARCH; IN-VIVO; GLUCOSE; LOCUS; 1Q21-Q24 AB A prior genome-wide linkage scan in Pima Indians indicated a young-onset (aged <45 years) type 2 diabetes susceptibility locus on chromosome lq21-q23. ARHGEF11, which encodes the Rho guanine nucleotide exchange factor 11, was analyzed as a positional candidate gene for this linkage because this protein may stimulate Rho-dependent signals, such as the insulin signaling cascade. The ARHGEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not firstdegree relatives. Sequencing of the coding regions, 5' and 3' untranslated regions and putative promoter regions of these genes, identified 28 variants in ARHGEF11, 11 variants in NTRK1, and 8 variants in INSSR. These 47 variants, as well as 84 additional public database variants within/ between these genes, were genotyped for association analysis in the same group of Pima Indians who had participated in the linkage study (n = 1,228). An R1467H in ARHGEF11, and several additional noncoding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset type 2 diabetes (P = 0.01; odds ratio 3.39) after adjusting for sex, family membership, and Pima heritage. The risk allele H had a frequency of 0.10. In a subgroup of 262 nondiabetic, full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H also was associated with a lower mean insulin-mediated glucose disposal rate and a lower mean nonoxidative glucose storage rate after adjusting for age, sex, nuclear family membership, and percentage of body fat (P <= 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance. C1 NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ 85004 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Baier, LJ (reprint author), NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, 445 N 5th St,Suite 210, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK073490] NR 29 TC 18 Z9 19 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2007 VL 56 IS 5 BP 1454 EP 1459 DI 10.2337/db06-0640 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 165GG UT WOS:000246291500032 PM 17287471 ER PT J AU Schneider, S Sobel, DO Iannotti, RJ Clark, L Haynie, DL Plotnick, LP Simons-Morton, B AF Schneider, Stefan Sobel, Douglas O. Iannotti, Ronald J. Clark, Loretta Haynie, Denise L. Plotnick, Leslie P. Simons-Morton, Bruce TI Identification of distinct self-management styles of adolescents with type 1 diabetes SO DIABETES CARE LA English DT Article ID REGIMEN ADHERENCE; GLYCEMIC CONTROL; CHILDREN; MODEL; CARE; PREDICTORS; CHILDHOOD; INTERVIEW; MELLITUS; OUTCOMES AB OBJECTIVE - Using a profile-based approach to the assessment of diabetes management, the purpose of this study was to identify and evaluate an empirically derived classification system of distinct self-management styles. RESEARCH DESIGN AND METHODS - Youth with type 1 diabetes (n = 156) aged 10-16 years and their parents were administered a modified version of the Diabetes Self-Management Profile (DSMP). Cluster analyses were performed independently on parent and youth report forms to categorize patients based on their patterns of scores in five diabetes self-management areas. RESULTS - Cluster analyses revealed three self-management styles that emerged from both youth and parent report: a "methodical style" (33%) with an emphasis on careful meal planning and correct insulin administration; an "adaptive style" (46%), characterized by high rates of blood glucose testing, exercise, and self-care adjustments; and an "inadequate style" (21%) with moderate rates of self-care adjustments and otherwise low DSMP scores. Convergence between parent and youth report classifications was moderate (Cohen's kappa = 0.47, P < 0.0001). A1C was 1.6% higher in the inadequate style group than in both other groups (P < 0.0001), and the classification significantly accounted for differences in A1C above what was explained by an overall DSMP score. CONCLUSIONS - The findings provide support for recognizing subgroups of patients with unique multidimensional patterns of self-care behaviors. The assessment of self-management styles may prove useful for customized treatments that are targeted directly to the patients needs. C1 NICHHD, DHHS, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Washington, DC USA. Mt Washington Pediat Hosp, Baltimore, MD USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Iannotti, RJ (reprint author), NICHHD, DHHS, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,&B05, Bethesda, MD 20892 USA. EM iannottr@mail.nih.gov RI Schneider, Stefan/K-2815-2012; OI Nansel, Tonja/0000-0002-8298-7595; Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 29 TC 24 Z9 25 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2007 VL 30 IS 5 BP 1107 EP 1112 DI 10.2337/dc06-2197 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 165GF UT WOS:000246291400013 PM 17322481 ER PT J AU Meigs, JB Rutter, MK Sullivan, LM Fox, CS D'Agostino, RB Wilson, PWF AF Meigs, James B. Rutter, Martin K. Sullivan, Lisa M. Fox, Caroline S. D'Agostino, Ralph B., Sr. Wilson, Peter W. F. TI Impact of insulin resistance on risk of type 2 diabetes and cardiovascular disease in people with metabolic syndrome SO DIABETES CARE LA English DT Article ID HOMEOSTASIS MODEL ASSESSMENT; FEDERATION; DEFINITIONS; POPULATION; PREVALENCE; CRITERIA; HEART; STATEMENT; MELLITUS; PROGRAM AB OBJECTIVE - Metabolic syndrome increases the risk for type 2 diabetes and cardiovascular disease (CVD) and may be associated with insulin resistance. RESEARCH DESIGN AND METHODS - We tested the hypothesis that the metabolic syndrome confers risk with or without concomitant insulin resistance among 2,803 Framingham Offspring Study subjects followed up to 11 years for new diabetes (135 cases) or CVD (240 cases). We classified subjects by presence of metabolic syndrome (using the National Cholesterol Education Program's [NCEPs] Third Adult Treatment Panel [ATP III], International Diabetes Federation [IDF], or European Group for the Study of Insulin Resistance [EGIR] criteria) and insulin resistance (homeostasis model assessment of insulin resistance >= 75th percentile) and, used separate risk factor-adjusted proportional hazards models to estimate relative risks (RRs) for diabetes or CVD using as references those without insulin resistance, metabolic syndrome, or without both. RESULTS - Fifty-six percent of individuals with ATP III, 52% with IDF, and 100% with EGIR definitions of metabolic syndrome had insulin resistance. Insulin resistance increased risk for diabetes (RR 2.6 [95% CI 1.7-4.0]) and CVD (1.8 [1.4-2.3]) as did metabolic syndrome for diabetes (ATP III, 3.5 [2.2-5.6]; IDF, 4.6 [2.7-7.7]; and EGIR, 3.3 [2.1-5.1]) and CVD (ATP III, 1.8 [1.4-2.3]; IDF, 1.7 [1.3-2.3]; and EGIR, 2.1 [1.6-2.7]). Relative to those without either I metabolic syndrome or insulin resistance, metabolic syndrome and insulin resistance increased risk for diabetes (ATP III, 6.0 [3.3-10.8] and IDF, 6.9 [3.7-13.0]) and CVD (ATP III, 2.3 [1.7-3.1] and IDF, 2.2 [1.6-3.0]). Any instance of metabolic syndrome without insulin resistance increased risk for diabetes approximately threefold (P < 0.001; IDF metabolic syndrome without insulin resistance (RR 1.6, P = 0.01), but not ATP III metabolic syndrome without insulin resistance (RR 1.3,P = 0.2), increased for CVD. CONCLUSIONS - Metabolic syndrome increased risk for diabetes regardless of insulin resistance. Metabolic syndrome by ATP III criteria may require insulin resistance to increase risk for CVD. The simultaneous presence of metabolic syndrome and insulin resistance identifies an especially high-risk individual. C1 Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Manchester Royal Infirm, Manchester Diabet Ctr, Manchester M13 9WL, Lancs, England. Univ Manchester, Sch Med, Div Cardiovasc & Endocrine Sci, Manchester M13 9PL, Lancs, England. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Brigham & Womens Hosp, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NHLBI, Framingham Mass Heart Study, Framingham, MA USA. Boston Univ, Dept Math, Stat & Consulting Unit, Boston, MA 02215 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Stanifort St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Rutter, Martin/0000-0001-6380-539X FU NHLBI NIH HHS [N01-HC-25195] NR 30 TC 128 Z9 133 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2007 VL 30 IS 5 BP 1219 EP 1225 DI 10.2337/dc06-2484 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 165GF UT WOS:000246291400031 PM 17259468 ER PT J AU Ingelsson, E Larson, MG Fox, CS Yin, X Wang, TJ Lipinska, I Pou, KM Hoffmann, U Benjamin, EJ Keaney, JF Vasan, RS AF Ingelsson, Erik Larson, Martin G. Fox, Caroline S. Yin, Xiaoyan Wang, Thomas J. Lipinska, Izabella Pou, Karla M. Hoffmann, Udo Benjamin, Emelia J. Keaney, John F., Jr. Vasan, Ramachandran S. TI Clinical correlates of circulating visfatin levels in a community-based sample SO DIABETES CARE LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; COLONY-ENHANCING FACTOR; PLASMA; GLUCOSE; HUMANS; WOMEN; FAT C1 Boston Univ, Sch Med, Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Boston Univ, Sch Med, Evans Mem Dept Med, Boston, MA 02115 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Vasan, RS (reprint author), Boston Univ, Sch Med, Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24HL4334, N01-HC-25195, R01-HL-076784, K23-HL-074077]; NIDDK NIH HHS [T32 DK007529] NR 14 TC 27 Z9 30 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2007 VL 30 IS 5 BP 1278 EP 1280 DI 10.2337/dc06-2353 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 165GF UT WOS:000246291400043 PM 17261750 ER PT J AU Bunt, JC Krakoff, J Ortega, E Knowler, WC Bogardus, C AF Bunt, Joy C. Krakoff, Jonathan Ortega, Emilio Knowler, William C. Bogardus, Clifton TI Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE type 2 diabetes; insulin action; insulin secretion; obesity ID PIMA-INDIANS; SECRETORY DYSFUNCTION; BETA-CELL; FOLLOW-UP; METABOLIC CHARACTERISTICS; NATURAL-HISTORY; RISK-FACTORS; LIFE-STYLE; RESISTANCE; TOLERANCE AB Background Earlier prospective studies have identified insulin action and secretion as predictors of T2DM in populations with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) (2-h OGTT < 7.8 and 7.8-11 mmol/L, respectively). Fasting plasma glucose (FPG), an additional and recently modified (normal <5.6 mmol/L) diagnostic criterion is associated with insulin secretion. We wanted to establish whether insulin secretion persists as an independent predictor of T2DM in individuals with no clinical evidence of impaired glucose regulation based on FPG and 2-h plasma glucose concentrations. Methods Insulin action (M, euglycemic-hyperinsulinemic clamp), insulin secretion (acute insulin response (AIR), IVGTT), and adiposity (%Fat, DXA or densitometry) were compared at baseline in 358 Pima Indians (232M/126F, 18-44 years old) with normal glucose regulation of whom 61 (35M/26F) developed diabetes (DIAB) during a median follow-up time of 7.6 years. Results In proportional-hazard analysis, % Fat (HR = 1.52, p = 0.03), M (HR = 0.51, p = 0.04) and AIR (HR = 0.64, p = 0.003) predicted the development of diabetes after adjustment for age and sex. In regression analysis adjusting for age, sex, %Fat and M at baseline, the non-diabetic group (NON-DM) had a higher AIR (p = 0.0002) than the DIAB group; the positive association of AIR with adiposity observed in the NON-DM group was absent in the DIAB group. Cumulative incidence rates (12y) for diabetes were highest (48%) in subjects with both M and AIR below the population median and lowest (11%) in subjects with both M and AIR above the population median. Conclusion AIR can predict diabetes prior to the current clinical indicators of impaired glucose regulation. Published in 2006 by John Wiley & Sons, Ltd. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Dept Hlth & Human Serv, Phoenix, AZ USA. RP Bunt, JC (reprint author), NIH, Obes & Diabet Clin Res Sect, Room 541-A,4212 N 16th St, Phoenix, AZ 85016 USA. EM jbunt@mail.nih.gov FU Intramural NIH HHS [Z01 DK069015-25] NR 42 TC 29 Z9 32 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1520-7552 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD MAY PY 2007 VL 23 IS 4 BP 304 EP 310 DI 10.1002/dmrr.686 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 176BX UT WOS:000247058800009 PM 17001619 ER PT J AU Traurig, M Hanson, RL Kobes, S Bogardus, C Baier, LJ AF Traurig, M. Hanson, R. L. Kobes, S. Bogardus, C. Baier, L. J. TI Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians SO DIABETOLOGIA LA English DT Article DE genotyping; insulin sensitivity; obesity; Pima Indians; PTPN1; SNPs; type 2 diabetes ID INSULIN-RESISTANCE; ASSOCIATION; POLYMORPHISMS; PTPN1; POPULATION; VARIANT; FAT AB Aim/hypothesis Single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase 1B gene (PTPN1) have been reported to be associated with type 2 diabetes in white subjects, and insulin sensitivity and fasting glucose levels in Hispanic Americans. In this study, we determined whether SNPs in PTPN1 also have a role in type 2 diabetes susceptibility in Pima Indians, a population with the world's highest reported prevalence and incidence rates of this disease. Materials and methods Thirty-one SNPs across a 161-kb region encompassing PTPN1 were genotyped in 1,037 Pima Indians for association studies with type 2 diabetes and obesity. Results Twenty-five of the SNPs had allele frequencies > 0.05, and these SNPs fell into two linkage disequilibrium blocks (D' > 0.9). Block 1 contains six SNPs that span a 61-kb region upstream of PTPN1, while block 2 contains 19 SNPs that cover the entire PTPN1 gene. None of the SNPs, analysed individually or as haplotypes, was associated with either type 2 diabetes or obesity. However, three SNPs located in block 1 were nominally associated (p values ranging from 0.01 to 0.05) with insulin sensitivity as measured by the hyperinsulinaemic-euglycaemic clamp technique. Conclusions/interpretation Based on our association results, we conclude that SNPs within PTPN1 are unlikely to have a major role in the aetiology of type 2 diabetes or obesity in Pima Indians. C1 NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 445 N 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS NR 12 TC 11 Z9 12 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAY PY 2007 VL 50 IS 5 BP 985 EP 989 DI 10.1007/s00125-007-0611-6 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 154QC UT WOS:000245521400013 PM 17333110 ER PT J AU Chan, KC Patri, AK Veenstra, TD McNeil, SE Issaq, HJ AF Chan, King C. Patri, Anil K. Veenstra, Timothy D. McNeil, Scott E. Issaq, Haleem J. TI Analysis of fullerene-based nanomaterial in serum matrix by CE SO ELECTROPHORESIS LA English DT Article DE CE; fullerenes; nanotechnology ID MICELLAR ELECTROKINETIC CHROMATOGRAPHY; CAPILLARY-ZONE-ELECTROPHORESIS; CARBOXYL-TERMINATED DENDRIMERS; POLY(AMIDOAMINE) DENDRIMERS; CANCER-THERAPY; DRUG-DELIVERY; MALONIC-ACID; SLAB-GEL; CARBOXYFULLERENE; SEPARATION AB With the increasing interest in using nanoparticles as vehicles for drug delivery and image contrast agents, there is a need to develop assays for their detection and quantitation in complex matrices to facilitate monitoring their biodistribution. In this study, we developed a CE approach for the analysis of two nanoparticles: carboxyfullerene (C3) and dendrofullerene (DF1) in both standard solutions and a serum matrix. These highly soluble, charged C-60 derivatives were characterized by CZE using either a bare or dynamically coated fused-silica capillaries. The resolution of both nanoparticles was slightly lower with the coated capillary; however, their migration times were faster. While separation of the DF1 nanoparticles using MEKC resulted in a greater number of observable peaks, the peak profile of C3 was basically unchanged regardless of whether SDS micelles were added to the running buffers or not. The MEKC and/or CZE assays were then used to quantitate the C3 and DF1 nanoparticles in spiked human serum samples. The quantitation of the nanoparticles was linear from 0-500 mu g/mL with detection limits ranging from 0.5 to 6 mu g/mL. C1 SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI Frederick, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Nanotechnol Characterizat Lab, NCI Frederick, Ft Detrick, MD USA. RP Chan, KC (reprint author), SAIC Frederick Inc, Lab Proteom & Analyt Technol, NCI Frederick, Ft Detrick, MD 21702 USA. EM chan@ncifcrf.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU NCI NIH HHS [N01 CO12400] NR 46 TC 17 Z9 19 U1 0 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD MAY PY 2007 VL 28 IS 10 BP 1518 EP 1524 DI 10.1002/elps.200600724 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 174EE UT WOS:000246923300008 PM 17447247 ER PT J AU Rizzo, C Bella, A Viboud, C Simonsen, L Miller, MA Rota, MC Salmaso, S degli Atti, MLC AF Rizzo, Caterina Bella, Antonino Viboud, Cecile Simonsen, Lone Miller, Mark A. Rota, Maria Cristina Salmaso, Stefania degli Atti, Marta Luisa Ciofi TI Trends for influenza-related deaths during pandemic and epidemic seasons, Italy, 1969-2001 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; POPULATION-DYNAMICS; MORTALITY; SYNCHRONY; IMPACT; AGE; SURVEILLANCE; VACCINATION; PNEUMONIA; PATTERNS AB Age-specific patterns of death from influenza vary, depending on whether the influenza season is epidemic or pandemic. We assessed age patterns and geographic trends in monthly influenza-related deaths in Italy from 1969 through 2001, focusing on differences between epidemic and pandemic seasons. We evaluated age-standardized excess deaths from pneumonia and influenza and from all causes, using a modified version of a cyclical Serfling model. Excess deaths were highest for elderly persons in all seasons except the influenza A (H3N2) pandemic season (1969-70), when rates were greater for younger persons, confirming a shift toward death of younger persons during pandemic seasons. When comparing northern, central, and southern Italy, we found a high level of synchrony in the amplitude of peaks of influenza-related deaths. C1 Ist Super Sanita, CNESPS, Infect Dis Unit, I-00169 Rome, Italy. Univ Bari, Bari, Italy. NIH, Bethesda, MD 20892 USA. RP Rizzo, C (reprint author), Ist Super Sanita, CNESPS, Infect Dis Unit, Viale Regina Elena 299, I-00169 Rome, Italy. EM caterina.rizzo@iss.it RI Rizzo, Caterina/H-4092-2012; OI Rizzo, Caterina/0000-0002-5583-7508; Simonsen, Lone/0000-0003-1535-8526 NR 34 TC 34 Z9 37 U1 0 U2 2 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAY PY 2007 VL 13 IS 5 BP 694 EP 699 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 164DD UT WOS:000246212400003 PM 17553246 ER PT J AU Marsh, AA Kozak, MN Ambady, N AF Marsh, Abigail A. Kozak, Megan N. Ambady, Nalini TI Accurate identification of fear facial expressions predicts prosocial behavior SO EMOTION LA English DT Article DE prosocial behavior; fear; facial expression; accuracy; nonverbal sensitivity ID INDIVIDUAL-DIFFERENCES; ANTISOCIAL-BEHAVIOR; PSYCHOPATHIC TENDENCIES; IMPAIRED RECOGNITION; NEURAL RESPONSES; SOCIAL-BEHAVIOR; EMOTION; EMPATHY; ALTRUISM; PERSPECTIVE AB The fear facial expression is a distress cue that is associated with the provision of help and prosocial behavior. Prior psychiatric studies have found deficits in the recognition of this expression by individuals with antisocial tendencies. However, no prior study has shown accuracy for recognition of fear to predict actual prosocial or antisocial behavior in an experimental setting. In 3 studies, the authors tested the prediction that individuals who recognize fear more accurately will behave more prosocially. In Study 1, participants who identified fear more accurately also donated more money and time to a victim in a classic altruism paradigm. In Studies 2 and 3, participants' ability to identify the fear expression predicted prosocial behavior in a novel task designed to control for confounding variables. In Study 3, accuracy for recognizing fear proved a better predictor of prosocial behavior than gender, mood, or scores on an empathy scale. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Tufts Univ, Dept Psychol, Medford, MA 02155 USA. RP Marsh, AA (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,300D,MSC 2670, Bethesda, MD 20892 USA. EM amarsh@post.harvard.edu FU Intramural NIH HHS; NIMH NIH HHS [R01 MH070833, F31 MH067332-01A1, 1R01MH70833-01A1, 1-F31-MH067332-01A1, F31 MH067332] NR 91 TC 80 Z9 82 U1 6 U2 42 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 J9 EMOTION JI Emotion PD MAY PY 2007 VL 7 IS 2 BP 239 EP 251 DI 10.1037/1528-3542.7.2.239 PG 13 WC Psychology, Experimental SC Psychology GA 166WT UT WOS:000246412200002 PM 17516803 ER PT J AU Holloway, MG Cui, YZ Laz, EV Hosui, A Hennighausen, L Waxman, DJ AF Holloway, Minita G. Cui, Yongzhi Laz, Ekaterina V. Hosui, Atsushi Hennighausen, Lothar Waxman, David J. TI Loss of sexually dimorphic liver gene expression upon hepatocyte-specific deletion of Stat5a-Stat5b locus SO ENDOCRINOLOGY LA English DT Article ID GROWTH-FACTOR-I; POSTNATAL BODY GROWTH; SIGNAL TRANSDUCER; TRANSCRIPTION 5B; IGF-I; HORMONE REGULATION; GENDER-DIFFERENCES; BINDING-SITES; STAT5B; MICE AB Hepatocyte-specific, albumin-Cre recombinase-mediated deletion of the entire mouse Stat5a-Stat5b locus was carried out to evaluate the role of signal transducer and activator of transcription 5a and 5b (STAT5ab) in the sex-dependent transcriptional actions of GH in the liver. The resultant hepatocyte STAT5ab-deficient mice were fertile, and unlike global STAT5b-deficient male mice, postnatal body weight gain was normal, despite a 50% decrease in serum IGF-I. Whole-liver STAT5ab RNA decreased by approximately 65 - 85%, and residual STAT5 immunostaining was observed in a minority of the hepatocytes, indicating incomplete excision by Cre-recombinase. Quantitative PCR analysis of 20 sexually dimorphic, liver-expressed genes revealed significant down-regulation of 10 of 11 male-specific genes in livers of male hepatocyte STAT5ab-deficient mice. Class I female-specific liver genes were markedly up-regulated (de-repressed), whereas the expression of class II female genes, belonging to the Cyp3a subfamily, was unaffected by the loss of hepatocyte STAT5ab. STAT5ab is thus required in the liver for positive regulation of male-specific genes and for negative regulation of a subset of female-specific genes. Continuous GH infusion strongly induced (> 500-fold) the class II female gene Cyp3a16 in both wild-type and hepatocyte STAT5ab-deficient male mice, indicating sex-specific transcriptional regulation by GH that is STAT5ab independent. In contrast, hepatocyte STAT5ab deficiency abolished the strong suppression of the male-specific Cyp2d9 by continuous GH seen in control mouse liver. Analysis of global STAT5a-deficient mice indicated no essential requirement of STAT5a for expression of these sex-specific liver Cyp genes. Thus, the major loss of liver sexual dimorphism in hepatocyte STAT5ab-deficient mice can primarily be attributed to the loss of STAT5b. C1 Boston Univ, Dept Biol, Div Cell & Mol Biol, Boston, MA 02215 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Waxman, DJ (reprint author), Boston Univ, Dept Biol, Div Cell & Mol Biol, 5 Cummington St, Boston, MA 02215 USA. EM djw@bu.edu OI Waxman, David/0000-0001-7982-9206 FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK033765, DK33765, R01 DK033765-27] NR 37 TC 50 Z9 51 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2007 VL 148 IS 5 BP 1977 EP 1986 DI 10.1210/en.2006-1419 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158RG UT WOS:000245810600006 PM 17317776 ER PT J AU Yuan, G Deng, JJ Wang, T Zhao, CX Xu, XZ Wang, PH Voltz, JW Edin, ML Xiao, X Chao, L Chao, J Zhang, XA Zeldin, DC Wang, DW AF Yuan, Gang Deng, Juanjuan Wang, Tao Zhao, Chunxia Xu, Xizheng Wang, Peihua Voltz, James W. Edin, Matthew L. Xiao, Xiao Chao, Lee Chao, Julie Zhang, Xin A. Zeldin, Darryl C. Wang, Dao Wen TI Tissue kallikrein reverses insulin resistance and attenuates nephropathy in diabetic rats by activation of phosphatidylinositol 3-kinase/protein kinase B and adenosine 5 '-monophosphate-activated protein kinase signaling pathways SO ENDOCRINOLOGY LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; EARLY NATURAL-HISTORY; SKELETAL-MUSCLE; HYPERTENSIVE-RATS; GENE-THERAPY; GLOMERULAR HYPERFILTRATION; RECEPTOR SUBSTRATE-1; GLUCOSE-UPTAKE; IN-VIVO; BRADYKININ AB We previously reported that iv delivery of the human tissue kallikrein (HK) gene reduced blood pressure and plasma insulin levels in fructose-induced hypertensive rats with insulin resistance. In the current study, we evaluated the potential of a recombinant adeno-associated viral vector expressing the HK cDNA (rAAV-HK) as a sole, long-term therapy to correct insulin resistance and prevent renal damage in streptozotocin-induced type-2 diabetic rats. Administration of streptozotocin in conjunction with a high-fat diet induced systemic hypertension, diabetes, and renal damage in rats. Delivery of rAAV-HK resulted in a long-term reduction in blood pressure, and fasting plasma insulin was significantly lower in the rAAV-HK group than in the control group. The expression of phosphatidylinositol 3-kinase p110 catalytic subunit and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B, and AMP-activated protein kinases were significantly decreased in organs from diabetic animals. These changes were significantly attenuated after rAAV-mediated HK gene therapy. Moreover, rAAV-HK significantly decreased urinary microalbumin excretion, improved creatinine clearance, and increased urinary osmolarity. HK gene therapy also attenuated diabetic renal damage as assessed by histology. Together, these findings demonstrate that rAAV-HK delivery can efficiently attenuate hypertension, insulin resistance, and diabetic nephropathy in streptozotocin-induced diabetic rats. C1 Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Gene Therapy Ctr, Wuhan 430030, Peoples R China. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Dept Mol Genet & Biochem, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Gene Therapy Ctr, Pittsburgh, PA 15260 USA. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Univ Tennessee, Ctr Hlth Sci, Vasc Biol Ctr, Memphis, TN 38163 USA. Univ Tennessee, Ctr Hlth Sci, Dept Med, Memphis, TN 38163 USA. Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X FU Intramural NIH HHS [Z01 ES025034-13] NR 62 TC 31 Z9 34 U1 0 U2 11 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2007 VL 148 IS 5 BP 2016 EP 2026 DI 10.1210/en.2006-0602 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 158RG UT WOS:000245810600010 PM 17272402 ER PT J AU Nuckols, JR Gunier, RB Riggs, P Miller, R Reynolds, P Ward, MH AF Nuckols, John R. Gunier, Robert B. Riggs, Philip Miller, Ryan Reynolds, Peggy Ward, Mary H. TI Linkage of the California Pesticide Use Reporting Database with spatial land use data for exposure assessment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agricultural land use; California; exposure assessment; GIS; pesticide use reporting ID RESIDENTIAL PROXIMITY; CHILDHOOD-CANCER; SPRAY DRIFT; AGRICULTURAL PESTICIDES; AERIAL APPLICATIONS; INFORMATION-SYSTEM; AIR CONCENTRATIONS; BREAST-CANCER; COMMUNITY; CHILDREN AB BACKGROUND: The State of California maintains a comprehensive Pesticide Use Reporting Database (CPUR). The California Department of Water Resources (CDWR) maps all crops in agricultural counties in California about once every 5 years. OBJECTIVE: We integrated crop maps with CPUR to more accurately locate where pesticides are applied and evaluated the effects for exposure assessment. METHODS: We mapped 577 residences and used the CPUR and CIDWR data to compute two exposure metrics based on putative pesticide use within a 500-m buffer. For the CPUR, metric, we assigned pesticide exposure to the residence proportionally for all square-mile Sections that intersected the buffer. For the CDWR metric, we linked CPUR crop-specific pesticide use to crops mapped within the buffer and assigned pesticide exposure. We compared the metrics for six pesticides: simazine, trifluralin (herbicides), dicofol, propargite (insecticides), methyl bromide, an metam. sodium (fumigants). RESULTS: For all six pesticides we found good agreement (88-98%) as to whether the pesticide use was predicted. When we restricted the analysis to residences with reported pesticide use in sections within 500 in, agreement was greatly reduced (35-58%). The CPUR metric estimates of pesticide use within 500 in were significantly higher than the CDWR metric for all six pesticides. CONCLUSIONS: Our findings may have important implications for exposure classification in epidemiologic studies of agricultural pesticide use using CPUR. There is a need to conduct environmental and biological measurements to ascertain which, if any, of these metrics best represent exposure. C1 Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. No Calif Canc Ctr, Berkeley, CA USA. USDA, Anim Plant Hlth Inspect Serv, Ft Collins, CO USA. US Dept HHS, Div Canc Epidemiol & Genet, NCI, NIH, Bethesda, MD USA. RP Nuckols, JR (reprint author), Colorado State Univ, Dept Environm & Radiol Hlth Sci, 1681 Campus Delivery, Ft Collins, CO 80523 USA. EM jnuckols@colostate.edu RI Miller, Ryan/G-6356-2010; OI Gunier, Robert/0000-0001-5485-9919; Miller, Ryan/0000-0003-3892-0251 FU Intramural NIH HHS; NCI NIH HHS [R01CA71745, R01 CA092683, R01CA092683, R03 CA83071] NR 36 TC 22 Z9 22 U1 3 U2 18 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2007 VL 115 IS 5 BP 684 EP 689 DI 10.1289/ehp.9518 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 163KZ UT WOS:000246159900025 PM 17520053 ER PT J AU Handal, AJ Lozoff, B Breilh, J Harlow, SD AF Handal, Alexis J. Lozoff, Betsy Breilh, Jaime Harlow, Sioban D. TI Neurobehavioral development in children with potential exposure to pesticides SO EPIDEMIOLOGY LA English DT Article ID CENTRAL WASHINGTON-STATE; AGRICULTURAL COMMUNITY; PRESCHOOL-CHILDREN; ADULT MICE; CHLORPYRIFOS; PATHWAYS; WORKERS; HEALTH; PARATHION; TOXICITY AB Background: Children may be at higher risk than adults from pesticide exposure, due to their rapidly developing physiology, unique behavioral patterns, and interactions with the physical environment. This preliminary study conducted in Ecuador examines the association between household and environmental risk factors for pesticide exposure and neurobehavioral development. Methods: We collected data over 6 months in the rural highland region of Cayambe, Ecuador (2003-2004). Children age 24-61 months residing in 3 communities were assessed with the Ages and Stages Questionnaire and the Visual Motor Integration Test. We gathered information on maternal health and work characteristics, the home and community environment, and child characteristics. Growth measurements and a hemoglobin finger-prick blood test were obtained. Multiple linear regression analyses were conducted. Results: Current maternal employment in the flower industry was associated with better developmental scores. Longer hours playing outdoors were associated with lower gross and fine motor and problem solving skills. Children who played with irrigation water scored lower on fine motor skills (8% decrease; 95% confidence interval = -9.31 to -0.53), problem-solving skills (7% decrease; -8.40 to -0.39), and Visual Motor Integration test scores (3% decrease; -12.00 to 1.08). Conclusions: These results suggest that certain environmental risk factors for exposure to pesticides may affect child development, with contact with irrigation water of particular concern. However, the relationships between these risk factors and social characteristics are complex, as corporate agriculture may increase risk through pesticide exposure and environmental contamination, while indirectly promoting healthy development by providing health care, relatively higher salaries, and daycare options. C1 Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. Hlth Res & Advisory Ctr, CEAS, Quito, Ecuador. RP Handal, AJ (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03B, Rockville, MD 20852 USA. EM handalal@mail.nih.gov FU FIC NIH HHS [D43-TW01276]; NIGMS NIH HHS [R25 GM58641-06] NR 36 TC 16 Z9 18 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2007 VL 18 IS 3 BP 312 EP 320 DI 10.1097/01.ede.0000259983.55716.bb PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 161DA UT WOS:000245993300004 PM 17435439 ER PT J AU Arai, AE AF Arai, Andrew E. TI False positive or true positive troponin in patients presenting with chest pain but normal' coronary arteries: lessons from cardiac MRI SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID ENHANCEMENT; INFARCTION C1 Natl Heart Lung & Blood Inst, NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), Natl Heart Lung & Blood Inst, NIH, Bldg 10,Room B1D416,MSC 1061 10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov NR 10 TC 8 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD MAY PY 2007 VL 28 IS 10 BP 1175 EP 1177 DI 10.1093/eurheartj/ehm113 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 181II UT WOS:000247430000001 PM 17395680 ER PT J AU Owen, PJD Ying, H Lang, D Tomlinson, D Lewis, MJ Cheng, SY Lazarus, JH AF Owen, P. J. D. Ying, H. Lang, D. Tomlinson, D. Lewis, M. J. Cheng, S. Y. Lazarus, J. H. TI Endothelial dysfunction in a murine model of thyroid hormone resistance SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE endothelial; knockin; mice; resistance; thyroid; vascular ID CENTRAL ARTERIAL STIFFNESS; VASCULAR SMOOTH-MUSCLE; NITRIC-OXIDE; ACUTE HYPERTHYROIDISM; THYROTROPIN; BETA; HYPOTHYROIDISM; EXPRESSION; MUTANT; CELLS AB Background The development of a knockin mouse model of resistance to thyroid hormone (RTH) has led to a greater understanding of both the molecular and clinical behaviour of this syndrome. We have investigated the vascular response in RTH using a specific (TR beta PV) knockin mouse model targeting the PV mutation to the thyroid hormone receptor beta gene locus. Materials and methods Ring segments of the thoracic aorta were used to assess the response of homozygous, heterozygous and wild-type controls to contractile agents, potassium chloride and phenylephrine. Each genotype after maximal contraction was exposed to increasing concentrations of relaxing agents, acetylcholine (ACh) and sodium nitroprusside (SNP). Results The response of these aortic ring segments to ACh and SNP demonstrates that endothelium-dependent relaxation to ACh was significantly impaired in both heterozygous and homozygous mice compared to controls (69.8 +/- 2.0%, 59.7 +/- 1.4% and 75.0 +/- 1.7%, respectively; P < 0.001). However, endothelium independent responses to SNP showed no difference between genotypes (114.4 +/- 3.2%, 116.8 +/- 2.6% and 106.9 +/- 4.9%; P = NS). Conclusion These data suggest that endothelial function is impaired in the RTH mouse aorta. The respective roles of elevated thyroid stimulating hormone (TSH), elevated thyroid hormone concentrations and the mutated thyroid hormone beta receptor require further elucidation. C1 Univ Cardiff Wales, Ctr Endocrine & Diabet Sci, Cardiff CF14 4XN, Wales. Natl Inst Hlth, Bethesda, MD USA. Univ Cardiff Wales, Sch Med, Dept Pharmacol, Cardiff CF14 4XN, Wales. RP Lazarus, JH (reprint author), Univ Cardiff Wales, Univ Wales Hosp, Ctr Endocrine & Diabet Sci, Cardiff CF14 4XN, Wales. EM lazarus@cf.ac.uk NR 27 TC 4 Z9 4 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAY PY 2007 VL 37 IS 5 BP 390 EP 395 DI 10.1111/j.1365-2362.2007.01799.x PG 6 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 161AI UT WOS:000245986300008 PM 17461985 ER PT J AU Kino, T Rice, KC Chrousos, GP AF Kino, T. Rice, K. C. Chrousos, G. P. TI The PPAR delta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE alpha 1-antichymotrypsin; inflammation; interleukin-6; peroxisome proliferator-activated receptor delta (PPAR delta); signal transducer and activator of transcription 3 (STAT3) ID PITUITARY-ADRENAL AXIS; GLUCOCORTICOID-RECEPTOR; GENE-EXPRESSION; RECOMBINANT INTERLEUKIN-6; TRANSCRIPTIONAL ACTIVITY; CLINICAL-IMPLICATIONS; FATTY-ACIDS; INFLAMMATION; GAMMA; ACTIVATION AB Background Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPAR delta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. Materials and methods We examined the ability of the synthetic PPAR delta agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein alpha 1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha 2-acid glycoprotein, beta-fibrinogen and alpha 2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPAR delta receptor, but not of PPAR alpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha 1-antichymotrypsin mRNA expression, indicating that PPAR delta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha 1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPAR delta on this promoter. Overexpression of PPAR delta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha 1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. Conclusions These findings indicate that agonist-activated PPAR delta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPAR delta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role. C1 NICHHD, Reprod Biol & Med Branch, NIH, Clin Res Ctr,Paediat Endocrinol Sect, Bethesda, MD 20892 USA. NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. Univ Athens, Dept Paediat 1, Athens 11527, Greece. RP Kino, T (reprint author), NICHHD, Reprod Biol & Med Branch, NIH, Clin Res Ctr,Paediat Endocrinol Sect, Bldg 10,Rm 1-3140 10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov FU Intramural NIH HHS NR 40 TC 39 Z9 40 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAY PY 2007 VL 37 IS 5 BP 425 EP 433 DI 10.1111/j.1365-2362.2007.01796.x PG 9 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 161AI UT WOS:000245986300012 PM 17461989 ER PT J AU Berardinelli, F di Masi, A Salvatore, M Banerjee, S Myung, K De Villartay, JP Revy, P Plebani, A Soresina, A Taruscio, D Tanzarella, C Antoccia, A AF Berardinelli, F. di Masi, A. Salvatore, M. Banerjee, S. Myung, K. De Villartay, J. P. Revy, P. Plebani, A. Soresina, A. Taruscio, D. Tanzarella, C. Antoccia, A. TI A case report of a patient with microcephaly, facial dysmorphism, chromosomal radiosensitivity and telomere length alterations closely resembling "Nijmegen breakage syndrome" phenotype SO EUROPEAN JOURNAL OF MEDICAL GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-LIGASE-IV; ATAXIA-TELANGIECTASIA; ATM ACTIVATION; INSTABILITY; PROTEIN; MUTATIONS; COMPLEX; REPAIR; GENE AB Genetic heterogeneity in Nijmegen breakage syndrome (NBS) is highlighted by patients showing clinical and cellular features of NBS but with no mutations in NBS1 and normal levels of nibrin. NBS is an autosomal recessive disorder, whose clinical cellular signs include growth and developmental defects, dysmorphic facies, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. NBS is caused by mutations in the NBS1 gene, whose product is part of the MRE11/RAD50/ NBS1 complex involved in the DNA double-strand break (DSB) response pathway. Since the identification of the NBS1 gene, patients with NBS clinical signs, particularly severe congenital microcephaly, are screened for mutations in the NBS1 gene. Further analyses include X-ray-induced chromosome aberrations, telomere analysis, kinetics of DSBs repair, levels of a panel of proteins involved in the maintenance of genetic stability, radiation-induced phosphorylation of various substrates and cell cycle analysis. We describe a patient with a NBS clinical phenotype, chromosomal sensitivity to X-rays but without mutations in the whole NBS1 or in the Cernunnos gene. Enhanced response to irradiation was mediated neither by DSBs rejoining defects nor by the NBS/AT-dependent DNA-damage response pathway. Notably, we found that primary fibroblasts from this patient displayed telomere length alterations. Cross-talk between pathways controlling response to DSBs and those involved in maintaining telomeres has been shown in the present patient. Dissecting the cellular phenotype of radiosensitive NBS-like. patients represents a useful tool for the research of new genes involved in the cellular response to DSBs. (c) 2007 Elsevier Masson SAS. All rights reserved. C1 Univ Roma Tre, Dept Biol, I-00146 Rome, Italy. Ist Super Sanita, Dept Biol & Neurosci, I-00161 Rome, Italy. NHGRI, Genet & Mol Biol Branch, Genome Instabil Sect, NIH, Bethesda, MD 20892 USA. Hop Necker Enfants Malad, INSERM, U768, Paris, France. Pediat Clin, Brescia, Italy. Ist Angelo Novicelli, Brescia, Italy. RP Antoccia, A (reprint author), Univ Roma Tre, Dept Biol, Vle Marconi 446, I-00146 Rome, Italy. EM antoccia@uniroma3.it RI Plebani, Alessandro/C-8593-2011; TARUSCIO, DOMENICA/A-6646-2015 OI TARUSCIO, DOMENICA/0000-0001-5403-233X FU Intramural NIH HHS NR 29 TC 9 Z9 10 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1769-7212 J9 EUR J MED GENET JI Eur. J. Med. Genet. PD MAY-JUN PY 2007 VL 50 IS 3 BP 176 EP 187 DI 10.1016/j.ejmg.2007.01.006 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 180ZK UT WOS:000247406300002 PM 17395558 ER PT J AU Braun, C Staudt, M Schmitt, C Preissl, H Birbaumer, N Gerloff, C AF Braun, Christoph Staudt, Martin Schmitt, Carmen Preissl, Hubert Birbaumer, Niels Gerloff, Christian TI Crossed cortico-spinal motor control after capsular stroke SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; FUNCTIONAL REORGANIZATION; CEREBRAL ACTIVATION; PREMOTOR CORTEX; CORTICAL REORGANIZATION; POSTSTROKE HEMIPARESIS; BRAIN ACTIVATION; RECOVERY; INFARCTION; MOVEMENTS AB While it is widely accepted that multiple nonprimary motor areas such as the dorsal premotor cortex contribute to recovery from stroke, the contribution of the ipsilesional and contralesional primary motor cortex (M1) is controversial. It has been suggested that re-instating 'near normal' activation patterns is a good strategy for recovery of function [Baron et at., (2004) Cerebrovasc. Dis., 18, 260-267; Ward & Cohen, (2004) Arch. Neurol., 61, 1844-1848]. The present study addressed this aspect of stroke recovery by combining transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) in a cross-sectional design on nine patients with well-recovered motor function 17.6 +/- 5.5 months (mean +/- SD) after subcortical stroke. While TMS was applied to probe the integrity of the cortico-spinal tract (CST) at rest, MEG was used to test for recruitment of CST pathways during a motor challenge [cortico-muscular coherence (CMC) in a precision grip task]. With both techniques, crossed cortico-spinal connectivity could be demonstrated. A significant correlation (r= 0.85) of CMC magnitude and recovered muscle strength underlined the functional relevance of crossed CST integrity for successful recovery. In conclusion, at the descriptive level, crossed CST connectivity is a common finding in well-recovered patients with capsular stroke. This renders it likely that maintaining or regaining use of crossed CST fibers is one way to achieve effective recovery. C1 Univ Tubingen, Inst Med Psychol, Tubingen, Germany. Univ Tubingen, MEG Ctr, D-72076 Tubingen, Germany. Univ Tubingen, Dept Neuropaediat, D-72076 Tubingen, Germany. Univ Hamburg, Dept Neurol, Med Ctr, Hamburg, Germany. NINDS, NIH, Human Cort Physiol, Washington, DC USA. RP Braun, C (reprint author), Univ Tubingen, Inst Med Psychol, Tubingen, Germany. EM christoph.braun@uni-tuebingen.de; christian.gerloff@uke.uni-hamburg.de RI Braun, Christoph/E-4561-2010; PreiSSl, Hubert/E-9070-2012; Braun, Christoph/J-4160-2014 OI Braun, Christoph/0000-0002-7836-4010; PreiSSl, Hubert/0000-0002-8859-4661; Braun, Christoph/0000-0002-7836-4010 NR 58 TC 18 Z9 18 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAY PY 2007 VL 25 IS 9 BP 2935 EP 2945 DI 10.1111/j.1460-9568.2007.05526.x PG 11 WC Neurosciences SC Neurosciences & Neurology GA 174SS UT WOS:000246963700031 PM 17561852 ER PT J AU Shetty, HU Zoghbi, SS Liow, JS Ichise, M Hong, J Musachio, JL Halldin, C Seidel, J Innis, RB Pike, VW AF Shetty, H. Umesha Zoghbi, Sami S. Liow, Jeih-San Ichise, Masanori Hong, Jinsoo Musachio, John L. Halldin, Christer Seidel, Jurgen Innis, Robert B. Pike, Victor W. TI Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [C-11]PE2I SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE dopamine transporter; brain; PET; [C-11]PE2I; metabolites ID POSITRON-EMISSION-TOMOGRAPHY; ALDEHYDE DEHYDROGENASE; ALCOHOL-DEHYDROGENASE; SELECTIVE RADIOLIGAND; PARKINSONS-DISEASE; HIGH-AFFINITY; BETA-CIT; IN-VIVO; BINDING; METABOLISM AB Purpose We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [C-11]PE2I. Methods PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [C-11]PE2I. Carrier-added [C-11]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [C-11]PE2I was assessed in rat brain homogenates. Results After peak brain uptake of no-carrier-added [C-11]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [C-11]PE2I represented 10.9 +/- 2.9% of the radioactivity in plasma, 67.1 +/- 11.0% in cerebellum, and 92.5 +/- 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [C-11]PE2I was stable in rat brain homogenate for at least 1 h at 37 degrees C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442 -> 424 transition due to H2O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [C-11]PE2I, [C-11]1, and [C-11]2 in striata to their cognates in cerebellum were 6.1 +/- 3.4, 3.7 +/- 2.2 and 1.33 +/- 0.38, respectively, showing binding selectivity of metabolite [C-11]1 to striata. Conclusion Radiometabolites [C-11]1 and [C-11]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [C-11]PE2I, respectively. The presence of the pharmacologically active [C-11]1 and the inactive [C-11]2 is a serious impediment to successful biomathematical analysis. C1 NIMH, PET Radiopharmaceut Sci, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Dept Clin Neurosci, Psychiat Sect, S-10401 Stockholm, Sweden. NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD USA. RP Shetty, HU (reprint author), NIMH, PET Radiopharmaceut Sci, Mol Imaging Branch, NIH, Bldg 10,Room B3 C351,MSC 1003,10 Ctr Dr, Bethesda, MD 20892 USA. EM shettyu@mail.nih.gov FU Intramural NIH HHS NR 44 TC 42 Z9 42 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD MAY PY 2007 VL 34 IS 5 BP 667 EP 678 DI 10.1007/s00259-006-0277-1 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 162NZ UT WOS:000246095900007 PM 17096093 ER PT J AU Liang, HY Tuan, RS Norton, PA AF Liang, Hongyan Tuan, Rocky S. Norton, Pamela A. TI Overexpression of SR proteins and splice variants modulates chondrogenesis SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE chondrogenesis; cellular condensation; fibronectin; mRNA splicing; alternative splicing ID PROCOLLAGEN MESSENGER-RNAS; IN-VIVO; CHONDROCYTE DIFFERENTIATION; PRO-ALPHA-2(XI) COLLAGEN; FIBRONECTIN ISOFORMS; SKELETAL DEVELOPMENT; AMINO-PROPEPTIDE; EXPRESSION; CARTILAGE; GROWTH AB Fibronectin alternative exon EIIIA is largely included in undifferentiated mesenchymal cells of the developing limb bud, whereas the exon is excluded in differentiated chondrocytes. inclusion of exon EIIIA in chondrocytic cells is increased by overexpression of SRp40, and, to a lesser extent, SRp75, but not SRp55. RT-PCR analysis using real-time PCR revealed that the levels of the mRNAs for these three proteins did not vary significantly in chick chondrocytes versus mesenchymal cells of the developing limb bud. However, a variant spliced form of SRp40, termed, SRp40LF, is detected preferentially in chondrocytes and in chondrifying mesenchymal cells. Forced overexpression of SRp40 or SRp75, but not SRp55, enhanced chondrogenic differentiation of chick limb mesenchymal cells in a high-density micromass assay. Overexpression of SRp40LF, which produces a truncated form of SRp40, also was strongly pro-chondrogenic. In a HeLa cell-based assay, SRp40LF fails to substitute for SRp40 in mediating an increase in exon EIIIA inclusion, suggesting that the latter event is not essential for the pro-chondro genic effect. These results demonstrate the ability of these highly conserved splicing factors to modulate chondrogenesis and are consistent with earlier results that implicated exon EIIIA-containing isoforms of fibronectin in formation of chondrogenic condensations. Published by Elsevier Inc. C1 Thomas Jefferson Univ, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Ctr Biomed Res, Philadelphia, PA 19107 USA. NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Norton, PA (reprint author), Drexel Inst Biotechnol & Virol Res, 700 E Butler Ave, Doylestown, PA 18901 USA. EM pamela.norton@drexel.edu OI Norton, Pamela/0000-0003-1327-9250 FU NIAMS NIH HHS [AR046821] NR 55 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 1 PY 2007 VL 313 IS 8 BP 1509 EP 1517 DI 10.1016/j.yexcr.2005.07.012 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 162ZO UT WOS:000246128300001 PM 16140295 ER PT J AU Han, F Gilbert, JR Harrison, G Adams, CS Freeman, T Tao, ZL Zaka, R Liang, HY Williams, C Tuan, RS Norton, PA Hickok, NJ AF Han, Fei Gilbert, James R. Harrison, Gerald Adams, Christopher S. Freeman, Theresa Tao, Zhuliang Zaka, Raihana Liang, Hongyan Williams, Charlene Tuan, Rocky S. Norton, Pamela A. Hickok, Noreen J. TI Transforming growth factor-beta 1 regulates fibronectin isoform expression and splicing factor SRp40 expression during ATDC5 chondrogenic maturation SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE fibronectin; TGF-beta 1; SRp40; alternative splicing; collagen type II; collagen type I; alcian blue ID GROWTH-FACTOR-BETA; PRE-MESSENGER-RNA; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; EDA SEGMENT; EIIIB EXON; V-SEGMENT; CELLS; DIFFERENTIATION; CARTILAGE AB Fibronectin (FN) isoform expression is altered during chondrocyte commitment and maturation, with cartilage favoring expression of FN isoforms that includes the type II repeat extra domain B (EDB) but excludes extra domain A (EDA). We and others have hypothesized that the regulated splicing of FN mRNAs is necessary for the progression of chondrogenesis. To test this, we treated the pre-chondrogenic cell line ATDC5 with transforming growth factor-beta 1, which has been shown to modulate expression of the EDA and EDB exons, as well as the late markers of chondrocyte maturation; it also slightly accelerates the early acquisition of a sulfated proteoglycan matrix without affecting cell proliferation. When chondrocytes are treated with TGF-beta 1, the EDA exon is preferentially excluded at all times whereas the EDB exon is relatively depleted at early times. This regulated alternative splicing of FN correlates with the regulation of alternative splicing of SRp40, a splicing factor facilitating inclusion of the EDA exon. To determine if overexpression of the SRp40 isoforms altered FN and FN EDA organization, cDNAs encoding these isoforms were overexpressed in ATDCS cells. Overexpression of the long-form of SRp40 yielded an FN organization similar to TGF-beta 1 treatment; whereas overexpression of the short form of SRp40 (which facilitates EDA inclusion) increased formation of long-thick FN fibrils. Therefore, we conclude that the effects of TGF-beta 1 on FN splicing during chondrogenesis may be largely dependent on its effect on SRp40 isoform expression. (c) 2007 Elsevier Inc. All rights reserved. C1 Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Dept Med, Div Rheumatol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Ctr Biomed Res, Philadelphia, PA 19107 USA. NIAMS, Cartilage Biol & Orthopaed Branch, Bethesda, MD 20892 USA. RP Hickok, NJ (reprint author), Thomas Jefferson Univ, Dept Orthopaed Surg, 1015 Walnut St,Suite 501, Philadelphia, PA 19107 USA. EM Noreen.Hickok@jefferson.edu OI Norton, Pamela/0000-0003-1327-9250; Adams, Christopher/0000-0003-2100-4417 FU NIAMS NIH HHS [AR45181, R01 AR045181-03, P01 AR039740-12A19004, R01 AR045181-04, R01 AR044360, R01 AR046821, AR39740, R01 AR044360-08, AR44360, R01 AR045181-02, P01 AR039740, R01 AR046821-03, R01 AR045181, AR46821]; NIDCR NIH HHS [R01 DE010875, DE-05748, F32 DE005748, R01 DE013319-01, DE-13310, DE-10875, R01 DE013319, R01 DE010875-12, F32 DE005748-03] NR 42 TC 17 Z9 19 U1 0 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 1 PY 2007 VL 313 IS 8 BP 1518 EP 1532 DI 10.1016/j.yexcr.2007.01.028 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 162ZO UT WOS:000246128300002 PM 17391668 ER PT J AU Wang, FE Shi, G Niesman, MR Rewolinski, DA Miller, SS AF Wang, F. E. Shi, G. Niesman, M. R. Rewolinski, D. A. Miller, S. S. TI Receptor tyrosine kinase inhibitors AG013764 and AG013711 reduce choroidal neovascularization in rat eye SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE age-related macular degeneration; choroidal neovascularization; gene transfer; adeno-associated viral vector; anti-angiogenesis; receptor tyrosine kinase; VEGF; PDGF; combination therapy ID ENDOTHELIAL GROWTH-FACTOR; FACTOR ANTIBODY FRAGMENT; AAV-MEDIATED EXPRESSION; MACULAR DEGENERATION; OCULAR NEOVASCULARIZATION; RETINAL DEGENERATION; NONHUMAN PRIMATE; FACTOR THERAPY; FACTOR VEGF; ANGIOGENESIS AB Age-related macular degeneration (AMD) is the major cause of blindness for people over 60. In the "wet" form of AMD compounds targeting growth factor signaling pathways such as VEGF have been a major focus for therapeutic interventions. In a previously developed rat model of CNV, we utilized two receptor tyrosine kinase inhibitors (RTKi) to block VEGFR-1, VEGFR-2 and PDGFR signaling following the establishment of CNV. AAV-VEGF(165) was injected into the subretinal space of rats at postnatal days 15-17. Six weeks later, a suspension of RTK inhibitors, AGO 13764 or AGO 13711, was injected intraperitoneally (IP, twice daily) or intravitreally (every five days) over a two week period. FITC-dextran whole-mounts of RPE-choroid-sclera were prepared after the animals were sacrificed. CNV area was quantified using Neurolucida to measure the hyperfluorescence on FITC-dextran whole-mounts. Histology and inummohistochemistry were performed as described previously. VEGF expression in control and treated eyes was confirmed by inummohistochemistry and histological sections indicated recovery of retinal morphology and CNV reduction in treated eyes. In the animals IP injected with AG013764 or AG013711 the mean CNV level was reduced by 25 to 33% compared to control, but this effect did not achieve statistical significance. Intravitreal injections of AG013764 or AG013711 reduced the level of CNV by approximately 60% compared to control (p < 0.005 or p < 0.05, respectively). These data show that two RTK inhibitors, AG013764 or AG013711, delivered intravitreally, significantly reduce blood vessel proliferation in this AAV-VEGF(165) model of CNV. (C) 2007 Elsevier Ltd. All rights reserved. C1 NEI, NIH, Bethesda, MD 20892 USA. Pfizer Global Res & Dev, Ophthamol Drug Discovery, San Diego, CA USA. RP Miller, SS (reprint author), NEI, NIH, 31 Ctr Dr,Bldg 31,Room 6A22, Bethesda, MD 20892 USA. EM millers@nei.nih.gov FU Intramural NIH HHS; NEI NIH HHS [Z01 EY000420-02] NR 59 TC 5 Z9 5 U1 1 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD MAY PY 2007 VL 84 IS 5 BP 922 EP 933 DI 10.1016/j.exer.2007.01.022 PG 12 WC Ophthalmology SC Ophthalmology GA 168ON UT WOS:000246534000015 PM 17399700 ER PT J AU Godlove, J Chiu, WK Weng, NP AF Godlove, Jason Chiu, Wai Kan Weng, Nan-ping TI Gene expression and generation of CD28(-)CD8 T cells mediated by interleukin 15 SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT 1st European Congress of Aging Research in Immunology - Impact of Genomics CY SEP, 2006 CL Paris, FRANCE SP European Commiss DE aging; NK cell receptor; co-stimulatory receptor ID REPLICATIVE SENESCENCE; MEMORY; CYTOKINES; LYMPHOCYTES; ACTIVATION; RECEPTORS; PHENOTYPE; EXPANSION; APOPTOSIS; SUBSET AB Accumulation of CD28(-)CDS T cells that are defective in response to antigenic stimulation is a hallmark of age-associated decline in T cell function. However, the underlying mechanism of this age-associated change is not fully understood. We recently analyzed the global gene expression profiles of CD8 T cell subsets from naive to memory (CD28(+) to CD28(-)) cells and the growth of CD28+ and CD28(-)CD8 memory T cells in response to homeostatic cytokine interleukin 15 (IL-15). At the gene expression level, one of the most striking changes is the altered expression of some co-stimulatory receptors and various NK cell receptors in CD28(-)CD8 T cells. Furthermore, CD28(-)CD8 T cells appear to have a normal proliferation response to IL-15 in vitro. Interestingly, IL-15 is also capable of inducing stable loss of CD28 expression in actively dividing CD28(+)CD8 memory T cells. Together, these findings provide the gene expression features of CD28(-)CD8 T cells that differ from their CD28(+) counterparts and suggest a possible role of IL-15 in the increase of CD28-CD8 T cells that occurs with aging. (C) 2006 Elsevier Inc. All rights reserved. C1 NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Weng, NP (reprint author), NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. EM Wengn@mail.nih.gov FU Intramural NIH HHS [Z01 AG000757-10, Z01 AG000756-10]; NIDA NIH HHS [R90 DA023426] NR 18 TC 9 Z9 14 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD MAY PY 2007 VL 42 IS 5 BP 412 EP 415 DI 10.1016/j.exger.2006.11.015 PG 4 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 168OC UT WOS:000246532900007 PM 17204390 ER PT J AU Nelson, RL Guo, Z Halagappa, VM Pearson, M Gray, AJ Matsuoka, Y Brown, M Martin, B Iyun, T Maudsley, S Clark, RF Mattson, MP AF Nelson, Rhonda L. Guo, Zhihong Halagappa, Veerendra Madala Pearson, Michelle Gray, Audrey J. Matsuoka, Yasuji Brown, Martin Martin, Bronwen Iyun, Titilola Maudsley, Stuart Clark, Robert F. Mattson, Mark P. TI Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice SO EXPERIMENTAL NEUROLOGY LA English DT Article DE amygdala; antidepressant; anxiety; brain derived neurotrophic factor; hippocampus; learning and memory ID MILD COGNITIVE IMPAIRMENT; TRIPLE-TRANSGENIC MODEL; ALZHEIMERS-DISEASE; A-BETA; PRECURSOR PROTEIN; MOUSE MODEL; NEUROTROPHIC-FACTOR; DECREASED-LEVELS; MEMORY LOSS; DEPOSITION AB A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old mate and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (A beta) and numbers of A beta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans. (C) 2007 Elsevier Inc. All rights reserved. C1 NIA, Neurosci Lab, Gerontol Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. Meharry Med Coll, Nashville, TN 37208 USA. Georgetown Univ, Washington, DC USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS [Z01 AG000312-05, Z01 AG000317-05]; NIA NIH HHS [K01 AG022455, AG022455] NR 66 TC 88 Z9 92 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2007 VL 205 IS 1 BP 166 EP 176 DI 10.1016/j.expneurol.2007.01.037 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 166TO UT WOS:000246403400019 PM 17368447 ER PT J AU Alayash, AI D'Agnillo, F Buehler, PW AF Alayash, Abdu I. D'Agnillo, Felice Buehler, Paul W. TI First-generation blood substitutes: what have we learned? Biochemical and physiological perspectives SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE blood substitutes; free radicals; hemoglobin; nitric oxide; vascular effects ID CROSS-LINKED HEMOGLOBIN; CELL-FREE HEMOGLOBIN; SUPEROXIDE-DISMUTASE CATALASE; ENDOTHELIAL-CELLS; HEMORRHAGIC-SHOCK; OXIDATIVE-STRESS; PROTEIN EXPRESSION; HYDROGEN-PEROXIDE; OXYGEN CARRIER; IN-VITRO AB Chemically modified or recombinant hemoglobin (Hb)-based oxygen carriers (HBOCs) have been developed as oxygen therapeutics or 'blood substitutes' for use in a variety of clinical settings. Oxidative and nitrosative reactions of acellular Hb can limit the effectiveness and compromise the safety of HBOCs. The reactions between Hb and biologically relevant redox active molecules may also perturb redox sensitive signaling pathways. In recent years, systematic in vitro and in vivo structural and functional evaluation of several HBOCs has been carried out and, in some cases, delineated the 'structural' origin of their toxicity. This enables potential protective strategies against Hb-mediated side reactions to be rationally suggested. Here the authors provide an overview of their research experiences, novel insights into the molecular basis of toxicities of these products and some lessons learned. C1 US FDA, CBER, Lab Biochem & vasc Biol, Div Hematol, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, CBER, Lab Biochem & vasc Biol, Div Hematol, NIH Campus,8800 Rockville Pike,Bldg 29,Room 112, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov NR 66 TC 30 Z9 30 U1 2 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2007 VL 7 IS 5 BP 665 EP 675 DI 10.1517/14712598.7.5.665 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 163KW UT WOS:000246159600010 PM 17477804 ER PT J AU Bedlack, RS Traynor, BJ Cudkowicz, ME AF Bedlack, Richard S. Traynor, Bryan J. Cudkowicz, Merit E. TI Emerging disease-modifying therapies for the treatment of motor neuron diseasd/amyotropic lateral sclerosis SO EXPERT OPINION ON EMERGING DRUGS LA English DT Review DE ALS; amyotropic lateral sclerosis; MND; motor neuron disease; neuroprotection ID TRANSGENIC MOUSE MODEL; CU/ZN SUPEROXIDE-DISMUTASE; GULF-WAR VETERANS; MUTANT SOD1; CLINICAL-TRIALS; CYCLOOXYGENASE-2 INHIBITORS; NEURODEGENERATIVE DISEASE; PROTEIN AGGREGATION; EXTEND SURVIVAL; SPINAL-CORDS AB It has been > 130 years since the first description of the upper and lower motor neuron disease called amyotropic lateral sclerosis (ALS). Sadly, there has been little change in the long interval over which this disease is diagnosed, or in its poor prognosis. Significant gains have been made, however, in understanding its pathophysiology and in symptomatic care. Disease-causing mutations have been identified and used to create animal models. Other identified mutations may increase susceptibility and cause disease only in a particular environment and at a particular age. A number of 'downstream' molecular pathways have been implicated, including transcriptional disturbances, protein aggregation, excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, cytoskeletal and axonal transport derangements, growth factor dysregulation and apoptosis. This knowledge has led to an impressive pipeline of candidate therapies that offer hope for finally being able to alter ALS disease progression. These are described and prioritized herein, and suggestions are offered for efficiently sifting through them. C1 Duke Univ, Med Ctr, Durham, NC 27705 USA. NIMH, Bethesda, MD 20892 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Bedlack, RS (reprint author), Duke Univ, Med Ctr, Box 3333, Durham, NC 27705 USA. EM bedla001@mc.duke.edu RI Traynor, Bryan/G-5690-2010 FU Intramural NIH HHS NR 147 TC 13 Z9 14 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8214 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD MAY PY 2007 VL 12 IS 2 BP 229 EP 252 DI 10.1517/14728214.12.2.229 PG 24 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 187CY UT WOS:000247826100006 PM 17604499 ER PT J AU Johann, DJ Veenstra, TD AF Johann, Donald J., Jr. Veenstra, Timothy D. TI Multiple biomarkers in molecular oncology SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Editorial Material ID OVARIAN-CANCER; SERUM C1 NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov NR 4 TC 0 Z9 1 U1 0 U2 0 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD MAY PY 2007 VL 7 IS 3 BP 223 EP 225 DI 10.1586/14737159.7.3.223 PG 3 WC Pathology SC Pathology GA 169SZ UT WOS:000246613300001 PM 17489728 ER PT J AU Malik, M Catherino, WH AF Malik, Minnie Catherino, William H. TI Novel method to characterize primary cultures of leiomyoma and myometrium with the use of confirmatory biomarker gene arrays SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 61st Annual Meeting of the American-Society-for-Reproductive-Medicine/51st Annual Meeting of the Canadian-Fertility-and-Andrology-Society CY OCT 15-19, 2005 CL Montreal, CANADA SP Amer Soc Reprod Med (ASRM), Canadian Fertil & Androl Soc DE leiomyoma; myometrium; primary cultures; microarray; RT-PCR; Western blot; alpha-actin; biomarkers ID SMOOTH-MUSCLE-CELLS; TRANSFORMING GROWTH FACTOR-BETA-3; DIFFERENTIALLY EXPRESSED GENES; ACTIVATED RECEPTOR-GAMMA; UTERINE LEIOMYOMAS; TRANSGENIC MICE; FACTOR-BETA; ESTROGEN; GROWTH-FACTOR-BETA-1; PROLIFERATION AB Objective: To develop a rapid biomarker method for confirming that leiomyoma and myometrium primary cultures maintain the molecular phenotype of the progenitor tissues. Design: Confirmation of primary cultures from leiomyoma and myometrium tissues. Setting: University hospital. Patient(s): Women undergoing hysterectomy for symptomatic leiomyomas. Intervention(s): Primary cell cultures, reverse-transcriptase polymerase chain reaction (RT-PCR), microarray, real time RT-PCR, and immunofluorescence. Main Outcome Measure: Relative messenger RNA and protein expression in leiomyoma and myometrial cell cultures. Result(s): We developed primary cell cultures from human leiomyoma and patient-matched myometrium obtained from hysterectomy specimens. In the primary cultures, we confirmed the presence of smooth muscle-specific a-actin as well as filamentous actin. Based on microarray analysis, we expected and confirmed, in the progenitor tissue and derived primary cultures, an overexpression of versican (8.31 fold +/- 2.2 SEM and 4.3 fold +/- 1.01 SEM, respectively), transforming growth factor beta-3 (5.66 fold +/- 0.82 SEM and 4.92 fold +/- 0.58 SEM, respectively), and cytochrome P450-26A 1 (6.76 fold +/- 0.80 SEM and 6.17 fold +/- 2.02 SEM, respectively), and an underexpression of dermatopontin (-5.6 fold +/- 1.82 SEM and -3.41 +/- 1.20 SEM, respectively). Conclusion(s): Primary cell cultures offer a reliable in vitro model system for leiomyorna disease, if confirmed. Analysis of a gene array that distinguishes between myometrium and leiomyoma molecular phenotypes offers a rapid and reliable confirmation method, and provides confidence that in vitro findings resemble in vivo disease. C1 Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil OI Malik, Minnie/0000-0003-1129-6575 FU Intramural NIH HHS NR 32 TC 31 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD MAY PY 2007 VL 87 IS 5 BP 1166 EP 1172 DI 10.1016/j.fertnstert.2006.08.111 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 169HP UT WOS:000246583600024 PM 17222838 ER PT J AU Rhodes, MC Bucher, JR Peckham, JC Kissling, GE Hejtmancik, MR Chhabra, RS AF Rhodes, M. C. Bucher, J. R. Peckham, J. C. Kissling, G. E. Hejtmancik, M. R. Chhabra, R. S. TI Carcinogenesis studies of benzophenone in rats and mice SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE benzophenone; liver tumors; kidney tumors; leukemia; histiocytic sarcomas; toxicity; carcinogenicity ID INDUCED RENAL CARCINOGENESIS; ZERO DOSE CONTROL; MECHANISMS; NEOPLASMS; RODENT AB Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and 1360 F1 mice were fed diets containing 0, 312, 625, and 1250 ppin benzophenone for 105 weeks. Survival of males exposed to 1250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1250 ppm groups. Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female 136C3F, mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female 136C3171 mice may have been related to benzophenone exposure. Published by Elsevier Ltd. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Battelle Mem Inst, Columbus, OH 43201 USA. RP Chhabra, RS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM Chhabrar@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 26 TC 30 Z9 41 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD MAY PY 2007 VL 45 IS 5 BP 843 EP 851 DI 10.1016/j.fct.2006.11.003 PG 9 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 164DR UT WOS:000246213800016 PM 17187913 ER PT J AU Aronovitch, Y Godinger, D Israeli, A Krishna, MC Samuni, A Goldstein, S AF Aronovitch, Yaacov Godinger, Dina Israeli, Avner Krishna, Murali C. Samuni, Amram Goldstein, Sara TI Dual activity of nitroxides as pro- and antioxidants: Catalysis of copper-mediated DNA breakage and H2O2 dismutation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE copper; o-phenanthroline; hydrogen peroxide; DNA breakage; catalase-mimic activity; nitroxide; antioxidant; pro-oxidant; free radicals ID RAT-LIVER MICROSOMES; HYDROGEN-PEROXIDE; CYCLIC NITROXIDES; OXOAMMONIUM CATION; 1,10-PHENANTHROLINE COPPER; QUINOLINIC AMINOXYLS; LIPID-PEROXIDATION; CARBONATE RADICALS; ORGANIC-CHEMISTRY; NUCLEASE ACTIVITY AB Nitroxide antioxidants can be reduced to hydroxylamines or oxidized to oxoammonium cations. Consequently, nitroxides can modify oxidative damage acting as reducing and/or as oxidizing agents, and in many cases the nitroxides are continuously recycled. They provide protection against oxidative stress via various mechanisms including SOD-mimic activity and detoxification of carbon-, oxygen-, and nitrogen-centered radicals, as well as oxidation of reduced transition metals. In contrast to the common concept, according to which the nitroxides' protective effect takes place via inhibition of the Fenton reaction, there are observations suggesting the opposite. In the present investigation, DNA breakage catalyzed by copper served as an experimental model for studying the anti- and pro-oxidative activity of nitroxides. Nitroxides provided protection in the presence of GSH, which is known to facilitate metal-catalyzed DNA damage. In the absence of a reductant, nitroxides enhanced DNA breakage under aerobic conditions with or without added H2O2 and facilitated H2O2 depletion. The rates of nitroxide-catalyzed DNA breakage and H2O2 depletion increased as the concentrations of copper, H2O2, and nitroxide increased. Although the catalytic activity of nitroxides is low, it is sufficient to induce DNA breakage. The efficacy of DNA breakage by the tested piperidine nitroxides correlated with the nitroxide-induced depletion of H2O2 with the exception of the pyrrolidine nitroxide 3-carbamoylproxyl. The results suggest that the nitroxide and the copper are continuously recycled while catalyzing DNA breakage and depletion of H2O2, which serves both as a source of reducing equivalents and as the electron sink. (c) 2007 Elsevier Inc. All rights reserved. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biol Mol, IL-91120 Jerusalem, Israel. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Dept Chem Phys, IL-91120 Jerusalem, Israel. RP Samuni, A (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biol Mol, IL-91120 Jerusalem, Israel. EM samuni@md.huji.ac.il NR 46 TC 20 Z9 21 U1 0 U2 9 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 MAY 1 PY 2007 VL 42 IS 9 BP 1317 EP 1325 DI 10.1016/j.freeradbiomed.2007.01.017 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 156NL UT WOS:000245656100002 PM 17395005 ER PT J AU Chokkalingam, AP Stanczyk, FZ Reichardt, JKV Hsing, AW AF Chokkalingam, Anand P. Stanczyk, Frank Z. Reichardt, Juergen K. V. Hsing, Ann W. TI Molecular epidemiology of prostate cancer: hormone-related genetic loci SO FRONTIERS IN BIOSCIENCE LA English DT Review DE neoplasia; neoplasm; tumor; prostate cancer; hormones; genetic Polymorphisms; epidemiology; review ID VITAMIN-D-RECEPTOR; GROWTH-FACTOR-I; 5-ALPHA-REDUCTASE TYPE-II; BINDING GLOBULIN CONCENTRATIONS; CAG REPEAT LENGTH; ANDROGEN RECEPTOR; JAPANESE POPULATION; CYP17 GENE; SERUM HORMONES; NO ASSOCIATION AB Prostate cancer is the most common non-skin cancer and the second leading cause of cancer deaths among men in most Western countries. Despite its high morbidity and mortality, the etiology of prostate cancer remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data, including serological and genetic studies, are inconclusive. In this chapter, we review the status of serologic studies and discuss the importance of intra-prostatic hormone levels in possibly clarifying the often-contradictory data on serologic studies. To provide insights and directions for epidemiologic research on hormones and prostate cancer, this review centers on the molecular epidemiology of hormone-related genetic loci. These loci have been investigated in a number of studies to date and will undoubtedly expand even further as rich new genetic information sources and high-throughput genotyping and analysis methods become available. Due to the enormous number of these loci, we recommend careful analysis and cautious interpretation of studies of genetic markers, including microsatellites and single nucleotide polymorphisms (SNPs), as false positive and negative results are likely due to limited statistical power, multiple hypothesis testing, population stratification, or non-representative population sampling. This review also highlights the need for replication in various populations, as well as reasons for performing functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for concerted, large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94707 USA. Univ So Calif, Womens & Childrens Hosp, Dept Obstet & Gynecol, Los Angeles, CA 90033 USA. Univ So Calif, Womens & Childrens Hosp, Dept Prevent Med, Los Angeles, CA 90033 USA. Univ Sydney, Plunkett Chair Mol Biol Med, Camperdown, NSW 2006, Australia. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, EPS MSC 7234,6120 Execut Blvd, Rockville, MD 20852 USA. EM hsinga@exchange.nih.gov OI Reichardt, Juergen/0000-0001-6458-2773 NR 212 TC 20 Z9 20 U1 0 U2 2 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY 1 PY 2007 VL 12 BP 3436 EP 3460 DI 10.2741/2325 PG 25 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163KG UT WOS:000246157900055 PM 17485312 ER PT J AU Ocak, I Baluk, P Barrett, T McDonald, DM Choyke, P AF Ocak, Iclal Baluk, Peter Barrett, Tristan McDonald, Donald M. Choyke, Peter TI The biologic basis of in vivo angiogenesis imaging SO FRONTIERS IN BIOSCIENCE LA English DT Article DE angiogenesis; tumor neovasculature; integrins; endothelial cell; DCE-MRI; PET; SPECT; review ID ENDOTHELIAL GROWTH-FACTOR; TUMOR BLOOD-VESSELS; POSITRON-EMISSION-TOMOGRAPHY; ADVANCED COLORECTAL-CANCER; RECEPTOR TYROSINE KINASES; HUMAN BREAST-TUMORS; PHASE-I; SOLID TUMORS; ANTIANGIOGENIC THERAPY; LIVER METASTASES AB Knowledge of the different physiology and endothelial markers present in tumor vessels is essential to enable both the development of new anti-angiogenic chemotherapeutic agents and of more specific imaging techniques. Tumor blood vessels are disorganized, irregular in caliber, tortuous, and do not have specialized features of normal arterioles, capillaries or venules. Neo-angiogenic tumor vessels have large gaps between or through cells, loose pericytes, and discontinuities or redundant layers within the basement membrane, rendering these vessels hyper-permeable. Furthermore, the endothelia of tumor vessels may express unique markers on their surface. Imaging is becoming increasingly important in the evaluation of angiogenesis. Clinical imaging is minimally invasive and enables sampling of the whole tumor in a nondestructive manner. The patterns of increased permeability seen on Dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) mirror the known ultrastructural defects associated with angiogenic vessels. Conventional low-molecular weight contrast agents are currently in clinical use for DCE-MRI studies and have proven successful in detecting changes related to novel angiogenic inhibitors. However, they are relatively nonspecific. Macromolecular contrast media may be more suitable for imaging tumor vessels. It is hoped that imaging modalities can be adapted to specifically target markers expressed on the endothelium of tumor vessels. The number of cell surface markers of angiogenesis is relatively low, and only small amounts of contrast agents can bind to these receptors; currently only Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) tracers have sufficient sensitivity to allow detection at this low level. Despite limitations in their spatial resolution, PET and SPECT imaging are more likely to enter the clinic as targeted angiogenesis imaging methods. The quest for selective targets on the tumor vasculature continues, currently the integrin family of receptors offer the most promise but other targets are being pursued by investigators. Serial analysis of gene expression or in vivo phage display may help identify new, more selective, markers that can be utilized for the targeted imaging and treatment of angiogenesis. C1 NIH, Mol Imaging Program, Bethesda, MD 20892 USA. Univ Calif San Francisco, Ctr Comprehens Canc, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. RP Choyke, P (reprint author), NIH, Mol Imaging Program, Bethesda, MD 20892 USA. EM pchoyke@nih.gov FU Intramural NIH HHS; NCI NIH HHS [CA82923]; NHLBI NIH HHS [HL24136, P01 HL024136, R01 HL059157] NR 94 TC 31 Z9 35 U1 0 U2 3 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY 1 PY 2007 VL 12 BP 3601 EP 3616 DI 10.2741/2336 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163KG UT WOS:000246157900067 PM 17485324 ER PT J AU Lobachev, KS Rattray, A Narayanan, V AF Lobachev, Kirill S. Rattray, Alison Narayanan, Vidhya TI Hairpin- and cruciform-mediated chromosome breakage: causes and consequences in eukaryotic cells SO FRONTIERS IN BIOSCIENCE LA English DT Review DE hairpin; cruciform; secondary structure; palindrome; double strand breaks; fragility; genome instability; rearrangements; review ID SISTER CHROMATID EXCHANGES; DOUBLE-STRAND BREAKS; RARE FRAGILE SITES; YEAST SACCHAROMYCES-CEREVISIAE; HOLLIDAY JUNCTION RESOLUTION; SIMPLE SEQUENCE REPEATS; INVERTED DNA REPEATS; HUMAN GENOME; PALINDROMIC SEQUENCES; TRINUCLEOTIDE REPEATS AB Chromosomes of many eukaryotic organisms including humans contain a large number of repetitive sequences. Several types of commonly present DNA repeats have the capacity to adopt hairpin and cruciform secondary structures. Inverted repeats, AT- and GC- rich micro- and minisatellites, comprising this class of sequence motifs, are frequently found in chromosomal regions that are prone for gross rearrangements in somatic and germ cells. Recent studies in yeast and mammals indicate that a double- strand break occurring at the sites of unstable repeats can be an initial event in the generation of chromosome rearrangements. The repeat- induced chromosomal instability is responsible for a number of human diseases and has been implicated in carcinogenesis. In this review, we discuss the molecular mechanisms by which hairpins and cruciforms can trigger chromosomal fragility and subsequent aberrations in eukaryotic cells. We also address the relationship between secondary structure-mediated genetic instability and human pathology. C1 Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA. NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Lobachev, KS (reprint author), Georgia Inst Technol, Sch Biol, 310 Ferst Dr, Atlanta, GA 30332 USA. EM kirill.lobachev@biology.gatech.edu NR 116 TC 52 Z9 52 U1 2 U2 6 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY 1 PY 2007 VL 12 BP 4208 EP 4220 DI 10.2741/2381 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163KG UT WOS:000246157900111 PM 17485368 ER PT J AU Kouzine, F Levens, D AF Kouzine, Fedor Levens, David TI Supercoil-driven DNA structures regulate genetic transactions SO FRONTIERS IN BIOSCIENCE LA English DT Review DE supercoils; DNA structure; c-myc; chromatin; DNA topology; transcription; DNA conformation; review ID RNA-POLYMERASE-II; SINGLE-STRANDED-DNA; C-MYC EXPRESSION; NUCLEOSOME CORE PARTICLE; TOPOLOGICAL DOMAIN SIZE; ESCHERICHIA-COLI-CELLS; HUMAN EDITING ENZYME; G-QUADRUPLEX DNA; IN-VIVO; CRYSTAL-STRUCTURE AB DNA is a living molecule, writhing, twisting and bending in response to the physical forces applied to it by genetic processes. Twisting and untwisting of the double helix by powerful molecular motors generates, at least transiently, high levels of torques. Although under relaxed conditions the double helical B-form is the predominant conformation of DNA, in response to physical stress, B-DNA strains inhomogeneously, adopting a variety of alternative structures. These structures are the sites of genetic damage that increase the fragility of the genome, but they may also participate in physiological processes performing functions not achievable using conventional duplex. The dynamic response of DNA to supercoiling forces contributes to control of genes such as c-myc whose physiological levels must be precisely regulated. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Levens, D (reprint author), NCI, Pathol Lab, Bethesda, MD 20892 USA. EM levens@helix.nih.gov RI Levens, David/C-9216-2009 OI Levens, David/0000-0002-7616-922X FU Intramural NIH HHS NR 161 TC 53 Z9 54 U1 1 U2 16 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY 1 PY 2007 VL 12 BP 4409 EP 4423 DI 10.2741/2398 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163KG UT WOS:000246157900128 PM 17485385 ER PT J AU Watson, LE Mock, J Lal, H Lu, GR Bourdeau, RW Tang, WJ Leppla, SH Dostal, DE Frankel, AE AF Watson, Linley E. Mock, Jonathan Lal, Hind Lu, Guangrong Bourdeau, Raymond W. Tang, Wei-Jen Leppla, Stephen H. Dostal, David E. Frankel, Arthur E. TI Lethal and edema toxins of anthrax induce distinct hemodynamic dysfunction SO FRONTIERS IN BIOSCIENCE LA English DT Article DE anthrax lethal toxin; anthrax edema toxin; echocardiography; ventricular dysfunction; left; shock ID BACILLUS-ANTHRACIS; INHALATIONAL ANTHRAX; RATS AB Fatalities due to anthrax are associated with severe hypotension suggesting that the toxins generated from Bacillus anthracis, lethal toxin (LeTx) and edema toxin (EdTx), have cardiovascular effects. Here, we demonstrate the effects of these toxins and characterize their effects by echocardiography. LeTx leads to a significant reduction in ejection fraction, decreased velocity of propagation (diastolic dysfunction), decreased velocity of circumferential fiber shortening (decreased contractility), and increased LV systolic area (pathophysiology). EdTx leads to a significant reduction in left ventricular volumes and cardiac output (reduced stroke volume) but does not cause significant change in ejection fraction or contractility. These results indicate that LeTx reduces left ventricular systolic function and EdTx reduces preload but does not have direct myocardial effects. Together, these findings suggest that LeTx and EdTx exert distinct hemodynamic dysfunction associated with anthrax infection. C1 Scott & White Mem Hosp & Clin, Inst Canc Res, Div Cardiol, Scott Sherwood & Brindley Fdn, Temple, TX 76502 USA. Texas A&M Univ, Coll Med, Cardiovasc Res Inst, Div Mol Cardiol,Hlth Sci Ctr, Temple, TX 76508 USA. Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. NIAID, Bacterial Toxins & Therapeut Sect, Bethesda, MD 20892 USA. Scott & White Canc Res Inst, Temple, TX USA. RP Frankel, AE (reprint author), Scott & White Mem Hosp & Clin, Inst Canc Res, Div Cardiol, Scott Sherwood & Brindley Fdn, 5701 S Airport Rd, Temple, TX 76502 USA. EM afrankel@swmail.sw.org OI Lal, Hind/0000-0001-8980-9874; Bourdeau, Raymond/0000-0003-2202-1980; Tang, Wei-Jen/0000-0002-8267-8995 FU NCI NIH HHS [R01 CA76178, R01 CA90263]; NHLBI NIH HHS [R01 HL68838] NR 16 TC 27 Z9 27 U1 0 U2 1 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY 1 PY 2007 VL 12 BP 4670 EP 4675 DI 10.2741/2416 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 163KG UT WOS:000246157900146 PM 17485403 ER PT J AU Bagni, R Whity, D AF Bagni, Rachel Whity, Denise TI Why is Kaposi's sarcoma-associated herpesvirus not ubiquitous in the human population? SO FUTURE VIROLOGY LA English DT Article DE environmental cofactors; horizontal transmission; host genetics; Kaposi's sarcoma-associated herpesvirus ID MOTHER-TO-CHILD; SICKLE-CELL-DISEASE; HUMAN-HERPESVIRUS-8 INFECTION; HOMOSEXUAL-MEN; SEXUAL TRANSMISSION; SEROLOGIC EVIDENCE; BLOOD-TRANSFUSION; UGANDAN CHILDREN; HIV-INFECTION; RISK-FACTORS AB Kaposi's sarcoma-associated herpesvirus (KSHV), a gamma-herpesvirus, is the causative agent of Kaposi's sarcoma. While the incidence of Kaposi's sarcoma may be explained by the differences in the prevalence of KSHV, there is currently no explanation for the variation of KSHV prevalence in different geographic locations and populations. This review summarizes the current understanding of KSHV transmission and aims to provide insight into how KHSV may be transmitted and maintained in the human population. C1 NCI, SAIC Frederick, AIDS Vaccine Program, Viral Oncol Sect, Frederick, MD 21702 USA. RP Whity, D (reprint author), NCI, SAIC Frederick, AIDS Vaccine Program, Viral Oncol Sect, Frederick, MD 21702 USA. EM whitbyd@ncifcrf.gov NR 51 TC 1 Z9 1 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0794 J9 FUTURE VIROL JI Future Virol. PD MAY PY 2007 VL 2 IS 3 BP 243 EP 246 DI 10.2217/17460794.2.3.2432007 PG 4 WC Virology SC Virology GA 209ZR UT WOS:000249427000009 ER PT J AU Lutchman, G Danehower, S Song, BC Liang, TJ Hoofnagle, JH Thomson, M Ghany, MG AF Lutchman, Glen Danehower, Susan Song, Byung-Cheol Liang, T. Jake Hoofnagle, Jay H. Thomson, Michael Ghany, Marc G. TI Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy SO GASTROENTEROLOGY LA English DT Article ID ANTIVIRAL ACTIVITY; PLUS RIBAVIRIN; RNA-POLYMERASE; REPLICON RNA; CELL-LINE; INTERFERON; REPLICATION; TRIAL; INFECTION; VIRAZOLE AB Background & Aims: Error catastrophe from an increase in mutation rate may be a possible mechanism of action of ribavirin in chronic hepatitis C (CHC). We sought to evaluate the mutagenic potential of ribavirin in vivo and to determine if conserved regions of hepatitis C virus (HCV) NS5B are mutated during ribavirin therapy. Methods: Thirty-one patients with CHC genotype 1 who participated in a randomized, placebo-controlled trial of ribavirin for 48 weeks were studied. After 48 weeks, patients on placebo were crossed-over to open-label ribavirin for 48 weeks. Viral RNA was extracted from paired, stored sera at day 0 and week 24 during the randomized phase and weeks 48, 52, and 72 during the cross-over phase. The entire NS5B region was sequenced and the mutation rates were calculated. Results: An increase in mutation rate was observed after 4 weeks (4.4 x 10(-2) vs 2.1 x 10(-3) per site/y, P = .02) but not after 24 weeks (4.0 x 10(-3) vs. 5.5 x 10(-3) per site/y, P = .1) in patients who crossed over to ribavirin. Similarly, during the randomized phase no increase in the number of mutations or the mutation rate was observed at week 24 between the ribavirin- and placebo-treated patients 6.6 vs 4.3 x 10(-3) per site/y, respectively (P = .4). No mutations were observed in conserved regions of NS5B. Conclusions: Ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV. Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for CHC. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. GlaxoSmithKline Inc, Dept Virol, Res Triangle Pk, NC USA. RP Ghany, MG (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov FU Intramural NIH HHS NR 36 TC 63 Z9 65 U1 0 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2007 VL 132 IS 5 BP 1757 EP 1766 DI 10.1053/j.gastro.2007.03.035 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 167MS UT WOS:000246456400020 PM 17484873 ER PT J AU Michalski, CW Laukert, T Sauliunaite, D Pacher, P Bergmann, F Agarwal, N Su, Y Giese, T Giese, NA Batkai, S Friess, H Kuner, R AF Michalski, Christoph W. Laukert, Tamara Sauliunaite, Danguole Pacher, Pal Bergmann, Frank Agarwal, Nitin Su, Yun Giese, Thomas Giese, Nathalia A. Batkai, Sandor Friess, Helmut Kuner, Rohini TI Cannabinoids ameliorate pain and reduce disease pathology in cerulein-induced acute pancreatitis SO GASTROENTEROLOGY LA English DT Article ID ENDOCANNABINOID SYSTEM; VISCERAL PAIN; LUNG INJURY; INFLAMMATION; MICE; PATHOPHYSIOLOGY; RATS; PHYSIOLOGY AB Background & Aims: The functional involvement of the endocannabinoid system in modulation of pancreatic inflammation, such as acute pancreatitis, has not been studied to date. Moreover, the therapeutic potential of cannabinoids in pancreatitis has not been addressed. Methods: We quantified endocannabinoid levels and expression of cannabinoid receptors 1 and 2 (CB1 and CB2) in pancreas biopsies from patients and mice with acute pancreatitis. Functional studies were performed in mice using pharmacological interventions. Histological examination, serological, and molecular analyses (lipase, myeloperoxidase, cytokines, and chemokines) were performed to assess disease pathology and inflammation. Pain resulting from pancreatitis was studied as abdominal hypersensitivity to punctate von Frey stimuli. Behavioral analyses in the open-field, light-dark, and catalepsy tests were performed to judge cannabinoid-induced central side effects. Results: Patients with acute pancreatitis showed an up-regulation of cannabinoid receptors and elevated levels of endocannabinoids in the pancreas. HU210, a synthetic agonist at CB1 and CB2, abolished abdominal pain associated with pancreatitis and also reduced inflammation and decreased tissue pathology in mice without producing central, adverse effects. Antagonists at CB1- and CB2-receptors were effective in reversing HU210-induced antinociception, whereas a combination of CB1- and CB2-antagonists was required to block the anti-inflammatory effects of HU210 in pancreatitis. Conclusions: In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids, in abolishing pain associated with acute pancreatitiis and in partially reducing inflammation and disease pathology in the absence of adverse side effects. C1 Univ Heidelberg, Inst Pharmacol, D-69120 Heidelberg, Germany. Univ Heidelberg, Dept Gen Surg, D-69120 Heidelberg, Germany. NIAAA, Sect Oxidative Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD USA. Univ Heidelberg, Inst Pathol, D-6900 Heidelberg, Germany. Univ Heidelberg, Inst Immunol, D-6900 Heidelberg, Germany. RP Kuner, R (reprint author), Univ Heidelberg, Inst Pharmacol, Neuenheimer Feld 366, D-69120 Heidelberg, Germany. EM rohini.kuner@pharma.uni-heidelberg.de RI Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014 OI Pacher, Pal/0000-0001-7036-8108; FU Intramural NIH HHS [Z01 AA000375-02]; NIAAA NIH HHS [Z01 AA000375] NR 23 TC 53 Z9 55 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2007 VL 132 IS 5 BP 1968 EP 1978 DI 10.1053/j.gastro.2007.02.035 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 167MS UT WOS:000246456400037 PM 17484889 ER PT J AU Ogden, CL Yanovski, SZ Carroll, MD Flegal, KM AF Ogden, Cynthia L. Yanovski, Susan Z. Carroll, Margaret D. Flegal, Katherine M. TI The epidemiology of obesity SO GASTROENTEROLOGY LA English DT Review ID BODY-MASS-INDEX; FATTY LIVER-DISEASE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; METABOLIC SYNDROME PHENOTYPE; CARDIOVASCULAR RISK-FACTORS; IMPAIRED GLUCOSE-TOLERANCE; TYPE-2 DIABETES-MELLITUS; SELF-REPORTED WEIGHT; UNITED-STATES AB In the United States, obesity among adults and overweight among children and adolescents have increased markedly since 1980. Among adults, obesity is defined as a body mass index of 30 or greater. Among children and adolescents, overweight is defined as a body mass index for age at or above the 95th percentile of a specified reference population. In 2003-2004, 32.9% of adults 20-74 years old were obese and more than 17% of teenagers (age, 12-19 y) were overweight. Obesity varies by age and sex, and by race-ethnic group among adult women. A higher body weight is associated with an increased incidence of a number of conditions, including diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease, and with an increased risk of disability. Obesity is associated with a modestly increased risk of all-cause mortality. However, the net effect of overweight and obesity on morbidity and mortality is difficult to quantify. It is likely that a gene-environment interaction, in which genetically susceptible individuals respond to an environment with increased availability of palatable energy-dense foods and reduced opportunities for energy expenditure, contributes to the current high prevalence of obesity. Evidence suggests that even without reaching an ideal weight, a moderate amount of weight loss can be beneficial in terms of reducing levels of some risk factors, such as blood pressure. Many studies of dietary and behavioral treatments, however, have shown that maintenance of weight loss is difficult. The social and economic costs of obesity and of attempts to prevent or to treat obesity are high. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Ogden, CL (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4414, Hyattsville, MD 20782 USA. EM COgden@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 163 TC 731 Z9 769 U1 23 U2 157 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2007 VL 132 IS 6 BP 2087 EP 2102 DI 10.1053/j.gastro.2007.03.052 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 166UA UT WOS:000246404700002 PM 17498505 ER PT J AU Kaplan, LM Klein, S Boden, G Brenner, DA Gostout, CJ Lavine, JE Popkin, BM Schirmer, BD Seeley, RJ Yanovski, SZ Cominelli, F AF Kaplan, Lee M. Klein, Samuel Boden, Guenther Brenner, David A. Gostout, Christopher J. Lavine, Joel E. Popkin, Barry M. Schirmer, Bruce D. Seeley, Randy J. Yanovski, Susan Z. Cominelli, Fabio TI Report of the American Gastroenterological Association (AGA) Institute Obesity Task Force SO GASTROENTEROLOGY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Washington Univ, Div Geriatr, St Louis, MO USA. Temple Univ, Div Endocrinol & Metab, Philadelphia, PA 19122 USA. Columbia Univ, Dept Med, New York, NY 10027 USA. Mayo Clin, Rochester, MN USA. Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. Univ N Carolina, Div Nutr Epidemiol, Chapel Hill, NC 27515 USA. Univ Virginia, Laparoscop Inst, Charlottesville, VA 22903 USA. Univ Cincinnati, Genome Res Ctr, Cincinnati, OH 45221 USA. NIDDKD, Bethesda, MD 20892 USA. Univ Virginia, Dept Gastroenterol & Hepatol, Charlottesville, VA 22903 USA. RP Kaplan, LM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. OI popkin, barry/0000-0001-9495-9324; Seeley, Randy/0000-0002-3721-5625 NR 0 TC 2 Z9 2 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2007 VL 132 IS 6 BP 2272 EP 2275 DI 10.1053/j.gastro.2007.03.061 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 166UA UT WOS:000246404700014 PM 17498517 ER PT J AU Li, L Yang, L Scudiero, DA Miller, SA Yu, ZX Stukenberg, PT Shoemaker, RH Kotin, RM AF Li, L. Yang, L. Scudiero, D. A. Miller, S. A. Yu, Z-X Stukenberg, P. T. Shoemaker, R. H. Kotin, R. M. TI Development of recombinant adeno-associated virus vectors carrying small interfering RNA (shHec1)-mediated depletion of kinetochore Hec1 protein in tumor cells SO GENE THERAPY LA English DT Article DE rAAV; Hec1; RNA interference; cancer ID MAMMALIAN-CELLS; GENE-EXPRESSION; MICROTUBULE ATTACHMENT; CHROMOSOME SEGREGATION; DOWN-REGULATION; IN-VIVO; APOPTOSIS; KINASE; CANCER; TRANSDUCTION AB Transcript depletion using small interfering RNA ( siRNA) technology represents a potentially valuable technique for the treatment of cancer. However, delivering therapeutic quantities of siRNA into solid tumors by chemical transfection is not feasible, whereas viral vectors efficiently transduce many human tumor cell lines. Yet producing sufficient quantities of viral vectors that elicit acute and selective cytotoxicity remains a major obstacle for preclinical and clinical trials. Using the invertebrate Spodoptera frugiperda (Sf9) cell line, we were able to produce high titer stocks of cytotoxic recombinant adeno-associated virus (rAAV) that express short hairpin RNA (shRNA) and that efficiently deplete Hec1 ( highly expressed in cancer 1), or Kntc2 (kinetochore-associated protein 2), a kinetochore protein directly involved in kinetochore microtubule interactions, chromosome congression and spindle checkpoint signaling. Depletion of Hec1 protein results in persistent spindle checkpoint activation followed by cell death. Because Hec1 expression and activity are only present in mitotic cells, non-dividing cells were not affected by rAAV treatment. On the basis of the results of screening 56 human tumor cell lines with three different serotype vectors, we used a tumor xenograft model to test the effects in vivo. The effects of the shHec1 vector were evident in sectioned and stained tumors. The experiments with rAAV-shRNA vectors demonstrate the utility of producing vectors in invertebrate cells to obtain sufficient concentrations and quantities for solid tumor therapy. This addresses an important requirement for cancer gene therapy, to produce cytotoxic vectors in sufficient quantities and concentrations to enable quantitative transduction and selective killing of solid tumor cells. C1 NHLBI, Biochem Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Screening Technol Branch, NIH, Frederick, MD 21701 USA. Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Kotin, RM (reprint author), NHLBI, Biochem Genet Lab, NIH, Bldg 10,Rm 7D05,10 Ctr Dr, Bethesda, MD 20892 USA. EM kotinr@nhlbi.nih.gov RI kotin, robert/B-8954-2008; OI Stukenberg, Todd/0000-0002-6788-2111 NR 43 TC 18 Z9 23 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD MAY PY 2007 VL 14 IS 10 BP 814 EP 827 DI 10.1038/sj.gt.3302933 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 164CS UT WOS:000246210900004 PM 17330085 ER PT J AU Zhang, H Zhang, H Li, ZH Zheng, G AF Zhang, Han Zhang, Hong Li, Zhaohai Zheng, Gang TI Statistical methods for haplotype-based matched case-control association studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE bias; estimation; haplotype-analysis; matching; Wald test ID UNPHASED GENOTYPE DATA; UNRELATED INDIVIDUALS; GENETIC INFORMATION; LINKAGE PHASE; INFERENCE; TRAITS; POLYMORPHISMS; DISEASE; DESIGN; CANCER AB Kraft et al. [2005] proposed a method for matched haplotype-based association studies and compared the performances of six analytic strategies for estimating the odds ratio parameters using a conditional likelihood function. Zhang et al. [2006] modified the conditional likelihood and proposed a new method for matched haplotype-based association studies. The main assumptions of Zhang et al. were that the disease was rare, the population was in Hardy-Weinberg equilibrium (HWE), and the haplotypes were independent of the covariates and matching variable(s). In this article, we modify the estimation procedure proposed by Zhang et al. and introduce a fixation index so that the assumption of HWE is relaxed. Using the Wald test, we compare the current modified method with the procedure developed by Kraft et al. through simulations. The results show that the modified method is uniformly more powerful than that described in Kraft et al. Furthermore, the results indicate that the modified method is quite robust to the rare disease assumption. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Univ Sci & Technol China, Dept Stat & Finance, Hefei, Peoples R China. George Washington Univ, Dept Stat, Washington, DC 20052 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Zhang, H (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 60 Coll St, New Haven, CT 06510 USA. EM zhangh@ustc.edu.cn RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 FU NEI NIH HHS [EY 014478] NR 31 TC 5 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD MAY PY 2007 VL 31 IS 4 BP 316 EP 326 DI 10.1002/gepi.20212 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 158VW UT WOS:000245824200005 PM 17285622 ER PT J AU Kemp, CA Song, MH Addepalli, MK Hunter, G O'Connell, K AF Kemp, Catherine A. Song, Mi Hye Addepalli, Murali Krishna Hunter, Ginger O'Connell, Kevin TI Suppressors of zyg-1 define regulators of centrosome duplication and nuclear association in Caenorhabditis elegans SO GENETICS LA English DT Article ID C-ELEGANS; CENTRIOLE DUPLICATION; CELL-DIVISION; ASPERGILLUS-NIDULANS; CYTOPLASMIC DYNEIN; PROTEIN SPD-2; GENE; EMBRYO; IDENTIFICATION; REPLICATION AB In Caenorhabdilis elegans, the kinase ZYG-1 is required for centrosome duplication. To identify factors that interact with ZYG-1, we used a classical genetic approach and identified 21 szy (suppressor of zyg-1) genes that when Mutated restore partial viability to a zyg-1 mutant. None of the suppressors render animals completely independent of zyg-1 activity and analysis of a subset of the suppressors indicates that all restore the normal process of centrosome duplication to zyg-1 mutants. Thirteen of these Suppressor mutations confer phenotypes of their own and cytological examination reveals that these genes function in a variety of cellular processes including cell cycle timing, microtubule organization, cytokinesis, chromosome segregation, and centrosome morphology. Interestingly, several of the szy genes play a role in attaching the centrosome to the nuclear envelope. We have found that one such szy gene is sun-1, a gene encoding a nuclear envelope component. We further show that the role of SUN-1 in centrosome duplication is distinct from its role in attachment. Our approach has thus identified numerous candidate regulators of centrosome duplication and uncovered all unanticipated regulatory mechanism involving factors that tether the centrosome to the nucleus. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP O'Connell, K (reprint author), NIDDKD, Lab Biochem & Genet, NIH, 8 Ctr Dr,Room 2A07, Bethesda, MD 20892 USA. EM kevino@intra.niddk.nih.gov OI Hunter, Ginger/0000-0001-7022-9482 FU Intramural NIH HHS NR 51 TC 23 Z9 32 U1 0 U2 2 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2007 VL 176 IS 1 BP 95 EP 113 DI 10.1534/genetics.107.071803 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 174RQ UT WOS:000246960900010 PM 17446307 ER PT J AU Mackwan, RR Carver, GT Drake, JW Grogan, DW AF Mackwan, Reena R. Carver, Geraldine T. Drake, John W. Grogan, Dennis W. TI An unusual pattern of spontaneous mutations recovered in the halophilic archaeon Haloferax volcanii SO GENETICS LA English DT Article ID SHORT SEQUENCE HOMOLOGIES; RATES; BACTERIA; DELETION; REPAIR AB Spontaneous mutations in the orotate:phosphoribosyl transferase (pyrE2) gene of the halophilic archaeon Haloferax volcanii were selected by 5-fluoroorotic acid plus uracil at a rate of similar to 2 X 10(-8)/cell division in fluctuation and null-fraction tests but similar to 6 X 10(-8)/cell division in mutation-accumulation tests. The corresponding genomic mutation rates were substantially lower than those observed for other mesophilic microbial DNA genomes on the basis of similar target genes. The mutational spectrum was dominated by indels adding or deleting Multiples of 3 bp. Properties of the organism contributing to this unusual mutational pattern may include phenotypic lag caused by a high chromosomal copy number and efficient promotion of strand misalignments by short direct repeats. C1 Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Grogan, DW (reprint author), Univ Cincinnati, Dept Biol Sci, 614 Rieveschl Hall, Cincinnati, OH 45221 USA. EM grogandw@email.uc.edu FU Intramural NIH HHS NR 26 TC 21 Z9 21 U1 0 U2 2 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2007 VL 176 IS 1 BP 697 EP 702 DI 10.1534/genetics.106.069666 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 174RQ UT WOS:000246960900056 PM 17194771 ER PT J AU Qasba, PK Ramakrishnan, B AF Qasba, Pradman K. Ramakrishnan, Boopathy TI Letter to the Glyco-Forum: Catalytic domains of glycosyltransferases with 'add-on' domains SO GLYCOBIOLOGY LA English DT Editorial Material ID LACTOSE SYNTHASE; STRUCTURAL BASIS; BETA-1,4-GALACTOSYLTRANSFERASE; REVEALS C1 NCI, Struct Glycobiol Sect, CCR Nanobiol Program, Frederick, MD 21702 USA. NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, CCR Nanobiol Program, Bldg 469,Room 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU Intramural NIH HHS; PHS HHS [N01-C0-12400] NR 15 TC 6 Z9 6 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAY PY 2007 VL 17 IS 5 BP 7G EP 9G DI 10.1093/glycob/cwm013 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 165HC UT WOS:000246294000001 PM 17283039 ER PT J AU Pakula, R Melchior, A Denys, A Vanpouille, C Mazurier, J Allain, F AF Pakula, Rachel Melchior, Aurelie Denys, Agnes Vanpouille, Christophe Mazurier, Joel Allain, Fabrice TI Syndecan-1/CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis SO GLYCOBIOLOGY LA English DT Article DE CD147; cyclophilin B; heparan sulphate; syndecan ID HEPARAN-SULFATE PROTEOGLYCANS; FIBROBLAST-GROWTH-FACTOR; MATRIX-METALLOPROTEINASE PRODUCTION; IMMUNODEFICIENCY-VIRUS TYPE-1; PERIPHERAL-BLOOD LYMPHOCYTES; LEWIS LUNG-CARCINOMA; CIS-TRANS ISOMERASE; RHEUMATOID-ARTHRITIS; EXTRACELLULAR-MATRIX; SIGNAL-TRANSDUCTION AB Many of the biological functions attributed to cell surface proteoglycans are dependent on the interaction with extracellular mediators through their heparan sulphate (HS) moieties and the participation of their core proteins in signaling events. A class of recently identified inflammatory mediators is secreted cyclophilins, which are mostly known as cyclosporin A-binding proteins. We previously demonstrated that cyclophilin B (CyPB) triggers chemotaxis and integrin-mediated adhesion of T lymphocytes mainly of the CD4(+)/CD45RO(+) phenotype. These activities are related to interactions with two types of binding sites, CD147 and cell surface HS. Here, we demonstrate that CyPB-mediated adhesion of CD4(+)/CD45RO(+) T cells is related to p44/42 mitogen-activated protein kinase (MAPK) activation by a mechanism involving CD147 and HS proteoglycans (HSPG). Although HSPG core proteins are represented by syndecan-1, -2, -4, CD44v3 and betaglycan in CD4(+)/CD45RO(+) T cells, we found that only syndecan-1 is physically associated with CD147. The intensity of the heterocomplex increased in response to CyPB, suggesting a transient enhancement and/or stabilization in the association of CD147 to syndecan-1. Pretreatment with anti-syndecan-1 antibodies or knockdown of syndecan-1 expression by RNA interference dramatically reduced CyPB-induced p44/p42 MAPK activation and consequent migration and adhesion, supporting the model in which syndecan-1 serves as a binding subunit to form the fully active receptor of CyPB. Altogether, our findings provide a novel example of a soluble mediator in which a member of the syndecan family plays a critical role in efficient interaction with signaling receptors and initiation of cellular responses. C1 Univ Sci & Technol Lille, Inst Rech Fed 147, CNRS,Unite Mixte Rech 8576, Unite Glycobiol Struct & Fonct, F-59655 Villeneuve Dascq, France. NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. RP Allain, F (reprint author), Univ Sci & Technol Lille, Inst Rech Fed 147, CNRS,Unite Mixte Rech 8576, Unite Glycobiol Struct & Fonct, F-59655 Villeneuve Dascq, France. EM fabrice.allain@univ-lille1.fr NR 55 TC 54 Z9 56 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAY PY 2007 VL 17 IS 5 BP 492 EP 503 DI 10.1093/glycob/cwm009 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 165HC UT WOS:000246294000007 PM 17267519 ER PT J AU Wildi, S Kleeff, J Mayerle, J Zimmermann, A Bottinger, EP Wakefield, L Buchler, MW Friess, H Korc, M AF Wildi, Stefan Kleeff, Jorg Mayerle, Julia Zimmermann, Arthur Bottinger, Erwin P. Wakefield, Lalage Buchler, Markus W. Friess, Helmut Korc, Murray TI Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations SO GUT LA English DT Article ID ACUTE NECROTIZING PANCREATITIS; TGF-BETA; TRYPSINOGEN ACTIVATION; ACINAR-CELL; TRANSGENIC MICE; CATHEPSIN-B; RAT; EXPRESSION; RECEPTOR; FIBROSIS AB Background: Transforming growth factors beta s (TGF-beta s) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-beta s modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor. Methods: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. Results: The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. Conclusion: Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis. C1 Dartmouth Med Sch, Dept Med & Pharmacol & Toxicol, Hanover, NH USA. Univ Heidelberg, Dept Surg, D-6900 Heidelberg, Germany. Univ Bern, Dept Pathol, CH-3012 Bern, Switzerland. Mt Sinai Sch Med, Dept Med, New York, NY USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Korc, M (reprint author), Dartmouth Hitchcock Med Ctr, Dept Med, Lebanon, NH 03756 USA. EM murray.korc@dartmouth.edu RI Kleeff, Jorg/B-2124-2009 OI Kleeff, Jorg/0000-0003-3432-6669 FU NCI NIH HHS [CA-75059]; NIDDK NIH HHS [R01 DK056077, R01 DK060043] NR 48 TC 24 Z9 25 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD MAY PY 2007 VL 56 IS 5 BP 685 EP 692 DI 10.1136/gut.2006.105833 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 158GR UT WOS:000245780200018 PM 17135311 ER PT J AU Eyster, ME Asaad, SM Gold, BD Cohn, SE Goedert, JJ AF Eyster, M. E. Asaad, S. M. Gold, B. D. Cohn, S. E. Goedert, J. J. CA Second Multicenter Hemophilia Stud TI Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs SO HAEMOPHILIA LA English DT Article DE arthropathy; clinical study; GI bleeding; H. pylori; hemophilia; NSAID ID HELICOBACTER-PYLORI INFECTION; RANDOMIZED CONTROLLED-TRIAL; MALLORY-WEISS SYNDROME; RHEUMATOID-ARTHRITIS; ARTHROPATHY; CHILDREN; ADULTS; CYCLOOXYGENASE-2; ACQUISITION; PREVALENCE AB This multicentre study sought to estimate the incidence of upper gastrointestinal (UGI) bleeding in haemophiliacs and its relationship to use of non-steroidal anti-inflammatory drugs (NSAIDs). Cox models were used to estimate relative hazards (RH) with 95% confidence intervals (CI) for postulated risk factors. Conditional logistic regression and stored sera were used to assess UGI bleeding risk with Heliobacter pylori seropositivity in cases compared with closely matched controls. During a mean of 17.4 months (range 2-34), 2285 participants, ages 13-89 (mean 36.5) were followed for 3309 person-years (py). Forty-two experienced a UGI bleeding event (incidence 1.3 per 100 py), most from ulcer (11), gastritis (four), varices (five) and Mallory Weiss tears (eight). RH was significantly increased with traditional NSAID use for < 1 month (OR: 3.66; 95% CI: 1.1-11.9), but not with coxibs use. RH was significantly and independently increased with age > 46 years (3.5; 95% CI: 1.1-10.6) and hepatic decompensation (4.4; 95% CI: 1.7-11.6). Likelihood of bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. These findings suggest that coxibs are a safer alternative than traditional NSAIDs in the treatment of haemophilic arthropathy. C1 Penn State Univ, Coll Med, Dept Med, Div Hematol & Oncol, Hershey, PA USA. Emory Univ, Sch Med, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Atlanta, GA USA. Res Triangle Inst, Rockville, MD USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Eyster, ME (reprint author), Penn State Milton S Hershey Med Ctr, Mail Code H046,POB 850, Hershey, PA 17033 USA. EM eeyster@psu.edu FU Intramural NIH HHS; NCI NIH HHS [N01-CP-01004] NR 39 TC 13 Z9 13 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD MAY PY 2007 VL 13 IS 3 BP 279 EP 286 DI 10.1111/j.1365-2516.2007.01453.x PG 8 WC Hematology SC Hematology GA 165PG UT WOS:000246316900008 PM 17498077 ER PT J AU Miller, FG Wertheimer, A AF Miller, Franklin G. Wertheimer, Alan TI Facing up to paternalism in research ethics SO HASTINGS CENTER REPORT LA English DT Article ID CLINICAL-RESEARCH AB Bioethicists have failed to understand the pervasively paternalistic character of research ethics. Not only is the overall structure of research review and regulation paternalistic in some sense; even the way informed consent is sought may imply paternalism. Paternalism has limits, however. Getting clear on the paternalism of research ethics may mean some kinds of prohibited research should be reassessed. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Vermont, Burlington, VT 05405 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 15 TC 56 Z9 57 U1 1 U2 6 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAY-JUN PY 2007 VL 37 IS 3 BP 24 EP 34 DI 10.1353/hcr.2007.0044 PG 11 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 174XL UT WOS:000246976100014 PM 17649900 ER PT J AU Polinski, JM Wang, PS Fischer, MA AF Polinski, Jennifer M. Wang, Philip S. Fischer, Michael A. TI Medicaid's prior authorization program and access to atypical antipsychotic medications SO HEALTH AFFAIRS LA English DT Article ID CYCLOOXYGENASE-2 INHIBITORS; PRESCRIPTION DRUGS; POLICY; POPULATION; DEMENTIA; PATTERNS; CHILDREN; QUALITY; COSTS AB State Medicaid programs use prior authorization (PA) to control drug spending by requiring that specific conditions be met before allowing reimbursement. The extent to which PA policies respond to new developments concerning medication safety is not known. In April 2005 the Food and Drug Administration (FDA) issued an advisory describing increased mortality among elderly people with dementia taking atypical antipsychotics. More than a year later, no state had changed its PA policy in response. We discuss the roles of Medicaid and other insurers in responding to emerging drug safety issues and their challenges in weighing drug risks and benefits. C1 Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. EM jpolinski@partners.org NR 27 TC 35 Z9 35 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAY-JUN PY 2007 VL 26 IS 3 BP 750 EP 760 DI 10.1377/hlthaff.26.3.750 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 167NL UT WOS:000246458300020 PM 17485754 ER PT J AU Fontana, R Biebauskas, LA Lindsay, KL Back-Madruga, C Wright, EC Snow, KK Lok, ASF Kronfol, Z Padmanabhan, L AF Fontana, Robert. Biebauskas, Linas A. Lindsay, Karen L. Back-Madruga, Carla Wright, Elizabeth C. Snow, Kristin K. Lok, Anna S. F. Kronfol, Ziad Padmanabhan, Latha TI Cognitive function does not worsen during pegylated interferon and ribavirin Retreatment of chronic hepatitis C SO HEPATOLOGY LA English DT Article ID QUALITY-OF-LIFE; MULTIPLE-SCLEROSIS; COMBINATION THERAPY; ADVANCED FIBROSIS; ALPHA; VIRUS; TRIAL; NEUROTOXICITY; RELIABILITY; IMPAIRMENT AB Treatment of chronic hepatitis C with pegylated interferon (peginterferon) and ribavirin can cause or exacerbate depression but its effects on cognitive function are largely unknown. The aim of this study was to determine whether treatment with peginterferon and ribavirin adversely impacts cognitive function in patients with chronic hepatitis C. Prior nonresponders to interferon were retreated with peginterferon alfa-2a and ribavirin for 24 (n = 177) or 48 weeks (n = 57) in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial. Cognitive function was prospectively assessed using a battery of 10 standardized neuropsychological tests at weeks 0, 24, 48, and 72. Cognitive impairment was defined based upon a global deficit score. The Beck Depression Inventory and Brief Symptom Inventory were used to assess mood status. The 57 subjects who completed 48 weeks of antiviral therapy reported significant increases in difficulty concentrating, emotional distress, and symptoms of depression, all of which improved after cessation of therapy [P < 0.0001, analysis of variance (ANOVA)]. Nonetheless, the frequency of cognitive impairment did not increase during the first 24 weeks of treatment in 177 patients (34% versus 32%, P = 0.64) nor in the 57 patients completing 48 weeks of treatment (P = 0.48, ANOVA). Conclusion: Retreatment of prior non-responders with peginterferon and ribavirin was not associated with objective evidence of cognitive impairment as measured by a comprehensive battery of neuropsychological tests. The lack of cognitive impairment is reassuring and suggests that self-reported symptoms of cognitive dysfunction are more likely related to the systemic and psychiatric side effects of antiviral treatment rather than measurable changes in cognition. C1 Univ Michigan, Dept Internal Med, Dept Psychiat, Div Gastroenterol, Ann Arbor, MI 48109 USA. Univ Michigan, Neuropsychol Sect, Dept Psychiat, Ann Arbor, MI 48109 USA. Vet Affairs Hlth Syst, Psychol Serv, Ann Arbor, MI USA. Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA. NIDDKD, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. RP Fontana, R (reprint author), 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU NCRR NIH HHS [M01RR-00042, M01RR-00043]; NIDDK NIH HHS [N01-DK-9-2323, N01-DK-9-2325, N01-DK-9-2328] NR 47 TC 23 Z9 23 U1 2 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD MAY PY 2007 VL 45 IS 5 BP 1154 EP 1163 DI 10.1002/hep.21633 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 163UC UT WOS:000246187700009 PM 17465000 ER PT J AU Wakabayashi, Y Chua, J Larkin, JM Lippincott-Schwartz, J Arias, IM AF Wakabayashi, Yoshiyuki Chua, Jennifer Larkin, Janet M. Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Four-dimensional imaging of filter-grown polarized epithelial cells SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE four-dimensional imaging; live cell imaging; polarized epithelial cells; permeable filter insert; MDCK cells ID CANINE KIDNEY-CELLS; MDCK CELLS; PLASMA-MEMBRANE; SURFACE POLARITY; GOLGI TRANSPORT; TRAFFICKING; ENDOCYTOSIS; ENDOSOMES; PROTEIN; ORGANIZATION AB Understanding how epithelial cells generate and maintain polarity and function requires live cell imaging. In order for cells to become fully polarized, it is necessary to grow them on a permeable membrane filter; however, the translucent filter obstructs the microscope light path required for quantitative live cell imaging. Alternatively, the membrane filter may be excised but this eliminates selective access to apical and basolateral surfaces. Conversely, epithelial cells cultured directly on glass exhibit different phenotypes and functions from filter grown cells. Here, we describe a new method for culturing polarized epithelial cells on a Transwel (R) stop filter insert that allows superior live cell imaging with spatial and temporal image resolution previously unachievable using conventional methods. Cells were cultured on the underside of a filter support. Epithelial cells grown in this inverted configuration exhibit a fully polarized architecture, including the presence of functional tight junctions. This new culturing system permits four-dimensional (three spatial dimension over time) imaging of endosome and Golgi apparatus dynamics, and permits selective manipulation of the apical and basolateral surfaces. This new technique has wide applicability for visualization and manipulation of polarized epithelial cells. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. RP Wakabayashi, Y (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM wakabayo@mail.nih.gov NR 26 TC 14 Z9 14 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0948-6143 J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD MAY PY 2007 VL 127 IS 5 BP 463 EP 472 DI 10.1007/s00418-007-0274-x PG 10 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA 158XV UT WOS:000245829800001 PM 17308935 ER PT J AU Kamari, Y Grossman, E Oron-Herman, M Peleg, E Shabtay, Z Shamiss, A Sharabi, Y AF Kamari, Y. Grossman, E. Oron-Herman, M. Peleg, E. Shabtay, Z. Shamiss, A. Sharabi, Y. TI Metabolic stress with a high carbohydrate diet increases adiponectin levels SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE adiponectin; metabolic syndrome; carbohydrates; diet ID SPONTANEOUSLY HYPERTENSIVE-RATS; INDUCED INSULIN-RESISTANCE; ADIPOSE-SPECIFIC PROTEIN; FATTY LIVER-DISEASE; LOW-CALORIE DIET; CIRCULATING ADIPONECTIN; GENE-EXPRESSION; BLOOD-PRESSURE; OBESE WOMEN; FRUCTOSE AB Background: Adiponectin is an adipose tissue-specific protein, which possesses anti-atherogenic and antidiabetic properties, yet its plasma levels are decreased in subjects with metabolic syndrome. Although high fat diet has been linked to hypoadiponectinemia, the effect of high-carbohydrate diet on adiponectin levels is not known. Therefore, we studied the effect of high-carbohydrate diet on adiponectin levels in the rat models of hypertension and insulin resistance. Methods: Rats were randomly assigned to the high carbohydrate diet [Sprague-Dawley rats with fructose enriched diet (SDR-F) and spontaneously hypertensive rats with sucrose enriched diet (SHR-S model)] or chow diet (Control group). Rats were followed for 6 weeks (SDR-F model) and 8 weeks (SHR-S model). Body weight, systolic blood pressure, plasma levels of glucose, insulin, triglycerides and adiponectin, were recorded. Results: Both models were associated with features of the metabolic syndrome, namely, high insulin levels, increased blood pressure and triglyceride levels. Plasma adiponectin levels did not change in the control groups. In contrast, adiponectin levels increased by 39 and 30% compared to baseline following four and six weeks of fructose enriched diet in SDR (from 3.3 +/- 0.2 to 4.5 +/- 0.4 and 4.3 +/- 0.2 mu g/ml, respectively, p < 0.05). Likewise, five and eight weeks of sucrose enriched diet in SHR, induced a 54 and 81% increase in adiponectin levels compared to baseline (from 4.2 +/- 0.3 to 6.3 +/- 0.3 and 7.3 +/- 0.5 mu g/ml, respectively, p < 0.01). Conclusion: Metabolic stress with a high-carbohydrate diet increases plasma levels of adiponectin. Further studies will elucidate whether this is a transitory compensatory mechanism or a sign of target organ resistance to adiponectin. C1 Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. NINDS, NIH, Bethesda, MD 20892 USA. RP Kamari, Y (reprint author), Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. EM yehuda.kamari@sheba.health.gov.il OI Grossman, Ehud/0000-0001-8353-0661 NR 46 TC 27 Z9 28 U1 1 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2007 VL 39 IS 5 BP 384 EP 388 DI 10.1055/s-2007-976534 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 179CX UT WOS:000247268000012 PM 17533582 ER PT J AU Eippert, F Veit, R Weiskopf, N Erb, M Birbaumer, N Anders, S AF Eippert, Falk Veit, Ralf Weiskopf, Nikolaus Erb, Michael Birbaumer, Niels Anders, Silke TI Regulation of emotional responses elicited by threat-related stimuli SO HUMAN BRAIN MAPPING LA English DT Article DE emotion; cognitive control; amygdala; prefrontal cortex; fMRI ID FUNCTIONAL MAGNETIC-RESONANCE; POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL THERAPY; HUMAN ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; NEGATIVE EMOTION; VOLUNTARY SUPPRESSION; AMYGDALA ACTIVATION; PREFRONTAL CORTEX; NEURAL CIRCUITRY AB The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events. Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and prefrontal regions to be associated with downregulation. To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self-report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat-related pictures and were asked to up- and downregulate their emotional responses using reappraisal strategies. While startle eyeblink responses (in successful regulators) and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation, amygdala activity was increased and decreased according to the regulation instructions. Trial-by-trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation. Downregulation was characterized by left-hemispheric activation peaks in anterior cingulate cortex, dorsolateral prefrontal cortex, and orbitofrontal cortex and upregulation was characterized by a pattern of prefrontal activation not restricted to the left hemisphere. Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up-arid downregulation, but also showed distinct activations in each condition. The present study demonstrates that amygdala responses to threat-related stimuli can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas, thereby changing the subject's affective state. C1 Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. Univ Tubingen, Grad Sch Neural & Behav Sci, Int Max Planck Res Sch, Tubingen, Germany. Univ Tubingen, Sect Expt MR CNS, Tubingen, Germany. UCL, Wellcome Dept Imaging Neurosci, Inst Neurol, London, England. NINDS, NIH, Human Cort Physiol, Bethesda, MD 20892 USA. RP Eippert, F (reprint author), Univ Hamburg, Med Ctr, Dept Syst Neurosci, D-20246 Hamburg, Germany. EM f.eippert@uke.uni-hamburg.de RI Weiskopf, Nikolaus/B-9357-2008; Frank, David/E-8213-2012; Eippert, Falk/M-6188-2013; Veit, Ralf/F-8907-2012; OI Weiskopf, Nikolaus/0000-0001-5239-1881; Veit, Ralf/0000-0001-9860-642X; Erb, Michael/0000-0002-9311-4693; Eippert, Falk/0000-0002-3986-1719 NR 78 TC 187 Z9 196 U1 8 U2 43 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAY PY 2007 VL 28 IS 5 BP 409 EP 423 DI 10.1002/hbm.20291 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 159HW UT WOS:000245857200005 PM 17133391 ER PT J AU Jansma, JM Ramsey, NF de Zwart, JA van Gelderen, P Duyn, JH AF Jansma, J. M. Ramsey, N. F. de Zwart, J. A. van Gelderen, P. Duyn, J. H. TI fMRI study of effort and information processing in a working memory task SO HUMAN BRAIN MAPPING LA English DT Article DE fmri; Stemberg task; effort; information processing; deactivation ID PREFRONTAL CORTEX; FUNCTIONAL-ANATOMY; BRAIN-FUNCTION; DEFAULT MODE; LOAD; PERFORMANCE; DEPRESSION; COMPONENTS; NETWORK; REGIONS AB It is unclear how effort translates into brain function. In this study we endeavored to identify the activity in a working memory task that is related to the allocation of mental resources. Such activity, if present, would be a likely candidate to explain how effort works in terms of brain function. Eleven healthy participants performed a Sternberg task with a memory-set of one, three, or five consonants in an fMRI study. Probe stimuli were either one consonant or one digit. We expected digits to be processed automatically and consonants to require working memory. Because the probe type was unpredictable and subjects had to respond as fast as possible, we expected subjects to allocate mental resources on the basis of the memory-set size, not the probe type. Accordingly, we anticipated that activity in regions involved in effort would be a function of the size of the memory-set, but independent of the type of probe. We found that the reaction-time for digits increased in line with our expectation of automatic processing and the reaction time for letters increased in line with our expectation of controlled processing. fMRI revealed that activity in the right ventral-prefrontal cortex changed as a function of effort. The ventral anterior cingulate cortex and hypothalamus showed reduced activity as a function of effort. Activity in regions regarded as pivotal for working memory (among others, the left dorsolateral prefrontal cortex, anterior cingulate cortex) appeared to be predominantly related to information processing and not involved in effort. C1 NINDS, LFMI, NIH, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Dept Psychiat, Funct Imaging Sect, Utrecht, Netherlands. RP Jansma, JM (reprint author), NINDS, LFMI, NIH, Bldg 10,Room B1D728,MSC1065,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jansmam@mail.nih.gov RI Duyn, Jozef/F-2483-2010 FU Intramural NIH HHS NR 29 TC 28 Z9 29 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAY PY 2007 VL 28 IS 5 BP 431 EP 440 DI 10.1002/hbm.20297 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 159HW UT WOS:000245857200007 PM 17133397 ER PT J AU Bondy, CA Matura, LA Wooten, N Troendle, J Zinn, AR Bakalov, VK AF Bondy, Carolyn A. Matura, Lea Ann Wooten, Nicole Troendle, James Zinn, Andrew R. Bakalov, Vladimir K. TI The physical phenotype of girls and women with Turner syndrome is not X-imprinted SO HUMAN GENETICS LA English DT Article DE X-chromosome; congenital heart disease; aortic valve; genomic imprinting; stature; renal defects; neck webbing ID GROWTH; CHROMOSOME; ASSOCIATION; PREVALENCE; PROFILE; ORIGIN; SHOX AB Certain behavioral and metabolic aspects of Turner syndrome (TS) are attributed to X-chromosome genomic imprinting. To investigate the possible contribution of imprinting to the physical features of the TS phenotype in live-born individuals, we genotyped the single normal X-chromosome in subjects with TS who all underwent a comprehensive evaluation as part of the NIH genotype-phenotype protocol. All had physical examinations, auxological measurements and imaging of the renal and cardiovascular systems. Absolute height and height as a percent of predicted height was the same in X-M (n = 56) and X-P (n = 23) subjects that had reached final height and were not growth hormone treated. Interestingly, adult height was significantly correlated with maternal but not paternal heights in both X-M and X-P groups. Neck webbing was found in 35% of the X-M (n = 133) and 22% of the X-P (n = 50) groups (P = 0.11). Renal anomalies were present in 24% of X-M and 25% of X-P groups (P = 0.9). Bicuspid aortic valve was found in 26% of X-M and 24% of X-P groups (P = 0.83), and any cardiovascular anomaly (abnormal aortic valve, aortic coarctation, elongated transverse aortic arch, anomalous pulmonary venous connection, left superior vena cava) affected 55% of X-M and 52% of X-P groups. Thus, we found no evidence for X-linked genomic imprinting effects on stature or lymphatic, renal or cardiovascular development in TS. Our sample size was sufficient to exclude such effects within 95% confidence limits. We did demonstrate a selective maternal effect on final stature that was independent of X-chromosome origin, suggesting potential autosomal imprinting effects on growth revealed by X monosomy. C1 NICHHD, Chief Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, DESPR, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Sch, McDermott Ctr, Dallas, TX 75230 USA. Univ Texas, SW Med Sch, Dept Internal Med, Dallas, TX 75230 USA. RP Bondy, CA (reprint author), NICHHD, Chief Dev Endocrinol Branch, NIH, 10 Ctr Dr,Rm 1-3330, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov OI Zinn, Andrew/0000-0002-4935-3291 FU Intramural NIH HHS; NINDS NIH HHS [NS42777, NS35554] NR 20 TC 17 Z9 17 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2007 VL 121 IS 3-4 BP 469 EP 474 DI 10.1007/s00439-007-0324-4 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 154GF UT WOS:000245494200017 PM 17242899 ER PT J AU Ramachandran, RD Perumalsamy, V Hejtmancik, JF AF Ramachandran, Ramya Devi Perumalsamy, Vijayalakshmi Hejtmancik, J. Fielding TI Autosomal recessive juvenile onset cataract associated with mutation in BFSP1 SO HUMAN GENETICS LA English DT Article ID INTERMEDIATE-FILAMENT PROTEIN; MISSENSE MUTATION; CONGENITAL CATARACT; NONSENSE MUTATION; GENETIC-LINKAGE; LENS; DELETION; FAMILY; CELLS; CYTOSKELETON AB A genome wide scan in a consanguineous family of Indian origin with autosomal recessive developmental cataracts was performed by two-point linkage analysis with 382 microsatellite markers. It showed linkage to markers on chromosome 20q, between D20S852 and D20S912, with a maximum lod score of 5.4 obtained with D20S860. This region encompasses the beaded filament structural protein 1 (BFSP1) gene. Direct sequencing revealed a 3343 bp deletion including exon 6 (c.736-1384_c.957-66 del) predicted to result in a shift of the open reading frame. This mutation was absent in 50 control individuals from south India. This is the first report of a mutation in the BFSP1 gene associated with human inherited cataracts. This further increases the genetic heterogeneity of inherited cataracts and provides clues as to the importance of BFSP1 in the cell biology of intermediate filaments and their role in the eye lens. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. Aravind Eye Hosp, Aravind Med Res Fdn, Dept Mol Biol, Madurai, Tamil Nadu, India. Aravind Eye Hosp, Paediat Ophthalmol Clin, Madurai, Tamil Nadu, India. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bldg 10,Rm 10B10,10 Ctr Dr, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 41 TC 61 Z9 64 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2007 VL 121 IS 3-4 BP 475 EP 482 DI 10.1007/s00439-006-0319-6 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 154GF UT WOS:000245494200018 PM 17225135 ER PT J AU Gaudet, MM Egan, KM Lissowska, J Newcomb, PA Brinton, LA Titus-Ernstoff, L Yeager, M Chanock, S Welch, R Peplonska, B Trentham-Dietz, A Garcia-Closas, M AF Gaudet, Mia M. Egan, Kathleen M. Lissowska, Jolanta Newcomb, Polly A. Brinton, Louise A. Titus-Ernstoff, Linda Yeager, Meredith Chanock, Stephen Welch, Robert Peplonska, Beata Trentham-Dietz, Amy Garcia-Closas, Montserrat TI Genetic variation in tumor necrosis factor and lymphotoxin-alpha (TNF-LTA) and breast cancer risk SO HUMAN GENETICS LA English DT Article ID ESTROGEN SYNTHESIS; MCF-7 CELLS; POLYMORPHISMS; ASSOCIATION; PROMOTER; CYTOKINES; DISEASE; LINKAGE; SUSCEPTIBILITY; EXPRESSION AB Tumor necrosis factor (TNF) is critical to regulation of inflammation. Genetic variation in the promoter region of TNF has been associated with expression differences, and a range of auto-immune, infectious, and oncologic diseases. We analyzed eight common single nucleotide polymorphisms (SNPs) (rs746868, rs909253, rs1799964, rs1800630, rs1800750, rs1800629, rs361525, and rs1800610) to capture most of the genetic variation in TNF in addition to SNPs in lymphotoxin-alpha (LTA), a pro-inflammatory cytokine in linkage disequilibrium with the TNF promoter region. SNPs were genotyped in a USA population-based case-control study (3,318 cases, 2,841 controls). Promising results were followed-up in an independent population-based case-control study in Poland (2,228 cases, 2,378 controls). In both studies, women carrying the variant allele of rs361525 were at elevated breast cancer risk compared to the GG genotype (per allele OR = 1.18, 95% CI 1.04-1.35; P for trend = 0.008). Other SNPs were not significantly associated with breast cancer risk. Haplotype analyses did not reveal any additional associations between TNF and breast cancer risk. Data from 5,269 cases and 4,982 controls suggested that the rs361525 A allele, located in the TNF promoter region, was associated with a modest increase in breast cancer risk. Additional studies are required to replicate these findings and to determine whether rs361525 is a causative SNP or is a marker of a causative SNP. C1 NCI, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. M Slodowska Curie Inst Oncol, Ctr Canc, Warsaw, Poland. Fred Hutchinson Canc Res Ctr, Canc Prevent Res Grp, Seattle, WA 98104 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI 53706 USA. Dartmouth Med Ctr, Lebanon, NH USA. Norris Cotton Canc Ctr, Lebanon, NH USA. NCI, Core Genotype Facil, Ctr Adv Technol, NIH,Dept Hlth & Human Serv, Gaithersburg, MD USA. NCI, Sect Genom Variat, Pediat Oncol Branch, Dept Hlth & Human Serv,Ctr Canc Res, Bethesda, MD USA. Nofer Inst Occupat Med, Lodz, Poland. RP Gaudet, MM (reprint author), NCI, 6120 Execut Blvd,EPS-5012, Rockville, MD 20852 USA. EM gaudetm@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS; NCI NIH HHS [CA47147, CA69664, R01 CA47305, R01 CA67264, R01 CA67338] NR 35 TC 48 Z9 49 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2007 VL 121 IS 3-4 BP 483 EP 490 DI 10.1007/s00439-006-0315-x PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 154GF UT WOS:000245494200019 PM 17216494 ER PT J AU Khan, SY Ahmed, ZM Shabbir, MI Kitajiri, SI Kalsoom, S Tasneem, S Shayiq, S Ramesh, A Srisailpathy, S Khan, SN Smith, RJH Riazuddin, S Friedman, TB Riazuddin, S AF Khan, Shahid Y. Ahmed, Zubair M. Shabbir, Muhammad I. Kitajiri, Shin-ichiro Kalsoom, Saeeda Tasneem, Saba Shayiq, Sara Ramesh, Arabandi Srisailpathy, Srikumari Khan, Shaheen N. Smith, Richard J. H. Riazuddin, Saima Friedman, Thomas B. Riazuddin, Sheikh TI Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus SO HUMAN MUTATION LA English DT Article DE deafness; nonsyndromic hearing loss; radixin; ezrin; RDX; ERM; cytoskeleton; hair cells; stereocilia ID AUTOSOMAL RECESSIVE DEAFNESS; ACTIN-BUNDLING PROTEINS; HAIR-CELL STEREOCILIA; ALLELIC MUTATIONS; RADIXIN; ENCODES; MOUSE; EAR; ELONGATION; MEMBRANES AB Ezrin, radixin, and moesin are paralogous proteins that make up the ERM family and function as cross-linkers between integral membrane proteins and actin filaments of the cytoskeleton. In the mouse, a null allele of Rdx encoding radixin is associated with hearing loss as a result of the degeneration of inner ear hair cells as well as with hyperbilirubinemia due to hepatocyte dysfunction. Two mutant alleles of RDX [c.1732G>A (p.D578N) and c.1404_1405insG (p.A469fsX487)] segregating in two consanguineous Pakistani families are associated with neurosensory hearing loss. Both of these mutant alleles are predicted to affect the actin,binding motif of radixin. Sequence analysis of RDX in the DNA samples from the original DFNB24 family revealed a c.463C > T transition substitution that is predicted to truncate the protein in the FERM domain (F for 4.1, E for ezrin, R for radixin, and M for moesin) (p.Q155X). We also report a more complete gene and protein structure of RDX, including four additional exons and five new isoforms of RDX that are expressed in human retina and inner ear. Further, high-resolution confocal microscopy in mouse inner ear demonstrates that radixin is expressed along the length of stereocilia of hair cells from both the organ of Corti and the vestibular system. C1 Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, Rockville, MD 20850 USA. Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. Univ Iowa, Mol Otolaryngol Res Lab, Dept Otolaryngol, Iowa City, IA USA. Univ Iowa, Interdept Program Genet, Iowa City, IA USA. Univ Madras, Dept Genet, Madras, Tamil Nadu, India. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, 5 Res Court,Room 2A-15, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov RI Nasim Khan, Shaheen/F-2135-2015 FU Intramural NIH HHS; NIDCD NIH HHS [R01-DC02842] NR 31 TC 44 Z9 45 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2007 VL 28 IS 5 BP 417 EP 423 DI 10.1002/humu.20469 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 158JV UT WOS:000245788700001 PM 17226784 ER PT J AU Gerstenblith, MR Goldstein, AM Fargnoli, MC Peris, K Landi, MT AF Gerstenblith, Meg R. Goldstein, Alisa M. Fargnoli, Maria Concetta Peris, Ketty Landi, Maria Teresa TI Comprehensive evaluation of allele frequency differences of MC1R variants across populations SO HUMAN MUTATION LA English DT Article DE MC1R; metanocortin 1 receptor; melanocyte-stimulating hormone receptor; melanoma; pigmentation; geographic locations; allele frequency ID MELANOCORTIN-1 RECEPTOR GENE; RED HAIR; CUTANEOUS MELANOMA; HUMAN PIGMENTATION; MEDITERRANEAN POPULATION; ULTRAVIOLET-RADIATION; DNA POLYMORPHISM; CDKN2A MUTATIONS; SUN SENSITIVITY; RISK-FACTORS AB The melanocortin 1 receptor (MC1R), a member of the G protein-coupled receptors superfamily, mediates the response to melanocortins and is currently the best-described contributor to normal pigment variation in humans. A remarkably large number of natural polymorphisms, or variants, of the MC1R gene have been identified in different populations. Some of these variants have been associated with specific hair and skin color phenotypes, the presence of freckling, and melanoma and nonmelanoma skin cancer risk. Interestingly, some MC1R variants have been associated with skin cancer beyond their effects on pigmentation. Although the red hair color variants (RHC variants) have been associated with skin cancer risk in the Celtic population, studies in darkly-pigmented Caucasian populations have demonstrated the importance of non-RHC MC1R variants on skin cancer risk as well. We have reviewed and compared allele frequency differences of MC1R variants across geographic regions. We observed large differences in the distribution of variants across populations, with a prominent difference between lightly and darkly-pigmented individuals. Moreover, among Caucasian groups, there were seven variants (p.V60L, p.V92M, p.D84E, p.R151C, p.R160W, p.R163Q, and p.D294H) with significantly different allele frequencies. Exploring differences in allele frequencies of MC1R variants across populations with varying pigmentation and differing skin cancer risk may improve our understanding of the complex relationship between MC1R, pigmentation, and carcinogenesis. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bldg EPS Room 7114,6120 Execut Blvd, Bethesda, MD 20892 USA. EM landim@mail.nih.gov OI Peris, Ketty/0000-0002-5237-0463; Fargnoli, Maria Concetta/0000-0002-7249-2556 FU Intramural NIH HHS NR 55 TC 95 Z9 97 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2007 VL 28 IS 5 BP 495 EP 505 DI 10.1002/humu.20476 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 158JV UT WOS:000245788700010 PM 17279550 ER PT J AU Peter, I Huggins, GS Shearman, AM Pollak, A Schmid, CH Cupples, LA Demissie, S Patten, RD Karas, RH Housman, DE Mendelsohn, ME Vasan, RS Benjamin, EJ AF Peter, Inga Huggins, Gordon S. Shearman, Amanda M. Pollak, Arthur Schmid, Christopher H. Cupples, L. Adrienne Demissie, Serkalem Patten, Richard D. Karas, Richard H. Housman, David E. Mendelsohn, Michael E. Vasan, Ramachandran S. Benjamin, Emelia J. TI Age-related changes in echocardiographic measurements - Association with variation in the estrogen receptor-alpha gene SO HYPERTENSION LA English DT Article DE echocardiography; left ventricular remodeling; estrogen receptor-alpha; restriction fragment length; single nucleotide polymorphism ID LEFT-VENTRICULAR MASS; CORONARY-HEART-DISEASE; MAGNETIC-RESONANCE; AMERICAN-INDIANS; ARTERY-DISEASE; BLOOD-PRESSURE; RISK-FACTORS; BODY-SIZE; ER-ALPHA; HERITABILITY AB Left ventricular (LV) mass and other LV measures have been shown to be heritable. In this study we hypothesized that functional variation in the gene coding for estrogen receptor-alpha(ESR1), known for mediating the effect of estrogens on myocardium, is associated with age-related changes in LV structure. Four genetic markers ( ESR1 TA repeat; rs2077647, or +30T > C; rs2234693, or PvuII; and rs9340799, or XbaI) were genotyped in 847 unrelated individuals ( 488 women) from the Framingham Offspring Study, who attended 2 examination cycles 16 years apart ( mean ages at first examination: 43 +/- 9 years; at follow-up: 59 +/- 9 years). ANCOVA was used to assess the association of polymorphisms and their haplotypes with cross-sectional measurements and longitudinal changes in LV mass, wall thickness, end-diastolic and end-systolic internal diameter, and fractional shortening after adjustment for factors known to influence these variables. Changes over time were detected for all of the LV measurements ( P ranging from < 0.0001 to 0.02), except for fractional shortening in men. The SS genotype of the ESR1 TA repeat polymorphism in the promoter region was associated with longitudinal changes in LV mass and LV wall thickness ( P ranging from 0.0006 to 0.01). Moreover, the TA[S] - + 30[ T] - PvuII[T] - XbaI[ A] haplotype ( frequency: 47.5%) was associated with greater LV changes as compared with the TA[ L] - +30[C] - PvuII[C] - XbaI[G] haplotype ( frequency: 31.8%). Our results are consistent with the hypothesis that common ESR1 polymorphisms are significantly associated with age-related changes in LV structure. Understanding the mechanisms predisposing to unfavorable LV remodeling of the heart with advancing age may aid in the discovery of new therapeutic targets for the prevention of heart failure. C1 Tufts Univ New England Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. MIT, Ctr Canc Res, Cambridge, England. Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Hadassah Hebrew Univ, Ctr Med, Cardiol Dept, Jerusalem, Israel. RP Peter, I (reprint author), Tufts Univ New England Med Ctr, Inst Clin Res & Hlth Policy Studies, 750 Washington St,NEMC 63, Boston, MA 02111 USA. EM ipeter@tufts-nemc.org OI Cupples, L. Adrienne/0000-0003-0273-7965; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24HL04334, P01 HL077378, P01-HL077378]; NINDS NIH HHS [6R01-NS 17950] NR 39 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2007 VL 49 IS 5 BP 1000 EP 1006 DI 10.1161/HYPERTENSIONAHA.106.083790 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 158RD UT WOS:000245810300012 PM 17372038 ER PT J AU Halcox, JPJ Nour, KRA Zalos, G Quyyumi, AA AF Halcox, Julian P. J. Nour, Khaled R. A. Zalos, Gloria Quyyumi, Arshed A. TI Endogenous endothelin in human coronary vascular function - Differential contribution of endothelin receptor types A and B SO HYPERTENSION LA English DT Article DE clinical science; blood flow regulation; endothelin; endothelium atherosclerosis ID NITRIC-OXIDE; SMOOTH-MUSCLE; ESSENTIAL-HYPERTENSION; HEART-FAILURE; RISK-FACTORS; HEALTHY-MEN; BLOCKADE; ARTERY; ATHEROSCLEROSIS; CIRCULATION AB Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET(A)) activation. However, the effects of selective endothelin receptor type B (ET(B)) and combined ET(A+B) receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and - independent vasomotor function before and after selective infusion of BQ-788 ( an ET(B) receptor antagonist) or combined infusion of BQ-788 + BQ-123 (an ET(A) antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation ( P < 0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123 + BQ-788 dilated epicardial ( P < 0.0001) and resistance ( P = 0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123 + BQ-788 ( P = 0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ- 123 + BQ- 788. We conclude that selective ET(B) receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET(A+B) blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET(A) receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET(B) activation mediates vasodilation in human coronaries. Our data suggest that selective ET(A) blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis. C1 UCL, Inst Child Hlth, London WC1N 1EH, England. Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. NHLBI, Cardiol Branch, Bethesda, MD USA. Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Halcox, JPJ (reprint author), UCL, Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England. EM j.halcox@ich.ucl.ac.uk OI Halcox, Julian/0000-0001-6926-2947 FU Intramural NIH HHS NR 47 TC 29 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAY PY 2007 VL 49 IS 5 BP 1134 EP 1141 DI 10.1161/HYPERTENSIONAHA.106.083303 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 158RD UT WOS:000245810300028 PM 17353514 ER PT J AU Shyu, CR Green, JM Lun, DR Kazic, T Schaeffer, M Coe, E AF Shyu, Chi-Ren Green, Jason M. Lun, Daniel Rk. Kazic, Toni Schaeffer, Mary Coe, Ed TI Image analysis for mapping immeasurable phenotypes in maize SO IEEE SIGNAL PROCESSING MAGAZINE LA English DT Article C1 Univ Missouri, Div Plant Sci, Columbia, MO 65201 USA. Natl Lib Med, Bethesda, MD 20894 USA. Hong Kong Polytech Univ, Dept Elect & Informat Engn, Hong Kong, Hong Kong, Peoples R China. ARS, USDA, Washington, DC 20550 USA. RP Shyu, CR (reprint author), Univ Missouri, Div Plant Sci, Columbia, MO 65201 USA. EM ShyuC@missouri.edu; jason@diglibl.cecs.missouri.edu; enpklun@polyu.edu.hk; KazicT@missouri.edu; SchaefferM@mis-souri.edu; CoeE@missouri.edu RI Magazine, Signal Processing/E-9947-2015 NR 8 TC 1 Z9 2 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1053-5888 J9 IEEE SIGNAL PROC MAG JI IEEE Signal Process. Mag. PD MAY PY 2007 VL 24 IS 3 BP 115 EP 118 DI 10.1109/MSP.2007.361609 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA 167AM UT WOS:000246422800015 ER PT J AU Bitter, I Van Uitert, R Wolf, I Ibanez, L Kuhnigk, JM AF Bitter, Ingmar Van Uitert, Robert Wolf, Ivo Ibanez, Luis Kuhnigk, Jan-Martin TI Comparison of four freely available frameworks for image processing and visualization that use ITK SO IEEE TRANSACTIONS ON VISUALIZATION AND COMPUTER GRAPHICS LA English DT Article DE visualization framework; image processing; user interface; comparison; evaluation ID MODELS AB Most image processing and visualization applications allow users to configure computation parameters and manipulate the resulting visualizations. SCIRun, VolView, MeVisLab, and the Medical Interaction Toolkit (MITK) are four image processing and visualization frameworks that were built for these purposes. All frameworks are freely available and all allow the use of the ITK C++ library. In this paper, the benefits and limitations of each visualization framework are presented to aid both application developers and users in the decision of which framework may be best to use for their application. The analysis is based on more than 50 evaluation criteria, functionalities, and example applications. We report implementation times for various steps in the creation of a reference application in each of the compared frameworks. The data-flow programming frameworks, SCIRun and MeVisLab, were determined to be best for developing application prototypes, while VolView was advantageous for nonautomatic end-user applications based on existing ITK functionalities, and MITK was preferable for automated end-user applications that might include new ITK classes specifically designed for the application. C1 Claron Technol Inc, MaRS Ctr, Toronto, ON M5G 1L7, Canada. NIH, Diagnost Radiol Dept, Bethesda, MD 20892 USA. Deutsch Krebsforschungszentrum, German Canc Res Ctr, Div Med & Biol Informat, D-69120 Heidelberg, Germany. Kitware Inc, Clifton Pk, NY 12065 USA. MeVis, D-28359 Bremen, Germany. RP Bitter, I (reprint author), Claron Technol Inc, MaRS Ctr, S Tower,101 Coll St,Suite 225, Toronto, ON M5G 1L7, Canada. EM ingmar@clarontech.com; uitertr@cc.nih.gov; wolf@dkfz-heidelberg.de; luis.ibanez@kitware.com; kuhnigk@mevis.de OI Kuhnigk, Jan-Martin/0000-0001-9255-2993 FU Intramural NIH HHS NR 28 TC 34 Z9 34 U1 0 U2 8 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1077-2626 EI 1941-0506 J9 IEEE T VIS COMPUT GR JI IEEE Trans. Vis. Comput. Graph. PD MAY-JUN PY 2007 VL 13 IS 3 BP 483 EP 493 DI 10.1109/TVCG.2007.1001 PG 11 WC Computer Science, Software Engineering SC Computer Science GA 145WA UT WOS:000244895300007 PM 17356215 ER PT J AU Du, HX Qin, H AF Du, Haixia Qin, Hong TI Free-form geometric modeling by integrating parametric and implicit PDEs SO IEEE TRANSACTIONS ON VISUALIZATION AND COMPUTER GRAPHICS LA English DT Article DE PDE techniques; geometric modeling; solid models; implicit models; free-form deformation; shape blending ID PARTIAL-DIFFERENTIAL EQUATIONS; DESIGN; SURFACES AB Parametric PDE techniques, which use partial differential equations (PDEs) defined over a 2D or 3D parametric domain to model graphical objects and processes, can unify geometric attributes and functional constraints of the models. PDEs can also model implicit shapes defined by level sets of scalar intensity fields. In this paper, we present an approach that integrates parametric and implicit trivariate PDEs to define geometric solid models containing both geometric information and intensity distribution subject to flexible boundary conditions. The integrated formulation of second-order or fourth-order elliptic PDEs permits designers to manipulate PDE objects of complex geometry and/or arbitrary topology through direct sculpting and free-form modeling. We developed a PDE-based geometric modeling system for shape design and manipulation of PDE objects. The integration of implicit PDEs with parametric geometry offers more general and arbitrary shape blending and free-form modeling for objects with intensity attributes than pure geometric models. C1 Natl Lib Med, Off High Performance Comp & Commun, NIH, Bethesda, MD 20894 USA. SUNY Stony Brook, Dept Comp Sci, Stony Brook, NY 11794 USA. RP Du, HX (reprint author), Natl Lib Med, Off High Performance Comp & Commun, NIH, 8600 Rockville Pike,Bldg 38A,Room B1N30, Bethesda, MD 20894 USA. EM haixia.du@gmail.com; qin@cs.sunysb.edu NR 25 TC 10 Z9 11 U1 0 U2 1 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1077-2626 EI 1941-0506 J9 IEEE T VIS COMPUT GR JI IEEE Trans. Vis. Comput. Graph. PD MAY-JUN PY 2007 VL 13 IS 3 BP 549 EP 561 DI 10.1109/TVCG.2007.1004 PG 13 WC Computer Science, Software Engineering SC Computer Science GA 145WA UT WOS:000244895300012 PM 17356220 ER PT J AU Woellner, C Schaffer, AA Pluck, JM Renner, ED Knebel, C Holland, SM Plebani, A Grimbacher, B AF Woellner, Cristina Schaeffer, Alejandro A. Pluck, Jennifer M. Renner, Eleonore D. Knebel, Constanze Holland, Steve M. Plebani, Alessandro Grimbacher, Bodo TI The hyper IgE syndrome and mutations in TYK2 SO IMMUNITY LA English DT Letter ID IMMUNITY C1 UCL, Royal Free Hosp, Dept Immunol & Mol Pathol, London, England. Univ Hosp Freiburg, Div Mol & Clin Rheumatol, D-79106 Freiburg, Germany. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Univ Munich, Dr Von Haunerschen Kinderspital, D-80337 Munich, Germany. Tech Univ Munich, Dept Pediat, D-80804 Munich, Germany. NIAID, NIH, Bethesda, MD 20892 USA. Univ Brescia, Pediat Clin, I-25123 Brescia, Italy. Univ Brescia, Inst Med Mol A Novicelli, I-25123 Brescia, Italy. RP Grimbacher, B (reprint author), UCL, Royal Free Hosp, Dept Immunol & Mol Pathol, London, England. EM b.grimbacher@medsch.ucl.ac.uk RI Plebani, Alessandro/C-8593-2011; Schaffer, Alejandro/F-2902-2012 FU Intramural NIH HHS NR 4 TC 33 Z9 35 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAY PY 2007 VL 26 IS 5 BP 535 EP 535 DI 10.1016/j.immuni.2007.05.007 PG 1 WC Immunology SC Immunology GA 173TR UT WOS:000246895900001 PM 17521577 ER PT J AU Ramaswamy, M Siegel, RM AF Ramaswamy, Madhu Siegel, Richard M. TI A FAScinating receptor in self-tolerance SO IMMUNITY LA English DT Editorial Material ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; APOPTOSIS; MICE; MUTATIONS AB In this issue of Immunity, Stranges et al. (2007) ablate expression of the death receptor Fas in T cells, B cells, and DC. Fas deficiency in any of these lineages is sufficient to break self-tolerance. C1 NIAMS, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMS, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 NR 10 TC 6 Z9 8 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAY PY 2007 VL 26 IS 5 BP 545 EP 547 DI 10.1016/j.immuni.2007.05.004 PG 3 WC Immunology SC Immunology GA 173TR UT WOS:000246895900005 PM 17521581 ER PT J AU Kitaura, Y Jang, IK Wang, Y Han, YC Inazu, T Cadera, EJ Schlissel, M Hardy, RR Gu, H AF Kitaura, Yasuyuki Jang, Ihn Kyung Wang, Yan Han, Yoon-Chi Inazu, Tetsuya Cadera, Emily J. Schlissel, Mark Hardy, Richard R. Gu, Hua TI Control of the B cell-intrinsic tolerance programs by ubiquitin ligases cbl and Cbl-b SO IMMUNITY LA English DT Article ID HEAT-STABLE ANTIGEN(HI); C-CBL; NEGATIVE REGULATION; SIGNAL-TRANSDUCTION; POSITIVE SELECTION; DEFICIENT MICE; IMMUNE-SYSTEM; LYMPHOCYTES-B; RECEPTOR; ACTIVATION AB B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl(-/-)Cblb(-/-)) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-gamma 2 (PLC-gamma 2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction. C1 Columbia Univ Coll Phys & Surg, Dept Microbiol, New York, NY 10032 USA. NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. RP Gu, H (reprint author), Columbia Univ Coll Phys & Surg, Dept Microbiol, 630 W 168th St, New York, NY 10032 USA. EM hg2065@columbia.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL 48702, R01 HL048702]; NIAID NIH HHS [AI 062931, R01 AI062931, R01 AI062931-01A2, R01 AI062931-02] NR 52 TC 50 Z9 55 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAY PY 2007 VL 26 IS 5 BP 567 EP 578 DI 10.1016/j.immuni.2007.03.015 PG 12 WC Immunology SC Immunology GA 173TR UT WOS:000246895900010 PM 17493844 ER PT J AU Firoved, AM Moayeri, M Wiggins, JF Shen, YQ Tang, WJ Leppla, SH AF Firoved, Aaron M. Moayeri, Mahtab Wiggins, Jason F. Shen, Yuequan Tang, Wei-Jen Leppla, Stephen H. TI Anthrax edema toxin sensitizes DBA/2J mice to lethal toxin SO INFECTION AND IMMUNITY LA English DT Article ID KINASE-KINASE; CYCLIC-AMP; SUSCEPTIBILITY; RECEPTOR; CELLS; INFECTION; CYCLASE; ALPHA AB Anthrax toxin is made up of three separate protein components: the receptor-binding protective antigen (PA), the adenylyl cyclase edema factor (EF), and the metalloproteinase lethal factor (LF). EF and PA constitute edema toxin (ET), which causes edema when injected subcutaneously. At higher doses, ET causes severe pathologies and death in BALB/cJ mice (A. M. Firoved et al., Am. J. Pathol. 167:1309-1320, 2005). A striking effect of ET at lethal doses is adrenal necrosis. Here we show that low doses of ET (10 jig) that produce no overt signs of illness in mice still cause substantial adrenal lesions. These lesions are not associated with reduced corticosterone production; instead, ET-treated mice have increased corticosterone production. Because the resistance of mice to the other component of anthrax toxin, lethal toxin (LT; LF plus PA), has been shown to be overcome by the perturbation of the endocrine system, we hypothesized that sublethal doses of ET might sensitize LT-resistant DBA/2J mice to LT-mediated lethality. We report that a low dose of ET (5 mu g) is sufficient to sensitize DBA/2J mice when given concurrently with LT. Higher doses of ET (e.g., 15 mu g) given to male and female DBA/2J mice 18 h prior to LT challenge also sensitize them to LT. This study using highly purified ET and LT demonstrates how the components of anthrax toxin can work together to increase lethality. C1 NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. RP Leppla, SH (reprint author), NIAID, Bacterial Toxins & Therapeut Sect, Lab Bacterial Dis, NIH, 30 Convent Dr Bldg 30,Room 303, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov OI Tang, Wei-Jen/0000-0002-8267-8995 FU Intramural NIH HHS; NIGMS NIH HHS [GM62548, R01 GM062548] NR 22 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2007 VL 75 IS 5 BP 2120 EP 2125 DI 10.1128/IAI.01781-06 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 165YY UT WOS:000246345000004 PM 17339348 ER PT J AU Donovan, MJ Messmore, AS Scrafford, DA Sacks, DL Kamhawi, S McDowell, MA AF Donovan, Michael J. Messmore, Andrew S. Scrafford, Deborah A. Sacks, David L. Kamhawi, Shaden McDowell, Mary Ann TI Uninfected mosquito bites confer protection against infection with malaria parasites SO INFECTION AND IMMUNITY LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; SALIVARY-GLAND EXTRACTS; IXODES-RICINUS TICKS; BORRELIA-BURGDORFERI; INTERFERON-GAMMA; IFN-GAMMA; IN-VITRO; CUTANEOUS LEISHMANIASIS; SPOROZOITE VACCINE; ARTHROPOD SALIVA AB Despite decades of research and multiple initiatives, malaria continues to be one of the world's most debilitating infectious diseases. New insights for malaria control and vaccine development will be essential to thwart the staggering worldwide impact of this disease (A. Bjorkman and A. Bhattarai, Acta Trop. 94:163-169, 2005); ultimately successful vaccine strategies will undoubtedly be multifactorial, incorporating multiple antigens and targeting diverse aspects of the malaria parasites' biology (M. F. Good et al., Immunol. Rev. 201:254-267, 2004). Using a murine model of malaria infection, we show here that exposure to bites from uninfected mosquitoes prior to Plasmodium yoelii infection influences the local and systemic immune responses and limits parasite development within the host. In hosts preexposed to bites from uninfected mosquitoes, reduced parasite burdens in the livers were detected early, and during the blood-stage of the life cycle, these burdens remained lower than those in hosts that received mosquito bites only at the time of infection. Repeated exposure to bites from uninfected mosquitoes skewed the immune response towards a T-helper 1 (Th1) phenotype as indicated by increased levels of interleukin-12, gamma interferon, and inducible nitric oxide synthase. These data suggest that the addition of mosquito salivary components to antimalaria vaccines may be a viable strategy for creating a Th1-biased environment known to be effective against malaria infection. Furthermore, this strategy may be important for the development of vaccines to combat other mosquito-transmitted pathogens. C1 Univ Notre Dame, Dept Biol Sci, Ctr Global Hlth & Infect Dis, Notre Dame, IN 46556 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP McDowell, MA (reprint author), Univ Notre Dame, Dept Biol Sci, 215 Galvin Life Sci, Notre Dame, IN 46656 USA. EM mcdowell.11@nd.edu NR 58 TC 52 Z9 56 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2007 VL 75 IS 5 BP 2523 EP 2530 DI 10.1128/IAI.01928-06 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 165YY UT WOS:000246345000051 PM 17339356 ER PT J AU Selmeczy, Z Csoka, B Pacher, P Vizi, ES Hasko, G AF Selmeczy, Z. Csoka, B. Pacher, P. Vizi, E. S. Hasko, G. TI The adenosine A(2A) receptor agonist CGS 21680 fails to ameliorate the course of dextran sulphate-induced colitis in mice SO INFLAMMATION RESEARCH LA English DT Article DE dextran sulphate; colitis; adenosine A(2A) receptor; CGS 21680 ID INFLAMMATORY-BOWEL-DISEASE; TRINITROBENZENE SULFONIC-ACID; SODIUM-INDUCED COLITIS; TNF-ALPHA; POSTTRANSCRIPTIONAL MECHANISM; REDUCES INFLAMMATION; ULCERATIVE-COLITIS; IMPROVES SURVIVAL; ENDOTOXEMIC MICE; MURINE COLITIS AB Objective: In this study we investigated the effect of CGS 21680 (2-p-(2-Carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine hydrochloride), an adenosine A(2A) receptor agonist, in a model of dextran sulphate sodium (DSS)-induced colitis. Methods: NMRI mice were fed 5% (w/v) DSS, and were treated intraperitoneally with 0.5 mg/kg CGS 21680 or vehicle for 10 days. Changes of bodyweight, colon length, the incidence of rectal bleeding, levels of macrophage inflammatory protein (MIP)-1 alpha, MIP-2, interferon gamma, interleukin (IL)-1 beta, IL-12 and tumour necrosis factor-alpha from homogenates of colon biopsies, and the release of [H-3]acetylcholine (ACh) from longitudinal muscle strip were determined. Results: DSS significantly decreased bodyweight, colon length, and it increased the incidence of rectal bleeding and levels of MIP-1 alpha, MIP-2 and IL-1 beta compared to DSS-untreated animals. CGS 21680 had no effect on these changes. No change could be observed in release of ACh in DSS-induced colitis with or without CGS 21680. Conclusion: In summary, CGS 21680 is ineffective in ameliorating DSS-induced colitis in mice. C1 Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1450 Budapest, Hungary. NIAAA, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. RP Selmeczy, Z (reprint author), Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, POB 67, H-1450 Budapest, Hungary. EM selmeczy@koki.hu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU Intramural NIH HHS [Z01 AA000375-02]; NIGMS NIH HHS [R01 GM066189-02, GM66189, R01 GM066189, R01 GM066189-01, R56 GM066189] NR 60 TC 12 Z9 12 U1 0 U2 2 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD MAY PY 2007 VL 56 IS 5 BP 204 EP 209 DI 10.1007/s00011-006-6150-7 PG 6 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 172KY UT WOS:000246804400005 PM 17588136 ER PT J AU Bornstein, MH Hahn, CS Haynes, OM Belsky, J Azuma, H Kwak, K Maital, S Painter, KM Varron, C Pascual, L Toda, S Venuti, P Vyt, A de Galperin, CZ AF Bornstein, Marc H. Hahn, Chun-Shin Haynes, O. Maurice Belsky, J. Azuma, Hiroshi Kwak, Keumjoo Maital, Sharone Painter, Kathleen M. Varron, Cheryl Pascual, Liliana Toda, Sueko Venuti, Paola Vyt, Andre Zingman de Galperin, Celia TI Maternal personality and parenting cognitions in cross-cultural perspective SO INTERNATIONAL JOURNAL OF BEHAVIORAL DEVELOPMENT LA English DT Review DE collectivism; individualism; parenting; parenting cognitions; personality ID CONFIRMATORY FACTOR-ANALYSIS; 5-FACTOR MODEL; MOTHERS PERSONALITY; TRAIT PSYCHOLOGY; ACT FREQUENCIES; SELF-EFFICACY; BIG 5; INVENTORY; BEHAVIOR; INDIVIDUALISM AB A total of 467 mothers of firstborn 20-month-old children from 7 countries (103 Argentine, 61 Belgian, 39 Israeli, 78 Italian, 57 Japanese, 69 Korean, and 60 US American) completed the jackson Personality Inventory (JPI), measures of parenting cognitions (self-perceptions and knowledge), and a social desirability scale. Our first analysis showed that the Five-Factor structure of personality (Openness, Neuroticism, Extraversion, Agreeableness, and Conscientiousness) could be extracted from the JPI scales when cross-cultural data from mothers in the 7 countries were analyzed; it was also replicable and generalizable in mothers from so-called individualist and collectivist cultures. Our second analysis showed that the five personality factors relate differently to diverse parenting cognitions in those individualist versus collectivist cultures. Maternal personality has significance in studies of normative parenting, child development, and family process across cultural contexts. C1 NICHHD, Child & Family Res, Bethesda, MD 20892 USA. Univ London, Inst Study Children Families & Social Issues, London, England. Seisen Jogakuin Coll, Tokyo, Japan. Seoul Natl Univ, Seoul, South Korea. Univ Haifa, IL-31999 Haifa, Israel. Univ Buenos Aires, Buenos Aires, DF, Argentina. Hokkaido Univ, Hokkaido, Japan. Sci & Tech Psicol Cognit Applicata, Treneto, Italy. Artevelde Inst, Ghent, Belgium. Univ Ghent, B-9000 Ghent, Belgium. Univ Belgrano, Buenos Aires, DF, Argentina. RP Bornstein, MH (reprint author), NICHHD, Child & Family Res, 6705 Rockledge Dr Suite 8030, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov OI Belsky, Jay/0000-0003-2191-2503 NR 177 TC 17 Z9 17 U1 4 U2 26 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0165-0254 J9 INT J BEHAV DEV JI Int. J. Behav. Dev. PD MAY PY 2007 VL 31 IS 3 BP 193 EP 209 DI 10.1177/0165025407074632 PG 17 WC Psychology, Developmental SC Psychology GA 177UP UT WOS:000247178300001 ER PT J AU Hsing, AW Gao, YT McGlynn, KA Niwa, S Zhang, MD Han, TQ Wang, BS Chen, JB Sakoda, LC Shen, MC Zhang, BH Deng, J Rashid, A AF Hsing, Ann W. Gao, Yu-Tang McGlynn, Katherine A. Niwa, Shelley Zhang, Mingdong Han, Tian-Quan Wang, Bing-Sheng Chen, Jinbo Sakoda, Lori C. Shen, Ming-Chang Zhang, Bai-He Deng, Jie Rashid, Asif TI Biliary tract cancer and stones in relation to chronic liver conditions: A population-based study in Shanghai, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE biliary tract cancer; family history; viral hepatitis; liver cirrhosis; family history of liver cancer; China ID B-VIRUS-INFECTION; RISK-FACTORS; HEPATITIS-B; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; GALLBLADDER; PREVALENCE; GALLSTONES; CIRRHOSIS; CHOLANGIOCARCINOMA AB Biliary tract cancers are relatively rare but fatal tumors. Apart from a close link with gallstones and cholangitis, risk factors for biliary tract cancer are obscure. Chronic liver conditions, including liver cirrhosis, have been linked to a higher risk of biliary tract cancer. In a population-based case-control study conducted in Shanghai, China, we investigated the relationships of a history of chronic hepatitis and liver cirrhosis as well as a family history of liver cancer with biliary tract cancer risk. The study included 627 patients with biliary tract cancers (368 gallbladder, 191 bile duct and 68 ampulla of Vater), 1,037 patients with biliary stones (774 gallbladder stones and 263 bile duct stones) and 959 healthy subjects randomly selected from the population. Bile duct cancer was associated with self-reports of chronic liver conditions, including a history of chronic hepatitis (OR = 2.0, 95% CI 0.9-4.4), liver cirrhosis (OR = 4.7, 95% CI 1.9-11.7) and a family history of primary liver cancer (OR = 2.0, 95% CI 1.0-3.9). The excess risk persisted after adjustment for gallstones and were more pronounced among subjects without gallstones (OR = 5.0, 95% CI 1.3-20.0 and OR = 4.9, 95% 2.0-12.2, respectively). History of liver conditions was also associated with an excess of biliary stones (OR = 1.9, 95% CI 1.2-3.0). No association was found for cancers of the gallbladder and ampulla of Vater. A history of chronic hepatitis and cirrhosis may be risk factors for extraheptic bile duct cancer. Given that chronic infection with hepatitis B virus (HBV) is the most common cause of liver disease in China, serologic markers of HBV need to be measured in future studies to examine the link between HBV and bile duct cancer. (c) 2007 Wiley-Liss, Inc. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Shanghai Canc Inst, Shanghai, Peoples R China. Hlth Studies Sector, Rockville, MD USA. Chinese Univ Hong Kong, Ctr Emerging Infect Dis, Hong Kong, Peoples R China. Raijin Hosp, Dept Surg, Shanghai, Peoples R China. Shanghai Med Univ, Zhongshan Hosp, Dept Surg, Shanghai 200032, Peoples R China. Sch Med, Dept Epidemiol & Biostat, Philadelphia, PA USA. Shanghai Tumor Hosp, Dept Pathol, Shanghai, Peoples R China. Second Mil Hosp, Dept Surg, Shanghai, Peoples R China. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Hsing, AW (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, EPS 5024,MSC 7234,6120 Execut Blvd, Rockville, MD 20852 USA. EM hsinga@mail.nih.gov NR 47 TC 19 Z9 20 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2007 VL 120 IS 9 BP 1981 EP 1985 DI 10.1002/ijc.22375 PG 5 WC Oncology SC Oncology GA 146ZA UT WOS:000244972000021 PM 17278101 ER PT J AU Trimble, EL Davis, J Disaia, P Fujiwara, K Gaffney, D Kristensen, G Ledermann, J Pfisterer, J Quinn, M Reed, N Schoenfeldt, M Thigpen, JT AF Trimble, E. L. Davis, J. Disaia, P. Fujiwara, K. Gaffney, D. Kristensen, G. Ledermann, J. Pfisterer, J. Quinn, M. Reed, N. Schoenfeldt, M. Thigpen, J. T. CA Gynecologic Canc Intergrp TI Clinical trials in gynecological cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Review DE gynecologic cancer; ovarian cancer; cervical cancer; endometrial cancer; clinical trials; GCIG ID PHASE-III TRIAL; ADVANCED CERVICAL-CANCER; HUMAN-PAPILLOMAVIRUS TYPE-16; PELVIC RADIATION-THERAPY; EARLY OVARIAN-CANCER; ONCOLOGY-GROUP; RANDOMIZED-TRIAL; UNITED-STATES; INTRAPERITONEAL CISPLATIN; NEOADJUVANT CHEMOTHERAPY AB The Gynecologic Cancer Intergroup is comprised representatives from international gynecological cancer trials organizations, which collaborate in multicenter studies to answer the clinical challenges in gynecological cancer. This review article highlights the key clinical questions facing clinical trialists over the next decade, the information and infrastructure resources available for trials, and the methods of trial development. We cover human papillomavirus (HPV)-associated neoplasia, including cervical cancer, together with endometrial cancer, ovarian cancer, and vulvar cancer. Infrastructure for clinical trials includes a database for trials, templates for protocol development, patient educational material, and financial support for clinical trials. Other critical issues include support from government and charities and government regulations. C1 NCI, Cancer Therapy Evaluat Program, Bethesda, MD 20892 USA. N Glasgow Univ Hosp NHS Trust, Glasgow, Lanark, Scotland. Univ Calif Irvine, Med Ctr, Irvine, CA 92717 USA. Saitama Med Univ, Urawa, Saitama, Japan. Univ Utah, Huntsman Canc Hosp, Salt Lake City, UT 84112 USA. Norwegian Radium Hosp, Oslo, Norway. Canc Res UK, London, England. UCL Canc Trials Ctr, London, England. Univ Klinikum Schleswig Holstein, Lubeck, Germany. Univ Melbourne, Parkville, Vic 3052, Australia. Beatson Oncol Ctr, Glasgow, Lanark, Scotland. EMMES Corp, Rockville, MD USA. Univ Mississippi, Sch Med, University, MS 38677 USA. RP Trimble, EL (reprint author), NCI, Cancer Therapy Evaluat Program, Room 741,MSC 7436,6130 Execut Blvd, Bethesda, MD 20892 USA. EM trimblet@ctep.nci.nih.gov OI Quinn, Michael/0000-0003-0694-3870 NR 47 TC 7 Z9 7 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAY-JUN PY 2007 VL 17 IS 3 BP 547 EP 556 DI 10.1111/j.1525-1438.2007.00667.x PG 10 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 167CX UT WOS:000246429600001 PM 17504371 ER PT J AU McClure, EM Goldenberg, RL Brandes, N Darmstadt, GL Wright, LL AF McClure, E. M. Goldenberg, R. L. Brandes, N. Darmstadt, G. L. Wright, L. L. CA CHX Working Grp TI The use of chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource settings SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Review DE chlorhexidine; maternal mortality; neonatal mortality; sepsis; oomphilitis ID CLINICAL-TRIAL; BACTERIAL-COLONIZATION; PERIPARTAL INFECTION; DEVELOPING-COUNTRIES; VAGINAL IRRIGATION; UMBILICAL-CORD; OUTCOMES; INTERVENTIONS; DISINFECTION; PREVENTION AB Of the 4 million neonatal deaths and 500,000 maternal deaths that occur annually worldwide, almost 99% are in developing countries and one-third are associated with infections. Implementation of proven interventions and targeted research on a select number of promising high-impact preventative and curative interventions are essential to achieve Millennium Development Goats for reduction of child and maternal mortality. Feasible, simple, low-cost interventions have the potential to significantly reduce the mortality and severe morbidity associated with infection in these settings. Studies of chlorhexidine in developing countries have focused on three primary uses: 1) intrapartum vaginal and neonatal wiping, 2) neonatal wiping alone, and 3) umbilical cord cleansing. A study of vaginal wiping and neonatal skin cleansing with chlorhexidine, conducted in Malawi in the 1990s suggested that chlorhexidine has potential to reduce neonatal infectious morbidity and mortality. A recent trial of cord cleansing conducted in Nepal also demonstrated benefit. Although studies have shown promise, widespread acceptance and implementation of chlorhexidine use has not yet occurred. This paper is derived in part from data presented at a conference on the use of chlorhexidine in developing countries and reviews the available evidence related to chlorhexidine use to reduce mortality and severe morbidity due to infections in mothers and neonates in low-resource settings. It also summarizes issues related to programmatic implementation. (C) 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 Res Triangle Inst, Dept State & Epidemiol, Res Triangle Pk, NC 27709 USA. Drexel Univ, Coll Med, Dept Obstet Gynecol, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Bloomberg Sch Pybl Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. NICHD, NIH, Washington, DC USA. RP McClure, EM (reprint author), Res Triangle Inst, Dept State & Epidemiol, 3400 Cornwallis Rd, Res Triangle Pk, NC 27709 USA. EM mcclure@rti.org RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Tielsch, James/0000-0002-1151-060X FU NICHD NIH HHS [U01 HD040636, U01 HD040636-06] NR 39 TC 32 Z9 34 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD MAY PY 2007 VL 97 IS 2 BP 89 EP 94 DI 10.1016/j.ijgo.2007.01.014 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 170EL UT WOS:000246645000009 PM 17399714 ER PT J AU Potischman, N Berrigan, D Ballard-Barbash, R AF Potischman, Nancy Berrigan, David Ballard-Barbash, Rachel TI Ethnic and anthropometric correlates of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in the United States SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 15th European Congress on Obesity CY APR 22-25, 2007 CL Budapest, HUNGARY C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2007 VL 31 SU 1 BP S207 EP S207 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 158YW UT WOS:000245832700815 ER PT J AU Tybitanclova, K Zorad, S Dou, JT Benicky, J Daniel, H Zhou, J Saavedra, JM AF Tybitanclova, Katarina Zorad, Stefan Dou, Jing-Tao Benicky, Julius Daniel, Hutanu Zhou, Jin Saavedra, Juan M. TI Anti-inflammatory effect of AT1 blockade in adipose tissue SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 15th European Congress on Obesity CY APR 22-25, 2007 CL Budapest, HUNGARY C1 NIMH, Inst Expt Endocrinol SAS, Bethesda, MD 20892 USA. NIMH, Pharmacol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2007 VL 31 SU 1 BP S90 EP S90 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 158YW UT WOS:000245832700353 ER PT J AU Tennstedt, SL Fitzgerald, MP Nager, CW Xu, Y Zimmern, P Kraus, S Goode, PS Kusek, JW Borello-France, D Mallett, V AF Tennstedt, Sharon L. Fitzgerald, Mary Pat Nager, Charles W. Xu, Yan Zimmern, Philippe Kraus, Stephen Goode, Patricia S. Kusek, John W. Borello-France, Diane Mallett, Veronica CA Urinary Incontinence Treatment TI Quality of life in women with stress urinary incontinence SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE quality of life; urinary incontinence ID UROGENITAL DISTRESS INVENTORY; PELVIC ORGAN PROLAPSE; IMPACT QUESTIONNAIRE; DYSFUNCTION; PREVALENCE; INSTRUMENT; WHITE; URGE AB The objective of this study was to identify clinical and demographic factors associated with incontinence-related quality of life (QoL) in 655 women with stress urinary incontinence who elected surgical treatment. The following factors were examined for their association with QoL as measured with the Incontinence Impact Questionnaire (IIQ): number of incontinence (UI) episodes/day; self-reported type of UI symptoms (stress and urge); sexual function as measured by the Prolapse/Urinary Incontinence Sexual Questionnaire; symptom bother as measured by the Urogenital Distress Inventory; as well as other clinical and sociodemographic factors. A stepwise least-squares regression analysis was used to identify factors significantly associated with QoL. Lower QoL was related to the greater frequency of stress UI symptoms, increasing severity, greater symptom bother, prior UI surgery or treatment, and sexual dysfunction (if sexually active). Health and sociodemographic factors associated with lower incontinence-related QoL included current tobacco use, younger age, lower socioeconomic status, and Hispanic ethnicity. C1 New England Res Inst, Watertown, MA 02472 USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Univ Calif San Diego, Med Ctr, San Diego, CA 92103 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Birmingham VA Med Ctr, Birmingham, AL USA. Univ Alabama, Birmingham, AL USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Duquesne Univ, Pittsburgh, PA 15219 USA. Univ Tennessee, Knoxville, TN USA. RP Tennstedt, SL (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM stennstedt@neriscience.com FU NIDDK NIH HHS [U01 DK, U01 DK 58225, U01 DK 58229, U01 DK 58231, U01 DK 58234, U01 DK 60379, U01 DK 60380, U01 DK 60393, U01 DK 60395, U01 DK 60397, U01 DK 60401] NR 22 TC 38 Z9 40 U1 2 U2 5 PU SPRINGER LONDON LTD PI ARTINGTON PA ASHBOURNE HOUSE, THE GUILDWAY, OLD PORTSMOUTH ROAD, ARTINGTON GU3 1LP, GUILDFORD, ENGLAND SN 0937-3462 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD MAY PY 2007 VL 18 IS 5 BP 543 EP 549 DI 10.1007/s00192-006-0188-5 PG 7 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA 153TK UT WOS:000245457900011 PM 17036169 ER PT J AU Lee, SS Kim, H Wang, NS Bungay, PM Gilger, BC Yuan, P Kim, J Csaky, KG Robinson, MR AF Lee, Susan S. Kim, Hyuncheol Wang, Nam Sun Bungay, Peter M. Gilger, Brian C. Yuan, Peng Kim, Jonghyeon Csaky, Karl G. Robinson, Michael R. TI A pharmacokinetic and safety evaluation of an episcleral cyclosporine implant for potential use in high-risk keratoplasty rejection SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CORNEAL ALLOGRAFT-REJECTION; GRAFT-REJECTION; RABBIT EYE; DRUG-DELIVERY; LYMPH-NODES; EFFICACY; MECHANISMS; SCLERA; MICROSPHERES; PROLONGATION AB PURPOSE. To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. METHODS. CsA episcleral implants were made with a high (implant A) or low (implant 13) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than I year. An ocular toxicity study was performed in dogs older than 1 year. RESULTS. A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 mu g/mg at sites centered 8, 13, and 18 m away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 mu g/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. CONCLUSIONS. Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours. C1 NEI, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. N Carolina State Univ, Coll Vet Med, Raleigh, NC 27695 USA. Emmes Corp, Rockville, MD USA. RP Lee, SS (reprint author), NEI, NIH, Bldg 10,Room,10N436,10 Ctr Dr, Bethesda, MD 20892 USA. EM susan.sh.lee@gmail.com RI Wang, Nam Sun/E-4253-2016 FU Intramural NIH HHS NR 55 TC 14 Z9 16 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2007 VL 48 IS 5 BP 2023 EP 2029 DI 10.1167/iovs.06-0985 PG 7 WC Ophthalmology SC Ophthalmology GA 162DU UT WOS:000246067800018 PM 17460256 ER PT J AU Zhu, ZZ Wang, AZ Jia, HR Jin, XX He, XL Hou, LF Zhu, GS AF Zhu, Zhong-Zheng Wang, Ai-Zhong Jia, Hang-Ruo Jin, Xia-Xiang He, Xiang-Lei Hou, Li-Fang Zhu, Guanshan TI Association of the TP53 codon 72 polymorphism with colorectal cancer in a Chinese population SO JAPANESE JOURNAL OF CLINICAL ONCOLOGY LA English DT Article DE TP53; colorectal cancer; single nucleotide polymorphism ID SQUAMOUS-CELL CARCINOMAS; P53 CODON-72; HUMAN-PAPILLOMAVIRUS; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; PROGNOSTIC-SIGNIFICANCE; GENETIC POLYMORPHISMS; ARGININE ALLELE; INCREASED RISK; COLON-CANCER AB A TP53 gene polymorphism, resulting in an arginine (R) to proline (P) at codon 72 (TP53 R72P), has been associated with the susceptibility to various cancers. To better understand the role of this polymorphism in colorectal cancer etiology, we examined the association between TP53 R72P and colorectal cancer risk in 345 patients with colorectal cancer and 670 controls in a Chinese population. We observed that subjects with RP and PP genotypes had a 1.60-fold and a 2.37-fold increased risk for colorectal cancer, respectively. The 72P allele conferred a more pronounced increase in colorectal cancer risk among alcohol consumers (heterozygotes: OR = 3.01; homozygotes: OR = 4.71). The TP53 R72P polymorphism was not linked to tumor location, histologic grade, lymph node metastases, Dukes stage, p53 positivity, or age at diagnosis, but to tumor size. We conclude that the TP53 R72P polymorphism may contribute to the etiology of colorectal cancer in the Chinese population, particularly among alcohol consumers. C1 Hosp Peoples Liberat Army 113, Dept Pathol, Ningbo 315040, Zhejiang, Peoples R China. Lihuili Hosp, Dept Pathol, Ningbo, Peoples R China. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Shanghai GeneCore Biotechnol Co Ltd, Shanghai, Peoples R China. RP Zhu, ZZ (reprint author), Hosp Peoples Liberat Army 113, Dept Pathol, 377 E Zhongshan Rd, Ningbo 315040, Zhejiang, Peoples R China. EM zzzhu1170@yahoo.com NR 40 TC 42 Z9 47 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0368-2811 J9 JPN J CLIN ONCOL JI Jpn. J. Clin. Oncol. PD MAY PY 2007 VL 37 IS 5 BP 385 EP 390 DI 10.1093/jjco/hym034 PG 6 WC Oncology SC Oncology GA 199HZ UT WOS:000248688100010 PM 17599946 ER PT J AU Gao, L Grant, AV Rafaels, N Stockton-Porter, M Watkins, T Gao, PS Chi, P Munoz, M Watson, H Dunston, G Togias, A Hansel, N Sevransky, J Maloney, JP Moss, M Shanholtz, C Brower, R Garcia, JGN Grigoryev, DN Cheadle, C Beaty, TH Mathias, RA Barnes, KC AF Gao, Li Grant, Audrey V. Rafaels, Nicholas Stockton-Porter, Maria Watkins, Tonya Gao, Peisong Chi, Peter Munoz, Melba Watson, Harold Dunston, Georgia Togias, Alkis Hansel, Nadia Sevransky, Jonathan Maloney, James P. Moss, Marc Shanholtz, Carl Brower, Roy Garcia, Joe G. N. Grigoryev, Dmitry N. Cheadle, Christopher Beaty, Terri H. Mathias, Rasika A. Barnes, Kathleen C. TI Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE SNPs; haplotype; MYLK/MLCK; asthma; total IgE; sepsis; ALI ID SMOOTH-MUSCLE MYOSIN; BARRIER DYSFUNCTION; LUNG INJURY; PROTEIN; MLCK; PHOSPHORYLATION; EXPRESSION; MIGRATION; DISEASE; SUSCEPTIBILITY AB Background: Myosin light chain kinase (MYLK) is a multifunctional protein involved in regulation of airway hyperreactivity and other activities relevant to asthma. Objective: To determine the role of MYLK gene variants in asthma among African Caribbean and African American populations. Methods: We performed association tests between single nucleotide polymorphisms (SNPs) in the MYLK gene and asthma susceptibility and total serum IgE concentrations in 2 independent, family-based populations of African descent. Previously we identified variants/haplotypes in MYLK that confer risk for sepsis and acute lung injury; we compared findings from our asthma populations to findings in the African American sepsis and acute lung injury groups. Results: Significant associations between MYLK SNPs and asthma and total serum IgE concentrations were observed in the African Caribbean families: a promoter SNP (rs936170) in the smooth muscle form gave the strongest association (P = .009). A haplotype including rs936170 corresponding to the actin-binding activity of the nonmuscle and smooth muscle forms was negatively associated with asthma (eg, decreased risk) in both the American (P = .005) and Caribbean families (P = .004), and was the same haplotype that conferred risk for severe sepsis (P = .002). RNA expression studies on PBMCs and rs936170 suggested a significant decrease in MYLK expression among patients with asthma with this variant (P = .025). Conclusion: MYLK polymorphisms may function as a common genetic factor in clinically distinct diseases involving bronchial smooth muscle contraction and inflammation. Clinical implications: Genetic variants in MYLK are significantly associated with both asthma and sepsis in populations of African ancestry. C1 Johns Hopkins Univ, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21218 USA. Howard Univ, Natl Genome Ctr, Washington, DC 20059 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Colorado, Hlth Sci Ctr, Boulder, CO 80309 USA. Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Barnes, KC (reprint author), Johns Hopkins Asthma & Allergy Ctr, 5501 Hopkins Bayview Circle,Room 3A-62, Baltimore, MD 21224 USA. EM kbarnes@jhmi.edu RI Garcia, Joe/E-8862-2010; maloney, james/K-9428-2015; Grigoryev, Dmitry/C-9422-2015; OI maloney, james/0000-0001-8348-4650; Grigoryev, Dmitry/0000-0002-1849-1763; Shanholtz, Carl/0000-0003-3938-178X FU Intramural NIH HHS; NHLBI NIH HHS [HL 73994, U01 HL66615, U01 HL72455]; NIAID NIH HHS [HL/AI-49612, AI50024-03] NR 52 TC 28 Z9 28 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2007 VL 119 IS 5 BP 1111 EP 1118 DI 10.1016/j.jaci.2007.03.019 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 167CB UT WOS:000246427200010 PM 17472811 ER PT J AU Freeman, AF Kleiner, DE Nadiminti, H Davis, J Quezado, M Anderson, V Puck, JM Holland, SM AF Freeman, Alexandra F. Kleiner, David E. Nadiminti, Hari Davis, Joie Quezado, Martha Anderson, Victoria Puck, Jennifer M. Holland, Steven M. TI Causes of death in hyper-IgE syndrome SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Aspergillus; hyper-IgE syndrome; immunodeficiency; pneumonia; Pseudomonas ID HYPERIMMUNOGLOBULIN-E SYNDROME; AMPHOTERICIN B; JOBS-SYNDROME; NEPHROTOXICITY; INFECTIONS AB Background: Hyper-IgE syndrome (HIES) is characterized by recurrent pyogenic infections, eczema, increased serum IgE levels, and a variety of connective tissue and skeletal system abnormalities. Little has been published regarding the causes of death in these patients or pathologic findings. Objective: To identify the cause of death in patients with HIES and to describe pathologic findings in fatal HIES. Methods: We reviewed the medical records and autopsy slides of 6 patients with HIES with autopsies performed at our institution. Results: All 6 patients with HIES were women and ranged in age from 24 to 40 years. All patients had a history of cystic lung disease and had pneumonia at the time of death, with Pseudomonas aeruginosa and fungal organisms predominating. Pulmonary fungal vascular invasion with fatal hemorrhage was observed in 3 patients, and metastatic fungal disease to the brain was observed in 2 patients caused by Aspergillus fumigatus and Scedosporium prolificans. Four patients had evidence of renal tubular injury, which was likely from amphotericin B toxicity; 3 patients had glomerulosclerosis; and I patient had 2 kidney angiomyolipomas. Conclusions: Our series highlights the important role Pseudomonas and Aspergillus species play in patients with HIES with cystic lung disease. Intensified antifungal and gram-negative bacterial prophylaxis need evaluation as possible strategies to prevent these infectious complications in patients with cystic lung disease. Clinical implications: Fungal and Pseudomonas infection of cystic lung disease in HIES may be life threatening, and the proper management and prevention of these infections need continued investigation. C1 NIAID, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Holland, SM (reprint author), NIAID, Bldg 10,CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS NR 13 TC 78 Z9 83 U1 2 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2007 VL 119 IS 5 BP 1234 EP 1240 DI 10.1016/j.jaci.2006.12.666 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 167CB UT WOS:000246427200027 PM 17335882 ER PT J AU Choi, PS Dawson, AJ Bernstein, HD AF Choi, Peter S. Dawson, Ashley J. Bernstein, Harris D. TI Characterization of a novel two-partner secretion system in Escherichia coli O157 : H7 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SERRATIA-MARCESCENS HEMOLYSIN; PERTUSSIS FILAMENTOUS HEMAGGLUTININ; INFLUENZAE HMW1 ADHESIN; BORDETELLA-PERTUSSIS; OUTER-MEMBRANE; GENOME SEQUENCE; PROTEIN; IDENTIFICATION; ACTIVATION; GENES AB Gram-negative bacteria contain multiple secretion pathways that facilitate the translocation of proteins across the outer membrane. The two-partner secretion (TPS) system is composed of two essential components, a secreted exoprotein and a pore-forming beta barrel protein that is thought to transport the exoprotein across the outer membrane. A putative TPS system was previously described in the annotation of the genome of Escherichia coli O157:H7 strain EDL933. We found that the two components of this system, which we designate OtpA and OtpB, are not predicted to belong to either of the two major subtypes of TPS systems (hemolysins and adhesins) based on their sequences. Nevertheless, we obtained direct evidence that OtpA and OtpB constitute a bona fide TPS system. We found that secretion of OtpA into the extracellular environment in E. coli O157:H7 requires OtpB and that when OtpA was produced in an E. coli K-12 strain, its secretion was strictly dependent on the production of OtpB. Furthermore, using OtpA/OtpB as a model system, we show that protein secretion via the TPS pathway is extremely rapid. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bldg 5,Room 201,5 Mem Dr, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU Intramural NIH HHS NR 48 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2007 VL 189 IS 9 BP 3452 EP 3461 DI 10.1128/JB.01751-06 PG 10 WC Microbiology SC Microbiology GA 161PS UT WOS:000246028400013 PM 17322314 ER PT J AU Chenoweth, MR Trun, N Wickner, S AF Chenoweth, Matthew R. Trun, Nancy Wickner, Sue TI In vivo modulation of a DnaJ homolog, CbpA, by CbpM SO JOURNAL OF BACTERIOLOGY LA English DT Article ID P-BAD PROMOTER; ESCHERICHIA-COLI; THERMUS-THERMOPHILUS; MOLECULAR CHAPERONE; EXPRESSION; SYSTEM; MACHINERY; PROTEINS; ANALOG AB CbpA, an Escherichia coli DnaJ homolog, can function as a cochaperone for the DnaK/Hsp70 chaperone system, and its in vitro activity can be modulated by CbpM. We discovered that CbpM specifically inhibits the in vivo activity of CbpA, preventing it from functioning in cell growth and division. Furthermore, we have shown that CbpM interacts with CbpA in vivo during stationary phase, suggesting that the inhibition of activity is a result of the interaction. These results reveal that the activity of the E. coli DnaK system can be regulated in vivo by a specific inhibitor. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Duquesne Univ, Dept Biol Sci, Pittsburgh, PA 15282 USA. RP Wickner, S (reprint author), 37 Convent Dr,Rm 5144, Bethesda, MD 20892 USA. EM WicknerS@mail.nih.gov FU Intramural NIH HHS NR 18 TC 12 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2007 VL 189 IS 9 BP 3635 EP 3638 DI 10.1128/JB.01757-06 PG 4 WC Microbiology SC Microbiology GA 161PS UT WOS:000246028400032 PM 17337578 ER PT J AU Muller, P van Bakel, H van de Sluis, B Holstege, F Wijmenga, C Klomp, LWJ AF Muller, Patricia van Bakel, Harm van de Sluis, Bart Holstege, Frank Wijmenga, Cisca Klomp, Leo W. J. TI Gene expression profiling of liver cells after copper overload in vivo and in vitro reveals new copper-regulated genes SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE copper; liver; microarray; gene expression; HepG2 ID INTESTINAL CACO-2 CELLS; OXIDATIVE STRESS; SACCHAROMYCES-CEREVISIAE; IRON-METABOLISM; KAPPA-B; PROTEIN; MURR1; IDENTIFICATION; ANTIOXIDANTS; MACROPHAGES AB Copper toxicity in the liver is mediated by free-radical generation, resulting in oxidative stress. To prevent toxic accumulation of copper, liver cells adapt to high copper levels. Here, we used microarray analysis to compare the adaptive responses on global gene expression in liver cells exposed to high copper levels in vitro and in vivo. In HepG2 cells we identified two clusters of upregulated genes over time, an "early" cluster that comprised metallothionein genes and a "late" cluster, highly enriched in genes involved in proteasomal degradation and in oxidative stress response. Concomitant with the "late" cluster, we detected a significant downregulation of several copper metabolism MURR1 domain (COMMD) genes that were recently implicated in copper metabolism and inhibition of nuclear transcription factor kappa B (NF-kappa B) signaling. As metal-induced oxidative stress increases NF-kappa B activity, our data suggest a role for reduced COMMD protein levels in prolonged activation of NF-kappa B, thus inducing cell survival. Mice exposed to a copper diet that highly exceeded normal daily intake accumulated only twofold more hepatic copper than control mice. Although a moderate, but significant upregulation of a set of 22 genes involved in immunity, iron and cholesterol metabolism was detected, these cannot account for direct mechanisms involved in copper excretion. In conclusion, we identified a novel set of genes that represent a delayed response to copper overload, thus providing insight into the adaptive transcriptional response to copper-induced oxidative stress. C1 Univ Utrecht, Med Ctr, Lab Metabol & Endocrine Dis, Utrecht, Netherlands. Univ Utrecht, Med Ctr, DBG Dept Med Genet, Complex Genet Sect, Utrecht, Netherlands. Univ Utrecht, Med Ctr, Genom Lab, Utrecht, Netherlands. NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. Wilhelmina Childrens Hosp, Lab Metab & Endocrine Dis, NL-3584 EA Utrecht, Netherlands. RP Klomp, LWJ (reprint author), Univ Utrecht, Med Ctr, Lab Metabol & Endocrine Dis, Utrecht, Netherlands. EM l.klomp@umcutrecht.nl RI Wijmenga, Cisca/D-2173-2009; OI van Bakel, Harm/0000-0002-1376-6916; Wijmenga, Cisca/0000-0002-5635-1614 NR 41 TC 48 Z9 48 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-8257 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD MAY PY 2007 VL 12 IS 4 BP 495 EP 507 DI 10.1007/s00775-006-0201-y PG 13 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 163SM UT WOS:000246183500006 PM 17211630 ER PT J AU Hama, Y Koyama, Y Choyke, PL Kobayashi, H AF Hama, Yukihiro Koyama, Yoshinori Choyke, Peter L. Kobayashi, Hisataka TI Two-color in vivo dynamic contrast-enhanced pharmacokinetic imaging SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE pharmacokinetics; near infrared (NIR); fluorescence imaging; in vivo dynamic imaging; two-color imaging ID HUMAN SERUM-ALBUMIN; AVIDIN CHASE; AGENTS; LIVER; CLEARANCE; RECEPTOR; TUMOR; MRI AB Optical imaging is unique among in vivo imaging methods because it is possible to simultaneously resolve two or more probes emitting at different wavelengths of light. We employed two near-infrared (NIR) fluorescent optical probes each labeled with a different, protein, to simultaneously evaluate the pharmacokinetics of each probe. Dynamic optical imaging was performed in live mice after the coinjection of bovine serum albumin (BSA) and galactosamine-conjugated bovine serum albumin (GmSA) labeled with either Cy5.5 or Cy7 NIR dyes. The pharmacokinetics of BSA and GmSA were independently and simultaneously visualized. Next, two-color dynamic imaging of biotinylated BSA (b-BSA) and BSA labeled with Cy5.5 or Cy7 was performed before and after an avidin "chase." Following avidin injection, fluorescently labeled b-BSA rapidly accumulated in the liver, while minimal liver uptake of BSA was noted. Thus, multicolor dynamic contrast-enhanced optical imaging can be performed to noninvasively track the pharmacokinetics of different proteins. This imaging technique can be applied to a wide variety of optically labeled proteins in order to simultaneously track their biodistribution. (C) 2007 Society of Photo-Optical Instrumentation Engineers. C1 NCI, NIH, Mol Imaging Program, Canc Res Ctr, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, NIH, Mol Imaging Program, Canc Res Ctr, Bldg 10,Rm 1840,MSC1088-10 Ctr Dr, Bethesda, MD 20892 USA. EM Kobayash@mai1.nih.gov FU Intramural NIH HHS NR 20 TC 9 Z9 9 U1 0 U2 8 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAY-JUN PY 2007 VL 12 IS 3 AR 034016 DI 10.1117/1.2745306 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 196TG UT WOS:000248504500020 PM 17614724 ER PT J AU Traicoff, JL Chung, JY Braunschweig, T Mazo, I Shu, YM Ramesh, A D'Amico, MW Galperin, MM Knezevic, V Hewitt, SM AF Traicoff, June L. Chung, Joon-Yong Braunschweig, Till Mazo, Ilya Shu, Youmin Ramesh, Arun D'Amico, Mark W. Galperin, Mikhail M. Knezevic, Vladimir Hewitt, Stephen M. TI Expression of EIF3-p48/INT6, TID1 and Patched in cancer, a profiling of multiple tumor types and correlation of expression SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article DE INT6; layered expression scanning; MLWestern; multiplex tissue immunoblotting; Patched; TID1 ID FISSION YEAST INT6; RET FINGER PROTEIN; COP9 SIGNALOSOME; MALIGNANT-TRANSFORMATION; CELLULAR-TRANSFORMATION; NUCLEAR-BODIES; TAX; HOMOLOG; GENE; P53 AB Alterations in eIF3-p48/INT6 gene expression have been implicated in murine and human mammary carcinogenesis. We examined levels of INT6 protein in human tumors and determined that breast and colon tumors clustered into distinct groups based on levels of INT6 expression and clinicopathological variables. We performed multiplex tissue immunoblotting of breast, colon, lung, and ovarian tumor tissues and found that INT6 protein levels positively correlated with those of TID1, Patched, p53, c-Jun, and phosphorylated-c-Jun proteins in a tissue-specific manner. INT6 and TID1 showed significant positive correlation in all tissue types tested. These findings were confirmed by immunohistochemical staining of INT6 and TID1. Further evidence supporting a cooperative role for INT6 and TID1 is the presence of endogenous INT6 and TID1 proteins as complexes. We detected co-immunoprecipitation between INT6 and TID1, as well as between INT6 and Patched. These findings suggest potential integrated roles for INT6, TID1, and Patched proteins in cell growth, development, and tumorigenesis. Additionally, these data suggest that the combination of INT6, TID1, and Patched protein levels may be useful biomarkers for the development of diagnostic assays. C1 20 20 GeneSystems Inc, Rockville, MD 20850 USA. NCI, Tissue Array Res Program, Pathol Lab, Bethesda, MD 20892 USA. Ariadne Genom Inc, Rockville, MD 20850 USA. GeneHarbor Inc, Rockville, MD 20850 USA. Inje Univ, Coll Med, PharmacoGenom Res Ctr, Pusan 614735, South Korea. Inje Univ, Coll Med, Mol Cell Physiol Res Grp, Pusan 614735, South Korea. RP Traicoff, JL (reprint author), Sci Applicat Int Corp, 1053 Patchel St,Room 101, Ft Detrick, MD 21702 USA. EM june.l.traicoff@saic.com RI Mazo, Ilya/G-6549-2014; OI Mazo, Ilya/0000-0002-8587-4895; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 NR 55 TC 15 Z9 16 U1 0 U2 0 PU NATL SCIENCE COUNCIL, TAIPEI PI TAIPEI PA 106 HO-PING E RD, SEC 2, TAIPEI 10622, TAIWAN SN 1021-7770 J9 J BIOMED SCI JI J. Biomed. Sci. PD MAY PY 2007 VL 14 IS 3 BP 395 EP 405 DI 10.1007/s11373-007-9149-3 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 180SQ UT WOS:000247386500009 PM 17385060 ER PT J AU Arena, R Shizukuda, Y Bolan, CD Tripodi, DJ Yau, YY Smith, KP Waclawiw, MA Leitman, SF Rosing, DR AF Arena, Ross Shizukuda, Yukitaka Bolan, Charles D. Tripodi, Dorothy J. Yau, Yu-Ying Smith, Kevin P. Waclawiw, Myron A. Leitman, Susan F. Rosing, Douglas R. TI Heart rate recovery is lower following supine exercise in asymptomatic hereditary hemochromatosis subjects compared with healthy controls SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Article DE arterial stiffness; baroreceptor; exercise test ID CORONARY-ARTERY-DISEASE; STRESS ECHOCARDIOGRAPHY; ENDOTHELIAL FUNCTION; MORTALITY AB INTRODUCTION: Heart rate recovery (HRR) has become an important diagnostic and prognostic marker in recent years. Subjects with hereditary hemochromatosis (HH) demonstrate arterial wall changes that reduce compliance. Arterial compliance may influence HRR by altering baroreceptor discharge. The purpose of the present study is to examine differences in HRR between subjects with HH and healthy controls during treadmill (TM) and supine lower extremity ergometry (SLEE) exercise testing. METHODS: Forty subjects with asymptomatic HH (27 men/13 women; mean age: 49.7 +/- 9.9 years) and 21 healthy controls (14 men/7 women; mean age: 47.8 +/- 8.4 years) participated in this study. Each subject underwent a symptom-limited 25-W Supine Lower Extremity Ergometry (SLEE) and Bruce TM exercise test within 1 week of each other. Heart rate recovery was the value obtained at 1 minute postexercise. Peak heart rate, systolic blood pressure, and the double product were also obtained during each exercise test. RESULTS: Peak heart rate was significantly higher, whereas HRR and peak systolic blood pressure were significantly lower during TM compared with SLEE exercise testing in both groups (P < .01). A significantly lower HRR during SLEE in subjects with HH was the only significant difference between groups (35.4 +/- 9.0 vs. 29.2 +/- 8.5, P < .01). DISCUSSION: Heart rate recovery was not significantly different between HH and control subjects during upright exercise. However, HRR was significantly lower during SLEE in HH subjects compared with controls. A higher venous return during SLEE may have allowed for differences in arterial compliance between groups to influence HRR. C1 Virginia Commonwealth Univ, Dept Phys Therapy, Richmond, VA 23298 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Arena, R (reprint author), Virginia Commonwealth Univ, Dept Phys Therapy, Box 980224,Hlth Sci Campus, Richmond, VA 23298 USA. EM raarena@vcu.edu RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 NR 15 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-7501 J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD MAY-JUN PY 2007 VL 27 IS 3 BP 157 EP 160 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 175BU UT WOS:000246988100008 PM 17558198 ER PT J AU Kellman, P Arai, AE AF Kellman, Peter Arai, Andrew E. TI Imaging sequences for first pass perfusion - A review SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE myocardial perfusion; cardiovascular MR; ischemia; parallel imaging ID MYOCARDIAL 1ST-PASS PERFUSION; CARDIOVASCULAR MAGNETIC-RESONANCE; CORONARY-ARTERY-DISEASE; STATE FREE PRECESSION; SNAPSHOT-FLASH MRI; GRADIENT-ECHO; CARDIAC PERFUSION; GADOLINIUM-DTPA; PULSE SEQUENCE; INPUT FUNCTION AB Myocardial perfusion imaging sequences and analysis techniques continue to improve. We review the state-of-the-art in cardiovascular magnetic resonance first pass perfusion pulse sequences including the application of parallel imaging. There are a wide range of sequence designs and parameters to consider when optimizing an acquisition protocol. The interdependence of these parameters forces the user to make compromises. We describe the technical issues and provide insights into the various performance tradeoffs. We also review the basic design for T1-weighted first pass myocardial perfusion imaging and go on to discuss the tradeoffs associated with various schemes to provide multi-slice coverage. Artifact mechanisms are discussed and related to sequence design and parameters. The selection of quantitative versus qualitative analysis affects various performance requirements, such as spatial and temporal resolution and linearity of enhancement. Understanding the interaction between the pulse sequence parameters and resulting image quality is important for improving myocardial perfusion imaging. C1 NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), NHLBI, Lab Cardiac Energet, NIH, 10 Ctr Dr,MSC-1061,Bldg 10,Room B1D416, Bethesda, MD 20892 USA. EM kellman@nih.gov NR 68 TC 71 Z9 71 U1 1 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD MAY PY 2007 VL 9 IS 3 BP 525 EP 537 DI 10.1080/10976640601187604 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 178GG UT WOS:000247208600002 PM 17365232 ER PT J AU Lee, Y Miyake, S Wakita, H McMullen, DC Azuma, Y Auh, S Hallenbeck, JM AF Lee, Yang-ja Miyake, Shin-ichi Wakita, Hideaki McMullen, David C. Azuma, Yoshiaki Auh, Sungyoung Hallenbeck, John M. TI Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE hypothermia; oxygen -glucose deprivation; tolerance ID NUCLEAR-PORE COMPLEX; IN-GROUND SQUIRRELS; MAMMALIAN HIBERNATION; TRANSLATIONAL CONTROLS; ORGAN PRESERVATION; REPERFUSION INJURY; SUMO; TOLERANCE; BRAIN; RANGAP1 AB Hibernation torpor provides an excellent natural model of tolerance to profound reductions in blood flow to the brain and other organs. Here, we report that during torpor of 13-lined ground squirrels, massive SUMOylation occurs in the brain, liver, and kidney. The level of small ubiquitin-related modifier ( SUMO) conjugation coincides with the expression level of Ubc9, the SUMO specific E2-conjugating enzyme. Hypothermia alone also increased SUMO conjugation, but not as markedly as hibernation torpor. Increased SUMO conjugation ( induced by Ubc9 overexpression, ischemic preconditioning ( PC)+/- hypothermia) was necessary and sufficient for tolerance of SHSY5Y neuroblastoma cells to oxygen/ glucose deprivation (OGD) (' in vitro ischemia'); decreased SUMO conjugation (induced by a dominant-negative Ubc9) severely reduced tolerance to OGD in these cells. These data indicate that post-translational modification of proteins by SUMOylation is a prominent feature of hibernation torpor and is critical for cytoprotection by ischemic PC +/- hypothermia in SHSY5Y cells subjected to OGD. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. NINDS, Off Clin Director, NIH, Bethesda, MD USA. RP Hallenbeck, JM (reprint author), NINDS, Stroke Branch, NIH, Bldg 49,Room 2A10,MSC 4476,49 Convent Dr, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 41 TC 109 Z9 114 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAY PY 2007 VL 27 IS 5 BP 950 EP 962 DI 10.1038/sj.jcbfm.9600395 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 161FG UT WOS:000245999300007 PM 16955077 ER PT J AU Kim, SK Jacobson, KA AF Kim, Soo-Kyung Jacobson, Kenneth A. TI Three-dimensional quantitative structure-activity relationship of nucleosides acting at the A(3) adenosine receptor: Analysis of binding and relative efficacy SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID MOLECULAR-FIELD ANALYSIS; HYDROGEN-BONDING PROPERTIES; BIOLOGICAL-ACTIVITY; PARTIAL AGONISTS; ANALYSIS COMSIA; DERIVATIVES; ANTAGONISTS; AFFINITY; LIGANDS; DESIGN AB The binding affinity and relative maximal efficacy of human A(3) adenosine receptor (AR) agonists were each subjected to ligand-based three-dimensional quantitative structure-activity relationship analysis. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) used as training sets a series of 91 structurally diverse adenosine analogues with modifications at the N(6) and C2 positions of the adenine ring and at the 3', 4', and 5' positions of the ribose moiety. The CoMFA and CoMSIA models yielded significant cross-validated q(2) values of 0.53 (r(2) = 0.92) and 0.59 (r(2) = 0.92), respectively, and were further validated by an external test set (25 adenosine derivatives), resulting in the best predictive r(2) values of 0.84 and 0.70 in each model. Both the CoMFA and the CoMSIA maps for steric or hydrophobic, electrostatic, and hydrogen-bonding interactions well reflected the nature of the putative binding site previously obtained by molecular docking. A conformationally restricted bulky group at the N(6) or C2 position of the adenine ring and a hydrophilic and/or H-bonding group at the 5 ' position were predicted to increase A(3)AR binding affinity. A small hydrophobic group at N(6) promotes receptor activation. A hydrophilic and hydrogen-bonding moiety at the 5 ' position appears to contribute to the receptor activation process, associated with the conformational change of transmembrane domains 5, 6, and 7. The 3D-CoMFA/CoMSIA model correlates well with previous receptor-docking results, current data of A(3)AR agonists, and the successful conversion of the A(3)AR agonist into antagonists by substitution (at N(6)) or conformational constraint (at 5 '-N-methyluronamide). C1 NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, 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 NR 39 TC 11 Z9 11 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD MAY-JUN PY 2007 VL 47 IS 3 BP 1225 EP 1233 DI 10.1021/ci60050lz PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 172AL UT WOS:000246776400055 ER PT J AU Vorobyov, I Anisimov, VM Greene, S Venable, RM Moser, A Pastor, RW MacKerell, AD AF Vorobyov, Igor Anisimov, Victor M. Greene, Shannon Venable, Richard M. Moser, Adam Pastor, Richard W. MacKerell, Alexander D., Jr. TI Additive and classical drude polarizable force fields for linear and cyclic ethers SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; FREE-ENERGY CALCULATIONS; AB-INITIO; NUCLEIC-ACIDS; AQUEOUS-SOLUTION; 1,2-DIMETHOXYETHANE/WATER SOLUTIONS; CONFORMATIONAL ENERGIES; POLY(ETHYLENE OXIDE); TETRAHYDROFURAN; LIQUID AB Empirical force field parameters consistent with the CHARMM additive and classical Drude based polarizable force fields are presented for linear and cyclic ethers. Initiation of the optimization process involved validation of the aliphatic parameters based on linear alkanes and cyclic alkanes. Results showed the transfer to cyclohexane to yield satisfactory agreement with target data; however, in the case of cyclopentane direct transfer of the Lennard-Jones parameters was not sufficient due to ring strain, requiring additional optimization of these parameters for this molecule. Parameters for the ethers were then developed starting with the available aliphatic parameters, with the nonbond parameters for the oxygens optimized to reproduce both gas-and condensed-phase properties. Nonbond parameters for the polarizable model include the use of an anisotropic electrostatic model on the oxygens. Parameter optimization emphasized the development of transferable parameters between the ethers of a given class. The ether models are shown to be in satisfactory agreement with both pure solvent and aqueous solvation properties, and the resulting parameters are transferable to test molecules. The presented force field will allow for simulation studies of ethers in condensed phase and provides a basis for ongoing developments in both additive and polarizable force fields for biological molecules. C1 Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP MacKerell, AD (reprint author), Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. EM amackere@rx.umaryland.edu RI Vorobyov, Igor/N-2309-2014; OI Vorobyov, Igor/0000-0002-4767-5297; MacKerell, Alex/0000-0001-8287-6804 NR 91 TC 148 Z9 148 U1 5 U2 42 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD MAY-JUN PY 2007 VL 3 IS 3 BP 1120 EP 1133 DI 10.1021/ct600350s PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 165CX UT WOS:000246282600049 PM 26627431 ER PT J AU Zito, JM Safer, DJ Valluri, S Gardner, JF Korelitz, JJ Mattison, DR AF Zito, Julie M. Safer, Daniel J. Valluri, Satish Gardner, James F. Korelitz, James J. Mattison, Donald R. TI Psychotherapeutic medication prevalence in Medicaid-insured preschoolers SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID ADVERSE DRUG-REACTIONS; PSYCHOTROPIC MEDICATIONS; MANAGED CARE; CHILDREN; TRENDS; ADOLESCENTS; YOUTHS; HEALTH; LABEL; AGE AB Objective: To update knowledge of the prevalence of the use of psychotherapeutic medications in preschoolers with Medicaid insurance as requested by the Best Pharmaceuticals for Children Act of 2002 (BPCA). Method: Prescription, enrollment, and outpatient visit data from 7 state Medicaid programs were used to identify 274,518 youths continuously enrolled in 2001 and aged 2 to 4 on January 1, 2001. Annual prevalence of use was defined as one or more dispensed prescriptions for a psychotherapeutic medication and adjusted for anticonvulsant and anxiolytic/sedative/hypnotic use according to ICD-9 diagnostic groupings. Prevalence ratios adjusted for age, race/ethnicity, and gender were estimated. Results: 2.30% (CI = 2.24, 2.36) of preschoolers received one or more dispensings for a psychotherapeutic medication in 2001, approximately doubling the usage of comparable youth from 2 other state Medicaid programs studied in 1995. Boys were 2.4 times more likely than girls to receive psychotherapeutic medication. Whites were 4 times more likely than Hispanics and twice as likely as Blacks to receive medication for psychiatric or behavioral conditions. Since the mid-1990s, usage increased, especially for atypical antipsychotics and antidepressants. The prominent use of anticonvulsants (78.8%) and anxiolytic/sedative/hypnotic drugs (91.4%) in those with no psychiatric diagnosis, but with other medical diagnoses, shows that much use therein reflects treatment for seizures, rather than mood stabilization, and for minor medical conditions, rather than psychiatric disorders. Conclusion: Preschool psychotherapeutic medication use increased across ages 2 to 4 for stimulants, antipsychotics, and antidepressants, reflecting use for psychiatric/behavioral disorders. However, the use of anxiolytic/sedative/hypnotics and anticonvulsants was more stable across these years, suggesting medical usage. Additional research to assess the benefits and risks of psychotherapeutic drugs is needed, particularly when such usage is off-label for both psychiatric and nonpsychiatric conditions. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Hlth Serv Res, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. Johns Hopkins Med Inst, Dept Psychiat, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Pediat, Baltimore, MD 21205 USA. Westat Corp, Rockville, MD USA. NIH, US Publ Hlth Serv, Obstet & Pediat Pharmacol Branch, Bethesda, MD 20892 USA. RP Zito, JM (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Hlth Serv Res, 220 Arch St, Baltimore, MD 21201 USA. EM jzito@rx.umaryland.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 33 TC 64 Z9 64 U1 1 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD MAY PY 2007 VL 17 IS 2 BP 195 EP 203 DI 10.1089/cap.2007.0006 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 167XP UT WOS:000246486200006 PM 17489714 ER PT J AU Hardin, MG Schroth, E Pine, DS Ernst, M AF Hardin, Michael G. Schroth, Elizabeth Pine, Daniel S. Ernst, Monique TI Incentive-related modulation of cognitive control in healthy, anxious, and depressed adolescents: development and psychopathology related differences SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE saccade; inhibition; motivation; valence; salience; eye movement; pediatric; adolescence; anxiety; cognition; depression; development ID RESPONSE-INHIBITION; PREFRONTAL CORTEX; EYE-MOVEMENT; PERFORMANCE; TASK; INVENTORY; ADULTS; SCALE; ANTISACCADE; RELIABILITY AB Background: Developmental changes in cognitive and affective processes contribute to adolescent risk-taking behavior, emotional intensification, and psychopathology. The current study examined adolescent development of cognitive control processes and their modulation by incentive, in health and psychopathology. Predictions include 1) better cognitive control in adults than adolescents, and in healthy adolescents than anxious and depressed adolescents, and 2) a stronger influence of incentives in adolescents than adults, and in healthy adolescents than their depressed and anxious counterparts. Methods: Antisaccadic eye movement parameters, which provide a measure of cognitive control, were collected during a reward antisaccade task that included parameterized incentive levels. Participants were 20 healthy adults, 30 healthy adolescents, 16 adolescents with an anxiety disorder, and 11 adolescents with major depression. Performance accuracy and saccade latency were analyzed to test both developmental and psychopathology hypotheses. Results: Development and psychopathology group differences in cognitive control were found. Specifically, adults performed better than healthy adolescents, and healthy adolescents than anxious and depressed adolescents. Incentive improved accuracy for all groups; however, incremental increases were not sufficiently large to further modulate performance. Incentives also affected saccade latencies, pushing healthy adolescent latencies to adult levels, while being less effective in adolescents with depression or anxiety. This latter effect was partially mediated by anxiety symptom severity. Conclusions: Current findings evidence the modulation of cognitive control processes by incentives. While seen in both healthy adults and healthy adolescents, this modulatory effect was stronger in youth. While anxious and depressed adolescents exhibited improved cognitive control under incentives, this effect was smaller than that in healthy adolescents. These findings suggest differential incentive and/or cognitive control processing in anxiety and depression, and across development. Differences could result from disorder specific, or combined developmental and pathological mechanisms. C1 NIMH, EDAN Branch, Mood & Anxiety Disorders Program, NIH DHHS, Bethesda, MD 20892 USA. RP Hardin, MG (reprint author), NIMH, EDAN Branch, Mood & Anxiety Disorders Program, NIH DHHS, 15K North Dr, Bethesda, MD 20892 USA. EM hardinm@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 33 TC 46 Z9 48 U1 3 U2 13 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD MAY PY 2007 VL 48 IS 5 BP 446 EP 454 DI 10.1111/j.1469-7610.2006.01722.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 166SE UT WOS:000246399500004 PM 17501725 ER PT J AU Rodriguez-Rosas, ME Lofwall, MR Strain, EC Siluk, D Wainer, IW AF Rodriguez-Rosas, Maria Esther Lofwall, Michelle R. Strain, Eric C. Siluk, Danuta Wainer, Irving W. TI Simultaneous determination of buprenorphine, norbuprenorphine and the enantiomers of methadone and its metabolite (EDDP) in human plasma by liquid chromatography/mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE buprenorphine; norbuprenorphine; (S)-methadone; (R)-methadone; (S)-EDDP; (R)-EDDP; chiral chromatography; AGP chiral stationary phase; LC-MS ID TANDEM MASS-SPECTROMETRY; GAS-CHROMATOGRAPHY; ELECTROCHEMICAL DETECTION; HAIR SAMPLES; HUMAN-URINE; RAT PLASMA; NORBUPRENORPHINE-3-BETA-D-GLUCURONIDE; MAINTENANCE; VALIDATION; DEPENDENCE AB A previously reported enantioselective LC-MS assay for the determination of (R)- and (S)-methadone [Met] and (R)- and (S)-2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine [EDDP] (the primary metabolite of Met) has been adapted for use in the simultaneous determination of the plasma concentrations of Met, EDDP, buprenorphine (Bu) and norbuprenorphine (norBu). All of the target compounds were separated within 15 min using an alpha(1)-acid glycoprotein chiral stationary phase, a mobile phase composed of acetonitrile: ammonium acetate buffer [10 mM, pH 7.0] in a ratio of 18:82 (v/v), a flow rate of 0.9 ml/min at 25 degrees C. Deuterium labeled compounds were used as internal standards [d(4)-Bu, d(3)-norBu, (R,S)-d(3)-Met and (R,S)-d(3)-EDDP] and linear relationships between peak height ratios and drug concentrations were obtained for Bu and norBu in the range 0.2-12 ng/ml with correlation coefficients greater than 0.999. The relative standard deviations (%R.S.D.) for the intra- and inter-day precision of the method were < 4.5% and for accuracy was < 4.0%. The method was validated and used to analyze plasma samples obtained from opioid dependent methadone-maintained adults enrolled in a research study. (c) 2006 Elsevier B.V. All rights reserved. C1 NIA, Bioanalyt & Drug Discovery Unit, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Univ Kentucky, Coll Med, Lexington, KY USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, Gdansk, Poland. RP Rodriguez-Rosas, ME (reprint author), NIA, Bioanalyt & Drug Discovery Unit, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rdrgzrss@yahoo.com FU Intramural NIH HHS; NIDA NIH HHS [DA00332, DA08045, K02 DA000332, R01 DA008045] NR 33 TC 22 Z9 22 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 MAY 1 PY 2007 VL 850 IS 1-2 BP 538 EP 543 DI 10.1016/j.jchromb.2006.11.025 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 170ZA UT WOS:000246703500070 PM 17141582 ER PT J AU Chang, FL Coakley, JA AF Chang, Fu-Lung Coakley, James A., Jr. TI Relationships between marine stratus cloud optical depth and temperature: Inferences from AVHRR observations SO JOURNAL OF CLIMATE LA English DT Article ID HIGH-RESOLUTION RADIOMETER; STRATOCUMULUS CLOUDS; AIRCRAFT OBSERVATIONS; BOUNDARY-LAYER; WATER-CONTENT; CLIMATE; SATELLITE; MODEL; THICKNESS; PARAMETERIZATION AB Studies using International Satellite Cloud Climatology Project (ISCCP) data have reported decreases in cloud optical depth with increasing temperature, thereby suggesting a positive feedback in cloud optical depth as climate warms. The negative cloud optical depth and temperature relationships are questioned because ISCCP employs threshold assumptions to identify cloudy pixels that have included partly cloudy pixels. This study applies the spatial coherence technique to one month of Advanced Very High Resolution Radiometer ( AVHRR) data over the Pacific Ocean to differentiate overcast pixels from the partly cloudy pixels and to reexamine the cloud optical depth-temperature relationships. For low-level marine stratus clouds studied here, retrievals from partly cloudy pixels showed 30% - 50% smaller optical depths, 1 degrees - 4 degrees C higher cloud temperatures, and slightly larger droplet effective radii, when they were compared to retrievals from the overcast pixels. Despite these biases, retrievals for the overcast and partly cloudy pixels show similar negative cloud optical depth - temperature relationships and their magnitudes agree with the ISCCP results for the midlatitude and subtropical regions. There were slightly negative droplet effective radius temperature relationships, and considerable positive cloud liquid water content - temperature relationships indicated by aircraft measurements. However, cloud thickness decreases appear to be the main reason why cloud optical depth decreases with increasing temperature. Overall, cloud thickness thinning may explain why similar negative cloud optical depth - temperature relationships are found in both overcast and partly cloudy pixels. In addition, comparing the cloud-top temperature to the air temperature at 740 hPa indicates that cloud-top height generally rises with warming. This suggests that the cloud thinning is mainly due to the ascending of cloud base. The results presented in this study are confined to the midlatitude and subtropical Pacific and may not be applicable to the Tropics or other regions. C1 NIA, Hampton, VA 23666 USA. Oregon State Univ, Coll Ocean & Atmospher Sci, Corvallis, OR 97331 USA. RP Chang, FL (reprint author), NIA, 100 Explorat Way,Room 214, Hampton, VA 23666 USA. EM f.chang@larc.nasa.gov NR 48 TC 11 Z9 11 U1 0 U2 4 PU AMER METEOROLOGICAL SOC PI BOSTON PA 45 BEACON ST, BOSTON, MA 02108-3693 USA SN 0894-8755 J9 J CLIMATE JI J. Clim. PD MAY PY 2007 VL 20 IS 10 BP 2022 EP 2036 DI 10.1175/JCLI4115.1 PG 15 WC Meteorology & Atmospheric Sciences SC Meteorology & Atmospheric Sciences GA 173WF UT WOS:000246902500005 ER PT J AU Ozawa, A Agarwal, SK Mateo, CM Burns, AL Rice, TS Kennedy, PA Quigley, CM Simonds, WF Weinstein, LS Chandrasekharappa, SC Collins, FS Spiegel, AM Marx, SJ AF Ozawa, Atsushi Agarwal, Sunita K. Mateo, Carmen M. Burns, A. Lee Rice, Terri S. Kennedy, Patricia A. Quigley, Caitlin M. Simonds, William F. Weinstein, Lee S. Chandrasekharappa, Settara C. Collins, Francis S. Spiegel, Allen M. Marx, Stephen J. TI The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27(Kip1) mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MEN1 GENE; CLINICAL-FEATURES; GERMLINE MEN1; FAMILIES; GROWTH AB Context: One variant of multiple endocrine neoplasia type 1 (MEN1) is defined by sporadic tumors of both the parathyroids and pituitary. The prevalence of identified MEN1 mutations in this variant is lower than in familial MEN1 (7% vs. 90%), suggesting different causes. Recently, one case of this variant had a germline mutation of p27(Kip1)/CDKN1B. Objective: The objective was to test p27 in germline DNA from cases with tumors of both the parathyroids and pituitary. Design: Medical record review and sequence analysis in DNA were performed. Setting: This study involved an inpatient and outpatient referral program for cases of endocrine tumors. Patients: Sixteen index cases had sporadic tumors of two organs, both the parathyroids and the pituitary. There were 18 additional index cases with related features of familial tumors. Five subjects were normal controls. No case had an identified MEN1 mutation. Interventions: Clinical status of endocrine tumors was tabulated. Sequencing of germline DNA from index cases and control cases for the p27 gene was performed by PCR. Main Outcome Measures: Endocrine tumor types and their expressions were measured, as were sequence changes in the p27 gene. Results: Tumor features were documented in index cases and families. One p27 germline single nucleotide change was identified. This predicted a silent substitution of Thr142Thr. Furthermore, there was a normal prevalence of heterozygosity for a common p27 polymorphism, making a large p27 deletion unlikely in all or most of these cases. Conclusions: The MEN1 variant with sporadic parathyroid tumors, sporadic pituitary tumor, and no identified MEN1 mutation is usually not caused by p27 germline mutations. It is usually caused by as yet unknown process(es). C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Ozawa, A (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM ozawaa@niddk.nih.gov RI Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 FU Intramural NIH HHS NR 21 TC 50 Z9 51 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2007 VL 92 IS 5 BP 1948 EP 1951 DI 10.1210/jc.2006-2563 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 164GI UT WOS:000246221200064 PM 17299066 ER PT J AU Li, HJ Watford, W Li, CL Parmelee, A Bryant, MA Deng, CX O'Shea, J Lee, SB AF Li, Hongjie Watford, Wendy Li, Cuiling Parmelee, Alissa Bryant, Mark A. Deng, Chuxia O'Shea, John Lee, Sean Bong TI Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RNA-BINDING PROTEIN; HUTCHINSON-GILFORD PROGERIA; ATYPICAL WERNERS-SYNDROME; EWS/FLI-1 FUSION GENE; A-TYPE LAMINS; MYXOID LIPOSARCOMA; POLYMERASE-II; TRANSCRIPTIONAL ACTIVATOR; CHROMOSOME-TRANSLOCATION; ONCOPROTEIN TLS/FUS AB Ewing sarcoma gene EWS encodes a putative RNA-binding protein with proposed roles in transcription and splicing, but its physiological role in vivo remains undefined. Here, we have generated Ews-deficient mice and demonstrated that EWS is required for the completion of B cell development and meiosis. Analysis of Ews(-/-) lymphocytes revealed a cell-autonomous defect in precursor B lymphocyte (pre-B lymphocyte) development. During meiosis, Ews-null spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Inactivation of Ews in mouse embryonic fibroblasts resulted in premature cellular senescence, and the mutant animals showed hypersensitivity to ionizing radiation. Finally, we showed that EWS interacts with lamin A/C and that loss of EWS results in a reduced lamin A/C expression. Our findings reveal essential functions for EWS in pre-B cell development and meiosis, with proposed roles in DNA pairing and recombination/repair mechanisms. Furthermore, we demonstrate a novel role of EWS in cellular senescence, possibly through its interaction and modulation of lamin A/C. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. NIH, Pathol Sect, Diagnost & Res Serv Branch, Div Vet Resources, Bethesda, MD 20892 USA. NIH, Off Res Serv, Bethesda, MD 20892 USA. RP Lee, SB (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike,Bldg 10,9N313, Bethesda, MD 20892 USA. EM seanL@intra.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 56 TC 69 Z9 71 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2007 VL 117 IS 5 BP 1314 EP 1323 DI 10.1172/JCI31222 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 165ZS UT WOS:000246347000025 PM 17415412 ER PT J AU Safaeian, M Herrero, R Hildesheim, A Quint, W Freer, E Van Doorn, LJ Porras, C Silva, S Gonzalez, P Bratti, MC Rodriguez, AC Castle, P AF Safaeian, Mahboobeh Herrero, Rolando Hildesheim, Allan Quint, Wim Freer, Enrique Van Doorn, Leen-Jan Porras, Carolina Silva, Sandra Gonzalez, Paula Bratti, M. Concepcion Rodriguez, Ana Cecilia Castle, Philip CA Costa Rican Vaccine Trial Grp TI Comparison of the SPF10-LiPA system to the hybrid capture 2 assay for detection of carcinogenic human papillomavirus genotypes among 5,683 young women in Guanacaste, Costa Rica SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CERVICAL-CANCER; PARTICLE VACCINE; BROAD-SPECTRUM; PCR; DNA; WORLDWIDE; INFECTION; EFFICACY; TYPE-18; TRIAL AB The objective of this analysis was to compare the performance characteristics of two human papillomavirus (HPV) DNA detections assays, the Hybrid Capture 2 assay (HC2) and the SPF10 assay, for the detection of carcinogenic HPV. Data are from the enrollment visits of women who participated in the randomized, double-blind, placebo-controlled phase III HPV16/18 Vaccine Trial in Guanacaste, Costa Rica. We compared. the results of HC2 and SPF10 testing of cervical specimens. Since the line probe assay (UPA) detection system does not distinguish between HPV type 68 (HPV68; which is targeted by HC2) and HPV73 (which is not targeted by HC2), for SPF10-LiPA, we defined the carcinogenic HPV types as the 12 HC2-targeted types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), HPV68/73, and the HC2-cross-reactive, carcinogenic type HPV66. The kappa values and the performance characteristics for the detection of cervical abnormalities were ascertained. Paired observations were available for 5,683 sexually active, young women (median age, 21 years). The prevalence of carcinogenic HPV types was 35% (n = 1,962) by HC2 and 35% (n = 2,003) by SPF10-LiPA. There were no differences in the prevalence of carcinogenic HPV types by HC2 and SPF10-LiPA among women with normal, atypical squamous cells of undetermined significance and high-grade squamous intraepithelial lesion cytology. Among women with low-grade squamous intraepithelial lesion cytology, HC2 was more likely to test positive than SPF10-LiPA for the carcinogenic HPV types (87% and 79%, respectively; P = 0.001) as a result of HC2 cross-reactivity with HPV types 40, 43, 44, 53, 54, 60, 70, and 74. The crude agreement between the two assays was 88%, with a kappa value of 0.75 (95% confidence limits, 0.73 to 0.76). We observed very good agreement between HC2 and SPF10-LiPA for carcinogenic HPV type detection. C1 NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Rockville, MD 20852 USA. Fdn INCIENSA, San Jose, Costa Rica. Univ Costa Rica, San Jose, Costa Rica. Delft Diagnost Lab, Delft, Netherlands. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov FU Intramural NIH HHS NR 27 TC 59 Z9 59 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2007 VL 45 IS 5 BP 1447 EP 1454 DI 10.1128/JCM.02580-06 PG 8 WC Microbiology SC Microbiology GA 169OA UT WOS:000246600300011 PM 17344361 ER PT J AU O'Mara, AM AF O'Mara, Ann M. TI "Will I suffer?" SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SYMPTOM DISTRESS; CANCER-PATIENTS C1 NCI, NIH, Bethesda, MD 20892 USA. RP O'Mara, AM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 13 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2007 VL 25 IS 13 BP 1645 EP 1646 DI 10.1200/JCO.2006.09.9820 PG 2 WC Oncology SC Oncology GA 165IY UT WOS:000246299500004 PM 17470855 ER PT J AU Nabors, LB Mikkelsen, T Rosenfeld, SS Hochberg, F Akella, NS Fisher, JD Cloud, GA Zhang, Y Carson, K Wittemer, SM Colevas, AD Grossman, SA AF Nabors, L. Burt Mikkelsen, Tom Rosenfeld, Steven S. Hochberg, Fred Akella, Narasimha S. Fisher, Joy D. Cloud, Gretchen A. Zhang, Yu Carson, Kathryn Wittemer, Sabine M. Colevas, A. Dimitrios Grossman, Stuart A. TI Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 9th Annual Meeting of the Society-for-Neuro-Oncology CY NOV 18-21, 2004 CL Toronto, CANADA SP Soc Neuro Oncol ID GROWTH-FACTOR; BRAIN-TUMORS; EGF RECEPTOR; INTEGRIN; ALPHA-V-BETA-3; EXPRESSION; GLIOBLASTOMA; ADHESION; PTK787/ZK-222584; VITRONECTIN AB Purpose This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. Patients and Methods Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. Results A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m(2) administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis ( 120 mg/m(2)), one grade 4 joint and bone pain ( 480 mg/m(2)), one thrombocytopenia (600 mg/m(2)) and one anorexia, hypoglycemia, and hyponatremia ( 800 mg/m(2)). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. Conclusion Cilengitide is well tolerated to doses of 2,400 mg/m(2), durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes. C1 NABTT CNS Consortium, Baltimore, MD 21231 USA. Univ Alabama, Birmingham, AL USA. Merk KGaA, Darmstadt, Germany. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Fisher, JD (reprint author), NABTT CNS Consortium, Canc Res Bldg 2,1550 Orleans St,Room 1M-16, Baltimore, MD 21231 USA. EM jfisher@jhmi.edu RI leng, xianwei/F-9073-2011 FU NCI NIH HHS [R21 CA091560, U01 CA 62475, U01 CA062475] NR 19 TC 192 Z9 200 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2007 VL 25 IS 13 BP 1651 EP 1657 DI 10.1200/JCO.2006.06.6514 PG 7 WC Oncology SC Oncology GA 165IY UT WOS:000246299500006 PM 17470857 ER PT J AU Jatoi, I Chen, BE Anderson, WF Rosenberg, PS AF Jatoi, Ismail Chen, Bingshu E. Anderson, William F. Rosenberg, Philip S. TI Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT CHEMOTHERAPY; ELDERLY-WOMEN; HAZARD RATES; OLDER; MAMMOGRAPHY; MANAGEMENT; RECURRENCE; TAMOXIFEN; SURVIVAL; INTERVAL AB Purpose Since 1990, overall breast cancer mortality rates in the United States decreased 24%. This decline has been attributed to mammography screening and adjuvant systemic therapy. However, the efficacy of these modalities may depend on estrogen receptor ( ER) expression and age. We therefore examined breast cancer mortality trends in the United States according to ER status and age. Methods Using the Surveillance, Epidemiology, and End Results ( SEER) program (1990-2003), we calculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths after diagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors. Relative hazard rates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratified by age at diagnosis. Results During the study period, IBM and annual hazard rates for breast cancer deaths decreased among women with ER-positive and ER-negative tumors, although declines were greater for those with ER-positive tumors. Among women younger than 70 years, relative hazard rates declined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors. Among women 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus no significant decline for those with ER-negative tumors. Conclusion In the United States, breast cancer mortality rates have declined among women with ER-positive and ER-negative tumors, with greater declines among younger women and those with ER-positive tumors. Although mortality in all groups remains unacceptably high, additional emphasis should be placed on improving outcomes of breast cancer patients older than 70 years and those of all ages with ER-negative tumors. C1 Natl Naval Med Ctr, Breast Care Ctr, Dept Surg, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NCI, Biostat Branch, US Dept HHS, NIH,Div Canc Epidemiol & Genet, Rockville, MD USA. RP Jatoi, I (reprint author), Natl Naval Med Ctr, Breast Care Ctr, Dept Surg, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ismail.jatoi@us.army.mil FU Intramural NIH HHS NR 37 TC 107 Z9 112 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2007 VL 25 IS 13 BP 1683 EP 1690 DI 10.1200/JCO.2006.09.2106 PG 8 WC Oncology SC Oncology GA 165IY UT WOS:000246299500011 PM 17404367 ER PT J AU Mascelli, MA Zhou, HH Sweet, R Getsy, J Davis, HM Graham, M Abernethy, D AF Mascelli, Mary Ann Zhou, Honghui Sweet, Raymond Getsy, Jay Davis, Hugh M. Graham, Martin Abernethy, Darrell TI Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: Impact of these parameters on early clinical development SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE monoclonal antibodies; first in human; phase I clinical trials; pharmacokinetics; pharmacodynamics ID RHEUMATOID-ARTHRITIS; PHASE-I; MULTIPLE-SCLEROSIS; HEALTHY-VOLUNTEERS; PLAQUE PSORIASIS; FC-RECEPTORS; HUMAN IGG1; EFFICACY; DESIGN; MOUSE AB Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities. The side effect profile of murine Mab therapeutic agents restricted the clinical development of these agents to indications with high morbidity and/or mortality (ie, oncology, graft vs host rejection). Advances in genetic engineering and protein expression technologies resulted in the development of Mabs composed either predominately ie, mouse/human chimeric, "humanized") or completely tie, "fully human" Mabs) of the human amino acid sequence. The production of chimeric, humanized, and fully human Mabs significantly reduced the immune-mediated toxicities and expanded the utility for these agents in numerous therapeutic areas, particularly in chronic disorders requiring either long-term administration (ie, rheumatoid arthritis) or treatment upon the flare up of disease (Crohn's disease, psoriasis). This review provides an overview of the molecular, biochemical, and pharmacokinetic properties and clinical development history of Mobs and details how these factors currently affect the scope and design of early clinical development strategies for these drug candidates. Emphasis is placed on the criteria for selecting appropriate subject populations for phase I testing of Mabs. C1 Centocor R & D, Malvern, PA 19355 USA. PK PD Inc, Philadelphia, PA USA. NIA, NIH, Baltimore, MD 21224 USA. RP Mascelli, MA (reprint author), Centocor R & D, 200 Great Valley Pkwy, Malvern, PA 19355 USA. NR 58 TC 44 Z9 50 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD MAY PY 2007 VL 47 IS 5 BP 553 EP 565 DI 10.1177/0091270006298360 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163IT UT WOS:000246154000002 PM 17379759 ER PT J AU Chaurasia, CS Muller, M Bashaw, ED Benfeldt, E Bolinder, J Bullock, R Bungay, PM DeLange, ECM Derendorf, H Elmquist, WF Hammarlund-Udenaes, M Joukhadar, C Kellogg, DL Lunte, CE Nordstrom, CH Rollema, H Sawchuk, RJ Cheung, BWY Shah, VP Stahle, L Ungerstedt, U Welty, DF Yeo, H AF Chaurasia, Chandra S. Muller, Markus Bashaw, Edward D. Benfeldt, Eva Bolinder, Jan Bullock, Ross Bungay, Peter M. DeLange, Elizabeth C. M. Derendorf, Hartmut Elmquist, William F. Hammarlund-Udenaes, Margareta Joukhadar, Christian Kellogg, Dean L., Jr. Lunte, Craig E. Nordstrom, Carl Henrik Rollema, Hans Sawchuk, Ronald J. Cheung, Belinda W. Y. Shah, Vinod P. Stahle, Lars Ungerstedt, Urban Welty, Devin F. Yeo, Helen TI AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE microdialysis; regulatory aspects; tissue pharmacokinetics ID IN-VIVO MICRODIALYSIS; BLOOD-BRAIN-BARRIER; ZERO-NET-FLUX; CEREBROSPINAL-FLUID; DIABETIC-PATIENTS; SKELETAL-MUSCLE; DRUG-DELIVERY; PHARMACOKINETICS; TRANSPORT; DOPAMINE C1 US FDA, Div Bioequivalence, Off Gener Drugs, Rockville, MD 20857 USA. Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria. US FDA, Div Clin Pharmacol 3, Off Clin Pharmacol, Silver Spring, MD USA. Univ Copenhagen, Dept Dermatol, Copenhagen NV, Denmark. Karolinska Univ, Huddinge Hosp, Dept Med, Stockholm, Sweden. Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. LACDR, Leiden, Netherlands. Univ Florida, Dept Pharmaceut, Gainesville, FL USA. Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden. Med Univ Vienna, Dept Clin Pathol, Vienna, Austria. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. Univ Lund Hosp, Dept Neurosurg, S-22185 Lund, Sweden. Pfizer Global Res, Dept Neurosci, Groton, CT USA. Astra Zeneca, Sodertalje, Sweden. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. Allergan Pharmaceut Inc, Pharmacokinet & Drug Metab, Irvine, CA USA. Roche Palo Alto, Dept Drug Metab & Pharmokinet, Palo Alto, CA USA. RP Chaurasia, CS (reprint author), US FDA, Div Bioequivalence, Off Gener Drugs, Rockville, MD 20857 USA. EM chandra.chaurasia@fda.hhs.gov RI Derendorf, Hartmut/B-4628-2012 OI Derendorf, Hartmut/0000-0003-4016-1370 NR 58 TC 44 Z9 46 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD MAY PY 2007 VL 47 IS 5 BP 589 EP 603 DI 10.1177/0091270006299091 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 163IT UT WOS:000246154000005 PM 17442685 ER PT J AU Loucks, TMJ De Nil, LF Sasisekaran, J AF Loucks, Toffey M. J. De Nil, Luc F. Sasisekaran, Jayanthi TI Jaw-phonatory coordination in chronic developmental stuttering SO JOURNAL OF COMMUNICATION DISORDERS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SPEECH-MOTOR CONTROL; FLUENT SPEECH; PROPRIOCEPTIVE COORDINATION; NONSTUTTERING ADULTS; MOVEMENT SEQUENCES; LARYNGEAL MOVEMENTS; CHILDREN; UTTERANCES; PERSISTENT AB A deficiency in sensorimotor integration in a person who stutters may be a factor in the pathophysiology of developmental stuttering. To test oral sensorimotor function in adults who stutter, we used a task that requires the coordination of a jaw-opening movement with phonation onset. The task was adapted from previous limb coordination studies, which show that movement coordination depends on intact proprioception. We hypothesized that adult stutterers would show deficient jaw-phonatory coordination relative to control participants. The task required initiation of phonation as a jaw-opening movement passed through a narrow spatial target. Target amplitude and jaw movement speed were varied. The stuttering group showed significantly higher movement error and spatial variability in jaw-phonatory coordination compared to the control group, but group differences in movement velocity or duration were not found. The aberrant jaw-phonatory coordination of the stuttering participants suggests that stuttering is associated with an oral proprioceptive limitation, although, the findings are also consistent with a motor control deficit. Learning outcomes: As a result of this activity, reader will (1) learn about a hypothesis and evidence supporting the view that a sensorimotor deficit contributes to chronic developmental stuttering and (2) will obtain information about the role of proprioception in multi-articulatory coordination and how it can be tested using an oral-phonatory coordination task. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Toronto, Grad Dept Speech Language Pathol, Toronto, ON M5G 1V7, Canada. RP Loucks, TMJ (reprint author), Natl Inst Neurol Disorders & Stroke, Laryngeal & Speech Sect, Bldg 10,Room 5D38, Bethesda, MD 20896 USA. EM louckst@ninds.nih.gov; luc.denil@utoronto.ca; jsasisek@purdue.edu NR 54 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0021-9924 J9 J COMMUN DISORD JI J. Commun. Disord. PD MAY-JUN PY 2007 VL 40 IS 3 BP 257 EP 272 DI 10.1016/j.jcomdis.2006.06.016 PG 16 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 162LV UT WOS:000246089800006 PM 16889790 ER PT J AU Elking, D Darden, T Woods, RJ AF Elking, Dennis Darden, Tom Woods, Robert J. TI Gaussian induced dipole polarization model SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE induced dipole; polarization; Gaussian; Thole ID MOLECULAR ELECTROSTATIC POTENTIALS; INITIO QUANTUM-CHEMISTRY; FORCE-FIELD; ATOMIC CHARGES; NUCLEIC-ACIDS; LIQUID WATER; GAS-PHASE; POLARIZABILITIES; SIMULATIONS; PROTEINS AB A new induced dipole polarization model based on interacting Gaussian charge densities is presented. In contrast to the original induced point dipole model, the Gaussian polarization model is capable of finite interactions at short distances. Aspects of convergence related to the Gaussian model will be explored. The Gaussian polarization model is compared with the damped Thole-induced dipole model and the point dipole model. It will be shown that the Gaussian polarization model performs slightly better than the Thole model in terms of fitting to molecular polarizability tensors. An advantage of the model based on Gaussian charge distribution is that it can be easily generalized to other multipole moments and provide effective damping for both permanent electrostatic and polarization models. Finally, a method of parameterizing polarizabilities is presented. This method is based on probing a molecule with point charges and fitting polarizabilities to electrostatic potential. In contrast to the generic atom type polarizabilities fit to molecular polarizability tensors, probed polarizabilities are significantly more accurate in terms of reproducing molecular polarizability tensors and electrostatic potential, while retaining conformational transferability. (C) 2007 Wiley Periodicals, Inc. C1 Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30607 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Woods, RJ (reprint author), Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30607 USA. EM rwoods@ccrc.uga.edu RI Woods, Robert/F-4962-2015 FU Intramural NIH HHS [Z01 ES090601-11]; NCRR NIH HHS [RR05357]; NIGMS NIH HHS [R01 GM055230, R29 GM055230, GM55230] NR 41 TC 57 Z9 58 U1 1 U2 14 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD MAY PY 2007 VL 28 IS 7 BP 1261 EP 1274 DI 10.1002/jcc.20574 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA 154TW UT WOS:000245531700013 PM 17299773 ER PT J AU Marsh, AA Elfenbein, HA Ambady, N AF Marsh, Abigail A. Elfenbein, Hillary Anger Ambady, Nalini TI Separated by a common language - Nonverbal accents and cultural stereotypes about Americans and Australians SO JOURNAL OF CROSS-CULTURAL PSYCHOLOGY LA English DT Article DE nonverbal behavior; facial expressions; culture; stereotyping; emotion ID FACIAL EXPRESSIONS; EMOTION; PERSONALITY; PERCEPTION; DISPLAY; EXTROVERSION; METAANALYSIS; RECOGNITION; IMPRESSIONS; VARIABILITY AB The expression of nonverbal cues may differ systematically across cultures. Common cues used in distinct ways cross-culturally may be termed nonverbal accents. The data in this study indicate that nonverbal accents can help perceivers to distinguish the nationality of expressers. In Study 1, American participants could determine the nationality of Australian and American adults with above-chance accuracy when viewing their emotional expressions but not neutral expressions. In Study 2, American participants could also determine the nationality of Australians and Americans seen walking or waving in greeting. The accuracy of nationality judgments was also correlated with the extent to which Australian targets were perceived to conform to stereotypes about Australians. It is argued that nonverbal accents may be a mechanism that perceivers can use to apply group stereotypes. C1 Harvard Univ, Cambridge, MA 02138 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Tufts Univ, Medford, MA 02155 USA. RP Marsh, AA (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM amarsh@post.harvard.edu NR 53 TC 12 Z9 12 U1 2 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0221 J9 J CROSS CULT PSYCHOL JI J. Cross-Cult. Psychol. PD MAY PY 2007 VL 38 IS 3 BP 284 EP 301 DI 10.1177/0022022107300275 PG 18 WC Psychology, Social SC Psychology GA 164BU UT WOS:000246208400003 ER PT J AU Cleary, S Phillips, JK Huynh, TT Pacak, K Elkahloun, AG Barb, J Worrell, RA Goldstein, DS Eisenhofer, G AF Cleary, Susannah Phillips, Jacqueline K. Huynh, Thanh-Truc Pacak, Karel Elkahloun, Abdel G. Barb, Jennifer Worrell, Robert A. Goldstein, David S. Eisenhofer, Graerne TI Neuropeptide Y expression in phaeochromocytomas: relative absence in turnours from patients with von Hippel-Lindau syndrome SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; NERVE GROWTH-FACTOR; CHROMAFFIN CELLS; ADRENAL-MEDULLA; PLASMA; TUMORS; TYPE-2; GENE; IMMUNOREACTIVITY; METANEPHRINES AB Phaeochromocytomas are rare neuroendocrine tumours that produce catecholamines and numerous secretory proteins and peptides, including neuropeptide Y (NPY), a vasoactive peptide with influences on blood pressure. The production of catecholamines and NPY by phaeochromocyromas is highly variable. This study examined influences of hereditary factors and differences in catecholamine production on tumour expression of NPY, as assessed by quantitative PCR, enzyme immunoassay and immunohistochemistry. Phaeochromocytomas included hereditary adrenaline-producing tumours (adrenergic phenotype) in multiple endocrine neoplasia type 2 (MEN 2), predominantly noradrenaline-producing tumours (noradrenergic phenotype) in von Hippel-Lindau (VHL) syndrome, and other adrenergic and noradrenergic tumours where there was no clear hereditary syndrome. NPY levels in phaeochromocytomas from VHL patients were lower (P<0 center dot 0001) than in those from MEN 2 patients for both mRNA (84-fold difference) and the peptide (99-fold difference). These findings were supported by immunohistochemistry. NPY levels were also lower in VHL tumours than in those where there was no hereditary syndrome. Relative absence of expression of NPY in phaeochromocytomas from VHL patients when compared with other groups appears to be largely independent of differences in catecholamine production and is consistent with a unique phenotype in VHL syndrome. C1 Murdoch Univ, Div Hlth Sci, Perth, WA 6150, Australia. Western Australian Biomed Res Inst, Perth, WA, Australia. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD USA. NCI, Math & Stat Comp Lab, Ct Informat Technol, NIH, Bethesda, MD 20892 USA. NCI, Math & Stat Comp Lab, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Cleary, S (reprint author), Murdoch Univ, Sch Vet & Biomed Sci, Perth, WA 6150, Australia. EM s.cleary@murdoch.edu.au RI Phillips, Jacqueline/G-7901-2011 OI Phillips, Jacqueline/0000-0002-4917-7734 FU Intramural NIH HHS NR 30 TC 8 Z9 8 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD MAY PY 2007 VL 193 IS 2 BP 225 EP 233 DI 10.1677/JOE-06-0138 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 170KH UT WOS:000246661800003 PM 17470513 ER PT J AU Muniyappa, R Quon, MJ AF Muniyappa, Ranganath Quon, Michael J. TI Is further research needed on glucosamine? SO JOURNAL OF FAMILY PRACTICE LA English DT Letter C1 NIH, Diabet Unit, Div Intramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Muniyappa, R (reprint author), NIH, Diabet Unit, Div Intramural Res, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. EM muniyapr@mail.nih.gov RI Quon, Michael/B-1970-2008 NR 4 TC 1 Z9 1 U1 0 U2 0 PU DOWDEN HEALTH MEDIA PI MONTVALE PA 110 SUMMIT AVE, MONTVALE, NJ 07645-1712 USA SN 0094-3509 J9 J FAM PRACTICE JI J. Fam. Pract. PD MAY PY 2007 VL 56 IS 5 BP 343 EP 343 PG 1 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 191GH UT WOS:000248119100002 PM 17475162 ER PT J AU Sullivan, J AF Sullivan, John TI Hurricane readiness and environmental risks on the bayous - an NIEHS community-based pilot project in South Terrebonne-Lafourche Parishes, Louisiana SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article C1 Univ Texas, Med Branch, Sealy Ctr Environm Hlth & Med, NIEHS,Ctr Environm Toxicol, Galveston, TX 77555 USA. RP Sullivan, J (reprint author), Univ Texas, Med Branch, Sealy Ctr Environm Hlth & Med, NIEHS,Ctr Environm Toxicol, Galveston, TX 77555 USA. EM josulliv@utmb.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD MAY PY 2007 VL 18 IS 2 BP 487 EP 491 DI 10.1353/hpu.2007.0049 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 163LY UT WOS:000246162500026 PM 17483574 ER PT J AU Menotti-Raymond, M David, VA Schaffer, AA Stephens, R Wells, D Kumar-Singh, R O'Brien, SJ Narfstrom, K AF Menotti-Raymond, Marilyn David, Victor A. Schaeffer, Alejandro A. Stephens, Robert Wells, David Kumar-Singh, Rajendra O'Brien, Stephen J. Narfstroem, Kristina TI Mutation in CEP290 discovered for cat, model of human retinal degeneration SO JOURNAL OF HEREDITY LA English DT Article ID RCS RAT MODEL; GENE-THERAPY; ABYSSINIAN CAT; DOMESTIC CAT; RETINITIS-PIGMENTOSA; INTRAFLAGELLAR TRANSPORT; CENTROSOMAL PROTEIN; SEQUENCE-ANALYSIS; JOUBERT-SYNDROME; FELIS-CATUS AB A mutation in the CEP290 gene is reported in a cat pedigree segregating for autosomal recessive (AR) late-onset photoreceptor degeneration (rdAc). An initial screen of 39 candidate genes and genomic locations failed to detect linkage to cat rdAc. Linkage was ultimately established on cat 134 with 15 simple tandem repeat markers (logarithm of odds [LOD] range 4.83-15.53, Theta = 0.0), in a region demonstrating conserved synteny to human chromosome 12, 84.9-90.63 Mb. The sequence of 10 genes with feline retinal expression was examined in affected and unaffected individuals. A single-nucleoticle polymorphism was characterized in intron 50 of CEP290 (IVS50 + 9T>G) that creates a strong canonical splice donor site, resulting in a 4-bp insertion and frameshift in the mRNA transcript, with subsequent introduction of a stop codon and premature truncation of the protein. A population genetic survey of 136 cats demonstrated that the rdAc mutation is in low frequency in Abyssinian populations (0.13, Sweden; 0.07, United States) and absent in breeds of non-Abyssinian heritage. Mutations in CEP290 have recently been shown to cause two human diseases, joubert syndrome, a syndromic retinal degeneration, and Leber's congenital amaurosis, an AR early-onset retinal dystrophy. Human AR retinitis pigmentosa is among the most common causes of retinal degeneration and blindness, with no therapeutic intervention available. This identification of a large animal model for human retinal blindness offers considerable promise in developing gene-based therapies. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. Univ Missouri, Coll Vet Med, Dept Vet Med & Surg, Columbia, MO 65211 USA. Univ Missouri, Dept Ophthalmol, Mason Eye Inst, Columbia, MO 65211 USA. RP Menotti-Raymond, M (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM raymond@ncifcrf.gov RI Schaffer, Alejandro/F-2902-2012 FU Intramural NIH HHS NR 56 TC 56 Z9 57 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD MAY-JUN PY 2007 VL 98 IS 3 BP 211 EP 220 DI 10.1093/jhered/esm019 PG 10 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 186YC UT WOS:000247813500003 PM 17507457 ER PT J AU Sargan, DR Aguirre-Hernandez, J Galibert, F Ostrander, EA AF Sargan, David R. Aguirre-Hernandez, Jesus Galibert, Francis Ostrander, Elaine A. TI An extended microsatellite set for linkage mapping in the domestic dog SO JOURNAL OF HEREDITY LA English DT Article ID RADIATION HYBRID MAP; CANINE GENOME; CONE DEGENERATION; LOCUS; MARKERS; FAMILIARIS; SEQUENCE; SCREENS; FAMILY; BREEDS AB The extremes of phenotype displayed by the domestic dog, as well as the largest number of naturally occurring inherited diseases in any mammalian species except man (>450), have generated a large interest in genomic linkage mapping in the species. Market sets for linkage mapping should ideally show both high levels of polymorphism among the target group of animals and an even spacing of markers across the whole genome. Currently a microsatellite marker set known as Minimal Screening Set 2 (MSS2) is widely used. Here, we have extended this marker set by fang in gaps as noted from the marker positions in the CanFam genome assembly (1.0) and the 5000cR radiation hybrid (RH) map. An additional 183 markers have been positioned to increase the coverage of the MSS2 set wherever it contains a gap >9 mb or 1000(5000) RH units. We have called the marker set derived from the MSS2 set and these 183 markers, MSS3. The average physical spacing of markers in the complete 507 marker MSS3 set is 5 mb, whereas average heterozygosity of the 183 new markers on a panel of 10 dogs of differing breeds is 0.74. This marker group will allow genome-wide scans in the dog to be conducted at close to 5 cM resolution. C1 Univ Cambridge, Dept Vet Med, Ctr Vet Sci, Cambridge CB3 0ES, England. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20896 USA. CNRS, UMR 6061, Fac Med, F-35043 Rennes, France. RP Sargan, DR (reprint author), Univ Cambridge, Dept Vet Med, Ctr Vet Sci, Madingley Rd, Cambridge CB3 0ES, England. EM drs20@cam.ac.uk OI Sargan, David Richard/0000-0001-9897-2489; Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS; NCI NIH HHS [K05 CA90754, R01 CA92167] NR 52 TC 18 Z9 19 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD MAY-JUN PY 2007 VL 98 IS 3 BP 221 EP 231 DI 10.1093/jhered/esm006 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 186YC UT WOS:000247813500004 PM 17406025 ER PT J AU Khaliq, AA Huang, CY Ganti, AK Invie, K Smego, RA AF Khaliq, Amir A. Huang, Chiung-Yu Ganti, Apar Kishor Invie, Kristie Smego, Raymond A., Jr. TI Comparison of resource utilization and clinical outcomes between teaching and nonteaching medical services SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article; Proceedings Paper CT 26th Annual Meeting of the Society-of-General-Internal-Medicine CY APR 30-MAY 03, 2003 CL VANCOUVER, CANADA SP Soc Gen Internal Med DE resource utilization; clinical outcomes; patient care costs; teaching hospital; medical residents ID QUALITY-OF-CARE; HOSPITALS; MORTALITY; UNIVERSITY; PHYSICIAN; SEVERITY; COST AB PURPOSE: To compare the resource utilization and clinical outcomes of medical care delivered on general internal medicine inpatient services at teaching and nonteaching services at an academic hospital. METHODS: From February to October 2002, 2189 patients admitted to a 450-bed university-affiliated community hospital were assigned either to a resident-staffed teaching service (n = 1637) or to a hospitalist- or clinic-based internist nonteaching service (n = 552). We compared total hospital costs per patient, length of hospital stay (LOS), hospital readmission within 30 days, in-hospital mortality, and costs for pharmacy, laboratory, radiology, and others between teaching and nonteaching services. RESULTS: Care on a teaching service was not associated with increased overall patient care costs ($5572 vs. $5576; P = .99), LOS (4.92 days vs. 5.10 days; P = .43), readmission rate (12.3% vs. 10.3%; P = .21), or in-hospital mortality (3.7% vs. 4.5%; P = .40). Mean laboratory and radiology costs were higher on the teaching service, but costs for the pharmacy and for speech therapy, occupational therapy, physical therapy, respiratory therapy, pulmonary function testing, and GI endoscopy procedures were not statistically different between the 2 services, and residents did not order more tests or procedures. Case mix and illness severity, as reflected by the distribution of the most frequent DRGs and mean number of secondary diagnoses per patient and DRG-specific LOS, were similar on the 2 services. CONCLUSIONS: At our academic hospital, admission to a general internal medicine teaching service resulted in patient care costs and clinical outcomes comparable to those admitted to a nonteaching service. C1 [Khaliq, Amir A.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Hlth Adm & Policy, Oklahoma City, OK 73104 USA. [Huang, Chiung-Yu] NIAID, NIH, Div Clin Res, Biostat Res Branch, Bethesda, MD 20892 USA. [Invie, Kristie] MeritCare Hlth Syst, Dept Qual Management, Fargo, ND USA. [Ganti, Apar Kishor; Smego, Raymond A., Jr.] N Dakota State Univ, Sch Med & Hlth Sci, Dept Med, Fargo, ND 58105 USA. RP Khaliq, AA (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Dept Hlth Adm & Policy, 801 NE 13th St,Room 345, Oklahoma City, OK 73104 USA. EM amir-khaliq@ouhsc.edu RI Ganti, Apar Kishor/D-5498-2015 OI Ganti, Apar Kishor/0000-0003-3724-2671 NR 17 TC 17 Z9 17 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD MAY-JUN PY 2007 VL 2 IS 3 BP 150 EP 157 DI 10.1002/jhm.174 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 292HP UT WOS:000255257400007 PM 17549749 ER PT J AU Jansson, LM Choo, RE Harrow, C Velez, M Schroeder, JR Lowe, R Huestis, MA AF Jansson, Lauren M. Choo, Robin E. Harrow, Cheryl Velez, Martha Schroeder, Jennifer R. Lowe, Ross Huestis, Marilyn A. TI Concentrations of methadone in breast milk and plasma in the immediate perinatal period SO JOURNAL OF HUMAN LACTATION LA English DT Article DE methadone; breastfeeding; lactation; breast milk ID MAINTAINED PREGNANT-WOMEN; MAINTENANCE; LACTATION; MOTHER; DRUGS; FETAL; MS AB This study evaluates concentrations of methadone in breast milk and plasma among a sample of methadone-maintained women in the immediate perinatal period. Twelve methadone-maintained, lactating women provided blood and breast milk specimens 1, 2, 3, and 4 days after delivery. Specimens were collected at the time of trough (just before methadone dose) and peak (3 hours after dosing) maternal methadone levels. Paired specimens of foremilk (prefeed) and hindmilk (postfeed) were obtained at each sampling time. Although there was a significant increase in methadone concentration in breast milk over time for the peak postfeed sampling time, t(22) = 2.40, P = .0255, methadone concentrations in breast milk were small, ranging from 21 to 314 ng/mL, and were unrelated to maternal methadone dose. Results obtained from this study contribute to the recommendation of breastfeeding for methadone-maintaind women regardless of methadone dose. C1 Johns Hopkins Univ, Sch Med, Ctr Addict & Pregnancy, JHBMC, Baltimore, MD 21224 USA. NIDA, Intramural Clin Res Program, Baltimore, MD USA. Johns Hopkins Bayview Med Ctr Full Term Nursery, Baltimore, MD USA. NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD USA. RP Jansson, LM (reprint author), Johns Hopkins Univ, Sch Med, Ctr Addict & Pregnancy, JHBMC, D5,4940 Eastern Ave, Baltimore, MD 21224 USA. EM ljansson@jhmi.edu FU Intramural NIH HHS [Z01 DA000412-10]; NIDA NIH HHS [K08 DA000495, K08 DA00495] NR 44 TC 36 Z9 37 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-3344 J9 J HUM LACT JI J. Hum. Lact. PD MAY PY 2007 VL 23 IS 2 BP 184 EP 190 DI 10.1177/0890334407300336 PG 7 WC Nursing; Obstetrics & Gynecology; Pediatrics SC Nursing; Obstetrics & Gynecology; Pediatrics GA 163JQ UT WOS:000246156300007 PM 17478871 ER PT J AU Tang, J Zhu, W Silver, PB Su, SB Chan, CC Caspi, RR AF Tang, Jun Zhu, Wei Silver, Phyllis B. Su, Shao-Bo Chan, Chi-Chao Caspi, Rachel R. TI Autoimmune uveitis elicited with antigen-pulsed dendritic cells has a distinct clinical signature and is driven by unique effector mechanisms: Initial encounter with autoantigen defines disease phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PERTUSSIS TOXIN; GENETIC SUSCEPTIBILITY; TH1 RESPONSES; IMMUNE-SYSTEM; TREATED MICE; FLT3 LIGAND; UVEORETINITIS; GAMMA; IRBP; IDENTIFICATION AB Human autoimmune uveitis is a heterogeneous group of potentially blinding ocular diseases in which most patients who exhibit immunity recognize the same retinal Ag. It is represented by the model of experimental autoimmune uveitis (EAU) induced in mice by immunization with retinal Ag in CFA. Murine EAU is characterized by a Th1/Th17 response pattern, which may not represent all types of human uveitis. We report in this study a new model of EAU induced by injection of matured dendritic cells loaded with a uveitogenic retinal peptide. Dendritic cell-induced EAU demonstrated unique characteristics compared with traditional EAU in terms of clinical manifestations, the nature of the inflammatory infiltrating cells, the cytokine response profile, and a strict requirement for IFN-gamma, whereas IL-17 appeared to play a minor role. Disease was self-limiting, but could be reinduced with the same Ag in CFA, albeit with reduced severity, suggesting postrecovery resistance. Our study demonstrates in a disease setting that the context in which the same autoantigen is initially presented to the immune system precipitates distinct forms of pathology via a distinct pathogenic pathway on the same genetic background. These findings may shed new light on the complex biology and the heterogeneous nature of human uveitis, and provide an alternative model for uveitic diseases of immune origin. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20893 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N222, Bethesda, MD 20893 USA. EM rcaspi@helix.nih.gov FU Intramural NIH HHS NR 40 TC 62 Z9 67 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2007 VL 178 IS 9 BP 5578 EP 5587 PG 10 WC Immunology SC Immunology GA 161YZ UT WOS:000246054400022 PM 17442940 ER PT J AU Fichtner-Feigl, S Fuss, IJ Young, CA Watanabe, T Geissler, EK Schlitt, HJ Kitani, A Strober, W AF Fichtner-Feigl, Stefan Fuss, Ivan J. Young, Cheryl A. Watanabe, Tomohiro Geissler, Edward K. Schlitt, Hans Juergen Kitani, Atsushi Strober, Warren TI Induction of IL-13 triggers TGF-beta(1)-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; T-CELLS; TGF-BETA; INTESTINAL INFLAMMATION; CROHNS-DISEASE; CUTTING EDGE; MURINE MODEL; AUTOIMMUNE INFLAMMATION; TGF-BETA-1 PRODUCTION AB To investigate the immunopathogenesis of inflammation-associated fibrosis, we analyzed the chronic colitis and late-developing fibrosis occurring in BALB/c mice administered weekly doses of intrarectal 2,4,6-trinitrobenzene sulfonic acid. We showed first in this model that an initial Th1 response involving IL-12p70 and IFN-gamma subsides after 3 wk to be supplanted by an IL-23/IL-25 response beginning after 4-5 wk. This evolution is followed by gradually increasing production of IL-17 and cytokines ordinarily seen in a Th2 response, particularly IL-13, which reaches a plateau at 8-9 wk. In vitro stimulation studies suggest that this IL-13 production is dependent on IL-23 and IL-25, but not on IL-12p70. We then show that IL-13 production results in the induction of an IL-13R formerly thought to function only as a decoy receptor, IL-13R alpha(2), and this receptor is critical to the production of TGF-beta(1), and the onset of fibrosis. Thus, if IL-13 signaling through this receptor is blocked by administration of soluble IL-13R alpha(2)-Fc, or by administration of IL-13R alpha 2-specific small interfering RNA, TGF-beta(1) is not produced and fibrosis does not occur. These studies show that in chronic 2,4,6-trinitrobenzene sulfonic acid colitis, fibrosis is dependent on the development of an IL-13 response that acts through a novel cell surface-expressed IL-13R to induce TGF-beta(1). A similar mechanism may obtain in certain forms of human inflammatory bowel disease. C1 Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany. NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Fichtner-Feigl, S (reprint author), Univ Regensburg, Dept Surg, Franz Josef Str Allee 11, D-93053 Regensburg, Germany. EM stefan.fichtner@klinik.uni-regensburg.de RI Geissler, Edward/R-4131-2016 NR 56 TC 102 Z9 106 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2007 VL 178 IS 9 BP 5859 EP 5870 PG 12 WC Immunology SC Immunology GA 161YZ UT WOS:000246054400052 PM 17442970 ER PT J AU Qian, Y Diaz, LA Ye, J Clarke, SH AF Qian, Ye Diaz, Luis A. Ye, Jian Clarke, Stephen H. TI Dissecting the anti-desmoglein autoireactive B cell repertoire in pemphigus vulgaris patients SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOLIACEUS FOGO SELVAGEM; REGION GENE ANALYSIS; LPR LPR MICE; RHEUMATOID FACTORS; IMMUNE-RESPONSE; VL GENES; AUTOANTIBODIES; IGG; ANTIBODIES; ADHESION AB Pemphigus vulgaris (PV) encompasses two clinical phenotypes, one producing mucosal blisters and the other mucosal and skin lesions (mcPV). The mucosal blister-producing PV variant is characterized by autoantibodies against desmoglein (Dsg)3, whereas mucosal and skin lesion-producing PV is characterized by autoantibodies to Dsg3 and Dsg1. The present study was aimed at disclosing the diversity and clonality of the anti-Dsg3 response, as well as whether anti-Dsg3 B cells are Ag selected. Human-mouse heterohybridomas were generated by fusion of EBV-transformed or freshly isolated PBLs from six PV patients with mouse myeloma cells. A total of 73 anti-Dsg hybridomas (47 IgM and 26 IgG) were isolated. Over 90% are specific for both Dsg1 and Dsg3 indicating extensive cross-reactivity between these responses. V-H gene segment use by IgM hybridomas is diverse, but is restricted among IgG hybridomas, where the majority uses one of two V-H genes. V-L gene segment use was diverse even among IgG hybridomas suggesting that the V-L is less critical to defining desmoglein specificity. Additionally, the IgG hybridomas were extensively mutated and the distribution and nature of the mutations suggested that they had been Ag selected. We conclude that the potentially pathogenic IgG anti-Dsg response is restricted in V-H use, is somatically mutated, and is Ag selected. C1 Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Diaz, LA (reprint author), Univ N Carolina, Dept Dermatol, 3100 Thurston Bldg,Campus Box 7287, Chapel Hill, NC 27599 USA. EM ldiaz@med.unc.edu FU NIAID NIH HHS [R01 AI 43587]; NIAMS NIH HHS [R01 AR 30281, R01 AR 32599, T32 AR 07369] NR 49 TC 17 Z9 18 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2007 VL 178 IS 9 BP 5982 EP 5990 PG 9 WC Immunology SC Immunology GA 161YZ UT WOS:000246054400065 PM 17442983 ER PT J AU Powell, DJ de Vries, CR Allen, T Ahmadzadeh, M Rosenberg, SA AF Powell, Daniel J., Jr. de Vries, Christiaan R. Allen, Tamika Ahmadzadeh, Mojgan Rosenberg, Steven A. TI Inability to mediate prolonged reduction of regulatory T cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; ACT; IL-2; human; CD25; regulatory T cells; depletion ID DOSE RECOMBINANT INTERLEUKIN-2; TUMOR-INFILTRATING LYMPHOCYTES; IMMUNOLOGICAL SELF-TOLERANCE; METASTATIC MELANOMA; IN-VIVO; AUTOIMMUNE-DISEASE; IMMUNE-RESPONSE; CANCER; IMMUNOTHERAPY; THERAPY AB CD25(+)CD4(+) regulatory T cells (Treg) regulate peripheral self-tolerance and possess the ability to suppress antitumor responses, which may explain the poor clinical response of cancer patients undergoing active immunization protocols, and provides the rationale for neutralizing Treg cells in vivo to strengthen local antitumor immune responses. Because interleukin-2 (IL-2) mediates tumor regression in about 15% of treated patients but simultaneously increases Treg cells, we hypothesized that transient elimination of Treg cells will enhance the clinical effectiveness of IL-2 therapy. In the current study, 5 patients with metastatic melanoma who were refractory to prior IL-2 received a lymphodepleting preparative regimen followed by the adoptive transfer of autologous lymphocytes depleted of CD25(+) Treg cells and high-dose IL-2 administration. CD25(+) cells were eliminated from patient leukapheresis samples using a clinical-grade, large-scale immunomagnetic system, leaving CD8(+) and CD25(-)CD4(+) T cells intact. In the early aftermath of CD25(+) Treg cell-depleted cell infusion, CD25(+)FOXP3(+) CD4(+) Treg cells rapidly repopulated the peripheral blood of treated patients with 18% to 63% of CD4(+) T cells expressing FOXP3. Recovering CD25(+)CD4(+) T cells exhibited suppressive activity against CD25(-)CD4(+) effector T-cell proliferation in vitro. No patient experienced objective tumor regression or autoimmunity. Our results indicate that in vivo transfer of autologous CD25-depleted mononuclear populations to lymphopenic patients in combination with high-dose IL-2 is not sufficient to mediate prolonged reduction of Treg cells after IL-2 administration. C1 NCI, Surg Branch, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. RP Powell, DJ (reprint author), NCI, Surg Branch, NIH, Clin Res Ctr, Room 3W-3888,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM Daniel_Powell@nih.gov FU Intramural NIH HHS [Z01 SC003811-32] NR 49 TC 40 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD MAY-JUN PY 2007 VL 30 IS 4 BP 438 EP 447 DI 10.1097/CJI.0b013e3180600ff9 PG 10 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 161QE UT WOS:000246029600008 PM 17457218 ER PT J AU Xi, LF Kiviat, NB Wheeler, CM Kreimer, A Ho, J Koutsky, LA AF Xi, Long Fu Kiviat, Nancy B. Wheeler, Cosette M. Kreimer, Aimee Ho, Jesse Koutsky, Laura A. TI Risk of cervical intraepithelial neoplasia grade 2 or 3 after loop electrosurgical excision procedure associated with human papillomavirus type 16 variants SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CANCER; WOMEN; E6; HUMAN-PAPILLOMAVIRUS-16 AB Identification of factors associated with risk of relapse after treatment for high-grade cervical intraepithelial neoplasia (CIN) has important clinical implications. Study subjects were women participating in the Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study who were treated for CIN3 by loop electrosurgical excision procedure (LEEP) and who had a baseline infection with human papillomavirus type 16 (HPV16). These women were followed every 6 months for 2 years. Post-LEEP CIN2-3 was found in 20 (10.0%) of the 201 women. An adjusted relative risk of 3.1 (95% confidence interval, 1.1-8.9) was associated with HPV16 non-European, compared with European, variants, a finding that is consistent with the variant-related risk of prevalent/incident high-grade CIN. C1 Univ Washington, Dept Pathol, Sch Med, Seattle, WA 98103 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98103 USA. Univ New Mexico, Sch Med, Dept Microbiol, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Dept Mol Genet, Albuquerque, NM 87131 USA. Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. RP Xi, LF (reprint author), Univ Washington, Dept Pathol, Sch Med, 1914 N 34th St,Ste 300, Seattle, WA 98103 USA. EM longfu@u.washington.edu FU NCI NIH HHS [CA 84396] NR 15 TC 10 Z9 11 U1 0 U2 3 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 MAY 1 PY 2007 VL 195 IS 9 BP 1340 EP 1344 DI 10.1086/513441 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 153AY UT WOS:000245405300017 PM 17397005 ER PT J AU Ozato, K Uno, K Iwakura, Y AF Ozato, Keiko Uno, Kazuko Iwakura, Yoichiro TI Another road to interferon: Yasuichi Nagano's journey SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Biographical-Item C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Louis Pasteur Ctr Med Res, Kyoto, Japan. Univ Tokyo, Inst Med Sci, Tokyo, Japan. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6A,Room 2A01, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI Iwakura, Yoichiro/E-5457-2011 OI Iwakura, Yoichiro/0000-0002-9934-5775 NR 0 TC 4 Z9 4 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD MAY PY 2007 VL 27 IS 5 BP 349 EP 352 DI 10.1089/jir.2007.9988 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 171NM UT WOS:000246742700001 PM 17523866 ER PT J AU Macy, RJ Nurius, PS Norris, J AF Macy, Rebecca J. Nurius, Paula S. Norris, Jeanette TI Latent profiles among sexual assault survivors - Understanding survivors and their assault experiences SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE coping; prevention; sexual assault; revictimization ID WOMENS ALCOHOL-CONSUMPTION; ACQUAINTANCE RAPE; REVICTIMIZATION; AGGRESSION; PREVENTION; RISK; RESISTANCE; BEHAVIORS; MODEL; VICTIMIZATION AB Little guidance exists about how to tailor empowerment and resistance sexual assault programming to be responsive to varying groups of women. Using an investigation of 415 college women who completeda self-administered survey about a range of sexually aggressive experiences by a known male assailant, this investigation tested for distinct multivariate profiles of contextual factors among sexually assaulted women to discern how these factors may differentially combine to influence women's vulnerability to sexual assault. We applied latent profile analysis (LPA) to determine meaningful subgroups of women based on interrelationships among factors that contextualize women's vulnerability to sexual assault, including prior victimization, alcohol consumption, relationship expectancies of the assailant, and assertive precautionary habits. LPA established four significantly distinct multivariate profiles of substantively different groups of women. Group difference tests reinforced the findings and aided in group profile interpretations. Implications for the development of tailored resistance and empowerment programs are discussed. C1 Univ N Carolina, Sch Social Work, Chapel Hill, NC 27599 USA. Univ Washington, NIMH, Prevent Res Training Program, Seattle, WA 98195 USA. Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. RP Macy, RJ (reprint author), Univ N Carolina, Sch Social Work, Tate Turner Kuralt Bldg,301 Pittsboro St CB 3550, Chapel Hill, NC 27599 USA. EM rjmacy@email.unc.edu FU NIMH NIH HHS [5 T32 MH20010, MH 53702] NR 46 TC 16 Z9 16 U1 3 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD MAY PY 2007 VL 22 IS 5 BP 520 EP 542 DI 10.1177/0886260506298839 PG 23 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 158LH UT WOS:000245792500003 PM 17429021 ER PT J AU Macy, RJ Nurius, PS Norris, J AF Macy, Rebecca J. Nurius, Paula S. Norris, Jeanette TI Latent profiles among sexual assault survivors - Implications for defensive coping and resistance SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE coping; empowerment; prevention; revictimization; sexual assault ID WOMENS ALCOHOL-CONSUMPTION; CONCEPTUAL-FRAMEWORK; ACQUAINTANCE RAPE; COLLEGE-WOMEN; RISK; AGGRESSION; REVICTIMIZATION; PREVENTION; BEHAVIORS; MODEL AB Rape resistance trainings need to prepare women to recognize and resist sexual assault across a range of experiences and contexts. To help address this need, this research used an investigation of 415 college women who completed a survey about their situational responding to an experience of acquaintance sexual assault. A previously established person-centered analysis model of four distinct risk and protective factor profiles was used to investigate the variability in women's responding. The profiling factors included women's prior victimization, alcohol consumption, relationship expectancies of the assailant, and assertive precautionary habits. Multivariate ANOVA was used to test for differences among the four profile groups on their cognitive, emotional, and behavioral responding. Results showed that the profile groups significantly differed in their assault responses. The findings highlight the utility of holistic, multivariate analyses for understanding women's sexual assault responses and help inform tailored resistance and empowerment trainings. C1 Univ N Carolina, Sch Social Work, Chapel Hill, NC 27599 USA. Univ Washington, NIMH, Prevent Res Training Program, Seattle, WA 98195 USA. Univ Washington, Inst Alcohol & Drug Abuse, Seattle, WA 98195 USA. RP Macy, RJ (reprint author), Univ N Carolina, Sch Social Work, Tate Turner Kuralt Bldg,301 Pittsboro St CB 3550, Chapel Hill, NC 27599 USA. EM rjmacy@email.unc.edu FU NIMH NIH HHS [MH 53702, 5 T32 MH20010] NR 47 TC 15 Z9 15 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD MAY PY 2007 VL 22 IS 5 BP 543 EP 565 DI 10.1177/0886260506298841 PG 23 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 158LH UT WOS:000245792500004 PM 17429022 ER PT J AU Markova, NG Karaman-Jurukovska, N Pinkas-Sarafova, A Marekov, LN Simon, M AF Markova, Nelli G. Karaman-Jurukovska, Nevena Pinkas-Sarafova, Adriana Marekov, Liuben N. Simon, Marcia TI Inhibition of histone deacetylation promotes abnormal epidermal differentiation and specifically suppresses the expression of the late differentiation marker profilaggrin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CULTURED HUMAN KERATINOCYTES; TRANSCRIPTION FACTORS; ICHTHYOSIS VULGARIS; GENE-EXPRESSION; TRICHOSTATIN-A; MESSENGER-RNA; COMPLEX; PROTEIN; CANCER; CELLS AB Reversible protein acetylation modulates higher-order chromatin structure and transcription activity of the genome. The reversible acetylation is executed by the intrinsic acetylase and deacetylase activities of coregulators associated with the regulatory regions. Compounds capable of inhibiting deacetylase activity are a powerful tool for dissecting the role of protein acetylation in gene function. The ability of the deacetylase inhibitors to preferentially affect the homeostasis of transformed cells has also prompted studies for their clinical application. We present evidence that deacetylase inhibition with trichostatin A (TSA) affects the normal epidermal tissue architecture and pattern of expression by a mechanism(s) that does not correlate directly with the hyperacetylated histone status. While promoting abnormal differentiation, TSA specifically represses transcription initiation of the differentiation marker profilaggrin. Multiple factors, among which we have identified decreased Sp1 binding, a local decrease in acetylation activity, and enhanced synthesis and recruitment of a repressor histone demethylase, alter the chromatin configuration over the promoter, ultimately blocking its activation by c-jun. As compromised profilaggrin production leads to epidermal and consequently allergic disorders, our findings emphasize the need for a detailed investigation of the role deacetylase inhibitors may play in the maintenance of epidermal homeostasis in order to optimize their clinical applicability. C1 SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Living Skin Bank, Stony Brook, NY 11794 USA. NIAMS, Struct Biol Lab, NIH, Bethesda, MD USA. RP Markova, NG (reprint author), SUNY Stony Brook, Sch Dent Med, Dept Oral Biol & Pathol, Living Skin Bank, Stony Brook, NY 11794 USA. EM nmarkova@notes.cc.sunysb.edu; marsimon@notes.cc.sunysb.edu NR 59 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2007 VL 127 IS 5 BP 1126 EP 1139 DI 10.1038/sj.jid.5700684 PG 14 WC Dermatology SC Dermatology GA 159TO UT WOS:000245889900018 PM 17195011 ER PT J AU Yamaguchi, Y Passeron, T Watabe, H Yasumoto, K Rouzaud, F Hoashi, T Hearing, VJ AF Yamaguchi, Yuji Passeron, Thierry Watabe, Hidenori Yasumoto, Ken-ichi Rouzaud, Francois Hoashi, Toshihiko Hearing, Vincent J. TI The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: Mechanisms underlying its suppression of melanocyte function and proliferation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; PROTEIN-KINASE-C; MESENCHYMAL-EPITHELIAL INTERACTIONS; BETA-CATENIN; PALMOPLANTAR FIBROBLASTS; TRANSCRIPTION FACTOR; P38 MAPK; RECEPTOR; PATHWAY; MITF AB Dickkopf 1 (DKK1), which is expressed at high mRNA levels by fibroblasts in the dermis of human skin on the palms and soles, inhibits the function and proliferation of melanocytes in the epidermis of those areas via the suppression of beta-catenin and microphthalmia-associated transcription factor (MITF). In this study, we investigated the protein expression levels of DKK1 between palmoplantar and non-palmoplantar areas and the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology, reverse transcriptase-PCR, Western blot, 3-dimensional reconstructed skin, immunocytochemistry, and immunohistochemistry. DKK1-responsive genes included those encoding proteins involved in the regulation of melanocyte development, growth, differentiation, and apoptosis (including Kremen 1, G-coupled receptor 51, lipoprotein receptor-related protein 6, low-density lipoprotein receptor, tumor necrosis factor receptor super-family 10, growth arrest and DNA-damage- inducible gene 45 beta, and MITF). Of special interest was the rapid decrease in expression of MITF in melanocytes treated with DKK1, which is concurrent with the decreased activities of beta-catenin and of glucose-synthase kinase 3 beta via phosphorylation at Ser9 and with the upregulated expression of protein kinase C alpha. These results further clarify the mechanism by which DKK1 suppresses melanocyte density and differentiation, and help explain why DKK1-rich palmoplantar epidermis is paler than non-palmoplantar epidermis via mesenchymal-epithelial interactions. C1 Osaka Univ, Grad Sch Med, Dept Dermatol, Osaka 5650871, Japan. NCI, Lab Cell Biol, NIH, Bethesda, MD 20892 USA. RP Yamaguchi, Y (reprint author), Osaka Univ, Grad Sch Med, Dept Dermatol, 2-2 Yamadaoka,Suita Shi, Osaka 5650871, Japan. EM yujin@derma.med.osaka-u.ac.jp RI Yamaguchi, Yuji/B-9312-2008; OI Passeron, Thierry/0000-0002-0797-6570 FU Intramural NIH HHS NR 49 TC 45 Z9 46 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2007 VL 127 IS 5 BP 1217 EP 1225 DI 10.1038/sj.jid.5700629 PG 9 WC Dermatology SC Dermatology GA 159TO UT WOS:000245889900029 PM 17159916 ER PT J AU Clarenbach, JJ Vega, GL Adams-Huet, B Considine, RV Ricks, M Summer, AE AF Clarenbach, Jacob J. Vega, Gloria Lena Adams-Huet, Beverley Considine, Robert V. Ricks, Madia Summer, Anne E. TI Variability in postheparin hepatic lipase activity is associated with plasma adiponectin levels in African Americans SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article DE adiponectin; African Americans; hepatic triglycericle lipase ID HIGH-DENSITY-LIPOPROTEIN; POSTPRANDIAL LIPID-METABOLISM; INSULIN-RESISTANCE; GENE LIPC; GLUCOSE-TOLERANCE; SERUM ADIPONECTIN; ADIPOSE-TISSUE; HEART-DISEASE; MEN; HYPOADIPONECTINEMIA AB Background: African Americans commonly have normal high-density lipoprotein cholesterol (HDL-C) and low triglycericle levels despite having insulin resistance and obesity. The higher than expected HDL-C levels are usually attributed to low levels of hepatic triglycericle lipase (HTGL) activity. Factors that regulate HTGL in African Americans are not well delineated. Methods: In the current study, HTGL activity was examined in relation to indices of body fat (body mass index [BMI] and waist circumference [WC]), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR] index), and adipokines (adiponectin and leptin). Sixty-three African Americans (33 men, 30 women; median age 31 years, range 20-50 years; median BMI 28.6 kg/m(2), range 19.7-54.7 kg/m(2)) had anthropometry and measurement of postheparin lipase activities (HTGL), plasma HDL-C, triglycerides, and plasma adiponectin. Results; HTGL correlated strongly with HDL-C (r = -.52, p <.0001) and adiponectin (r = -.49, p <.001). HTGL increased with BMI and WC (r =.297, p =.018 and r =.301, p =.016, respectively). Adiponectin correlated strongly with HDL-C (r =.50, p <.0001) and triglycericles (r = -.493, p <.001). From multiple regression models, 28% of HTGL variability among African Americans can be explained by adiponectin levels in combination with gender and 35% of HTGL is explained with HDL-C included in the model. Conclusion: The data suggest that adiponectin is a significant metabolic concomitant of HTGL activity in African Americans. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Donald W Reynolds Cardiovasc Clin Res Ctr, Ctr Human Nutr, Dallas, TX USA. Vet Affairs Med Ctr, Metab Unit, Dallas, TX USA. Indiana Univ, Sch Med, Div Endocrinol & Metab, Indianapolis, IN USA. RP Vega, GL (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10-CRC,Rm 6-5940,MSC 1612,9000 Rockville Pik, Bethesda, MD 20892 USA. EM Gloria.Vega@utsouthwestern.edu; AnneS@intra.niddk.nih.gov FU Intramural NIH HHS NR 40 TC 6 Z9 6 U1 0 U2 0 PU B C DECKER INC PI HAMILTON PA 50 KING STREET EAST, 2ND FLOOR, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAY PY 2007 VL 55 IS 4 BP 187 EP 194 DI 10.2310/6650.2007.07001 PG 8 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 221OV UT WOS:000250238100015 PM 17651673 ER PT J AU Rosenberg, HF Slifka, MK AF Rosenberg, Helene F. Slifka, Mark K. TI CTLA4, T cell function, and long term immunity: an interview with Dr. Mark K. Slifka SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID CTLA-4-DEFICIENT MICE; LYMPHOPROLIFERATION; SMALLPOX; VACCINATION; MEMORY C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 16 TC 1 Z9 1 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2007 VL 81 IS 5 BP 1176 EP 1178 DI 10.1189/jlb.1306535 PG 3 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 162XC UT WOS:000246121800004 PM 17475786 ER PT J AU Charo, J Robbins, PF AF Charo, Jehad Robbins, Paul F. TI Contrasting effects of FLIPL overexpression in human T cells on activation-induced cell death and cytokine production SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE tumor; autoimmunity; apoptosis; cellular activation; tolerance ID FLICE-INHIBITORY PROTEIN; NF-KAPPA-B; LONG FORM; C-FLIP; CASPASE-8; RECEPTOR; LYMPHOCYTES; PROLIFERATION; EXPRESSION; SURVIVAL AB There have been disparate findings about the role of FLIP in the survival of mouse T cells and human tumor cell lines. The role of cellular FLIP in human T cell activation and function needs to be clarified further. To study this role, we have overexpressed long transcript FLIP (FLIPL) in primary T cells, including self-antigen-reactive, melanoma-specific T cells. We found that FLIPL overexpression protects human T cells from activation-induced cell death and enhances their prolifertive capacity but suppresses the ability of these cells to produce the proinflammatory cytokines IL-2 and IFN-gamma in response to CD3 or antigen-specific stimulation. The multiple effects of FLIPL indicate that this protein may influence T cell responses to antigenic stimulation. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Charo, J (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13092 Berlin, Germany. EM j.charo@mdc-berlin.de RI Charo, Jehad/K-4433-2013 OI Charo, Jehad/0000-0002-5409-9160 NR 33 TC 1 Z9 1 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAY PY 2007 VL 81 IS 5 BP 1297 EP 1302 DI 10.1189/jlb.0306218 PG 6 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 162XC UT WOS:000246121800018 PM 17311934 ER PT J AU Igarashi, M DeMar, JC Ma, KZ Chang, L Bell, JM Rapoport, SI AF Igarashi, Miki DeMar, James C., Jr. Ma, Kaizong Chang, Lisa Bell, Jane M. Rapoport, Stanley I. TI Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is unaffected by dietary n-3 PUFA deprivation SO JOURNAL OF LIPID RESEARCH LA English DT Article DE n-3 polyunsaturated fatty acid; diet; elongation; fatty acid; synthesis ID ESSENTIAL FATTY-ACIDS; NUTRITIONAL DEPRIVATION; DELTA-5 DESATURASE; LIVER CONVERSION; ADULT-RATS; PLASMA; PHOSPHOLIPIDS; RETINA; OMEGA-3-FATTY-ACIDS; DEFICIENT AB Rates of conversion of alpha-linolenic acid (alpha-LNA, 18:3n-3) to docosahexaenoic acid (DHA, 22:6n-3) by the mammalian brain and the brain's ability to upregulate these rates during dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) are unknown. To answer these questions, we measured conversion coefficients and rates in post-weaning rats fed an n-3 PUFA deficient (0.2% alpha-LNA of total fatty acids, no DHA) or adequate (4.6% alpha-LNA, no DHA) diet for 15 weeks. Unanesthetized rats in each group were infused intravenously with [1-C-14]alpha-LNA, and their arterial plasma and microwaved brains collected at 5 minutes were analyzed. The deficient compared with adequate diet reduced brain DHA by 37% and increased brain arachidonic (20:4n-6) and docosapentaenoic 22:5n-6) acids. Only 1% of plasma [1-C-14]alpha-LNA entering brain was converted to DHA with the adequate diet, and conversion coefficients of alpha-LNA to DHA were unchanged by the deficient diet. In summary, the brain's ability to synthesize DHA from alpha-LNA is very low and is not altered by n-3 PUFA deprivation. Because the liver's reported ability is much higher, and can be up-regulated by the deficient diet, DHA converted by the liver from circulating alpha LNA is the source of the brain's DHA when DHA is not in the diet. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Igarashi, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM mikii@mail.nih.gov RI Igarashi, Miki/B-1085-2017 FU Intramural NIH HHS NR 57 TC 86 Z9 89 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAY PY 2007 VL 48 IS 5 BP 1150 EP 1158 DI 10.1194/jlr.M600549-JLR200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 163JF UT WOS:000246155200016 PM 17277380 ER PT J AU Haas, D Morgenthaler, J Lacbawan, F Long, B Runz, H Garbade, SF Zschocke, J Kelley, RI Okun, JG Hoffmann, GF Muenke, M AF Haas, D. Morgenthaler, J. Lacbawan, F. Long, B. Runz, H. Garbade, S. F. Zschocke, J. Kelley, R. I. Okun, J. G. Hoffmann, G. F. Muenke, M. TI Abnormal sterol metabolism in holoprosencephaly: studies in cultured lymphoblasts SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID NEWLY SYNTHESIZED CHOLESTEROL; LEMLI-OPITZ-SYNDROME; HUMAN FIBROBLASTS; SONIC-HEDGEHOG; MUTATIONS; BIOSYNTHESIS; CELLS; ACCUMULATION; INHIBITION; ZYMOSTEROL AB Background: Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans. The aetiology is heterogeneous and remains unexplained in approximately 75% of patients. Objective: To examine cholesterol biosynthesis in lymphoblastoid cell lines of 228 patients with HPE, since perturbations of cholesterol homeostasis are an important model system to study HPE pathogenesis in animals. Methods: An in vitro loading test that clearly identifies abnormal increase of C27 sterols in lymphoblast-derived cells was developed using [2-C-14] acetate as substrate. Results: 22 (9.6%) HPE cell lines had abnormal sterol pattern in the in vitro loading test. In one previously reported patient, Smith-Lemli-Opitz syndrome was diagnosed, whereas others also had clearly reduced cholesterol biosynthesis of uncertain cause. The mean (SD) cholesterol levels were 57% (15.3%) and 82% (4.7%) of total sterols in these cell lines and controls, respectively. The pattern of accumulating sterols was different from known defects of cholesterol biosynthesis. In six patients with abnormal lymphoblast cholesterol metabolism, additional mutations in genes known to be associated with HPE or chromosomal abnormalities were observed. Conclusions: Impaired cholesterol biosynthesis may be a contributing factor in the cause of HPE and should be considered in the evaluation of causes of HPE, even if mutations in HPE-associated genes have already been found. C1 Univ Hosp Pediat & Adolescent Med, Dept Gen Pediat, Div Inborn Metab Dis, D-69120 Heidelberg, Germany. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Haas, D (reprint author), Univ Hosp Pediat & Adolescent Med, Dept Gen Pediat, Div Inborn Metab Dis, Neuenheimer Feld 153, D-69120 Heidelberg, Germany. EM dorothea.haas@med.uni-heidelberg.de RI Garbade, Sven/S-2804-2016 OI Garbade, Sven/0000-0002-7420-4757 FU Intramural NIH HHS NR 35 TC 17 Z9 18 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD MAY PY 2007 VL 44 IS 5 BP 298 EP 305 DI 10.1136/jmg.2006.047258 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 163QM UT WOS:000246177200002 PM 17237122 ER PT J AU Zavitsanou, A Sypsa, V Petrodaskalaki, M Kalapothaki, V Whitby, D Hatzakis, A AF Zavitsanou, Assimina Sypsa, Vana Petrodaskalaki, Maria Kalapothaki, Victoria Whitby, Denise Hatzakis, Angelos TI Human herpesvirus 8 (HHV-8) infection in healthy urban employees from Greece: Seroprevalence and associated factors SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE HHV-8; risk factors; seroepidemiology ID SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; SEXUAL TRANSMISSION; BLOOD-DONORS; RISK-FACTORS; NONSEXUAL TRANSMISSION; CENTRAL-AFRICA; PREVALENCE; ANTIBODIES; POPULATION AB A cross-sectional study was carried out in healthy company employees from Greece with the aim of assessing the prevalence of human herpesvirus 8 (HHV-8) and identifying risk factors for this herpesviral infection. Serum samples obtained from 955 subjects were tested for antibodies to HHV-8 by the K8.1 enzyme-linked immunosorbent assay (ELISA). Associations between HHV-8 serostatus and potential risk factors were examined using t-test, chi square test, and multivariate logistic regression analysis. HHV-8 prevalence was 7.6% (95% confidence interval (0): 6.0%, 9.5%) and it increased with age from 6.5% among < 30 years old to 13.8% among >= 50 years old subjects (P=0.006). HHV-8 seropositivity was independently associated with endoscopic examination (odds ratio (OR): 2.01; 95% Cl: 1.09, 3.70; P=0.026), HBsAg positivity (OR: 5.16; 95% Cl: 2.02, 13.20; P=0.001) and age (OR >= 50 years old vs. < 50 years old: 2.09; 95% Cl: 1.23, 3.52; P= 0.006). No statistically significant associations between HHV-8 positive status and gender, occupational status, surgery, transfusion, tattoos/body piercing, multiple sex partners, weakness/fatigue, HCV status were observed. HHV-8 is prevalent in Greece. The strong association between HBV infection and HHV-8 positive status supports the hypothesis of an association between these two viral infections. The association between HHV-8 seropositivity and endoscopic examination requires further investigation. C1 Univ Athens, Sch Med, Dept Hyg & Epidemiol, GR-11527 Athens, Greece. NCI, Viral Epidemiol Sect, AIDS Vaccine Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Hatzakis, A (reprint author), Univ Athens, Sch Med, Dept Hyg & Epidemiol, 75 Mikras Asias St, GR-11527 Athens, Greece. EM ahatzak@med.uoa.gr RI SYPSA, VANA/A-5082-2008 FU NCI NIH HHS [N01-CO-12400] NR 42 TC 12 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD MAY PY 2007 VL 79 IS 5 BP 591 EP 596 DI 10.1002/jmv.20812 PG 6 WC Virology SC Virology GA 154CP UT WOS:000245484700016 PM 17385692 ER PT J AU Kwak, J Lee, K Shin, DH Maeng, JS Park, DS Oh, HW Son, KH Bae, KS Park, HY AF Kwak, Jangyul Lee, Kieun Shin, Dong-Ha Maeng, Jin-Soo Park, Doo-Sang Oh, Hyun Woo Son, Kwang-Hee Bae, Kyung-Sook Park, Ho-Yong TI Biochemical and genetic characterization of arazyme, an extracellular metalloprotease produced from Serratia proteamaculans HY-3 SO JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE arazyme; metalloprotease; Serratia proteamaculans; HY-3; serralysin; enzymatic kinetics ID STREPTOMYCES-GRISEUS; ESCHERICHIA-COLI; PSEUDOMONAS-AERUGINOSA; ALKALINE PROTEASE; ERWINIA-CHRYSANTHEMI; MARCESCENS; SECRETION; IDENTIFICATION; PURIFICATION; CLONING AB Serratia proteamaculans HY-3 isolated from the digestive tract of a spider produces an extracellular protease named arazyme, with an estimated molecular mass of 51.5 kDa. The purified enzyme was characterized as having high activities at wide pH and temperature ranges. We further characterized biochemical features of the enzymatic reactions under various reaction conditions. The protease efficiently hydrolyzed a broad range of protein substrates including albumin, keratin, and collagen. The dependence of enzymatic activities on the presence of metal ions such as calcium and zinc indicated that the enzyme is a metalloprotease, together with the previous observation that the proteolytic activity of the enzyme was not inhibited by aspartate, cysteine, or serine protease inhibitors, but strongly inhibited by 1, 10-phenanthroline and EDTA. The araA gene encoding the exoprotease was isolated as a 5.6 kb BamHl fragment after PCR amplification using degenerate primers and subsequent Southern hybridization. The nucleotide sequence revealed that the deduced amino acid sequences shared extensive similarity with those of the serralysin family of metal loproteases from other enteric bacteria. A gene (inh) encoding a putative protease inhibitor was also identified immediately adjacent to the araA structural gene. C1 Korea Res Inst Biosci & Biotechnol, Insect Resources Res Ctr, Taejon 305806, South Korea. Insect BioTech Co Ltd, Taejon 305811, South Korea. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Park, HY (reprint author), Korea Res Inst Biosci & Biotechnol, Insect Resources Res Ctr, Taejon 305806, South Korea. EM hypark@kribb.re.kr NR 40 TC 14 Z9 14 U1 0 U2 2 PU KOREAN SOC MICROBIOLOGY & BIOTECHNOLOGY PI SEOUL PA KOREA SCI TECHNOL CENTER #507, 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1017-7825 J9 J MICROBIOL BIOTECHN JI J. Microbiol. Biotechnol. PD MAY PY 2007 VL 17 IS 5 BP 761 EP 768 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 173FT UT WOS:000246859600009 PM 18051297 ER PT J AU Kajdacsy-Balla, A Geynisman, JM Macias, V Setty, S Nanaji, NM Berman, JJ Dobbin, K Melamed, J Kong, X Bosland, M Orenstein, J Bayerl, J Becich, MJ Dhir, R Datta, MW AF Kajdacsy-Balla, A. Geynisman, J. M. Macias, V. Setty, S. Nanaji, N. M. Berman, J. J. Dobbin, K. Melamed, J. Kong, X. Bosland, M. Orenstein, J. Bayerl, J. Becich, M. J. Dhir, R. Datta, M. W. CA Cooperative Prostate Canc TI Practical aspects of planning, building, and interpreting tissue microarrays: The Cooperative Prostate Cancer Tissue Resource experience SO JOURNAL OF MOLECULAR HISTOLOGY LA English DT Article; Proceedings Paper CT Experimental Biology 2004 Annual Meeting CY APR 17-21, 2004 CL Washington, DC DE tissue microarrays; experimental design; immunohistochemistry; prostate cancer ID BREAST-CANCER; INEXPENSIVE METHOD; CULTURED-CELLS; CARCINOMA; EXPRESSION; REPRODUCIBILITY; ANTIBODIES AB This is a review of several new approaches developed at or adopted by the Cooperative Prostate Cancer Tissue Resource (CPCTR) to resolve issues involved in tissue microarray (TMA) construction and use. CPCTR developed the first needle biopsy TMA, allowing researchers to obtain 200 or more consecutive cancer sections from a single biopsy core. Using radiographs of original paraffin blocks to measure tissue thickness we developed a method to produce TMAs with a larger number of usable sections. The modular approach to plan TMA construction is also a novel concept wherein TMAs of different types, such as tumor grade TMAs, metastasis TMA and hormone refractory tumors TMA can be combined to form an ensemble of TMAs with expanded research utility, such as support for tumor progression studies. We also implemented an open access TMA Data Exchange Specification that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. It ensures inter-laboratory reproducibility because it offers information describing the preparation of TMA blocks and slides. There are many important aspects that may be missed by both beginners and experienced investigators in areas of TMA experimental design, human subjects protection, population sample size, selection of tumor areas to sample, strategies for saving tissues, choice of antibodies for immunohistochemistry, and TMA data management. C1 Univ Illinois, Dept Pathol, Chicago, IL 60637 USA. NCI, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Pathol, New York, NY USA. NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA. NYU, Sch Med, Dept Urol, New York, NY 10016 USA. George Washington Univ, Dept Pathol, Washington, DC 20052 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA. Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. RP Kajdacsy-Balla, A (reprint author), Univ Illinois, Dept Pathol, 1818 W Polk St, Chicago, IL 60637 USA. EM aballa@uic.edu OI Melamed, Jonathan/0000-0003-2844-7990 NR 22 TC 27 Z9 28 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1567-2379 J9 J MOL HISTOL JI J. Mol. Histol. PD MAY PY 2007 VL 38 IS 2 BP 113 EP 121 DI 10.1007/s10735-006-9054-5 PG 9 WC Cell Biology SC Cell Biology GA 160XO UT WOS:000245977700002 PM 17318343 ER PT J AU Chung, JY Braunschweig, T Tuttle, K Hewitt, SM AF Chung, Joon-Yong Braunschweig, Till Tuttle, Kimberly Hewitt, Stephen M. TI Tissue microarrays as a platform for proteomic investigation SO JOURNAL OF MOLECULAR HISTOLOGY LA English DT Article; Proceedings Paper CT Experimental Biology 2004 Annual Meeting CY APR 17-21, 2004 CL Washington, DC DE tissue microarray; proteomics; immunohistochemistry; cell line; xenograft ID HUMAN CYTOME PROJECT; PROTEIN EXPRESSION; RNA AB Tissue microarrays have become an essential tool in translational pathology. They are used to confirm results from other experimental platforms, such as expression microarrays, as well as a primary tool to explore the expression profile of proteins by immunohistochemical analysis. Tissue microarrays are routinely used molecular epidemiology, drug development and determining the diagnostic, prognostic and predictive value of new biomarkers. By applying traditional protein based assays, as well as novel assays to the platform, tissue microarrays have gained a new utility as a proteomic tool for both basic science as well as clinical investigation. This article will explore the new approaches that are being applied to tissue microarrays to, characterize the human proteome, and new technologies that allow tissue microarrays to function as a protein array. C1 NCI, Tissue Array Res Program, Pathol Lab, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Hewitt, SM (reprint author), NCI, Tissue Array Res Program, Pathol Lab, Canc Res Ctr,NIH, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural NIH HHS NR 21 TC 9 Z9 9 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1567-2379 J9 J MOL HISTOL JI J. Mol. Histol. PD MAY PY 2007 VL 38 IS 2 BP 123 EP 128 DI 10.1007/s10735-006-9049-2 PG 6 WC Cell Biology SC Cell Biology GA 160XO UT WOS:000245977700003 PM 16953460 ER PT J AU Dat, NT Bae, K Wamiru, A McMahon, JB Le Grice, SFJ Bona, M Beutler, JA Kim, YH AF Dat, Nguyen Tien Bae, KiHwan Wamiru, Antony McMahon, James B. Le Grice, Stuart F. J. Bona, Marion Beutler, John A. Kim, Young Ho TI A dimeric lactone from Ardisia japonica with inhibitory activity for HIV-1 and HIV-2 ribonuclease H SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID VIRUS REVERSE-TRANSCRIPTASE; CONSTITUENTS; PLANTS AB A new dimeric lactone, ardimerin digallate (1), was isolated from the whole plants of Ardisia japonica, along with six known constituents. The structure of 1 was established on the basis of spectroscopic analysis including 1D- and 2D-NMR techniques. Compound 1 inhibited HIV-1 and HIV-2 RNase H in vitro with IC50 values of 1.5 and 1.1 mu M, respectively. C1 Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. NCI, Mol Targets Dev Program, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, SAIC Frederick, Frederick, MD 21702 USA. RP Kim, YH (reprint author), Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. EM yhk@cnu.ac.kr RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 23 TC 25 Z9 27 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD MAY PY 2007 VL 70 IS 5 BP 839 EP 841 DI 10.1021/np060359m PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 171VU UT WOS:000246764300022 PM 17397219 ER PT J AU Kessler, RC Berglund, PA Borges, G Castilla-Puentes, RC Glantz, MD Jaeger, SA Merikangas, KR Nock, MK Russo, LJ Stang, PE AF Kessler, Ronald C. Berglund, Patricia A. Borges, Guilherme Castilla-Puentes, Ruby C. Glantz, Meyer D. Jaeger, Savina A. Merikangas, Kathleen R. Nock, Matthew K. Russo, Leo J. Stang, Paul E. TI Smoking and suicidal behaviors in the national comorbidity survey: Replication SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE epidemiology; mental health; mental disorders; nicotine; smoking; suicidal ideation; suicide plans; suicide attempts ID DUTY ARMY SOLDIERS; PSYCHIATRIC-DISORDERS; NICOTINE DEPENDENCE; CIGARETTE-SMOKING; UNITED-STATES; FAGERSTROM TEST; SUBSTANCE USE; FOLLOW-UP; NCS-R; RISK AB Controversy exists about the role of mental disorders in the consistently documented association between smoking and suicidal behavior. This controversy is addressed here with data from the nationally representative National Comorbidity Survey-Replication (NCS-R). Assessments were made of 12-month smoking, suicidal behaviors (ideation, plans, attempts), and DSM-IV disorders (anxiety, mood, impulse-control, and substance use disorders). Statistically significant odds ratios (2.9 -3.1) were found between 12-month smoking and 12-month suicidal behaviors. However, the associations of smoking with the outcomes became insignificant with controls for DSM-IV mental disorders. Although clear adjudication among contending hypotheses about causal mechanisms cannot be made from the cross-sectional NCS-R data, the results make it clear that future research on smoking and suicidal behaviors should focus more centrally than previous research on mental disorders either as common causes, markers, or mediators. C1 Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Univ Michigan, Inst Social Res, Ann Arbor, MI 48109 USA. Inst Nacl Psiquiatria, Mexico City, DF, Mexico. Univ Autonoma Metropolitana, Mexico City, DF, Mexico. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. NIDA, NIH, Rockville, MD USA. NIMH, NIH, Bethesda, MD 20892 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Galt Associates, Sterling, VA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu OI Borges, Guilherme/0000-0002-3269-0507 FU NIDA NIH HHS [R01 DA016558, R01 DA016558-04]; NIMH NIH HHS [R13 MH066849-04, R13 MH066849, R01-MH069864, R01 MH070884, R01 MH069864, U01 MH060220, U13 MH066849, R13-MH066849, U01 MH060220-06A1, R01 MH070884-02, U01-MH60220, R01 MH069864-03] NR 42 TC 47 Z9 48 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD MAY PY 2007 VL 195 IS 5 BP 369 EP 377 DI 10.1097/NMD.0b013e3180303eb8 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 168AH UT WOS:000246493800002 PM 17502801 ER PT J AU Reimold, M Smolka, MN Schumann, G Zimmer, A Wrase, J Mann, K Hu, XZ Goldman, D Reischl, G Solbach, C Machulla, HJ Bares, R Heinz, A AF Reimold, M. Smolka, M. N. Schumann, G. Zimmer, A. Wrase, J. Mann, K. Hu, X.-Z. Goldman, D. Reischl, G. Solbach, C. Machulla, H.-J. Bares, R. Heinz, A. TI Midbrain serotonin transporter binding potential measured with [C-11]DASB is affected by serotonin transporter genotype SO JOURNAL OF NEURAL TRANSMISSION LA English DT Article DE 5-HTT; SCL6A4; PET; DASB ID POSITRON-EMISSION-TOMOGRAPHY; HEALTHY HUMANS; HUMAN BRAIN; GENETIC-VARIATION; PROMOTER REGION; HUMAN AMYGDALA; POLYMORPHISM; DEPRESSION; AVAILABILITY; ASSOCIATION AB Background. Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [C-11]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. Method. We assessed 5-HTT binding potential (BP2) in the midbrain of 19 healthy subjects with positron emission tomography and [C-11]DASB. Accounting for the hypothesized functional similarity of L (G) and S in driving 5-HTT transcription, we assessed whether LALA homozygotes display increased midbrain BP2 compared with carriers of at least one S allele. Results. BP2 in the midbrain was significantly increased in LALA homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. Conclusions. This in vivo study provides further evidence that subjects homozygous for the L-A allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections. C1 Charite Univ Med Berlin, Dept Psychiat, D-10117 Berlin, Germany. Univ Tubingen, Dept Nucl Med, Tubingen, Germany. Univ Tubingen, PET Ctr, Tubingen, Germany. Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, Mannheim, Germany. Kings Coll London, Inst Psychiat, Sect Addict Biol, London WC2R 2LS, England. NIAAA, NIH, Bethesda, MD USA. RP Heinz, A (reprint author), Charite Univ Med Berlin, Dept Psychiat, Campus Charite Mitte,Schumannstr 20-21, D-10117 Berlin, Germany. EM Andreas.Heinz@charite.de RI Smolka, Michael/B-4865-2011; Goldman, David/F-9772-2010 OI Smolka, Michael/0000-0001-5398-5569; Goldman, David/0000-0002-1724-5405 NR 32 TC 95 Z9 97 U1 3 U2 8 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD MAY PY 2007 VL 114 IS 5 BP 635 EP 639 DI 10.1007/s00702-006-0609-0 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 160XP UT WOS:000245977800015 PM 17225932 ER PT J AU Tang, SC Arumugam, TV Cutler, RG Jo, DG Magnus, T Chan, SL Mughal, MR Telljohann, RS Nassar, M Xin, OY Calderan, A Ruzza, P Guiotto, A Mattson, MP AF Tang, Sung-Chun Arumugam, Thiruma V. Cutler, Roy G. Jo, Dong-Gyu Magnus, Tim Chan, Sic L. Mughal, Mohamed R. Telljohann, Richard S. Nassar, Matthew Xin Ouyang Calderan, Andrea Ruzza, Paolo Guiotto, Andrea Mattson, Mark P. TI Neuroprotective actions of a histidine analogue in models of ischemic stroke SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE camosine analogue; ischemic stroke; lipid peroxidation; neuroprotection ID CENTRAL-NERVOUS-SYSTEM; MEMBRANE LIPID-PEROXIDATION; CEREBRAL-ARTERY OCCLUSION; AMYLOID BETA-PEPTIDE; ENDOGENOUS NEUROPROTECTOR; CARNOSINE PROTECTS; NATURAL HISTIDINE; ALDEHYDIC PRODUCT; SKELETAL-MUSCLE; FREE-RADICALS AB Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Natl Taiwan Univ Hosp, Stroke Ctr, Dept Neurol, Taipei, Taiwan. Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea. Sez Padova, Inst Chim Biomol, Padua, Italy. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21218 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Guiotto, Andrea/A-4720-2009; Arumugam, Thiruma/C-7969-2009; Mat Zain, Mazatulikhma/B-2025-2010; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; Ruzza, Paolo/N-6030-2015; OI Ruzza, Paolo/0000-0002-5596-9295; Tang, Sung-Chun/0000-0003-3731-5973; CALDERAN, ANDREA/0000-0003-4763-0782; nassar, matthew/0000-0002-5397-535X FU Intramural NIH HHS NR 48 TC 45 Z9 46 U1 0 U2 10 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2007 VL 101 IS 3 BP 729 EP 736 DI 10.1111/j.1471-4159.2006.04412.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 158SA UT WOS:000245813600014 PM 17254011 ER PT J AU Shirley, TL Lewers, JC Egami, K Majumdar, A Kelly, M Ceballos-Picot, I Seidman, MM Jinnah, HA AF Shirley, Thomas L. Lewers, J. Chris Egami, Kiyoshi Majumdar, Alokes Kelly, Mairead Ceballos-Picot, Irene Seidman, Michael M. Jinnah, H. A. TI A human neuronal tissue culture model for Lesch-Nyhan disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE high performance liquid chromatography; hypoxanthine-guanine phosphoribosyltransferase; Lesch-Nyhan disease; monoamines; purines; triple helix-forming oligonucleotides ID HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE; PURINE NUCLEOTIDE-METABOLISM; MONOAMINE-OXIDASE ACTIVITY; DEFICIENT TRANSGENIC MICE; GENETIC MOUSE MODEL; CELL-LINES; DOPAMINERGIC-NEURONS; PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE; HUMAN NEUROBLASTOMA; PYRIDINE COENZYMES AB Mutations in the gene encoding the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease, a neurodevelopmental disorder characterized by cognitive, neurological, and behavioral abnormalities. Despite detailed knowledge of the enzyme's function, the key pathophysiological changes that accompany loss of purine recycling are unclear. To facilitate delineating the consequences of HPRT deficiency, four independent HPRT-deficient sublines of the human dopaminergic neuroblastoma, SK-N-BE(2) M17, were isolated by targeted mutagenesis with triple helix-forming oligonucleotides. As a group, these HPRT-deficient cells showed several significant abnormalities: (i) impaired purine recycling with accumulation of hypoxanthine, guanine, and xanthine, (ii) reduced guanylate energy charge and GTP : GDP ratio, but normal adenylate energy charge and no changes in any adenine nucleotide ratios, (iii) increased levels of UTP and NADP(+), (iv) reduced DOPA decarboxylase, but normal monoamines, and (v) reduction in cell soma size. These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency. C1 Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Hop Necker Enfants Malad, Dept Biol, Paris, France. Fac Med Rene Descartes, Paris, France. RP Jinnah, HA (reprint author), Johns Hopkins Univ, Dept Neurol, Meyer Room 6-181,600 N Wolfe St, Baltimore, MD 21287 USA. EM hjinnah@jhmi.edu FU NICHD NIH HHS [HD39795]; NINDS NIH HHS [F32 NS052040] NR 71 TC 19 Z9 19 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2007 VL 101 IS 3 BP 841 EP 853 DI 10.1111/j.1471-4159.2007.04472.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 158SA UT WOS:000245813600024 PM 17448149 ER PT J AU Bang, H Mazumdar, M Zaykin, D AF Bang, Heejung Mazumdar, Madhu Zaykin, Dmitri TI A letter to the editor in reply to "susceptibility to guillain-barre syndrome is associated to polymorphisms of CM genes" by Caporale et al. in the J of Neuroimmunology (2006) 177 : 112-118 SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Letter ID DISEASE C1 Cornell Univ, Div Biostat & Epidemiol, Dept Publ Hlth, Weill Med Coll, New York, NY USA. NIEHS, NIH, Res Triangle Pk, NC USA. RP Bang, H (reprint author), Cornell Univ, Div Biostat & Epidemiol, Dept Publ Hlth, Weill Med Coll, New York, NY USA. EM heb2013@med.cornell.edu FU Intramural NIH HHS [Z01 ES101866-03] NR 17 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAY PY 2007 VL 186 IS 1-2 BP 201 EP 202 DI 10.1016/j.jneuroim.2007.03.004 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 181RB UT WOS:000247452700025 PM 17434603 ER PT J AU Durastanti, V Tovar-Moll, F Evangelou, I Pellegrini, S Ohayon, J Ehrmantraut, M Gaindh, D Cantor, F McFarland, H Bagnato, F AF Durastanti, V. Tovar-Moll, F. Evangelou, I. Pellegrini, S. Ohayon, J. Ehrmantraut, M. Gaindh, D. Cantor, F. McFarland, H. Bagnato, F. TI Macroscopic and microscopic changes in deep grey matter structures of patients with multiple sclerosis SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 17th Meeting of the European-Neurological-Society CY JUN 16-20, 2007 CL Rhodes, GREECE SP European Neurolog Soc C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAY PY 2007 VL 254 SU 3 BP 14 EP 14 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 175SN UT WOS:000247034400042 ER PT J AU Di Prospero, N Baker, A Jeffries, N Fischbeck, K AF Di Prospero, N. Baker, A. Jeffries, N. Fischbeck, K. TI A phase 2 double-blind, placebo-controlled study of idebenone in patients with Friedreich's ataxia SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 17th Meeting of the European-Neurological-Society CY JUN 16-20, 2007 CL Rhodes, GREECE SP European Neurolog Soc C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAY PY 2007 VL 254 SU 3 BP 29 EP 29 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 175SN UT WOS:000247034400096 ER PT J AU O'Toole, O Traynor, BJ Brennan, PN Sheehan, C Corr, B Hardiman, O AF O'Toole, O. Traynor, B. J. Brennan, P. N. Sheehan, C. Corr, B. Hardiman, O. TI Temporal trends in the epidemiology lateral sclerosis in Ireland between 1995 and 2004 SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 17th Meeting of the European-Neurological-Society CY JUN 16-20, 2007 CL Rhodes, GREECE SP European Neurolog Soc C1 Beaumont Hosp, Dublin 9, Ireland. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAY PY 2007 VL 254 SU 3 BP 53 EP 53 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 175SN UT WOS:000247034400185 ER PT J AU Brennan, PN Traynor, BJ Sheehan, C Corr, B Hardiman, O AF Brennan, P. N. Traynor, B. J. Sheehan, C. Corr, B. Hardiman, O. TI ALS - An indicator of neurodegenerative susceptibility? A pilot study SO JOURNAL OF NEUROLOGY LA English DT Meeting Abstract CT 17th Meeting of the European-Neurological-Society CY JUN 16-20, 2007 CL Rhodes, GREECE SP European Neurolog Soc C1 RCSI, Dublin, Ireland. Beaumont Hosp, Dublin 9, Ireland. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAY PY 2007 VL 254 SU 3 BP 185 EP 185 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 175SN UT WOS:000247034400713 ER PT J AU Scagnolari, C Duda, P Bagnato, F De Vito, G Alberelli, A Lavolpe, V Girardi, E Durastanti, V Trojano, M Kappos, L Antonelli, G AF Scagnolari, Carolina Duda, Petra Bagnato, Francesca De Vito, Gabriella Alberelli, Alessia Lavolpe, Vito Girardi, Enrico Durastanti, Valentina Trojano, Maria Kappos, Ludwig Antonelli, Guido TI Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies SO JOURNAL OF NEUROLOGY LA English DT Article DE interferon beta; neutralizing antibodies; multiple sclerosis; MxA; PKR; beta2-microglobulin; neopterin ID SECONDARY PROGRESSIVE MS; IFN-BETA; FOLLOW-UP; EFFICACY; IFN-BETA-1A; THERAPY; DISEASE; REDUCE; TRIAL AB To analyze the in vivo biological effect of anti-interferon beta (IFN-beta) neutralizing antibodies (NABs), blood concentrations of neopterin, beta2microglobulin (Beta2-MG), mRNA-dependent myxovirusresistant protein A (MxA) and dsRNA-dependent protein kinase (PKR) were measured before (predose) and 24 hours after (postdose) IFN-beta administration in 49 patients with multiple sclerosis (MS) with (n = 25) and without (n = 24) NABs. The results indicated that predose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients. A lower inter-individual variability was observed for pre-dose levels of Beta2-MG and neopterin (CVs of 29% and 44%, respectively). Significantly lower pre- and post-dose blood levels of IFN induced markers, except for postdose PKR-mRNA (p = 0.09), were seen in NAB+ compared with NAB-patients and between patients with high (> 200 t(1/10)) and low (<= 200 t(1/10)) NAB titers. A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-induced markers was found. In summary, our findings confirm that NABs affect absolute concentrations of IFN-beta induced markers and suggest that such an effect occurs in a titer-dependent manner. C1 Univ Basel Hosp, Dept Neurol & Res, CH-4031 Basel, Switzerland. Univ Roma La Sapienza, Dept Expt Med, Virol Sect, I-00185 Rome, Italy. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Bari, Dept Neurol & Psychiat Sci, Bari, Italy. Natl Inst Infect Dis L Spallanzani, Rome, Italy. RP Kappos, L (reprint author), Univ Basel Hosp, Dept Neurol & Res, CH-4031 Basel, Switzerland. EM lkappos@uhbs.ch RI SCAGNOLARI, CAROLINA/G-3837-2011 OI SCAGNOLARI, CAROLINA/0000-0003-1044-1478 NR 33 TC 19 Z9 19 U1 0 U2 0 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAY PY 2007 VL 254 IS 5 BP 597 EP 604 DI 10.1007/s00415-006-0332-7 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 169AG UT WOS:000246564500006 PM 17420930 ER PT J AU Litvan, I Chesselet, MF Gasser, T Di Monte, DA Parker, D Hagg, T Hardy, J Jenner, P Myers, RH Price, D Hallett, M Langston, WJ Lang, AE Halliday, G Rocca, W Duyckaerts, C Dickson, DW Ben-Shlomo, Y Goetz, CG Melamed, E AF Litvan, Irene Chesselet, Marie-Francoise Gasser, Thomas Di Monte, Donato A. Parker, Davis, Jr. Hagg, Theo Hardy, John Jenner, Peter Myers, Richard H. Price, Donald Hallett, Mark Langston, William J. Lang, Anthony E. Halliday, Glenda Rocca, Walter Duyckaerts, Charles Dickson, Dennis W. Ben-Shlomo, Yoav Goetz, Christopher G. Melamed, Eldad TI The etiopathogenesis of Parkinson disease and suggestions for future research. Part II SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Review DE Lewy bodies; Parkinson disease; synucleinopathics ID DOPAMINERGIC CELL DEGENERATION; CHAPERONE-MEDIATED AUTOPHAGY; SYNUCLEIN TRANSGENIC MICE; MUTANT ALPHA-SYNUCLEIN; GENOME-WIDE SCAN; OXIDATIVE STRESS; NEURODEGENERATIVE DISEASE; CAENORHABDITIS-ELEGANS; PROTEASOME INHIBITION; LIPID-PEROXIDATION C1 Univ Louisville, Sch Med, Dept Neurol, Movement Disorder Program, Louisville, KY 40202 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Univ Tubingen, D-72074 Tubingen, Germany. Parkinson Inst, Sunnyvale, CA USA. Univ Virginia, Hlth Syst, Charlottesville, VA 22903 USA. NINDS, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. Kings Coll London, London WC2R 2LS, England. Boston Univ, Sch Med, Boston, MA 02215 USA. Johns Hopkins Sch Med, Bethesda, MD USA. Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. Prince Wales Med Res Inst, Sydney, NSW, Australia. Mayo Clin, Coll Med, Rochester, MN USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. Univ Bristol, Bristol BS8 1TH, Avon, England. Rush Univ, Med Ctr, Rush Med Coll, Chicago, IL 60612 USA. RP Litvan, I (reprint author), Univ Louisville, Sch Med, Dept Neurol, Movement Disorder Program, A Bldg,Room 113,500 S Preston St, Louisville, KY 40202 USA. EM i.litvan@louisville.edu RI Hardy, John/C-2451-2009; Halliday, Glenda/E-8555-2011; OI Halliday, Glenda/0000-0003-0422-8398; Dickson, Dennis W/0000-0001-7189-7917; Litvan, Irene/0000-0002-3485-3445 FU Medical Research Council [G0701075]; NIA NIH HHS [R01 AG024040]; Parkinson's UK [G-0907] NR 80 TC 35 Z9 35 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2007 VL 66 IS 5 BP 329 EP 336 DI 10.1097/nen.0b013e318053716a PG 8 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 173DE UT WOS:000246852900001 PM 17483689 ER PT J AU Iacono, D O'Brien, R Resnick, S Zonderman, A Pletnikova, O Rudow, G Crain, B Troncoso, J AF Iacono, Diego O'Brien, Richard Resnick, Susan Zonderman, Alan Pletnikova, Olga Rudow, Gay Crain, Barbara Troncoso, Juan TI Differential nuclear and nucleolar hypertrophy of anterior and posterior cingulate neurons in asymptomatic subjects with AD pathology SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Neuropathologists CY APR 27-30, 2007 CL Washington, DC SP Amer Assoc Neuropathologists C1 Johns Hopkins Univ, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21224 USA. NIA, Triad Technol Ctr, Lab Personal & Cognit, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2007 VL 66 IS 5 BP 419 EP 419 DI 10.1097/01.jnen.0000268934.77826.cf PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 173DE UT WOS:000246852900016 ER PT J AU Londono, D Marques, A Cadavid, D AF Londono, Diana Marques, Adriana Cadavid, Diego TI IL-10 protects the cerebral microcirculation from spirochetal injury SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Neuropathologists CY APR 27-30, 2007 CL Washington, DC SP Amer Assoc Neuropathologists C1 Univ Med & Dent New Jersey, Newark, NJ 07103 USA. NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2007 VL 66 IS 5 BP 432 EP 432 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 173DE UT WOS:000246852900071 ER PT J AU Carter, JJ Lahousse, S Roper, N de la Monte, S AF Carter, Jade Jesika Lahousse, Stephanie Roper, Nitin de la Monte, Suzanne TI Ethanol inhibition of aspartyl-(asparaginyl)-beta-hydroxylase: relevance to impaired neuronal migration in fetal alcohol syndrome SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Neuropathologists CY APR 27-30, 2007 CL Washington, DC SP Amer Assoc Neuropathologists C1 Brown Univ, Providence, RI 02903 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Rhode Isl Hosp, Providence, RI 02903 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2007 VL 66 IS 5 BP 436 EP 436 DI 10.1097/01.jnen.0000268881.06054.0b PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 173DE UT WOS:000246852900090 ER PT J AU Bian, XW Yao, XH Ping, YF Chen, JH Wang, JM AF Bian, Xiu-wu Yao, Xiao-hong Ping, Yi-fang Chen, Jian-hong Wang, Ji Ming TI Glioblastoma stem cells produce angiogenic factors through activation of cbemokine receptor CXCR4 SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 83rd Annual Meeting of the American-Association-of-Neuropathologists CY APR 27-30, 2007 CL Washington, DC SP Amer Assoc Neuropathologists C1 Third Mil Med Univ, SW Hosp, Inst Pathol, Chongqing 400038, Peoples R China. Natl Canc Inst, Ctr Canc Res, Lab Mol Immunoregulat, Frederick, MD 21702 USA. RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2007 VL 66 IS 5 BP 459 EP 459 DI 10.1097/01.jnen.0000268979.21782.6e PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 173DE UT WOS:000246852900185 ER PT J AU McMahon, DBT Olson, CR AF McMahon, David B. T. Olson, Carl R. TI Repetition suppression in monkey inferotemporal cortex: Relation to behavioral priming SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID INFERIOR TEMPORAL CORTEX; LATERAL OCCIPITAL COMPLEX; TERM IMPLICIT MEMORY; EVENT-RELATED FMRI; VISUAL-CORTEX; OBJECT RECOGNITION; NEURAL ACTIVITY; SINGLE NEURONS; REPRESENTATION; ADAPTATION AB In tasks requiring judgments about visual stimuli, humans exhibit repetition priming, responding with increased speed when a stimulus is repeated. Repetition priming might depend on repetition suppression, a phenomenon first observed in monkey inferotemporal cortex (IT) whereby, when a stimulus is repeated, the strength of the neuronal visual response is reduced. If the reduction resulted in sharpening of the cortical representation of the stimulus, and did not just scale it down, then speeded processing might result. To explore the relation between repetition priming and repetition suppression, we monitored neuronal activity in IT while monkeys performed a symmetry decision task. We found 1) that monkeys exhibit repetition priming, 2) that IT neurons simultaneously exhibit repetition suppression, 3) that repetition priming and repetition suppression do not vary in a significantly correlated fashion across trials, and 4) that repetition suppression scales down the representation of the stimulus without sharpening it. We conclude that repetition suppression accompanies repetition priming but is unlikely to be its cause. C1 Univ Pittsburgh, Mellon Inst, Ctr Neural Basis Cognit, Pittsburgh, PA USA. Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. RP McMahon, DBT (reprint author), NIH, Neuropsychol Lab, 49 Convent Dr, Bethesda, MD 20892 USA. EM dbtm@mit.edu FU NCRR NIH HHS [P41-RR-03631]; NEI NIH HHS [EY-08098, EY-11831]; NINDS NIH HHS [NS-43876] NR 50 TC 54 Z9 55 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAY PY 2007 VL 97 IS 5 BP 3532 EP 3543 DI 10.1152/jn.01042.2006 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 188QD UT WOS:000247933500035 PM 17344370 ER PT J AU Liang, ZQ Wang, XX Li, LY Wang, YM Chen, RW Chuang, DM Chase, TN Qin, ZH AF Liang, Zhorig-Qin Wang, Xiaoxia Li, Ling-Yun Wang, Yumei Chen, Ren-Wu Chuang, De-Maw Chase, Thomas N. Qin, Zheng-Hong TI Nuclear factor-kappa B-dependent cyclin D1 induction and DNA replication associated with N-methyl-D-aspartate receptor-mediated apoptosis in rat striatum SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE excitotoxicity; apoptosis; NF-kappa B; cell cycle; cyclin D1; DNA replication ID NEURONAL CELL-DEATH; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; POSTMITOTIC NEURONS; KINASE INHIBITORS; CEREBRAL-ISCHEMIA; NERVOUS-SYSTEM; IN-VIVO; EXPRESSION; SURVIVAL AB Cell cycle reentry has been found during apoptosis of postmitotic neurons under certain pathological conditions. To evaluate whether nuclear factor-kappa B (NF-kappa B) activation promotes cell cycle entry and neuronal apoptosis, we studied the relation among NF-kappa B-mediated cyclin induction, bromodeoxyuridine (BrdU) incorporation, and apoptosis initiation in rat striatal neurons following excitotoxic insult. Intrastriatally injected N-methyl-D-aspartate receptor agonist quinolinic acid (QA, 60 nmol) elicited a rise in cyclin D1 mRNA and protein levels (P < 0.05). QA-induced NF-kappa B activation occurred in striatal neurons and nonneuronal cells and partially colocalized with elevated cyclin D1 immunoreactivity and TUNEL-positive nuclei. QA triggered DNA replication as evidenced by BrdU incorporation; some striatal BrdU-positive cells were identified as neurons by colocalization with NeuN. Blockade of NF-kappa B nuclear translocation with the recombinant peptide NF-kappa B SN50 attenuated the QA-induced elevation in cyclin D1 and BrdU incorporation. QA-induced internucleosomal DNA fragmentation was blunted by G(1)/S-phase cell cycle inhibitors. These findings suggest that NF-kappa B activation stimulates cyclin D1 expression and triggers DNA replication in striatal neurons. Excitotoxin-induced neuronal apoptosis may thus result from, at least partially, a failed cell cycle attempt. (C) 2007 Wiley-Liss, Inc. C1 Soochow Univ, Sch Med, Dept Pharmacol, Suzhou 215007, Peoples R China. Soochow Univ, Sch Med, Lab Aging & Nervous Dis, Suzhou 215007, Peoples R China. NIMH, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Qin, ZH (reprint author), Soochow Univ, Sch Med, Dept Pharmacol, Suzhou 215007, Peoples R China. EM zhqin5@hotmail.com NR 70 TC 15 Z9 19 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 1 PY 2007 VL 85 IS 6 BP 1295 EP 1309 DI 10.1002/jnr.21248 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 174GG UT WOS:000246929600015 PM 17385714 ER PT J AU Foroud, T Koller, D Lai, DB Woo, D Sauerbeck, L Hornung, R Wiebers, D Connolly, ES Andcrson, C Rouleau, G Deka, R Meissner, I Bailey-Wilson, J Huston, J Brown, RD Broderick, JP AF Foroud, Tatiana Koller, Daniel Lai, Dongbing Woo, Daniel Sauerbeck, Laura Hornung, Richard Wiebers, David Connolly, E. Sander Andcrson, Craig Rouleau, Guy Deka, Ranjan Meissner, Irtne Bailey-Wilson, Joan Huston, John, III Brown, Robert D., Jr. Broderick, Joseph P. TI Genome-wide SNP linkage screen for intracranial aneurysm susceptibility genes SO JOURNAL OF NEUROSURGERY LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Univ Cincinnati, Cincinnati, OH USA. Indiana Univ, Indianapolis, IN 46204 USA. Mayo Clin, Rochester, MN USA. Columbia Univ, New York, NY USA. Univ Sydney, Sydney, NSW 2006, Australia. Univ Montreal, Montreal, PQ, Canada. NHGRI, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD MAY PY 2007 VL 106 IS 5 BP A943 EP A944 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 161WQ UT WOS:000246047800035 ER PT J AU Alexander, S Kerr, ME Kim, Y Kamboh, MI Beers, SR Conley, YP AF Alexander, Sheila Kerr, Mary E. Kim, Yookyung Kamboh, M. Ilyas Beers, Sue R. Conley, Yvette P. TI Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE apolipoprotein E; genotype; outcome; traumatic brain injury ID SYSTEM INFLAMMATORY RESPONSE; NERVOUS-SYSTEM; HEAD-INJURY; TRANSGENIC MICE; APOE GENOTYPE; AMYLOID ANGIOPATHY; E EPSILON-4; E4; CHOLESTEROL; PROTEIN AB Presence of the apolipoprotein E (APOE) 4 allele has been associated with increased incidence and faster progression of neurodegenerative diseases, poorer recovery from neurologic insult, and decreased cognitive function in the well-elderly. The specific association between APOE genotype and recovery from severe traumatic brain injury (TBI) is conflicting with many groups finding the APOE 4 allele to be associated with poorer outcome while others have found no association. The purpose of this study was to investigate the association between APOE 4 allele presence and recovery during the two years after injury from severe TBI in light of other potential covariates, such as age, race, gender, hypotension or hypoxia before hospital admission and severity of injury. APOE genotype was determined for 123 subjects with severe TBI. Glasgow outcome score (GOS) and mortality were collected at 3, 6, 12, and 24 months after injury. Results showed individuals improved over the two year period following injury and those with the 4 allele had a slower recovery rate than those without the APOE 4 allele over the two year period. We did not however find significant differences in GOS at individual time points when controlling for other covariates. Our findings suggest that APOE 4 allele presence influences recovery rate from severe TBI independent of other covariates. The findings of this study are unique in that they address not only the relationship between APOE 4 allele presence and outcome from severe TBI, but also describe differences in trajectory of recovery by APOE 4 allele presence. C1 Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. NINR, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15261 USA. RP Conley, YP (reprint author), Univ Pittsburgh, Dept Human Genet, 440 Victoria Bldg,3500 Victoria St, Pittsburgh, PA 15261 USA. EM yconley@pitt.edu OI Kamboh, M. Ilyas/0000-0002-3453-1438 FU NINDS NIH HHS [NS30318]; NINR NIH HHS [NR04801] NR 37 TC 42 Z9 44 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAY PY 2007 VL 24 IS 5 BP 790 EP 797 DI 10.1089/neu/2006.0133 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 167YT UT WOS:000246489300004 PM 17518534 ER PT J AU Uthus, EO Ross, SA AF Uthus, Eric O. Ross, Sharon A. TI Dietary selenium affects homocysteine metabolism differently in Fisher-344 rats and CD-1 mice SO JOURNAL OF NUTRITION LA English DT Article ID GLYCINE N-METHYLTRANSFERASE; YEAST-BASED DIET; S-ADENOSYLMETHIONINE; PLASMA GLUTATHIONE; DNA METHYLATION; DEFICIENCY; METHIONINE; CYSTEINE; TISSUES; FOLATE AB In our previous work with rats, plasma and tissue homocysteine concentrations were decreased by selenium deprivation. The purpose of this study was to follow up and expand on that work by determining the effects of selenium status (deficient, adequate, and supranutritional) on several aspects of homocysteine metabolism involving methionine recycling and transsulfuration. A 2nd objective was to determine whether there are differences in how selenium status affects homocysteine metabolism in rats and mice. Male weanling Fischer-344 rats and male weaning CD-1 mice were fed diets containing 0, 0.2, or 2.0 mu g selenium (as sodium selenite)/g for 72 d or 60 d, respectively. Plasma homocysteine and cysteine were significantly decreased by feeding rats or mice the selenium-deficient diet compared with feeding adequate or supranutritional selenium. On the other hand, plasma glutathione was increased by selenium deficiency only in rats. Also, the specific activities of liver betaine homocysteine methyltransferase and glycine N-methyltransferase were decreased by selenium deficiency in rats, but were unaffected by selenium status in mice. Real-time RT-PCR was used to determine the expression of the subunits of glutamate-cysteine ligase, which catalyzes the rate-limiting step in glutathione biosynthesis. The expression of Gclc, the catalytic subunit of glutamate-cysteine ligase, was upregulated by selenium deprivation in both rat and mouse liver. Gclm, the modifier subunit of glutamate-cysteine ligase, was downregulated in rats fed 2 mu g Se/g compared with rats fed adequate or deficient selenium. Based on these findings, it is evident that selenium deficiency has different outcomes in mice and rats. These variables are all related to methionine/methyl metabolism. Although only one strain of rat was compared with one strain of mouse, this work suggests that differences between species may prove vital in determining which animal model is used in studies of selenium deficiency or in studies that are designed to ascertain chemopreventive mechanisms of selenium. C1 USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. NCI, NIH, Nutr Sci Res Grp, Rockville, MD 20892 USA. RP Uthus, EO (reprint author), USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. EM euthus@gfhnrc.ars.usda.gov NR 35 TC 21 Z9 22 U1 1 U2 3 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAY PY 2007 VL 137 IS 5 BP 1132 EP 1136 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 159QZ UT WOS:000245882600002 PM 17449570 ER PT J AU Lawrance, AK Deng, LY Brody, LC Finnell, RH Shane, B Rozen, R AF Lawrance, Andrea K. Deng, Liyuan Brody, Lawrence C. Finnell, Richard H. Shane, Barry Rozen, Rima TI Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apc(min/+) mice SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE folate metabolism; folate transport; tumorigenesis; intestinal neoplasia ID DEOXYNUCLEOTIDE POOL IMBALANCE; METHIONINE SYNTHASE GENE; FOLIC-ACID DEFICIENCY; HAMSTER OVARY CELLS; METHYLENETETRAHYDROFOLATE REDUCTASE; COLORECTAL-CANCER; INTESTINAL TUMORIGENESIS; URACIL MISINCORPORATION; DNA METHYLATION; DIETARY-FOLATE AB Epidemiological studies indicate that adequate dietary folate is protective against colon cancer, although mechanisms remain largely elusive. We investigated the effects of genetic disruptions of folate transport and metabolism and of dietary folate deficiency in a mouse model of colon cancer, the Apc(min/+) mouse. Apc(min/+) mice with heterozygous knockout of the gene for reduced folate carrier 1 (Rfc1(+/-)) developed significantly fewer adenomas compared to Rfc1(+/+)Apc mice [30.3 +/- 4.6 vs. 60.4 +/- 9.4 on a control diet (CD) and 42.6 +/- 4.4 vs. 55.8 +/- 7.6 on a folate-deficient diet, respectively]. Rfc1(+/-)Apc(min/+) mice also carried a lower tumor load, an indicator of tumor size as well as of tumor number. In contrast, there were no differences in adenoma formation between Apcmin/+ mice carrying a knockout allele for methionine synthase (Mtr(+/-) an enzyme that catalyzes folate-dependent homocysteine remethylation, and Mtr(+/+)Apc(min/+) mice. However, in both Mtr groups of mice, dietary folate deficiency significantly increased adenoma number (from 32.3 +/- 3.8 on a CD to 48.1 +/- 4.2 on a folate-deficient diet), increased plasma homocysteine, decreased global DNA methylation in preneoplastic intestines and increased apoptosis in tissues. There were no genotype-associated differences in these parameters in the Rfc1 group, suggesting that the protection conferred by Rfc1 deficiency is carried out through a different mechanism. In conclusion, genetic and nutritional disturbances in folate metabolism can have distinct influences on tumorigenesis in Apc(min/+) mice; altered levels of homocysteine, global DNA methylation and apoptosis may contribute mechanistically to dietary influence. (c) 2007 Elsevier Inc. All rights reserved. C1 McGill Univ, Res Inst, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada. McGill Univ, Montreal Childrens Hosp, Inst Res, Dept Pediat, Montreal, PQ, Canada. McGill Univ, Dept Biol, Montreal Childrens Hosp, Res Inst, Montreal, PQ, Canada. NHGRI, Genome Technol Branch, Bethesda, MD USA. Texas A&M Univ, Ctr Hlth Sci, Inst Biosci & Technol, Houston, TX USA. Univ Calif Berkeley, Dept Nutr Sci, Berkeley, CA 94720 USA. RP Rozen, R (reprint author), McGill Univ, Res Inst, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada. EM rima.rozen@mcgill.ca FU Intramural NIH HHS; NIDDK NIH HHS [DK42033] NR 45 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD MAY PY 2007 VL 18 IS 5 BP 305 EP 312 DI 10.1016/j.jnutbio.2006.06.001 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 164LY UT WOS:000246236500003 PM 16963246 ER PT J AU Lee, M Bae, MA AF Lee, Myoungsook Bae, Myung-Ae TI Docosahexaenoic acid induces apoptosis in CYP2E1-containing HepG2 cells by activating the c-Jun N-terminal protein kinase related mitochondrial damage SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE DHA; apoptosis; HepG2 cells; CYP2E1; lipid peroxides (LPOs); JNK activation; MAP kinases ID CYTOCHROME-P450 2E1; OXIDATIVE STRESS; GENE-EXPRESSION; MAP KINASES; FATTY-ACIDS; RAT-LIVER; DEATH; ACETAMINOPHEN; CYTOTOXICITY; ALCOHOL AB Docosahexaenoic acid (DHA) causes apoptosis of various cancer cells, but the mechanism of DHA-induced cell death is still unclear. We hypothesized that the early signaling of apoptosis may be important in causing cell death as well as the production of free radical metabolites. DHA caused time- and dose-dependent cell death in human HepG2 hepatoma cells transduced with CYP2E1 (E47) but not in C34 (without CYP2E1), suggesting an important role of CYP2E1 in the DHA-mediated damage. DHA increased the c-Jun N-terminal protein kinase (JNK) activity until 8 h without activating other mitogen-activated protein kinases. The contents of proapoptotic Bad and FasL at 4 h and cytochrome c and caspase 3 activity at 8 h were increased and accompanied by the INK activation in a successive manner. In contrast, Bax and Bcl-2 were not changed. Levels of lipid peroxides (LPOs) were elevated three- and fivefold at 8 and 24 h, respectively, in DHA-induced E47 cells. However, pretreatment with chlonnethiazole (CMZ), a specific inhibitor of CYP2E1, significantly reduced the levels of LPO, CYP2E1, JNK activity and the rate of cell death. In addition, pretreatment with quercetin (one as a JNK inhibitor and one as an antioxidant) significantly reduced the cell death rate and JNK and SEK-1 activities. Our results indicated that DHA-mediated apoptosis in E47 cells was induced through the activation of the JNK-related cell death pathway, which may be involved in the production of LPO or reactive oxygen species during the CYP2E1 catalytic cycle, followed by mitochondrial injury and apoptosis. (c) 2007 Elsevier Inc. All rights reserved. C1 Sungshin Womens Univ, Dept Food & Nutr, Seoul 136742, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD USA. RP Lee, M (reprint author), Sungshin Womens Univ, Dept Food & Nutr, Seoul 136742, South Korea. EM mlee@sungshin.ac.kr OI Lee, Myoungsook/0000-0003-1344-6979 NR 37 TC 17 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD MAY PY 2007 VL 18 IS 5 BP 348 EP 354 DI 10.1016/j.jnutbio.2006.06.003 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 164LY UT WOS:000246236500008 PM 16963249 ER PT J AU Bakke, B Stewart, PA Waters, MA AF Bakke, Berit Stewart, Patricia A. Waters, Martha A. TI Uses of and exposure to trichloroethylene in US industry: A systematic literature review SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HYGIENE LA English DT Review DE case-control study; degreasing; exposure assessment; SIC; trichloroethylene ID ACUTE RENAL-FAILURE; OCCUPATIONAL-EXPOSURE; ORGANIC-COMPOUNDS; VAPOR DEGREASERS; CELL CANCER; WORKERS; INHALATION; MORTALITY; SOLVENTS; DISEASE AB This article describes a systematic review of the industrial hygiene literature for uses of trichloroethylene (TCE) in industry for the exposure assessment of two population-based case control studies of brain cancer in the United States. Papers and reports that address uses of and exposures to TCE were identified from MEDLINE, TOXLINE, NIOSHTIC, the NIOSH Health Hazard Evaluation database (keywords: chlorinated solvents and trichloroethylene), and in other reviews. This search was complemented by reviewing the reference lists from the identified literature. The collected information was systematized by the Standard Industrial Classification (SIC) system, and measurement data reported in the literature were summarized in a database. TCE use was extensive front the early 1920s through the 1970s mainly as a degreasing agent in metal-fabricating operations. After the 1970s it became less popular because of environmental concerns. TCE historically has had a multitude of uses in many other industries, e.g., dry cleaning, textile, electronics, leather, and rubber. Also, many products like adhesives, drugs, paints, inks, and various industrial products have contained TCE. It was banned as a food additive and in cosmetics in 1977. The arithmetic mean (AM) of the measurements across all industries and decades was 38.2 ppm. The highest personal and area air levels were reported in vapor degreasing (AM of 44.6 ppm). Most TCE measurements were performed in the 1950s, 1970s, and 1980s. The data described here could be used by exposure assessors as is to identify the presence and approximate levels of exposure. Using the same information as a basis should increase the reliability of the assessments, making it easier to compare both the exposure assessment methods and the epidemiologic results across different studies. C1 NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, US Dept HHS,NIH, Rockville, MD 20852 USA. Natl Inst Occupat Hlth, Oslo, Norway. NIOSH, Cincinnati, OH 45226 USA. RP Stewart, PA (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, US Dept HHS,NIH, 6120 Execut Blvd,Bldg EPS 8102, Rockville, MD 20852 USA. EM stewartt@epndce.nci.nih.gov RI Waters, Martha/B-7441-2011 FU Intramural NIH HHS NR 174 TC 46 Z9 46 U1 4 U2 28 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1545-9624 J9 J OCCUP ENVIRON HYG JI J. Occup. Environ. Hyg. PD MAY PY 2007 VL 4 IS 5 BP 375 EP 390 DI 10.1080/15459620701301763 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 165WS UT WOS:000246338600012 PM 17454505 ER PT J AU Valcin, M Henneberger, PK Kullman, GJ Umbach, DM London, SJ Alavanja, MCR Sandler, DP Hoppin, JA AF Valcin, Martin Henneberger, Paul K. Kullman, Greg J. Umbach, David M. London, Stephanie J. Alavanja, Michael C. R. Sandler, Dale P. Hoppin, Jane A. TI Chronic bronchitis among nonsmoking farm women in the agricultural health study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; CHRONIC RESPIRATORY SYMPTOMS; PESTICIDE APPLICATORS; LUNG-DISEASES; YOUNG-ADULTS; RISK-FACTORS; EXPOSURE; ASTHMA; ASSOCIATION; OCCUPATION AB Objective: The purpose of this study was to examine agricultural risk factors for chronic bronchitis among nonsmoking farm women. Methods: We used self-reported enrollment data from the 21,541 nonsmoking women in the Agricultural Health Study to evaluate occupational risk factors for prevalent chronic bronchitis among farm women. Odds ratios (ORs) for chronic bronchitis for occupational exposures were adjusted and related agricultural exposures. Results: Applying for age state,, manure and driving combines were independently associated with chronic bronchitis. Off-farm job exposures associated with chronic bronchitis were organic dusts, asbestos, gasoline, and solvents. Five pesticides were associated with chronic bronchitis after multivariate adjustment and sensitivity analyses: dichlorvos (OR = 1.63, 95% CI = 1.01, 2.61), DDT (OR = 1.67, 95% CI = 1.13, 2.47), cyanazine (OR = 1.88, 95% CI = 1.00, 3.54), paraquat (OR = 1.91, 95% CI = 1.02, 3.55), and methyl bromide (OR = 1.82, 95% CI = 1.02, 3.24). Conclusion: Pesticides as well as grain and dust exposures were associated with chronic bronchitis among nonsmoking farm women. C1 NIEHS, Biostat Branch, DHHS, NIH, Res Triangle Pk, NC 27709 USA. NIOSH, Field Studies Branch, Morgantown, WV USA. NCI, Occupat Epidemiol Branch, DHHS, NIH, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS [Z01 ES049030-11] NR 35 TC 25 Z9 27 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD MAY PY 2007 VL 49 IS 5 BP 574 EP 583 DI 10.1097/JOM.0b013e3180577768 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 167ZX UT WOS:000246492600013 PM 17495700 ER PT J AU Ito, Y Yamanoshita, O Asaeda, N Tagawa, Y Lee, CH Aoyama, T Ichihara, G Furuhashi, K Kamijima, M Gonzalez, FJ Nakajima, T AF Ito, Yuki Yamanoshita, Osamu Asaeda, Nobuyuki Tagawa, Yoshiaki Lee, Chul-Ho Aoyama, Toshifumi Ichihara, Gaku Furuhashi, Koichi Kamijima, Michihiro Gonzalez, Frank J. Nakajima, Tarnie TI Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor alpha-independent pathway SO JOURNAL OF OCCUPATIONAL HEALTH LA English DT Article DE di(2-ethylhexyl)phthalate; Ppar alpha-null mouse; tumorigenesis; NF-kappa B; 8-OHdG; c-jun; inflammation ID OXIDATIVE DNA-DAMAGE; NF-KAPPA-B; PPAR-ALPHA; PHTHALATE DEHP; ENVIRONMENTAL CHEMICALS; MICE; LIVER; RATS; MECHANISMS; CANCER AB Di(2-ethyl hexyl) phthal ate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPAR(alpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPAR alpha, we compared DEHP-induced tumorigenesis in wild-type and Ppar alpha-null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Ppara-null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10.0%). These results suggest the existence of pathways for DEHP-induced hepatic tumorigenesis that are independent of PPARa. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Ppara-null than in wild-type mice. NF kappa B levels also significantly increased in a dose-dependent manner in Ppar alpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Ppar alpha-null mice fed a 0.05% DEHP-containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Ppar alpha-null mice. C1 Nagoya Univ, Dept Environm & Occupat Hlth, Grad Sch Med, Showa Ku, Nagoya, Aichi 4668550, Japan. Chubu Univ, Dept Biomed Sci, Coll Life & Hlth Sci, Kasugai, Aichi 487, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Dept Environm & Occupat Hlth, Grad Sch Med, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp RI Ito, Yuki/C-3698-2008 NR 36 TC 68 Z9 74 U1 3 U2 6 PU JAPAN SOC OCCUPATIONAL HEALTH PI TOKYO PA 1-29-8 SHINJUKU, SHINJUKU-KU, TOKYO, 160, JAPAN SN 1341-9145 J9 J OCCUP HEALTH JI J. Occup. Health PD MAY PY 2007 VL 49 IS 3 BP 172 EP 182 DI 10.1539/joh.49.172 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 178AJ UT WOS:000247193300002 PM 17575397 ER PT J AU Kim, H Morimoto, Y Ogami, A Nagatomo, H Hirohashi, M Oyabu, T Kawanami, Y Kuroda, E Higashi, T Tanaka, I AF Kim, Heungnam Morimoto, Yasuo Ogami, Akira Nagatomo, Hiroko Hirohashi, Masami Oyabu, Takako Kawanami, Yukiko Kuroda, Etsushi Higashi, Toshiaki Tanaka, Isamu TI Differential expression of EC-SOD, Mn-SOD and CuZn-SOD in rat lung exposed to crystalline silica SO JOURNAL OF OCCUPATIONAL HEALTH LA English DT Article DE extracellular superoxide dismutase; manganese-containing superoxide dismutase; copper- and zinc-containing superoxide dismutase; reactive oxygen species; crystalline silica ID EXTRACELLULAR-SUPEROXIDE-DISMUTASE; ANTIOXIDANT ENZYMES; EPITHELIAL-CELLS; FREE-RADICALS; INHALATION; ASBESTOS; DISEASE; GENERATION AB Superoxide dismutases (SODs) are antioxidant enzymes that catalyze the dismutation of superoxide into hydrogen peroxide. There are 3 kinds of isozymes: extracellular superoxide dismutase (EC-SOD), manganese-containing superoxide dismutase (Mn-SOD) and copper- and zinc-containing superoxide dismutase (CuZn-SOD). To examine the expression of SOD isozymes in lungs injured by crystalline silica, we intratracheally instilled male Wistar rats with 2 mg (8 mg/kg) of crystalline silica and investigated the mRNA, protein level and distribution of SOD isozymes in the rat lungs using RTPCR, western blot analysis and immunostaining, respectively at from 3 d to 180 d of recovery following the exposure. EC-SOD mRNA levels significantly increased from 3 d to 90 d and the EC-SOD protein level was significantly higher after 90 and 180 d recovery in the crystalline silica exposed groups than in the control groups. Mn-SOD increased in silica treated rat lungs at both mRNA and protein levels, peaking at 30 d post-exposure. CuZn-SOD mRNA levels were decreased at 3, 7 and 30 cl, and CuZn-SOD protein levels were also significantly lower than the control group at 90 and 180 d recovery. There was prominent EC-SOD immunostaining mainly in the plasma and alveolar macrophages and strong Mn-SOD staining in alveolar macrophages and interstitial cells of the proximal and distal portions of the alveolar duct following crystalline silica exposure. There was less CuZn-SOD staining in epithelial cells at terminal bronchioles in the crystalline silica-exposed group. These findings suggest that these SOD isozymes may be related to lung injury induced by crystalline silica. C1 Univ Occupat & Environm Hlth, Dept Occupat Pneumol, Inst Ind Ecol Sci, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Occupat & Environm Hlth, Dept Environm Hlth Engn, Inst Ind Ecol Sci, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Dept Resp Dis, Sch Med, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Dept Immunol & Parasitol, Sch Med, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Dept Work Syst & Hlth, Inst Ind Ecol Sci, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. RP Morimoto, Y (reprint author), Univ Occupat & Environm Hlth, Dept Occupat Pneumol, Inst Ind Ecol Sci, Yahatanishi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan. EM yasuom@med.uoeh-u.ac.jp NR 29 TC 8 Z9 8 U1 1 U2 5 PU JAPAN SOC OCCUPATIONAL HEALTH PI TOKYO PA 1-29-8 SHINJUKU, SHINJUKU-KU, TOKYO, 160, JAPAN SN 1341-9145 J9 J OCCUP HEALTH JI J. Occup. Health PD MAY PY 2007 VL 49 IS 3 BP 242 EP 248 DI 10.1539/joh.49.242 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 178AJ UT WOS:000247193300010 PM 17575405 ER PT J AU Stjernsward, J Ferris, FD Khleif, SN Jamous, W Treish, IM Milhem, M Bushnaq, M Al Khateib, A Al Shtiat, MN Wheeler, S Alwan, A AF Stjernsward, Jan Ferris, Frank D. Khleif, Samir N. Jamous, Walid Treish, Imad M. Milhem, Mohammed Bushnaq, Mohammed Al Khateib, Ahmad Al Shtiat, Mohammad Nayef Wheeler, S. Alwan, Ala TI Jordan palliative care initiative: A WHO demonstration project SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Jordan; palliative care; policy; drug availability; education; implementation AB A model for pain relief and palliative care for the Middle East has been established in Jordan. King Hussein Cancer Centre (KHCC) in Amman is now a truly comprehensive cancer center as it includes palliative care for inpatients, outpatients, and patients at home. This is especially important in a country and a region where over 75 % of the cancer patients are incurable when diagnosed. To support effective palliative care delivery, there have been many significant changes in Jordan between 2001 and 2006 Regulations governing opioid prescribing have been changed to facilitate effective Pain management. The national opioid quota has been increased. Cost-effective, generic, immediate-release morphine tablets are being produced in Jordan. Intensive, interactive bedside training courses for doctors, nurses, and clinical pharmacologists have started to overcome opiophobia and motivate health care Professionals to take up palliative care as a profession. "Champions " for palliative care have emerged who are leading the development of palliative care in Jordan's health care systems and starting to support neighboring countries to develop pain relief and palliative care. While before 2003, fewer than 250 patients per year received palliative care, by 2006 more than 800 patients per year were receiving pain relief and palliative care through the KHCC and Al Basheer Hospital. The achieved changes and the unusually rapid and effective institutionalization of palliative care serve as a model for other countries in the Middle East region as to what should be done and how. C1 WHO, Canc Control & Palliat Care, Oxford, England. WHO, Collaborating Ctr Palliat Canc Care, Oxford, England. San Diego Hospice & Palliat Care, San Diego, CA USA. NCI, Vaccine Branch, Bethesda, MD 20892 USA. HIKMA Pharmaceut, Amman, Jordan. King Hussein Canc Ctr, Amman, Jordan. Al Basheer Hosp, Amman, Jordan. Capital Hospice, Fairfax, VA USA. WHO, CH-1211 Geneva, Switzerland. RP Stjernsward, J (reprint author), Borringekloster, SE-23391 Svendala, Sweden. EM janstjernsward@hotmail.com NR 20 TC 23 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAY PY 2007 VL 33 IS 5 BP 628 EP 633 DI 10.1016/j.jpainsymman.2007.02.032 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 171OO UT WOS:000246745500026 PM 17482059 ER PT J AU Baid, SK Merke, DP AF Baid, Smita K. Merke, Deborah P. TI Aplasia cutis congenita following in utero methimazole exposure SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material C1 NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Baid, SK (reprint author), NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. EM baids@mail.nih.gov FU Intramural NIH HHS NR 2 TC 10 Z9 11 U1 0 U2 0 PU FREUND PUBLISHING HOUSE LTD PI TEL AVIV PA PO BOX 35010, TEL AVIV 61350, ISRAEL SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD MAY PY 2007 VL 20 IS 5 BP 585 EP 586 PG 2 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 181QT UT WOS:000247451900005 PM 17642418 ER PT J AU Bowden, SA Sotos, JF Stratakis, CA Weil, RJ AF Bowden, Sasigarn A. Sotos, Juan F. Stratakis, Constantine A. Weil, Robert J. TI Successful treatment of an invasive growth hormone-secreting pituitary macroadenoma in an 8 year-old boy SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 88th Annual Meeting of the Endocrine-Society CY JUN 24-27, 2006 CL Boston, MA SP Endocrine Soc DE somatostatin analog; acromegaly; gigantism; microsurgery; growth hormone receptor antagonist; radiotherapy ID PREOPERATIVE OCTREOTIDE TREATMENT; TRANSSPHENOIDAL SURGERY; ADENOMAS; EXPERIENCE; GIGANTISM; TERM AB We describe an 8 year-old boy with growth acceleration due to an invasive growth hormone (GH)-secreting pituitary macroadenoma who was successfully treated with the somatostatin analogue octreotide prior to transsphenoidal microsurgery. His tumor was resected completely and the patient remains in remission. C1 Columbus Childrens Hosp, Div Endocrinol, Dept Pediat, Columbus, OH 43205 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Cleveland Clin, Brain Tumor Inst, Cleveland, OH 44106 USA. Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. RP Bowden, SA (reprint author), Columbus Childrens Hosp, Div Endocrinol, Dept Pediat, 700 Childrens Dr, Columbus, OH 43205 USA. EM bowdens@pediatrics.ohio-state.edu NR 19 TC 2 Z9 2 U1 0 U2 2 PU FREUND PUBLISHING HOUSE LTD PI TEL AVIV PA PO BOX 35010, TEL AVIV 61350, ISRAEL SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD MAY PY 2007 VL 20 IS 5 BP 643 EP 647 PG 5 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 181QT UT WOS:000247451900013 PM 17642426 ER PT J AU Leverich, GS Post, RM Keck, PE Altshuler, LL Frye, MA Kupka, RW Nolen, WA Suppes, T McElroy, SL Grunze, H Denicoff, K Moravec, MKM Luckenbaugh, D AF Leverich, Gabriele S. Post, Robert M. Keck, Paul E., Jr. Altshuler, Lori L. Frye, Mark A. Kupka, Ralph W. Nolen, Willem A. Suppes, Trisha McElroy, Susan L. Grunze, Heinz Denicoff, Kirk Moravec, Maria K. M. Luckenbaugh, David TI The poor prognosis of childhood-onset bipolar disorder SO JOURNAL OF PEDIATRICS LA English DT Article ID SUBSTANCE USE DISORDERS; MENTAL-DISORDERS; CLINICAL-COURSE; I-DISORDER; NETWORK I; CHILDREN; ADOLESCENTS; ILLNESS; GUIDELINES; MANIA AB Objective We examined age of onset of bipolar disorder as a potential course-of-iflness modifier with the hypothesis that early onset will engender more severe illness. Study design A total of 480 carefully diagnosed adult outpatients with bipolar disorder (mean age, 42.5 +/- 11.6 years) were retrospectively rated for age of illness onset, time to first pharmacotherapy, and course of illness. Clinicians prospectively rated daily mood fluctuations over I year. Results Of the 480 patients, 14% experienced onset in childhood (12 years or younger); 36% in adolescence (13 to 18 years); 32% in early adulthood (19 to 29 years); and 19% in late adulthood (after 30 years). Childhood-onset bipolar illness was associated with long delays to first treatment, averaging more than 16 years. The patients with childhood or adolescent onset reported more episodes, more comorbidities, and rapid cycling retrospectively; prospectively, they demonstrated more severe mania, depression, and fewer days wen. Conclusions This study demonstrates that childhood onset of bipolar disorder is common and is associated with long delays to first treatment. Physicians and clinicians should be alert to a possible bipolar diagnosis in children in hopes of shortening the time to initiating treatment and perhaps ameliorating the otherwise adverse course of illness. C1 NIMH, DHHS, NIH, Biol Psychiat Branch,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Cincinnati, Psychopharmacol Res Program, Dept Psychiat, Coll Med, Cincinnati, OH 45221 USA. Cincinnati VA Med Ctr, Ment Hlth Care Line & Gen Clin Res Ctr, Cincinnati, OH USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehv Sci, Los Angeles, CA USA. W Los Angeles VA Med Ctr, Los Angeles, CA USA. Altrecht Inst Ment Hlth Care, Utrecht, Netherlands. Univ Groningen Hosp, Dept Psychiat, Groningen, Netherlands. Univ Texas, SW Med Ctr, Dallas, TX USA. LMU, Psychiat Klin, Munich, Germany. RP Leverich, GS (reprint author), NIMH, DHHS, NIH, Biol Psychiat Branch,Dept Hlth & Human Serv, Bldg 10,Room 3S239,10 Ctr Dr,MSC-1272, Bethesda, MD 20892 USA. EM levericg@mail.nih.gov RI Nolen, Willem/E-9006-2014; OI Grunze, Heinz/0000-0003-4712-8979 NR 45 TC 120 Z9 121 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2007 VL 150 IS 5 BP 485 EP 490 DI 10.1016/j.jpeds.2006.10.070 PG 6 WC Pediatrics SC Pediatrics GA 164PH UT WOS:000246245600012 PM 17452221 ER PT J AU Kavey, REW Kveselis, DA Atallah, N Smith, FC AF Kavey, Rae-Ellen W. Kveselis, Daniel A. Atallah, Nader Smith, Frank C. TI White coat hypertension in childhood: Evidence for end-organ effect SO JOURNAL OF PEDIATRICS LA English DT Article ID LEFT-VENTRICULAR MASS; AMBULATORY BLOOD-PRESSURE; YOUNG-ADULTS; CARDIOVASCULAR RISK; TREADMILL EXERCISE; HEALTHY-CHILDREN; HEART-RATE; BODY-SIZE; ADOLESCENTS; HYPERTROPHY AB Objective To evaluate the hypothesis that white coat hypertension (WCH) represents a prehypertensive state by correlating ambulatory blood pressure monitoring (ABPM) results, with BP response to treadmill exercise (TE) and echocardiographic measurement of left ventricular mass index (LVMI) in children with high blood pressure (HBP). Study design We evaluated 119 consecutive children age 6 to 18 years (mean = 11.3 years; 65% male) referred for HBP. Office systolic BP (SBP) exceeded the 95th percentile for age/sex/height in all of the children; 10% also had elevated diastolic BP (DBP). WCH was defined as elevated office SBP +/- elevated DBP with normal mean awake ABPM-SBP. ABPM classified 62 subjects as having WCH and 57 as having HBP. Results Office BP did not differ between the 2 groups. As defined, awake ABPM-SBP was lower in the WCH group (males: HBP, 142 +/- 12 vs WCH, 124 +/- 5; females: HBP, 137 +/- 8 vs WCH, 121 +/- 5). Awake and asleep Ill and asleep SBP were significantly lower in the WCH group. On TE, maximal SBP exceeded norms for age/sex/body surface area in 63% of the HBP group and 38% of the WCH group. LVMI exceeded the 95th percentile for age/sex in 59% of the males and 90% of the females in the HBP group and in 33% of the males and 36% of the females in the WCH group. Conclusions Exaggerated exercise BP and/or increased LVMI in 62% of those subjects with WCH suggest that this diagnosis in children may represent a prehypertensive state. C1 SUNY Syracuse, Hlth Sci Ctr, Div Pediat Cardiol, Syracuse, NY USA. RP Kavey, REW (reprint author), NHLBI, Pediat Cardiovasc Risk Reduct Program, NIH, Bethesda, MD 20892 USA. EM kaveyr@nhlbi.nih.gov NR 55 TC 46 Z9 48 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2007 VL 150 IS 5 BP 491 EP 497 DI 10.1016/j.jpeds.2007.01.033 PG 7 WC Pediatrics SC Pediatrics GA 164PH UT WOS:000246245600013 PM 17452222 ER PT J AU Mager, DE Abernethy, DR AF Mager, Donald E. Abernethy, Darrell R. TI Use of wavelet and fast Fourier transforms in pharmacodynamics SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HEART-RATE-VARIABILITY; IMAGE CORRELATION SPECTROSCOPY; SPECTRAL-ANALYSIS; RECEPTOR; DYNAMICS; PHARMACOKINETICS; MICROSCOPY; SYSTEMS; HUMANS; MODELS AB Progress has been made in the development and application of mechanism- based pharmacodynamic models for describing the drug- specific and physiological factors influencing the time course of responses to the diverse actions of drugs. However, the biological variability in biosignals and the complexity of pharmacological systems often complicate or preclude the direct application of traditional structural and nonstructural models. Mathematical transforms may be used to provide measures of drug effects, identify structural and temporal patterns, and visualize multidimensional data from analyses of biomedical signals and images. Fast Fourier transform ( FFT) and wavelet analyses are two methodologies that have proven to be useful in this context. FFT converts a signal from the time domain to the frequency domain, whereas wavelet transforms colocalize in both domains and may be utilized effectively for nonstationary signals. Nonstationary drug effects are common but have not been well analyzed and characterized by other methods. In this review, we discuss specific applications of these transforms in pharmacodynamics and their potential role in ascertaining the dynamics of spatiotemporal properties of complex pharmacological systems. C1 SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Abernethy, DR (reprint author), SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. EM abernethyd@grc.nia.nih.gov FU Intramural NIH HHS NR 61 TC 11 Z9 13 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2007 VL 321 IS 2 BP 423 EP 430 DI 10.1124/jpet.106.113183 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 157TW UT WOS:000245744900001 PM 17142645 ER PT J AU Martelle, JL Claytor, R Ross, JT Reboussin, BA Newman, AH Nader, MA AF Martelle, Jennifer L. Claytor, Renee Ross, Jason T. Reboussin, Beth A. Newman, Amy Hauck Nader, Michael A. TI Effects of two novel D-3-selective compounds, NGB 2904 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxa mide] and CJB 090 [N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benza mide], on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID D-3 RECEPTOR ANTAGONIST; DRUG-SEEKING BEHAVIOR; DOPAMINE D3 RECEPTOR; MEDICATION DEVELOPMENT; INDUCED REINSTATEMENT; PARTIAL AGONISTS; HIGH-AFFINITY; BRAIN REWARD; RATS; SB-277011A AB The present study examined the effects of two novel dopamine D 3 receptor compounds, NGB 2904 [ N-( 4-( 4-( 2,3- dichlorophenyl) piperazin- 1- yl) butyl)- 9H- fluorene- 2- carboxamide], an antagonist, and CJB 090 [ N-( 4-( 4-( 2,3- dichlorophenyl) piperazin-1- yl) butyl)- 4-( pyridin- 2- yl) benzamide], a partial agonist, in two models of cocaine abuse in rhesus monkeys. To establish a dose range and time course of effects, both compounds were shown to block quinpirole- induced yawning when administered i. m. 15, 30, or 120 min before quinpirole. Next, rhesus monkeys were trained to discriminate i. m. injections of saline ( 0.5 ml) and cocaine ( 0.3 mg/ kg). Neither D-3 compound ( 0.03 - 3.0 mg/ kg; n = 3) substituted for cocaine in any monkey. When given in combination with cocaine, CJB 090 but not NGB 2904 attenuated the discriminative stimulus effects of cocaine, shifting the cocaine dose-response curve to the right. In a separate group monkeys, responding was maintained under a second- order schedule of either food ( 1.0- g pellets; n = 3) or cocaine ( 0.1 mg/ kg/ injection; n = 4) presentation. When responding was stable, a dose of NGB 2904 ( 1.0 - 5.6 mg/ kg i. v.) or CJB 090 ( 0.3 - 3.0 mg/ kg i. v.) was administered for 5 consecutive days, immediately before the session. CJB 090, but not NGB 2904, decreased cocaine- and food- maintained responding. These data indicate that compounds with relatively high affinity and selectivity for the D 3 receptor can attenuate the discriminative and reinforcing stimulus effects of cocaine while not producing cocaine- like effects. The present findings support the continued examination of D 3 compounds as pharmacological tools for better understanding the role of this receptor subtype in cocaine addiction and as potential lead compounds for novel therapeutic agents. C1 Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Ctr Neurobiol Invest Drug Abuse, Winston Salem, NC 27103 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Nader, MA (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Ctr Neurobiol Invest Drug Abuse, 300 S Hawthorne Rd, Winston Salem, NC 27103 USA. EM mnader@wfubmc.edu FU Intramural NIH HHS; NIDA NIH HHS [DA 12460, DA 016279] NR 40 TC 54 Z9 55 U1 2 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2007 VL 321 IS 2 BP 573 EP 582 DI 10.1124/jpet.106.113571 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 157TW UT WOS:000245744900019 PM 17272677 ER PT J AU Tang, L Chen, Y Chen, ZL Blumberg, PM Kozikowski, AP Wang, ZJ AF Tang, Lei Chen, Yan Chen, Zili Blumberg, Peter M. Kozikowski, Alan P. Wang, Zaijie Jim TI Antinociceptive pharmacology of N-(4-chlorobenzyl)-N '-(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea, a high-affinity competitive antagonist of the transient receptor potential vanilloid 1 receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID VANILLOID RECEPTOR-1 TRPV1; IN-VIVO CHARACTERIZATION; DORSAL-ROOT GANGLION; CAPSAICIN RECEPTOR; NEUROPATHIC PAIN; SPINAL-CORD; IODO-RESINIFERATOXIN; THERMAL NOCICEPTION; OPIOID RECEPTOR; INFLAMMATION AB The transient receptor potential vanilloid 1 receptor (TRPV1) is expressed predominantly in a subset of primary afferent nociceptors. Due to its specific anatomical location and its pivotal role as a molecular integrator for noxious thermal and chemical stimuli, there is considerable interest to develop TRPV1 antagonists for the treatment of pain. Recently, N-(4-chlorobenzyl)-N' -(4-hydroxy-3-iodo-5-methoxybenzyl) thiourea (IBTU) was synthesized, and it was found in vitro to be a high-affinity competitive antagonist of cytoplasmic, but not intracellular, TRPV1. In this study, we examined the in vivo antinociceptive activity of IBTU in several acute and inflammatory pain models in mice. Our emphasis was on nociceptive pathways that are likely mediated by TRPV1, including capsaicin-, noxious heat-, and proton ( including inflammation)- induced nociception tests. Capsazepine was used as a positive control in these experiments. IBTU dose-dependently blocked the capsaicin- induced nociception, confirming its antagonism at TRPV1 in vivo. By itself, IBTU produced significant antinociception, because it significantly prolonged the tail-flick latency in a dose-dependent manner. IBTU also blocked both early and late phases of the formalin-induced flinching response as well as acetic acid-induced writhing behavior. Moreover, IBTU inhibited the complete Freund's adjuvant-induced persistent hyperalgesia. Taken together, these data demonstrate that IBTU acts as a TRPV1 antagonist in vivo, and they suggest that it may be of therapeutic use for the treatment of pain. C1 Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA. Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. Univ Illinois, Ctr Canc, Chicago, IL 60612 USA. NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Wang, ZJ (reprint author), Univ Illinois, Dept Biopharmaceut Sci, 833 S Woods St, Chicago, IL 60612 USA. EM zjwang@uic.edu FU Intramural NIH HHS NR 40 TC 41 Z9 42 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAY PY 2007 VL 321 IS 2 BP 791 EP 798 DI 10.1124/jpet.106.117572 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 157TW UT WOS:000245744900045 PM 17312187 ER PT J AU Wu, J Lu, YH Lee, A Pan, XG Yang, XJ Zhao, XB Lee, RJ AF Wu, Jun Lu, Yanhui Lee, Alice Pan, Xiaogang Yang, Xiaojuan Zhao, Xiaobin Lee, Robert J. TI Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil SO JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES LA English DT Article ID TARGETED DRUG-DELIVERY; IN-VITRO; ANTICANCER DRUGS; SOLID TUMORS; CELLS; DAUNORUBICIN; CANCER; PHARMACOKINETICS; ACCUMULATION; MODULATION AB Purpose. Liposomes co-encapsulating doxorubicin (DOX) and verapamil (VER), and conjugated to transferrin (Tf-LDOX/VER) were synthesized and evaluated in K562 leukemia cells. The design of this formulation was aimed at selective targeting of tumor cells, reducing cardiotoxicity of DOX and VER, as well as overcoming P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) phenotype. Methods. The liposomes were prepared by polycarbonate membrane extrusion, followed by pH-gradient driven remote loading and Tf conjugation. Kinetics of in vitro release of DOX and VER from liposomes was determined by measuring changes in the concentration of encapsulated drugs. Uptake of Tf-conjugated liposomes by K562 cells was evaluated by fluorescence microscopy and by fluorometry. Cytotoxicities of various formulations of DOX were determined by a 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolum bromide (MTT) assay. Results. Efficiencies for liposomal loading of DOX and VER were 95% and 70%, respectively. The mean particle diameter for the liposomes was approximately 110nm. Rates of release for DOX and VER were similar in singly-loaded and co-loaded liposomes. Tf-L-DOX/VER showed efficient uptake by the TfR+K562 cells. In DOX-resistant K562 cells (K562/DOX), Tf-LDOX/VER showed 5.2 and 2.8 times greater cytotoxicity (IC50 = 4.18 mu M) than non-targeted liposomes (L-DOX/VER) (IC50 = 21.7 mu M) and Tftargeted liposomes loaded with DOX alone (Tf-L-DOX) (IC50 = 11.5 mu M), respectively. Conclusions. The combination of TfR targeting and co-encapsulation of DOX and VER was highly effective in overcoming drug resistance in K562 leukemia cells. C1 [Wu, Jun; Lu, Yanhui; Lee, Alice; Pan, Xiaogang; Yang, Xiaojuan; Zhao, Xiaobin; Lee, Robert J.] Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA. [Lee, Alice; Pan, Xiaogang; Yang, Xiaojuan; Lee, Robert J.] Ohio State Univ, NSF, NSEC, CANPBD, Columbus, OH USA. [Zhao, Xiaobin; Lee, Robert J.] Ohio State Univ, NCI, Ctr Comprehens Canc, Columbus, OH USA. RP Lee, RJ (reprint author), Ohio State Univ, Coll Pharm, Div Pharmaceut, 500 W 12Th Ave, Columbus, OH 43210 USA. EM lee.1339@osu.edu NR 31 TC 121 Z9 128 U1 2 U2 27 PU CANADIAN SOC PHARMACEUTICAL SCIENCES PI EDMONTON PA 3118 DENTISTRY-PHARMACY CENTRE UNIV ALBERTA CAMPUS, EDMONTON, ALBERTA T6G2N8, CANADA SN 1482-1826 J9 J PHARM PHARM SCI JI J. Pharm. Pharm. Sci. PD MAY-AUG PY 2007 VL 10 IS 3 BP 350 EP 357 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 266QI UT WOS:000253451600010 PM 17727798 ER PT J AU Gougelet, A Mueller, SO Korach, KS Renoir, JM AF Gougelet, Angelique Mueller, Stefan O. Korach, Ken S. Renoir, Jack-Michel TI Oestrogen receptors pathways to oestrogen responsive elements: The transactivation function-1 acts as the keystone of oestrogen receptor (ER)beta-mediated transcriptional repression of ER alpha SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT 17th International Symposium of the Journal-of-Steroid-Biochemistry-and-Molecular-Biology CY MAY 31-JUN 03, 2006 CL Seefeld, AUSTRIA SP Journal Steroid Biochem & Mol Biol DE oestrogen receptors; breast cancer cells; anti-oestrogens; transactivation ID BREAST-CANCER CELLS; GENE-EXPRESSION; COACTIVATOR RECRUITMENT; PROMOTER-CONTEXT; BETA-ISOFORM; WILD-TYPE; ACTIVATION; LIGAND; PROLIFERATION; PROTEIN AB Oestrogen receptors (ER)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (EREs) located in a number of gene promoters. Transient transfection of different luciferase reporter vectors 3xEREs-Vit, 2xEREs-tk and ERE-C3 showed that the transactivation capacity of both ER subtypes was influenced by 1) the nature of the inducer (oestradiol (EA phyto- and anti-oestrogen (AE)), 2) the structure of the promoter (nucleotidic sequence, number of ERE, length of the promoter sequence) and 3) the cell line (containing endogenous ER (MCF-7) or in which ER was stably expressed (MDA-MB-23 1 -HE-5 (ER alpha+) or MDA-MB-23 1 -HERB (ERP+)). ER subtype did not display the same efficacy on the different constructions in the presence of E-2 and of AE according to the cell (e.g. in MCF-7 cells: tk>>Vit>>C3 similar to 0 while in MDA-MB-231 cells: Vit>>tk similar to C3). E2 response was higher in MCF-7 cells, probably due to higher ER expression level (maximal at 10(-10) M instead of 10(-8) M for E-2 in HE-5 cells). Finally, the same ligand could exert opposite activities on the same promoter according to the ER isoform expressed: in the MDA-MB-231 cells, AE acted as inducers of the C3 promoter via ERP whereas ER alpha/AE complexes down-regulated this promoter. Approximately 70% of breast tumours express ER and most turnour cells coexpress both ER isotypes. Thus, different types of ER dimers can be formed in such turnours (ERP or ER alpha homodimers or ER alpha-/ER beta heterodimers). We therefore studied the influence of the coexistence of the two ERs on the ligand-induced transcriptional process following transient transfection of ER alpha in ER beta(+) cells, and inversely ERP in ER alpha+ cells. ERP-transfection inhibited the E-2- and genistein-induced ER(x-dependent transcription on all promoters in all cell lines except C3 in MCF-7; this inhibitory effect was lost following transfection of ERP deleted of its AF-1 (ERP-AF-2). These results suggest that the dominant negative properties of ERP are mainly due to its AF-I function. Interestingly, transfection of an ERP-AF-2 construct into MCF-7 cells potentiated the transcription inhibitory capacity of 4-OH-tamoxifen (OHT) on the Vit and tk promoters. Thus, (1) OHT exerts an agonistic activity through the AF-I function of ER and (2) expression of ERP in breast cancer cells seems to favour the AE treatment. Contrary to ERP, ER alpha-transfection had little effect on ERP transactivation capacity in HERB cells. Finally, the ratio ER alpha/ER beta constitutes one decisive parameters to orientate the transcriptional mechanism of a target gene in the presence of agonist as well as of antagonist ligands. (C) 2007 Elsevier Ltd. All rights reserved. C1 CNRS, UMR 8612, F-92296 Chatenay Malabry, France. MERck KGaA, Inst Toxicol, Darmstadt, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. RP Renoir, JM (reprint author), CNRS, UMR 8612, 5 Rue JB Clement, F-92296 Chatenay Malabry, France. EM michel.renoir@cep.u-psud.fr RI Gougelet, Angelique/E-2071-2017; OI Gougelet, Angelique/0000-0001-7464-9804; Korach, Kenneth/0000-0002-7765-418X NR 63 TC 28 Z9 31 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD MAY PY 2007 VL 104 IS 3-5 BP 110 EP 122 DI 10.1016/j.jsbmb.2007.03.002 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 191DL UT WOS:000248110100004 PM 17478088 ER PT J AU Finzi, D Dieffenbach, CW Basavappa, R AF Finzi, Diana Dieffenbach, Carl W. Basavappa, Ravi TI Defining and solving the essential protein-protein interactions in HIV infection SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Conference on Structural Analysis of Supramolecular Assemblies by Hybrid Methods CY MAR 15-19, 2006 CL Lake Tahoe, CA SP Agouron Inst, NIGMS, NIAID, NIEHS, Sidec Technologies DE HIV; HIV replication cycle; HIV capsid; HIV core; preintegration complex; optical microscopy; cryoelectron tomography; coherent anti-Stokes Raman scattering microscopy; structural genomics ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; STRUCTURAL GENOMICS PIPELINE; GP120 ENVELOPE GLYCOPROTEIN; NUCLEAR-PORE COMPLEX; ATOMIC-STRUCTURE; IN-VITRO; PREINTEGRATION COMPLEXES; COUPLED RECEPTORS; LIVING CELLS AB The structure determination of macromolecular complexes is entering a new era. The methods of optical microscopy, electron microscopy, X-ray crystallography, and nuclear magnetic resonance increasingly are being combined in hybrid method approaches to achieve an integrated view of macromolecular complexes that span from cellular context to atomic detail. A particularly important application of these hybrid method approaches is the structural analysis of the Human Immunodeficiency Virus (HIV) proteins with their cellular binding partners. High resolution structure determination of essential HIV - host cell protein complexes and correlative analysis of these complexes in the live cell can serve as critical guides in the design of a broad, new class of therapeutics that function by disrupting such complexes. Here, with the hope of stimulating some discussion, we will briefly review some of the literature in the context of what could be done to further apply structural methods to HIV research. We have chosen to focus our attention on certain aspects of the HIV replication cycle where we think that structural information would contribute substantially to the development of new therapeutic and vaccine targets for HIV. Published by Elsevier Inc. C1 Natl Inst Gen Med Sci, Div Cell Biol & Biophys, Bethesda, MD 20892 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Basavappa, R (reprint author), Natl Inst Gen Med Sci, Div Cell Biol & Biophys, Bldg 45, Bethesda, MD 20892 USA. EM basavapr@nigms.nih.gov NR 75 TC 1 Z9 2 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2007 VL 158 IS 2 BP 148 EP 155 DI 10.1016/j.jsb.2006.10.028 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 173HK UT WOS:000246863900003 PM 17175170 ER PT J AU Conway, JF Cheng, NQ Ross, PD Hendrix, RW Duda, RL Steven, AC AF Conway, James F. Cheng, Naiqian Ross, Philip D. Hendrix, Roger W. Duda, Robert L. Steven, Alasdair C. TI A thermally induced phase transition in a viral capsid transforms the hexamers, leaving the pentamers unchanged SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article; Proceedings Paper CT 3rd International Conference on Structural Analysis of Supramolecular Assemblies by Hybrid Methods CY MAR 15-19, 2006 CL Lake Tahoe, CA SP Agouron Inst, NIGMS, NIAID, NIEHS, Sidec Technologies DE differential scanning calorimetry; cryo-electron microscopy; virus capsid structure; bacteriophage HK97; conformational changes ID DOUBLE-STRANDED-RNA; CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; CONFORMATIONAL-CHANGES; VIRUS MATURATION; CROSS-LINKING; PROTEIN; DYNAMICS; LATTICE; MUTANT AB Scanning calorimetry combined with cryo-clectron microscopy affords a powerful approach to investigating hierarchical interactions in multi-protein complexes. Calorimetry can detect the temperatures at which certain interactions are disrupted and cryo-EM can reveal the accompanying structural changes. The procapsid of bacteriophage HK97 (Prohead 1) is a 450 angstrom-diameter shell composed of 60 hexamers and 12 pentamers of gp5, organized with icosahedral symmetry. Gp5 consists of the N-terminal Delta-domain (11 kDa) and gp5* (31 kDa): gp5* forms the contiguous shell from which clusters of A-domains extend inwards. At neutral pH, Prohead I exhibits an endothermic transition at 53 degrees C with an enthalpy change of 14 kcal/mole (of gp5 monomer). We show that this transition is reversible. To capture its structural expression, we incubated Prohead I at 60 degrees C followed by rapid freezing and, by cryo-EM, observed a capsid species 10% larger than Prohead I. At 11 angstrom resolution, visible changes are confined to the gp5 hexamers. Their Delta-domain clusters have disappeared and are presumably disordered, either by unfolding or dispersal. The gp5* hexamer rings are thinned and flattened as they assume the conformation observed in Expansion Intermediate 1, a transition state of the normal, proteolysis-induced, maturation pathway. We infer that, at ambient temperatures, the hexamer A-domains restrain their gp5* rings from switching to a lower free energy, EI-I-like, state; above 53 degrees, this restraint is overcome. Pentamers, on the other hand, are more stably anchored and resist this thermal perturbation. (c) 2006 Elsevier Inc. All rights reserved. C1 NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bldg 50,Room 1517,50 South Dr,MSC8025, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 FU Intramural NIH HHS [Z01 AR027002-29, Z99 AR999999]; NIGMS NIH HHS [R01 GM047795, R01 GM047795-30, R01 GM47795] NR 36 TC 24 Z9 24 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2007 VL 158 IS 2 BP 224 EP 232 DI 10.1016/j.jsb.2006.11.006 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 173HK UT WOS:000246863900011 PM 17188892 ER PT J AU Sparling, MJD Hong, CH Brahim, JS Moss, J Darling, TN AF Sparling, Maj Joshua D. Hong, Chien-Hui Brahim, Jaime S. Moss, Joel Darling, Thomas N. TI Oral findings in 58 adults with tuberous sclerosis complex SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID GINGIVAL OVERGROWTH; COWDENS DISEASE; LESIONS; NEOPLASIA; MARKER AB Background: Gingival fibromas and dental pitting are among the diagnostic criteria for tuberous sclerosis complex (TSC). Objective: Our goal was to document the oral findings in 58 adult patients with TSC. Results: Forty patients (69%) had oral fibromas, appearing mostly on the attached or interdental gingiva. Other oral mucosal sites with fibromas included buccal and labial mucosa, the Superior labial frenulum, palate, and tongue. In all, 56 patients (97%) had multiple dental enamel pits. Limitations: This case series comprised predominantly adult women with TSC and lymphangioleiomyomatosis. Conclusions: Oral fibromas in TSC are mostly, but not exclusively, gingival. Dental pits are present in nearly all patients. The multiple oral papules in TSC may appear similar to those observed in Cowden syndrome, Birt-Hogg-Dube syndrome, and rarely in Multiple endocrine neoplasia type 1. C1 Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Natl Capital Consortium Residency Program, Washington, DC 20307 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM tdarling@usuhs.mil OI Darling, Thomas/0000-0002-5161-1974 FU Intramural NIH HHS [Z01 HL002541-12]; NCI NIH HHS [R01 CA100907-03, R01 CA100907, R01 CA100907-01A1, R01 CA100907-02] NR 30 TC 14 Z9 15 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2007 VL 56 IS 5 BP 786 EP 790 DI 10.1016/j.jaad.2006.11.019 PG 5 WC Dermatology SC Dermatology GA 161UJ UT WOS:000246041400009 PM 17239986 ER PT J AU Sebring, NG Denkinger, BI Menzie, CM Yanoff, LB Parikh, SJ Yanovski, JA AF Sebring, Nancy G. Denkinger, Blakeley I. Menzie, Carolyn M. Yanoff, Lisa B. Parikh, Shamik J. Yanovski, Jack A. TI Validation of three food frequency questionnaires to assess dietary calcium intake in adults SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article; Proceedings Paper CT 85th Annual Meeting of the Endocrine-Society CY JUN 19-22, 2003 CL PHILADELPHIA, PA SP Endocrine Soc ID BLOOD-PRESSURE; WOMEN; OSTEOPOROSIS; VALIDITY; METAANALYSIS; CONSUMPTION; PRODUCTS; OBESITY AB Objective To assess the accuracy of three self-administered food frequency questionnaires (FFQs) to measure dietary calcium intake in healthy adults. Design Estimates of dietary calcium intake from one previously validated and two recently developed FFQs were compared with those from 7-day food records. Subjects/setting Healthy adults enrolled in an outpatient study of calcium supplementation completed the 36-page Dietary History Questionnaire (DHQ), a 3-page Calcium Questionnaire, and a 1-page Short Calcium Questionnaire. Subjects then completed a 7-day food record. Main outcome measures Differences between calcium intake reported on FFQs and calcium intake from food records were compared. Statistical analyses Spearman correlations were used to measure associations among variables; Bland-Altman pairwise comparisons were conducted to assess systematic and magnitude biases. Results We studied 341 subjects, 74.5% female, mean (+/- standard deviation) age of 38 +/- 11 years and body mass index (calculated as kg/m(2)) of 31.8 +/- 7.1. Mean (+/- standard deviation) food record calcium intake was 896 +/- 380 mg/day; data from all three FFQs were positively related to food record calcium intake, but accounted for < 40% of the variance in food record dietary calcium intake (DHQ: r(2)=0.21; Calcium Questionnaire: r(2)=0.33; Short Calcium Questionnaire: r(2)=0.37; all P < 0.001). The DHQ underestimated daily calcium intake (systematic bias: -94 mg/ day, P < 0.001; magnitude bias r=-0.40; P < 0.001), whereas the Calcium Questionnaire overestimated calcium intake (systematic bias + 177 mg/day, P < 0.001), but had no significant magnitude bias (r=-0.09; P=0.11). The Short Calcium Questionnaire showed minimal systematic bias (+34 mg/day, P=0.09), but had magnitude bias (r=-0.33; P < 0.001). Conclusions All three FFQs performed reasonably well at estimating dietary calcium intake compared to food records; each may be appropriate for use in select clinical and research settings. C1 NICHHD, Unit Growth & Obes, NIH, Dev Endocrinol Branch,Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. AstraZeneca LP, Wilmington, DE USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, NIH, Dev Endocrinol Branch,Hatfield Clin Res Ctr, 10 Ctr Dr,Rm 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NICHD NIH HHS [Z01 HD000641] NR 40 TC 35 Z9 35 U1 1 U2 9 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAY PY 2007 VL 107 IS 5 BP 752 EP 759 DI 10.1016/j.jada.2007.02.007 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 165UD UT WOS:000246330400016 PM 17467370 ER PT J AU Thompson, FE Midthune, D Subar, AF Kipnis, V Kahle, LL Schatzkin, A AF Thompson, Frances E. Midthune, Douglas Subar, Amy F. Kipnis, Victor Kahle, Lisa L. Schatzkin, Arthur TI Development and evaluation of a short instrument to estimate usual dietary intake of percentage energy from fat SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID DOUBLY LABELED WATER; FOOD-FREQUENCY QUESTIONNAIRE; 24-HOUR RECALL; VALIDATION; WOMEN; BEHAVIOR; PROTEIN; HEALTH; COHORT; CHOLESTEROL AB Objective To describe the data-based development of a short dietary assessment instrument, a 16-item screener; and to evaluate the performance of the screener, comparing its performance with a complete 120-item food frequency questionnaire (FFQ) in assessing percentage energy from fat intake. Design A subsample (n=404) of participants in the National Institutes of Health-AARP Diet and Health Study, who had completed an FFQ and two 24-hour dietary recalls, also completed the fat screener. Percentage energy from fat from the screener and from the FFQ were compared with estimated true usual intake using a measurement error model. Results For men, the mean percentage energy from fat estimates for the different methods were: recalls, 30.1%, screener, 29.9%; FFQ, 30.4%. For women, the results were: recalls, 31.3%, screener, 28.4%, FFQ, 30.0%. Estimated correlations between true intake and screener were 0.64 and 0.58 for men and women, respectively, and between true intake and FFQ were 0.67 for men and 0.72 for women. Estimated attenuation coefficients for the screener were 1.29 (men) and 0.98 (women) and for the FFQ were 0.56 (men) and 0.57 (women). Conclusions The percentage energy from fat screener, when used in conjunction with external reference data, may be useful to compare mean intakes of fat for different population subgroups, and to examine relationships between fat intake and other factors. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Biometry Res Grp, Bethesda, MD 20892 USA. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Thompson, FE (reprint author), MPH,EPN 4016,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM thompsof@mail.nih.gou NR 43 TC 56 Z9 58 U1 1 U2 8 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAY PY 2007 VL 107 IS 5 BP 760 EP 767 DI 10.1016/j.jada.2007.02.006 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 165UD UT WOS:000246330400017 PM 17467371 ER PT J AU Krebs-Smith, SM Kris-Etherton, P AF Krebs-Smith, Susan M. Kris-Etherton, Penny TI How does MyPyramid compare to other population-based recommendations for controlling chronic disease? SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Review ID FOOD GUIDANCE-SYSTEM AB The Department of Agriculture's MyPyramid is presented as food guidance for the US general public and not "a therapeutic diet for any specific health condition," although many adults in this country are overweight or obese and many experience diet-related disorders. This paper shows the recommendations in MyPyramid are remarkably consistent with the various recommendations to control obesity and diabetes, heart disease and stroke,. hypertension, cancer, and osteoporosis. Specifically, the food intake recommendations are similar to those recommended by the Dietary Approaches to Stop Hypertension Eating Plan, the American Heart Association, and the American Cancer Society; plus, the calculated nutrient intakes associated with following the guide are generally within the ranges of nutrient recommendations from the Clinical Guidelines on Overweight and Obesity, the American Diabetes Association, the National Cholesterol Education Program, the American Heart Association, the National Committee on High Blood Pressure, and the American Institute for Cancer Research. However, for actual nutrient levels to conform to dietary guidance, key assumptions regarding how closely individuals will follow the MyPyramid patterns must be made: an appropriate energy level must be selected and adhered to, and an appropriate profile of foods must be selected. These issues must be understood by food and nutrition professionals and disseminated to the public for MyPyramid to reach its potential. C1 NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. RP Krebs-Smith, SM (reprint author), NCI, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM sk52r@nih.gov NR 32 TC 20 Z9 20 U1 0 U2 0 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAY PY 2007 VL 107 IS 5 BP 830 EP 837 DI 10.1016/j.jada.2007.02.016 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 165UD UT WOS:000246330400027 PM 17467381 ER PT J AU Pennington, J Kandiah, J Nicklas, T Pitman, S Stitzel, K Cummings, S Denny, S Hager, MH Leveille, G Myers, E Quagliani, D Stumbo, PJ Jortberg, B Zelman, K Schaaf, P Lane, HW AF Pennington, Jean Kandiah, Jay Nicklas, Theresa Pitman, Susan Stitzel, Kimberly Cummings, Sue Denny, Sharon Hager, Mary H. Leveille, Gilbert Myers, Esther Quagliani, Diane Stumbo, Phyllis J. Jortberg, Bonnie Zelman, Kathleen Schaaf, Patricia Lane, Helen W. TI Practice paper of the American Dietetic Association: Nutrient density: Meeting nutrient goals within calorie needs SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Editorial Material ID CHRONIC DISEASE PREVENTION; UNITED-STATES POPULATION; DIETARY GUIDELINES; ENERGY-DENSE; US CHILDREN; POOR FOODS; ADULTS; ADOLESCENTS; PREVALENCE; QUALITY C1 NIH, Bethesda, MD 20892 USA. RP Pennington, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 51 TC 15 Z9 15 U1 0 U2 7 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAY PY 2007 VL 107 IS 5 BP 860 EP 869 DI 10.1016/j.jada.2007.03.020 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 165UD UT WOS:000246330400032 PM 17526129 ER PT J AU Katula, JA Kritchevsky, SB Guralnik, JM Glynn, NW Pruitt, L Wallace, K Walkup, MP Hsu, FC Studenski, SA Gill, TM Groessl, EJ Wallace, JM Pahor, M AF Katula, Jeffrey A. Kritchevsky, Stephen B. Guralnik, Jack M. Glynn, Nancy W. Pruitt, Leslie Wallace, Kristin Walkup, Michael P. Hsu, Fang-Chi Studenski, Stephanie A. Gill, Thomas M. Groessl, Erik J. Wallace, Jason M. Pahor, Marco TI Lifestyle interventions and independence for elders pilot study: Recruitment and baseline characteristics SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY MAY 11-15, 2005 CL Orlando, FL SP Amer Geriatr Soc DE recruitment; clinical trials; prevention of mobility disability; physical activity ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; CLINICAL-TRIAL; SUBSEQUENT DISABILITY; STRATEGIES; PREVENTION; PROGRAM; RISK AB OBJECTIVES: To describe several recruitment parameters derived from the Lifestyle Interventions and Independence for Elders pilot (LIFE-P) study for use in a full-scale trial of mobility disability prevention. DESIGN: A description of the recruiting methods and baseline characteristics of a four-site randomized, controlled trial testing the effectiveness of a physical activity intervention at preventing mobility disability. SETTING: The Cooper Institute, Dallas, Texas; Stanford University, Stanford, California; University of Pittsburgh, Pittsburgh, Pennsylvania; and Wake Forest University, Winston-Salem, North Carolina. PARTICIPANTS: Community-living persons aged 70 to 89 who were able to walk 400 m within 15 minutes and were at high risk for disability (scoring < 10 on the Short Physical Performance Battery (SPPB)) but without comorbidity severe enough to preclude full study participation. MEASUREMENTS: Measures of efficiency included number of randomized participants per recruitment technique and costs per randomized participant across randomization techniques. RESULTS: The 9-month recruiting period resulted in 3,141 telephone screens, of which 424 (13.5%) participants were randomized (68.9% women, 25.7% minorities, 41.5% with SPPB scores < 8). Forty percent of telephone-screened participants were excluded primarily because of regular participation in physical activity, health exclusions, or self-reported mobility disability. Of the 1,252 persons attempting the physical performance assessments, 41% scored above the SPPB cutoff. Of the 566 remaining eligible, 9.9% could not complete the 400-m walk, and another 18.9% had various medical exclusions. Direct mailing was the most productive recruitment strategy (61.6% of all randomized participants). Recruitment cost approximately $439 per randomized participant. CONCLUSION: The LIFE study achieved all recruitment goals and demonstrated the feasibility of recruiting high-risk community-dwelling older persons for trials of disability prevention in diverse geographic areas. C1 Wake Forest Univ, Dept Hlth & Exercise Sci, Reynolda Stn, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Internal Med Geriatr, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Biostat, Winston Salem, NC 27109 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. Stanford Univ, Dept Med, Stanford, CA 94305 USA. Yale Univ, Dept Internal Med Geriatr, New Haven, CT USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Cooper Inst, Dallas, TX USA. Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. RP Katula, JA (reprint author), Wake Forest Univ, Dept Hlth & Exercise Sci, Reynolda Stn, POB 7868, Winston Salem, NC 27109 USA. EM katulaj@wfu.edu RI Katula, Jeffrey/K-5905-2013; OI Kritchevsky, Stephen/0000-0003-3336-6781; Glynn, Nancy/0000-0003-2265-0162 FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR000064]; NCRR NIH HHS [UL1 RR029890]; NIA NIH HHS [U01 AG022376, K07AG0236, K24AG021507, P30 AG024827, P30 AG028740, P30 AG21332, U01 AG22376] NR 20 TC 42 Z9 42 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2007 VL 55 IS 5 BP 674 EP 683 DI 10.1111/j.1532-5415.2007.01136.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 161RA UT WOS:000246031900005 PM 17493186 ER PT J AU Delmonico, MJ Harris, TB Lee, JS Visser, M Nevitt, M Kritchevsky, SB Tylavsky, FA Newman, AB AF Delmonico, Matthew J. Harris, Tamara B. Lee, Jung-Sun Visser, Marjolein Nevitt, Michael Kritchevsky, Stephen B. Tylavsky, Frances A. Newman, Anne B. CA Hlth Aging Body Composition Study TI Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE lean mass; physical function; elderly; sarcopenia; methods ID BODY-MASS INDEX; FAT-FREE MASS; PHYSICAL PERFORMANCE; ELDERLY-MEN; EPIDEMIOLOGY; DISABILITY; ASSOCIATIONS; LIMITATION; OBESITY; DECLINE AB OBJECTIVES: To compare two methods for classifying an individual as sarcopenic for predicting decline in physical function in the Health, Aging and Body Composition Study. DESIGN: Observational cohort study with 5 years of follow-up. SETTING: Communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Men and women aged 70 to 79 (N=2,976, 52% women, 41% black). MEASUREMENTS: Appendicular lean mass (aLM) was measured using dual energy x-ray absorptiometry, and participants were classified as sarcopenic first using aLM divided by height squared and then using aLM adjusted for height and body fat mass (residuals). Incidence of persistent lower extremity limitation (PLL) was measured according to self-report, and change in objective lower extremity performance (LEP) measures were observed using the Short Physical Performance Battery. RESULTS: There was a greater risk of incident PLL in women who were sarcopenic using the residuals sarcopenia method than in women who were not sarcopenic (hazard ratio (HR)=1.34, 95% confidence interval (CI)=1.11-1.61) but not in men. Those defined as sarcopenic using the aLM/ht(2) method had lower incident PLL than nonsarcopenic men (HR=0.76, 95% CI=0.60-0.96) and women (HR=0.75, 95% CI=0.60-0.93), but these were no longer significant with adjustment for body fat mass. Using the residuals method, there were significantly poorer LEP scores in sarcopenic men and women at baseline and Year 6 and greater 5-year decline, whereas sarcopenic men defined using the aLM/ht(2) method had lower 5-year decline. Additional adjustment for fat mass attenuated this protective effect. CONCLUSION: These findings suggest that sarcopenia defined using the residuals method, a method that considers height and fat mass together, is better for predicting disability in an individual than the aLM/ht(2) method, because it considers fat as part of the definition. C1 Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Georgia, Dept Foods & Nutr, Athens, GA 30602 USA. VU Univ, Inst Hlth Sci, Amsterdam, Netherlands. VU Med Ctr, EMGO Inst, Amsterdam, Netherlands. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Wake Forest Univ, Stricht Ctr Aging, Winston Salem, NC 27109 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP Delmonico, MJ (reprint author), Univ Pittsburgh, Dept Epidemiol, 130 N Bellefield Ave,Room 519, Pittsburgh, PA 15213 USA. EM delmonicom@edc.pitt.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 19 TC 226 Z9 240 U1 2 U2 23 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAY PY 2007 VL 55 IS 5 BP 769 EP 774 DI 10.1111/j.1532-5415.2007.01140.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 161RA UT WOS:000246031900018 PM 17493199 ER PT J AU Ide, NC Loane, RF Demner-Fushman, D AF Ide, Nicholas C. Loane, Russell F. Demner-Fushman, Dina TI Essie: A concept-based search engine for structured biomedical text SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID RETRIEVAL; FEEDBACK; MEDLINE; SYSTEM AB This article describes the algorithms implemented in the Essie search engine that is currently serving several Web sites at the National Library of Medicine. Essie is a phrase-based search engine with term and concept query expansion and probabilistic relevancy ranking. Essie's design is motivated by an observation that query terms are often conceptually related to terms in a document, without actually occurring in the document text. Essie's performance was evaluated using data and standard evaluation methods from the 2003 and 2006 Text REtrieval Conference (TREC) Genomics track. Essie was the best-performing search engine in the 2003 TREC Genomics track and achieved results comparable to those of the highest-ranking systems on the 2006 TREC Genomics track task. Essie shows that a judicious combination of exploiting document structure, phrase searching, and concept based query expansion is a useful approach for information retrieval in the biomedical domain. C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. Thoughtful Solut Inc, Mclean, VA USA. RP Ide, NC (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. EM ide@nlm.nih.gov NR 38 TC 43 Z9 43 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY-JUN PY 2007 VL 14 IS 3 BP 253 EP 263 DI 10.1197/jamia.M2233 PG 11 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 170NS UT WOS:000246670800001 PM 17329729 ER PT J AU Greenes, RA Buchanan, BG Ellison, D AF Greenes, Robert A. Buchanan, Bruce G. Ellison, Donald TI Presentation of the 2006 Morris F. Collen Award to Edward H. (Ted) Shortliffe SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Biographical-Item C1 Harvard Univ, Decis Syst Grp, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Natl Lib Med, Bethesda, MD 20209 USA. RP Greenes, RA (reprint author), Harvard Univ, Decis Syst Grp, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM greenes@harvard.edu NR 1 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY-JUN PY 2007 VL 14 IS 3 BP 376 EP 385 DI 10.1197/jamia.M2374 PG 10 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 170NS UT WOS:000246670800017 PM 17557382 ER PT J AU Schiffmann, R Askari, H Timmons, M Robinson, C Benko, W Brady, RO Ries, M AF Schiffmann, Raphael Askari, Hasan Timmons, Margaret Robinson, Chevalia Benko, William Brady, Roscoe O. Ries, Markus TI Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CLINICAL-MANIFESTATIONS; ALPHA-GALACTOSIDASE; GAUCHER-DISEASE; EFFICACY; KIDNEY; GLOBOTRIAOSYLCERAMIDE; STORAGE; SAFETY; COHORT; PREVALENCE AB This study was performed to determine whether adult male patients with Fabry disease who demonstrate a continuing decline in renal function despite 2 to 4 yr of conventionally dosed agalsidase alfa therapy (0.2 mg/kg every other week [EOW]) show an improved slope of decline with weekly administration using the same dosage. Eleven (27%) of 41 adult male patients with Fabry disease who participated in long-term agalsidase alfa clinical trials and who had demonstrated a slope of decline in estimated GFR (eGFR) of <= 5 ml/min per 1.73 m(2)/yr while receiving long-term treatment with agalsidase alfa at the currently recommended dosage of 0.2 mg/kg, infused EOW, were enrolled in this open-label, prospective study. Patients were switched from EOW to weekly infusions and followed for an additional 24 mo. Before switching to weekly dosing, eGFR was 53.7 +/- 6.3 ml/min per 1.73 m(2) (mean +/- SEM), and mean rate of change in eGFR was -8.0 +/- 0.8 ml/min per 1.73 m(2)/yr. During the 24-mo follow-up period after switching to weekly dosing, the mean rate of change in eGFR was observed to slow to -3.3 +/- 1.4 ml/min/1.73 m(2)/yr (P = 0.01 versus EOW). After switching to weekly dosing, three patients demonstrated an improvement in eGFR and six patients demonstrated a slowing in the rate of eGFR decline; only two patients failed to improve their eGFR slope. A multiple regression model confirmed that the weekly infusion regimen was the strongest explanatory variable for the change in eGFR (P = 0.0008), with a weaker contribution from the concomitant use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (P = 0.02). These results suggest that weekly infusions of agalsidase alfa at a dosage of 0.2 mg/kg may be beneficial in the subgroup of patients who have Fabry disease and whose kidney function continues to decline after 2 to 4 yr or more of standard EOW dosing. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rs4e@nih.gov OI Ries, Markus/0000-0002-5054-5741 FU Intramural NIH HHS [Z01 NS002984-09] NR 34 TC 84 Z9 89 U1 0 U2 2 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAY PY 2007 VL 18 IS 5 BP 1576 EP 1583 DI 10.1681/ASN.2006111263 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 164NV UT WOS:000246241700026 PM 17409308 ER PT J AU Thompson, IM Tangen, CM Goodman, PJ Lucia, MS Parnes, HL Lippman, SM Coltman, CA AF Thompson, Ian M. Tangen, Catherine M. Goodman, Phyllis J. Lucia, M. Scott Parnes, Howard L. Lippman, Scott M. Coltman, Charles A., Jr. TI Finasteride improves the sensitivity of digital rectal examination for prostate cancer detection SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; mass screening; digital rectal examination; finasteride ID PREVENTION TRIAL; DIAGNOSIS AB Purpose: Men undergoing screening for prostate cancer are recommended to undergo digital rectal examination and prostate specific antigen measurement. We previously presented data from the Prostate Cancer Prevention Trial indicating that finasteride improves the performance characteristics of prostate specific antigen for cancer detection. In the current study we report the impact; of finasteride on digital rectal examination sensitivity and specificity. Materials and Methods: We examined the sensitivity and specificity of digital rectal examination in Prostate Cancer Prevention Trial subjects receiving finasteride or placebo who underwent prostate biopsy, had prostate specific antigen measurement and digital rectal examination within 1 year before biopsy and were on treatment at biopsy. Results: Of 9,423 men in the finasteride group 4,579 and 5,112 of 9,459 in the placebo group met study evaluation requirements. Of 4,579 men in the finasteride group 695, including 264 with Gleason 7 or greater and 81 with Gleason 8 or greater, and 1,111 of 5,112 in the placebo group, including 240 with Gleason 7 or greater and 55 with Gleason 8 or greater, were diagnosed with prostate cancer. In men in the placebo and finasteride groups digital rectal examination sensitivity was greater for detecting higher grade tumors. The sensitivity of digital rectal examination was significantly greater for cancer detection in men receiving finasteride than placebo (21.3% vs 16.7%, p = 0.015). Digital rectal examination sensitivity was also greater for detecting high grade (Gleason 7 or greater and 8 or greater) cancers in men receiving finasteride but this did not attain statistical significance. Digital rectal examination specificity was similar in men receiving finasteride or placebo. Conclusions: Finasteride significantly improves prostate cancer detection with digital rectal examination. C1 Univ Texas, Hlth Sci Ctr, Dept Urol, San Antonio, TX 78229 USA. MD Anderson Canc Ctr, Dept Canc Prevent, Houston, TX USA. SW Oncol Grp, San Antonio, TX USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO 80262 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Thompson, IM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Urol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM thompsoni@uthscsa.edu FU NCI NIH HHS [CA 86402, CA35178, CA 37429, CA 45808] NR 8 TC 58 Z9 63 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2007 VL 177 IS 5 BP 1749 EP 1752 DI 10.1016/j.juro.2007.01.071 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 158BC UT WOS:000245764900039 PM 17437804 ER PT J AU Albo, M Wruck, L Baker, J Brubaker, L Chai, T Dandreo, KJ Diokno, A Goode, P Kraus, S Kusek, JW Lemack, G Lowder, J Steers, W AF Albo, Michael Wruck, Lisa Baker, Jan Brubaker, Linda Chai, Toby Dandreo, Kimberly J. Diokno, Ananias Goode, Patricia Kraus, Stephen Kusek, John W. Lemack, Gary Lowder, Jerry Steers, William CA Urinary Incontinence Treatment TI The relationships among measures of incontinence severity in women undergoing surgery for stress urinary incontinence SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder; female; quality of life; urinary incontinence, stress; urodynamics ID LEAK-POINT PRESSURE; URETHRAL CLOSURE PRESSURE; QUALITY-OF-LIFE; IMPACT; TESTS; MULTICENTER; PREDICTOR; SYMPTOMS; DIARY; ICIQ AB Purpose: We assessed the relationships among severity measures of urinary incontinence in women with stress predominant symptoms enrolled in a randomized clinical trial comparing 2 surgical techniques (Burch colposuspension vs pubovaginal sling) for stress urinary incontinence. Materials and Methods: A total of 655 women underwent a standardized preoperative assessment that included the Medical, Epidemiological and Social Aspects of Aging questionnaire, Urogenital Distress Inventory, Incontinence Impact Questionnaire, 3-day voiding diary, 24-hour pad test, a supine empty bladder stress test and Valsalva leak point pressure measurements. Correlations were estimated using Spearman correlation coefficients and 95% confidence intervals. T tests at alpha = 0.05 were conducted to compare the distributions of the continuous severity measure between patients with positive and negative supine empty bladder stress test. Results: Baseline mean scores on Medical, Epidemiological and Social Aspects of Aging, Urogenital Distress Inventory and Incontinence Impact Questionnaire were 25.8, 151 and 171, respectively. Mean incontinence episode frequency and pad weight were 3.2 per day and 43.5 gm, respectively. Supine empty bladder stress test was positive in 218 patients, and 428 patients had valid Valsalva leak point pressure measurements with a mean Valsalva leak point pressure of 80 cm H2O. Weak to moderate correlations were observed between Medical, Epidemiological and Social Aspects of Aging, incontinence episode frequency, pad weight, Incontinence Impact Questionnaire and Urogenital Distress Inventory. On the other hand, Valsalva leak point pressure correlated poorly with all variables measured. The sensitivity and specificity of the supine empty bladder stress test to predict intrinsic sphincter dysfunction were 49% and 60%, respectively. Conclusions: Urinary incontinence severity measures correlate moderately with each other at best. While Medical, Epidemiological and Social Aspects of Aging demonstrated stronger correlations with the other measures of severity and quality of life, Valsalva leak point pressure did not. Supine empty bladder stress test did not demonstrate a clinically significant association among severity measures. C1 New England Res Inst, Boston, MA USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT 84112 USA. Loyola Univ, Dept Obstet & Gynecol, Maywood, IL 60153 USA. Loyola Univ, Dept Urol, Maywood, IL 60153 USA. Univ Maryland, Div Urol, Baltimore, MD 21201 USA. NIDDK, NIH, Bethesda, MD USA. William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. Univ Alabama, Birmingham Atlanta Vet Affairs Geriatr Res Educ &, Birmingham, AL USA. Univ Alabama, Div Gerontol & Geriatr Med, Birmingham, AL USA. Univ Texas, Dept Urol, San Antonio, TX 78285 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Pittsburgh, Div Urogynecol & Pelv Reconstruct Surg, Pittsburgh, PA 15260 USA. Univ Virginia, Dept Urol, Charlottesville, VA 22903 USA. RP Albo, M (reprint author), Univ Calif San Diego, Med Ctr, Div Urol, 200 W Arbor Dr, San Diego, CA 92103 USA. EM malbo@ucsd.edu FU NIDDK NIH HHS [U01 DK60397, U01 DK58229, U01 DK60395, U01 DK60380, U01 DK58225, U01 DK58234, U01 DK60379, U01 DK60401, U01 DK58231, U01 DK60393] NR 25 TC 36 Z9 37 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2007 VL 177 IS 5 BP 1810 EP 1814 DI 10.1016/j.juro.2007.01.032 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 158BC UT WOS:000245764900061 PM 17437826 ER PT J AU Nickel, JC Tripp, D Teal, V Propert, KJ Burks, D Foster, HE Hanno, P Mayer, R Payne, CK Peters, KM Kusek, JW Nyberg, LM AF Nickel, J. Curtis Tripp, Dean Teal, Valerie Propert, Kathleen J. Burks, David Foster, Harris E. Hanno, Philip Mayer, Robert Payne, Christopher K. Peters, Kenneth M. Kusek, John W. Nyberg, Leroy M. CA Interstitial Cystitis Collabora TI Sexual function is a determinant of poor quality of life for women with treatment refractory interstitial cystitis SO JOURNAL OF UROLOGY LA English DT Article DE sexual behavior; cystitis, interstitial; pelvic pain ID CHRONIC PELVIC PAIN; CONSEQUENCES; ADJUSTMENT; DEPRESSION; TRIAL; INDEX AB Purpose: Interstitial cystitis significantly negatively impacts quality of life. The demographic and clinical factors associated with decreased quality of life in these patients have not been well studied. Materials and Methods: Women with moderate/severe interstitial cystitis enrolled in a clinical trial of intravesical bacillus Calmette-Guerin were studied. Demographic data and responses to questionnaires were evaluated at baseline, including the O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index, University of Wisconsin Interstitial Cystitis Inventory, Medical Outcomes Study sexual functioning scale, and the physical composite and mental composite scales of the Medical Outcomes Study Short Form Health Status Survey. Three composite indexes were constructed (from the O'Leary-Sant Interstitial Cystitis Symptom Index, O'Leary-Sant Interstitial Cystitis Problem Index, pain/urgency Likert scales and 24-hour voiding diary) to document the severity, frequency and bother of pain, urinary urgency and frequency (frequency composite index). Linear and multivariate regression models were used to examine predictors of the physical composite and mental composite scales of the Medical Outcomes Study Short Form Health Status Survey. Medical Outcomes Study sexual functioning scale data were available for 163 of the 217 women in the trial. Results: Physical composite scale (median 36) and mental composite scale (median 42) were lower than the standard population value of 50. Multivariate models showed that employment, pain composite index and Medical Outcomes Study sexual functioning scale (all p <0.001) predicted physical composite scale, while only Medical Outcomes Study sexual functioning scale (p <0.001) remained a strong predictor of mental composite scale. Conclusions: Sexual functioning, employment and pain issues predict mental and physical quality of life. In particular, this study identifies sexual functioning as a primary predictor of mental quality of life in women with long-standing interstitial cystitis. It is suggested that sexual functioning may be a salient therapeutic target in the multifaceted treatment of patients with interstitial cystitis. C1 Queens Univ, Kingston Gen Hosp, Dept Urol, Kingston, ON K7L 2V7, Canada. Univ Penn, Philadelphia, PA 19104 USA. Henry Ford Hosp, Detroit, MI 48202 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Yale Univ, New Haven, CT 06520 USA. Univ Rochester, Rochester, NY 14627 USA. Stanford Univ, Stanford, CA 94305 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Nickel, JC (reprint author), Queens Univ, Kingston Gen Hosp, Dept Urol, Kingston, ON K7L 2V7, Canada. EM jcn@post.queensu.ca OI Teal, Valerie/0000-0001-7116-5353 FU NCRR NIH HHS [M01 RR 16500]; NIDDK NIH HHS [U01 DK54127, U01 DK54138, U01 DK54133, U01 DK54125, U01 DK54158, U01 DK54108] NR 20 TC 41 Z9 44 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAY PY 2007 VL 177 IS 5 BP 1832 EP 1836 DI 10.1016/j.juro.2007.01.060 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 158BC UT WOS:000245764900066 PM 17437831 ER PT J AU Kato, T Matsumura, T Heller, T Saito, S Sapp, RK Murthy, K Wakita, T Liang, TJ AF Kato, Takanobu Matsumura, Takuya Heller, Theo Saito, Satoru Sapp, Ronda K. Murthy, Krishna Wakita, Takaji Liang, T. Jake TI Production of infectious hepatitis C virus of various genotypes in cell cultures SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN HEPATOMA-CELLS; EFFICIENT REPLICATION; SUBGENOMIC REPLICON; IN-VITRO; CHIMPANZEES; RNA; 2A; MUTATIONS; CHIMERAS; SEQUENCE AB A unique hepatitis C virus (HCV) strain JFH-1 has been shown to replicate efficiently in cell culture with production of infectious HCV. We previously developed a DNA expression system containing HCV cDNA flanked by two self-cleaving ribozymes to generate HCV particles in cell culture. In this study, we produced HCV particles of various genotypes, including la (1177), 1b (CG1b), and 2a (J6 and JFH-1), in the HCV-ribozyme system. The constructs also contain the secreted alkaline phosphatase gene to control for transfection efficiency and the effects of culture conditions. After transfection into the Huh7-derived cell line Huh7.5.1, continuous HCV replication and secretion were confirmed by the detection of HCV RNA and core antigen in the culture medium. HCV replication levels of strains H77, CG1b, and J6 were comparable, whereas the JFH-1 strain replicates at a substantially higher level than the other strains. To evaluate the infectivity in vitro, the culture medium of JFH-1-transfected cells was inoculated into naive Huh7.5.1 cells. HCV proteins were detected by immunofluorescence 3 days after inoculation. To evaluate the infectivity in vivo, the culture medium from HCV genotype 1b-transfected cells was inoculated into a chimpanzee and caused a typical course of HCV infection. The HCV 1b propagated in vitro and in vivo had sequences identical to those of the HCV genomic cDNA used for cell culture transfection. The development of culture systems for production of various HCV genotypes provides a valuable tool not only to study the replication and pathogenesis of HCV but also to screen for antivirals. C1 Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. SW Fdn Biomed Res, San Antonio, TX 78227 USA. Tokyo Metropolitan Inst Neurosci, Dept Microbiol, Tokyo, Japan. RP Liang, TJ (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, 10 Ctr Dr,Rm 9B16, Bethesda, MD 20892 USA. EM JakeL@bdg10.niddk.nih.gov FU Intramural NIH HHS NR 26 TC 81 Z9 85 U1 0 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 MAY PY 2007 VL 81 IS 9 BP 4405 EP 4411 DI 10.1128/JVI.02334-06 PG 7 WC Virology SC Virology GA 168DE UT WOS:000246501900003 PM 17301131 ER PT J AU Mitchell, MS Bodine, ET Hill, S Princler, G Lloyd, P Mitsuya, H Matsuoka, M Derse, D AF Mitchell, Michael S. Bodine, Ellen T. Hill, Shawn Princler, Gerald Lloyd, Patricia Mitsuya, Hiroaki Matsuoka, Masao Derse, David TI Phenotypic and genotypic comparisons of human T-cell leukemia virus type I reverse transcriptases from infected T-cell lines and patient samples SO JOURNAL OF VIROLOGY LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; NUCLEOTIDE-SEQUENCE ANALYSIS; LYMPHOTROPIC VIRUS; HTLV-I; LYMPHOMA VIRUS; PHYLOGENETIC SUBTYPES; CEREBROSPINAL-FLUID; MOLECULAR CLONE; TRANSMISSION; BLOOD AB It is well established that cell-free infection with human T-cell leukemia virus type 1 (HTLV-1) is less efficient than that with other retrovinises, though the specific infectivities of only a limited number of HTLV-1 isolates have been quantified. Earlier work indicated that a postentry step in the infectious cycle accounted for the poor cell-free infectivity of HTLV-1. To determine whether variations in the pol gene sequence correlated with virus infectivity, we sequenced and phenotypically tested pol genes from a variety of HTLV-1 isolates derived from primary sources, transformed cell lines, and molecular clones. The pol genes and deduced amino acid sequences from 23 proviruses were sequenced and compared with 14 previously published sequences, revealing a limited number of amino acid variations among isolates. The variations appeared to be randomly dispersed among primary isolates anti proviruses from cell lines and molecular clones. In addition, there was no correlation between reverse transcriptase sequence and the disease phenotype of the original source of the virus isolate. HTLV-1 pol gene fragments encoding reverse transcriptase were amplified from a variety of isolates and were subcloned into HTLV-1 vectors for both single-cycle infection and spreading-infection assays. Vectors carrying pol genes that matched the consensus sequence had the highest titers, and those with the largest number of variations from the consensus had the lowest titers. The molecular clone from CS-1 cells had four amino acid differences from the consensus sequence and yielded infectious titers that were approximately eight times lower than those of vectors encoding a consensus reverse transcriptase. C1 Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. HIV & AIDS Malignancy Branch, NCI, Bethesda, MD 20892 USA. Kyoto Univ, Inst Virus Res, Kyoto 6068507, Japan. RP Derse, D (reprint author), Natl Canc Inst, HIV Drug Resistance Program, POB Box B,Bldg 535-134, Frederick, MD 21702 USA. EM derse@ncifcrf.gov FU Intramural NIH HHS NR 61 TC 9 Z9 11 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2007 VL 81 IS 9 BP 4422 EP 4428 DI 10.1128/JVI.02660-06 PG 7 WC Virology SC Virology GA 168DE UT WOS:000246501900005 PM 17287279 ER PT J AU Barro, M Patton, JT AF Barro, Mario Patton, John T. TI Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3, IRF5, and IRF7 SO JOURNAL OF VIROLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; ALPHA/BETA GENE INDUCTION; TRANSCRIPTION FACTORS; VIRAL-INFECTION; INNATE IMMUNITY; HOST-DEFENSE; VIRUS; REPLICATION; CELLS; DEGRADATION AB Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the "master regulator" of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function. C1 NIAID, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Lab Infect Dis, NIH, 50 S Dr MSC 8026,Rm 6314, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural NIH HHS NR 37 TC 104 Z9 118 U1 0 U2 8 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 MAY PY 2007 VL 81 IS 9 BP 4473 EP 4481 DI 10.1128/JVI.02498-06 PG 9 WC Virology SC Virology GA 168DE UT WOS:000246501900011 PM 17301153 ER PT J AU Meade-White, K Race, B Trifilo, M Bossers, A Favara, C Lacasse, R Miller, M Williams, E Oldstone, M Race, R Chesebro, B AF Meade-White, Kimberly Race, Brent Trifilo, Matthew Bossers, Alex Favara, Cynthia Lacasse, Rachel Miller, Michael Williams, Elizabeth Oldstone, Michael Race, Richard Chesebro, Bruce TI Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein SO JOURNAL OF VIROLOGY LA English DT Article ID CERVUS-ELAPHUS-NELSONI; WHITE-TAILED DEER; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; CREUTZFELDT-JAKOB-DISEASE; PRP KNOCKOUT MICE; MULE DEER; IN-VITRO; SCRAPIE; ELK; SUSCEPTIBILITY AB Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer or elk PrP in transgenic mice has induced susceptibility to chronic wasting disease (CWD), the prion disease of cervids. In the current experiments, transgenic mice expressing two naturally occurring allelic variants of deer PrP with either glycine (G) or serine (S) at residue 96 were found to differ in susceptibility to CWD infection. G96 mice were highly susceptible to infection, and disease appeared starting as early as 160 days postinfection. In contrast, S96 mice showed no evidence of disease or generation of disease-associated protease-resistant PrP (PrPres) over a 600-day period. At the time of clinical disease, G96 mice showed typical vacuolar pathology and deposition of PrPres in many brain regions, and in some individuals, extensive neuronal loss and apoptosis were noted in the hippocampus and cerebellum. Extraneural accumulation of PrPres was also noted in spleen and intestinal tissue of clinically ill G96 mice. These results demonstrate the importance of deer PrP polymorphisms in susceptibility to CWD infection. Furthermore, this deer PrP transgenic model is the first to demonstrate extraneural accumulation of PrPres in spleen and intestinal tissue and thus may prove useful in studies of CWD pathogenesis and transmission by oral or other natural routes of infection. C1 NIAID, Rocky Mt Labs, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. Scripps Res Inset, Dept Mol, Viral Immunobiol Lab, La Jolla, CA USA. Scripps Res Inset, Dept Integrat Neurosci & Infectol, Viral Immunobiol Lab, La Jolla, CA USA. Cent Inst Anim Dis Control, Dept Bacteriol & TSEs, NL-8203 AA Lelystad, Netherlands. Colorado Div Wildlife, Wildlife Res Ctr, Ft Collins, CO 80526 USA. Univ Wyoming, Dept Vet Sci, Laramie, WY 82070 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Lab Persistent Viral Dis, 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@nih.gov OI Bossers, Alex/0000-0002-6586-717X NR 38 TC 43 Z9 44 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 MAY PY 2007 VL 81 IS 9 BP 4533 EP 4539 DI 10.1128/JVI.02762-06 PG 7 WC Virology SC Virology GA 168DE UT WOS:000246501900017 PM 17314157 ER PT J AU Thomas, DC Voronin, YA Nikolenko, GN Chen, JB Hu, WS Pathak, VK AF Thomas, David C. Voronin, Yegor A. Nikolenko, Galina N. Chen, Jianbo Hu, Wei-Shau Pathak, Vinay K. TI Determination of the ex vivo rates of human immunodeficiency virus type 1 reverse transcription by using novel strand-specific amplification analysis SO JOURNAL OF VIROLOGY LA English DT Article ID POLYMERASE-CHAIN-REACTION; ROLLING-CIRCLE AMPLIFICATION; CENTRAL DNA FLAP; NUCLEAR IMPORT; PADLOCK PROBES; IN-VITRO; KINETICS; INFECTION; BINDING; CELLS AB Replication of human immunodeficiency virus type 1 (HIV-1), like all organisms, involves synthesis of a minus-strand and a plus-strand of nucleic acid. Currently available FICR methods cannot distinguish between the two strands of nucleic acids. To carry out detailed analysis of HIV-1 reverse transcription from infected cells, we have developed a novel strand-specific amplification (SSA) assay using single-stranded padlock probes that are specifically hybridized to a target strand, ligated, and quantified for sensitive analysis of the kinetics of HIV-1 reverse transcription in cells. Using SSA, we have determined for the first time the ex vivo rates of HIV-1 minus-strand DNA synthesis in 293T and human primary CD4(+) T cells (similar to 68 to 70 nucleotides/min). We also determined the rates of minus-strand DNA transfer (similar to 4 min), plus-strand DNA transfer (similar to 26 min), and initiation of plus-strand DNA synthesis (similar to 9 min) in 293T cells. Additionally, our results indicate that plus-strand DNA synthesis is initiated at multiple sites and that several reverse transcriptase inhibitors influence the kinetics of minus-strand DNA synthesis differently, providing insights into their mechanism of inhibition. The SSA technology provides a novel approach to analyzing DNA replication processes and should facilitate the development of new antiretroviral drugs that target specific steps in HIV-1 reverse transcription. C1 NCI, Ctr Canc Res, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Viral Recombinat Sect, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, Ctr Canc Res, Viral Mutat Sect, HIV Drug Resistance Program, POB B,Room 334, Frederick, MD 21702 USA. EM vpathak@ncifcrf.gov RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01 CO 12400] NR 28 TC 20 Z9 21 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2007 VL 81 IS 9 BP 4798 EP 4807 DI 10.1128/JVI.02471-06 PG 10 WC Virology SC Virology GA 168DE UT WOS:000246501900042 PM 17314159 ER PT J AU Bihl, F Narayan, M Chisholm, JV Henry, LM Suscovich, TJ Brown, EE Welzel, TM Kaufmann, DE Zaman, TM Dollard, S Martin, JN Wang, F Scadden, DT Kaye, KM Brander, C AF Bihl, Florian Narayan, Murli Chisholm, John V. Henry, Leah M. Suscovich, Todd J. Brown, Elizabeth E. Welzel, Tania M. Kaufmann, Daniel E. Zaman, Tauheed M. Dollard, Sheila Martin, Jeff N. Wang, Fred Scadden, David T. Kaye, Kenneth M. Brander, Christian TI Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTION; EPITOPES; IMPACT; HUMAN-HERPESVIRUS-8; IMMUNODOMINANCE; IDENTIFICATION; COINFECTION; LYMPHOCYTES; EVOLUTION AB The cellular immunity against Kaposils sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HILA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, US Dept HHS,NIH, Rockville, MD USA. Harvard Univ, Lemuel Shattuck Hosp, Sch Med, Boston, MA 02115 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Ctr,Ctr Regenerat Med & Technol, Boston, MA 02115 USA. Harvard Univ, Stem Cell Inst, Boston, MA 02115 USA. RP Brander, C (reprint author), MGH E, Partners AIDS Res Ctr, 5th Floor,5239,13th St, Charlestown, MA 02129 USA. EM cbrander@partners.org OI Brander, Christian/0000-0002-0548-5778 FU NCI NIH HHS [N01 CP 21121]; NIAID NIH HHS [P30 AI060354, P30 AI 060534]; NIDCR NIH HHS [P01 DE 01438-01] NR 33 TC 21 Z9 21 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 MAY PY 2007 VL 81 IS 9 BP 4904 EP 4908 DI 10.1128/JVI.02509-06 PG 5 WC Virology SC Virology GA 168DE UT WOS:000246501900057 PM 17329344 ER PT J AU Wessels, E Duijsings, D Lanke, KHW Melchers, WJG Jackson, CL van Kuppeveld, FJM AF Wessels, Els Duijsings, DanieL Lanke, Kjerstin H. W. Melchers, Willem J. G. Jackson, Catherine L. van Kuppeveld, Frank J. M. TI Molecular determinants of the interaction between coxsackievirus protein 3A and guanine nucleotide exchange factor GBF1 SO JOURNAL OF VIROLOGY LA English DT Article ID ADP-RIBOSYLATION FACTOR; MEMBRANE ASSOCIATION; GOLGI TRANSPORT; POLIOVIRUS; ARF; INHIBITION; REPLICATION; DOMAIN; 2B; DYNAMICS AB The 3A protein of coxsackievirus B3 (CVB3), a small membrane protein that forms homodimers, inhibits endoplasmic reticulum-to-Golgi complex transport. Recently, we described the underlying mechanism by showing that the CVB3 3A protein binds to and inhibits the function of GBF1, a guanine nucleotide exchange factor for ADP-ribosylation factor 1 (Arf1), thereby interfering with Arf1-mediated COP-1 recruitment. This study was undertaken to gain more insight into the molecular determinants underlying the interaction between 3A and GBF1. Here we show that 3A mutants that have lost the ability to dimerize are no longer able to bind to GBF1 and trap it on membranes. Moreover, we identify a conserved region in the N terminus of 3A that is crucial for GBF1 binding but not for 3A dimerization. Analysis of the binding domain in GBF1 showed that the extreme N terminus, the dimerization/cyclophilin binding domain, and the homology upstream of Sec7 domain are required for the interaction with 3A. In contrast to that of full-length GBF1, overexpression of a GBF1 mutant lacking its extreme N terminus failed to rescue the effects of 3A. Together, these data provide insight into the molecular requirements of the interaction between 3A and GBF1. C1 Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP van Kuppeveld, FJM (reprint author), Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Med Microbiol, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM f.vankuppeveld@ncmls.ru.nl RI Jackson, Catherine/A-3421-2013; Melchers, Willem/C-8819-2015 OI Jackson, Catherine/0000-0002-0843-145X; Melchers, Willem/0000-0002-5446-2230 NR 35 TC 36 Z9 38 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 MAY PY 2007 VL 81 IS 10 BP 5238 EP 5245 DI 10.1128/JVI.02680-06 PG 8 WC Virology SC Virology GA 167PS UT WOS:000246464200032 PM 17329336 ER PT J AU Luckay, A Sidhu, MK Kjeken, R Megati, S Chong, SY Roopchand, V Garcia-Hand, D Abdullah, R Braun, R Montefiori, DC Rosati, M Felber, BK Pavlakis, GN Mathiesen, I Israel, ZR Eldridge, JH Egan, MA AF Luckay, Amara Sidhu, Maninder K. Kjeken, Rune Megati, Shakuntala Chong, Siew-Yen Roopchand, Vidia Garcia-Hand, Dorys Abdullah, Rashed Braun, Ralph Montefiori, David C. Rosati, Margherita Felber, Barbara K. Pavlakis, George N. Mathiesen, Iacob Israel, Zimra R. Eldridge, John H. Egan, Michael A. TI Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 REVERSE-TRANSCRIPTASE; B SURFACE-ANTIGEN; GENE-TRANSFER; INTRAMUSCULAR INJECTION; ANTIBODY-RESPONSES; SKELETAL-MUSCLE; PHASE-I; HIV-1-INFECTED PATIENTS; RATIONAL DESIGN AB Since human immunodeficiency virus (HIV)-specific cell-mediated immune (CMI) responses are critical in the early control and resolution of HIV infection and correlate with postchallenge outcomes in rhesus macaque challenge experiments, we sought to identify a plasmid DNA (pDNA) vaccine design capable of eliciting robust and balanced CMI responses to multiple HIV type 1 (HIV-1)-derived antigens for further development. Previously, a number of two-, three-, and four-vector pDNA vaccine designs were identified as capable of eliciting HIV-1 antigen-specific CMI responses in mice (M. A. Egan et al., Vaccine 24:4510-4523, 2006). We then sought to further characterize the relative immunogenicities of these two-, three-, and four-vector pDNA vaccine designs in nonhuman primates and to determine the extent to which in vivo electroporation (EP) could improve the resulting immune responses. The results indicated that a two-vector pDNA vaccine design elicited the most robust and balanced CMI response. In addition, vaccination in combination with in vivo EP led to a more rapid onset and enhanced vaccine-specific immune responses. In macaques immunized in combination with in vivo EP, we observed a 10- to 40-fold increase in HIV-specific enzyme-linked immunospot assay responses compared to those for macaques receiving a 5-fold higher dose of vaccine without in vivo EP. This increase in CMI responses translates to an apparent 50- to 200-fold increase in pDNA vaccine potency. Importantly, in vivo EP enhanced the immune response against the less immunogenic antigens, resulting in a more balanced immune response. In addition, in vivo EP resulted in an approximate 2.5-log(10) increase in antibody responses. The results further indicated that in vivo EP was associated with a significant reduction in pDNA persistence and did not result in an increase in pDNA associated with high-molecular-weight DNA relative to macaques receiving the pDNA without EP. Collectively, these results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection. C1 Wyeth Vaccines Res, Vaccine Discovery, Pearl River, NY 10965 USA. Inovio AS, N-0373 Oslo, Norway. Duke Univ, Ctr Med, Dept Surg, Durham, NC 27710 USA. Natl Canc Inst Frederick, Human Retrovirus Sect, Ft Detrick, MD 21702 USA. Natl Canc Inst Frederick, Human Retrovirus Pathogenesis Sect, Ft Detrick, MD 21702 USA. RP Egan, MA (reprint author), Wyeth Vaccines Res, Vaccine Discovery, 401 N Middletown Rd, Pearl River, NY 10965 USA. EM eganm@wyeth.com FU NIAID NIH HHS [N01AI50010, N01AI25458, N01-AI-50010, N01-AI-25458] NR 86 TC 143 Z9 150 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 MAY PY 2007 VL 81 IS 10 BP 5257 EP 5269 DI 10.1128/JVI.00055-07 PG 13 WC Virology SC Virology GA 167PS UT WOS:000246464200034 PM 17329330 ER PT J AU Finnegan, CM Rawat, SS Cho, EH Guiffre, DL Lockett, S Merrill, AH Blumenthal, R AF Finnegan, Catherine M. Rawat, Satinder S. Cho, Edward H. Guiffre, Danielle L. Lockett, Stephen Merrill, Alfred H., Jr. Blumenthal, Robert TI Sphingomyelinase restricts the lateral diffusion of CD4 and inhibits human immunodeficiency virus fusion SO JOURNAL OF VIROLOGY LA English DT Article ID MEDIATED FUSION; HIV-1 ENTRY; MEMBRANE CHOLESTEROL; 6-HELIX BUNDLE; LIVING CELLS; LIPID RAFTS; CERAMIDE; RECEPTOR; ENDOCYTOSIS; INFECTION AB Previously, we reported that treatment of cells with sphingomyelinase inhibits human immunodeficiency virus type 1 (HIV-1) entry. Here, we determined by measuring fluorescence recovery after photobleaching that the lateral diffusion of CD4 decreased 4-fold following sphingomyelinase treatment, while the effective diffusion rate of CCR5 remained unchanged. Notably, sphingomyelinase treatment of cells did not influence gp120 binding, HIV-1 attachment, or fluid-phase and receptor-mediated endocytosis. Furthermore, sphingomyelinase treatment did not affect the membrane disposition of the HIV receptor proteins CD4, CXCR4, and CCR5, as determined by Triton X-100 extraction. Restriction of CD4 diffusion by antibody cross-linking also inhibited HIV infection. We therefore interpret the decrease in CD4 lateral mobility following sphingomyelinase treatment in terms of clustering of CD4 molecules. Examination of fusion intermediates indicated that sphingomyelinase treatment inhibited HIV at a step in the fusion process after CD4 engagement. Maximal inhibition of fusion was observed following short coculture times and with target cells that express low levels of CD4. As HIV entry into cells requires the sequential engagement of viral envelope protein with CD4 and coreceptor, we propose that sphingomyelinase inhibits HIV infection by inducing CD4 clustering that prevents coreceptor engagement and HIV fusion. C1 NCI, Ctr Canc Res Nanobiol Program, NIH, Ft Detrick, MD 21702 USA. NCI, Inage Anal Lab, SAIC Frederick, Ft Detrick, MD 21702 USA. Georgia Inst Technol, Sch Biol, Atlanta, GA 30322 USA. Georgia Inst Technol, Petit Inst Bioengn & Biosci, Atlanta, GA 30322 USA. RP Blumenthal, R (reprint author), POB B,bldg 469,Room 151,Miller Dr, Ft Detrick, MD 21702 USA. EM blumen@helix.nih.gov RI Cho, Edward/B-3727-2012 OI Cho, Edward/0000-0002-0278-334X FU Intramural NIH HHS; NCI NIH HHS [N01-CO56000]; NIGMS NIH HHS [U54 GM069338, GM069338] NR 45 TC 34 Z9 35 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2007 VL 81 IS 10 BP 5294 EP 5304 DI 10.1128/JVI.02553-06 PG 11 WC Virology SC Virology GA 167PS UT WOS:000246464200037 PM 17344303 ER PT J AU Pepine, CJ Von Mering, GO Kerensky, RA Johnson, BD McGorray, SP Kelsey, SF Pohost, G Rogers, WJ Reis, SE Sopko, G Merz, CNB AF Pepine, Carl J. Von Mering, Gregory O. Kerensky, Richard A. Johnson, B. Delia McGorray, Susan P. Kelsey, Sheryl F. Pohost, Gerald Rogers, William J. Reis, Steven E. Sopko, George Merz, C. Noel Bairey CA WISE Study Grp TI Phytoestrogens and coronary microvascular function in women with suspected myocardial ischemia: A report from the Women's Ischemia Syndrome Evaluation (WISE) study SO JOURNAL OF WOMENS HEALTH LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; HEALTHY POSTMENOPAUSAL WOMEN; SOY PROTEIN; ENDOTHELIAL FUNCTION; FLOW VELOCITY; HEART-DISEASE; DOUBLE-BLIND; PILOT PHASE; DIETARY SOY; CHEST-PAIN AB Aims: Soy phytoestrogens are popular, but information on their coronary effects in patients with suspected ischemic heart disease is limited. Accordingly, we investigated the relationship between blood phytoestrogen levels and coronary reactivity in women with suspected myocardial ischemia referred for coronary angiography. Methods: Coronary flow velocity reserve (CFVR) and volumetric flow reserve (VFR) to adenosine (ADO) and nitroglycerin (NTG) (nonendothelial-dependent responses) and acetylcholine (ACH) (endothelial-dependent response) were assessed in 106 women from the Women's Ischemia Syndrome Evaluation (WISE). Blood phytoestrogen (daidzein and genistein) and estrogen (estradiol) levels were correlated with coronary reactivity measures. Results: Participants were mostly postmenopausal (79%), mean age 56 years, and 24% had obstructive coronary artery disease (CAD) at angiography. Genistein blood levels were negatively correlated with nonendothelial-dependent coronary flow responses. The highest genistein tertile (>6.1 ng/mL) had a CFVR of 2.1 +/- 0.5 (mean +/- SD) and VFRADO of 1.0 +/- 0.6, and both were significantly (p = 0.0001) lower compared with the other genistein tertiles combined. Similar associations were noted for CFVRNTG and VFRNTG (p = 0.03 and p = 0.01, respectively). The highest genistein tertile was associated with lower CFVRACH compared with the other tertiles (p = 0.03). In multivariable modeling, blood genistein levels were significant independent predictors of coronary flow responses to ADO. There were no significant correlations between coronary reactivity variables and daidzein or endogenous estrogen. Conclusions: In women with suspected myocardial ischemia, higher genistein blood levels are associated with impaired nonendothelial-dependent and endothelial-dependent coronary microvascular function. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. Univ So Calif, Dept Cardiovasc Med, Los Angeles, CA USA. Univ Alabama, Div Cardiovasc Dis, Birmingham, AL USA. NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. RP Pepine, CJ (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. EM pepincj@medicine.ufl.edu RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [U01-HL-64914-01, U01-HL-64829-01, N01-HV-68164, U01-HL-65924-01, N01-HV-68161, N01-HV-68162] NR 37 TC 5 Z9 5 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAY PY 2007 VL 16 IS 4 BP 481 EP 488 DI 10.1089/jwh.2006.0104 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 171DD UT WOS:000246714200006 PM 17521251 ER PT J AU Ferrucci, L AF Ferrucci, Luigi TI A year of excellence in geriatric research-and some new dishes on the menu SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID BODY-COMPOSITION; OLDER PERSONS; DELIRIUM; FRAILTY; HEALTH C1 NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit,Harbor Hosp, Baltimore, MD 21225 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit,Harbor Hosp, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 12 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2007 VL 62 IS 5 BP 516 EP 517 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 228WP UT WOS:000250763600006 PM 17522355 ER PT J AU Vogelzangs, N Beekman, ATF Kritchevsky, SB Newman, AB Pahor, M Yaffe, K Rubin, SM Harris, TB Satterfield, S Simonsick, EM Penninx, BWJH AF Vogelzangs, Nicole Beekman, Aartjan T. F. Kritchevsky, Stephen B. Newman, Anne B. Pahor, Marco Yaffe, Kristine Rubin, Susan M. Harris, Tamara B. Satterfield, Suzanne Simonsick, Eleanor M. Penninx, Brenda W. J. H. TI Psychosocial risk factors and the metabolic syndrome in elderly persons: Findings from the health, aging and body composition study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID CORONARY-HEART-DISEASE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; DEHYDROEPIANDROSTERONE-SULFATE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; INSULIN-RESISTANCE; MAJOR DEPRESSION; OLDER PERSONS; STRESS AB Background. Psychosocial factors have been associated with metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. This study investigated the cross-sectional relationship between psychosocial risk factors and the metabolic syndrome in a community-based sample of older persons. Methods. Participants were 2917 persons aged 70-79 years enrolled in the Health, Aging and Body Composition study. Depressive and anxiety symptoms, negative life events, and inadequate emotional support were assessed, and a summary psychosocial risk index was calculated. Metabolic syndrome was defined as three or more of the following criteria: abdominal obesity, high triglycerides, low high-density lipoprotein (HDL cholesterol, high fasting glucose, and high blood pressure. Results. Negative life events and inadequate emotional support increased the odds of having metabolic syndrome after adjustment for demographic and lifestyle variables (odds ratio [OR] per life event = 1.13, 95% confidence interval [CI] = 1.05-1.22; OR = 1.35, 95% CI = 1.10-1.66, respectively). The relationship between depressive symptoms and metabolic syndrome was only found in white (OR per standard deviation [SD] = 1.11, 95% CI = 1.0 1-1.23), but not in black (OR per SD = 0.97, 95% CI = 0.86-1.11) persons. Anxiety symptoms were significantly associated with metabolic syndrome in men (OR per SD = 1.13, 95% CI = 1.00-1.28), but not in women (OR per SD = 0.98, 95% CI = 0.89-1.08). Moreover, a higher score on the psychosocial risk index was associated with an increased probability of having the metabolic syndrome (OR = 1.30, 95% CI = 1.12-1.52). Conclusions. In the elderly population, different psychosocial risk factors are associated with a higher prevalence of the metabolic syndrome. Whether reduction or better management of psychosocial risk factors can improve the metabolic profile remains to be demonstrated. C1 VU Med Ctr, Dept Psychiat, NL-1081 HJ Amsterdam, Netherlands. VU Med Ctr, Inst Res Extramural Med, NL-1081 HJ Amsterdam, Netherlands. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Florida, Gainesville, FL USA. Vet Affairs Med Ctr, Gainesville, FL 32608 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Tennessee, Memphis, TN USA. NIA, Baltimore, MD 21224 USA. RP Vogelzangs, N (reprint author), VU Med Ctr, Dept Psychiat, Oldenaller 1, NL-1081 HJ Amsterdam, Netherlands. EM nicolev@ggzba.nl RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Intramural NIH HHS; NHLBI NIH HHS [1R01-HL972972]; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 36 TC 44 Z9 46 U1 1 U2 2 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2007 VL 62 IS 5 BP 563 EP 569 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 228WP UT WOS:000250763600014 PM 17522363 ER PT J AU Schooler, C Revell, AJ Caplan, LJ AF Schooler, Carmi Revell, Andrew J. Caplan, Leslie J. TI Parental practices and willingness to ask for children's help later in life SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article ID EARLY FAMILY RELATIONSHIPS; ADULT CHILDREN; OLDER-ADULTS; PERSPECTIVE AB We examine how parents' relationships with their 13- to 25-year-old offspring affect the parents' willingness to ask them for help with financial and personal problems 20 years later. Husbands and wives were interviewed in 1974 and 1994; a child was interviewed in 1974. We used two aspects of parental style, responsiveness and restrictive dominance, to predict parents' willingness to request help from a child 20 years later. Structural equation modeling analyses revealed the following: (a) mothers' willingness to ask an adult child for help with a personal problem was increased by higher levels of responsiveness; (b) mothers' willingness to ask for financial help was increased by responsive and decreased by restrictive-dominant maternal behavior; and (c) neither responsive nor restrictive-dominant paternal behavior affected fathers' later willingness to ask an adult child for help of either kind. C1 [Schooler, Carmi; Revell, Andrew J.; Caplan, Leslie J.] NIMH, Natl Inst Hlth, Intramural Res Program, Sect Socioenvironm Studies, Bethesda, MD 20892 USA. RP Schooler, C (reprint author), NIMH, Natl Inst Hlth, Intramural Res Program, Sect Socioenvironm Studies, 6101 Execut Blvd,Suite 360,Room 362,MSC 8408, Bethesda, MD 20892 USA. EM carmi.schooler@nih.gov FU Intramural NIH HHS NR 24 TC 1 Z9 1 U1 0 U2 1 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAY PY 2007 VL 62 IS 3 BP P165 EP P170 PG 6 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 272CH UT WOS:000253835800004 PM 17507584 ER PT J AU Bell, JB Poosala, S Smith, R AF Bell, Jeffrey B. Poosala, Suresh Smith, Rebekah TI IACUC must review SO LAB ANIMAL LA English DT Editorial Material C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Bell, JB (reprint author), NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD MAY PY 2007 VL 36 IS 5 BP 14 EP 15 DI 10.1038/laban0507-14b PG 2 WC Veterinary Sciences SC Veterinary Sciences GA 164IZ UT WOS:000246228400004 PM 17450162 ER PT J AU Matarin, M Brown, WM Scholz, S Simon-Sanchez, J Fung, HC Hernandez, D Gibbs, JR De Vrieze, FW Crews, C Britton, A Longefeld, CD Brott, TG Brown, RD Worrall, BB Frankel, M Silliman, S Case, LD Singleton, A Hardy, JA Rich, SS Meschia, JF AF Matarin, Mar Brown, W. Mark Scholz, Sonja Simon-Sanchez, Javier Fung, Hon-Chung Hernandez, Dena Gibbs, J. Raphael De Vrieze, Fabienne Wavrant Crews, Cynthia Britton, Angela Longefeld, Carl D. Brott, Thomas G. Brown, Robert D., Jr. Worrall, Bradford B. Frankel, Michael Silliman, Scott Case, L. Douglas Singleton, Andrew Hardy, John A. Rich, Stephen S. Meschia, James F. TI A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release SO LANCET NEUROLOGY LA English DT Article ID EPSTEIN-BARR VIRUS; MYOCARDIAL-INFARCTION; CHANNEL FAMILY; CONFERS RISK; CELL-LINE; GENE; CLASSIFICATION; ASSOCIATION; RELIABILITY; SUBTYPE AB Background Despite evidence of a genetic role in stroke, the identification of common genetic risk factors for this devastating disorder remains problematic. We aimed to identify any common genetic variability exerting a moderate to large effect on risk of ischaemic stroke, and to generate publicly available genome-wide genotype data to facilitate others doing the same. Methods We applied a genome-wide high-density single-nucleotide-polymorphism (SNP) genotyping approach to a cohort of samples with and without ischaemic stroke (n=278 and 275, respectively), and did an association analysis adjusted for known confounders in a final cohort of 249 cases and 268 controls. More than 400 000 unique SNPs were assayed. Findings We produced more than 200 million genotypes in 553 unique participants. The raw genotypes of all the controls have been posted publicly in a previous study of Parkinson's disease. From this effort, results of genotype and allele association tests have been publicly posted for 88% of stroke patients who provided proper consent for public release. Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke. Interpretation The data generated here comprise the first phase of a genome-wide association analysis in patients with stroke. Release of phase I results generated in these publicly available samples from each consenting individual makes this dataset a valuable resource for data-mining and augmentation. C1 NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Inst Biomed Valencia, CSIC, Unitat Genet Mol, Dept Genom & Proteom, Valencia, Spain. Chang Gung Univ, Dept Neurol, Chang Gung Mem Hosp, Taipei, Taiwan. UCL, Reta Lila Weston Inst Neurol Studies, London, England. Inst Neurol, Dept Mol Neurosci, London, England. Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Winston Salem, NC 27109 USA. Mayo Clin, Dept Neurol, Jacksonville, FL USA. Mayo Clin, Dept Neurol, Rochester, MN USA. Univ Virginia, Dept Neurol, Charlottesville, VA 22903 USA. Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. RP Singleton, A (reprint author), NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Gibbs, J. Raphael/A-3984-2010; Hardy, John/C-2451-2009; Matarin, Mar/F-1771-2016; OI Matarin, Mar/0000-0002-4717-5735; Scholz, Sonja/0000-0002-6623-0429 FU Intramural NIH HHS; Medical Research Council [G0701075]; NINDS NIH HHS [K08 NS045802, K08 NS045802-01A2, R01 NS042733, R01 NS42733] NR 45 TC 117 Z9 125 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAY PY 2007 VL 6 IS 5 BP 414 EP 420 DI 10.1016/S1474-4422(07)70081-9 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 161XO UT WOS:000246050600017 PM 17434096 ER PT J AU Kappos, L Bates, D Hartung, HP Havrdova, E Miller, D Polman, CH Ravnborg, M Houser, SL Rudick, RA Weiner, HL O'Connor, PW King, J Radue, EW Yousry, T Major, E Clifford, DB AF Kappos, Ludwig Bates, David Hartung, Hans-Peter Havrdova, Eva Miller, David Polman, Chris H. Ravnborg, Mods Houser, Stephen L. Rudick, Richard A. Weiner, Howard L. O'Connor, Paul W. King, John Radue, Ernst Wilhelm Yousry, Tarek Major, Eugene O. Clifford, David B. TI Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring SO LANCET NEUROLOGY LA English DT Review ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; JC VIRUS-DNA; PLACEBO-CONTROLLED TRIAL; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PERIPHERAL-BLOOD LEUKOCYTES; CENTRAL-NERVOUS-SYSTEM; HUMAN POLYOMAVIRUS JC; CEREBROSPINAL-FLUID; DOUBLE-BLIND AB Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed. C1 Univ Basel Hosp, Dept Res & Neurol, CH-4031 Basel, Switzerland. Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. Univ Dusseldorf, D-4000 Dusseldorf, Germany. Gen Teaching Hosp, Prague, Czech Republic. Inst Neurol, London, England. Vrije Univ Amsterdam, Med Ctr, Free Univ Hosp, Amsterdam, Netherlands. Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. UCSF, Multiple Sclerosis Ctr, San Francisco, CA USA. Cleveland Clin Fdn, Mellen Ctr Multiple Sclerosis Treatment & Res, Cleveland, OH 44195 USA. Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. St Michaels Hosp, Toronto, ON M5B 1W8, Canada. Royal Melbourne Hosp, Melbourne, Vic, Australia. NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. RP Kappos, L (reprint author), Univ Basel Hosp, Dept Res & Neurol, CH-4031 Basel, Switzerland. EM lkappos@uhbs.ch RI Yousry, Tarek/B-3417-2009 FU Multiple Sclerosis Society [748] NR 89 TC 133 Z9 135 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAY PY 2007 VL 6 IS 5 BP 431 EP 441 DI 10.1016/S1474-4422(07)70078-9 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 161XO UT WOS:000246050600019 PM 17434098 ER PT J AU Calu, DJ Stalnaker, TA Franz, TM Singh, T Shaham, Y Schoenbaum, G AF Calu, Donna J. Stalnaker, Thomas A. Franz, Theresa M. Singh, Teghpal Shaham, Yavin Schoenbaum, Geoffrey TI Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats SO LEARNING & MEMORY LA English DT Article ID ORBITAL PREFRONTAL CORTEX; DECISION-MAKING; EXPERIENCED RATS; CENTRAL AMYGDALA; DRUG-ADDICTION; INVOLVEMENT; INCUBATION; ABUSERS; LESIONS; NEUROADAPTATIONS AB Drug addicts make poor decisions. These decision-making deficits have been modeled in addicts and laboratory animals using reversal-learning tasks. However, persistent reversal-learning impairments have been shown in rats and monkeys only after noncontingent cocaine injections. Current thinking holds that to represent the human condition effectively, animal models of addiction must utilize self-administration procedures in which drug is earned contingently; thus, it remains unclear whether reversal-learning deficits caused by noncontingent cocaine exposure are relevant to addiction. To test whether reversal learning deficits are caused by contingent cocaine exposure, we trained rats to self-administer cocaine, assessed cue-induced cocaine seeking in extinction tests after 1 and 30 d of withdrawal, and then tested for reversal learning more than a month later. We found robust time-dependent increases in cue- induced cocaine seeking in the two extinction tests (incubation of craving) and severe reversal- learning impairments. C1 Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. EM schoenbg@schoenbaumlab.org RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA015718, R01 DA015718-05, R01-DA015718]; PHS HHS [T32-14074] NR 35 TC 72 Z9 72 U1 1 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD MAY PY 2007 VL 14 IS 5 BP 325 EP 328 DI 10.1101/lm.534807 PG 4 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 163GW UT WOS:000246148600001 PM 17522022 ER PT J AU Duncko, R Cornwell, B Cui, LH Merikangas, KR Grillon, C AF Duncko, Roman Cornwell, Brian Cui, Lihong Merikangas, Kathleen R. Grillon, Christian TI Acute exposure to stress improves performance in trace eyeblink conditioning and spatial learning tasks in healthy men SO LEARNING & MEMORY LA English DT Article ID NMDA RECEPTOR ANTAGONISM; BASOLATERAL AMYGDALA; WORKING-MEMORY; RECOGNITION MEMORY; DECLARATIVE MEMORY; PSYCHOSOCIAL STRESS; CORTISOL REACTIVITY; EMOTIONAL AROUSAL; PLACE NAVIGATION; ENHANCES MEMORY AB The present study investigated the effects of acute stress exposure on learning performance in humans using analogs of two paradigms frequently used in animals. Healthy male participants were exposed to the cold pressor test (CPT) procedure, i. e., insertion of the dominant hand into ice water for 60 sec. Following the CPT or the control procedure, participants completed a trace eyeblink conditioning task followed by a virtual navigation Morris water task (VNMWT). Hypothalamic-pituitary-adrenocortical ( HPA) axis and sympathetic autonomic system ( SAS) activity were assessed by measuring salivary cortisol, heart rate, and skin conductance at selected timepoints. Results revealed positive effects of stress on performance in both tasks. The stress group showed significantly more conditioned blinks than the control group during acquisition of trace eyeblink conditioning. The stress group also performed significantly better in the VNMWT than the control group, with the former showing significantly fewer failures to locate the hidden platform in the allotted time and smaller heading errors than the latter. Regression analyses revealed positive relationships between HPA axis and SAS activity during stress and eyeblink conditioning performance. Our results directly extend findings from animal studies and suggest potential physiological mechanisms underlying stress and learning. C1 NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Duncko, R (reprint author), NIMH, Sect Dev Genet Epidemiol, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM dunckor@mail.nih.gov FU Intramural NIH HHS NR 69 TC 51 Z9 51 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD MAY PY 2007 VL 14 IS 5 BP 329 EP 335 DI 10.1101/lm.483807 PG 7 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 163GW UT WOS:000246148600002 PM 17522023 ER PT J AU Subramaniam, DS Fowler, DH Pavletic, SZ AF Subramaniam, D. S. Fowler, D. H. Pavletic, S. Z. TI Chronic graft-versus-host disease in the era of reduced-intensity conditioning SO LEUKEMIA LA English DT Review DE chronic graft-versus-host disease; reduced-intensity conditioning; hematopoietic stem cell transplantation ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; COMPLETE DONOR CHIMERISM; REGULATORY T-CELLS; MIXED HEMATOPOIETIC CHIMERISM; ALLOGENEIC TRANSPLANTATION; HEMATOLOGIC MALIGNANCIES; REGIMEN; ENGRAFTMENT; CD4(+) AB In the past decade the field of hematopoietic stem cell transplantation has entered a new era with the introduction of reduced intensity conditioning (RIC) regimens. The impact of RIC on the incidence of chronic graft-versus-host disease (GVHD) has not been evaluated systematically. Factors confounding such analyses include short follow-up in studies, absence of prospective comparison trials, use of a variety of RIC regimens, lack of uniform GVHD prophylaxis and lack of rigorous criteria for the diagnosis and staging of chronic GVHD. This review discusses factors that appear to influence the incidence and clinical presentation of chronic GVHD in the RIC transplantation era. Overall, RIC seems to decrease the incidence and severity of acute GVHD through day 100 posttransplant when compared to conventional conditioning; however, there is little evidence to suggest that chronic GVHD is reduced after RIC. For the more definitive assessments of chronic GVHD after RIC it will be important to study this question in prospective comparison trials with long duration of follow-up. The recent National Institutes of Health chronic GVHD consensus project recommendations provide now the critically needed standardized guidelines for the diagnosis, classification and staging of chronic GVHD. C1 NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. Georgetown Univ Hosp, Lombardi Canc Ctr, Div Hematol Oncol, Washington, DC 20007 USA. RP Pavletic, SZ (reprint author), NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, 9000 Rockville Pike,Room CRC 3-3330, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov FU Intramural NIH HHS NR 55 TC 19 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2007 VL 21 IS 5 BP 853 EP 859 DI 10.1038/sj.leu.2404642 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 161FM UT WOS:000245999900001 PM 17377592 ER PT J AU Young, NS Barrett, AJ Sloand, EM AF Young, N. S. Barrett, A. J. Sloand, E. M. TI The immune pathophysiology of bone marrow failure and the emergence of clonal hematologic diseases SO LEUKEMIA RESEARCH LA English DT Meeting Abstract C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD MAY PY 2007 VL 31 SU 1 BP S4 EP S4 DI 10.1016/S0145-2126(07)70007-3 PG 1 WC Oncology; Hematology SC Oncology; Hematology GA 187JV UT WOS:000247844700007 ER PT J AU Dehan, E Ben-Dor, A Liao, W Lipson, D Frimer, H Rienstein, S Simansky, D Krupsky, M Yaron, P Friedman, E Rechavi, G Perlman, M Aviram-Goldring, A Izraeli, S Bittner, M Yakhini, Z Kaminski, N AF Dehan, E. Ben-Dor, A. Liao, W. Lipson, D. Frimer, H. Rienstein, S. Simansky, D. Krupsky, M. Yaron, P. Friedman, E. Rechavi, G. Perlman, M. Aviram-Goldring, A. Izraeli, S. Bittner, M. Yakhini, Z. Kaminski, N. TI Chromosomal aberrations and gene expression profiles in non-small cell lung cancer SO LUNG CANCER LA English DT Article DE non-small cell lung cancer; chromosomal aberrations; expression profiling; expression microarrays; array CGH ID COMPARATIVE GENOMIC HYBRIDIZATION; HIGH-RESOLUTION ANALYSIS; HOMOZYGOUS DELETION REGION; TUMOR-SUPPRESSOR GENE; COPY NUMBER; BREAST-CANCER; WNT PATHWAY; EARLY-STAGE; REVEALS; 3P21.3 AB Alterations in genomic content and changes in gene expression levels are central characteristics of tumors and pivotal to the tumorigenic process. We analyzed 23 non-small cell lung cancer (NSCLC) tumors by array comparative genomic hybridization (array CGH). Aberrant regions identified included well-characterized chromosomal aberrations such as amplifications of 3q and 8q and deletions of 3p21.31. Less frequently identified aberrations such as amplifications of 7q22.3-31.31 and 12p11.23-13.2, and previously unidentified aberrations such as deletion of 11q12.3-13.3 were also detected. To enhance our ability to identify key acting genes residing in these regions, we combined array CGH results with gene expression profiting performed on the same tumor samples. We identified a set of genes with concordant changes in DNA copy number and expression levels, i.e. overexpressed genes located in amplified regions and underexpressed genes located in deleted regions. This set included members of the Wnt/beta-catenin pathway, genes involved in DNA replication, and matrix metalloproteases (MMPs). Functional enrichment analysis of the genes both overexpressed and amplified revealed significant enrichment for DNA replication and repair, and extracellular matrix component gene ontology annotations. We verified the changes in expressions of MCM2, MCM6, RUVBL1, MMP1, MMP12 by real-time quantitative PCR. Our results provide a high resolution map of copy number changes in non-small cell lung cancer. The joint analysis of array CGH and gene expression analysis highlights genes with concordant changes in expression and copy number that may be critical to lung cancer development and progression. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Pittsburgh, Dorothy P & Richard P Simmons Ctr Interstitial Lu, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. Agilent Labs, Palo Alto, CA USA. NHGRI, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Haifa, Israel. Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. RP Kaminski, N (reprint author), Univ Pittsburgh, Dorothy P & Richard P Simmons Ctr Interstitial Lu, Div Pulm Allergy & Crit Care Med, NW 628 MUH,3459 5th Ave, Pittsburgh, PA 15261 USA. EM kaminskin@upmc.edu NR 50 TC 80 Z9 82 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD MAY PY 2007 VL 56 IS 2 BP 175 EP 184 DI 10.1016/j.lungcan.2006.12.010 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 172BR UT WOS:000246779600005 PM 17258348 ER PT J AU Fishbein, KW Canuto, HC Bajaj, P Camacho, NP Spencer, RG AF Fishbein, Kenneth W. Canuto, Holly C. Bajaj, Preeti Camacho, Nancy Pleshko Spencer, Richard G. TI Optimal methods for the preservation of cartilage samples in MRI and correlative biochemical studies SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cartilage; magnetization transfer; T-2; preservation; MRI; storage ID PORCINE ARTICULAR-CARTILAGE; BOVINE NASAL CARTILAGE; FIXED-CHARGE-DENSITY; T2 RELAXATION-TIME; MAGNETIZATION-TRANSFER; BIOMECHANICAL PROPERTIES; PATELLAR CARTILAGE; T-2 RELAXATION; TISSUE; PROTEOGLYCAN AB MRI studies of cartilage require the prevention of sample degradation before and during scanning and during shipment for correlative studies. Methods to achieve this include immersion in protease inhibitors (Pis), refrigeration, and freezing. In this study, bovine nasal cartilage (BNC) samples were stored in Dulbecco's phosphate-buffered saline (DPBS), DPBS with standard Pis, or Pi solution with GM6001, a potent metalloproteinase inhibitor. For each buffer, three samples were scanned at +4 degrees C and stored at +4 degrees C or at -20 degrees C with thawing prior to imaging. T-2 and magnetization transfer (MT) rate, k(m), were measured weekly over 4 months, after which time water and glycosaminoglycan (GAG) contents were compared with those of matching tissue excised pre-storage. Samples in DPBS exhibited increased T2 (+33.6% after 1 month at +4 degrees C, P = 0.040) and decreased k(m) (-20.6%, P = 0.004), while refrigeration in DPBS with PI and GM6001 yielded good stability (T-2: +2.7%, P = 0.874; km: -4.2%, P = 0.654 after 108 days at +4 degrees C). Water content increased while GAG content markedly decreased in all samples. Thus, stability in cartilage MRI parameters can be optimized with appropriate storage conditions, but storage time should nonetheless be minimized. C1 NIA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. Hosp Special Surg, New York, NY 10021 USA. RP Spencer, RG (reprint author), NIA, NIH, GRC 4D-06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencerri@grc.nia.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS NR 39 TC 19 Z9 20 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAY PY 2007 VL 57 IS 5 BP 866 EP 873 DI 10.1002/mrm.21189 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161YJ UT WOS:000246052800008 PM 17457874 ER PT J AU Kellman, P Aletras, AH Mancini, C McVeigh, ER Arai, AE AF Kellman, Peter Aletras, Anthony H. Mancini, Christine McVeigh, Elliot R. Arai, Andrew E. TI T-2-prepared SSFP improves diagnostic confidence in edema imaging in acute myocardial infarction compared to turbo spin echo SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; heart; myocardial infarction; acute MI; edema; free-breathing; motion correction; parallel imaging ID INVERSION-RECOVERY; DELAYED ENHANCEMENT; CONTRAST; HEART AB T-2-weighted MRI of edema in acute myocardial infarction (MI) provides a means of differentiating acute and chronic MI, and assessing the area at risk of infarction. Conventional T-2-weighted imaging of edema uses a turbo spin-echo (TSE) readout with darkblood preparation. Clinical applications of darkblood TSE methods can be limited by artifacts such as posterior wall signal loss due to through-plane motion, and bright subendocardial artifacts due to stagnant blood. Single-shot imaging with a T-2-prepared SSFP readout provides an alternative to dark-blood TSE and may be conducted during free breathing. We hypothesized that T-2-prepared SSFP would be a more reliable method than dark-blood TSE for imaging of edema in patients with MI. In patients with MI (22 acute and nine chronic MI cases), T-2-weighted imaging with both methods was performed prior to contrast administration and delayed enhancement imaging. The T-2-weighted images using TSE were nondiagnostic in three of 31 cases, while six additional cases rated as being of diagnostic quality yielded incorrect diagnoses. In all 31 cases the T-2-prepared SSFP images were rated as diagnostic quality, correctly differentiated acute or chronic MI, and correctly determined the coronary territory. Free-breathing T-2-prepared SSFP provides T-2-weighted images of acute MI with fewer artifacts and better diagnostic accuracy than conventional dark-blood TSE. C1 NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kellman, P (reprint author), NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Room B1D416,Bldg 10,MSC-1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM kellman@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 FU Intramural NIH HHS [Z01 HL004608-08] NR 18 TC 129 Z9 133 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAY PY 2007 VL 57 IS 5 BP 891 EP 897 DI 10.1002/mrm.21215 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 161YJ UT WOS:000246052800011 PM 17457880 ER PT J AU Chatterjee, B Richards, K Bucan, M Lo, C AF Chatterjee, Bishwanath Richards, Katharina Bucan, Maja Lo, Cecilia TI Nt mutation causing laterality defects associated with deletion of rotatin SO MAMMALIAN GENOME LA English DT Article ID LEFT-RIGHT ASYMMETRY; LEFT-RIGHT AXIS; LEFT-RIGHT SPECIFICATION; NODAL EXPRESSION; SITUS-INVERSUS; MOUSE; PROTEIN; GENE; LACKING; FLOW AB No turning (nt), a recessive lethal mutation causing left-right and axial patterning defects, was recovered in outbred CD-1 mice. Homozygous mutant embryos die at E11.5, exhibiting randomized heart tube looping and a failure to undergo embryonic turning. Previous studies showed notochordal defects associated with abnormal expression of HNF3 beta, lefty, and nodal. To identify the genetic alteration underlying nt mutants, we intercrossed this mutation into a Mus musculus castaneus strain background and conducted a full-genome scan using polymorphic microsatellite DNA markers. We mapped the mutation to an 18-Mb interval in mouse chromosome 18, spanning marker D18mit189 and the distal end of the chromosome. RT-PCR analysis of known genes in the mapped interval showed no transcripts for four genes, including Rttn, CD226, Dok6, and Txndc10. Chromosome walking by serial PCR amplification of genomic DNA from homozygous mutants revealed a 1.6-Mb deletion spanning these four genes. A gene-trap mouse line with disruption of Rttn was previously also shown to have randomized heart tube looping, defects in embryonic turning, and abnormal expression of HNF3 beta, lefty, and nodal. Together these findings suggest that nt is likely elicited by Rttn deficiency. C1 NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Lo, C (reprint author), NHLBI, Dev Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chatterb@mail.nih.gov; RICHARDK1@niaid.nih.gov; bucan@pobox.upenn.edu; loc@nhlbi.nih.gov FU NHLBI NIH HHS [Z01-HL005701] NR 23 TC 7 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD MAY PY 2007 VL 18 IS 5 BP 310 EP 315 DI 10.1007/s00335-007-9023-7 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 194FC UT WOS:000248328800003 PM 17551791 ER PT J AU Melzer, D Frayling, TM Murray, A Hurst, AJ Harries, LW Song, HL Khaw, K Luben, R Surtees, PG Bandinelli, SS Corsi, AM Ferrucci, L Guralnik, JM Wallace, RB Hattersley, AT Pharoah, PD AF Melzer, David Frayling, Timothy M. Murray, Anna Hurst, Alison J. Harries, Lorna W. Song, Honglin Khaw, KayTee Luben, Robert Surtees, Paul G. Bandinelli, Stefania S. Corsi, Anna-Maria Ferrucci, Luigi Guralnik, Jack M. Wallace, Robert B. Hattersley, Andrew T. Pharoah, Paul D. TI A common variant of the p16(INK4a) genetic region is associated with physical function in older people SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE cell senescence; ageing; physical function; polymorphism ID LOWER-EXTREMITY FUNCTION; SUBSEQUENT DISABILITY; CELLULAR SENESCENCE; TUMOR-SUPPRESSOR; GRIP STRENGTH; FEMALE TWINS; CANCER; EXPRESSION; AGE; EPIDEMIOLOGY AB p16(INK4a), is active in cell senescence, ageing and tumor suppression. Deletion of the small p16(INKa)/ARF/p15(lNK4b) region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16(INK4a)/ARF locus and p15(INK4b)) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk samples (p-value = 0.013, total n = 2257), and on independent replication in the InCHIANTI study (n = 709,p = 0.015), and at one-sided significance in Iowa-EPESE (n = 419, p = 0.079). Overall (n = 3372), the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele odds ratio = 1.48, 95% CI: 1.17-1.88, p = 0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR = 1.45, 95% CI: 1.09-1.92, p = 0.010, n = 2434). These findings require further replication, but provide the first direct evidence that the p16 (INK4a)/ARF/p15(INK4b) genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 RD&E Wonford Site, Peninsula Med Sch, Exeter EX2 5DW, Devon, England. Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. Italian Natl Res Council Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Univ Florence, Dept Med & Surg Crit Care, Florence, Italy. Tuscany Reg Agcy, Florence, Italy. NIA, Gerontol Res Ctr, Clin Res Branch, Longitudianal Studies Sect, Baltimore, MD 21224 USA. NIA, Lab Epidemiol, Bethesda, MD USA. RP Melzer, D (reprint author), RD&E Wonford Site, Peninsula Med Sch, Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk RI Harries, Lorna/D-2241-2014; OI Murray, Anna/0000-0002-2351-2522; Luben, Robert/0000-0002-5088-6343; Melzer, David/0000-0002-0170-3838 FU Cancer Research UK [10124, A10119, A10124]; Intramural NIH HHS [Z99 AG999999]; Medical Research Council [G0300128]; NIA NIH HHS [N01-AG-821336, N01-AG-916413, R01 AG024233, R01 AG024233-04, R01 AG24233-01]; NIMHD NIH HHS [R01 MD009164] NR 45 TC 46 Z9 47 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD MAY-JUN PY 2007 VL 128 IS 5-6 BP 370 EP 377 DI 10.1016/j.mad.2007.03.005 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 199SF UT WOS:000248714800003 PM 17459456 ER PT J AU Connell-Crowley, L Vo, D Luke, L Giniger, E AF Connell-Crowley, Lisa Vo, Duc Luke, Lori Giniger, Edward TI Drosophila lacking the Cdk5 activator, p35, display defective axon guidance, age-dependent behavioral deficits and reduced lifespan SO MECHANISMS OF DEVELOPMENT LA English DT Article DE axon guidance; neurodegeneration; lifespan; Drosophila; behaviour ID DIRECTED PROTEIN-KINASE; NEURONAL MIGRATION; NEURITE OUTGROWTH; NERVOUS-SYSTEM; P35(-/-) MICE; IN-VIVO; TAU; BRAIN; PHOSPHORYLATION; DISRUPTION AB The cyclin-dependent kinase Cdk5 has attracted a great deal of attention both because of its roles in cell migration and axon patterning, and the extensive data implicating it in adult-onset neurodegeneration in mammals. Both the kinase activity and the biological effects of Cdk5 are absolutely dependent on association with an activating subunit, called p35. We show here that Drosophila lacking the Cdk5 activator, D-p35, display a wide range of defects in embryonic axon patterning. We further show that, while viable and fertile, p35 mutant adults display progressive, age-dependent loss of motor function and have a significantly shortened lifespan. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 NINDS, NHGRI, Axon Guidance & Neural Connect Unit, Basic Neurosci Program,NIH, Bethesda, MD 20892 USA. RP Giniger, E (reprint author), NINDS, NHGRI, Axon Guidance & Neural Connect Unit, Basic Neurosci Program,NIH, Bldg 37,Rm 1016,37 Convent Dr, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU Intramural NIH HHS; NIGMS NIH HHS [R01-GM57830, R01 GM057830-05]; NINDS NIH HHS [Z01 NS003013-02] NR 36 TC 11 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD MAY PY 2007 VL 124 IS 5 BP 341 EP 349 DI 10.1016/j.mod.2007.02.002 PG 9 WC Developmental Biology SC Developmental Biology GA 164EX UT WOS:000246217400002 PM 17368005 ER PT J AU Wright, GE Barlow, WE Green, P Baldwin, LM Taplin, SH AF Wright, George E. Barlow, William E. Green, Pamela Baldwin, Laura-Mae Taplin, Stephen H. TI Differences among the elderly in the treatment costs of colorectal cancer - How important is race? SO MEDICAL CARE LA English DT Article DE cancer cost of care; Medicare; race and ethnicity; disparities; economics ID SEER-MEDICARE DATA; III COLON-CANCER; ADJUVANT THERAPY; CHEMOTHERAPY USE; BREAST-CANCER; RECTAL-CANCER; STAGE; CARE; SURGERY; BENEFICIARIES AB Background: Medical expenditures adjusted for price differences are a barometer of total resources devoted to patient care and thus may reflect treatment differentials. Objective: We sought to estimate costs of the surgical and adjuvant treatment phases of colorectal cancer (CRC) care and cost differences by race (African American-white) and other patient characteristics. Methods: We used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for stage II-III rectal and stage III colon cancer cases diagnosed in 1992-1996 to track Medicare approved payments for fee-for-service beneficiaries 66 and older in surgical (within 3 months of diagnosis) and postsurgical phases (13 months after the surgical phase). Net costs adjusted for expected noncancer expenditures were estimated with generalized linear models using pooled CRC and non-CRC cohorts. Using model results, we projected adjusted net costs for different patient groups (eg, by race, age). Results: Total unstandardized CRC costs for African American recipients were $44,199, a statistically significant 15% higher than for white recipients ($38,378). Adjusting for covariates and expected non-CRC costs decreased the estimate for African American recipients to $34,588, a statistically insignificant $974 (2.9%) more than white recipients. Differential expenditures by age, urban-rural setting, region, and neighborhood median income were all much larger than differences by race, although only region was statistically significant. Conclusions: African American CRC patients cost more than their white counterparts, but adjusted differences were nonsignificant and trivial. Several nonracial cost differences were considerably larger (but not all statistically significant), and suggest that future research pay more attention to these characteristics. C1 Univ Washington, Dept Family Med, Seattle, WA 98195 USA. Canc Res & Biostat, Seattle, WA USA. Natl Canc Inst, Appl Res Program, Bethesda, MD USA. RP Baldwin, LM (reprint author), Univ Washington, Dept Family Med, Box 354932, Seattle, WA 98195 USA. EM lmb@fammed.washington.edu FU NCI NIH HHS [R01 CA089544, R01 CA089544-01, R01CA089544] NR 39 TC 7 Z9 8 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2007 VL 45 IS 5 BP 420 EP 430 DI 10.1097/01.mlr.0000257184.93944.80 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 166JE UT WOS:000246374200008 PM 17446828 ER PT J AU Ader, DN AF Ader, Deborah N. TI Developing the Patient-Reported Outcomes Measurement Information System (PROMIS) SO MEDICAL CARE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Ader, DN (reprint author), Samueli Inst, 1700 Diagonal Rd,Suite 400, Alexandria, VA 22314 USA. EM dader@siib.org NR 6 TC 49 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2007 VL 45 IS 5 SU 1 BP S1 EP S2 DI 10.1097/01.mlr.0000260537.45076.74 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 167PA UT WOS:000246462400001 ER PT J AU Cella, D Yount, S Rothrock, N Gershon, R Cook, K Reeve, B Ader, D Fries, JF Bruce, B Rose, M AF Cella, David Yount, Susan Rothrock, Nan Gershon, Richard Cook, Karon Reeve, Bryce Ader, Deborah Fries, James F. Bruce, Bonnie Rose, Mattias CA PROMIS Cooperative Grp TI The Patient-Reported Outcomes Measurement Information System (PROMIS) Progress of an NIH roadmap cooperative group during its first two years SO MEDICAL CARE LA English DT Article DE outcomes; patient reported outcomes; quality of life; health-related quality of life ID ITEM RESPONSE THEORY; HEADACHE IMPACT; FATIGUE; HEALTH; DISEASE; SCALE; BANK; CARE AB Background: The National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Roadmap initiative (www.nihpromis.org) is a 5-year cooperative group program of research designed to develop, validate, and standardize item banks to measure patient-reported outcomes (PROs) relevant across common medical conditions. In this article, we will summarize the organization and scientific activity of the PROMIS network during its first 2 years. Design: The network consists of 6 primary research sites (PRSs), a statistical coordinating center (SCC), and NIH research scientists. Governed by a steering committee, the network is organized into functional subcommittees and working groups. In the first year, we created an item library and activated 3 interacting protocols: Domain Mapping, Archival Data Analysis, and Qualitative Item Review (QIR). In the second year, we developed and initiated testing of item banks covering 5 broad domains of self-reported health. Results: The domain mapping process is built on the World Health Organization (WHO) framework of physical, mental, and social health. From this framework, pain, fatigue, emotional distress, physical functioning, social role participation, and global health perceptions were selected for the first wave of testing. Item response theory (IRT)-based analysis of I I large datasets supplemented and informed item-level qualitative review of nearly 7000 items from available PRO measures in the item library. Items were selected for rewriting or creation with further detailed review before the first round of testing in the general population and target patient populations. Conclusions: The NIH PROMIS network derived a consensus-based framework for self-reported health, systematically reviewed available instruments and datasets that address the initial PROMIS domains. Qualitative item research led to the first wave of network testing which began in the second year. C1 Evanston Northwestern Healthcare, Ctr Outcomes Res & Educ, Evanston, IL 60201 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NCI, Bethesda, MD 20892 USA. Samueli Inst, Alexandria, VA USA. Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. Hlth Assessment Lab, Boston, MA USA. RP Cella, D (reprint author), Evanston Northwestern Healthcare, Ctr Outcomes Res & Educ, 1001 Univ Pl,Suite 100, Evanston, IL 60201 USA. EM d-cella@northwestem.edu RI Rose, Matthias/A-8920-2015; Fries, James/F-6271-2011 FU NIAMS NIH HHS [1U01-AR052177, U01 AR052177, U01 AR052177-01] NR 35 TC 537 Z9 545 U1 1 U2 47 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2007 VL 45 IS 5 SU 1 BP S3 EP S11 DI 10.1097/01.mlr.0000258615.42478.55 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 167PA UT WOS:000246462400002 PM 17443116 ER PT J AU Reeve, BB Hays, RD Bjorner, JB Cook, KF Crane, PK Teresi, JA Thissen, D Revicki, DA Weiss, DJ Hambleton, RK Liu, HH Gershon, R Reise, SP Lai, JS Cella, D AF Reeve, Bryce B. Hays, Ron D. Bjorner, Jakob B. Cook, Karon F. Crane, Paul K. Teresi, Jeanne A. Thissen, David Revicki, Dennis A. Weiss, David J. Hambleton, Ronald K. Liu, Honghu Gershon, Richard Reise, Steven P. Lai, Jin-shei Cella, David CA PROMIS Cooperative Grp TI Psychometric evaluation and calibration of health-related quality of life item banks - Plans for the patient-reported outcomes measurement information system (PROMIS) SO MEDICAL CARE LA English DT Article DE item response theory; unidimensionality; model fit; differential item functioning; computerized adaptive testing ID RESPONSE THEORY MODELS; ADAPTIVE TEST; PERFORMANCE; DEPENDENCE; FIT; UNIDIMENSIONALITY; SIMULATION; STRATEGIES; INDEXES; TESTS AB Background: The construction and evaluation of item banks to measure unidimensional constructs of health-related quality of life (HRQOL) is a fundamental objective of the Patient-Reported Outcomes Measurement Information System (PROMIS) project. Objectives: Item banks will be used as the foundation for developing short-form instruments and enabling computerized adaptive testing. The PROMIS Steering Committee selected 5 HRQOL domains for initial focus: physical functioning, fatigue, pain, emotional distress, and social role participation. This report provides an overview of the methods used in the PROMIS item analyses and proposed calibration of item banks. Analyses: Analyses include evaluation of data quality (eg, logic and range checking, spread of response distribution within an item), descriptive statistics (eg, frequencies, means), item response theory model assumptions (unidimensionality, local independence, monotonicity), model fit, differential item functioning, and item calibration for banking. Recommendations: Summarized are key analytic issues; recommendations are provided for future evaluations of item banks in HRQOL assessment. C1 NCI, Outcomes Res Branch, NIH, EPN 4005, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. QualityMetric Inc, Lincoln, RI USA. Hlth Assessment Lab, Waltham, MA USA. Univ Washington, Seattle, WA 98195 USA. Columbia Univ, Stroud Ctr, New York, NY 10027 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Hebrew Home Aged, Div Res, New York, NY USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC 27515 USA. Uniteb BioSource Corp, Ctr Hlth Outcomes Res, Bethesda, MD USA. Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. Univ Massachusetts, Ctr Educ Assessment, Amherst, MA 01003 USA. Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA. Evanston Northwestern Healthcare, Evanston, IL 60208 USA. RP Reeve, BB (reprint author), NCI, Outcomes Res Branch, NIH, EPN 4005, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM reeveb@mail.nih.gov RI Hays, Ronald/D-5629-2013; Crane, Paul/C-8623-2014 FU NIA NIH HHS [AG015815] NR 83 TC 436 Z9 437 U1 2 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2007 VL 45 IS 5 SU 1 BP S22 EP S31 DI 10.1097/01.mlr.0000250483.85507.04 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 167PA UT WOS:000246462400004 PM 17443115 ER PT J AU Yao, JH Summers, RM AF Yao, Jianhua Summers, Ronald M. TI Adaptive deformable model for colonic polyp segmentation and measurement on CT colonography SO MEDICAL PHYSICS LA English DT Article DE polyp segmentation; adaptive deformable model; CT colonography ID TOMOGRAPHIC VIRTUAL COLONOSCOPY; ACTIVE CONTOUR MODELS; BALLOONS; SHAPE AB Polyp size is one important biomarker for the malignancy risk of a polyp. This paper presents an improved approach for colonic polyp segmentation and measurement on CT colonography images. The method is based on a combination of knowledge-guided intensity adjustment, fuzzy clustering, and adaptive deformable model. Since polyps on haustral folds are the most difficult to be segmented, we propose a dual-distance algorithm to first identify voxels on the folds, and then introduce a counter-force to control the model evolution. We derive linear and volumetric measurements from the segmentation. The experiment was conducted on 395 patients with 83 polyps, of which 43 polyps were on haustral folds. The results were validated against manual measurement from the optical colonoscopy and the CT colonography. The paired t-test showed no significant difference, and the R-2 correlation was 0.61 for the linear measurement and 0.98 for the volumetric measurement. The mean Dice coefficient for volume overlap between automatic and manual segmentation was 0.752 (standard deviation 0.154). (c) 2007 American Association of Physicists in Medicine. C1 Ctr Clin, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), Ctr Clin, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 23 TC 7 Z9 7 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD MAY PY 2007 VL 34 IS 5 BP 1655 EP 1664 DI 10.1118/1.2717411 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 169ZE UT WOS:000246629800015 PM 17555247 ER PT J AU Jaluria, P Betenbaugh, M Konstantopoulos, K Frank, B Shiloach, J AF Jaluria, Pratik Betenbaugh, Michael Konstantopoulos, Konstantinos Frank, Bryan Shiloach, Joseph TI Application of microarrays to identify and characterize genes involved in attachment dependence in HeLa cells SO METABOLIC ENGINEERING LA English DT Article DE HeLa; laminin; sialyltransferase; cellular adhesion; sialic acid; aggregation; genomics ID ALPHA-SERIES GANGLIOSIDES; SYNTHASE ST6GALNAC V; DNA MICROARRAYS; SURFACE SIALYLATION; EXPRESSION; ADHESION; BINDING; SYSTEM; TISSUE; CDNA AB The ability to modify cellular properties such as adhesion is of interest in the design and performance of biotechnology-related processes. The current study was undertaken in order to evaluate the effectiveness of modulating cellular adhesion in HeLa cells from a genomics perspective. Using DNA microarrays, differences in gene expression between two phenotypically distinct, anchorage-dependent and anchorage-independent, HeLa cell lines were identified. With the aid of several statistical methods and an extensive literature search, two genes were selected as potential targets for further study: siat7e and lama4. Subsequently, experiments were carried out to investigate the effects of siat7e and lama4 separately, on adhesion in HeLa cells by altering their expression in vivo. Decreasing the expression of siat7e, a type II membrane glycosylating sialyltransferase, in anchorage-independent HeLa cells using short interfering RNA (siRNA) resulted in greater aggregation (i.e. clumping) and morphological changes as compared to untreated anchorage-independent HeLa cells. Similar effects were seen in anchorage-independent HeLa cells when the expression of lama4 which encodes laminin alpha 4, a member of the laminin family of glycoproteins, was enhanced as compared to untreated anchorage-independent HeLa cells. Using a shear flow chamber, an attachment assay was developed; illustrating either increased expression of siat7e or decreased expression of lama4 in anchorage-dependent HeLa cells reduced cellular adhesion. Collectively, the results of this study are consistent with the roles siat7e and lama4 play in adhesion processes in vivo and indicate modifying the expression of either gene can influence adhesion in HeLa cells. The strategy of applying bioinformatics techniques to characterize and manipulate phenotypic behaviors is a powerful tool for altering the properties of various cell lines for desired biotechnology objectives. (c) 2006 Elsevier Inc. All rights reserved. C1 NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. Inst Genom Res, Rockville, MD 20850 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bldg 14A Room 173, Bethesda, MD 20892 USA. EM yossi@nih.gov RI Konstantopoulos, Konstantinos/A-7045-2011; Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU Intramural NIH HHS [Z01 DK015500-46] NR 51 TC 15 Z9 17 U1 3 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7176 J9 METAB ENG JI Metab. Eng. PD MAY PY 2007 VL 9 IS 3 BP 241 EP 251 DI 10.1016/j.ymben.2006.12.001 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 183JY UT WOS:000247570300001 PM 17240181 ER PT J AU Bayfield, MA Kaiser, TE Intine, RV Maraia, RJ AF Bayfield, Mark A. Kaiser, Trish E. Intine, Robert V. Maraia, Richard J. TI Conservation of a masked nuclear export activity of La proteins and its effects on tRNA maturation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID POLYMERASE-III TRANSCRIPTS; PRECURSOR TRANSFER-RNAS; SS-B AUTOANTIGEN; NASCENT RNA; SACCHAROMYCES-CEREVISIAE; NUCLEOLAR LOCALIZATION; RIBOSOMAL-SUBUNITS; RECOGNITION MOTIF; NONCODING RNAS; PHOSPHORYLATION AB La is an RNA-processing-associated phosphoprotein so highly conserved that the human La protein (hLa) can replace the tRNA-processing function of the fission yeast La protein (Sla1p) in vivo. La proteins contain multiple trafficking elements that support interactions with RNAs in different subcellular locations. Prior data indicate that deletion of a nuclear retention element (NRE) causes nuclear export of La and dysfunctional processing of associated pre-tRNAs that are spliced but 5' and 3' unprocessed, with an accompanying decrease in tRNA-mediated suppression, in fission yeast. To further pursue these observations, we first identified conserved residues in the NREs of hLa and Sla1p that when substituted mimic the NRE deletion phenotype. NRE-defective La proteins then deleted of other motifs indicated that RNA recognition motif I (RRM1) is required for nuclear export. Mutations of conserved RRM1 residues restored nuclear accumulation of NRE-defective La proteins. Some RRM1 mutations restored nuclear accumulation, prevented disordered pre-tRNA processing, and restored suppression, indicating that the tRNA-related activity of RRM1 and its nuclear export activity could be functionally separated. When mapped onto an hLa structure, the export-sensitive residues comprised surfaces distinct from the RNA-binding surface of RRM1 The data indicate that the NRE has been conserved to mask or functionally override an equally conserved nuclear export activity of RRM1 The data suggest that conserved elements mediate nuclear retention, nuclear export, and RNA-binding activities of the multifunctional La protein and that their interrelationship contributes to the ability of La to engage its different classes of RNA ligands in different cellular locations. C1 NICHHD, Intramural Res Program, US NIH, Bethesda, MD 20892 USA. RP Maraia, RJ (reprint author), 31 Ctr Dr,Rm 2A25, Bethesda, MD 20892 USA. EM maraiar@mail.nih.gov FU Intramural NIH HHS NR 45 TC 21 Z9 21 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2007 VL 27 IS 9 BP 3303 EP 3312 DI 10.1128/MCB.00026-07 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 162UN UT WOS:000246115100005 PM 17308035 ER PT J AU Yoon, YS Jeong, S Rong, Q Park, KY Chung, JH Pfeifer, K AF Yoon, Young Soo Jeong, Sangkyun Rong, Qi Park, Kye-Yoon Chung, Jae Hoon Pfeifer, Karl TI Analysis of the H19ICR insulator SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; IMPRINTING CONTROL REGION; BETA-GLOBIN INSULATOR; IGF2/H19 LOCUS; REGULATORY INTERACTIONS; EPIGENETIC MECHANISMS; NUCLEAR-ORGANIZATION; CHROMATIN INSULATORS; DNA METHYLATION; PARENTAL-ORIGIN AB Transcriptional insulators are specialized cis-acting elements that protect promoters from inappropriate activation by distal enhancers. The H19 imprinting control region (ICR) functions as a CTCF-dependent, methylation-sensitive transcriptional insulator. We analyzed several insertional mutations and demonstrate that the ICR can function as a methylation-regulated maternal chromosome-specific insulator in novel chromosomal contexts. We used chromosome conformation capture and chromatin immunoprecipitation assays to investigate the configuration of cis-acting elements at these several insertion sites. By comparing maternal and paternal organizations on wild-type and mutant chromosomes, we hoped to identify mechanisms for ICR insulator function. We found that promoter and enhancer elements invariably associate to form DNA loop domains at transcriptionally active loci. Conversely, active insulators always prevent these promoter-enhancer interactions. Instead, the ICR insulator forms novel loop domains by associating with the blocked promoters and enhancers. We propose that these associations are fundamental to insulator function. C1 NICHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. RP Pfeifer, K (reprint author), NICHD, Lab Mammalian Genes & Dev, NIH, Bldg 6B-2B206,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X FU Intramural NIH HHS NR 68 TC 77 Z9 78 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 MAY PY 2007 VL 27 IS 9 BP 3499 EP 3510 DI 10.1128/MCB.02170-06 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 162UN UT WOS:000246115100021 PM 17339341 ER PT J AU Bakowska, JC Jupille, H Fatheddin, P Puertollano, R Blackstone, C AF Bakowska, Joanna C. Jupille, Henri Fatheddin, Parvin Puertollano, Rosa Blackstone, Craig TI Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; GROWTH-FACTOR-RECEPTOR; E VPS PROTEINS; MEDIATED ENDOCYTOSIS; NERVE-TERMINALS; EPS15; CLATHRIN; COMPLEX; MONOUBIQUITINATION; IDENTIFICATION AB Troyer syndrome is an autosomal recessive hereditary spastic paraplegia caused by mutation in the spartin (SPG20) gene, which encodes a widely expressed protein of unknown function. This mutation results in premature protein truncation and thus might signify a loss-of-function disease mechanism. In this study, we have found that spartin is monoubiquitinated and functions in degradation of the epidermal growth factor receptor (EGFR). Upon EGF stimulation, spartin translocates from the cytoplasm to the plasma membrane and colocalizes with internalized EGF-Alexa. Knock-down of spartin by small interfering RNA decreases the rate of EGFR degradation and also affects EGFR internalization, recycling, or both. Furthermore, overexpression of spartin results in a prominent decrease in EGFR degradation. Taken together, our data suggest that spartin is involved in the intracellular trafficking of EGFR and that impaired endocytosis may underlie the pathogenesis of Troyer syndrome. C1 NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. NINDS, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bakowska, JC (reprint author), NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. EM bakowskj@ninds.nih.gov; blackstc@ninds.nih.gov FU Intramural NIH HHS; NINDS NIH HHS [K22 NS 50137-01, K22 NS050137] NR 54 TC 52 Z9 54 U1 1 U2 6 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 MAY PY 2007 VL 18 IS 5 BP 1683 EP 1692 DI 10.1091/mbc.E06-09-0833 PG 10 WC Cell Biology SC Cell Biology GA 166US UT WOS:000246406700012 PM 17332501 ER PT J AU Watson, H Bonifacino, JS AF Watson, Hadiya Bonifacino, Juan S. TI Direct binding to Rsp5p regulates ubiquitination-independent vacuolar transport of Sna3p SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MULTIVESICULAR-BODY; SACCHAROMYCES-CEREVISIAE; PROTEIN LIGASE; INTERNALIZATION STEP; ACTIN CYTOSKELETON; MEMBRANE-PROTEINS; FLUID-PHASE; WW DOMAINS; ENDOCYTOSIS; YEAST AB The sorting of integral membrane proteins such as carboxypeptidase S (Cps1p) into the luminal vesicles of multivesicular bodies (MVBs) in Saccharomyces cerevisiae requires ubiquitination of their cytosolic domains by the ubiquitin ligases Rsp5p and/or Tul1p. An exception is Sna3p, which does not require ubiquitination for entry into MVBs. The mechanism underlying this ubiquitination-independent MVB sorting pathway has not yet been characterized. Here, we show that Sna3p sorting into the MVB pathway depends on a direct interaction between a PPAY motif within its C-terminal cytosolic tail and the WW domains of Rsp5p. Disruption of this interaction inhibits vacuolar targeting of Sna3p and causes its accumulation in a compartment that overlaps only partially with MVBs. Surprisingly, Sna3p does require a functional ubiquitin-ligase HECT domain within Rsp5p; however, the dependence of Sna3p on HECT domain activity is distinct from that of Cps1p. Last, we show that Sna3p requires neither Tul1p nor the transmembrane adaptor protein Bsd2p for its MVB sorting. Our data demonstrate that Sna3p follows a novel ubiquitination-independent, but Rsp5p-mediated, sorting pathway to the vacuole. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 32 TC 26 Z9 26 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 MAY PY 2007 VL 18 IS 5 BP 1781 EP 1789 DI 10.1091/mbc.E06-10-0887 PG 9 WC Cell Biology SC Cell Biology GA 166US UT WOS:000246406700021 PM 17332499 ER PT J AU Kim, Y Deng, Y Philpott, CC AF Kim, Youngwoo Deng, Yi Philpott, Caroline C. TI GGA2-and ubiquitin-dependent trafficking of Arn1, the ferrichrome transporter of Saccharomyces cerevisiae SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID YEAST PLASMA-MEMBRANE; DIVALENT-METAL TRANSPORTER-1; MEDIATED IRON UPTAKE; AMINO-ACID PERMEASE; GGA PROTEINS; TRYPTOPHAN PERMEASE; BINDING-PROTEINS; URACIL PERMEASE; DOWN-REGULATION; LIGASE RSP5 AB The intracellular trafficking of Arn1, a ferrichrome transporter in Saccharomyces cerevisiae, is controlled in part by the binding of ferrichrome to the transporter. In the absence of ferrichrome, Arn1 is sorted directly from the Golgi to endosomes. Ferrichrome binding triggers the redistribution of Arn1 to the plasma membrane, whereas ferrichrome transport is associated with the cycling of Arn1 between the plasma membrane and endosomes. Here, we report that the clathrin adaptor Gga2 and ubiquitination by the Rsp5 ubiquitin ligase are required for trafficking of Arn1. Gga2 was required for Golgi-to-endosomal trafficking of Arn1, which was sorted from endosomes to the vacuole for degradation. Trafficking into the vacuolar lumen was dependent on ubiquitination by Rsp5, but ubiquitination was not required for plasma membrane accumulation of Arn1 in the presence of ferrichrome. Retrograde trafficking via the retromer complex or Snx4 was also not required for plasma membrane accumulation. High concentrations of ferrichrome led to higher levels of ubiquitination of Arn1, but they did not induce degradation. Without this ubiquitination, Arn1 remained on the plasma membrane, where it was active for transport. Arn1 was preferentially modified with polyubiquitin chains on a cluster of lysine residues at the amino terminus of the transporter. C1 NIDDKD, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), NIDDKD, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU Intramural NIH HHS NR 63 TC 31 Z9 32 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 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAY PY 2007 VL 18 IS 5 BP 1790 EP 1802 DI 10.1091/mbc.E06-09-0861 PG 13 WC Cell Biology SC Cell Biology GA 166US UT WOS:000246406700022 PM 17344478 ER PT J AU Bokko, PB Francione, L Bandala-Sanchez, E Ahmed, AU Annesley, SJ Huang, XL Khurana, T Kimmel, AR Fisher, PR AF Bokko, Paul B. Francione, Lisa Bandala-Sanchez, Esther Ahmed, Afsar U. Annesley, Sarah J. Huang, Xiuli Khurana, Taruna Kimmel, Alan R. Fisher, Paul R. TI Diverse cytopathologies in mitochondrial disease are caused by AMP-activated protein kinase signaling SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CELL-CYCLE PROGRESSION; DICTYOSTELIUM-DISCOIDEUM; SKELETAL-MUSCLE; ENERGY; MUTATIONS; PHOTOTAXIS; EXPRESSION; APOPTOSIS; SUBUNIT; PATHWAY AB The complex cytopathology of mitochondrial diseases is usually attributed to insufficient ATP. AMP-activated protein kinase (AMPK) is a highly sensitive cellular energy sensor that is stimulated by ATP-depleting stresses. By antisense-inhibiting chaperonin 60 expression, we produced mitochondrially diseased strains with gene dose-dependent defects in phototaxis, growth, and multicellular morphogenesis. Mitochondrial disease was phenocopied in a gene dose-dependent manner by overexpressing a constitutively active AMPK alpha subunit (AMPK alpha T). The aberrant phenotypes in mitochondrially diseased strains were suppressed completely by antisense-inhibiting AMPK alpha expression. Phagocytosis and macropinocytosis, although energy consuming, were unaffected by mitochondrial disease and AMPK alpha expression levels. Consistent with the role of AMPK in energy homeostasis, mitochondrial "mass" and ATP levels were reduced by AMPK alpha antisense inhibition and increased by AMPK alpha T overexpression, but they were near normal in mitochondrially diseased cells. We also found that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, a pharmacological AMPK activator in mammalian cells, mimics mitochondrial disease in impairing Dictyostelium phototaxis and that AMPK alpha antisense-inhibited cells were resistant to this effect. The results show that diverse cytopathologies in Dictyostelium mitochondrial disease are caused by chronic AMPK signaling not by insufficient ATP. C1 La Trobe Univ, Dept Microbiol, Melbourne, Vic 3086, Australia. NIH, Bethesda, MD 20892 USA. RP Fisher, PR (reprint author), La Trobe Univ, Dept Microbiol, Melbourne, Vic 3086, Australia. EM P.Fisher@latrobe.edu.au RI Ahmed, Afsar/I-7084-2013; Fisher, Paul/F-2870-2011 OI Ahmed, Afsar/0000-0001-9209-7089; Fisher, Paul/0000-0003-1884-6306 FU Intramural NIH HHS NR 64 TC 31 Z9 32 U1 0 U2 3 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 MAY PY 2007 VL 18 IS 5 BP 1874 EP 1886 DI 10.1091/mbc.E06-09-0881 PG 13 WC Cell Biology SC Cell Biology GA 166US UT WOS:000246406700029 PM 17332500 ER PT J AU Schwartz, DR Moin, K Yao, B Matrisian, LM Coussens, LM Bugge, TH Fingleton, B Acuff, HB Sinnamon, M Nassar, H Platts, AE Krawetz, SA Linebaugh, BE Sloane, BF AF Schwartz, Donald R. Moin, Kamiar Yao, Bin Matrisian, Lynn M. Coussens, Lisa M. Bugge, Thomas H. Fingleton, Barbara Acuff, Heath B. Sinnamon, Mark Nassar, Hind Platts, Adrian E. Krawetz, Stephen A. Linebaugh, Bruce E. Sloane, Bonnie F. TI Hu/Mu protin oligonucleotide microarray: Dual-species array for profiling protease and protease inhibitor gene expression in tumors and their microenvironment SO MOLECULAR CANCER RESEARCH LA English DT Article ID CATHEPSIN-B; CANCER; MATRIX; DISCOVERY; CELL; METALLOPROTEINASES; DEGRADOMICS; PROTEOLYSIS; MODEL; LUNG AB Proteolysis is a critical regulatory mechanism for a wide variety of physiologic and pathologic processes. To assist in the identification of proteases, their endogenous inhibitors, and proteins that interact with proteases or proteolytic pathways in biological tissues, a dual-species oligonucleotide microarray has been developed in conjunction with Affymetrix. The Hu/Mu Protin microarray contains 516 and 456 probe sets that survey human and mouse genes of interest (proteases, protease inhibitors, or interactors), respectively. To investigate the performance of the array, gene expression profiles were analyzed in pure mouse and human samples (reference RNA; normal and tumor cell lines/tissues) and orthotopically implanted xenografts of human A549 lung and MDA-MB-231 breast carcinomas. Relative gene expression and "present-call" P values were determined for each probe set using dChip and MAS5 software, respectively. Despite the high level of sequence identity of mouse and human protease/inhibitor orthologues and the theoretical potential for cross-hybridization of some of the probes, > 95% of the "present calls" (P < 0.01) resulted from same-species hybridizations (e.g., human transcripts to human probe sets). To further assess the performance of the microarray, differential gene expression and false discovery rate analyses were carried out on human or mouse sample groups, and data processing methods to optimize performance of the mouse and human probe sets were identified. The Hu/Mu Protin microarray is a valuable discovery tool for the identification of components of human and murine proteolytic pathways in health and disease and has particular utility in the determination of cellular origins of proteases and protease inhibitors in xenograft models of human cancer. C1 Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA. Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. Wayne State Univ, Inst Comp Sci, Detroit, MI 48201 USA. Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA. Univ Calif San Francisco, Dept Pathol, Canc Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pathol, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Schwartz, DR (reprint author), Biodiscovery LLC, 5692 Plymouth Rd, Ann Arbor, MI 48105 USA. EM dschwartz@biodiscovery-llc.com RI Sloane, Bonnie/A-1050-2009; Platts, Adrian/H-5633-2013 OI Platts, Adrian/0000-0001-9238-9647 FU Intramural NIH HHS; NCI NIH HHS [P30 CA22453, P50 CA58207, P50 CA90949] NR 26 TC 10 Z9 17 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD MAY PY 2007 VL 5 IS 5 BP 443 EP 454 DI 10.1158/1541-7786.MCR-06-0337 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 174DK UT WOS:000246921200004 PM 17510311 ER PT J AU Woynarowski, JM AF Woynarowski, Jan M. TI Christopher J. Michejda - Obituary SO MOLECULAR CANCER THERAPEUTICS LA English DT Biographical-Item C1 NCI, NIH, Bethesda, MD 20892 USA. RP Woynarowski, JM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAY PY 2007 VL 6 IS 5 BP 1475 EP 1476 DI 10.1158/1535-7163.MCT-07-0270 PG 2 WC Oncology SC Oncology GA 169YB UT WOS:000246626900001 ER PT J AU Blower, PE Verducci, JS Lin, SL Zhou, J Chung, JH Dai, ZY Liu, CG Reinhold, W Lorenzi, PL Kaldjian, EP Croce, CM Weinstein, JN Sadee, W AF Blower, Paul E. Verducci, Joseph S. Lin, Shili Zhou, Jin Chung, Ji-Hyun Dai, Zunyan Liu, Chang-Gong Reinhold, William Lorenzi, Philip L. Kaldjian, Eric P. Croce, Carlo M. Weinstein, John N. Sadee, Wolfgang TI MicroRNA expression profiles for the NCI-60 cancer cell panel SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ANTICANCER DRUG DISCOVERY; GENE-EXPRESSION; MOLECULAR PHARMACOLOGY; LINES; DATABASE; CHEMOSENSITIVITY; TARGETS; GROWTH; CHEMORESISTANCE; MICROARRAYS AB Advances in the understanding of cancer cell biology and response to drug treatment have benefited from new molecular technologies and methods for integrating information from multiple sources. The NCl-60, a panel of 60 diverse human cancer cell lines, has been used by the National Cancer Institute to screen > 100,000 chemical compounds and natural product extracts for anticancer activity. The NCl-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. Recently, microRNAs have been shown to target particular sets of mRNAs, thereby preventing translation or accelerating mRNA turnover. To complement the existing NCl-60 data sets, we have measured expression levels of microRNAs in the NCl-60 and incorporated the resulting data into the CellMiner program package for integrative analysis. Cell line groupings based on microRNA expression were generally consistent with tissue type and with cell line clustering based on mRNA expression. However, mRNA expression seemed to be somewhat more informative for discriminating among tissue types than was microRNA expression. In addition, we found that there does not seem to be a significant correlation between microRNA expression patterns and those of known target transcripts. Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance. C1 Ohio State Univ, Dept Pharmacol, Program Pharmacogenom, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Coll Med, Dept Stat, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Math Biosci Inst, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. NCI, Genom & Bioinformat Grp, Lab Mol Pharmacol, Canc Res Ctr, Bethesda, MD 20892 USA. GeneLog Inc, Gaithersburg, MD USA. RP Blower, PE (reprint author), Ohio State Univ, Dept Pharmacol, Program Pharmacogenom, 5072 Graves Hall,333 W 10th Ave, Columbus, OH 43210 USA. EM blower.7@osu.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM61390] NR 49 TC 175 Z9 183 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAY PY 2007 VL 6 IS 5 BP 1483 EP 1491 DI 10.1158/1535-7163.MCT-07-0009 PG 9 WC Oncology SC Oncology GA 169YB UT WOS:000246626900004 PM 17483436 ER PT J AU Jimeno, A Hallur, G Chan, A Zhang, XF Cusatis, G Chan, F Shah, P Chen, RB Hamel, E Garrett-Mayer, E Khan, S Hidalgo, M AF Jimeno, Antonio Hallur, Gurulingappa Chan, Audrey Zhang, Xiangfeng Cusatis, George Chan, Fonda Shah, Preeti Chen, Rongbing Hamel, Ernest Garrett-Mayer, Elizabeth Khan, Saeed Hidalgo, Manuel TI Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BETA-TUBULIN GENE; ANTITUMOR ACTIVITIES; BREAST-CANCER; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; ANTIMITOTIC AGENTS; MUTATIONS; PACLITAXEL; MISSENSE; IDENTIFICATION AB In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent. C1 Johns Hopkins Univ, Sch Med, Gastrointestinal Canc Program, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Chem Therapeut Program, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Div Stat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. NCI, NIH, Toxicol & Pharmacol Branch, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Khan, S (reprint author), 1650 Orleans St,Room 1M88, Baltimore, MD 21231 USA. EM khansa@jhmi.edu; mhidalg1@jhmi.edu RI Cusatis, Gianluca/G-2539-2011; HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 NR 36 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAY PY 2007 VL 6 IS 5 BP 1509 EP 1516 DI 10.1158/1535-7163.MCT-06-0592 PG 8 WC Oncology SC Oncology GA 169YB UT WOS:000246626900007 PM 17483439 ER PT J AU Akunda, JK Chun, KS Sessoms, AR Lao, HC Fischer, SM Langenbach, R AF Akunda, Jacqueline K. Chun, Kyung-Soo Sessoms, Alisha R. Lao, Huei-Chen Fischer, Susan M. Langenbach, Robert TI Cyclooxygenase-2 deficiency increases epidermal apoptosis and impairs recovery following acute UVB exposure SO MOLECULAR CARCINOGENESIS LA English DT Article DE cyclooxygenase; prostaglandin; UV; apoptosis ID SKIN-CANCER; MOUSE SKIN; ULTRAVIOLET-IRRADIATION; INDUCED INFLAMMATION; COX-2 INHIBITORS; GENE DISRUPTION; HAIRLESS MICE; CARCINOGENESIS; CELECOXIB; INDOMETHACIN AB The cyclooxygenases, COX-1 and COX-2, are involved in cutaneous responses to both acute and chronic UV exposure. In the present study, wild-type (WT), COX-1-/- and COX-2-/- mice were used to determine the influence of the individual isoform on mouse skin responses to acute UVB treatment. Immunohistochemistry and Western analysis indicated that COX-2, and not COX-1, was induced by UVB,2.5 or 5.0 kJ/m(2)), but that COX-1 remained the major source of prostaglandin E-2 production. UVB exposure significantly increased epidermal apoptosis in all genotypes compared to untreated mice. However, while the number of apoptotic cells in WT and COX-1-/- mice were about equal, the number of apoptotic cells was 2.5-fold greater in COX-2-/- mice. Apoptosis in WT and COX-2-/- mice peaked at 24 h post-exposure. The increased apoptosis and reduced proliferation in COX-2-/- mice resulted in about a 50% decrease in epidermal thickness at 24-48 h post-exposure compared to about a 50% increase in epidermal thickness in WT mice. UVB-induced cell replication, as measured by BrdU labeling, was reduced in COX-2-/- compared to WT mice at 24-96 h. However, by 96 h post-exposure, both WT and COX-2-/- mice showed epidermal hyperplasia. The data indicate that COX-2 induction initially protects against the acute sunburn effects of UVB, but that continuous induction of COX-2 may contribute to skin cancer in chronic UVB exposure. (c) 2007 Wiley-Liss, Inc. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. RP Langenbach, R (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS NR 36 TC 24 Z9 24 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2007 VL 46 IS 5 BP 354 EP 362 DI 10.1002/mc.20290 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 164ET UT WOS:000246217000003 PM 17238138 ER PT J AU Fischer, SM Pavone, A Mikulec, C Langenbach, R Rundhaug, JE AF Fischer, Susan M. Pavone, Amy Mikulec, Carol Langenbach, Robert Rundhaug, Joyce E. TI Cyclooxygenase-2 expression is critical for chronic UV-induced murine skin carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE COX-2; prostaglandins; UV carcinogenesis ID MOUSE SKIN; MULTISTAGE CARCINOGENESIS; CHEMOPREVENTIVE ACTIVITY; COLON CARCINOGENESIS; INDUCED INFLAMMATION; CANCER PREVENTION; TUMOR-DEVELOPMENT; INHIBITION; SUPPRESSION; COX-2 AB While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX-1 and COX-2, respectively) play important roles in chemical initiation-promotion protocols with phorbol ester tumor promoters, the contribution of these two enzymes to ultraviolet (UV) light-induced skin tumors has not been fully assessed. To better understand the contribution of COX-1 and COX-2 to UV carcinogenesis, we transferred the null allele for each isoform onto the SKH-1 hairless strain of mouse. Due to low viability on this background with complete knockout of COX-2, heterozygous mice were used in UV carcinogenesis experiments. While the lack of one allele of COX-1 had no effect on tumor outcome, the lack of one allele of COX-2 resulted in a 50-65% reduction in tumor multiplicity and a marked decrease in tumor size. Additionally, transgenic SKH-1 mice that overexpress COX-2 under the control of a keratin 14 promoter developed 70% more tumors than wild-type SKH-1 mice. The lack of one allele of either COX-1 or COX-2 reduced prostaglandin (PG) E-2 levels in response to a single UV treatment. The proliferative response to UV was significantly reduced in COX-2, but not COX-1, heterozygous mice. UV-induced apoptosis, however, was greater in COX-2 heterozygous mice. Collectively, these results clearly establish the requirement for COX-2 in the development of skin tumors. (c) 2007 Wiley-Liss, Inc. C1 Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Fischer, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, POB 389, Smithville, TX 78957 USA. FU Intramural NIH HHS [Z01 ES021229-08]; NCI NIH HHS [R01 CA100140, P30 CA016672, CA-16672, CA100140]; NIEHS NIH HHS [P30 ES007784, ES07784] NR 36 TC 67 Z9 67 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD MAY PY 2007 VL 46 IS 5 BP 363 EP 371 DI 10.1002/mc.20284 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 164ET UT WOS:000246217000004 PM 17219415 ER PT J AU Matsuda, H Paul, BD Choi, CY Shi, YB AF Matsuda, Hiroki Paul, Bindu D. Choi, Cheol Young Shi, Yun-Bo TI Contrasting effects of two alternative splicing forms of coactivator-associated arginine methyltransferase 1 on thyroid hormone receptor-mediated transcription in Xenopus laevis SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN METHYLTRANSFERASE; AMPHIBIAN METAMORPHOSIS; EXPRESSION PROFILES; COREPRESSOR COMPLEX; NUCLEAR RECEPTORS; GENE-EXPRESSION; HISTONE H3; METHYLATION; BINDING; SUPERFAMILY AB Thyroid hormone receptors (TRs) can repress or activate target genes depending on the absence or presence of thyroid hormone (T-3), respectively. This hormone-dependent gene regulation is mediated by the recruitment of corepressors in the absence of T-3 and coactivators in its presence. Many TR-interacting coactivators have been characterized in vitro. Among them is coactivator-associated arginine methyltransferase 1 (CARM1), which methylates histone H3. We are interested in investigating the role of CARM1 in TR-mediated gene expression in vivo during postembryonic development by using T-3-dependent frog metamorphosis as a model. We first cloned the Xenopus laevis CARM1 and obtained two alternative splicing forms, CARM1a and CARM1b. Both isoforms are expressed throughout metamorphosis, supporting a role for these isoforms during the process. To investigate whether Xenopus CARM1s participate in gene regulation by TRs, transcriptional analysis was conducted in Xenopus oocyte, where the effects of cofactors can be studied in the context of chromatin in vivo. Surprisingly, overexpression of CARM1b had little effect on TR-mediated transcription, whereas CARM1a enhanced gene activation by liganded TR. Chromatin immunoprecipitation assays showed that both endogenous CARM1a and overexpressed CARM1a and b were recruited to the promoter by liganded TR. However, the binding of liganded TR to the target promoter was reduced when CARM1b was overexpressed, accompanied by a slight reduction in histone methylation at the promoter. These results suggest that CARM1 may play a role in TR-mediated transcriptional regulation during frog development and that its function is regulated by alternative splicing. C1 NICHHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Korea MAritime Univ, Div Marine Environm & Biosci, Pusan 606791, South Korea. EM Shi@helix.nih.gov FU Intramural NIH HHS NR 63 TC 21 Z9 21 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2007 VL 21 IS 5 BP 1082 EP 1094 DI 10.1210/me.2006-0448 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 160XE UT WOS:000245975800007 PM 17312273 ER PT J AU Jones, I Ng, L Liu, H Forrest, D AF Jones, Iwan Ng, Lily Liu, Hong Forrest, Douglas TI An intron control region differentially regulates expression of thyroid hormone receptor beta 2 in the cochlea, pituitary, and cone photoreceptors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID CELL FATE DETERMINATION; GENE-EXPRESSION; MOUSE RETINA; IN-VIVO; XENOPUS-LAEVIS; MESSENGER-RNAS; TR-BETA; RESISTANCE; ALPHA; PROMOTER AB The Thrb gene, encoding thyroid hormone receptor beta (TR beta), serves key roles in endocrine regulation and the development of the senses of hearing and color vision. The versatile functions of this gene depend upon its expression of distinct receptor isoforms by differential promoter activation. The TR beta 2 isoform has a particularly specialized distribution including in the anterior pituitary and cochlea. TR beta 2 is also found in immature cone photoreceptors where it has a unique role in programming the expression pattern of opsin photopigments that mediate color vision. Given the importance of precise, tissue-specific expression for the function of TR beta 2, we investigated the genomic control elements that direct this expression in vivo using lacZ reporter transgenes in mice. The TR beta 2 promoter region is sufficient for cochlear expression, whereas a complex intron control region is necessary for pituitary and retinal expression. In the retina, the intron region directs peak expression in the embryo in postmitotic, immature cones. The retinal control region is further subdivided into domains that specify and amplify expression, respectively, indicating that timely, cone-specific expression reflects an integrated response to complex signals. The mammalian Thrb gene has therefore incorporated several mechanisms into a multifunctional intron control region that regulates developmental induction of the distant promoter. This specialized genomic organization underlies the unique expression pattern and functions of TR beta 2. C1 NIDDKD, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. RP Forrest, D (reprint author), NIDDKD, NIH, Clin Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU Intramural NIH HHS; NCI NIH HHS [R24-CA095823-01, R24-CA88302]; PHS HHS [03441] NR 56 TC 33 Z9 34 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2007 VL 21 IS 5 BP 1108 EP 1119 DI 10.1210/me.2007-0037 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 160XE UT WOS:000245975800009 PM 17341594 ER PT J AU Hatae, N Aksentijevich, N Zemkova, HW Kretschmannova, K Tomic, M Stojilkovic, SS AF Hatae, Noriyuki Aksentijevich, Nadia Zemkova, Hana W. Kretschmannova, Karla Tomic, Melanija Stojilkovic, Stanko S. TI Cloning and functional identification of novel endothelin receptor type A isoforms in pituitary SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; INTRACELLULAR TRAFFICKING PATHWAYS; SMOOTH-MUSCLE-CELLS; SIGNAL-TRANSDUCTION; CA2+ INFLUX; LIGAND-BINDING; SPLICE VARIANT; B RECEPTORS; EXPRESSION; SUBTYPE AB Mammalian endothelin (ET) receptors, termed ETAR and ETBR, are derived from two intron-containing genes and the functional splice variants of ETBR but not ETAR have been identified. Here, we report about the isolation of cDNAs of ETAR transcripts from rat anterior pituitary, which are generated by alternative RNA splicing. Deletion of exon 2 and insertion of fragments from intron 1 and 2 accounted for formation of three misplaced proteins, whereas the insertion of a fragment from intron 6 resulted in generation of a functional plasma membrane receptor, termed ETAR-C13. In this splice variant, the C-terminal 382S-426N sequence of ETAR was substituted with a shorter 382A-399L sequence, resulting in alteration of the putative domains responsible for coupling to G(q/11) and G(s) proteins and the endocytotic recycling, as well as in deletion of the predicted protein kinase C/casein kinase 2 phosphorylation sites. The mRNA transcripts for ETAR-C13 were identified in normal and immortalized pituitary cells and several other tissues. The pharmacological profiles of recombinant ETAR and ETAR-C13 were highly comparable, but the coupling of ETAR-C13 to the calcium-mobilizing signaling pathway was attenuated, causing a rightward shift in the potency for agonist. Furthermore, the efficacy of ETAR-C13 to stimulate adenylyl cyclase signaling pathway and to internalize was significantly reduced. These results indicate for the first time the presence of a novel ETA splice receptor, which could contribute to the functional heterogeneity among secretory pituitary cell types. C1 NICHD, Sect Cellular Signalling, NIH, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Sect Cellular Signalling, NIH, Endocrinol & Reprod Res Branch, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Tomic, Melanija/C-3371-2016 FU Intramural NIH HHS NR 65 TC 14 Z9 16 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2007 VL 21 IS 5 BP 1192 EP 1204 DI 10.1210/me.2006-0343 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 160XE UT WOS:000245975800015 PM 17312275 ER PT J AU Lem, KE Brinster, LR Tjurmina, O Lizak, M Lal, S Centeno, JA Liu, PC Godwin, SC Kaler, SG AF Lem, Kristen E. Brinster, Lauren R. Tjurmina, Olga Lizak, Martin Lal, Simina Centeno, Jose A. Liu, Po-Ching Godwin, Sarah C. Kaler, Stephen G. TI Safety of intracerebroventricular copper histidine in adult rats SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE copper histidine; intracerebral administration; maximum tolerated dose; Menkes disease; copper transport ID MANGANESE-ENHANCED MRI; MENKES-DISEASE; CANDIDATE GENE; RODENT BRAIN; EXPRESSION; INJECTION; MUTATION; THERAPY; ENCODES; ATPASE AB Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in a P-type ATPase (ATP7A) that normally delivers copper to the developing central nervous system. Infants with large deletions, or other mutations in ATP7A that incapacitate copper transport to the brain, show poor clinical outcomes and subnormal brain copper despite early subcutaneous copper histidine (CuHis) injections. These findings suggest a need for direct central nervous system approaches in such patients. To begin to evaluate an aggressive but potentially useful new strategy for metabolic improvement of this disorder, we studied the acute and chronic effects of CuHis administered by intracerebroventricular (ICV) injection in healthy adult rats. Magnetic resonance imaging (MRI) after ICV CuHis showed diffuse Ti-signal enhancement, indicating wide brain distribution of copper after ICV administration, and implying the utility of this paramagnetic metal as a MRI contrast agent. The maximum tolerated dose (MTD) of CuHis, defined as the highest dose that did not induce overt toxicity, growth retardation, or reduce lifespan, was 0.5 mcg. Animals receiving multiple infusions of this MTD showed increased brain copper concentrations, but no significant differences in activity, behavior, and somatic growth, or brain histology compared to saline-injected controls. Based on estimates of the brain copper deficit in Menkes disease patients, CuHis doses 10-fold lower than the MTD found in this study may restore proper brain copper concentration. Our results suggest that ICV CuHis administration have potential as a novel treatment approach in Menkes disease infants with severe mutations. Future trials of direct CNS copper administration in mouse models of Menkes disease will be informative. Published by Elsevier Inc. C1 NICHHD, Unit Pediat Genet, Lab Clin Genom, Bethesda, MD 20892 USA. Div Vet Resources, Bethesda, MD USA. Ctr Sci Review, Bethesda, MD USA. NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Div Biophys Toxicol, Washington, DC USA. RP Kaler, SG (reprint author), NICHHD, Unit Pediat Genet, Lab Clin Genom, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU NICHD NIH HHS [Z01 HD008768-02] NR 27 TC 5 Z9 6 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAY PY 2007 VL 91 IS 1 BP 30 EP 36 DI 10.1016/j.ymgme.2007.01.010 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 168QX UT WOS:000246540200005 PM 17336116 ER PT J AU Frank, JA Kalish, H Jordan, EK Anderson, SA Pawelczyk, E Arbab, AS AF Frank, Joseph A. Kalish, Heather Jordan, E. Kay Anderson, Stasta A. Pawelczyk, Edyta Arbab, Ali S. TI Color transformation and fluorescence of Prussian-Blue-positive cells: Implications for histologic verification of cells labeled with superparamagnetic iron oxide nanoparticles SO MOLECULAR IMAGING LA English DT Article ID STEM-CELLS; TRANSFECTION AGENT; MOUSE MODEL AB Superparamagnetic iron oxide (SPIO) nanoparticles, either modified or in combination with other macromolecules, are being used for magnetic labeling of stem cells and other cells to monitor cell trafficking by magnetic resonance imaging (MRI) in experimental models. The correlation of histology to MRI depends on the ability to detect SPIO-labeled cells using Prussian blue (PB) stain and fluorescent tags to cell surface markers. Exposure of PB-positive sections to ultraviolet light at a wavelength of 365 nm commonly used fluorescence microscopy can result in color transformation of PB-positive material from blue to brown. Although the PB color transformation is primarily an artifact that may occur during fluorescence microscopy, the transformation can be manipulated using imaging process software for the detection of low levels of iron labeled cells in tissues samples. C1 NINDS, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Henry Ford Hlth Syst, Detroit, MI USA. RP Frank, JA (reprint author), NINDS, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, NIH, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. EM jafrank@helix.nih.gov FU Intramural NIH HHS NR 15 TC 6 Z9 7 U1 1 U2 6 PU B C DECKER INC PI HAMILTON PA 50 KING STREET EAST, 2ND FLOOR, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD MAY-JUN PY 2007 VL 6 IS 3 BP 212 EP 218 DI 10.2310/7290.2007.00014 PG 7 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 186NP UT WOS:000247785700007 PM 17532887 ER PT J AU Lee, H Chang, YC Nardone, G Kwon-Chung, KJ AF Lee, Hyeseung Chang, Yun C. Nardone, Glenn Kwon-Chung, Kyung J. TI TUP1 disruption in Cryptococcus neoformans uncovers a peptide-mediated density-dependent growth phenomenon that mimics quorum sensing SO MOLECULAR MICROBIOLOGY LA English DT Article ID CANDIDA-ALBICANS; HISTOPLASMA-CAPSULATUM; CERATOCYSTIS-ULMI; BACILLUS-SUBTILIS; YEAST; MOLECULE; FARNESOL; COMPETENCE; DIMORPHISM; PHEROMONE AB Cryptococcus neoformans is a pathogenic yeast that causes life-threatening meningoencephalitis and grows well on mycological media regardless of inoculum size. Interestingly, a deletion of the global repressor TUP1 in C. neoformans uncovered a density-dependent growth phenotype reminiscent of the quorum-sensing phenomenon. An inoculum size of lower than 10(3) cells of the tup1 Delta strain failed to form colonies on agar media while inocula of 10(5)-10(6) cells per plate formed a lawn. This phenotype, expressed as the inability to grow at low cell densities, was rescued by the culture filtrate from a high cell density tup1 Delta culture and the active molecule in this culture filtrate was identified to be an oligopeptide composed of 11 amino acids. Activity assays, using a synthetic version of the peptide with strains harbouring a deletion of the corresponding gene, proved that the oligopeptide functioned as an autoregulatory molecule responsible for the density-dependent phenotype. Although a density-dependent growth phenotype has been reported in several species of Ascomycetes, no peptide has been reported to function as an autoregulator in the Kingdom Fungi. The identification of an 11-mer peptide as an autoregulatory molecule in C. neoformans suggests that a diverse mechanism of cell-to-cell communication exists in the Kingdom Fungi. C1 NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM June_Kwon-Chung@nih.gov FU Intramural NIH HHS NR 35 TC 28 Z9 32 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2007 VL 64 IS 3 BP 591 EP 601 DI 10.1111/j.1365-2958.2007.05666.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 161CD UT WOS:000245991000003 PM 17462010 ER PT J AU Chang, YC Bien, CM Lee, H Espenshade, PJ Kwon-Chung, KJ AF Chang, Yun C. Bien, Clara M. Lee, Hyeseung Espenshade, Peter J. Kwon-Chung, Kyung J. TI Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans SO MOLECULAR MICROBIOLOGY LA English DT Article ID ELEMENT-BINDING PROTEIN; SACCHAROMYCES-CEREVISIAE; INTRAMEMBRANE PROTEOLYSIS; NATURAL HABITAT; SREBP PATHWAY; FISSION YEAST; LIVING TREES; IRON UPTAKE; BLOOD-FLOW; GENE AB Cryptococcus neoformans is an environmental pathogen requiring atmospheric levels of oxygen for optimal growth. Upon inhalation, C. neoformans disseminates to the brain and causes meningoencephalitis, but the mechanisms by which the pathogen adapts to the low-oxygen environment in the brain have not been investigated. We found that SRE1, a homologue of the mammalian sterol regulatory element-binding protein (SREBP), functions in an oxygen-sensing pathway. Low oxygen decreased sterol synthesis in C. neoformans and triggered activation of membrane-bound Sre1p by the cleavage-activating protein, Scp1p. Microarray and Northern blot analysis demonstrated that under low oxygen, Sre1p activates genes required for ergosterol biosynthesis and iron uptake. Consistent with these regulatory functions, sre1 Delta cells were hypersensitive to azole drugs and failed to grow under iron-limiting conditions. Importantly, sre1 Delta cells failed to produce fulminating brain infection in mice. Our in vitro data support a model in which Sre1p is activated under low oxygen leading to the upregulation of genes required for sterol biosynthesis and growth in a nutrient-limiting environment. Animal studies confirm the importance of SRE1 for C. neoformans to adapt to the host environment and to cause fatal meningoencephalitis, thereby identifying the SREBP pathway as a therapeutic target for cryptococcosis. C1 NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. RP Kwon-Chung, KJ (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM peter.espenshade@jhmi.edu; June_Kwon-Chung@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL077588, R01 HL077588, R01 HL077588-03] NR 38 TC 105 Z9 108 U1 0 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2007 VL 64 IS 3 BP 614 EP 629 DI 10.1111/j.1365-2958.2007.05676.x PG 16 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 161CD UT WOS:000245991000005 PM 17462012 ER PT J AU Kawano, M Aravind, L Storz, G AF Kawano, Mitsuoki Aravind, L. Storz, Gisela TI An antisense RNA controls synthesis of an SOS-induced toxin evolved from an antitoxin SO MOLECULAR MICROBIOLOGY LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; PROGRAMMED CELL-DEATH; ESCHERICHIA-COLI K-12; P-BAD PROMOTER; MESSENGER-RNA; GENETIC ELEMENTS; PLASMID R1; IDENTIFICATION; EXPRESSION; SYSTEM AB Only few small, regulatory RNAs encoded opposite another gene have been identified in bacteria. Here, we report the characterization of a locus where a small RNA (SymR) is encoded in cis to an SOS-induced gene whose product shows homology to the antitoxin MazE (SymE). Synthesis of the SymE protein is tightly repressed at multiple levels by the LexA repressor, the SymR RNA and the Lon protease. SymE co-purifies with ribosomes and overproduction of the protein leads to cell growth inhibition, decreased protein synthesis and increased RNA degradation. These properties are shared with several RNA endonuclease toxins of the toxin-antitoxin modules, and we show that the SymE protein represents evolution of a toxin from the AbrB fold, whose representatives are typically antitoxins. We suggest that SymE promotion of RNA cleavage may be important for the recycling of RNAs damaged under SOS-inducing conditions. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM storz@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 NR 53 TC 110 Z9 112 U1 1 U2 8 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2007 VL 64 IS 3 BP 738 EP 754 DI 10.1111/j.1365-2958.2007.05688.x PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 161CD UT WOS:000245991000013 PM 17462020 ER PT J AU Koike, C Moore, R Negishi, M AF Koike, Chika Moore, Rick Negishi, Masahiko TI Extracellular signal-regulated kinase is an endogenous signal retaining the nuclear constitutive active/androstane receptor (CAR) in the cytoplasm of mouse primary hepatocytes SO MOLECULAR PHARMACOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; CYP2B GENE; HEPG2 CELLS; X-RECEPTOR; INDUCTION; LIVER; CULTURES; IDENTIFICATION; TRANSLOCATION AB The nuclear receptor constitutive active/androstane receptor ( CAR) is sequestered in the cytoplasm of liver cells before its activation by therapeutic drugs and xenobiotics such as phenobarbital (PB) and 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene ( TCPOBOP) in mouse liver, the regulatory mechanism of which remains poorly understood. Given the finding that epidermal growth factor repressed PB activation of CAR-mediated transcription (Mol Pharmacol 65: 172 - 180, 2004), here we investigated the regulatory role of hepatocyte growth factor (HGF)mediated signal in sequestering CAR in the cytoplasm of mouse primary hepatocytes. HGF treatment effectively repressed the induction of endogenous CYP2b10 gene by PB and TCPOBOP in mouse primary hepatocytes. On the other hand, inhibition by 1,4-diamino-2,3-dicyano-1,4-bis( methylthio) butadiene (U0126) of an HGF downstream kinase mitogen-activated protein kinase kinase (MEK) induced the Cyp2b10 gene and up-regulated the CAR-regulated promoter activity in the absence of TCPOBOP. HGF treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the cytosol, thus decreasing the TCPOBOP-induced nuclear accumulation of CAR. In contrast, U0126 dephosphorylated ERK1/2 and increased nuclear CAR accumulation in the absence of TCPOBOP. These results are consistent with the conclusion that the HGF-dependent phosphorylation of ERK1/2 is the endogenous signal that sequesters CAR in the cytoplasm of mouse primary hepatocytes. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural NIH HHS [Z01 ES071005-09, Z01 ES080040-22, Z99 ES999999] NR 28 TC 47 Z9 49 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2007 VL 71 IS 5 BP 1217 EP 1221 DI 10.1124/mol.107.034538 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160XB UT WOS:000245974900006 PM 17314319 ER PT J AU Bolan, EA Kivell, B Jaligam, V Oz, M Jayanthi, LD Han, Y Sen, N Urizar, E Gomes, I Devi, LA Ramamoorthy, S Javitch, JA Zapata, A Shippenberg, TS AF Bolan, Elizabeth A. Kivell, Bronwyn Jaligam, Vanaja Oz, Murat Jayanthi, Lankupalle D. Han, Yang Sen, Namita Urizar, Eneki Gomes, Ivone Devi, Lakshmi A. Ramamoorthy, Sammanda Javitch, Jonathan A. Zapata, Agustin Shippenberg, Toni S. TI D-2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism SO MOLECULAR PHARMACOLOGY LA English DT Article ID RESONANCE ENERGY-TRANSFER; ELEMENT-BINDING PROTEIN; TRANSMEMBRANE SEGMENT; STRIATAL TRANSPORTER; D2 RECEPTORS; IN-VITRO; OLIGOMERIZATION; ACTIVATION; PHOSPHORYLATION; INTERNALIZATION AB The dopamine transporter (DAT) terminates dopamine (DA) neurotransmission by reuptake of DA into presynaptic neurons. Regulation of DA uptake by D-2 dopamine receptors (D-2 R) has been reported. The high affinity of DA and other DAT substrates for the D2R, however, has complicated investigation of the intracellular mechanisms mediating this effect. The present studies used the fluorescent DAT substrate, 4-[4-(diethylamino)styryl]- N-methylpyridinium iodide (ASP(+)) with live cell imaging techniques to identify the role of two D2R-linked signaling pathways, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and phosphoinositide 3 kinase (PI3K) in mediating D2R regulation of DAT. Addition of the D-2/D-3 receptor agonist quinpirole (0.1 - 10 mu M) to human embryonic kidney cells coexpressing human DAT and D-2 receptor ( short splice variant, D2SR) induced a rapid, concentration-dependent and pertussis toxin-sensitive increase in ASP(+) accumulation. The D-2/D-3 agonist (S)-(+)-(4aR, 10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H, 5H-[1] benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride (PD128907) also increased ASP(+) accumulation. D2SR activation increased phosphorylation of ERK1/2 and Akt, a major target of PI3K. The mitogen-activated protein kinase kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) prevented the quinpirole-evoked increase in ASP(+) accumulation, whereas inhibition of PI3K was without effect. Fluorescence flow cytometry and biotinylation studies revealed a rapid increase in DAT cell-surface expression in response to D2R stimulation. These experiments demonstrate that D2SR stimulation increases DAT cell surface expression and therefore enhances substrate clearance. Furthermore, they show that the increase in DAT function is ERK1/2-dependent but PI3K-independent. Our data also suggest the possibility of a direct physical interaction between DAT and D2R. Together, these results suggest a novel mechanism by which D2SR autoreceptors may regulate DAT in the central nervous system. C1 NIDA, IRP, DHHS,Integrat Neurosci Sect, NIH, Baltimore, MD 21224 USA. Med Univ S Carolina, Div Neurosci Res, Dept Neurosci, Charleston, SC 29425 USA. Columbia Univ, Coll Phys & Surg, Ctr Mol Recognit, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY USA. Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, New York, NY USA. RP Shippenberg, TS (reprint author), NIDA, IRP, DHHS,Integrat Neurosci Sect, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tshippen@intra.nida.nih.gov RI Oz, Murat/E-2148-2012; Kivell, Bronwyn/P-3140-2014 OI Kivell, Bronwyn/0000-0001-9699-553X FU Intramural NIH HHS; NIDA NIH HHS [P50DA015369, DA0019521, DA08863, DA11495, K05 DA022413]; NIMH NIH HHS [MH062612, MH54137, MH57324] NR 44 TC 104 Z9 105 U1 3 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2007 VL 71 IS 5 BP 1222 EP 1232 DI 10.1124/mol.106.027763 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160XB UT WOS:000245974900007 PM 17267664 ER PT J AU Lisk, G Scott, S Solomon, T Pillai, AD Desai, SA AF Lisk, Godfrey Scott, Seth Solomon, Tsione Pillai, Ajay D. Desai, Sanjay A. TI Solute-inhibitor interactions in the plasmodial surface anion channel reveal complexities in the transport process SO MOLECULAR PHARMACOLOGY LA English DT Article ID RED-BLOOD-CELLS; FALCIPARUM-INFECTED ERYTHROCYTES; PERMEATION PATHWAYS; CHLORIDE CHANNEL; MEMBRANE; DANTROLENE; PARASITE AB Human red blood cells infected with the malaria parasite Plasmodium falciparum have markedly increased permeabilities to diverse organic and inorganic solutes. The plasmodial surface anion channel (PSAC), recently identified with electrophysiological methods, contributes to the uptake of many small solutes. In this study, we explored the effects of known PSAC antagonists on transport of different solutes. We were surprised to find that the transport of two solutes, phenyltrimethylammonium and isoleucine, was only partially inhibited by concentrations of three inhibitors that abolish sorbitol or alanine uptake. Residual uptake via endogenous transporters could not account for this finding because uninfected red blood cells (RBCs) do not have adequate permeability for these solutes. In infected RBCs, the residual uptake of these solutes could be abolished by higher concentrations of specific and nonspecific PSAC antagonists. Adding sorbitol or alanine, permeant solutes that do not exhibit residual uptake, could also abolish it. The residual uptake did not exhibit anomalous mole fraction behavior and had a steep activation energy. These observations exclude uptake via unrelated pathways and instead point to differences in how PSAC recognizes and transports various solutes. We propose a possible model that also may help explain the unique selectivity properties of PSAC. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Room 3W-01,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov RI Desai, Sanjay/B-7110-2009 FU Intramural NIH HHS [Z01 AI000882-07] NR 32 TC 10 Z9 10 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2007 VL 71 IS 5 BP 1241 EP 1250 DI 10.1124/mol.106.030734 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160XB UT WOS:000245974900009 PM 17287402 ER PT J AU Li, WM Xue, J Niu, CY Fu, HJ Lam, CSC Luo, JL Chan, HHN Xue, HG Kan, KKW Lee, NTK Li, CY Pang, YP Li, MT Tsim, KWK Jiang, HL Chen, KX Li, XY Han, YF AF Li, Wenming Xue, Jian Niu, Chunying Fu, Hongjun Lam, Colin S. C. Luo, Jialie Chan, Hugh H. N. Xue, Huaiguo Kan, Kelvin K. W. Lee, Nelson T. K. Li, Chaoying Pang, Yuanping Li, Mingtao Tsim, Karl W. K. Jiang, Hualiang Chen, Kaixian Li, Xiaoyuan Han, Yifan TI Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase SO MOLECULAR PHARMACOLOGY LA English DT Article ID ANTI-ALZHEIMERS AGENT; ACETYLCHOLINESTERASE INHIBITOR; NEURODEGENERATIVE DISORDERS; MULTIFUNCTIONAL DRUGS; CEREBRAL-ISCHEMIA; CNS TARGETS; DISEASE; NMDA; APOPTOSIS; PROTEIN AB The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide ( NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase ( NOS) inhibitor, N-G-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis( 7)tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate. Moreover, like L-NMMA but not like 5H-dibenzo[a, d] cyclohepten-5,10- imine (MK-801) and memantine, bis( 7)-tacrine showed greater neuroprotection and inhibition on NO release when neurons were pretreated for a prolonged time between 0 and 24 h and remained quite potent even when neurons were post-treated 1 h after the glutamate challenge. Bis(7)-tacrine was additionally found to be as moderately potent as memantine in competing with [H-3] MK-801, inhibiting NMDA-evoked currents and reducing glutamate-triggered calcium influx, which eventually reduced neuronal NOS activity. More importantly, at neuroprotective concentrations, bis(7)-tacrine substantially reversed the overactivation of neuronal NOS caused by glutamate without interfering with the basal activity of NOS. Furthermore, in vitro pattern analysis demonstrated that bis( 7)tacrine competitively inhibited both purified neuronal and inducible NOS with IC50 values at 2.9 and 9.3 mu M but not endothelial NOS. This result was further supported by molecular docking simulations that showed hydrophobic interactions between bis( 7)-tacrine and three NOS isozymes. Taken together, these results strongly suggest that the substantial neuroprotection against glutamate by bis( 7)-tacrine might be mediated synergistically through the moderate blockade of NMDAR and selective inhibition of neuronal NOS. C1 Hong Kong Univ Sci & Technol, Dept Biochem, Hong Kong, Peoples R China. Hong Kong Univ Sci & Technol, Dept Chem, Hong Kong, Peoples R China. Hong Kong Univ Sci & Technol, Dept Biol, Hong Kong, Peoples R China. Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Discovery & Design, Shanghai, Peoples R China. NIAAA, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD USA. Mayo Fdn Med Educ & Res, Rochester, MN USA. Sun Yat Sen Univ, Zhongshan Med Coll, Dept Pharmacol & Proteom Lab, Guangzhou, Peoples R China. RP Han, YF (reprint author), Hong Kong Univ Sci & Technol, Dept Biochem, Hong Kong, Peoples R China. EM bcyfhan@ust.hk RI FU, HONGJUN/H-4498-2011; OI Han, Yifan/0000-0002-5833-069X; Pang, Yuan-Ping/0000-0003-0838-2560 NR 36 TC 35 Z9 38 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2007 VL 71 IS 5 BP 1258 EP 1267 DI 10.1124/mol.106.029108 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160XB UT WOS:000245974900011 PM 17299028 ER PT J AU Grados, MA Samuels, J Shugart, YY Willour, VL Wang, Y Cullen, B Bienvenu, OJ Hoehn-Saric, R Valle, D Liang, KY Riddle, MA Wendland, JR Murphy, DL Nestadt, G Detera-Wadleigh, S AF Grados, M. A. Samuels, J. Shugart, Y. Y. Willour, V. L. Wang, Y. Cullen, B. Bienvenu, O. J. Hoehn-Saric, R. Valle, D. Liang, K-Y Riddle, M. A. Wendland, J. R. Murphy, D. L. Nestadt, G. Detera-Wadleigh, S. TI Rare plus common SERT variants in obsessive-compulsive disorder SO MOLECULAR PSYCHIATRY LA English DT Letter ID SEROTONIN TRANSPORTER GENE; ASSOCIATION; POLYMORPHISM; 5-HTTLPR; FAMILY C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Behav Sci, Baltimore, MD 21205 USA. Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD USA. Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Grados, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. EM mjgrados@jhmi.edu RI Liang, Kung-Yee/F-8299-2011; Wendland, Jens/A-1809-2012 NR 10 TC 6 Z9 6 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAY PY 2007 VL 12 IS 5 BP 422 EP 423 DI 10.1038/sj.mp.4001970 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 160NA UT WOS:000245947900003 PM 17453059 ER PT J AU Sato, T Neschadim, A Konrad, M Fowler, DH Lavie, A Medin, JA AF Sato, Takeya Neschadim, Anton Konrad, Manfred Fowler, Daniel H. Lavie, Arnon Medin, Jeffrey A. TI Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy SO MOLECULAR THERAPY LA English DT Article ID GRAFT-VERSUS-LEUKEMIA; IN-VIVO; THYMIDINE KINASE; NUCLEOSIDE ANALOGS; AZT ACTIVATION; T-LYMPHOCYTES; CELLS; CANCER; MICE; ZIDOVUDINE AB Gene therapy and stem cell transplantation safety could be enhanced by control over the fate of therapeutic cells. Suicide gene therapy uses enzymes that convert prodrugs to cytotoxic entities; however, heterologous moieties with poor kinetics are employed. We describe a novel enzyme/prodrug combination for selectively inducing apoptosis in lentiviral vector - transduced cells. Rationally designed variants of human thymidylate kinase (tmpk) that effectively phosphorylate 3'-azido-3'- deoxythymidine (AZT) were efficiently delivered. Transduced Jurkat cell lines were eliminated by AZT. We demonstrate that this schema targeted both dividing and non-dividing cells, with a novel killing mechanism involving apoptosis induction via disruption of the mitochondrial inner membrane potential and activation of caspase-3. Primary murine and human T cells were also transduced and responded to AZT. Furthermore, low-dose AZT administration to non-obese diabetic/ severe combined immunodeficiency (NOD/SCID) mice injected with transduced K562 cells suppressed tumor growth. This novel suicide gene therapy approach can thus be integrated as a safety switch into therapeutic vectors. C1 Ontario Canc Inst, Div Stem Cell & Dev Biol, Toronto, ON M4X 1K9, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany. NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL USA. Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. RP Medin, JA (reprint author), Univ Hlth Network, Room 406,67 Coll St, Toronto, ON M5G 2M1, Canada. EM jmedin@uhnres.utoronto.ca RI Lavie, Arnon/H-4927-2012; OI Neschadim, Anton/0000-0003-1750-9703 NR 39 TC 57 Z9 59 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAY PY 2007 VL 15 IS 5 BP 962 EP 970 DI 10.1038/mt.sj.6300122 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 161FI UT WOS:000245999500015 PM 17375075 ER PT J AU Hibbett, DS Binder, M Bischoff, JF Blackwell, M Cannon, PF Eriksson, OE Huhndorf, S James, T Kirk, PM Lucking, R Lumbsch, HT Lutzoni, F Matheny, PB Mclaughlin, DJ Powell, MJ Redhead, S Schoch, CL Spatafora, JW Stalpers, JA Vilgalys, R Aime, MC Aptroot, A Bauer, R Begerow, D Benny, GL Castlebury, LA Crous, PW Dai, YC Gams, W Geiser, DM Griffith, GW Gueidan, C Hawksworth, DL Hestmark, G Hosaka, K Humber, RA Hyde, KD Ironside, JE Koljalg, U Kurtzman, CP Larsson, KH Lichtwardt, R Longcore, J Miadlikowska, J Miller, A Moncalvo, JM Mozley-Standridge, S Oberwinkler, F Parmasto, E Reeb, V Rogers, JD Roux, C Ryvarden, L Sampaio, JP Schussler, A Sugiyama, J Thorn, RG Tibell, L Untereiner, WA Walker, C Wang, Z Weir, A Weiss, M White, MM Winka, K Yao, YJ Zhang, N AF Hibbett, David S. Binder, Manfred Bischoff, Joseph F. Blackwell, Meredith Cannon, Paul F. Eriksson, Ove E. Huhndorf, Sabine James, Timothy Kirk, Paul M. Luecking, Robert Lumbsch, H. Thorsten Lutzoni, Francois Matheny, P. Brandon Mclaughlin, David J. Powell, Martha J. Redhead, Scott Schoch, Conrad L. Spatafora, Joseph W. Stalpers, Joost A. Vilgalys, Rytas Aime, M. Catherine Aptroot, Andre Bauer, Robert Begerow, Dominik Benny, Gerald L. Castlebury, Lisa A. Crous, Pedro W. Dai, Yu-Cheng Gams, Walter Geiser, David M. Griffith, Gareth W. Gueidan, Cecile Hawksworth, David L. Hestmark, Geir Hosaka, Kentaro Humber, Richard A. Hyde, Kevin D. Ironside, Joseph E. Koljalg, Urmas Kurtzman, Cletus P. Larsson, Karl-Henrik Lichtwardt, Robert Longcore, Joyce Miadlikowska, Jolanta Miller, Andrew Moncalvo, Jean-Marc Mozley-Standridge, Sharon Oberwinkler, Franz Parmasto, Erast Reeb, Valerie Rogers, Jack D. Roux, Claude Ryvarden, Leif Sampaio, Jose Paulo Schuessler, Arthur Sugiyama, Junta Thorn, R. Greg Tibell, Leif Untereiner, Wendy A. Walker, Christopher Wang, Zheng Weir, Alex Weiss, Michael White, Merlin M. Winka, Katarina Yao, Yi-Jian Zhang, Ning TI A higher-level phylogenetic classification of the Fungi SO MYCOLOGICAL RESEARCH LA English DT Review ID RIBOSOMAL DNA-SEQUENCES; LSU RDNA SEQUENCES; MOLECULAR PHYLOGENY; ORD-NOV; MITOCHONDRIAL SEQUENCES; NATURAL CLASSIFICATION; BASIDIOMYCETOUS YEASTS; BAYESIAN-ANALYSIS; LARGE SUBUNITS; NUCLEAR RDNA AB A comprehensive phylogenetic classification of the kingdom Fungi is proposed, with reference to recent molecular phylogenetic analyses, and with input from diverse members of the fungal taxonomic community. The classification includes 195 taxa, down to the level of order, of which 16 are described or validated here: Dikarya subkingdom nov.; Chytridiomycota, Neocallimastigomycota phyla nov.; Monoblepharidomycetes, Neocallimastigomycetes class. nov.; Eurotiomycetidae, Lecarioromycetidae, Mycocaliciomycetidae subclass. nov.; Acarosporales, Corticiales, Baeomycetales, Candelariales, Gloeophyllales, Melanosporales, Trechisporales, Umbilicariales ords. nov. The clade containing Ascomycota and Basidiomycota is classified as subkingdom Dikarya, reflecting the putative synapomorphy of dikaryotic hyphae. The most dramatic shifts in the classification relative to previous works concern the groups that have traditionally been included in the Chytridiomycota and Zygomycota. The Chytridiomycota is retained in a restricted sense, with Blastocladiomycota and Neocallimastigomycota representing segregate phyla of flagellated Fungi. Taxa traditionally placed in Zygomycota are distributed among Glomeromycota and several subphyla incertae sedis, including Mucoromycotina, Entomophthoromycotina, Kickxellomycotina, and Zoopagomycotiria. Microsporidia are included in the Fungi, but no further subdivision of the group is proposed. Several genera of 'basal' Fungi of uncertain position are not placed in any higher taxa, including Basidiobolus, Caulochytrium, Olpidium, and Rozella. (c) 2007 The British Mycological Society. Published by Elsevier Ltd. All rights reserved. C1 Clark Univ, Dept Biol, Worcester, MA 01610 USA. Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. CABI UK, Surrey TW20 9TY, England. Umea Univ, Dept Ecol & Environm Sci, S-90187 Umea, Sweden. Field Museum Nat Hist, Dept Bot, Chicago, IL 60605 USA. Duke Univ, Dept Biol, Durham, NC 27708 USA. Univ Minnesota, Dept Plant Biol, St Paul, MN 55108 USA. Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. ECORC, Agr & Agri Food Canada, Ottawa, ON K1A 0C6, Canada. Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. Cent Bur Schimmelcultures, NL-3584 CT Utrecht, Netherlands. USDA ARS, Systemat Bot & Mycol Lab, Beltsville, MD 20705 USA. ABL, Herbarium, NL-3762 XK Soest, Netherlands. Univ Tubingen, Inst Bot, D-72076 Tubingen, Germany. Max Planck Inst Terr Microbiol, D-35043 Marburg, Germany. Univ Florida, Dept Plant Pathol, Gainesville, FL 32611 USA. Chinese Acad Sci, Inst Appl Ecol, Shenyang 110016, Peoples R China. Penn State Univ, Dept Plant Pathol, University Pk, PA 16802 USA. Univ Wales, Inst Biol Sci, Aberystwyth SY23 3DA, Dyfed, Wales. Univ Complutense Madrid, Fac Farm, Dept Biol Vegetal 2, E-28040 Madrid, Spain. Univ Oslo, Dept Biol, N-0316 Oslo, Norway. Field Museum Nat Hist, Dept Bot, Chicago, IL 60605 USA. USDA ARS, Plant Protect Res Unit, US Plant Soil & Nutr Lab, Ithaca, NY 14853 USA. Univ Hong Kong, Dept Ecol & Biodivers, Ctr Res Fungal Divers, Hong Kong, Hong Kong, Peoples R China. Univ Tartu, Inst Bot & Ecol, EE-51005 Tartu, Estonia. USDA ARS, Natl Ctr Agr Utilizat Res, Peoria, IL 61604 USA. Univ Gothenburg, Dept Plant & Environm Sci, SE-40530 Gothenburg, Sweden. Univ Kansas, Dept Ecol & Evolutionary Biol, Lawrence, KS 66045 USA. Univ Maine, Dept Biol Sci, Orono, ME 04469 USA. Illinois Nat Hist Survey, Ctr Biodivers, Champaign, IL 61820 USA. Royal Ontario Museum, Ctr Biodivers & Conservat Biol, Toronto, ON M5S 2C6, Canada. Middle Georgia Coll, Div Nat Sci Math & Engn, Cochran, GA 31014 USA. Estonian Univ Life Sci, Inst Agr & Environm Sci, EE-51014 Tartu, Estonia. Washington State Univ, Dept Plant Pathol, Pullman, WA 99164 USA. Chemin Vignes Vielles, F-84120 Mirabeau, France. Univ Oslo, Bot Inst, N-0316 Oslo, Norway. Univ Nova Lisboa, Fac Ciencias & Tecnol, SABT, CREM, P-2829516 Caparica, Portugal. Univ Munich, Dept Biol 1, Inst Genet, D-80638 Munich, Germany. TechnoSuruga Co Ltd, Tokyo Off, Chiyoda Ku, Tokyo 1010052, Japan. Univ Western Ontario, Dept Biol, London, ON N6A 5B7, Canada. Uppsala Univ, Evolut Biol Ctr, Dept Systemat Bot, SE-75236 Uppsala, Sweden. Brandon Univ, Dept Bot, Brandon, MB R7A 6A9, Canada. Royal Bot Gardens, Edinburgh EH3 5LR, Midlothian, Scotland. SUNY Coll, Fac Environm & Forest Biol, Syracuse, NY 13210 USA. Boise State Univ, Dept Biol, Boise, ID 83725 USA. Chinese Acad Sci, Inst Microbiol, Systmat Mycol & Lichenol Lab, Beijing 100080, Peoples R China. Cornell Univ, Dept Plant Pathol, Geneva, NY 14456 USA. RP Hibbett, DS (reprint author), Clark Univ, Dept Biol, Worcester, MA 01610 USA. EM dhibbett@clarku.edu RI Dai, Yu-Cheng/A-6589-2015; SchuSSler, Arthur/F-1681-2011; Gueidan, Cecile/C-8803-2014; Wang, Zheng/A-2318-2011; Sampaio, Jose Paulo/C-5532-2011; WeiSS, Michael/F-6206-2012; Crous, Pedro/H-1489-2012; Thorn, R Greg/I-3398-2012; Schoch, Conrad/J-4825-2012; Lumbsch, Thorsten/K-3573-2012; Zhang, Ning/K-3046-2012; Binder, Manfred/C-8571-2013; REQUIMTE, MM/M-6160-2013; REQUIMTE, UCIBIO/N-9846-2013; griffith, gareth/A-1970-2009; Geiser, David/J-9950-2013 OI Sampaio, Jose/0000-0001-8145-5274; Vilgalys, Rytas/0000-0001-8299-3605; Wang, Zheng/0000-0002-8849-8549; WeiSS, Michael/0000-0002-4869-9186; Crous, Pedro/0000-0001-9085-8825; Lumbsch, Thorsten/0000-0003-1512-835X; Zhang, Ning/0000-0003-0755-2505; NR 225 TC 973 Z9 1047 U1 39 U2 371 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0953-7562 J9 MYCOL RES JI Mycol. Res. PD MAY PY 2007 VL 111 BP 509 EP 547 DI 10.1016/j.mycres.2007.03.004 PN 5 PG 39 WC Mycology SC Mycology GA 187RM UT WOS:000247865900002 PM 17572334 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Metagenomic sorcery and the expanding protein universe SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID DIVERSITY; SEA AB A metagenomic study of the Atlantic and Pacific oceans reveals dominant bacterial species, remarkable microdiversity and a wealth of new proteins. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 13 TC 8 Z9 8 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD MAY PY 2007 VL 25 IS 5 BP 540 EP 542 DI 10.1038/nbt0507-540 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 166HK UT WOS:000246369400019 PM 17483838 ER PT J AU Macdonald, RL Pluta, RM Zhang, JH AF Macdonald, R. Loch Pluta, Ryszard M. Zhang, John H. TI Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution SO NATURE CLINICAL PRACTICE NEUROLOGY LA English DT Review DE cerebral vasospasm; cortical spreading depression; endothelin; International Conference on Cerebral Vasospasm; subarachnoid hemorrhage ID ISCHEMIC NEUROLOGICAL DEFICITS; ENDOTHELIN RECEPTOR ANTAGONIST; EARLY BRAIN-INJURY; BLOOD-FLOW; NITRIC-OXIDE; MORPHOLOGICAL-CHANGES; PIAL-ARTERIES; RAT; MODEL; DOGS AB Cerebral vasospasm is the classic cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage, leading and thus to poor outcome and to cerebral ischemia and infarction occasionally death. Advances in diagnosis and treatment-principally the use of nimodipine, intensive care management, hemodynamic manipulations and endovascular neuroradiology procedures-have a improved the prospects for these patients, but outcomes remain disappointing. Recent clinical trials have demonstrated marked prevention of vasospasm with the endothelin receptor antagonist clazosentan, yet patient outcome was not improved. This Review considers possible explanations for this result and proposes alternative causes of neurological deterioration and poor outcome after subarachnoid hemorrhage, including delayed effects of global cerebral ischemia, thromboembolism, microcirculatory dysfunction and cortical spreading depression. C1 Univ Toronto, St Michaels Hosp, Div Neurosurg, Toronto, ON M5B 1W8, Canada. NINDS, Surg Neurol Branch, NIH, Bethesda, MD USA. Loma Linda Univ, Physiol Grad Program, Loma Linda, CA 92350 USA. RP Macdonald, RL (reprint author), Univ Toronto, St Michaels Hosp, Div Neurosurg, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM macdonaldio@smh.toronto.on.ca OI Zhang, John H./0000-0002-4319-4285 FU Intramural NIH HHS NR 57 TC 188 Z9 200 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-834X J9 NAT CLIN PRACT NEURO JI Nat. Clin. Pract. Neurol. PD MAY PY 2007 VL 3 IS 5 BP 256 EP 263 DI 10.1038/ncpneuro0490 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 164BC UT WOS:000246206600007 PM 17479073 ER PT J AU Ward, MM AF Ward, Michael M. TI Primer: measuring the effects of treatment in clinical trials SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Review DE clinical trial; effect size; intention to treat analysis; responsiveness; statistical power ID SURROGATE END-POINTS; RANDOMIZED-TRIALS; MEDICAL LITERATURE; CONSORT STATEMENT; USERS GUIDES; EQUIVALENCE; PREVENTION; BIOMARKERS; THERAPY; ARTICLE AB The results of clinical trials are often used as the basis for changes in clinical practice. Proper execution and interpretation of the results of trials are, therefore, of paramount importance to the welfare of patients. The results of a clinical trial are based on four key elements: the choice of the primary study end point, the method used to compare end points between groups, the clinically meaningful difference in the primary end point selected a priori by the investigators, and the power of the study to detect as statistically significant a difference between groups that is as large as the preselected clinically meaningful difference. These key elements directly follow from the primary hypothesis tested by the trial. This article reviews the basic features of these four elements, and the influence they have on the interpretation of clinical trials. C1 NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS NR 29 TC 1 Z9 1 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8382 J9 NAT CLIN PRACT RHEUM JI Nat. Clin. Pract. Rheumatol. PD MAY PY 2007 VL 3 IS 5 BP 291 EP 297 DI 10.1038/ncprheum0478 PG 7 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 163TR UT WOS:000246186600010 PM 17471248 ER PT J AU Yeager, M Orr, N Hayes, RB Jacobs, KB Kraft, P Wacholder, S Minichiello, MJ Fearnhead, P Yu, K Chatterjee, N Wang, ZM Welch, R Staats, BJ Calle, EE Feigelson, HS Thun, MJ Rodriguez, C Albanes, D Virtamo, J Weinstein, S Schumacher, FR Giovannucci, E Willett, WC Cancel-Tassin, G Cussenot, O Valeri, A Andriole, GL Gelmann, EP Tucker, M Gerhard, DS Fraumeni, JF Hoover, R Hunter, DJ Chanock, SJ Thomas, G AF Yeager, Meredith Orr, Nick Hayes, Richard B. Jacobs, Kevin B. Kraft, Peter Wacholder, Sholom Minichiello, Mark J. Fearnhead, Paul Yu, Kai Chatterjee, Nilanjan Wang, Zhaoming Welch, Robert Staats, Brian J. Calle, Eugenia E. Feigelson, Heather Spencer Thun, Michael J. Rodriguez, Carmen Albanes, Demetrius Virtamo, Jarmo Weinstein, Stephanie Schumacher, Fredrick R. Giovannucci, Edward Willett, Walter C. Cancel-Tassin, Geraldine Cussenot, Olivier Valeri, Antoine Andriole, Gerald L. Gelmann, Edward P. Tucker, Margaret Gerhard, Daniela S. Fraumeni, Joseph F., Jr. Hoover, Robert Hunter, David J. Chanock, Stephen J. Thomas, Gilles TI Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 SO NATURE GENETICS LA English DT Article ID GENETIC ALTERATIONS; ATTRIBUTABLE RISK; POPULATIONS; HOTSPOTS; MAP AB Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study ( 1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies ( total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus ( P = 9.42 x 10(-13;) heterozygote odds ratio (OR): 1.26, 95% confidence interval ( c. i.): 1.13 - 1.41; homozygote OR: 1.58, 95% c. i.: 1.40 - 1.78). Each SNP remained significant in a joint analysis after adjusting for the other ( rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 ( 21% versus 9%). C1 NCI, Div Canc Epidemiol & Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. Univ Lancaster, Dept Math & Stat, Lancaster LA1 4YF, England. Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. Natl Inst Publ Hlth, Dept Hlth Promot & Chron Dis Prevent, FIN-00300 Helsinki, Finland. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Hop Tenon, AP HP, CeRePP, F-75970 Paris, France. Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63108 USA. Columbia Univ, Div Hematol & Oncol, New York, NY 10032 USA. NCI, Off Canc Genom, NIH, DHHS, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Fearnhead, Paul/A-1653-2008; Fearnhead, Paul/A-5938-2015; Tucker, Margaret/B-4297-2015; Albanes, Demetrius/B-9749-2015; OI Fearnhead, Paul/0000-0002-9386-2341; Hayes, Richard/0000-0002-0918-661X; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU CCR NIH HHS [N01-RC-37004, N01-RC-45035]; Intramural NIH HHS; NCI NIH HHS [CA55075, 5U01CA098233-04, N01-CN-45165, T32 CA 09001, U01 CA098710]; Wellcome Trust NR 26 TC 762 Z9 790 U1 0 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2007 VL 39 IS 5 BP 645 EP 649 DI 10.1038/ng2022 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 160VU UT WOS:000245971300020 PM 17401363 ER PT J AU Hong, S Lim, S Li, AG Lee, C Lee, YS Lee, EK Park, SH Wang, XJ Kim, SJ AF Hong, Suntaek Lim, Seunghwan Li, Allen G. Lee, Chan Lee, Youn Sook Lee, Eun-Kyung Park, Seok Hee Wang, Xiao-Jing Kim, Seong-Jin TI Smad7 binds to the adaptors TAB2 and TAB3 to block recruitment of the kinase TAK1 to the adaptor TRAF2 SO NATURE IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; GROWTH-FACTOR-BETA; BREAST-CANCER CELLS; TGF-BETA; TRANSCRIPTIONAL ACTIVATION; SIGNAL-TRANSDUCTION; NEGATIVE REGULATION; IKK ACTIVATION; NULL MOUSE; IN-VIVO AB Transforming growth factor-beta 1 (TGF-beta 1) regulates inflammation and can inhibit activation of the transcription factor NF-kappa B in certain cell types. Here we show that the TGF-beta-induced signaling protein Smad7 bound to TAB2 and TAB3, which are adaptors that link the kinase TAK1 to 'upstream' regulators in the proinflammatory tumor necrosis factor (TNF) signaling pathway. Smad7 thereby promoted TGF-beta-mediated anti-inflammatory effects. The formation of Smad7-TAB2 and Smad7-TAB3 complexes resulted in the suppression of TNF signaling through the adaptors TRAF2, TAB2 and/or TAB3, and TAK1. Furthermore, expression of a transgene encoding Smad7 in mouse skin suppressed inflammation and NF-kappa B nuclear translocation substantially and disrupted the formation of endogenous TRAF2-TAK1-TAB2 and TRAF2-TAK1-TAB3 complexes. Thus, Smad7 is a critical mediator of TGF-beta signals that block proinflammatory TNF signals. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97239 USA. Inha Univ, Coll Med, Dept Pathol, Inchon 400712, South Korea. Inha Res Inst Med Sci, Inchon 400712, South Korea. Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon 406840, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. EM kims@mail.nih.gov FU Intramural NIH HHS NR 49 TC 69 Z9 75 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAY PY 2007 VL 8 IS 5 BP 504 EP 513 DI 10.1038/ni1451 PG 10 WC Immunology SC Immunology GA 158YM UT WOS:000245831600015 PM 17384642 ER PT J AU Ryan, RM Mindell, JA AF Ryan, Renae M. Mindell, Joseph A. TI The uncoupled chloride conductance of a bacterial glutamate transporter homolog SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID SCANNING MUTAGENESIS REVEALS; BACILLUS-STEAROTHERMOPHILUS; REENTRANT LOOP; TRANSLOCATION PATHWAY; PERMEATION PATHWAY; SUBSTRATE-BINDING; ION FLUXES; CHANNEL; CARRIER; STATES AB Glutamate transporters (EAATs) are pivotal in mammalian synaptic transmission, tightly regulating synaptic levels of this excitatory neurotransmitter. In addition to coupled glutamate transport, the EAATs also show an uncoupled Cl- conductance, whose physiological importance has recently been demonstrated. Little is yet known about the molecular mechanism of chloride permeation. Here we show that Glt(Ph), a bacterial EAAT homolog whose structure has been determined, displays an uncoupled Cl- conductance that can determine the rate of substrate uptake. A mutation analogous to one known to specifically affect Cl movement in EAAT1 has similar effects on GltPh, suggesting that this protein is an excellent structural model for understanding Cl- permeation through the EAATs. We also observed an uncoupled Cl- conductance in another bacterial EAAT homolog but not in a homolog of the Na+/Cl--coupled neurotransmitter transporters. C1 NINDS, Membrane transport Biophys Unit, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), NINDS, Membrane transport Biophys Unit, US Natl Inst Hlth, 35 Convent Dr,Bldg 35,MSC 3701, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247; Ryan, Renae/0000-0002-8680-4610 NR 50 TC 65 Z9 68 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2007 VL 14 IS 5 BP 365 EP 371 DI 10.1038/nsmb1230 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 163TZ UT WOS:000246187400008 PM 17435767 ER PT J AU Nicolas, E Yamada, T Cam, HP FitzGerald, PC Kobayashi, R Grewal, SIS AF Nicolas, Estelle Yamada, Takatomi Cam, Hugh P. FitzGerald, Peter C. Kobayashi, Ryuji Grewal, Shiv I. S. TI Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID H3 LYSINE-9 METHYLATION; GENOME-WIDE ANALYSIS; STRAND BREAK REPAIR; FISSION YEAST; SACCHAROMYCES-CEREVISIAE; HISTONE ACETYLATION; GENE-EXPRESSION; TRANSCRIPTION ELONGATION; CHROMOSOME SEGREGATION; DEACETYLASE COMPLEX AB Histone acetylation is important in regulating DNA accessibility. Multifunctional Sin3 proteins bind histone deacetylases (HDACs) to assemble silencing complexes that selectively target chromatin. We show that, in fission yeast, an essential HDAC, Clr6, exists in two distinct Sin3 core complexes. Complex I contains an essential Sin3 homolog, Pst1, and other factors, and predominantly targets gene promoters. Complex II contains a nonessential Sin3 homolog, Pst2, and several conserved proteins. It preferentially targets transcribed chromosomal regions and centromere cores. Defects in complex II abrogate global protective functions of chromatin, causing increased accessibility of DNA to genotoxic agents and widespread antisense transcripts that are processed by the exosome. Notably, the two Clr6 complexes differentially repress forward and reverse centromeric repeat transcripts, suggesting that these complexes regulate transcription in heterochromatin and euchromatin in similar manners, including suppression of spurious transcripts from cryptic start sites. C1 NCI, NIH, Lab Biochem & Mol Biol, Bethesda, MD 20892 USA. NCI, NIH, Genome Anal Inst, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA. RP Grewal, SIS (reprint author), NCI, NIH, Lab Biochem & Mol Biol, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov RI Nicolas, Estelle/C-4425-2008 OI Nicolas, Estelle/0000-0003-0412-8477 FU Intramural NIH HHS NR 60 TC 101 Z9 103 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2007 VL 14 IS 5 BP 372 EP 380 DI 10.1038/nsmb1239 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 163TZ UT WOS:000246187400009 PM 17450151 ER PT J AU Colina, C Rosenthal, JJC DeGiorgis, JA Srikumar, D Iruku, N Holmgren, M AF Colina, Claudia Rosenthal, Joshua J. C. DeGiorgis, Joseph A. Srikumar, Deepa Iruku, Nikhila Holmgren, Miguel TI Structural basis of Na+/K+-ATPase adaptation to marine environments SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NA,K-ATPASE ALPHA-SUBUNIT; SQUID GIANT-AXON; CYSTEINE-SCANNING MUTAGENESIS; CURRENT-VOLTAGE RELATIONSHIP; NA/K PUMP; TRANSMEMBRANE SEGMENT; SODIUM-PUMP; ACTIVE TRANSPORT; XENOPUS OOCYTES; CATION-BINDING AB Throughout evolution, enzymes have adapted to perform in different environments. The Na+/K+ pump, an enzyme crucial for maintaining ionic gradients across cell membranes, is strongly influenced by the ionic environment. In vertebrates, the pump sees much less external Na+ (100 - 160 mM) than it does in osmoconformers such as squid (450 mM), which live in seawater. If the extracellular architecture of the squid pump were identical to that of vertebrates, then at the resting potential, the pump's function would be severely compromised because the negative voltage would drive Na+ ions back to their binding sites, practically abolishing forward transport. Here we show that four amino acids that ring the external mouth of the ion translocation pathway are more positive in squid, thereby reducing the pump's sensitivity to external Na+ and explaining how it can perform optimally in the marine environment. C1 NINDS, NIH, Mol Neurophysiol Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. Univ Puerto Rico, Inst Neurobiol, San Juan, PR 00901 USA. NINDS, NIH, Struct Cell Biol Sect, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Rosenthal, JJC (reprint author), NINDS, NIH, Mol Neurophysiol Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. EM jrosenthal@neuro.upr.edu; holmgren@ninds.nih.gov FU Intramural NIH HHS; NCRR NIH HHS [G12RR03051]; NINDS NIH HHS [NS039405-06] NR 45 TC 22 Z9 23 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAY PY 2007 VL 14 IS 5 BP 427 EP 431 DI 10.1038/nsmb1237 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 163TZ UT WOS:000246187400016 PM 17460695 ER PT J AU Orient, A Donko, A Szabo, A Leto, TL Geiszt, M AF Orient, Anna Donko, Agnes Szabo, Attila Leto, Thomas L. Geiszt, Miklos TI Novel sources of reactive oxygen species in the human body SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Editorial Material DE hydrogen peroxide; NADPH oxidase; Nox; reactive oxygen species; ROS; superoxide ID SMOOTH-MUSCLE-CELLS; SUPEROXIDE-GENERATING OXIDASE; INTESTINAL EPITHELIAL-CELLS; NOX4 NAD(P)H OXIDASE; NADPH-OXIDASE; HYDROGEN-PEROXIDE; ENDOTHELIAL-CELLS; NOX1-DEFICIENT MICE; TRANSGENIC MICE; DUAL OXIDASES C1 Semmelweis Univ, Fac Med, Dept Physiol, H-1444 Budapest, Hungary. Semmelweis Univ, Fac Med, Dept Pediat 1, H-1444 Budapest, Hungary. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Geiszt, M (reprint author), Semmelweis Univ, Fac Med, Dept Physiol, POB 259, H-1444 Budapest, Hungary. EM geiszt@puskin.sote.hu FU Wellcome Trust NR 77 TC 42 Z9 43 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAY PY 2007 VL 22 IS 5 BP 1281 EP 1288 DI 10.1093/ndt/gfm077 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 162XZ UT WOS:000246124100001 PM 17347280 ER PT J AU Anantharam, V Lehrmann, E Kanthasamy, A Yang, Y Banerjee, P Becker, KG Freed, WJ Kanthasamy, AG AF Anantharam, Vellareddy Lehrmann, Elin Kanthasamy, Arthi Yang, Yongjie Banerjee, Probal Becker, Kevin G. Freed, William J. Kanthasamy, Anumantha G. TI Microarray analysis of oxidative stress regulated genes in mesencephalic dopaminergic neuronal cells: Relevance to oxidation damage in Parkinson's disease SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE mitochondria; oxidative stress; gene expression; caspases; PKC delta; Parkinson's disease ID KINASE-C-DELTA; METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL; CASPASE-3-DEPENDENT PROTEOLYTIC CLEAVAGE; SUBSTANTIA-NIGRA; CDNA MICROARRAY; NEURODEGENERATIVE DISEASES; EXPRESSION ANALYSIS; MEDIATED APOPTOSIS; 14-3-3 PROTEINS; SPINAL-CORD AB Oxidative stress and apoptotic cell death have been implicated in the dopaminergic cell loss that characterizes Parkinson's disease. While factors contributing to apoptotic cell death are not well characterized, oxidative stress is known to activate an array of cell signaling molecules that participate in apoptotic cell death mechanisms. We investigated oxidative stress-induced cytotoxicity of hydrogen peroxide (H(2)O(2)) in three cell lines, the dopaminergic mesencephalon-derived N27 cell line, the GABAergic striatum-derived M213-20 cell line, and the hippocampal HN2-5 cell line. N27 cells were more sensitive to H(2)O(2)-induced cell death than M213-20 and HN2-5 cells. H(2)O(2) induced significantly greater increases in caspase-3 activity in N27 cells than in M213-20 cells. H(2)O(2)-induced apoptotic cell death in N27 cells was mediated by caspase-3-dependent proteolytic activation of PKC delta. Gene expression microarrays were employed to examine the specific transcriptional changes in N27 cells exposed to 100 mu M H(2)O(2) for 4 h. Changes in genes encoding pro- or anti-apoptotic proteins included up-regulation of BIK, PAWR, STAT5B, NPAS2, Jun B, MEK4, CCT7, PPP3CC, and PSDM3, while key down-regulated genes included BNIP3, NPTXR, RAGA, STK6, YWHAH, and MAP2K1. Overall, the changes indicate a modulation of transcriptional activity, chaperone activity, kinase activity, and apoptotic activity that appears highly specific, coordinated and relevant to cell survival. Utilizing this in vitro model to identify novel oxidative stress-regulated genes may be useful in unraveling the molecular mechanisms underlying dopaminergic degeneration in Parkinson's disease. (c) 2007 Elsevier Ltd. All rights reserved. C1 Iowa State Univ Sci & Technol, Parkinsons Disorder Res Lab, Dept Biomed Sci, Iowa Ctr Adv Neurotoxicol, Ames, IA 50011 USA. NIDA, Cellular Neurobiol Res Branch, Intraural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. CUNY Staten Isl, Dept Chem, Staten Isl, NY USA. CUNY Staten Isl, Neurosci Program, Staten Isl, NY USA. NIA, Gene Express & Genom Unit, Res Resources Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Kanthasamy, AG (reprint author), Iowa State Univ Sci & Technol, Parkinsons Disorder Res Lab, Dept Biomed Sci, Iowa Ctr Adv Neurotoxicol, 2062 Vet Med Bldg, Ames, IA 50011 USA. EM akanthas@iastate.edu FU Intramural NIH HHS; NIEHS NIH HHS [ES 10586, R01 ES010586, R01 ES010586-06A1]; NINDS NIH HHS [NS 386644, NS 45133, R01 NS038644-07A1, R01 NS045133, R01 NS045133-04, R01 NS038644] NR 81 TC 43 Z9 46 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD MAY PY 2007 VL 50 IS 6 SI SI BP 834 EP 847 DI 10.1016/j.neuint.2007.02.003 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 177IP UT WOS:000247147100006 PM 17397968 ER PT J AU Bandaru, VVR McArthur, JC Sacktor, N Cutler, RG Knapp, EL Mattson, MP Haughey, NJ AF Bandaru, V. V. R. McArthur, J. C. Sacktor, N. Cutler, R. G. Knapp, E. L. Mattson, M. P. Haughey, N. J. TI Associative and predictive biomarkers of dementia in HIV-1-infected patients SO NEUROLOGY LA English DT Article ID VITAMIN-E; ANTIRETROVIRAL THERAPY; OXIDATIVE STRESS; NERVOUS-SYSTEM; HIV-DEMENTIA; CHOLESTEROL; GLIA; ADRENOLEUKODYSTROPHY; ANTIOXIDANTS; DEFICIENCY AB Background: Infection with HIV can result in a debilitating CNS disorder known as HIV dementia ( HIV- D). Since the advent of highly active antiretroviral therapy ( HAART), the incidence of HIV- D has declined, but the prevalence continues to increase. In this new era of HIV- D, traditional biomarkers such as CSF viral load and monocyte chemotactic protein 1 levels are less likely to be associated with dementia in patients on HAART and biomarkers that can predict HIV- D have not yet been identified. Objective: To identify biomarkers that are associated with and can predict HIV- D. Methods: We grouped patients with HIV based on changes in cognitive status over a 1- year period and analyzed sphingolipid, sterol, triglyceride, antioxidant, and lipid peroxidation levels in CSF. Results: We found that increased levels of the vitamin E and triglyceride C52 predicted the onset or worsening of dementia. Elevated levels of sphingomyelin were associated with inactive dementia. Elevated levels of ceramide and the accumulation of 4- hydroxynonenals were associated with active dementia. Conclusions: We interpret these findings to indicate that early in the pathogenesis of HIV dementia, there is an up- regulation of endogenous antioxidant defenses in brain. The failure of this attempted neuroprotective mechanism leads to the accumulation of sphingomyelin and moderate cognitive dysfunction. The breakdown of this enlarged pool of sphingomyelin to ceramide and the accumulation of highly reactive aldehydes are associated with declining cognitive function. Thus, elevations in endogenous protective mechanisms may identify patients who are at increased risk of the development of HIV dementia. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD USA. RP Haughey, NJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Meyer 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. EM nhaughe1@jhmi.edu RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS; NIA NIH HHS [AG023471, R01 AG023471, R21 AG034849]; NIAAA NIH HHS [R01 AA017408]; NIMH NIH HHS [MH068388, MH071150, P30 MH075673, R01 MH071150, R01 MH077542, R21 MH072534]; NINDS NIH HHS [NS49465, R01 NS049465] NR 23 TC 63 Z9 66 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 1 PY 2007 VL 68 IS 18 BP 1481 EP 1487 DI 10.1212/01.wnl.0000260610.79853.47 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 163AM UT WOS:000246130800008 PM 17470750 ER PT J AU Schottenbauer, MA Momenan, R Kerick, M Hommer, DW AF Schottenbauer, Michele A. Momenan, Reza Kerick, Michael Hommer, Daniel W. TI Relationships among aging, IQ, and intracranial volume in alcoholics and control subjects SO NEUROPSYCHOLOGY LA English DT Article DE alcoholism; brain; intelligence; aging ID BRAIN VOLUMES; YOUNG MEN; FOLLOW-UP; HIGH-RISK; OLD-AGE; PERFORMANCE; INTELLIGENCE; MRI; HYPOTHESIS; ATROPHY AB The current article examined the relationships among aging, intelligence, intracranial volume, and brain shrinkage in alcoholics and nonalcoholic controls. Magnetic resonance imaging was used to measure intracranial and cerebral volumes in 146 subjects with alcohol use disorders and 42 comparison subjects who were not alcoholic. The authors' findings show that performance on Block Design decreases as alcoholics age, and this decrease is predicted by brain shrinkage. This is consistent with a process of cumulative brain damage related to alcohol use. However, the authors' data also show that vocabulary does not decrease with age and is correlated with premorbid brain size as measured by intracranial volume, suggesting that lower verbal ability precedes heavy alcohol use and may be a risk factor for alcoholism. C1 NIAAA, Sect Brain Electrophysiol & Brain Imaging, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. RP Hommer, DW (reprint author), NIAAA, Sect Brain Electrophysiol & Brain Imaging, Clin Studies Lab, NIH, Room 3C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM danh@mail.nih.gov FU Intramural NIH HHS NR 50 TC 15 Z9 16 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD MAY PY 2007 VL 21 IS 3 BP 337 EP 345 DI 10.1037/0894-4105.21.3.337 PG 9 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 164RM UT WOS:000246251700008 PM 17484597 ER PT J AU Apud, JA Mattay, V Chen, JS Kolachana, BS Callicott, JH Rasetti, R Alce, G Iudicello, JE Akbar, N Egan, MF Goldberg, TE Weinberger, DR AF Apud, Jose A. Mattay, Venkata Chen, Jingshan Kolachana, Bhaskar S. Callicott, Joseph H. Rasetti, Roberta Alce, Guilna Iudicello, Jennifer E. Akbar, Natkai Egan, Michael F. Goldberg, Terry E. Weinberger, Daniel R. TI Tolcapone improves cognition and cortical information processing in normal human subjects SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE tolcapone; COMT; dorsolateral prefrontal cortex; working memory; fMRI; DA ID CATECHOL-O-METHYLTRANSFERASE; RAT PREFRONTAL CORTEX; PARKINSONS-DISEASE; WORKING-MEMORY; DOPAMINE TRANSPORTER; INDIVIDUAL VARIATION; METHYL TRANSFERASE; GENE POLYMORPHISM; FRONTAL-CORTEX; MESSENGER-RNA AB Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase ( COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging ( fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex. C1 NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH,HHS, Bethesda, MD 20854 USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH,HHS, 10 Ctr Dr,Bldg 10,Rm 4S235, Bethesda, MD 20854 USA. EM weinberd@mail.nih.gov RI Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 42 TC 133 Z9 134 U1 4 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2007 VL 32 IS 5 BP 1011 EP 1020 DI 10.1038/sj.npp.1301227 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 157YZ UT WOS:000245758800004 PM 17063156 ER PT J AU Corvol, JC Valjent, E Pascoli, V Robin, A Stipanovich, A Luedtke, RR Belluscio, L Girault, JA Herve, D AF Corvol, Jean-Christophe Valjent, Emmanuel Pascoli, Vincent Robin, Aurelie Stipanovich, Alexandre Luedtke, Robert R. Belluscio, Leonardo Girault, Jean-Antoine Herve, Denis TI Quantitative changes in G alpha olf protein levels, but not D1 receptor, alter specifically acute responses to psychostimulants SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine D1a receptor; G protein; Gnal; Drd1a; psychostimulants; addiction ID INDUCED BEHAVIORAL SENSITIZATION; CONDITIONED PLACE PREFERENCE; SENSITIVE ADENYLATE-CYCLASE; D-1A DOPAMINE-RECEPTORS; NUCLEUS-ACCUMBENS; MICE LACKING; GLUTAMATE RELEASE; KINASE CASCADE; KNOCKOUT MICE; IN-VIVO AB Striatal dopamine D1 receptors (D1R) are coupled to adenylyl cyclase through G alpha olf. Although this pathway is involved in important brain functions, the consequences of quantitative alterations of its components are not known. We explored the biochemical and behavioral responses to cocaine and D-amphetamine (D-amph) in mice with heterozygous mutations of genes encoding D1R and G alpha olf (Drd1a +/- and Gnal +/-), which express decreased levels of the corresponding proteins in the striatum. Dopamine-stimulated cAMP production in vitro and phosphorylation of AMPA receptor GluR1 subunit in response to D-amph in vivo were decreased in Gnal +/-, but not Drd1a +/- mice. Acute locomotor responses to D1 agonist SKF81259, D-amph and cocaine were altered in Gnal +/- mice, and not in Drd1a +/- mice. This haploinsufficiency showed that Gaolf but not D1R protein levels are limiting for D1R-mediated biochemical and behavioral responses. Gnal +/- mice developed pronounced locomotor sensitization and conditioned locomotor responses after repeated injections of D-amph (2 mg/kg) or cocaine (20 mg/kg). They also developed normal D-amph-conditioned place preference. The D1R/cAMP pathway remained blunted in repeatedly treated Gnal +/- mice. In contrast, D-amph-induced ERK activation was normal in the striatum of these mice, possibly accounting for the normal development of long-lasting behavioral responses to psychostimulants. Our results clearly dissociate biochemical mechanisms involved in acute and delayed behavioral effects of psychostimulants. They identify striatal levels of Gaolf as a key factor for acute responses to psychostimulants and suggest that quantitative alterations of its expression may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine function. C1 INSERM, Inst Fer Moulin, F-75005 Paris, France. INSERM, U536, Paris, France. Univ Paris 06, Paris, France. Hop La Pitie Salpetriere, Serv Pharm, Paris, France. Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX USA. NINDS, Dev Neural Plast Unit, NIH, Bethesda, MD 20892 USA. RP Corvol, JC (reprint author), INSERM, Inst Fer Moulin, 17 Rue Fer Moulin, F-75005 Paris, France. EM jean-christophe.corvol@psl.aphp.fr RI Girault, Jean-Antoine/F-7518-2013; corvol, jean-christophe/I-6387-2012; HERVE, Denis/E-2929-2017 OI Girault, Jean-Antoine/0000-0002-7900-1705; corvol, jean-christophe/0000-0001-7325-0199; HERVE, Denis/0000-0003-1376-1522 NR 57 TC 41 Z9 41 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2007 VL 32 IS 5 BP 1109 EP 1121 DI 10.1038/aj.npp.1301230 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 157YZ UT WOS:000245758800012 PM 17063155 ER PT J AU Crooks, DR Welch, N Smith, DR AF Crooks, Daniel R. Welch, Nicholas Smith, Donald R. TI Low-level manganese exposure alters glutamate metabolism in GABAergic AF5 cells SO NEUROTOXICOLOGY LA English DT Article DE GABA; glutamate; manganese; rat; glutamic acid decarboxylase ID ENERGY-METABOLISM; PC12 CELLS; DIFFERENTIAL REGULATION; TAURINE TRANSPORTER; MAGNETIC-RESONANCE; IRON REGULATION; BRAIN DOPAMINE; MESSENGER-RNA; RAT-BRAIN; NEUROTOXICITY AB Recent studies have suggested that the globus pallidus may be a particularly sensitive target of manganese (Mn), however, in vitro studies of the effects of Mn on GABAergic neurons have been restricted by the lack of a cell model expressing GABAergic properties. Here, we investigated the effects of low-level Mn treatment on cellular GABA and glutamate metabolism using the newly characterized AF5 rat neural-derived cell line, which displays GABAergic properties during culture in vitro. Intracellular GABA and glutamate levels were measured along with measurement of the release of GABA and glutamate into the culture medium, glutamine uptake from the culture medium, and the specific effects of Mn on the enzymes directly responsible for the synthesis and degradation of GABA, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). Our results demonstrate that Mn had no effect on the activities of GAD or GABA-T. Similarly, low-level Mn treatment of AF5 cultures had only a small effect on intracellular GABA levels (114% of control) and no effect on the release of GABA. In contrast, intracellular and extracellular glutamate levels were enhanced to 170 and 198% of control during Mn treatment, respectively, while extracellular glutamine decreased to 73% of controls. Together, these results suggest that glutamate homeostasis may be preferentially affected over GABA in AF5 cells during low-level Mn treatment, suggesting a novel mechanism by which Mn-induced excitotoxicity might arise. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Calif Santa Cruz, Dept Environm Toxicol, Santa Cruz, CA 95064 USA. RP Smith, DR (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. EM smith@etox.ucsc.edu FU NIEHS NIH HHS [R01 ES010788, ES 010788, R01 ES010788-04] NR 46 TC 18 Z9 20 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAY PY 2007 VL 28 IS 3 BP 548 EP 554 DI 10.1016/j.neuro.2007.01.003 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 186WH UT WOS:000247808700013 PM 17320182 ER PT J AU Salisbury, AL Lester, BM Seifer, R LaGasse, L Bauer, CR Shankaran, S Bada, H Wright, L Liu, J Poole, K AF Salisbury, Amy L. Lester, Barry M. Seifer, Ronald LaGasse, Linda Bauer, Charles R. Shankaran, Seetha Bada, Henrietta Wright, Linda Liu, Jing Poole, Ken TI Prenatal cocaine use and maternal depression: Effects on infant neurobehavior SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE cocaine; depression; infant; neurobehavior; postpartum ID ADDICTION SEVERITY INDEX; LIFE-STYLE; POSTPARTUM DEPRESSION; POSTNATAL DEPRESSION; SUBSTANCE EXPOSURE; SLEEP PROBLEMS; DRUG-USE; PREGNANCY; PREVALENCE; SYMPTOMS AB Objective: The present study examined the impact of both perinatal maternal depression and cocaine use on infant neurobehavior at I month of age in a large, multi-site study. Methods: Infant neurobehavior was examined in 1053 infants at I month of age using the NICU Network Neurobehavioral Scale (NNNS). Mothers were interviewed using The Addiction Severity Index to determine present and past psychiatric history. Four groups were derived from the total sample: 385 prenatally cocaine-exposed infants, 76 whose mothers reported current postpartum depression (DEP/COC) and 309 without current postpartum depression (nonDEP/COC); 668 infants were not exposed to cocaine, 104 whose mothers reported current postpartum depression (DEP/nonCOC), 564 without current postpartum depression (nonDEP/nonCOC). A 2x2 Analysis of Covariance was used with covariates (birthweight, maternal age, SES, nicotine, alcohol, and research site) to examine infant neurobehavior in these four conditions. Secondary analyses were conducted to examine the effects of amount and timing of prenatal cocaine exposure. Results: DEP group by COC exposure status interactions were significant; there was only a DEP effect in the nonCOC infants. Infants in the nonCOC/DEP group had poorer self-regulation and more stress signs, excitability, and arousal than infants in the other groups. Conclusions: Postpartum maternal depression has negative effects on infant neurobehavior at I month of age. Prenatal cocaine exposure may serve to suppress or buffer the effects of postpartum depression on infant neurobehavior. Maternal mood could explain some of the inconsistencies found in the prenatal cocaine exposure literature. (C) 2006 Elsevier Inc. All rights reserved. C1 Brown Univ, Sch Med, Providence, RI 02912 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Bradley Hosp, Providence, RI USA. Univ Miami, Sch Med, Miami, FL USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Kentucky, Lexington, KY USA. NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Res Triangle Inst, Div Stat Res, Res Triangle Pk, NC 27709 USA. RP Salisbury, AL (reprint author), Brown Univ, Ctr Study Children Risk, Women & Infants Hosp, 101 Dudley St, Providence, RI 02905 USA. EM Amy_Salisbury@brown.edu OI Seifer, Ronald/0000-0003-4879-2839 FU NICHD NIH HHS [U10 HD021385, U10 HD021397, U10 HD027856, U10 HD027904]; NIMH NIH HHS [K23 MH065479-05, K23 MH065479, T32 MH019927] NR 72 TC 31 Z9 31 U1 5 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2007 VL 29 IS 3 BP 331 EP 340 DI 10.1016/j.ntt.2006.12.001 PG 10 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 185YS UT WOS:000247746900002 PM 17258430 ER PT J AU Cokic, VP Beleslin-Cokic, BB Noguchi, CT Schechter, AN AF Cokic, Vladan P. Beleslin-Cokic, Bojana B. Noguchi, Constance T. Schechter, Alan N. TI Hydroxyurea increases eNOS protein levels through inhibition of proteasome activity SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE nitric oxide; hydroxyurea; proteasome; endothelial cells ID NITRIC-OXIDE SYNTHASE; SICKLE-CELL-DISEASE; HISTONE DEACETYLASE INHIBITORS; VASCULAR ENDOTHELIAL-CELLS; GENE-EXPRESSION; KAPPA-B; MULTIPLE-MYELOMA; PHASE-I; PATHWAY; BORTEZOMIB AB Recent reports have identified the proteasome as the primary degradation pathway for inducible, neuronal and endothelial nitric oxide synthase (NOS). We have demonstrated that hydroxyurea increased nitric oxide (NO) production in endothelial cells through phosphorylation of eNOS as a short-term effect. We find now that NO production in endothelial cells is dose-dependently stimulated by hydroxyurea, as well as both specific and non-specific proteasome inhibitors, as a long term effect. Prolonged treatment of primary human umbilical vein endothelial cells (HUVEC) with hydroxyurea was found to increase eNOS protein levels without an effect on eNOS mRNA levels, suggesting posttranscriptional control. We observed that the inhibitors of proteasomes that we tested also increased eNOS protein levels in HUVEC. In a proteasome assay, we showed that hydroxyurea inhibited protein degradation in a dose-dependent manner, in both purified 20S proteasome and HUVEC lysates. The NO production induced by hydroxyurea in endothelial cells appears to be mediated by long term posttranscriptional augmentation in eNOS levels via inhibition of the proteasome activity. Published by Elsevier Inc. C1 Inst Med Res, Lab Expt Hematol, Belgrade 11129, Serbia. Univ Clin Ctr, Sch Med, Inst Endocrinol Diabet & Dis Metab, Belgrade 11000, Serbia. NIDDK, Natl Inst Hlth, Mol Cell Biol Sect, Mol Med Branch, Bethesda, MD 20892 USA. RP Cokic, VP (reprint author), Inst Med Res, Lab Expt Hematol, Dr Subotica 4,POB 102, Belgrade 11129, Serbia. EM vl@imi.bg.ac.yu; aschecht@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 33 TC 13 Z9 13 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD MAY PY 2007 VL 16 IS 3 BP 371 EP 378 DI 10.1016/j.niox.2007.01.001 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 160GX UT WOS:000245930000008 PM 17306993 ER PT J AU Anderson, SA Frank, JA AF Anderson, Stasia A. Frank, Joseph A. TI MRI of mouse models of neurological disorders SO NMR IN BIOMEDICINE LA English DT Review DE MRI; mouse; brain; spinal cord; central nervous system diseases ID MAGNETIC-RESONANCE MICROSCOPY; FOCAL CEREBRAL-ISCHEMIA; STEM-CELL MIGRATION; SPINAL-CORD-INJURY; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; APPARENT DIFFUSION-COEFFICIENT; ALZHEIMERS AMYLOID PLAQUES; IN-VIVO MRI; TRANSGENIC MICE; HUNTINGTONS-DISEASE AB MRI has contributed to significant advances in the understanding of neurological diseases in humans. It has also been used to evaluate the spectrum of mouse models spanning from developmental abnormalities during embryogenesis, evaluation of transgenic and knockout models, through various neurological diseases such as stroke, tumors, degenerative and inflammatory diseases. The MRI techniques used clinically are technically more challenging in the mouse because of the size of the brain; however, mouse imaging provides researchers with the ability to explore cellular and molecular imaging that one day may translate into clinical practice. This article presents an overview of the use of MRI in mouse models of a variety of neurological disorders and a brief review of cellular imaging using magnetically tagged cells in the mouse central nervous system. Published in 2007 by John Wiley & Sons, Ltd. C1 NHLBI, Anim MRI Imaging Core, NIH, Bethesda, MD 20892 USA. NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP Anderson, SA (reprint author), NHLBI, Anim MRI Imaging Core, NIH, 10 Ctr Dr,Bldg 10,Room 2N240, Bethesda, MD 20892 USA. EM sanderso@helix.nih.gov FU Intramural NIH HHS NR 96 TC 15 Z9 15 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD MAY PY 2007 VL 20 IS 3 BP 200 EP 215 DI 10.1002/nbm.1167 PG 16 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 168XJ UT WOS:000246557000004 PM 17451184 ER PT J AU Nieman, BJ Bishop, J Dazai, J Bock, NA Lerch, JP Feintuch, A Chen, XJ Sled, JG Henkelman, RM AF Nieman, Brian J. Bishop, Jonathan Dazai, Jun Bock, Nicholas A. Lerch, Jason P. Feintuch, Akiva Chen, X. Josette Sled, John G. Henkelman, R. Mark TI MR technology for biological studies in mice SO NMR IN BIOMEDICINE LA English DT Review DE mouse imaging; multiple-mouse MRI; mouse phenotype ID SINGLE-NUCLEOTIDE POLYMORPHISMS; DEFICIT-HYPERACTIVITY DISORDER; AUTOMATED IMAGE REGISTRATION; MAGNETIZATION-TRANSFER MRI; MULTIPLE-MOUSE MRI; MYOCARDIAL-FUNCTION; ALZHEIMERS-DISEASE; TRANSGENIC MICE; HUNTINGTONS-DISEASE; CORPUS-CALLOSUM AB Mouse models are crucial for the study of genetic factors and processes that influence human disease. In addition to tools for measuring genetic expression and establishing genotype, tools to accurately and comparatively assess mouse phenotype are essential in order to characterize pathology and make comparisons with human disease. MRI provides a powerful means of evaluating various anatomical and functional changes and hence is growing in popularity as a phenotypic readout for biomedical research studies. To accommodate the large numbers of mice needed in most biological studies, mouse MRI must offer high-throughput image acquisition and efficient image analysis. This article reviews the technology of multiple-mouse MRI, a method that images multiple mice or specimens simultaneously as a means of enabling high-throughput studies. Aspects of image acquisition and computational analysis in multiple-mouse studies are also described. Copyright (C) 2007 John Wiley & Sons, Ltd. C1 Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Henkelman, RM (reprint author), Hosp Sick Children, Mouse Imaging Ctr, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM mhenkel@phenogenomics.ca RI Sled, John/D-8268-2012; Henkelman, Mark/F-3662-2011 OI Sled, John/0000-0002-4461-283X; NR 90 TC 27 Z9 27 U1 1 U2 10 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD MAY PY 2007 VL 20 IS 3 BP 291 EP 303 DI 10.1002/nbm.1142 PG 13 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 168XJ UT WOS:000246557000010 PM 17451169 ER PT J AU Jang, BS Lim, E Park, SH Shin, IS Danthi, N Hwang, IS Le, N Yu, S Xie, JW Li, KCP Carrasquillo, JA Paik, CH AF Jang, Beom-Su Lim, Esther Park, Seung Hee Shin, In Soo Danthi, Narasimhan Hwang, In Sook Le, Nhat Yu, Sarah Xie, Jianwu Li, King C. P. Carrasquillo, Jorge A. Paik, Chang H. TI Radiolabeled high affinity peptidomimetic antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in mice SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE peptidomimetic alpha(v)beta(3) antagonists; in-111 labels; alpha(v)beta(3)-mediated tumor uptake ID ARG-GLY-ASP; RGD PEPTIDE; RADIONUCLIDE THERAPY; RENAL UPTAKE; AMINO-ACIDS; EXPRESSION; ANGIOGENESIS; RADIOIMMUNOTHERAPY; CANCER; BIODISTRIBUTION AB Objectives: The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonists that selectively target integrin alpha(v)beta(3) receptor and clear rapidly from the whole body. Methods: Integrin alpha(v)beta(3) antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)etbyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-beta-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2-p-isothiocyanatobenzyl-DOTA at the amino terminus and labeled with In-111. The In-111 labeled IA and JAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts. Results: The In-111-labeled IA (40%) and -IAC (72%) specifically bound in vitro to 003 (0.8 mu M) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to alpha(v)beta(3). The higher receptor-binding affinity of the In-111-labeled IAC was reflected in higher tumor uptake and retention: 5.6 +/- 1.4 and 4.5 +/- 0.7 %ID/g vs. 3.8 +/- 0.9 and 2.0 +/- 0.3 %ID/g for the In-111-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 mu g of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The In-111 activity retained in the whole body was quite comparable between the In-111-labeled IA (24% ID) and the In-111-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the In-111-labeled IAC at 2 h with 9.7, 2.3, 0.8, 1.9, 7.1, 2.2, 0.9, 3.7 and 9.9 for blood, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively. The imaging studies with the In-111-labeled IAC also clearly visualized the receptor-positive tumor at 4 h. Conclusions: The In-111-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the alpha(v)beta(3) receptor-positive tumor. This together with the rapid whole-body clearance pharmacokinetics warrants further studies on this IAC analog for molecular imaging of tumor-induced angiogenic vessels and various malignant human tumors expressing the receptor. (c) 2007 Elsevier Inc. All rights reserved. C1 NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Paik, CH (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. EM cpaik@mail.nih.gov RI Carrasquillo, Jorge/E-7120-2010; Danthi, Simhan/B-7639-2014 NR 39 TC 15 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAY PY 2007 VL 34 IS 4 BP 363 EP 370 DI 10.1016/j.nucmedbio.2007.02.002 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 172AD UT WOS:000246775600003 PM 17499725 ER PT J AU Vuong, BK Kiesewetter, DO Lang, LX Ma, Y Eckelman, WC Channing, MA AF Vuong, Bik-Kee Kiesewetter, Dale O. Lang, Lixin Ma, Ying Eckelman, William C. Channing, Michael A. TI An automated one-step one-pot [F-18]FCWAY synthesis: development and minimization of chemical impurities SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE [F-18]FCWAY; 5-HT1A receptors; WAY 100635 analogue; automated synthesis; positron emission tomography radiopharmaccutical; chemical impurities ID 5-HT1A RECEPTOR-BINDING; TEMPORAL-LOBE EPILEPSY; RADIOSYNTHESIS; METABOLITES; ANTAGONIST; WAY-100635; DISORDER AB [F-18]FCWAY (N-{2-[4-(2-methoxyphenyl)piperazino]}-N-(2-pyridinyl)trans-4-fluorocyclohexanecarboxamide) has been prepared routinely as a serotonin 5-HT1A receptor ligand for clinical human studies. We have developed an automated one-step radiosynthesis using a modified Nuclear Interface C-11 Methylation System. The chemical synthesis of an appropriate methanesulfonate precursor for single-step nucleophilic substitution with [F-18]fluoride ion and the adaptation of radiochemical synthesis to an automated production module were accomplished. Following purification of a substrate using countercurrent chromatography, radiochemical yield increased from 18.9 +/- 0.3% to 21.9 +/- 2.2%. In addition, reduction of chemical impurities from about 40% to about 20% of total mass was observed. Further improvements in chemical purity were achieved by minimization of side reactions by modification of reaction conditions and optimization of the high-performance liquid chromatography method for the purification of the final radiopharmaceutical. Optimized automated synthesis produced [F-18]FCWAY in a radiochemical yield of 28 +/- 6% at a chemical purity of 99.3% based on the absorbance of FCWAY at 254 nm and with a specific activity of 3433 +/- 1015 mCi/mu mol at the end of bombardment, all calculated from the same 50 runs. (c) 2007 Elsevier Inc. All rights reserved. C1 Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. Mol Tracer LLC, Bethesda, MD 20892 USA. RP Vuong, BK (reprint author), Warren Grant Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. EM bv1u@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 15 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD MAY PY 2007 VL 34 IS 4 BP 433 EP 438 DI 10.1016/j.nucmedbio.2007.03.001 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 172AD UT WOS:000246775600011 PM 17499733 ER PT J AU Pursell, ZF Isoz, I Lundstrom, EB Johansson, E Kunkel, TA AF Pursell, Zachary F. Isoz, Isabelle Lundstrom, Else-Britt Johansson, Erik Kunkel, Thomas A. TI Regulation of B family DNA polymerase fidelity by a conserved active site residue: characterization of M644W, M644L and M644F mutants of yeast DNA polymerase epsilon SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SACCHAROMYCES-CEREVISIAE; REPLICATION FIDELITY; FRAMESHIFT MUTATIONS; MOTIF-A; S-PHASE; DELTA; ALPHA; REPAIR; IDENTIFICATION; ANTIMUTATOR AB To better understand the functions and fidelity of DNA polymerase e ( Pol e), we report here on the fidelity of yeast Pol e mutants with leucine, tryptophan or phenylalanine replacing Met644. The Met644 side chain interacts with an invariant tyrosine that contacts the sugar of the incoming dNTP. M644W and M644L Pol epsilon synthesize DNA with high fidelity, but M644F Pol epsilon has reduced fidelity resulting from strongly increased misinsertion rates. When Msh6dependent repair of replication errors is defective, the mutation rate of a pol2- M644F strain is 16- fold higher than that of a strain with wild- type Pol epsilon. In conjunction with earlier studies of low- fidelity mutants with replacements for the homologous amino acid in yeast Pol alpha ( L868M/ F) and Pol delta ( L612M), these data indicate that the active site location occupied by Met644 in Pol epsilon is a key determinant of replication fidelity by all three B family replicative polymerases. Interestingly, error specificity of M644F Pol epsilon is distinct from that of L868M/ F Pol alpha or L612M Pol delta, implying that each polymerase has different active site geometry, and suggesting that these polymerase alleles may generate distinctive mutational signatures for probing functions in vivo. C1 NIH, DHHS, NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIH, DHHS, NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Umea Univ, Dept Med Biochem & Biophys, S-90187 Umea, Sweden. RP Kunkel, TA (reprint author), NIH, DHHS, NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Pursell, Zachary/0000-0001-5871-7192 FU Intramural NIH HHS NR 40 TC 29 Z9 30 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY PY 2007 VL 35 IS 9 BP 3076 EP 3086 DI 10.1093/nar/gkm132 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 180GK UT WOS:000247350800025 PM 17452367 ER PT J AU Greene, E Mahishi, L Entezam, A Kumari, D Usdin, K AF Greene, Eriko Mahishi, Lata Entezam, Ali Kumari, Daman Usdin, Karen TI Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GAA TRIPLET REPEAT; DNA METHYLATION; IN-VIVO; TRANSCRIPTION; EXPRESSION; EXPANSION; ELONGATION; PROMOTER; ELEMENTS; RNA AB Friedreich ataxia (FRDA), the most common hereditary ataxia, is caused by mutations in the frataxin (FXN) gene. The vast majority of FRDA mutations involve expansion of a GAA circle TTC-repeat tract in intron 1, which leads to an FXN mRNA deficit. Bisulfite mapping demonstrates that the region adjacent to the repeat was methylated in both unaffected and affected individuals. However, methylation was more extensive in patients. Additionally, three residues were almost completely methylation-free in unaffected individuals but almost always methylated in those with FRDA. One of these residues is located within an E-box whose deletion caused a significant drop in promoter activity in reporter assays. Elevated levels of histone H3 dimethylated on lysine 9 were seen in FRDA cells consistent with a more repressive chromatin organization. Such chromatin is known to reduce transcription elongation. This may be one way in which the expanded repeats contribute to the frataxin deficit in FRDA. Our data also suggest that repeat-mediated chromatin changes may also affect transcription initiation by blocking binding of factors that increase frataxin promoter activity. Our results also raise the possibility that the repeat-mediated increases in DNA methylation in the FXN gene in FRDA patients are secondary to the chromatin changes. C1 NIDDK, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU Intramural NIH HHS NR 28 TC 107 Z9 107 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAY PY 2007 VL 35 IS 10 BP 3383 EP 3390 DI 10.1093/nar/gkm271 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186ZO UT WOS:000247817300020 PM 17478498 ER PT J AU Brock, KE Gridley, G Lynch, CF Ershow, AG Cantor, KP AF Brock, Kaye E. Gridley, Gloria Lynch, Charles F. Ershow, Abby G. Cantor, Kenneth P. TI Obesity and hypertension interact to increase risk of renal cell carcinoma in Iowa, USA SO OBESITY RESEARCH & CLINICAL PRACTICE LA English DT Article DE Renal cell carcinoma; Kidney epidemiology; Obesity; Hypertension; Interaction/effect modification AB Renal cell carcinoma (RCC) rates in the US have risen, along with those of obesity and hypertension. We investigated the interactive relationship with obesity and hypertension (HT) through a population-based case-control study of RCC in Iowa consisting of 406 cases and 2434 controls. Data on height and weight at various ages and history of HT were collected and interaction tested by log-likelihood ratio tests. After adjustment, both obesity and HT were independently and interactively associated with increased RCC risk. Hypertensive subjects, obese (BMI >= 30) at age 40 were 4.2 (CI: 2.38-6.53) times more likely to develop RCC as normotensive individuals of normal weight (BMI < 25). A similar interactive pattern was observed for obesity at age 60 (p=0.02). Interaction with obesity was more evident in women (p(interaction)=0.04 age 40, p(interaction)=0.01 age 60). Our findings suggest that maintaining body weight and/or controlling HT are strategies for preventing RCC. (c) 2007 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved. C1 [Brock, Kaye E.] Univ Sydney, Dept Behav & Community Hlth Sci, Fac Hlth Sci, Sydney, NSW 2006, Australia. [Gridley, Gloria; Cantor, Kenneth P.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Ershow, Abby G.] NHLBI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Brock, KE (reprint author), Univ Sydney, Dept Behav & Community Hlth Sci, Fac Hlth Sci, Sydney, NSW 2006, Australia. EM k.brock@fhs.usyd.edu.au FU Intramural Research Program of the NIH; National Cancer Institute, DCEG; The University of Sydney Sabbatical Program FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, DCEG and the University of Sydney Sabbatical Program for Dr. Kaye Brock. Thanks to David Check (USA) and Cristian Alegria (AUST) for technical support. NR 52 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1871-403X J9 OBES RES CLIN PRACT JI Obes. Res. Clin. Pract. PD MAY PY 2007 VL 1 IS 2 BP 147 EP 153 DI 10.1016/j.orcp.2007.02.004 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA V89RL UT WOS:000206061700009 ER PT J AU Brubaker, L Bradley, CS Handa, VL Richter, HE Visco, A Brown, MB Weber, AM AF Brubaker, Linda Bradley, Catherine S. Handa, Victoria L. Richter, Holly E. Visco, Anthony Brown, Morton B. Weber, Anne M. TI Anal sphincter laceration at vaginal delivery - Is this event coded accurately? SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID HOSPITAL DISCHARGE DATA; INTERNATIONAL-CLASSIFICATION; PERINEAL LACERATIONS; ADMINISTRATIVE DATA; CLAIMS DATA; COMPLICATIONS; DIAGNOSIS; REVISION AB OBJECTIVE: To determine the error rate for discharge coding of anal sphincter laceration at vaginal delivery in a cohort of primiparous women. METHODS: As part of the Childbirth and Pelvic Symptoms study performed by the National Institutes of Health Pelvic Floor Disorders Network, we assessed the relationship between perineal lacerations and corresponding discharge codes in three groups of primiparous women: 393 women with anal sphincter laceration after vaginal delivery, 383 without anal sphincter laceration after vaginal delivery, and 107 after cesarean delivery before labor. Discharge codes for perineal lacerations were compared with data abstracted directly from the medical record shortly after delivery. Patterns of coding and coding error rates were described. RESULTS: The coding error rate varied by delivery group. Of 393 women with clinically recognized and repaired anal sphincter lacerations by medical record documentation, 92 (23.4%) were coded incorrectly (four as first- or second-degree perineal laceration and 88 with no code for perineal diagnosis or procedure). One (0.3%) of the 383 women who delivered vaginally without clinically reported anal sphincter laceration was coded with a sphincter tear. No women in the cesarean delivery group had a perineal laceration diagnostic code. Coding errors were not related to the number of deliveries at each clinical site. CONCLUSION: Discharge coding errors are common after delivery-associated anal sphincter laceration, with omitted codes representing the largest source of errors. Before diagnostic coding can be used as a quality measure of obstetric care, the clinical events of interest must be appropriately defined and accurately coded. C1 Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. Johns Hopkins Univ, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. NICHHD, Bethesda, MD 20892 USA. RP Brubaker, L (reprint author), Loyola Univ Coll, 2160 S 1st Ave, Maywood, IL 60153 USA. EM Lbrubaker@lumc.edu FU NICHD NIH HHS [U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41267, U01 HD41249, U10 HD41268, U10 HD041261, U10 HD41269, U10 HD41248] NR 20 TC 9 Z9 9 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 MAY PY 2007 VL 109 IS 5 BP 1141 EP 1145 DI 10.1097/01.AOG.0000260958.94655.f2 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171YP UT WOS:000246771600020 PM 17470596 ER PT J AU Hoppin, JA Umbach, DM Kullman, GJ Henneberger, PK London, SJ Alavanja, MCR Sandler, DP AF Hoppin, Jane A. Umbach, David M. Kullman, Greg J. Henneberger, Paul K. London, Stephanie J. Alavanja, Michael C. R. Sandler, Dale P. TI Pesticides and other agricultural factors associated with self-reported farmer's lung among farm residents in the Agricultural Health Study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID MATCHED CONTROL FARMERS; HYPERSENSITIVITY PNEUMONITIS; FOLLOW-UP; EXPOSURE; MACROPHAGES; APPLICATORS; DISEASE; ASTHMA; RISK; SELECTION AB Background: Farmer's lung, or hypersensitivity pneumonitis, is an important contributor to respiratory morbidity among farmers. Methods: Using the 1993 - 7 enrolment data from the Agricultural Health Study, we conducted a cross-sectional study of occupational risk factors for farmer's lung among,50 000 farmers and farm spouses in Iowa and North Carolina using hierarchical logistic regression controlling for age, state, and smoking status. Participants provided information on agricultural exposures, demographic characteristics, and medical history via self- administered questionnaires. Approximately 2% of farmers (n = 481) and 0.2% of spouses (n = 51) reported doctor- diagnosed farmer's lung during their lifetime. We assessed farmers and spouses separately due to different information on occupational exposure history. Only pesticide exposures represented lifetime exposure history, all other farm exposures represented current activities at enrolment. Results: Among farmers, handling silage (OR = 1.41, 95% CI 1.10 to 1.82), high pesticide exposure events (OR = 1.75, 95% CI 1.39 to 2.21), and ever use of organochlorine (OR = 1.34, 95% CI 1.04 to 1.74) and carbamate pesticides (OR = 1.32, 95% CI 1.03 to 1.68) were associated with farmer's lung in mutually-adjusted models. The insecticides DDT, lindane, and aldicarb were positively associated with farmer's lung among farmers. Current animal exposures, while not statistically significant, were positively associated with farmer's lung, particularly for poultry houses (OR = 1.55, 95% CI 0.93 to 2.58) and dairy cattle (OR = 1.28, 95% CI 0.86 to 1.89). The occupational data were more limited for spouses; however, we saw similar associations for dairy cattle (OR = 1.50, 95% CI 0.72 to 3.14) and organochlorine pesticides (OR = 1.29, 95% CI 0.64 to 2.59). Conclusion: While historic farm exposures may contribute to the observed associations with pesticides, these results suggest that organochlorine and carbamate pesticides should be further evaluated as potential risk factors for farmer's lung. C1 NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIOSH, Div Resp Dis Studies, Ctr Dis Control & Prevent, Dept Hlth & Human Sci, Morgantown, WV USA. NCI, Occupat Epidemiol Branch, NIH, Dept Hlth & Human Sci, Rockville, MD USA. RP Hoppin, JA (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM hoppin1@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES049030-09] NR 40 TC 24 Z9 26 U1 1 U2 2 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 MAY PY 2007 VL 64 IS 5 BP 334 EP 342 DI 10.1136/oem.2006.028480 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 163MB UT WOS:000246162800007 PM 17182642 ER PT J AU Waldmann, TA AF Waldmann, T. A. TI Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma SO ONCOGENE LA English DT Review DE IL-2 receptor; adult T-cell leukemia; anti-Tac; monoclonal antibody ID T-CELL LEUKEMIA; ANTI-CD25 MONOCLONAL-ANTIBODY; IN-VIVO BLOCKADE; INTERLEUKIN-2 RECEPTOR; MURINE MODEL; TRANSPLANT RECIPIENTS; MULTIPLE-SCLEROSIS; HUMANIZED ANTIBODY; ACUTE REJECTION; GROWTH-FACTOR AB Daclizumab (Zenapax) identifies the alpha subunit of the interleukin-2 (IL-2) receptor and blocks the interaction of this cytokine with its growth factor receptor. The scientific basis for the choice of the IL-2 receptor alpha subunit as a target for monoclonal antibody-mediated therapy of leukemia/lymphoma is that very few normal cells express IL-2R alpha, whereas the abnormal T cells in patients with an array of lymphoid malignancies express this receptor. In 1997, daclizumab was approved by the FDA for use in the prevention of renal allograft rejection. In addition, anti-Tac provided effective therapy for select patients with T-cell malignancies and an array of inflammatory autoimmune disorders. Finally, therapy with this antibody armed with Y-90 has led to clinical responses in the majority of patients with adult T-cell leukemia. These insights concerning the IL-2/IL-2 receptor system facilitated the development of effective daclizumab antibody therapy for select patients with leukemia/lymphoma. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4N115,10 Ctr Dr 1374, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS NR 42 TC 44 Z9 46 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2007 VL 26 IS 25 BP 3699 EP 3703 DI 10.1038/sj.onc.1210368 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 172PK UT WOS:000246816100012 PM 17530023 ER PT J AU Kupferman, ME Patel, V Sriuranpong, V Amornphimoltham, P Jasser, SA Mandal, M Zhou, G Wang, J Coombes, K Multani, A Pathak, S Gutkind, JS Myers, JN AF Kupferman, Michael E. Patel, Vyomesh Sriuranpong, Virote Amornphimoltham, Panamwat Jasser, Samar A. Mandal, Mahitosh Zhou, Ge Wang, Jing Coombes, Kevin Multani, Asha Pathak, Sen Gutkind, J. Silvio Myers, Jeffrey N. TI Molecular analysis of anoikis resistance in oral cavity squamous cell carcinoma SO ORAL ONCOLOGY LA English DT Article DE oral cancer; anoikis; tongue; tumor progression; cytogenetics ID CORNIFIED ENVELOPE; APOPTOSIS; GROWTH; PROTEIN; CANCER; DEATH; IDENTIFICATION; SUPPRESSION; FAMILY AB Oral cavity squamous cell carcinoma (OSCC) is one of the leading causes of cancer deaths worldwide and most of these deaths result from local-regional recurrence and metastases. Evasion of apoptosis is an important hallmark of cancer development and progression, and previous studies have shown that evasion of anoikis, or detachment-induced apoptosis, correlates with a more aggressive phenotype of carcinoma cells in OSCC. To elucidate the cytogenetic and molecular characteristics of anoikis resistance, we generated several cell lines and clones that displayed this cellular phenotype. To test the hypothesis that chromosomal alterations may underlie this phenotypic transformation, we used karyotype analysis to observe changes in the chromosomal structure of anoikis-sensitive and anoikis-resistant cell tines. We further hypothesized that a unique pattern of gene expression was induced by cell-detachment of anoikis-resistant cell lines, and cDNA microarray analysis was performed using a panel of anoikis-resistant oral cancer cell lines grown under attached and detached growth conditions. We identified S100P, KLK6 and CTNNAL1 as genes whose expression levels were differentially regulated in the anoikis-resistant cell tines compared to the anoikis-sensitive cells under detached conditions. These results were verified using real-time RT-PCR. The anoikis-resistant phenotype of squamous cell carcinoma has a distinct genetic expression pattern that is marked by chromosomal alterations that may contribute to differential expression of genes involved in diverse cellular functions. Therapies targeting these potential mediators of anoikis resistance may prove to be beneficial in the treatment of metastatic squamous cell carcinoma. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Genet, Houston, TX 77030 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Myers, JN (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Surg, 1515 Holcombe Blvd,Unit 441, Houston, TX 77030 USA. EM jmyers@mdanderson.org RI Gutkind, J. Silvio/A-1053-2009 FU NIDCR NIH HHS [R01 DE014612-01] NR 29 TC 24 Z9 24 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD MAY PY 2007 VL 43 IS 5 BP 440 EP 454 DI 10.1016/j.oraloncology.2006.04.016 PG 15 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 168RN UT WOS:000246541800004 PM 16978912 ER PT J AU Galban, CJ Ling, SM Galban, CJ Taub, DD Gurkan, I Fishbein, KW Spencer, RG AF Galban, C. J. Ling, S. M. Galban, C. J. Taub, D. D. Gurkan, I. Fishbein, K. W. Spencer, R. G. TI Effects of knee injection on skeletal muscle metabolism and contractile force in rats SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE magnetic resonance spectroscopy; skeletal muscle; cartilage; cytokine ID MAGNETIC-RESONANCE-SPECTROSCOPY; OBSTRUCTIVE PULMONARY-DISEASE; VASTUS LATERALIS MUSCLE; EXERCISING HUMAN-MUSCLE; INFLAMMATORY MYOPATHIES; OSTEOARTHRITIS; PHOSPHOCREATINE; EXPRESSION; CYTOKINES; ATP AB Objective: We tested the hypothesis that intrusion of the knee joint capsule alters quadriceps muscle metabolism and function independently from the damage induced to knee cartilage. Methods: Adult rats were separated into four groups: intraarticular injections of saline (SAL; n = 9); intraarticular injections of papain, a model for osteoarthritis (PIA; n = 7); sham injections (SHAM; n = 8); and controls (CTL; n = 5). P-31 magnetic resonance spectroscopy (P-31-MRS) was performed after 2 weeks. Spectra were obtained from the left quadriceps: two at baseline, eight during electrical stimulation with simultaneous measurement of contractile force, and 15 during recovery. P-31-MRS data were presented as the ratio of inorganic phosphate (Pi) to phosphocreatine (PCr), concentrations of PCr [PCr], intramuscular pH, and the rates and time constants of PCr breakdown during stimulation and PCr recovery. Intramuscular cytokine concentrations were measured within the quadriceps. Histologic slides of the knees were scored for severity of cartilage damage. Results: The interventional groups produced values of Pi/PCr ratio, [PCr], contractile force and pH that were significantly different from CTL. These changes in muscle function were accompanied by higher concentrations of interleukin-1 observed with PIA and SAL. We did not observe any effect of cartilage damage on muscle function or metabolism. Conclusions: Knee joint intrusion alters quadriceps muscle metabolism with accelerated depletion of energy stores and fatigue during stimulation. This study demonstrates that needle intrusion into the knee joint results in muscle dysfunction, independently from the extent of cartilage damage. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. C1 NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. NIA, NMR Unit, Clin Invest Lab, IRP, Baltimore, MD 21224 USA. NIA, Immunol Lab, IRP, Baltimore, MD 21224 USA. Johns Hopkins Univ, Inst Med, Dept Orthoped Surg, Baltimore, MD USA. RP Galban, CJ (reprint author), NIH, Div Bioengn & Phys Sci, Off Res Serv, Bldg 13,Room 2N05 MSC 5766, Bethesda, MD 20892 USA. EM galbanc@ors.od.nih.gov OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS NR 40 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD MAY PY 2007 VL 15 IS 5 BP 550 EP 558 DI 10.1016/j.joca.2006.10.007 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 171SC UT WOS:000246754700009 PM 17157038 ER PT J AU Romano-Riquera, SP Hernandez-Avila, M Gladen, BC Cupul-Uicab, LA Longnecker, MP AF Romano-Riquera, S. Patricia Hernandez-Avila, Mauricio Gladen, Beth C. Cupul-Uicab, Lea A. Longnecker, Matthew P. TI Reliability and determinants of anogenital distance and penis dimensions in male newborns from Chiapas, Mexico SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE anogenital distance; length of penis; width of penis; birthweight; gestational age; reliability; fetal androgen; reliability ID BODY-FAT DISTRIBUTION; MALE INFANTS; MALE-RAT; PHTHALATE; GENITALIA; EXPOSURE; GROWTH AB Development of the perineum as well as the external genitalia is determined by dihydrotestosterone, resulting in a greater anogenital distance (AGD) in males than females. In animal experiments with hormonally active agents, anogenital distance is used as a bioassay of fetal androgen action. Use of anogenital distance in human studies has been rare. Because anogenital distance has been an easy-to-measure, sensitive outcome in animal studies, we developed an anthropometric protocol for measurement of anogenital distance in human males. In this paper we describe the method for measurement of three anogenital distances, their reliability, and an assessment of predictors for each in the context of an epidemiological study. We compare the reliabilities and predictors to those for stretched penis length and penis width. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-03 in Chiapas, Mexico. Replicate measures were obtained on nearly all subjects. The reliability of the measures of anogenital distance (0.82-0.91) were higher than for stretched penis length (0.78) and width (0.75). Birthweight and gestational length were more strongly related to anogenital distance than to penis length. Anogenital distance was not related to penis length (r = 0.03). Our large study clearly shows that AGD can be measured well in newborn males, and that the measurements were more reliable than those of penis length. Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiological studies. C1 NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. RP Longnecker, MP (reprint author), NIEHS, NIH, US Dept HHS, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM longnec1@niehs.nih.gov RI CUPUL UICAB, LEA/C-8699-2014; OI CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS [Z01 ES044009-07]; NIEHS NIH HHS [N01-ES-15468] NR 24 TC 27 Z9 29 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2007 VL 21 IS 3 BP 219 EP 228 DI 10.1111/j.1365-3016.2007.00810.x PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 156UT UT WOS:000245676100004 PM 17439530 ER PT J AU Murray, KD El-Mohandes, AAE El-Khorazaty, MN Kiely, M AF Murray, Kennan D. El-Mohandes, Ayman A. E. El-Khorazaty, M. Nabil Kiely, Michele TI Low-income minority mothers' reports of infant health care utilisation compared with medical records SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE immunisation; health care; maternal recall; medical records; recall bias ID PROXY RESPONDENTS; URBAN-POPULATION; SELF-REPORT; ACCURACY; GUIDELINES; SERVICES; VALIDITY; EMERGENCY; CHILDREN; INTERVENTION AB This study aimed to investigate mothers' reporting of the nature, location, frequency and content of health care visits for their infants, as compared with data abstracted from the infants' medical records. It was part of a community-based parenting intervention designed to improve preventive health care utilisation among minority mothers in Washington, DC. Mothers >= 18 years old with newborn infants and with poor or no prenatal care were enrolled in the study. A total of 160 mother-infant dyads completed the 12-month study. Mothers were interviewed when the infants were 4, 8 and 12 months old, and were asked to recall infant visits to all health care providers. Medical records from identified providers were used for verification. The number and type of immunisations given, types of providers visited, and reason for the visits were compared. Only about a quarter of mothers agreed with their infants' medical records on the number of specific immunisations received. The mothers reported fewer polio (1.8 vs. 2.1, P = 0.006), diphtheria and tetanus toxoids and pertussis (DTP) (1.8 vs. 2.2, P = 0.002), and Haemophilus influenzae type b (HiB) (1.3 vs. 2.1, P < 0.0001) immunisations than were recorded. Similarly, about a quarter of the mothers were unaware of any polio, DTP or hepatitis B immunisations given, as documented in the medical records, and 38% did not know that their infant was immunised for HiB. Nearly half of the mothers recalled more infant doctors' visits than were recorded in the medical records (4.1 vs. 3.6 visits, P = 0.017). The mothers generally disagreed with the providers about the reason for a particular visit and reported fewer sick-baby visits (1.5 vs. 3.3, P < 0.0001) than the providers recorded. Mothers' reports and medical records matched in only 19% of the cases. In 47%, mothers under-reported and in 34% over-reported the total number of visits. The strongest agreement between mothers' reports and medical records was in the case of emergency room visits (63%). In conclusion, in this population, mothers' reporting did not match that of providers with respect to specific information: the number of immunisations, the location where services were provided, and the classification of sick- vs. well-baby visits. Future studies that evaluate health care utilisation data should take these discrepancies into consideration in their selection of information source, and in their interpretation of the data. C1 George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Prevent & Community Hlth, Washington, DC 20037 USA. RTI Int, Stat & Epidmeiol Unit, Rockville, MD USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Rockville, MD USA. RP El-Mohandes, AAE (reprint author), George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Prevent & Community Hlth, 2175 K St NW, Washington, DC 20037 USA. EM sphaxe@gwumc.edu FU NICHD NIH HHS [U18-HD30445, U18-HD30454, U18-HD31919, U18-HD30458, U18-HD31206, U18-HD30450, U18-HD30447] NR 31 TC 2 Z9 2 U1 2 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2007 VL 21 IS 3 BP 274 EP 283 DI 10.1111/j.1365-3016.2007.00800.x PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 156UT UT WOS:000245676100010 PM 17439537 ER PT J AU Nicholson, CE AF Nicholson, Carol E. TI Critical pertussis may model organ failure in critical illness and injury SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Editorial Material DE organ failure; G proteins; immunophenotyping ID BORDETELLA-PERTUSSIS; CYTOKINE PRODUCTION; TH1 CELLS; TOXIN; EXPRESSION; INFECTION; CHILDREN; IMMUNITY; ANTIGEN C1 NICHD, NIH, NCMRR, Bethesda, MD 20892 USA. RP Nicholson, CE (reprint author), NICHD, NIH, NCMRR, Bethesda, MD 20892 USA. NR 21 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD MAY PY 2007 VL 8 IS 3 BP 288 EP 289 DI 10.1097/01.PCC.0000265500.59962.B8 PG 2 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 171DE UT WOS:000246714300017 PM 17496512 ER PT J AU Woroniecki, RP Kopp, JB AF Woroniecki, Robert P. Kopp, Jeffrey B. TI Genetics of focal segmental glomerulosclerosis SO PEDIATRIC NEPHROLOGY LA English DT Article DE gene mutations; filtration barrier; linkage analysis; positional cloning ID CONGENITAL NEPHROTIC SYNDROME; GLOMERULAR SLIT DIAPHRAGM; NPHS2 MUTATIONS; WILMS-TUMOR; CD2-ASSOCIATED PROTEIN; RENAL-DISEASE; NEPHRIN GENE; FINNISH TYPE; PODOCIN; ALPHA-ACTININ-4 AB The recent advances in understanding the pathophysiology of focal segmental glomerulosclerosis (FSGS) and molecular function of glomerular filtration barrier come directly from genetic linkage and positional cloning studies. The exact role and function of the newly discovered genes and proteins are being investigated by in vitro and in vivo mechanistic studies. Those genes and proteins interactions seem to change susceptibility to kidney disease progression. Better understanding of their exact role in the development of FSGS may influence future therapies and outcomes in this complex disease. C1 Childrens Hosp, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NIDDKD, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Woroniecki, RP (reprint author), Childrens Hosp, 111 E 210th St, Bronx, NY 10467 USA. EM rworonie@aecom.yu.edu OI Woroniecki, Robert/0000-0002-5578-4514; Kopp, Jeffrey/0000-0001-9052-186X NR 47 TC 14 Z9 18 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD MAY PY 2007 VL 22 IS 5 BP 638 EP 644 DI 10.1007/s00467-007-0445-y PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 162HI UT WOS:000246077100003 PM 17347836 ER PT J AU Hartman, AL Gasior, M Vining, EPG Rogawski, MA AF Hartman, Adam L. Gasior, Maciej Vining, Eileen P. G. Rogawski, Michael A. TI The neuropharmacology of the ketogenic diet SO PEDIATRIC NEUROLOGY LA English DT Review ID EXCITATORY AMINO-ACIDS; GAMMA-VINYL GABA; ANTIEPILEPTIC DRUGS; KETONE-BODIES; IN-VIVO; ANTICONVULSANT PROPERTIES; ELECTROCONVULSIVE THRESHOLD; EXPERIMENTAL SEIZURES; GLUTAMATE METABOLISM; MAXIMAL ELECTROSHOCK AB The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease. (C) 2007 by Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ Hosp, John M Freeman Pediat Epilepsy Ctr, Baltimore, MD 21287 USA. NINDS, Epilepsy Res Stn, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. Univ Calif Davis, Sch Med, Dept Neurol, Sacramento, CA 95817 USA. RP Hartman, AL (reprint author), Johns Hopkins Med Inst, John M Freeman Pediat Epilepsy Ctr, 600 N Wolfe St,Meyer 2-147, Baltimore, MD 21287 USA. EM ahartma2@jhmi.edu RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU Intramural NIH HHS [Z01 NS002877-13] NR 108 TC 124 Z9 126 U1 1 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAY PY 2007 VL 36 IS 5 BP 281 EP 292 DI 10.1016/j.pediatrneurol.2007.02.008 PG 12 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 172SM UT WOS:000246824400001 PM 17509459 ER PT J AU Babovic-Vuksanovic, D Widemann, BC Dombi, E Gillespie, A Wolters, PL Toledo-Tamula, MA O'Neill, BP Fox, E MacDonald, T Beck, H Packer, RJ AF Babovic-Vuksanovic, Dusica Widemann, Brigitte C. Dombi, Eva Gillespie, Andrea Wolters, Pamela L. Toledo-Tamula, Mary Anne O'Neill, Brian P. Fox, Elizabeth MacDonald, Tobey Beck, Heather Packer, Roger J. TI Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas SO PEDIATRIC NEUROLOGY LA English DT Article ID TYPE-1 AB We aimed to define the dose of pirfenidone in children and adolescents with neurofibromatosis 1 and plexiform neurofibromas that is pharmacokinetically comparable to the active adult dose. Pirfenidone was administered orally on a continuous dosing schedule. The starting dose level was 250 mg/m(2)/dose. The second dose level (500 mg/m2/dose) corresponded to the adult dose that previously showed activity in sclerosing conditions. A dose was considered pharmacokinetically comparable if the drug exposure in children was < 1 standard deviation below the drug exposure in adults treated with 800 mg three times a day. Pharmacokinetic sampling was performed for 24 hours after the first dose. Response to treatment was evaluated using automated volumetric magnetic resonance imaging analysis; quality of life was evaluated using the Impact of Pediatric Illness Scale. Sixteen patients were entered and evaluated for toxicity. Dose-limiting toxicities were observed in 2 of 12 patients receiving 500 mg/m(2) three times a day. The plasma pharmacokinetics of pirfenidone were highly variable, but not age dependent. The second dose level was the pharmacokinetically comparable dose and is being used in an ongoing phase II trial of pirfenidone for children with neurofibromatosis I and progressive plexiform neurofibroma. (C) 2007 by Elsevier Inc. All rights reserved. C1 Mayo Coll Med, Dept Med Genet, Rochester, MN USA. Mayo Coll Med, Dept Neurol, Rochester, MN USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Med Illness Counseling Ctr, Chevy Chase, MD USA. Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. RP Babovic-Vuksanovic, D (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM dbabovic@mayo.edu RI MacDonald, Tobey/D-4554-2013 FU Intramural NIH HHS NR 17 TC 39 Z9 40 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD MAY PY 2007 VL 36 IS 5 BP 293 EP 300 DI 10.1016/j.pediatrneurol.2007.01.009 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 172SM UT WOS:000246824400002 PM 17509460 ER PT J AU Salem, N AF Salem, Norman, Jr. TI What is the right level of DHA in the infant diet? Commentary on article by Hsieh et al. on page 537 SO PEDIATRIC RESEARCH LA English DT Editorial Material ID DOCOSAHEXAENOIC ACID; SUPPLEMENTATION; SURVIVAL C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Salem, N (reprint author), 5625 Fishers Lane,Room 3N-07, Bethesda, MD 20892 USA. EM nsalem@niaaa.nih.gov FU Intramural NIH HHS NR 15 TC 1 Z9 1 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAY PY 2007 VL 61 IS 5 BP 518 EP 519 DI 10.1203/pdr.0b013e318057fa93 PN 1 PG 2 WC Pediatrics SC Pediatrics GA 161HJ UT WOS:000246005100002 PM 17413853 ER PT J AU Walsh, M Laptook, A Kazzi, SN Engle, WA Yao, Q Rasmussen, M Buchter, S Heldt, G Rhine, W Higgins, R Poole, K AF Walsh, Michele Laptook, Abbott Kazzi, S. Nadya Engle, William A. Yao, Qing Rasmussen, Maynard Buchter, Susie Heldt, Gregory Rhine, William Higgins, Rose Poole, Kenneth CA Natl Inst of Child Hlth TI A cluster-randomized trial of benchmarking and multimodal quality improvement to improve rates of survival free of bronchopulmonary dysplasia for infants with birth weights of less than 1250 grams SO PEDIATRICS LA English DT Article DE quality improvement; randomized trial; bronchopulmonary dysplasia ID ACUTE MYOCARDIAL-INFARCTION; CHRONIC LUNG-DISEASE; PRETERM INFANTS; OINTMENT THERAPY; INTENSIVE-CARE; OUTCOMES; PERFORMANCE; STRATEGIES; MANAGEMENT; MORTALITY AB OBJECTIVE. We tested whether NICU teams trained in benchmarking and quality improvement would change practices and improve rates of survival without bronchopulmonary dysplasia in inborn neonates with birth weights of < 1250 g. METHODS. A cluster-randomized trial enrolled 4093 inborn neonates with birth weights of < 1250 g at 17 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Three centers were selected as best performers, and the remaining 14 centers were randomized to intervention or control. Changes in rates of survival free of bronchopulmonary dysplasia were compared between study year 1 and year 3. RESULTS. Intervention centers implemented potentially better practices successfully; changes included reduced oxygen saturation targets and reduced exposure to mechanical ventilation. Five of 7 intervention centers and 2 of 7 control centers implemented use of high-saturation alarms to reduce oxygen exposure. Lower oxygen saturation targets reduced oxygen levels in the first week of life. Despite these changes, rates of survival free of bronchopulmonary dysplasia were all similar between intervention and control groups and remained significantly less than the rate achieved in the best-performing centers (73.3%). CONCLUSIONS. In this cluster-randomized trial, benchmarking and multimodal quality improvement changed practices but did not reduce bronchopulmonary dysplasia rates. C1 Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02912 USA. Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. Indiana Univ, Riley Hosp Children, Dept Pediat, Indianapolis, IN 46204 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Univ Calif San Diego, Sharp Mary Birch Hosp, Dept Pediat, San Diego, CA 92103 USA. Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Stanford Univ, Lucille Packard Childrens Hosp, Dept Pediat, Palo Alto, CA 94304 USA. Natl Inst Child Hlth & Human Dev, Rockville, MD USA. RP Walsh, M (reprint author), Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, 11100 Euclid Ave,Mailstop 6010, Cleveland, OH 44106 USA. EM michele.walsh@cwru.edu FU NCRR NIH HHS [M01 RR00070, M01 RR00750, M01 RR00997, M01 RR01032, M01 RR02172, M01 RR02635, M01 RR06022, M01 RR08084]; NICHD NIH HHS [U10 HD21373, U01 HD36790, U10 HD21364, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34167, U10 HD34216] NR 54 TC 62 Z9 62 U1 2 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAY PY 2007 VL 119 IS 5 BP 876 EP 890 DI 10.1542/peds.2006-2656 PG 15 WC Pediatrics SC Pediatrics GA 163IM UT WOS:000246153300002 PM 17473087 ER PT J AU Freeman, AF Collura-Burke, CJ Patronas, NJ Ilcus, LS Darnell, D Davis, J Puck, JM Holland, SM AF Freeman, Alexandra F. Collura-Burke, Christina J. Patronas, Nicholas J. Ilcus, Lidia Stana Darnell, Dirk Davis, Joie Puck, Jennifer M. Holland, Steven M. TI Brain abnormalities in patients with hyperimmunoglobulin E syndrome SO PEDIATRICS LA English DT Article DE immunodeficiency; lacunar infarction; brain imaging; Chiari malformation; hyperintensities ID HYPER-IGE-SYNDROME; WHITE-MATTER; NEUROFIBROMATOSIS TYPE-1; CARDIOVASCULAR HEALTH; ELDERLY-PEOPLE; DISEASE; EVOLUTION; CHILDREN AB OBJECTIVES. Hyperimmunoglobulin E syndrome is a multisystem disorder with abnormalities of the immunologic, connective tissue, and skeletal tissue systems. Central nervous system abnormalities have not been considered a feature of hyperimmunoglobulin E syndrome. We aimed to determine whether central nervous system abnormalities detected on brain MRI exist in hyperimmunoglobulin E syndrome and to characterize any identified abnormalities. PATIENTS AND METHODS. Fifty patients aged from 3 to 52 years ( mean: 24 years) with established diagnoses of hyperimmunoglobulin E syndrome had MRI of the brain as part of an hyperimmunoglobulin E syndrome natural history protocol. Abnormalities were described, measured, counted, and mapped. Patient charts were reviewed for neurologic findings and blood pressure measurements. RESULTS. Focal brain lesions exhibiting high signal intensities on flow-attenuated inversion recovery and on T2-weighted techniques were found in 35 of the 50 patients. The focal hyperintensities were predominantly in the white matter of the cerebral hemispheres, and the number ranged from 2 to > 50. The hyperintensities occurred more frequently in adults than in children, and no association with elevated blood pressure was found. Five patients had lacunar infarctions. Chiari type 1 malformations were found in 9 of 50 patients. Two patients had infectious complications presenting on MRI as cerebritis in 1 patient and as a hemorrhagic infarct in the other; both were found on autopsy to be fungal. Neurologic abnormalities were present in 1 patient with a lacunar infarction, the 2 patients with infectious complications, and in 1 patient with a subarachnoid hemorrhage secondary to a berry aneurysm. CONCLUSIONS. Central nervous system abnormalities are common in hyperimmunoglobulin E syndrome. Focal T2 hyperintensities, not appreciated previously, represent a prominent feature of this rare disease that may assist in diagnosis. The etiology and clinical implications of these abnormalities remain to be investigated. C1 Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NIH, Clin Ctr, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), Bldg 10,CRC B3-4141,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural NIH HHS NR 20 TC 34 Z9 37 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAY PY 2007 VL 119 IS 5 BP E1121 EP E1125 DI 10.1542/peds.2006-2649 PG 5 WC Pediatrics SC Pediatrics GA 163IM UT WOS:000246153300054 PM 17438082 ER PT J AU Johnson, KJ Spector, LG Klebanoff, MA Ross, JA AF Johnson, Kimberly J. Spector, Logan G. Klebanoff, Mark A. Ross, Julie A. TI Childhood cancer and birthmarks in the collaborative perinatal project SO PEDIATRICS LA English DT Article DE birthmarks; childhood cancer; etiology; risk factors ID BECKWITH-WIEDEMANN-SYNDROME; LYMPHOBLASTIC-LEUKEMIA; INCREASED PREVALENCE; MINOR ANOMALIES; MILD ERRORS; II GENE; CHILDREN; RISK; MORPHOGENESIS; ANGIOGENESIS AB OBJECTIVE. Three previous retrospective studies noted a positive association between birthmarks and childhood cancer. The objective of this study was to determine whether the incidence of cancer is increased in children with birthmarks relative to those without birthmarks using data from the Collaborative Perinatal Project cohort, a large, prospective study. METHODS. Our study population comprised 49 503 US children who were born between 1959 and 1968. Birthmarks were documented as definite or suspected during the first year through history or medical examinations and included hemangiomas (port-wine, strawberry, or cavernous), pigmented nevi, lymphangiomas, and cafe-au-lait spots. The association between birthmarks and childhood cancer was determined using Cox proportional hazards regression. RESULTS. In the Collaborative Perinatal Project, 2505 individuals had a documented definite or suspected birthmark, including 7 of 47 children who developed cancer. Birthmarks were associated with a significant increase in the risk for cancer. There was a slight attenuation of the risk estimate when cases that were diagnosed in the first year of life were excluded. No specific childhood malignancies were notably affected by birthmarks. CONCLUSIONS. Although this study was based on a small number of cases, we found birthmarks to be in excess in children who received a diagnosis of cancer using prospective data. These findings provide additional support for the possibility of a shared etiology between birthmarks and childhood cancer that could offer insight into the pathogenesis of pediatric malignancy. C1 Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Ross, JA (reprint author), Univ Minnesota, Dept Pediat, 420 Delaware St SE,MMC 422, Minneapolis, MN 55455 USA. EM ross@epi.umn.edu OI Spector, Logan/0000-0003-2516-0222 NR 34 TC 5 Z9 5 U1 0 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAY PY 2007 VL 119 IS 5 BP E1088 EP E1093 DI 10.1542/peds.2006-2315 PG 6 WC Pediatrics SC Pediatrics GA 163IM UT WOS:000246153300050 PM 17473081 ER PT J AU Limdi, NA Goldstein, JA Blaisdell, JA Beasley, TM Rivers, CA Acton, RT AF Limdi, Nita A. Goldstein, J. A. Blaisdell, J. A. Beasley, T. M. Rivers, C. A. Acton, R. T. TI Influence of CYP2C9 genotype on warfarin dose among African-Americans and European-Americans SO PERSONALIZED MEDICINE LA English DT Article DE African-American; CYP2C9; European-American; pyrosequencing; warfarin dose ID ADVERSE DRUG-REACTIONS; CYTOCHROME P4502C9; IN-VIVO; FUNCTIONAL-CHARACTERIZATION; ANTICOAGULATION STATUS; GENETIC POLYMORPHISMS; MOLECULAR-BASIS; UNITED-STATES; THERAPY; SENSITIVITY AB Background: Cytochrome P450 (CYP)2C9 plays a vital role in drug metabolism. There has been an increased effort to identify polymorphisms within the gene and to determine their clinical consequences. However, most of these efforts have focused on populations of European descent. Herein we report the influence of CYP2C9 genotype on warfarin dose among European-American and African-American patients. We also identify two new mutations, one in the coding region and one in the noncoding region of the CYP2C9 gene. Methods: Patients (aged >20 years) were enrolled after obtaining medical, lifestyle and concomitant medication history. Changes in international normalized ratio, warfarin dose, co-medications, diet, physical activity and the occurrence of complications were documented. CYP2C9 genotype was determined using PCR with restriction fragment length polymorphisms, and pyrosequencing. Differences in genotype frequencies and Hardy-Weinberg equilibrium assumptions were assessed using chi(2) statistics and exact tests. The genotype-dose association was evaluated using multivariable linear regression. Results: This report includes 490 patients (mean age: 60.6 +/- 15.6 years; 51.3% men). African-American patients comprised 48.9% of the cohort, with a mean follow-up of 13.5 (+/- 10.6) months. Both the CYP2C9*2 and *3 allele were more frequent in European-Americans (11.24 and 5.1%, respectively) compared with African-Americans (1.1 and 1.8%). CYP2C9*5 (0.9%), *6 (0.4%) and *11 (1.1%) variants were only observed in African-Americans. The variant genotype is more frequent among European-Americans compared with African-Americans (29.8 vs 9.73%; p < 0.0001). Warfarin dose was significantly related to CYP2C9 genotype (p < 0.0001), both in univariate and multivariate analyses. Multivariable race-specific analyses highlight the contribution of CYP2C9 genotype among European-American but not among African-American patients. Conclusion: The variant CYP2C9 genotype is more frequent among European-Americans compared with African-Americans. Among African-Americans the variant genotype frequency is higher than previously reported. CYP2C9 genotype predicts warfarin dose in European-Americans, but not in African-Americans. C1 Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. Univ Alabama, NIEHS, Birmingham, AL USA. Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Genet, Birmingham, AL 35294 USA. Univ Alabama, Dept Epidemiol & Int Hlth, Birmingham, AL 35294 USA. RP Limdi, NA (reprint author), Univ Alabama, Dept Neurol, 1719 6th Ave S,CICR-312, Birmingham, AL 35294 USA. EM nlimdi@uab.edu RI Goldstein, Joyce/A-6681-2012 FU NINDS NIH HHS [K23 NS045598, K23 NS045598-03] NR 50 TC 33 Z9 34 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD MAY PY 2007 VL 4 IS 2 BP 157 EP 169 DI 10.2217/17410541.4.2.157 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 178VZ UT WOS:000247249500009 PM 19802360 ER PT J AU Chaurasia, CS Muller, M Bashaw, ED Benfeldt, E Bolinder, J Bullock, R Bungay, PM DeLange, ECM Derendorf, H Elmquist, WF Hammarlund-Udenaes, M Joukhadar, C Kellogg, DL Lunte, CE Nordstrom, CH Rollema, H Sawchuk, RJ Cheung, BWY Shah, VP Stahle, L Ungerstedt, U Welty, DF Yeo, H AF Chaurasia, Chandra S. Mueller, Markus Bashaw, Edward D. Benfeldt, Eva Bolinder, Jan Bullock, Ross Bungay, Peter M. DeLange, Elizabeth C. M. Derendorf, Hartmut Elmquist, William F. Hammarlund-Udenaes, Margareta Joukhadar, Christian Kellogg, Dean L., Jr. Lunte, Craig E. Nordstrom, Carl Henrik Rollema, Hans Sawchuk, Ronald J. Cheung, Belinda W. Y. Shah, Vinod P. Stahle, Lars Ungerstedt, Urban Welty, Devin F. Yeo, Helen TI AAPS-FDA workshop white paper: Microdialysis principles, application and regulatory perspectives SO PHARMACEUTICAL RESEARCH LA English DT Article DE clinical pharmacology; microdialysis; recovery; regulatory aspects ID IN-VIVO MICRODIALYSIS; BLOOD-BRAIN-BARRIER; ZERO-NET-FLUX; CEREBROSPINAL-FLUID; DIABETIC-PATIENTS; SKELETAL-MUSCLE; DRUG-DELIVERY; PHARMACOKINETICS; TRANSPORT; DOPAMINE AB Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (mu D) is the only tool available that explicitly provides data on the extracellular space. Although mu D as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of mu D in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of mu D in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on mu D as a tool in drug research and development. C1 US FDA, Off Gener Drugs, Div Bioequivalence, Rockville, MD 20857 USA. Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria. US FDA, Off Clin Pharmacol, Div Clin Pharmacol 3, Silver Spring, MD USA. Univ Copenhagen, Dept Dermatol, Copenhagen, Denmark. Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Stockholm, Sweden. Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. Off Res Serv, Div Bioengn & Phys Sci, NIH, Bethesda, MD USA. LACDR, Leiden, Netherlands. Univ Florida, Dept Pharmaceut, Gainesville, FL USA. Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. Univ Hosp, Dept Neurosurg, Lund, Sweden. Pfizer Global Res, Dept Neurosci, Groton, CT USA. Pharmaceut Federat, N Potomac, MD USA. Astra Zeneca, Sodertalje, Sweden. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. Allergan Pharmaceut Inc, Irvine, CA USA. Dept Drug Metab & Pharmacokinet, Palo Alto, CA USA. RP Chaurasia, CS (reprint author), US FDA, Off Gener Drugs, Div Bioequivalence, Rockville, MD 20857 USA. EM chandra.chaurasia@fda.hhs.gov RI Derendorf, Hartmut/B-4628-2012 OI Derendorf, Hartmut/0000-0003-4016-1370 NR 63 TC 110 Z9 116 U1 2 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES JI Pharm. Res. PD MAY PY 2007 VL 24 IS 5 BP 1014 EP 1025 DI 10.1007/s11095-006-9206-z PG 12 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 162TL UT WOS:000246112300019 PM 17458685 ER PT J AU Lee, CR North, KE Bray, MS Couper, DJ Heiss, G Zeldin, DC AF Lee, Craig R. North, Kari E. Bray, Molly S. Couper, David J. Heiss, Gerardo Zeldin, Darryl C. TI CYP2J2 and CYP2C8 polymorphisms and coronary heart disease risk: the Atherosclerosis Risk in Communities (ARIC) study SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE cigarette smoking; coronary heart disease; CYP2J2; CYP2C8; polymorphism ID EPOXYGENASE-DERIVED EICOSANOIDS; EPOXYEICOSATRIENOIC ACIDS; MYOCARDIAL-INFARCTION; ARACHIDONIC-ACID; GENOTYPE; GENE; IDENTIFICATION; METABOLISM; PACLITAXEL; SYNTHASE AB Objective The cytochromes P450 epoxygenases CYP2J2 and CYP2C8 synthesize epoxyeicosatrienoic acids, which regulate endothelial function. We sought to determine if genetic variation in CYP2J2 and CYP2C8 was associated with coronary heart disease risk. Methods We genotyped 2065 Atherosclerosis Risk in Communities study participants (1085 incident coronary heart disease cases, 980 noncases) for polymorphisms in CYP2J2 and CYP2C8. Using a case-cohort design, associations between genotype and incident coronary heart disease risk were evaluated using proportional hazards regression. The influence of cigarette smoking on these associations was also evaluated. False discovery rate q-values were estimated to minimize the impact of the multiple statistical comparisons completed. All analyses were race stratified. Results The CYP2J2 G-50T polymorphism variant -50T allele was associated with significantly lower risk of incident coronary heart disease in African-Americans (adjusted hazard rate ratio 0.58, 95% confidence interval 0.35-0.96, P = 0.036, q = 0.051); however, no significant association was observed in Caucasians. Overall, the 1264M, 1269F, and K399R polymorphisms in CYP2C8 were not significantly associated with risk of incident coronary heart disease. In Caucasians, the relationship between the 1264M and K399R polymorphisms and incident coronary heart disease risk was significantly modified by cigarettesmoking status (P for interaction= 0.008, q=0.064), with the highest risk observed in smokers carrying at least one variant allele. Conclusions The G-50Tpolymorphism in CYP2J2 may be an important risk factor for the development of coronary heart disease events in African -Americans, whereas cigarette smoking may modify the relationship between the 1264M and K399R polymorphisms in CYP2C8 and coronary heart disease risk in Caucasians. Confirmation of these findings in an independent population is warranted. Pharmacogenetics and Genomics 17:349-358 (c) 2007 Lippincott Williams & Wilkins. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Sch Pharm, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Lee, Craig/0000-0003-3595-5301 FU Intramural NIH HHS [Z01 ES025034-13]; NHLBI NIH HHS [HL 073366, N01 HC 55015, N01 HC 55016, N01 HC 55018, N01 HC 55019, N01 HC 55020, N01 HC 55021, N01 HC 55022, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, R01 HL073366]; NIEHS NIH HHS [ES 012856, F32 ES012856, F32 ES012856-01, F32 ES012856-02, F32 ES012856-03] NR 39 TC 50 Z9 53 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD MAY PY 2007 VL 17 IS 5 BP 349 EP 358 DI 10.1097/FPC.0b013e32809913ea PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 160SL UT WOS:000245962500006 PM 17429317 ER PT J AU Fostel, JM AF Fostel, Jennifer M. TI Future of toxicogenomics and safety signatures: balancing public access to data with proprietary drug discovery SO PHARMACOGENOMICS LA English DT Editorial Material ID HEPATIC GENE-EXPRESSION; MICROARRAY DATA; RISK-ASSESSMENT; TOXICITY; IDENTIFICATION; CHEMOGENOMICS; MECHANISMS; PROFILES; PLATFORM; MARKERS C1 NIEHS, US Natl Ctr Toxicogenom, LMIT ITSS Contract, Res Triangle Pk, NC 27709 USA. RP Fostel, JM (reprint author), NIEHS, US Natl Ctr Toxicogenom, LMIT ITSS Contract, F1-05,111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM fostel@niehs.nih.gov FU Intramural NIH HHS NR 36 TC 6 Z9 8 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD MAY PY 2007 VL 8 IS 5 BP 425 EP 430 DI 10.2217/14622416.8.5.425 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 167PY UT WOS:000246464800002 PM 17465705 ER PT J AU Shi, J Zhao, LY Epstein, DH Zhang, XL Lu, L AF Shi, Jie Zhao, Li-Yan Epstein, David H. Zhang, Xiao-Li Lu, Lin TI Long-term methadone maintenance reduces protracted symptoms of heroin abstinence and cue-induced craving in Chinese heroin abusers SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE heroin dependence; methadone maintenance; craving; protracted withdrawal symptoms; mood; somatization; dyssomnia ID RISK-FACTORS; ADDICTION; USERS; DEPENDENCE; MORTALITY; HEPATITIS; STRESS; TRIAL; DRUGS AB Background: Cession of heroin use may be followed by a protracted-abstinence (PA) syndrome consisting of craving, negative mood, and physiological changes. PA symptoms have rarely been compared between drug-free and methadone-maintained former heroin users after similar lengths of heroin abstinence. Methods: Seventy former heroin users were included in one of four groups: in day 15-45 of methadone maintenance therapy (short-term MMT), in month 5-6 of MMT (long-term MMT), opiate-free for 15-45 days after methadone-assisted heroin detoxification (short-term post-methadone), and opiate-free for 5-6 months after methadone-assisted heroin detoxification (long-term post-methadone). PA symptoms (negative mood, dyssomnia, somatization, and craving), and blood pressure and pulse were assessed pre- and post-neutral videotape and pre- and post-heroin videotape. Results: Dyssomnia and the total PA score were worst in short-term post-methadone participants, mood was best in long-term MMT participants, and cue-induced craving was least severe in long-term MMT participants. Blood pressure and pulse did not differ across groups. Conclusions: Even after acute withdrawal, the first months of heroin abstinence after methadone-assisted detoxification may be more difficult in terms of cue-induced craving and other PA symptoms than the first months of heroin abstinence during MMT. Our findings add to the literature supporting MMT for prevention of cue-induced heroin craving. (c) 2007 Elsevier Inc. All rights reserved. C1 Peking Univ, Natl Inst Drug Dependence, Dept Clin Pharmacol, Beijing 100083, Peoples R China. Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, Dept Clin Pharmacol, Beijing 100083, Peoples R China. EM llu@bjmu.edu.cn NR 28 TC 34 Z9 37 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD MAY PY 2007 VL 87 IS 1 BP 141 EP 145 DI 10.1016/j.pbb.2007.04.010 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 185WE UT WOS:000247740300017 PM 17532034 ER PT J AU Wielgus, AR Chignell, CF Miller, DS Van Houten, B Meyer, J Hu, DN Roberts, JE AF Wielgus, Albert R. Chignell, Colin F. Miller, David S. Van Houten, Ben Meyer, Joel Hu, Dan-Ning Roberts, Joan E. TI Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 30-MAY 05, 2005 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol ID ENDOTHELIAL GROWTH-FACTOR; LIPID-PEROXIDATION; NASOPHARYNGEAL CANCER; MACULAR DEGENERATION; UVEAL MELANOCYTES; FACTOR EXPRESSION; OXIDATIVE STRESS; ALPHA-CRYSTALLIN; DNA-DAMAGE; HUMAN LENS AB St. John's wort (SJW), an over-the-counter antidepressant, contains hypericin, which absorbs light in the UV and visible ranges. In vivo studies have determined that hypericin is phototoxic to skin and our previous in vitro studies with lens tissues have determined that it is potentially phototoxic to the human lens. To determine if hypericin might also be phototoxic to the human retina, we exposed human retinal pigment epithelial (hRPE) cells to 10(-7) to 10(-5) M hypericin. Fluorescence emission detected from the cells (lambda(ex) = 488 nm; lambda(em) = 505 nm) confirmed hypericin uptake by human RPE. Neither hypericin exposure alone nor visible light exposure alone reduced cell viability. However when irradiated with 0.7 J cm(-2) of visible light (lambda > 400 nm) there was loss of cell viability as measured by MTS and lactate dehydrogenase assays. The presence of hypericin in irradiated hRPE cells significantly changed the redox equilibrium of glutathione and a decrease in the activity of glutathione reductase. Increased lipid peroxidation as measured by the thiobarbituric acid reactive substances assay correlated to hypericin concentration in hRPE cells and visible light radiation. Thus, ingested SJW is potentially phototoxic to the retina and could contribute to retinal or early macular degeneration. C1 Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Genet Mol Lab, Res Triangle Pk, NC USA. Eye & Ear Hosp, New York, NY 10023 USA. Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Roberts, JE (reprint author), Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. EM jroberts@fordham.edu FU Intramural NIH HHS NR 47 TC 15 Z9 15 U1 1 U2 5 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAY-JUN PY 2007 VL 83 IS 3 BP 706 EP 713 DI 10.1562/2006-08-09-RA-1001 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 179YU UT WOS:000247327400033 PM 17576381 ER PT J AU Buice, MA Cowan, JD AF Buice, Michael A. Cowan, Jack D. TI Field-theoretic approach to fluctuation effects in neural networks SO PHYSICAL REVIEW E LA English DT Article ID SELF-ORGANIZED CRITICALITY; SYNCHRONIZATION; TRANSITIONS; AVALANCHES; LATTICE; MODELS AB A well-defined stochastic theory for neural activity, which permits the calculation of arbitrary statistical moments and equations governing them, is a potentially valuable tool for theoretical neuroscience. We produce such a theory by analyzing the dynamics of neural activity using field theoretic methods for nonequilibrium statistical processes. Assuming that neural network activity is Markovian, we construct the effective spike model, which describes both neural fluctuations and response. This analysis leads to a systematic expansion of corrections to mean field theory, which for the effective spike model is a simple version of the Wilson-Cowan equation. We argue that neural activity governed by this model exhibits a dynamical phase transition which is in the universality class of directed percolation. More general models (which may incorporate refractoriness) can exhibit other universality classes, such as dynamic isotropic percolation. Because of the extremely high connectivity in typical networks, it is expected that higher-order terms in the systematic expansion are small for experimentally accessible measurements, and thus, consistent with measurements in neocortical slice preparations, we expect mean field exponents for the transition. We provide a quantitative criterion for the relative magnitude of each term in the systematic expansion, analogous to the Ginsburg criterion. Experimental identification of dynamic universality classes in vivo is an outstanding and important question for neuroscience. C1 NIDDK, LBM, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Math, Chicago, IL 60637 USA. RP Buice, MA (reprint author), NIDDK, LBM, NIH, Bldg 12A Room 4007,MSC 5621, Bethesda, MD 20892 USA. EM buicem@niddk.nih.gov FU Intramural NIH HHS NR 26 TC 64 Z9 64 U1 3 U2 14 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAY PY 2007 VL 75 IS 5 AR 051919 DI 10.1103/PhysRevE.75.051919 PN 1 PG 14 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 173RL UT WOS:000246890100106 PM 17677110 ER PT J AU Kim, JS Romero, R Cushenberry, E Kim, YM Erez, O Nien, JK Yoon, BH Espinoza, J Kim, CJ AF Kim, J.-S. Romero, R. Cushenberry, E. Kim, Y. M. Erez, O. Nien, J. K. Yoon, B. H. Espinoza, J. Kim, C. J. TI Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor SO PLACENTA LA English DT Article DE macrophage; CD14; CD68; basal plate; placental bed; preeclampsia ID ENDOVASCULAR TROPHOBLAST INVASION; HUMAN DECIDUAL MACROPHAGES; TISSUE MACROPHAGES; SPIRAL ARTERIES; BLOOD; PREGNANCY; DIFFERENTIATION; PATHOGENESIS; PARTURITION; EXPRESSION AB Objective: Macrophages play a key role in implantation, placentation and parturition. Yet, whether or not the number of macrophages at the fetomaternal interface (basal plate of the placenta and placental bed) is altered in women with preeclampsia is the subject of controversy. The purpose of this study was to compare the immunoreactivity and distribution patterns of CD14 and CD68 positive macrophages in both the basal plate and placental bed from preeclamptic and non-preeclamptic pregnancies. Methods: A cross-sectional study was conducted. Paraffin embedded sections of placental tissues and placental bed biopsies were obtained from patients with early onset preeclampsia (n = 10) and from those with preterm labor/delivery (n = 10) without preeclampsia matched for gestational age. Double immunohistochemistry using antibodies to CD 14 and CD68 was performed, and the density of double or single positive cells in the basal plate and placental bed was evaluated. Non-parametric statistics were used for analysis. Results: 1) A unique subset of CD14-/CD68+ cells was identified. The cells in question were present at a higher level in the decidua than in the myometrial segment of the placental bed (p < 0.01); 2) The density and proportion of CD14+/CD68+ cells (double positive cells) were significantly higher in the myometrial segment than in the basal plate (p = 0.0003); and 3) There were no significant differences in the density and patterns of immunopositive macrophages in the basal plate, the decidua, and the myometrium between women with preeclampsia and those with preterm labor/delivery (p > 0.05). Conclusion: The macrophages at the fetomaternal interface can be dichotomized by CD14 and CD68 immunoreactivity. A gradient of CD14+/ CD68+ macrophages was demonstrated between the superficial myometrium and the basal plate regardless of the etiology of preterm birth (preeclampsia or spontaneous preterm labor). The biological function of single positive (CD14-/CD68+) and double positive (CD14+/CD68+) macrophages at the fetomaternal interface remains to be established. The overall findings also suggest that the discrepancies in the literature are due to the varying markers used to detect macrophages and in the anatomical plane of the fetomaternal junction analyzed. (c) 2006 Elsevier Ltd. All rights reserved. C1 NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. Seoul Natl Univ, Dept Obstet & Gynecol, Seoul 151, South Korea. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD, NIH,DHHS, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov; cjki@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011 FU Intramural NIH HHS NR 37 TC 34 Z9 37 U1 0 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD MAY-JUN PY 2007 VL 28 IS 5-6 BP 571 EP 576 DI 10.1016/j.placenta.2006.07.007 PG 6 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 167KD UT WOS:000246449700026 PM 17052752 ER PT J AU Bannister, LA Pezza, RJ Donaldson, JR de Rooij, DG Schimenti, KJ Camerini-Otero, RD Schimenti, JC AF Bannister, Laura A. Pezza, Roberto J. Donaldson, Janet R. de Rooij, Dirk G. Schimenti, Kerry J. Camerini-Otero, R. Daniel Schimenti, John C. TI A dominant, recombination-defective allele of Dmc1 causing male-specific sterility SO PLOS BIOLOGY LA English DT Article ID DNA STRAND-EXCHANGE; SEX-CHROMOSOME INACTIVATION; MEIOTIC RECOMBINATION; SYNAPTONEMAL COMPLEXES; MOUSE SPERMATOCYTES; MAMMALIAN MEIOSIS; RECA PROTEIN; MICE LACKING; GERM-CELLS; XO MICE AB DMC1 is a meiosis-specific homolog of bacterial RecA and eukaryotic RAD51 that can catalyze homologous DNA strand invasion and D-loop formation in vitro. DMC1-deficient mice and yeast are sterile due to defective meiotic recombination and chromosome synapsis. The authors identified a male dominant sterile allele of Dmc1, Dmc1(Mei11), encoding a missense mutation in the L2 DNA binding domain that abolishes strand invasion activity. Meiosis in male heterozygotes arrests in pachynema, characterized by incomplete chromosome synapsis and no crossing-over. Young heterozygous females have normal litter sizes despite having a decreased oocyte pool, a high incidence of meiosis I abnormalities, and susceptibility to premature ovarian failure. Dmc1(Mei11) exposes a sex difference in recombination in that a significant portion of female oocytes can compensate for DMC1 deficiency to undergo crossing-over and complete gametogenesis. Importantly, these data demonstrate that dominant alleles of meiosis genes can arise and propagate in populations, causing infertility and other reproductive consequences due to meiotic prophase I defects. C1 Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14850 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. Univ Utrecht, Dept Endocrinol, NL-3508 TC Utrecht, Netherlands. Univ Utrecht, Med Ctr, Dept Cell Biol, NL-3508 TC Utrecht, Netherlands. RP Schimenti, JC (reprint author), Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14850 USA. EM jcs92@cornell.edu OI de Rooij, Dirk/0000-0003-3932-4419 FU NICHD NIH HHS [P01 HD42137, P01 HD042137] NR 53 TC 41 Z9 40 U1 0 U2 3 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 MAY PY 2007 VL 5 IS 5 BP 1016 EP 1025 AR e105 DI 10.1371/journal.pbio.0050105 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 171EC UT WOS:000246716700010 PM 17425408 ER PT J AU Kadota, M Yang, HH Hu, N Wang, CY Hu, Y Taylor, PR Buetow, KH Lee, MP AF Kadota, Mitsutaka Yang, Howard H. Hu, Nan Wang, Chaoyu Hu, Ying Taylor, Philip R. Buetow, Kenneth H. Lee, Maxwell P. TI Allele-specific chromatin immunoprecipitation studies show genetic influence on chromatin state in human genome SO PLOS GENETICS LA English DT Article ID GERMLINE EPIMUTATION; EXPRESSION; INHERITANCE; MAIZE; MOUSE; METHYLATION; PATTERNS; FAMILY; CANCER; OCCURS AB Several recent studies have shown a genetic influence on gene expression variation, including variation between the two chromosomes within an individual and variation between individuals at the population level. We hypothesized that genetic inheritance may also affect variation in chromatin states. To test this hypothesis, we analyzed chromatin states in 12 lymphoblastoid cells derived from two Centre d'Etude du Polymorphisme Humain families using an allelespecific chromatin immunoprecipitation ( ChIP- on- chip) assay with Affymetrix 10K SNP chip. We performed the allelespecific ChIP- on- chip assays for the 12 lymphoblastoid cells using antibodies targeting at RNA polymerase II and five post- translation modified forms of the histone H3 protein. The use of multiple cell lines from the Centre d'Etude du Polymorphisme Humain families allowed us to evaluate variation of chromatin states across pedigrees. These studies demonstrated that chromatin state clustered by family. Our results support the idea that genetic inheritance can determine the epigenetic state of the chromatin as shown previously in model organisms. To our knowledge, this is the first demonstration in humans that genetics may be an important factor that influences global chromatin state mediated by histone modification, the hallmark of the epigenetic phenomena. C1 NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lee, MP (reprint author), NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM leemax@mail.nih.gov FU Intramural NIH HHS NR 30 TC 40 Z9 41 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2007 VL 3 IS 5 BP 768 EP 778 AR e81 DI 10.1371/journal.pgen.0030081 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 183LI UT WOS:000247573900011 PM 17511522 ER PT J AU Mosher, DS Quignon, P Bustamante, CD Sutter, NB Mellersh, CS Parker, HG Ostrander, EA AF Mosher, Dana S. Quignon, Pascale Bustamante, Carlos D. Sutter, Nathan B. Mellersh, Cathryn S. Parker, Heidi G. Ostrander, Elaine A. TI A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs SO PLOS GENETICS LA English DT Article ID SKELETAL-MUSCLE; DOMESTIC DOG; CATTLE; HYPERTROPHY; DELETION; BREED; MICE AB Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin ( MSTN) gene ( previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet dog breed that results in a double- muscled phenotype known as the "bully'' whippet. Individuals with this phenotype carry two copies of a two- base- pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wildtype individuals ( p = 7.43 x 10(-6); Kruskal- Wallis Test) and are significantly faster than individuals carrying the wild type genotype in competitive racing events ( Kendall's nonparametric measure, tau = 0.3619; p approximate to 0.00028). These results highlight the utility of performance- enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY USA. Anim Hlth Trust, Ctr Prevent Med, Newmarket, Suffolk, England. RP Ostrander, EA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov RI Parker, Heidi/C-6954-2008; OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS NR 33 TC 354 Z9 378 U1 7 U2 82 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2007 VL 3 IS 5 BP 779 EP 786 AR e79 DI 10.1371/journal.pgen.0030079 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 183LI UT WOS:000247573900012 PM 17530926 ER PT J AU Schunemann, HJ Hill, SR Kakad, M Vist, GE Bellamy, R Stockman, L Wisloff, TF Del Mar, C Hayden, F Uyeki, TM Farrar, J Yazdanpanah, Y Zucker, H Beigel, J Chotpitayasunondh, T Hien, TT Ozbay, B Sugaya, N Oxman, AD AF Schunemann, Holger J. Hill, Suzanne R. Kakad, Meetali Vist, Gunn E. Bellamy, Richard Stockman, Lauren Wisloff, Torbjorn Fosen Del Mar, Chris Hayden, Frederick Uyeki, Timothy M. Farrar, Jeremy Yazdanpanah, Yazdan Zucker, Howard Beigel, John Chotpitayasunondh, Tawee Hien, Tran Tinh Ozbay, Bulent Sugaya, Norio Oxman, Andrew D. TI Transparent development of the WHO rapid advice guidelines SO PLOS MEDICINE LA English DT Editorial Material ID CLINICAL GUIDELINES; QUALITY; RECOMMENDATIONS; STRENGTH AB Emerging health problems require rapid advice. We describe the development and pilot testing of a systematic, transparent approach used by the World Health Organization ( WHO) to develop rapid advice guidelines in response to requests from member states confronted with uncertainty about the pharmacological management of avian influenza A ( H5N1) virus infection. We first searched for systematic reviews of randomized trials of treatment and prevention of seasonal influenza and for nontrial evidence on H5N1 infection, including case reports and animal and in vitro studies. A panel of clinical experts, clinicians with experience in treating patients with H5N1, influenza researchers, and methodologists was convened for a two-day meeting. Panel members reviewed the evidence prior to the meeting and agreed on the process. It took one month to put together a team to prepare the evidence profiles ( i. e., summaries of the evidence on important clinical and policy questions), and it took the team only five weeks to prepare and revise the evidence profiles and to prepare draft guidelines prior to the panel meeting. A draft manuscript for publication was prepared within 10 days following the panel meeting. Strengths of the process include its transparency and the short amount of time used to prepare these WHO guidelines. The process could be improved by shortening the time required to commission evidence profiles. Further development is needed to facilitate stakeholder involvement, and evaluate and ensure the guideline's usefulness. C1 Italian Natl Canc Inst Regina Elena, Dept Epidemiol, Rome, Italy. WHO, CH-1211 Geneva, Switzerland. Norwegian Knowledge Ctr Hlth Serv, Oslo, Norway. James Cook Univ Hosp, Dept Infect & Travel Med, Middlesbrough, Cleveland, England. Bond Univ, Fac Hlth Sci & Med, Gold Coast, Qld, Australia. Univ Virginia, Hlth Sci Ctr, Dept Internal Med, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA USA. Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. Ctr Hosp Tourcoing, Serv Univ Maladies Infect, Fac Med Lille, Tourcoing, France. NIH, Bethesda, MD 20892 USA. Queen Sirikit Natl Inst Child Hlth, Minist Publ Hlth, Bangkok, Thailand. Yuzuncu Yil Univ, Dept Pulm, Van, Turkey. Keio Univ, Dept Pediat, Fac Med, Keiyu Hosp, Yokohama, Kanagawa 223, Japan. RP Schunemann, HJ (reprint author), Italian Natl Canc Inst Regina Elena, Dept Epidemiol, Rome, Italy. EM Schuneh@mcmaster.ca RI Del Mar, Christopher/B-1136-2008; Beigel, John/A-7111-2009; OI Del Mar, Christopher/0000-0003-3821-8163; Farrar, Jeremy/0000-0002-2700-623X NR 23 TC 50 Z9 52 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD MAY PY 2007 VL 4 IS 5 BP 786 EP 793 AR e119 DI 10.1371/journal.pmed.0040119 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 173RH UT WOS:000246889700005 PM 17535099 ER PT J AU Fotheringham, J Donati, D Akhyani, N Fogdell-Hahn, A Vortmeyer, A Heiss, JD Williams, E Weinstein, S Bruce, DA Gaillard, WD Sato, S Theodore, WH Jacobson, S AF Fotheringham, Julie Donati, Donatella Akhyani, Nahid Fogdell-Hahn, Anna Vortmeyer, Alexander Heiss, John D. Williams, Elizabeth Weinstein, Steven Bruce, Derek A. Gaillard, William D. Sato, Susumu Theodore, William H. Jacobson, Steven TI Association of human herpesvirus-6B with mesial temporal lobe epilepsy SO PLOS MEDICINE LA English DT Article ID MULTIPLE-SCLEROSIS LESIONS; POLYMERASE-CHAIN-REACTION; FEBRILE CONVULSIONS; UNPROVOKED SEIZURES; CLINICAL-FEATURES; GLUTAMATE UPTAKE; UNITED-STATES; BRAIN-TISSUE; VARIANT-B; HUMAN-HERPESVIRUS-6 AB Background Human herpesvirus- 6 ( HHV- 6) is a beta-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV- 6 variants are known: HHV- 6A and HHV- 6B. Active infection or reactivation of HHV- 6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV- 6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy ( MTLE) and have localized viral antigen to glial fibrillary acidic protein ( GFAP) - positive glia in the same brain sections. We sought, first, to determine the extent of HHV- 6 infection in brain material resected from MTLE and non- MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters. Methods and Findings HHV- 6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non- MTLE patients using PCR and immunofluorescence. HHV- 6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 ( 69%) additional patients with MTLE and from zero of seven ( 0%) additional patients without MTLE. All brain regions that tested positive by HHV- 6B variant- specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV- 6 gp116/ 54/ 64 antigen was detected in primary cultured GFAP- positive astrocytes from resected tissue that was HHV- 6 DNA positive the first demonstration of an ex vivo HHV- 6 - infected astrocyte culture isolated from HHV- 6 positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV- 6 and found a marked decrease in glutamate transporter EAAT- 2 expression. Conclusions Overall, we have now detected HHV- 6B in 15 of 24 patients with mesial temporal sclerosis/ MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE. C1 NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. Univ Siena, Azienda Osped, I-53100 Siena, Italy. Karolinska Inst, Dept Clin Neurosci, Div Neurol, Stockholm, Sweden. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov OI Heiss, John/0000-0002-3890-0165 NR 53 TC 65 Z9 69 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD MAY PY 2007 VL 4 IS 5 BP 848 EP 857 AR e180 DI 10.1371/journal.pmed.0040180 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 173RH UT WOS:000246889700014 PM 17535102 ER PT J AU Dushoff, J Plotkin, JB Viboud, C Simonsen, L Miller, M Loeb, M Earn, DJD AF Dushoff, Jonathan Plotkin, Joshua B. Viboud, Cecile Simonsen, Lone Miller, Mark Loeb, Mark Earn, David J. D. TI Vaccinating to protect a vulnerable subpopulation SO PLOS MEDICINE LA English DT Article ID INFLUENZA VACCINE; PANDEMIC INFLUENZA; PUBLIC-HEALTH; SCHOOLCHILDREN; EFFICACY; RISK; AGE; POPULATION; STRATEGIES; EPIDEMICS AB Background Epidemic influenza causes serious mortality and morbidity in temperate countries each winter. Research suggests that schoolchildren are critical in the spread of influenza virus, while the elderly and the very young are most vulnerable to the disease. Under these conditions, it is unclear how best to focus prevention efforts in order to protect the population. Here we investigate the question of how to protect a population against a disease when one group is particularly effective at spreading disease and another group is more vulnerable to the effects of the disease. Methods and Findings We developed a simple mathematical model of an epidemic that includes assortative mixing between groups of hosts. We evaluate the impact of different vaccine allocation strategies across a wide range of parameter values. With this model we demonstrate that the optimal vaccination strategy is extremely sensitive to the assortativity of population mixing, as well as to the reproductive number of the disease in each group. Small differences in parameter values can change the best vaccination strategy from one focused on the most vulnerable individuals to one focused on the most transmissive individuals. Conclusions Given the limited amount of information about relevant parameters, we suggest that changes in vaccination strategy, while potentially promising, should be approached with caution. In particular, we find that, while switching vaccine to more active groups may protect vulnerable groups in many cases, switching too much vaccine, or switching vaccine under slightly different conditions, may lead to large increases in disease in the vulnerable group. This outcome is more likely when vaccine limitation is stringent, when mixing is highly structured, or when transmission levels are high. C1 Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. NIAID, NIH, Bethesda, MD 20892 USA. McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. McMaster Univ, Dept Math & Stat, Hamilton, ON, Canada. RP Dushoff, J (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM dushoff@eno.princeton.edu RI Plotkin, Joshua/E-6947-2013; OI Earn, David/0000-0002-7562-1341; Simonsen, Lone/0000-0003-1535-8526 NR 31 TC 41 Z9 41 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD MAY PY 2007 VL 4 IS 5 BP 921 EP 927 AR e174 DI 10.1371/journal.pmed.0040174 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 173RH UT WOS:000246889700020 PM 17518515 ER PT J AU Simmons, CP Bernasconi, NL Suguitan, AL Mills, K Ward, JM Chau, NVV Hien, TT Sallusto, F Ha, DQ Farrar, J de Jong, MD Lanzavecchia, A Subbarao, K AF Simmons, Cameron P. Bernasconi, Nadia L. Suguitan, Amorsolo L., Jr. Mills, Kimberly Ward, Jerrold M. Chau, Nguyen Van Vinh Hien, Tran Tinh Sallusto, Federica Ha, Do Quang Farrar, Jeremy de Jong, Menno D. Lanzavecchia, Antonio Subbarao, Kanta TI Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza SO PLOS MEDICINE LA English DT Article ID A VIRUS; NEONATAL FERRETS; HONG-KONG; MICE; HEMAGGLUTININ; INFECTION; IMMUNITY; MOUSE; IGG; PREVENTION AB Background New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza ( HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies ( mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection. Methods and Findings Using Epstein- Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross- reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/ Vietnam/ 1203/04 ( H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/ Vietnam/ 1203/ 04 ( H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/ Indonesia/ 5/2005 ( H5N1). Conclusions These studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross- reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. Hosp Trop Dis, Ho Chih Minh City, Vietnam. Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chih Minh City, Vietnam. Inst Res Biomed, Bellinzona, Switzerland. RP Lanzavecchia, A (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM lanzavecchia@irb.unisi.ch; ksubbarao@niaid.nih.gov OI Simmons, Cameron P./0000-0002-9039-7392; Farrar, Jeremy/0000-0002-2700-623X FU Intramural NIH HHS; Wellcome Trust [077078/Z/05/Z, 079864, 079864/Z/06/Z] NR 29 TC 144 Z9 153 U1 4 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD MAY PY 2007 VL 4 IS 5 BP 928 EP 936 AR e178 DI 10.1371/journal.pmed.0040178 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 173RH UT WOS:000246889700021 PM 17535101 ER PT J AU Sougrat, R Bartesaghi, A Lifson, JD Bennett, AE Bess, JW Zabransky, DJ Subramaniam, S AF Sougrat, Rachid Bartesaghi, Alberto Lifson, Jeffrey D. Bennett, Adam E. Bess, Julian W. Zabransky, Daniel J. Subramaniam, Sriram TI Electron tomography of the contact between T cells and SIV/HIV-1: Implications for viral entry SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN TRIMERS; MEMBRANE-FUSION; HIV-1 GP41; CD4; MOLECULES; RECEPTOR; VIRIONS; INTERMEDIATE; QUANTITATION AB The envelope glycoproteins of primate lentiviruses, including human and simian immunodeficiency viruses (HIV and SIV), are heterodimers of a transmembrane glycoprotein (usually gp41), and a surface glycoprotein (gp120), which binds CD4 on target cells to initiate viral entry. We have used electron tomography to determine the three-dimensional architectures of purified SIV virions in isolation and in contact with CD4(+) target cells. The trimeric viral envelope glycoprotein surface spikes are heterogeneous in appearance and typically; 120 A long and; 120 A wide at the distal end. Docking of SIV or HIV-1 on the T cell surface occurs via a neck-shaped contact region that is; similar to 400 angstrom wide and consistently consists of a closely spaced cluster of five to seven rod-shaped features, each; similar to 100 angstrom long and; similar to 100 angstrom wide. This distinctive structure is not observed when viruses are incubated with T lymphocytes in the presence of anti-CD4 antibodies, the CCR5 antagonist TAK779, or the peptide entry inhibitor SIVmac251 C34. For virions bound to cells, few trimers were observed away from this cluster at the virion-cell interface, even in cases where virus preparations showing as many as 70 envelope glycoprotein trimers per virus particle were used. This contact zone, which we term the "entry claw'', provides a spatial context to understand the molecular mechanisms of viral entry. Determination of the molecular composition and structure of the entry claw may facilitate the identification of improved drugs for the inhibition of HIV-1 entry. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov OI Sougrat, Rachid/0000-0001-6476-1886 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 34 TC 93 Z9 94 U1 1 U2 10 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 MAY PY 2007 VL 3 IS 5 BP 571 EP 581 AR e63 DI 10.1371/journal.ppat.0030063 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 196VU UT WOS:000248511100002 PM 17480119 ER PT J AU Bryant, JE Holmes, EC Barrett, ADT AF Bryant, Juliet E. Holmes, Edward C. Barrett, Alan D. T. TI Out of Africa: A molecular perspective on the introduction of yellow fever virus into the Americas SO PLOS PATHOGENS LA English DT Article ID GENETIC-VARIATION; STRAINS; INFERENCE; HETEROGENEITY; EVOLUTION; REGION AB Yellow fever virus (YFV) remains the cause of severe morbidity and mortality in South America and Africa. To determine the evolutionary history of this important reemerging pathogen, we performed a phylogenetic analysis of the largest YFV data set compiled to date, representing the prM/E gene region from 133 viral isolates sampled from 22 countries over a period of 76 years. We estimate that the currently circulating strains of YFV arose in Africa within the last 1,500 years and emerged in the Americas following the slave trade approximately 300-400 years ago. These viruses then spread westwards across the continent and persist there to this day in the jungles of South America. We therefore illustrate how gene sequence data can be used to test hypotheses of viral dispersal and demographics, and document the role of human migration in the spread of infectious disease. C1 Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77550 USA. Univ Texas, Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77550 USA. Univ Texas, Med Branch, Inst Human Infect & Immun, Galveston, TX 77550 USA. Inst Pasteur, Natl Ctr Lab & Epidemiol, Viangchan, Laos. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bryant, JE (reprint author), Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77550 USA. EM jebryant@pasteur.fr; abarrett@utmb.edu OI Holmes, Edward/0000-0001-9596-3552 FU NIAID NIH HHS [N01 AI 30027, N01AI30027]; PHS HHS [T01/CCT62292] NR 37 TC 87 Z9 89 U1 0 U2 10 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 MAY PY 2007 VL 3 IS 5 BP 668 EP 673 AR e75 DI 10.1371/journal.ppat.0030075 PG 6 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 196VU UT WOS:000248511100012 PM 17511518 ER PT J AU Barr-Anderson, DJ Young, DR Sallis, JF Neumark-Sztainer, DR Gittelsohn, J Webber, L Saunders, R Cohen, S Jobe, JB AF Barr-Anderson, Dahela J. Young, Deborah R. Sallis, James F. Neumark-Sztainer, Dianne R. Gittelsohn, Joel Webber, Larry Saunders, Ruth Cohen, Stuart Jobe, Jared B. TI Structured physical activity and psychosocial correlates in middle-school girls SO PREVENTIVE MEDICINE LA English DT Article DE female adolescents; self-efficacy; physical activity enjoyment; enjoyment of physical education; school climate; race/ethnicity ID ADOLESCENT GIRLS; ACTIVITY INTERVENTION; ENJOYMENT; GENDER; QUESTIONNAIRES; PREDICTORS; CHILDREN; SCALE; LEVEL; SPORT AB Objective. Little is known about the types of physical activity (PA) in which adolescent girls participate. Understanding this, along with examining specific psychosocial correlates of PA, may help guide the development of effective interventions to prevent the decline in PA in female youth. Methods. 2791 sixth grade girls participating in the Trial of Activity for Adolescent Girls from six geographical locations completed surveys assessing participation in sports teams and activity classes/lessons in and out of school, self-efficacy for PA, PA enjoyment, physical education (PE) enjoyment, and perceived school climate for girls' PA (data collection: January-May 2003). Correlates of girls' participation in structured PA and sociodemographic differences were explored. Results. 89.5% of girls participated in structured PA: 39% at school and 86% outside of school. Across race/ethnicity, most reported activities were basketball (44%), cheerleading/dance (41%), and swimming (39%). Controlling for socioeconomic status, geographical location, and race/ ethnicity, girls with a higher self-efficacy (OR=3.44, CI= 1.72-6.92) and higher enjoyment of PE class (OR= 1.97, CI= 1.25-3.120) were more likely to participate in structured PA. PA enjoyment and perceived school climate for girls' PA were not associated with participation in structured PA. Conclusion. Interventions that increase self-efficacy and enjoyment of PE could result in greater participation in structured PA and higher overall PA levels among adolescent girls. (C) 2007 Elsevier Inc. All rights reserved. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21218 USA. Tulane Univ, Dept Biostat, New Orleans, LA 70118 USA. Univ S Carolina, Dept Hlth Promot Educ & Behav, Columbia, SC 29208 USA. Univ Arizona, Div Hlth Promot Sci, Tucson, AZ 85721 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Barr-Anderson, DJ (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM barranderson@epi.umn.edu OI Neumark-Sztainer, Dianne/0000-0001-9435-1669 FU NHLBI NIH HHS [U01HL066845, U01HL066852, U01HL066853, U01HL066855, U01HL066856, U01HL066857, U01HL066858] NR 25 TC 59 Z9 62 U1 4 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD MAY PY 2007 VL 44 IS 5 BP 404 EP 409 DI 10.1016/j.ypmed.2007.02.012 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 177OE UT WOS:000247161600006 PM 17363050 ER PT J AU Schmitt, J Benavente, R Hodzic, D Hoog, C Stewarts, CL Alsheimer, M AF Schmitt, Johannes Benavente, Ricardo Hodzic, Didier Hoog, Christer Stewarts, Colin L. Alsheimer, Manfred TI Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE meiosis; SUN-domain proteins; telomere attachment ID SPINDLE POLE BODY; A-TYPE LAMIN; FISSION YEAST; SYNAPTONEMAL COMPLEX; MEMBRANE PROTEIN; SCHIZOSACCHAROMYCES-POMBE; CAENORHABDITIS-ELEGANS; EXPRESSION PATTERN; BOUQUET FORMATION; ATTACHMENT SITES AB Dynamic repositioning of telomeres is a unique feature of meiotic prophase I that is highly conserved among eukaryotes. At least in fission yeast it was shown to be required for proper alignment and recombination of homologous chromosomes. On entry into meiosis telomeres attach to the nuclear envelope and transiently cluster at a limited area to form a chromosomal bouquet. Telomere clustering is thought to promote chromosome recognition and stable pairing of the homologs. However, the molecular basis of telomere attachment and movement is largely unknown. Here we report that mammalian SUN-domain protein Sun2 specifically localizes to the nuclear envelope attachment sites of meiotic telorneres. Sun2-telomere association is maintained throughout the dynamic movement of telomeres. This association does not require the assembly of chromosomal axial elements or the presence of A-type lamins. Detailed EM analysis revealed that Sun2 is part of a membrane-spanning fibrillar complex that interconnects attached telomeres with cytoplasmic structures. Togetherwith recentf inclings in fission yeast, ourstudy indicates that the molecular mechanisms required for tethering meiotic telonneres and their dynamic movements during bouquet formation are conserved among eukaryotes. C1 Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. Natl Canc Inst, Canc & Dev Biol Lab, Ft Detrick, MD 21702 USA. RP Alsheimer, M (reprint author), Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. EM alsheimer@biozentrum.uni-wuerzburg.de NR 49 TC 99 Z9 102 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 MAY 1 PY 2007 VL 104 IS 18 BP 7426 EP 7431 DI 10.1073/pnas.0609198104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164MY UT WOS:000246239400024 PM 17452644 ER PT J AU Hatchett, RJ Mecher, CE Lipsitch, M AF Hatchett, Richard J. Mecher, Carter E. Lipsitch, Marc TI Public health interventions and epidemic intensity during the 1918 influenza pandemic SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitigation; nonpharmaceutical interventions; closures ID MORTALITY AB Nonpharmaceutical interventions (NPIs) intended to reduce infectious contacts between persons form an integral part of plans to mitigate the impact of the next influenza pandemic. Although the potential benefits of NPIs are supported by mathematical models, the historical evidence for the impact of such interventions in past pandemics has not been systematically examined. We obtained data on the timing of 19 classes of NPI in 17 U.S. cities during the 1918 pandemic and tested the hypothesis that early implementation of multiple interventions was associated with reduced disease transmission. Consistent with this hypothesis, cities in which multiple interventions were implemented at an early phase of the epidemic had peak death rates approximate to 50% lower than those that did not and had less-steep epidemic curves. Cities in which multiple interventions were implemented at an early phase of the epidemic also showed a trend toward lower cumulative excess mortality, but the difference was smaller (approximate to 20%) and less statistically significant than that for peak death rates. This finding was not unexpected, given that few cities maintained NPls longer than 6 weeks in 1918. Early implementation of certain interventions, including closure of schools, churches, and theaters, was associated with lower peak death rates, but no single intervention showed an association with improved aggregate outcomes for the 1918 phase of the pandemic. These findings support the hypothesis that rapid implementation of multiple NPIs can significantly reduce influenza transmission, but that viral spread will be renewed upon relaxation of such measures. C1 NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. VA SE Network, Dept Vet Affairs, Duluth, GA 30096 USA. Homeland Secur Council, Execut Off President, EEOB, Washington, DC 20502 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Hatchett, RJ (reprint author), NIAID, Div Allergy Immunol & Transplantat, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hatchettr@niaid.nih.gov OI Lipsitch, Marc/0000-0003-1504-9213 FU NIGMS NIH HHS [U01 GM076497, 5U01GM076497] NR 12 TC 133 Z9 143 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 MAY 1 PY 2007 VL 104 IS 18 BP 7582 EP 7587 DI 10.1073/pnas.0610941104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164MY UT WOS:000246239400051 PM 17416679 ER PT J AU Hampson, K Dushoff, J Bingham, J Bruckner, G Ali, YH Dobson, A AF Hampson, Katie Dushoff, Jonathan Bingham, John Bruckner, Gideon Ali, Y. H. Dobson, Andy TI Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE disease dynamics; epidemics; infectious disease; mathematical model; vaccination ID POPULATION SYNCHRONY; VACCINATION CAMPAIGN; SPATIAL HIERARCHIES; DISEASE-CONTROL; EPIDEMIOLOGY; DYNAMICS; PATTERNS; ZIMBABWE; SPREAD; WAVES AB Rabies is a fatal neurological pathogen that is a persistent problem throughout the developing world where it is spread primarily by domestic dogs. Although the disease has been extensively studied in wildlife populations in Europe and North America, the dynamics of rabies in domestic dog populations has been almost entirely neglected. Here, we demonstrate that rabies epidemics in southern and eastern Africa cycle with a period of 3-6 years and show significant synchrony across the region. The observed period is shorter than predictions based on epidemiological parameters for rabies in domestic dogs. We find evidence that rabies prevention measures, including vaccination, are affected by disease prevalence and show that a simple model with intervention responses can capture observed disease periodicity and host dynamics. We suggest that movement of infectious or latent animals combined with coordinated control responses may be important in coupling populations and generating synchrony at the continental scale. These findings have important implications for rabies prediction and control: large-scale synchrony and the importance of intervention responses suggest that control of canine rabies in Africa will require sustained efforts coordinated across political boundaries. C1 Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. CSIRO, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. Chief Directorate Vet Serv, Dept Agr, ZA-7607 Elsenburg, South Africa. Cent Vet Res Lab, Dept Virol, Khartoum, Sudan. RP Hampson, K (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM khampson@princeton.edu RI Bingham, John/H-8591-2013; OI Hampson, Katie/0000-0001-5392-6884 NR 69 TC 56 Z9 58 U1 0 U2 16 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 MAY 1 PY 2007 VL 104 IS 18 BP 7717 EP 7722 DI 10.1073/pnas.0609122104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 164MY UT WOS:000246239400074 PM 17452645 ER PT J AU Brown, MW Brooks, JP Albert, PS Poggi, MM AF Brown, M. W. Brooks, J. P. Albert, P. S. Poggi, M. M. TI An analysis of erectile function after intensity modulated radiation therapy for localized prostate carcinoma SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE IMRT; erectile dysfunction; penile bulb; radiation dose ID 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; SPARING RADICAL PROSTATECTOMY; EXTERNAL-BEAM IRRADIATION; QUALITY-OF-LIFE; SEXUAL FUNCTION; PENILE BULB; CANCER TREATMENT; DOSE-ESCALATION; NITRIC-OXIDE; DYSFUNCTION AB Radiation therapy for prostate cancer can cause erectile dysfunction ( ED). Intensity Modulated Radiation Therapy ( IMRT) can reduce the amount of radiation to surrounding tissues associated with ED. We characterize the incidence of and factors associated with ED in prostate cancer patients after IMRT at the National Naval Medical Center ( NNMC). Patients potent by definition of the Sexual Health Inventory for Men ( SHIM) before treatment completed the specific erectile questions of the SHIM after IMRT. Statistical analyses were performed to examine the relationships between several factors and ED. Thirty-two of 45 patients with mean age of 68.2 years ( 50 - 86 years) completed the SHIM. The median follow-up was 36.8 months ( 16 - 63.6 months) as defined by the time from completion of therapy to reassessment with the SHIM. Eight of 32 patients ( 25%) had no post- treatment ED ( SHIM score 22 - 25), three of 32 ( 9%) had mild post- treatment ED ( SHIM score 17 - 21), five of 32 ( 16%) had mild to moderate ED ( SHIM score 12 - 16), five of 32 ( 16%) had moderate ED ( SHIM score 8 - 11) and 11 of 32 ( 34%) had severe post- treatment ED ( SHIM score < 8). Posttreatment potency was significantly associated with the pre- treatment SHIM score ( P = 0.001) and history of hypertension ( P = 0.03). The mean radiation dose to the penile bulb and volume of penile bulb treated were not associated with post- treatment potency ( P = 0.38, 0.76, respectively). IMRT maintains potency in the majority of patients. This analysis compares favorably in preserving erectile function to previously reported series using conventional external beam radiation therapy techniques. The dose of radiation received by the penile bulb and volume of penile bulb were not associated with post- treatment ED in this analysis. C1 Natl Naval Med Ctr, Div Radiat Oncol, Dept Radiol, Bethesda, MD 20889 USA. Madigan Army Med Ctr, Sect Radiat Oncol, Dept Radiol, Tacoma, WA 98431 USA. Natl Canc Inst, Biometr Res Branch, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. RP Poggi, MM (reprint author), Natl Naval Med Ctr, Div Radiat Oncol, Dept Radiol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM mmpoggi@bethesda.med.navy.mil NR 46 TC 28 Z9 28 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAY PY 2007 VL 10 IS 2 BP 189 EP 193 DI 10.1038/sj.pcan.4500938 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 175PU UT WOS:000247026300013 PM 17189954 ER PT J AU Goodin, JL Nellis, DF Powell, BS Vyas, VV Enama, JT Wang, LC Clark, PK Giardina, SL Adamovicz, JJ Michiel, DF AF Goodin, Jeremy L. Nellis, David F. Powell, Bradford S. Vyas, Vinay V. Enama, Jeffrey T. Wang, Lena C. Clark, Patrick K. Giardina, Steven L. Adamovicz, Jeffery J. Michiel, Dennis F. TI Purification and protective efficacy of monomeric and modified Yersinia pestis capsular F1-V antigen fusion proteins for vaccination against plague SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE F1-V; fusion protein; vaccine; development; yersinia pestis; monodisperse; alhydrogel; protective efficacy ID PNEUMONIC PLAGUE; ESCHERICHIA-COLI; INCLUSION-BODIES; LIGHT-SCATTERING; IN-VITRO; MICE; SOLUBILIZATION; EXPRESSION; VACCINES AB The F1-V vaccine antigen, protective against Yersinia pestis, exhibits a strong tendency to multimerize that affects larger-scale manufacture and characterization. In this work, the sole FIN cysteine was replaced with serine by site-directed mutagenesis for characterization of FIN non-covalent multimer interactions and protective potency without participation by disulfide-linkages. FIN and F1-V-C424S proteins were overexpressed in Escherichia coli, recovered using mechanical lysis/pH-modulation and purified from urea-solubilized soft inclusion bodies, using successive ion-exchange, ceramic hydroxyapatite, and size-exclusion chromatography. This purification method resulted in up to 2 mg/g of cell paste of 95% pure, mono-disperse protein having <= 0.5 endotoxin units per mg by a kinetic chromogenic limulus amoebocyte lysate reactivity assay. Both F1-V and F1-V-C424S were monomeric at pH 10.0 and progressively self-associated as pH conditions decreased to pH 6.0. Solution additives were screened for their ability to inhibit FIN self-association at pH 6.5. An L-argmine buffer provided the greatest stabilizing effect. Conversion to > 500-kDa multimers occurred between pH 6.0 and 5.0. Conditions for efficient F1-V adsorption to the cGMP-compatible alhydrogelo adjuvant were optimized. Side-by-side evaluation for protective potency against subcutaneous plague infection in mice was conducted for F1-V-C424S monomer; cysteine-capped FIN monomer; cysteine-capped F1-V multimer; and a F1-V standard reported previously. After a two-dose vaccination with 2 x 20 mu g of F1-V, respectively, 100%, 80%, 80%, and 70% of injected mice survived a subcutaneous lethal plague challenge with 10(8) LD50 Y pestis CO92, Thus, vaccination with FIN monomer and multimeric forms resulted in significant, and essentially equivalent, protection. Published by Elsevier Inc. C1 NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Bacteriol Div, Ft Detrick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Michiel, DF (reprint author), NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM dfm@ncifrcf.gov FU NCI NIH HHS [N01CO12400, N01 CO012400, N01-CO-12400] NR 26 TC 16 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAY PY 2007 VL 53 IS 1 BP 63 EP 79 DI 10.1016/j.pep.2006.12.018 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 164PB UT WOS:000246245000008 PM 17293124 ER PT J AU Yeliseev, A Zoubak, L Gawrisch, K AF Yeliseev, Alexel Zoubak, Lioudmila Gawrisch, Klaus TI Use of dual affinity tags for expression and purification of functional peripheral cannabinoid receptor SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE peripheral cannabinoid receptor; CB2; affinity tags; chromatographic purification; reconstitution; functional; heterologous expression ID RECOMBINANT PROTEINS; IDENTIFICATION AB The human peripheral cannabinoid receptor (CB2) was expressed as a fusion with the maltose-binding protein (at the N-terminus), thioredoxin A (at the C-terminus) and two small affinity tags (a Strep-tag and a polyhistidine tag). Expression levels of the recombinant receptor in Escherichia coli BL21(DE3) cells were dependent on location and type of tags in the expression construct, and were as high as 1-2 mg per liter of bacterial culture. The recombinant receptor was ligand binding-competent, and activated cognate G-proteins in an in vitro coupled assay. The fusion CB2-125 protein was purified by immobilized metal affinity chromatography on a Ni-NTA resin. Maltose-binding protein, thioredoxin and a decahistidine tag were removed from the fusion by treatment with Tobacco etch virus (Tev) protease. Purification to over 90% homogeneity of the resulting CB2, containing an N-terminal Strep-tag was achieved by affinity chromatography on a StrepTactin resin. Circular dichroism spectroscopy indicated an alpha-helical content of the purified recombinant protein of similar to 54%. The expression and purification protocol allows for production of large (milligram) quantities of functional peripheral cannabinoid receptor, suitable for subsequent structural characterization. Preliminary results of reconstitution experiments indicate that the CB2 has retained its ligand-binding properties. (c) 2006 Elsevier Inc. All rights reserved. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Yeliseev, A (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM yeliseeva@mail.nih.gov RI Yeliseev, Alexei/B-3143-2009 FU Intramural NIH HHS [Z99 AA999999] NR 13 TC 30 Z9 33 U1 3 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAY PY 2007 VL 53 IS 1 BP 153 EP 163 DI 10.1016/j.pep.2006.12.003 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 164PB UT WOS:000246245000019 PM 17223358 ER PT J AU Arora, NK Rutten, LJF Gustafson, DH Moser, R Hawkins, RP AF Arora, Neeraj K. Rutten, Lila J. Finney Gustafson, David H. Moser, Richard Hawkins, Robert P. TI Perceived helpfulness and impact of social support provided by family, friends, and health care providers to women newly disgnosed with breast cancer SO PSYCHO-ONCOLOGY LA English DT Article DE social support; breast cancer; health-related quality of life; coping; self regulation; longitudinal analysis ID QUALITY-OF-LIFE; FUNCTIONAL ASSESSMENT; PSYCHOSOCIAL ADJUSTMENT; YOUNGER WOMEN; SURVIVAL; THERAPY; CHEMOTHERAPY; COMMUNICATION; PROFESSIONALS; PERCEPTIONS AB We evaluated the helpfulness of informational, emotional, and decision-making support received by women newly diagnosed with breast cancer from their family, friends, and health care providers. Data were collected at two time points via patient surveys: baseline on an average 2 months post-diagnosis and follow-up at 5 months post-baseline. In the period closer to diagnosis, majority of the women received helpful informational support from health care providers (84.0%); helpful emotional support from family (85%), friends (80.4%), and providers (67.1%); and helpful decision-making support from providers (75.2%) and family (71.0%). Emotional support at baseline and emotional and informational support at 5-month follow-up were significantly associated with patients' health-related quality of life and self-efficacy outcomes (p < 0.01). Perceived helpfulness of informational, emotional, and decision-making support provided by family, friends, and providers however significantly decreased over time (p < 0.001). Cancer patients desire significant amount of support throughout their cancer journey. Our results show that while patients receive a lot of support during the period closer to diagnosis, receipt of helpful support drops significantly within the first year itself. In order to facilitate cancer patients' adjustment to their illness, efforts need to be made to understand and address their support needs throughout the cancer experience. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, SAIC Frederick, Bethesda, MD 20892 USA. Univ Wisconsin, Ctr Hlth Syst Res & Anal, Madison, WI 53706 USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,Execut Plaza N 4005, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov FU NICHD NIH HHS [5R01HD32922] NR 50 TC 110 Z9 110 U1 3 U2 15 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD MAY PY 2007 VL 16 IS 5 BP 474 EP 486 DI 10.1002/pon.1084 PG 13 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 172DC UT WOS:000246783300009 PM 16986172 ER PT J AU Thomsen, M Wortwein, G Fink-Jensen, A Woldbye, DPD Wess, J Caine, SB AF Thomsen, Morgane Wortwein, Gitta Fink-Jensen, Anders Woldbye, David P. D. Wess, Juergen Caine, S. Barak TI Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M-5 muscarinic acetylcholine receptor knockout mice SO PSYCHOPHARMACOLOGY LA English DT Article DE prepulse inhibition; muscarinic; acetylcholine receptor; psychostimulant; antipsychotic; knockout mice; M-5 ID DISCRIMINATIVE STIMULUS PROPERTIES; VENTRAL TEGMENTAL AREA; SUBTYPE-SPECIFIC ANTIBODIES; ANTIPSYCHOTIC-LIKE ACTIVITY; ACOUSTIC STARTLE RESPONSE; PLACEBO-CONTROLLED TRIAL; RAT NUCLEUS-ACCUMBENS; DOUBLE-BLIND; N-DESMETHYLCLOZAPINE; CHOLINERGIC-RECEPTORS AB Rationale Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition of startle (PPI). In preclinical models, these measures may be used to predict antipsychotic activity. While current antipsychotic drugs act largely at dopamine receptors, the muscarinic acetylcholine receptors offer promising novel pharmacotherapy targets. Of these, the M-5 receptor gene was recently implicated in susceptibility to schizophrenia. Due to the lack of selective ligands, muscarinic receptor knockout mice have been generated to elucidate the roles of the five receptor subtypes (M-1-M-5). Objectives Here, we used M-5 receptor knockout (M-5-/-) mice to investigate the involvement of M-5 receptors in behavioral measures pertinent to schizophrenia. We tested the hypothesis that disruption of M-5 receptors affected PPI or the effects of muscarinic or dopaminergic agents in PPI or psychomotor stimulation. Materials and methods We measured PPI in M-5-/-, heterozygous and wild-type mice without drugs, and with clozapine (0.56-3.2 mg/kg) or haloperidol (0.32-3.2 mg/kg) alone, and as pretreatment to D-amphetamine. In addition, we evaluated locomotor stimulation by the muscarinic antagonist trihexyphenidyl (0.56-56 mg/kg) and by cocaine (3.2-56 mg/kg). Results The M-5-/- mice showed decreased PPI relative to wild-type mice, and clozapine appeared to reduce this difference, while haloperidol increased PPI regardless of genotype. The M-5-/- mice also showed more locomotor stimulation by trihexyphenidyl than wild-type mice, while cocaine had similar effects between genotypes. Conclusions These data suggest that disruption of the M-5 receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs. C1 Harvard Univ, McLean Hosp, Sch Med, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. Univ Copenhagen Hosp, Rigshosp, Lab Neuropsychiat, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Dept Pharmacol, DK-2100 Copenhagen, Denmark. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. 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 NIDA NIH HHS [P01-DA14528, T32-DA07252] NR 88 TC 20 Z9 21 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2007 VL 192 IS 1 BP 97 EP 110 DI 10.1007/s00213-006-0682-y PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 162PO UT WOS:000246100300011 PM 17310388 ER PT J AU Cornwell, BR Echiverri, AM Grillon, C AF Cornwell, Brian R. Echiverri, Aileen M. Grillon, Christian TI Sensitivity to masked conditioned stimuli predicts conditioned response magnitude under masked conditions SO PSYCHOPHYSIOLOGY LA English DT Article DE awareness; fear conditioning; masking; signal detection; skin conductance ID FACIAL EXPRESSIONS; AWARENESS; FEAR; ANXIETY; HUMANS; FACES AB Expression of conditioned fear has been reported to be independent of perceptual awareness of conditioned stimuli (CSs). Previous studies have been criticized, however, for not adequately assessing perceptual awareness. We fear-conditioned participants to one of two symbols and measured skin conductance responses to dichoptically masked and unmasked CSs. Participants also performed a target detection task and sensitivity (d') to the masked conditioned stimuli (CS+, CS-) was measured. Results showed that sensitivity under masking conditions was related to conditioned responses to masked CSs but not unmasked CSs. Thus, a strong relationship between expression of conditioned fear and awareness of the CS+ emerges when the latter is assessed by signal detection methods. Without consensus on how awareness should be defined, these findings bring balance to previous studies that have typically used less sensitive assessments of awareness. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Cornwell, BR (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, 15K North Dr, Bethesda, MD 20892 USA. EM cornwellb@mail.nih.gov FU Intramural NIH HHS [Z01 MH002798-06] NR 23 TC 8 Z9 8 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAY PY 2007 VL 44 IS 3 BP 403 EP 406 DI 10.1111/j.1469-8986.2007.00519.x PG 4 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 156JY UT WOS:000245645200007 PM 17433097 ER PT J AU Black, WC Aberle, DR Berg, CD AF Black, William C. Aberle, Denise R. Berg, Christine D. CA NLST TI Large field trial for lung cancer screening: Putting the wrong cart before the horse? SO RADIOLOGY LA English DT Editorial Material ID BREAST-CANCER; GROWTH-RATE; CT; PROJECT C1 Dartmouth Hitchcock Med Ctr, Dept Radiol, Lebanon, NH 03756 USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90024 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Black, WC (reprint author), Dartmouth Hitchcock Med Ctr, Dept Radiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM william.black@hitchcock.org OI Aberle, Denise/0000-0002-8858-3401 NR 19 TC 2 Z9 2 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2007 VL 243 IS 2 BP 314 EP 316 DI 10.1148/radiol.2431060903 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 170UP UT WOS:000246691500003 PM 17456862 ER PT J AU Huang, A Roy, DA Summers, RM Franaszek, M Petrick, N Choi, JR Pickhardt, PJ AF Huang, Adam Roy, Dave A. Summers, Ronald M. Franaszek, Marek Petrick, Nicholas Choi, J. Richard Pickhardt, Perry J. TI Teniae coli-based circumferential localization system for CT colonography: Feasibility study SO RADIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY COLONOGRAPHY; VIRTUAL COLONOSCOPY; POLYP DETECTION; SUPINE AB This HIPAA-compliant study, with institutional review board approval and informed patient consent, was conducted to retrospectively develop a teniae coli-based circumferential localization method for guiding virtual colon navigation and colonic polyp registration. Colonic surfaces (n = 72) were depicted at computed tomographic (CT) colonography performed in 36 patients (26 men, 10 women; age range, 47-72 years) in the supine and prone positions. For 70 (97%) colonic surfaces, the tenia omentalis (TO), the most visible of the three teniae coli on a well-distended colonic surface, was manually extracted from the cecum to the descending colon. By virtually dissecting and flattening the colon along the TO, the authors developed a localization system involving 12 grid lines to estimate the circumferential positions of polyps. A sessile polyp would most likely (at 95% confidence level) be found within +/- 1.2 grid lines (one grid line equals 1/12 the circumference) with use of the proposed method. By orienting and positioning the virtual cameras with use of the new localization system, synchronized prone and supine navigation was achieved. The teniae coli are extractable landmarks, and the teniae coli-based circumferential localization system helps guide virtual navigation and polyp registration at CT colonography. (c) RSNA, 2007. C1 NIH, Dept Diagnost Radiol, Clin Ctr, Bethesda, MD 20892 USA. US FDA, Joint Lab Assessment Med Imaging Syst, CDRH, NIBIB, Rockville, MD 20857 USA. Uniformed Serv Univ hlth Sci, Bethesda, MD USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Natl Naval Med Ctr, Bethesda, MD USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, Clin Ctr, 10 Ctr Dr,MSC 1182,bldg 10,Room 1C351, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural NIH HHS NR 17 TC 25 Z9 25 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2007 VL 243 IS 2 BP 551 EP 560 DI 10.1148/radiol.2432060353 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 170UP UT WOS:000246691500031 PM 17456877 ER PT J AU Edwards, R Patrizio, P Edgar, D Field, C Brinton, L AF Edwards, Robert Patrizio, Pasquale Edgar, David Field, Catherine Brinton, Louise TI Defining IVF terminology SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Editorial Material DE in-vitro fertilization; IVF; IVM; natural cycle; oocyte maturation in vitro AB Rapid recent advances in in-vitro fertilization (IVF) and in-vitro maturation (IVM) of human oocytes are leading to vast changes in the practice of IVF. This article attempts to define the various approaches to these new methods. C1 Reprod BioMed Online, Cambridge CB3 8DB, England. Yale Univ, Fertil Ctr, New Haven, CT 06511 USA. Royal Hosp Women, Reprod Serv Melbourne IVF, Carlton, Vic 3053, Australia. Univ Melbourne, Dept Obstet & Gynaecol, Parkville, Vic 3052, Australia. NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. RP Edwards, R (reprint author), Reprod BioMed Online, Cambridge CB3 8DB, England. EM rge@rbmonline.com RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 5 Z9 5 U1 0 U2 2 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD MAY PY 2007 VL 14 IS 5 BP 553 EP 554 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 167IJ UT WOS:000246445000003 PM 17509191 ER PT J AU Rao, AJ Ramachandra, SG Ramesh, V Krishnamurthy, HN Ravindranath, N Moudgal, NR AF Rao, A. Jagannadha Ramachandra, S. G. Ramesh, V. Krishnamurthy, H. N. Ravindranath, N. Moudgal, N. R. TI Establishment of the need for oestrogen during implantation in non-human primates SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article DE anti-oestrogen; aromatase inhibitors; fertility; non-human primates; tamoxifen ID MONKEY MACACA-RADIATA; EPIDERMAL GROWTH-FACTOR; BABOON PAPIO-ANUBIS; EARLY-PREGNANCY; CHORIONIC-GONADOTROPIN; RHESUS-MONKEYS; CORPUS-LUTEUM; HUMAN OVIDUCT; EARLY EMBRYOS; FACTOR-ALPHA AB Deprivation of oestrogen during post-ovulatory mated cycles in proven fertile female bonnet monkeys by tamoxifen, aromatase inhibitor or oestrogen antiserum resulted in inhibition of pregnancy establishment in all three groups of animals. However, more than 85% of the animals became pregnant within three exposures to proven fertile males in the control group. These results suggest the requirement for oestrogen in pregnancy establishment in primates. Based on this conclusion, it is suggested that use of a suitable and potent anti-oestrogenic compound can be exploited as an alternative approach to contraception. C1 Indian Inst Sci, Bangalore 560012, Karnataka, India. NIH, Bethesda, MD 20892 USA. RP Rao, AJ (reprint author), Indian Inst Sci, Bangalore 560012, Karnataka, India. EM ajrao@biochem.iisc.ernet.in RI G, Ramachandra/C-2776-2012 NR 53 TC 4 Z9 4 U1 0 U2 0 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD MAY PY 2007 VL 14 IS 5 BP 563 EP 571 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 167IJ UT WOS:000246445000007 PM 17509195 ER PT J AU Juruena, MF Marques, AH Mello, AF Mello, MF AF Juruena, Mario Francisco Marques, Andrea H. Mello, Andrea Feijo Mello, Marcelo Feijo TI A paradigm for understanding and treating psychiatric illness SO REVISTA BRASILEIRA DE PSIQUIATRIA LA Portuguese DT Editorial Material ID HEALTH C1 Kings Coll London, Inst Psychiat, Dept Psychol Med, Sect Neurobiol Mood Disorders, London WC2R 2LS, England. Kings Coll London, SPI Lab, London WC2R 2LS, England. NIMH, Sect Neuroendocrine Immunol, NIH, Bethesda, MD 20892 USA. NIMH, Behav Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. Univ Fed Sao Paulo, Dept Psiquiatria, PRODAF, Sao Paulo, Brazil. Univ Fed Sao Paulo, Dept Psiquiatria, PROVE, Sao Paulo, Brazil. RP Juruena, MF (reprint author), Kings Coll London, Inst Psychiat, Dept Psychol Med, Sect Neurobiol Mood Disorders, London WC2R 2LS, England. RI marques, andrea/H-5297-2012; Mello, Andrea/Q-1795-2015; Juruena, Mario/D-5571-2009; OI Juruena, Mario/0000-0001-8558-3396; Juruena, Mario F./0000-0002-4063-2278 NR 5 TC 3 Z9 5 U1 0 U2 3 PU ASSOCIACAO BRASILEIRA DE PSIQUIATRIA PI SAO PAULO PA SUBSCRIPTION DEPARTMENT, RUA PEDRO DE TOLEDO, 967 - CASA 01, SAO PAULO, SP, BRAZIL SN 1516-4446 J9 REV BRAS PSIQUIATR JI Rev. Bras. Psiquiatr. PD MAY PY 2007 VL 29 SU 1 BP S1 EP S2 DI 10.1590/S1516-44462007000500001 PG 2 WC Psychiatry SC Psychiatry GA 174TH UT WOS:000246965200001 PM 17546341 ER PT J AU Marques, AH Cizza, G Sternberg, E AF Marques, Andrea H. Cizza, Giovanni Sternberg, Esther TI Brain-immune interactions and implications in psychiatric disorders SO REVISTA BRASILEIRA DE PSIQUIATRIA LA Portuguese DT Article ID NECROSIS-FACTOR-ALPHA; MAJOR DEPRESSIVE DISORDER; CORONARY-HEART-DISEASE; PLASMA-LEVELS; PROINFLAMMATORY CYTOKINES; SOLUBLE INTERLEUKIN-2; INFLAMMATORY MARKERS; GENE POLYMORPHISM; KOREAN POPULATION; ACUTE STATE AB Objective: This review will focus on the role of cytokines in the central nervous system and its implications to depressive disorder We will then discuss the main findings of cytokine measurements in patients with major depressive disorder Method: We searched Pubmed for studies published from 1999-2007, using the keywords depression and cytokine; and depressive disorder and cytokine. We have focused on pro-inflammatory cytokine measurements in patients with depression syndrome using DSM-criteria. Results: Several lines of evidence suggest that cytokines have effects on depression, such as the induction of sickness behavior; clinical conditions related to cytokines that also overlap depressive symptoms; and immunotherapy that can lead to depressive symptoms attenuated by antidepressant treatment. Finally, patients with depression exhibit increased levels of pro-inflammatory cytokines, although conflicting results have been described. Conclusion: Cytokines may play a role in the pathophysiology of some cases of depression, although a causal link has not been established yet. Further longitudinal studies are needed to determine patterns of cytokine in patients with major depressive disorder, taking into account confounding factors closely associated with the activation of pro-inflammatory cytokines. In addition, simultaneous measurements of multiple biomarkers could provide critical insights into mechanisms underlying major depressive disorder and a variety of common cytokine-related diseases. C1 NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, Rockville, MD 20852 USA. NIH, Inst Nacl Diabet & Doencas Digest, Div Endocrinol Clin, Secao Endocrina Clin, Bethesda, MD 20892 USA. NIH, Inst Nacl Rins, Bethesda, MD 20892 USA. RP Marques, AH (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, 5625 Fishers Lane,Room 4Nn13, Rockville, MD 20852 USA. EM marquesa@mail.nih.gov RI marques, andrea/H-5297-2012 NR 60 TC 14 Z9 15 U1 0 U2 1 PU ASSOCIACAO BRASILEIRA DE PSIQUIATRIA PI SAO PAULO PA SUBSCRIPTION DEPARTMENT, RUA PEDRO DE TOLEDO, 967 - CASA 01, SAO PAULO, SP, BRAZIL SN 1516-4446 J9 REV BRAS PSIQUIATR JI Rev. Bras. Psiquiatr. PD MAY PY 2007 VL 29 SU 1 BP S27 EP S32 DI 10.1590/S1516-44462007000500006 PG 6 WC Psychiatry SC Psychiatry GA 174TH UT WOS:000246965200006 PM 17546344 ER PT J AU Bellack, AS Green, MF Cook, JA Fenton, W Harvey, PD Heaton, RK Laughren, T Leon, AC Mayo, DJ Patrick, DL Patterson, TL Rose, A Stover, E Wykes, T AF Bellack, Alan S. Green, Michael F. Cook, Judith A. Fenton, Wayne Harvey, Philip D. Heaton, Robert K. Laughren, Thomas Leon, Andrew C. Mayo, Donna J. Patrick, Donald L. Patterson, Thomas L. Rose, Andrew Stover, Ellen Wykes, Til TI Assessment of community functioning in people with schizophrenia and other severe mental illnesses: A white paper based on an NIMH-sponsored workshop SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; assessment; outcomes ID QUALITY-OF-LIFE; PSYCHIATRIC-PATIENTS; RATING-SCALE; PSYCHOSOCIAL REHABILITATION; NEUROCOGNITIVE DEFICITS; SOCIAL-ADJUSTMENT; NEGATIVE SYMPTOMS; PERFORMANCE; VALIDATION; OUTCOMES AB People with schizophrenia frequently have significant problems in community functioning. Progress in developing effective interventions to ameliorate these problems has been slowed by the absence of reliable and valid measures that are suitable for use in clinical trials. The National Institute of Mental Health convened a workgroup in September 2005 to examine this issue and make recommendations to the field that would foster research in this area. This article reports on issues raised at the meeting. Many instruments have been developed to assess community functioning, but overall insufficient attention has been paid to psychometric issues and many instruments are not suitable for use in clinical trials. Consumer self-report, informant report, ratings by clinicians and trained raters, and behavioral assessment all can provide useful and valid information in some circumstances and may he practical for use in clinical trials. However, insufficient attention has been paid to when and how different forms of assessment and sources of information are useful or how to understand inconsistencies. A major limiting factor in development of reliable and valid instruments is failure to develop a suitable model of functioning and its primary mediators and moderators. Several examples that can guide thinking are presented. Finally, the field is limited by the absence of an objective gold standard of community functioning. Hence, outcomes must be evaluated in part by "clinical significance." This criterion is problematic because different observers and constituencies often have different opinions about what types of change are clinically important and how much change is significant. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Univ Illinois, Chicago, IL 60680 USA. Mt Sinai Sch Med, New York, NY 10029 USA. Univ Calif San Diego, San Diego, CA 92103 USA. US FDA, Div Psychiat Prod, Rockville, MD 20857 USA. Cornell Univ, Weill Med Coll, Ithaca, NY 14853 USA. NIMH, Bethesda, MD 20892 USA. Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Bellack, AS (reprint author), Univ Maryland, Sch Med, 737 Lombard St,Suite 551, Baltimore, MD 21201 USA. EM abellack@psych.umaryland.edu RI Wykes, Til/B-7894-2008; Wykes, Til/B-3812-2011; Cook, Judith/B-9107-2013 OI Wykes, Til/0000-0002-5881-8003; NR 95 TC 94 Z9 96 U1 6 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAY PY 2007 VL 33 IS 3 BP 805 EP 822 DI 10.1093/schbul/sbl035 PG 18 WC Psychiatry SC Psychiatry GA 178SZ UT WOS:000247241700028 PM 16931542 ER PT J AU Chang, H AF Chang, Henry TI Another aging theory SO SCIENTIST LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Chang, H (reprint author), NIH, Bethesda, MD 20892 USA. EM changh@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAY PY 2007 VL 21 IS 5 BP 14 EP 14 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 161EY UT WOS:000245998500004 ER PT J AU Dear, JW Leelahavanichkul, A Aponte, A Hu, X Constant, SL Yuen, PST Star, RA AF Dear, J. W. Leelahavanichkul, A. Aponte, A. Hu, X. Constant, S. L. Yuen, P. S. T. Star, R. A. TI Liver proteomics for therapeutic drug discovery: Inhibition the cyclophilin receptor CD147 attenuates sepsis-induce acute renal failure SO SCOTTISH MEDICAL JOURNAL LA English DT Meeting Abstract C1 Univ Edinburgh, Queens Med Res Inst, Ctr Cardiovasc Sci, Clin Pharmacol Unit, Edinburgh EH8 9YL, Midlothian, Scotland. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SCOTTISH MEDICAL JOURNAL PI GLASGOW PA MR K BURNSIDE, 12 BUCCLEUCH DRIVE, BEARSDEN, GLASGOW, G61 3LW, SCOTLAND SN 0036-9330 J9 SCOT MED J JI Scott. Med. J. PD MAY PY 2007 VL 52 IS 2 BP 53 EP 54 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 179NM UT WOS:000247296600040 ER PT J AU Rehermann, B AF Rehermann, Barbara TI Chronic infections with hepatotropic viruses: Mechanisms of impairment of cellular immune responses SO SEMINARS IN LIVER DISEASE LA English DT Review DE HBV; HCV; T cell; infection; virus; liver ID HEPATITIS-C-VIRUS; REGULATORY T-CELLS; CHRONIC VIRAL-INFECTION; IMMUNOLOGICAL SELF-TOLERANCE; FRIEND RETROVIRUS INFECTION; IN-VITRO PROLIFERATION; B-VIRUS; LYMPHOCYTE RESPONSE; THERAPEUTIC VACCINATION; HCV INFECTION AB Chronic hepatitis B and C cause significant morbidity and mortality worldwide. Antiviral therapy suppresses but does not eliminate chronic hepatitis B virus (HBV) infection, and it is effective in only half of all hepatitis C virus (HCV)-infected patients. Because adaptive immune responses are associated with spontaneous resolution of acute HBV and HCV infection, therapeutic enhancement of immune responses has been proposed as alternative or supplementary therapy for chronic infection. However, all efforts have been hampered by poor proliferation and effector functions of HBV- and HCV-specific CD4 and CD8 T cells, which are thought to be due to T cell exhaustion, high antigenic load, and viral escape. Recent studies revealed that endogenous factors, such as regulatory T cells, immuno suppressive cytokines, and inhibitory receptors, also contribute to the impairment of virus-specific T cell responses in chronic infection, perhaps reflecting the host's attempt to protect itself against immune-mediated pathology. These endogenous mechanisms and potential avenues to revert them are the subject of this review. C1 NIDDK, Liver Dis Branch, Immunol Sect, US Dept HHS,NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Branch, Immunol Sect, US Dept HHS,NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 109 TC 77 Z9 89 U1 0 U2 3 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 MAY PY 2007 VL 27 IS 2 BP 152 EP 160 DI 10.1055/s-2007-979468 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 174TU UT WOS:000246966500004 PM 17520515 ER PT J AU Clark, JL Long, CM Giron, JM Cuadros, JA Caceres, CF Coates, TJ Klausner, JD AF Clark, Jesse L. Long, Corey M. Giron, Jessica M. Cuadros, Julio A. Caceres, Carlos F. Coates, Thomas J. Klausner, Jeffrey D. CA NIMH Collaborative HIV STD Prevent TI Partner notification for sexually transmitted diseases in Peru: Knowledge, attitudes, and practices in a high-risk community SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID CONTROLLED-TRIAL; UNITED-STATES; PSYCHOSOCIAL DETERMINANTS; CHLAMYDIA-TRACHOMATIS; INFECTION; UGANDA; STD; HIV; MEDICATION; STRATEGIES AB Notification and treatment of sex partners after diagnosis of a sexually transmitted disease (STD) is essential to reduce reinfection and further transmission. Goal: The goal of this study was to determine the prevalence of partner notification and subsequent health-seeking behavior in a high-risk population in Lima, Peru. Study Design: STD-infected participants of an HIV/STD prevention trial completed a questionnaire concerning partner notification. Results: Of the 502 STD-positive subjects, 287 completed the survey. Among survey participants, 65% informed their primary partner and 10.5% informed casual or anonymous partners. Reasons for failure to notify varied by partner type and included not understanding the importance of partner notification, embarrassment, fear of rejection, and inability to locate the partner. When notified, approximately one third of all partners sought medical attention. Conclusions: Partner notification in Peru is limited by relationship dynamics, social stigma, and limited contact information. Interventions could emphasize the importance of notification, improvement of communication skills, and introduce contact tracing programs (including Internet-based systems) and expedited partner therapy. C1 Univ Calif Los Angeles, Med Ctr, Div Infect Dis, Dept Med, Los Angeles, CA 90024 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. NIMH, Multisite Int Grp, Bethesda, MD 20892 USA. RP Clark, JL (reprint author), Univ Calif Los Angeles, Med Ctr, Div Infect Dis, Dept Med, 10940 Wilshire Blvd,Suite 1220, Los Angeles, CA 90024 USA. EM jlclark@mednet.ucla.edu OI Caceres, Carlos/0000-0002-8101-0790 FU NIMH NIH HHS [U10 MH61536, U10 MH061536] NR 42 TC 25 Z9 25 U1 0 U2 2 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 MAY PY 2007 VL 34 IS 5 BP 309 EP 313 DI 10.1097/01.olq.0000240289.84094.93 PG 5 WC Infectious Diseases SC Infectious Diseases GA 162IR UT WOS:000246080900012 PM 17016236 ER PT J AU Spierings, E Hendriks, M Absi, L Canossi, A Chhaya, S Crowley, J Dolstra, H Eliaou, JF Ellis, T Enczmann, J Fasano, M Gervais, T Gorodezky, C Kircher, B Laurin, D Leffell, M Loiseau, P Malkki, M Markiewicz, M Martinetti, M Maruya, E Mehra, N Oguz, F Oudshoorn, M Pereira, N Rani, R Sergeant, R Thomson, J Tran, TH Turpeinen, H Yang, KL Zunec, R Carrington, M de Knijff, P Goulmy, E AF Spierings, E. Hendriks, M. Absi, L. Canossi, A. Chhaya, S. Crowley, J. Dolstra, H. Eliaou, J. F. Ellis, T. Enczmann, J. Fasano, M. Gervais, T. Gorodezky, C. Kircher, B. Laurin, D. Leffell, M. Loiseau, P. Malkki, M. Markiewicz, M. Martinetti, M. Maruya, E. Mehra, N. Oguz, F. Oudshoorn, M. Pereira, N. Rani, R. Sergeant, R. Thomson, J. Tran, T. H. Turpeinen, H. Yang, K. L. Zunec, R. Carrington, M. de Knijff, P. Goulmy, E. TI Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among ethnic populations SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 21st European Immunogenetics and Histocompatibility Conference CY MAY 05-08, 2007 CL Barcelona, SPAIN C1 Leiden Univ, Med Ctr, Immunohematol & Blood Transfus, Leiden, Netherlands. EFS Auvergne Loire, Lab Histocompatibil, St Etienne, France. Inst CNR Trapianti Organo Immunocitol, Laquila, Italy. Tata Mem Hosp, Bombay 400012, Maharashtra, India. Natl Blood Ctr, Natl Histocompatibil & Immunogenet Reference Lab, Dublin, Ireland. Radboud Univ Nijmegen, Med Ctr, Cent Hematol Lab, Nijmegen, Netherlands. Hop St Eloi, CHU, Immunol Lab, Unit Immunogenet, Montpellier, France. Blood Ctr Southeastern Wisconsin, Milwaukee, WI USA. Univ Hosp, Inst Transplantat Immunol, Dusseldorf, Germany. UOADU, Az Osped S Giovanni Battista, Turin, Italy. Catholic Univ Louvain, Clin St Luc Clos Chapelle Champs, Brussels, Belgium. InDRE SSA, Dept Immunol & Immunogenet, Mexico City, DF, Mexico. Innsbruck Med Univ, Div Hematol & Oncol, Immunobiol & Stem Cell Lab, Innsbruck, Austria. EFS Rhone Alpes, Lab Immunol R&D, Grenoble, France. Johns Hopkins Univ, Sch Med, Immunogenet Lab, Baltimore, MD USA. Hop St Louis, Immunol Lab, Paris, France. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Med Univ Silesia, Hematol & BMT Dept, Katowice, Poland. IRCCS Polyclin S Matteo, Lab HLA, Serv Immunoematol & Tranfus, Pavia, Italy. NPO, HLA Lab, Kyoto, Japan. All India Inst Med Sci, Dept Transplant Immunol & Immunogenet, New Delhi, India. Istanbul Univ, Fac Med, Dept Med Biol, Istanbul, Turkey. Stichting Europdonor, Leiden, Netherlands. Univ Fed Parana, Hosp Clin, Immunogenet Lab, BR-80060000 Curitiba, Parana, Brazil. Natl Inst Immunol, New Delhi, India. Hammersmith Hosp, Clin Immunol Lab, London, England. Univ Cape Town, Sch Med, Lab Tissue Immunol, ZA-7925 Cape Town, South Africa. Univ Heidelberg, Inst Immunol, Dept Transplantat Immunol, D-6900 Heidelberg, Germany. Finnish Red Cross & Blood Transfus Serv, Res & Dev, SF-00310 Helsinki, Finland. Tzu Chi Stem Cells Ctr, Cord Blood Bank, Hualien, Taiwan. Clin Hosp, Tissue Typing Ctr, Zagreb, Croatia. NCI, SAIC Frederick Inc, Lab Genom Divers, Frederick, MD 21701 USA. Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. RI Dolstra, H./L-4276-2015 NR 0 TC 1 Z9 1 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAY PY 2007 VL 69 IS 5 BP 374 EP 375 PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 160ZV UT WOS:000245985000006 ER PT J AU Baltadjieva, D Grant, A Gao, P Berg, T Chi, P Zhang, S Zambelli-Weiner, A Zardkoohi, O Brummet, M Stockton, M Watkins, T Gao, L Gittens, M Wills-Krap, M Cheadle, C Beck, L Beaty, T Becker, K Garcia, J Mathias, R Barnes, C Barnes, K AF Baltadjieva, D. Grant, A. Gao, P. Berg, T. Chi, P. Zhang, S. Zambelli-Weiner, A. Zardkoohi, O. Brummet, M. Stockton, M. Watkins, T. Gao, L. Gittens, M. Wills-Krap, M. Cheadle, C. Beck, L. Beaty, T. Becker, K. Garcia, J. Mathias, R. Barnes, C. Barnes, K. TI Synergistic effect between the CD14(-260) polymorphism and markers in a novel candidate gene acyloxyacyl hydroxylase (AOAH) among asthmatics SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 21st European Immunogenetics and Histocompatibility Conference CY MAY 05-08, 2007 CL Barcelona, SPAIN C1 Alexandra Univ Hosp, Cent Lab Clin Immunol, Sofia, Bulgaria. Johns Hopkins Univ, Dept Med, Div Clin Immunol & Allergy, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Childrens Hosp, Med Ctr, Div Immunol, Cincinnati, OH USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NIA, DNA Array Unit, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD USA. NIA, NHGRI, Inherited Dis Res Branch, Genometr Sect, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAY PY 2007 VL 69 IS 5 BP 381 EP 381 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 160ZV UT WOS:000245985000022 ER PT J AU Gourraud, PA Feolo, M Dauber, EM Mayr, W Thomsen, M Mickelson, E Hansen, J Shiina, T Doxiadis, GG Cambon-Thomsen, A AF Gourraud, P. A. Feolo, M. Dauber, E. M. Mayr, W. Thomsen, M. Mickelson, E. Hansen, J. Shiina, T. Doxiadis, G. G. Cambon-Thomsen, A. TI Overall achievements of the HLA region microsatellites international working group following the 14th IHIWS SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 21st European Immunogenetics and Histocompatibility Conference CY MAY 05-08, 2007 CL Barcelona, SPAIN C1 Univ Toulouse 3, Fac Med Purpan, INSERM, Dept Epidemiol & Publ Hlth,UMR558, F-31062 Toulouse, France. NIH, Natl Ctr Biotechnol Informat, Natl Library Med, Bethesda, MD 20892 USA. Med Univ Vienna, Div Blood Grp Serol, Vienna, Austria. Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Div Clin Res, Seattle, WA 98195 USA. Tokai Univ, Sch Med, Dept Mol Life Sci, Div Basic Med Sci & Mol Med, Isehara, Kanagawa 25911, Japan. Biomed Primate Res Ctr, Dept Comparat Genet & Refinement, Rijswijk, Netherlands. RI Thomsen, Mogens/B-7651-2011; Gourraud, Pierre-Antoine/O-3024-2015 OI Thomsen, Mogens/0000-0002-4546-0129; NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAY PY 2007 VL 69 IS 5 BP 426 EP 427 PG 2 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 160ZV UT WOS:000245985000141 ER PT J AU Pacyniak, EK Cheng, XG Cunningham, ML Crofton, K Klaassen, CD Guo, GL AF Pacyniak, Erik K. Cheng, Xingguo Cunningham, Michael L. Crofton, Kevin Klaassen, Curtis D. Guo, Grace L. TI The flame retardants, polybrominated diphenyl ethers, are pregnane X receptor activators SO TOXICOLOGICAL SCIENCES LA English DT Article DE PBDE; nuclear receptor; PXR; induction; cyp3a; cyp2b ID CONSTITUTIVE ANDROSTANE RECEPTOR; HUMAN ADIPOSE-TISSUE; NUCLEAR RECEPTOR; POLYCHLORINATED-BIPHENYLS; DIFFERENTIAL EXPRESSION; SIGNALING PATHWAY; DRUG-INTERACTIONS; THYROID-HORMONES; OXIDATIVE STRESS; VITAMIN-A AB Polybrominated diphenyl ethers (PBDEs) are used as flame retardants and are universally present in the environment. An exponential increase in PBDE concentrations in the U.S. population have been reported over the last 3 decades. PBDEs 47 (tetraBDE) and 99 (pentaBDE) are the most commonly detected PBDE congeners in the environment and in human samples. PBDE209 (decaBDE) is the only remaining PBDE flame retardant commercially manufactured in the United States. Several PBDEs are known to induce cyp3a in rats, but the mechanism of induction remains unclear. The goal of this study was to clarify the mechanism by which PBDE congeners induce cyp3a. Treatment of C57BL6 mice with PBDEs 47, 99, and 209 induced gene expressions of cyp3a11 and 2b10, but not cyp1a1/2. Because the first two genes are known target genes of pregnane X receptor (PXR), a ligand-activated transcription factor in the nuclear hormone receptor superfamily, we hypothesized that PBDE congeners are PXR activators. Using reporter gene luciferase assays, the present data show that PBDEs 47, 99, and 209 activated PXR and its human counterpart, steroid X receptor, but not aryl hydrocarbon receptor. Furthermore, induction of cyp3a11 and 2b10 by PBDEs 47, 99, and 209 was markedly suppressed in PXR-knockout mice, indicating that PBDE congeners activate PXR in vivo. In summary, our study provides the first evidence that PBDEs are activators for xenobiotic nuclear receptor. C1 Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. NIEHS, Res Triangle Pk, NC 27709 USA. US EPA, Res Triangle Pk, NC 27709 USA. RP Guo, GL (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM lguo@kumc.edu RI Crofton, Kevin/J-4798-2015 OI Crofton, Kevin/0000-0003-1749-9971 FU NCRR NIH HHS [P20 RR021940, P20 RR015563]; NICHD NIH HHS [K12 HD052027]; NIEHS NIH HHS [R01 ES013714] NR 47 TC 79 Z9 82 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2007 VL 97 IS 1 BP 94 EP 102 DI 10.1093/toxsci/kfm025 PG 9 WC Toxicology SC Toxicology GA 173QB UT WOS:000246886500011 PM 17324954 ER PT J AU Miller, DS Shaw, JR Stanton, CR Barnaby, R Karlson, KH Hamilton, JW Stanton, BA AF Miller, David S. Shaw, Joseph R. Stanton, Caitlin R. Barnaby, Roxanna Karlson, Katherine H. Hamilton, Joshua W. Stanton, Bruce A. TI MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus) SO TOXICOLOGICAL SCIENCES LA English DT Article DE adaptation; xenobiotic transport; Abcc2; environmental toxicant ID RENAL PROXIMAL TUBULE; RESISTANCE-ASSOCIATED PROTEIN-2; DRUG EFFLUX; SHORT-TERM; CELL-LINE; MULTIDRUG; TRANSPORT; EXPRESSION; ENDOTHELIN; TOXICITY AB We used proximal tubules isolated from the killifish, Fundulus heteroclitus, to examine the effect of environmentally relevant, sublethal levels of arsenic on the function and expression of MRP2, an ABC transporter that transports xenobiotics into urine, including arsenic-glutathione conjugates. Exposure of fish to arsenic as sodium arsenite (4-14 days) increased both MRP2 expression in the apical membrane of proximal tubules and MRP2-mediated transport activity. The level of MRP2 mRNA was not affected, suggesting a posttranslational mechanism of action. Acute exposure of proximal tubules isolated from control fish to 75-375 ppb arsenic decreased mitochondrial function (inner membrane electrical potential). However, in tubules from fish that were preexposed to arsenic (4-14 days), no such effect on mitochondrial function was observed. Thus, chronic in vivo exposure to arsenic induces mechanisms that protect proximal tubules during subsequent arsenic exposure. Upregulation of MRP2 expression and activity is one likely contributing factor. C1 Dartmouth Coll Sch Med, Dept Physiol, Hanover, NH 03755 USA. Dartmouth Coll Sch Med, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Mt Desert Isl Biol Lab, Salsbury Cove, ME 04672 USA. Dartmouth Coll, Dept Biol Sci, Hanover, NH 03755 USA. Dartmouth Coll Sch Med, Ctr Environm Hlth Sci, Hanover, NH 03755 USA. RP Stanton, BA (reprint author), Dartmouth Coll Sch Med, Dept Physiol, N Coll St, Hanover, NH 03755 USA. EM bas@dartmouth.edu FU Intramural NIH HHS; NIEHS NIH HHS [P30-ES03828, P42 ES07373] NR 33 TC 26 Z9 27 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2007 VL 97 IS 1 BP 103 EP 110 DI 10.1093/toxsci/kfm030 PG 8 WC Toxicology SC Toxicology GA 173QB UT WOS:000246886500012 PM 17324950 ER PT J AU Chai, ZF Bai, ZT Zhang, XY Liu, T Pang, XY Ji, YH AF Chai, Zhi-Fang Bai, Zhan-Tao Zhang, Xu-Ying Liu, Tong Pang, Xue-Yan Ji, Yong-Hua TI Rat epileptic seizures evoked by BmK alpha IV and its possible mechanisms involved in sodium channels SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE BmK alpha IV; epileptic seizure; cerebrocortical synaptosomes; glutamate release; sodium channels; ion imaging ID SERRULATUS SCORPION-VENOM; BUTHUS-MARTENSI KARSCH; GLUTAMATE RELEASE; ANTIEPILEPTIC DRUGS; FEBRILE SEIZURES; INTRAHIPPOCAMPAL INJECTION; CORTICAL SYNAPTOSOMES; GENERALIZED EPILEPSY; NA+; TOXIN AB This study showed that rat unilateral intracerebroventricular injection of BmK alpha IV, a sodium channel modulator derived from scorpion Buthus martensi Karsch, induced clusters of spikes, epileptic discharges and convulsion-related behavioral changes. BmK alpha IV potently promoted the release of endogenous glutamate from rat cerebrocortical synaptosomes. In vitro examination of the effect of BmK alpha IV on intrasynaptosomal free calcium concentration [Ca2+](i) and sodium concentration [Na+](i) revealed that BmK alpha-IV-evoked glutamate release from synaptosomes was associated with an increase in Ca2+ and Na+ influx. Moreover, BmK alpha IV-mediated glutamate release and ion influx was completely blocked by tetrodotoxin, a blocker of sodium channel. Together, these results suggest that the induction of BmK alpha IV-evoked epileptic seizures may be involved in the modulation of BmK alpha IV on tetrodotoxin-sensitive sodium channels located on the nerve terminal, which subsequently enhances the Ca2+ influx to cause an increase of glutamate release. These findings may provide some insight regarding the mechanism of neuronal action of BmK alpha IV in the central nervous system for understanding epileptogenesis involved in sodium channels. (c) 2007 Elsevier Inc. All rights reserved. C1 Shanghai Univ, Sch Life Sci, Shanghai 200444, Peoples R China. Chinese Acad Sci, Shanghai Inst Physiol, Inst Biol Sci, Grad Sch, Shanghai 200031, Peoples R China. NIEHS, Membrane Signaling Grp, Lab Neurobiol, NIH, Res Triangle Pk, NC 27709 USA. RP Ji, YH (reprint author), Shanghai Univ, Sch Life Sci, Shang Da Rd 99, Shanghai 200444, Peoples R China. EM yhji@server.shcnc.ac.cn RI Liu, Tong/E-3648-2010; Liu, Tong/C-7810-2012; Ji, Yonghua/B-7769-2014 NR 51 TC 2 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 1 PY 2007 VL 220 IS 3 BP 235 EP 242 DI 10.1016/j.taap.2007.01.006 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 165SK UT WOS:000246325600002 PM 17320922 ER PT J AU Liu, J Xie, YX Cooper, R Duchanne, DMK Tennant, R Diwan, BA Waalkes, MP AF Liu, Jie Xie, Yaxiong Cooper, Ryan Duchanne, Danica M. K. Tennant, Raymond Diwan, Blialchandra A. Waalkes, Michael P. TI Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; In utero exposure; fetal liver; gene expression; estrogen signaling; steroid metabolism ID X-CHROMOSOME INACTIVATION; IN-UTERO; RECEPTOR-ALPHA; DRINKING-WATER; POSTNATAL DIETHYLSTILBESTROL; HEPATOCELLULAR-CARCINOMA; GESTATIONAL EXPOSURE; TREFOIL FACTOR-1; ADULT MICE; CANCER AB Exposure to inorganic arsenic in utero in OH mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17 beta-hydroxysteroid dehydrogenase-7 (HSD17 beta 7; involved in estradiol production) and decreased expression of HSD17 beta 5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-la, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. Published by Elsevier Inc. C1 NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. SAIC Frederick Inc, NCI, Basic Res Program, Frederick, MD USA. RP Liu, J (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis, NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA. EM Liu6@niehs.nih.gov FU Intramural NIH HHS [NIH0011069698, ]; NCI NIH HHS [N01-CO-12400, N01CO12400]; PHS HHS [NIH0011069698] NR 48 TC 31 Z9 31 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 1 PY 2007 VL 220 IS 3 BP 284 EP 291 DI 10.1016/j.taap.2007.01.018 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 165SK UT WOS:000246325600008 PM 17350061 ER PT J AU Loovers, HM Kortholt, A de Groote, H Whitty, L Nussbaum, RL van Haastert, PJM AF Loovers, Harriet M. Kortholt, Arjan de Groote, Hendrie Whitty, Leslie Nussbaum, Robert L. van Haastert, Peter J. M. TI Regulation of phagocytosis in Dictyostelium by the inositol 5-phosphatase OCRL homolog Dd5P4 SO TRAFFIC LA English DT Article DE OCRL; phagocytosis; 5-phosphatase; phosphoinositide; pinocytosis ID SYNDROME PROTEIN OCRL1; TRANS-GOLGI NETWORK; LOWE-SYNDROME; POLYPHOSPHATE 5-PHOSPHATASE; ACTIN CYTOSKELETON; RAC GTPASE; CHEMOTAXIS; 4,5-BISPHOSPHATE; ENDOCYTOSIS; DEFICIENCY AB Phosphoinositides are involved in endocytosis in both mammalian cells and the amoeba Dictyostelium discoideum. Dd5P4 is the Dictyostelium homolog of human OCRL (oculocerebrorenal syndrome of Lowe); both have a RhoGAP domain and a 5-phosphatase domain that acts on phosphatidylinositol 4,5-bisphosphate/phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P-3). Inactivation of Dd5P4 inhibits growth on liquid medium and on bacteria. Dd5p4-null cells are impaired in phagocytosis of yeast cells. In wild-type cells, PI(3,4,5)P-3 is formed and converted to PI(3,4)P-2 just before closure of the phagocytic cup. In dd5p4-null cells, a phagocytic cup is formed upon contact with the yeast cell, and PI(3,4,5)P-3 is still produced, but the phagocytic cup does not close. We suggest that Dd5P4 regulates the conversion of PI(3,4,5)P-3 to PI(3,4)P-2 and that this conversion is essential for closure of the phagocytic cup. Phylogenetic analysis of OCRL-like 5-phosphatases with RhoGAP domains reveal that D. discoideum Dd5P4 is a surprisingly close homolog of human OCRL, the protein responsible for Lowe syndrome. We expressed human OCRL in dd5p4-null cells. Growth on bacteria and axenic medium is largely restored, whereas the rate of phagocytosis of yeast cells is partly restored, indicating that human OCRL can functionally replace Dictyostelium Dd5P4. C1 Univ Groningen, Dept Mol Cell Biol, NL-9751 NN Haren, Netherlands. NHGRI, Bethesda, MD 20892 USA. RP van Haastert, PJM (reprint author), Univ Groningen, Dept Mol Cell Biol, Kerklaan 30, NL-9751 NN Haren, Netherlands. EM p.j.m.van.haastert@rug.nl NR 35 TC 25 Z9 25 U1 0 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD MAY PY 2007 VL 8 IS 5 BP 618 EP 628 DI 10.1111/j.1600-0854.2007.00546.x PG 11 WC Cell Biology SC Cell Biology GA 160MK UT WOS:000245945500014 PM 17343681 ER PT J AU Kino, T Chrousos, GP AF Kino, Tomoshige Chrousos, George P. TI Virus-mediated modulation of the host endocrine signaling systems: clinical implications SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID ACCESSORY PROTEIN VPR; ANGIOTENSIN-CONVERTING ENZYME; PARATHYROID-HORMONE; MOLECULAR MIMICRY; SARS CORONAVIRUS; HTLV-1 TAX; RECEPTOR; HIV-1; CELL; INFECTION AB Viruses, which are among the simplest infective pathogens, can produce characteristic endocrine manifestations in infected patients. In addition to the classic modification of the host endocrine system by either direct or indirect destruction of the endocrine organs and/or effects exerted by systemic production of inflammatory and/or stress mediators, recent progress in molecular virology and endocrinology has revealed that virus-encoded molecules might alter the host endocrine-signaling systems by affecting extracellular and/or intracellullar signal transduction and hormone sensitivity of host target tissues. Here, we provide a brief overview of such viral-mediated modulation of host endocrine signaling systems. We propose that virus-encoded molecules and the signaling systems they influence are potential therapeutic targets for the treatment of disorders that are associated with some viral infections. C1 NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Kino, T (reprint author), NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov FU Intramural NIH HHS NR 69 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAY-JUN PY 2007 VL 18 IS 4 BP 159 EP 166 DI 10.1016/j.tem.2007.03.003 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 169CR UT WOS:000246570800005 PM 17400471 ER PT J AU Peterson, K Haque, R Mondal, D Duggal, P Sher, A Ricklefs, S Porcella, S Petri, W AF Peterson, K. Haque, R. Mondal, D. Duggal, P. Sher, A. Ricklefs, S. Porcella, S. Petri, W. TI The study of associations between Entamoeba histolytica infection and disease with single nucleotide polymorphisms in immune response genes SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Meeting Abstract C1 [Peterson, K.; Petri, W.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Haque, R.; Mondal, D.] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Duggal, P.] Natl Ctr Human Genome Res, NIH, Baltimore, MD USA. [Sher, A.] NIAID, NIH, Bethesda, MD 20892 USA. [Ricklefs, S.; Porcella, S.] NIAID, NIH, Rocky Mt Labs, Hamilton, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD MAY PY 2007 VL 12 SU 1 BP 149 EP 150 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 302FP UT WOS:000255954500423 ER PT J AU Deter, RL Li, J Lee, W Liu, S Romero, R AF Deter, R. L. Li, J. Lee, W. Liu, S. Romero, R. TI Quantitative assessment of gestational sac shape: the gestational sac shape score SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE gestational sac; gestational sac shape score; quantitative shape analysis ID 3-DIMENSIONAL ULTRASOUND; VOLUME; PREGNANCY AB Objective To develop a quantitative method for characterizing gestational sac shape. Methods Twenty first-trimester gestational sacs in normal pregnancies were studied with three-dimensional (3D) ultrasonography. The 3D coordinates of surface-point sets were obtained for each sac using 30-, 15- and six-slice sampling. Cubic spline interpolation was used with the 15- and six-slice surface-point samples to generate coordinates for those 30-slice surface points not measured. Interpolated and measured values, the latter from the 30-slice sample, were compared and the percent error calculated. Cubic spline interpolation was used to determine the coordinates of a standard surface-point sample (3660) for each sac in each slice sample. These coordinate data were used to give each sac a standard configuration by moving its center of gravity to the origin, aligning its inertial axes along the coordinate axes and converting its volume to 1.0 mL. In this form, a volume shape descriptor could be generated for each sac that was then transformed into a vector containing only shape information. The 20 shape vectors of each slice sample were subjected to principal components analysis, and principal component scores (PCSs) calculated. The first four PCSs were used to define a gestational sac shape score (GSSS-30, GSSS-15 or GSSS-6) for each sac in a given slice sample. The characteristics of each set of GSSSs were determined and those for the GSSS-15 and GSSS-6 were compared with the GSSS-30 characteristics. Results Cubic spline interpolations were very accurate in most cases, with means close to 0%, and approximately 95% of the errors being less than 10%. GSSS-30 accounted for 67.6% of the shape variance, had a mean of zero and an SD of 1.1, was normally distributed and was not related to menstrual age (R = -0.16, P = 0.51). GSSS-15 and GSSS-6 had essentially the same characteristics. No significant differences between individual GSSS-30 values and those for GSSS-15 or GSSS-6 were found, indicating the absence of a slice sample effect. Conclusion Using sophisticated mathematical methods, the gestational sac shape, initially represented by the 3D coordinates of 3660 surface points, was converted to a single number, the GSSS. This score had the appropriate properties for quantitatively characterizing normal, first-trimester gestational sac shapes. As it can be obtained from as few as six slices, it should be useful in many clinical situations. This novel approach has the potential for providing quantitative shape information about a variety of biological shapes and how they change over time. Copyright (c) 2007 ISUOG. Published by John Wiley & Sons, Ltd. C1 Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Oakland Univ, Dept Comp Sci & Engn, Rochester, MI USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Deter, RL (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, 1 Baylor Pl, Houston, TX 77030 USA. EM russelld@bcm.tmc.edu FU Intramural NIH HHS [ZIA HD002401-17] NR 25 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD MAY PY 2007 VL 29 IS 5 BP 574 EP 582 DI 10.1002/uog.3994 PG 9 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 173NC UT WOS:000246878800016 PM 17444551 ER PT J AU Chandler, RJ Tsai, MS Dorko, K Sloan, J Korson, M Freeman, R Strom, S Venditti, CP AF Chandler, Randy J. Tsai, Matthew S. Dorko, Kenneth Sloan, Jennifer Korson, Mark Freeman, Richard Strom, Stephen Venditti, Charles P. TI Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes SO BMC MEDICAL GENETICS LA English DT Article ID LIVER-KIDNEY TRANSPLANTATION; INTERALLELIC COMPLEMENTATION; MITOCHONDRIAL IMPORT; METABOLIC STROKE; GLOBUS-PALLIDUS; GENOMIC SYSTEMS; GENE-TRANSFER; INBORN ERROR; ACIDEMIA; ACIDURIA AB Background: Methylmalonic acidemia ( MMA), a common organic aciduria, is caused by deficiency of the mitochondrial localized, 5'deoxyadenosylcobalamin dependent enzyme, methylmalonyl-CoA mutase (MUT). Liver transplantation in the absence of gross hepatic dysfunction provides supportive therapy and metabolic stability in severely affected patients, which invites the concept of using cell and gene delivery as future treatments for this condition. Methods: To assess the effectiveness of gene delivery to restore the defective metabolism in this disorder, adenoviral correction experiments were performed using murine Mut embryonic fibroblasts and primary human methylmalonyl-CoA mutase deficient hepatocytes derived from a patient who harbored two early truncating mutations, E224X and R228X, in the MUT gene. Enzymatic and expression studies were used to assess the extent of functional correction. Results: Primary hepatocytes, isolated from the native liver after removal subsequent to a combined liver-kidney transplantation procedure, or Mut murine fibroblasts were infected with a second generation recombinant adenoviral vector that expressed the murine methylmalonyl-CoA mutase as well as eGFP from distinct promoters. After transduction, [1-C-14] propionate macromolecular incorporation studies and Western analysis demonstrated complete correction of the enzymatic defect in both cell types. Viral reconstitution of enzymatic expression in the human methylmalonyl-CoA mutase deficient hepatocytes exceeded that seen in fibroblasts or control hepatocytes. Conclusion: These experiments provide proof of principle for viral correction in methylmalonic acidemia and suggest that hepatocyte-directed gene delivery will be an effective therapeutic treatment strategy in both murine models and in human patients. Primary hepatocytes from a liver that was unsuitable for transplantation provided an important resource for these studies. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Biochem & Mol Biol, Washington, DC 20057 USA. Univ Miami, Miller Sch Med, Miami, FL 33136 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. Tufts Univ, Sch Med, Div Metab, Boston, MA 02111 USA. Tufts Univ, Sch Med, Div Transplantat, Boston, MA 02111 USA. RP Venditti, CP (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM rchandler@mail.nih.gov; matt.tsai@gmail.com; dorkok@pitt.edu; jsloan@mail.nih.gov; mkorson@tufts-nemc.org; RFreeman@tufts-nemc.org; strom@pitt.edu; venditti@mail.nih.gov OI Strom, Stephen/0000-0002-2889-3387 FU Intramural NIH HHS [Z01 HG200318-04, Z01 HG200318-05, Z99 HG999999]; NIDDK NIH HHS [DK-9-2310] NR 42 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD APR 30 PY 2007 VL 8 AR 24 DI 10.1186/1471-2350-8-24 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 170XX UT WOS:000246700600001 PM 17470278 ER PT J AU Kim, MA Kim, HJ Brown, AL Lee, MY Bae, YS Park, JI Kwak, JY Chung, JH Yun, J AF Kim, Myoung-Ae Kim, Hyun-Ju Brown, Alexandra L. Lee, Min-Young Bae, Yoe-Sik Park, Joo-In Kwak, Jong-Young Chung, Jay H. Yun, Jeanho TI Identification of novel substrates for human checkpoint kinase Chk1 and Chk2 through genome-wide screening using a consensus Chk phosphorylation motif SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE checkpoint kinase 1; checkpointkinase 2; DNA damage; phosphorylation; substrate specificity ID DNA-DAMAGE-RESPONSE; HISTONE DEACETYLASES; PROTEIN; P53; EXPRESSION; MUTATIONS; CELLS; PROLIFERATION; TRANSCRIPTION; INSTABILITY AB Checkpoint kinase 1 (Chkl) and Chk2 are effector kinases in the cellular DNA damage response and impairment of their function is closely related to tumorigenesis. Previous studies revealed several substrate proteins of Chk1 and Chk2, but identification of additional targets is still important in order to understand their tumor suppressor functions. In this study, we screened novel substrates for Chkl and Chk2 using substrate target motifs determined previously by an oriented peptide library approach. The potential candidates were selected by genome-wide peptide database searches and were examined by in vitro kinase assays. ST5, HDAC5, PGC-1 alpha, PP2A PR130, FANCG, GATA3, cyclin G, Rad51D and MAD1a were newly identified as in vitro substrates for Chk1 and/or Chk2. Among these, HDAC5 and PGC-1 alpha were further analyzed to substantiate the screening results. Immunoprecipitation kinase assay of full-length proteins and site-directed mutagenesis analysis of the target motifs demonstrated that HDAC5 and PGC-1 alpha were specific targets for Chk1 and/or Chk2 at least in vitro. C1 Dong A Univ, Med Res Ctr Canc Mol Therapy, Coll Med, Pusan 602714, South Korea. Dong A Univ, Dept Biochem, Coll Med, Pusan 602714, South Korea. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Yun, J (reprint author), Dong A Univ, Med Res Ctr Canc Mol Therapy, Coll Med, Pusan 602714, South Korea. EM yunj@dau.ac.kr NR 32 TC 30 Z9 30 U1 1 U2 3 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD APR 30 PY 2007 VL 39 IS 2 BP 205 EP 212 PG 8 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 164EZ UT WOS:000246217600009 PM 17464182 ER PT J AU Kurlan, R Murphy, D AF Kurlan, Roger Murphy, Diane TI Parkinson's disease data and organizing center SO MOVEMENT DISORDERS LA English DT Letter C1 Univ Rochester, Sch Med, Dept Neurol, Rochester, NY 14627 USA. NINDS, Neurodegenerat Program, Bethesda, MD 20892 USA. RP Kurlan, R (reprint author), Univ Rochester, Sch Med, Dept Neurol, Rochester, NY 14627 USA. EM Roger_Kurlan@urmc.rochester.edu FU NINDS NIH HHS [U01 NS050095, U01 NS050095-04, U01NS050095] NR 0 TC 6 Z9 6 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR 30 PY 2007 VL 22 IS 6 BP 904 EP 905 DI 10.1002/mds.21415 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 163KQ UT WOS:000246159000031 PM 17343272 ER PT J AU Scarpa, B Dunson, DB AF Scarpa, Bruno Dunson, David B. TI Bayesian methods for searching for optimal rules for timing intercourse to achieve pregnancy SO STATISTICS IN MEDICINE LA English DT Article DE Bayesian model selection; conception probability; decision theory; Gibbs sampler; loss function; stochastic search; time to pregnancy ID DECISION-ANALYSIS; MENSTRUAL-CYCLE; FERTILITY; OVULATION; CONCEPTION; FECUNDABILITY; PROBABILITIES; INFERTILITY; SIMULATION; STERILITY AB With societal trends towards increasing age at starting a pregnancy attempt, many women are concerned about achieving conception before the onset of infertility, which precedes menopause. Couples failing to conceive a pregnancy within 12 months are classified as clinically infertile, and may be recommended for assisted reproductive therapy (ART). Because many ART procedures are expensive and may convey an increased risk of adverse outcomes for the offspring, it is advantageous to decrease time to pregnancy by natural methods. One possibility is to intentionally time intercourse during the days of the menstrual cycle having the highest conception probabilities. This article proposes a Bayesian decision theoretic approach for searching for optimal rules for timing intercourse based on cycle day, secretions and other information. Good rules result in high conception probabilities while requiring minimal targeted intercourse. A biologically based statistical model is used to relate cycle day and biomarkers to the conception probability. A stochastic search procedure is then developed to search for rules with high expected utility, and the methods are applied to data from a recent Italian study. Copyright (c) 2007 John Wiley & Sons, Ltd. C1 NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Univ Padua, Dept Stat Sci, Padua, Italy. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. EM dunson1@niehs.nih.gov NR 41 TC 10 Z9 10 U1 1 U2 3 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 APR 30 PY 2007 VL 26 IS 9 BP 1920 EP 1936 DI 10.1002/sim.2846 PG 17 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 154AQ UT WOS:000245479600002 PM 17328097 ER PT J AU Fay, MP Feuer, EJ AF Fay, Michael P. Feuer, Eric J. TI A semi-parametric estimate of extra-Poisson variation for vital rates - Authors' reply SO STATISTICS IN MEDICINE LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 6700-B Rockledge Dr, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 4 TC 0 Z9 0 U1 0 U2 0 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 APR 30 PY 2007 VL 26 IS 9 BP 2133 EP 2135 DI 10.1002/sim.2745 PG 3 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 154AQ UT WOS:000245479600015 ER PT J AU Cook, NR Cutler, JA Obarzanek, E Buring, JE Rexrode, KM Kumanyika, SK Appel, LJ Whelton, PK AF Cook, Nancy R. Cutler, Jeffrey A. Obarzanek, Eva Buring, Julie E. Rexrode, Kathryn M. Kumanyika, Shiriki K. Appel, Lawrence J. Whelton, Paul K. TI Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP) SO BRITISH MEDICAL JOURNAL LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; JOINT NATIONAL COMMITTEE; NORMAL BLOOD-PRESSURE; SALT REDUCTION; NONPHARMACOLOGIC INTERVENTIONS; RANDOMIZED-TRIALS; URINARY SODIUM; PUBLIC-HEALTH; WEIGHT-LOSS; PHASE-I AB Objective To examine the effects of reduction in dietary sodium intake on cardiovascular events using data from two completed randomised trials, TOHP I and TOHP II. Design Long term follow-up assessed 10-15 years after the original trial. Setting 10 clinic sites in 1987-90 (TOHP I) and nine sites in 1990-5 (TOHP II). Central follow-up conducted by post and phone. Participants Adults aged 30-54 years with prehypertension. Intervention Dietary sodium reduction, including comprehensive education and counselling on reducing intake, for 18 months (TOHP I) or 36-48 months (TOHP II). Main outcome measure Cardiovascular disease (myocardial infarction, stroke, coronary revascularisation, or cardiovascular death). Results 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2415 (77016), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P=0.34). Conclusion Sodium-reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Baltimore, MD USA. Loyola Univ Hlth Syst, Maywood, IL USA. RP Cook, NR (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM ncook@rics.bwh.harvard.edu OI Rexrode, Kathryn/0000-0003-3387-8429 FU NHLBI NIH HHS [HL37906, HL057915, HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37907, HL37924, R01 HL057915] NR 46 TC 525 Z9 548 U1 12 U2 60 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD APR 28 PY 2007 VL 334 IS 7599 BP 885 EP 888B DI 10.1136/bmj.39147.604896.55 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 164FB UT WOS:000246217800029 PM 17449506 ER PT J AU Golin, J Ambudkar, SV May, L AF Golin, John Ambudkar, Suresh V. May, Leopold TI The yeast Pdr5p multidrug transporter: How does it recognize so many substrates? SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Review DE yeast multidrug resistance; Pdr5; ABC transporter; substrate specificity ID MULTIPLE-DRUG RESISTANCE; HUMAN P-GLYCOPROTEIN; SACCHAROMYCES-CEREVISIAE; ABC TRANSPORTERS; GENE-PRODUCT; PROTEIN; MECHANISM; BINDING; EFFLUX; TRANSCRIPTION AB Multidrug transporters are of considerable importance because they present problems in the treatment of infectious disease and cancer. A central issue is the ability of efflux pumps to recognize an astounding array of structurally diverse compounds. The yeast Pdr5p efflux pump, which is a member of the ATP-binding cassette superfamily, has at least 3 substrate-binding sites, each of which appears to use different chemical properties to transport compounds. All Pdr5p substrates, however, have a size requirement that is independent of hydrophobicity. (c) 2007 Elsevier Inc. All rights reserved. C1 Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. RP Golin, J (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. EM golin@cua.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM066026] NR 34 TC 27 Z9 28 U1 2 U2 8 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 APR 27 PY 2007 VL 356 IS 1 BP 1 EP 5 DI 10.1016/j.bbrc.2007.02.011 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 153GE UT WOS:000245419300001 PM 17316560 ER PT J AU Nacak, TG Alajati, A Leptien, K Fulda, C Weber, H Miki, T Czepluch, FS Waltenberger, J Wieland, T Augustin, HG Kroll, J AF Nacak, Tanju G. Alajati, Abdullah Leptien, Kerstin Fulda, Christine Weber, Holger Miki, Toru Czepluch, Frauke S. Waltenberger, Johannes Wieland, Thomas Augustin, Hellmut G. Kroll, Jens TI The BTB-Kelch protein KLEIP controls endothelial migration and sprouting angiogenesis SO CIRCULATION RESEARCH LA English DT Article DE BTB-kelch protein KLEIP; angiogenesis; migration; hypoxia; G proteins ID RENAL-CELL CARCINOMA; VEGF RECEPTOR-2 KDR; GROWTH-FACTOR; ACTIN REORGANIZATION; NITRIC-OXIDE; EXPRESSION; ACTIVATION; HYPOXIA; ECT2; CYTOKINESIS AB Sprouting and invasive migration of endothelial cells are important steps of the angiogenic cascade. Vascular endothelial growth factor ( VEGF) induces angiogenesis by activating intracellular signal transduction cascades, which regulate endothelial cell morphology and function. BTB-kelch proteins are intracellular proteins that control cellular architecture and cellular functions. The BTB-kelch protein KLEIP has been characterized as an actin-binding protein that interacts with the nucleotide exchange factor ECT2. We report that KLEIP is preferentially expressed in endothelial cells, suggesting that it may play a critical role in controlling the functions of migrating, proliferating, and invading endothelial cells during angiogenesis. KLEIP mRNA level in endothelial cells is strongly regulated by hypoxia which is controlled by hypoxia-inducible factor-1 alpha. Functional analysis of KLEIP in endothelial cells revealed that it acts as an essential downstream regulator of VEGF- and basic fibroblast growth factor-induced migration and in-gel sprouting angiogenesis. Yet, it is not involved in controlling VEGF- or basic fibroblast growth factor-mediated proliferative responses. The depletion of KLEIP in endothelial cells blunted the VEGF- induced activation of the monomeric GTPase RhoA but did not alter the VEGF- stimulated activation of extracellular signal-regulated kinase 1/2. Moreover, VEGF induced a physical association of KLEIP with the guanine nucleotide-exchange factor ECT2, the depletion of which also blunted VEGF- induced sprouting. We conclude that the BTB-kelch protein KLEIP is a novel regulator of endothelial function during angiogenesis that controls the VEGF- induced activation of Rho GTPases. C1 Univ Heidelberg, Med Fac Mannheim, Joint Res Div Vasc Biol, D-68167 Mannheim, Germany. Univ Heidelberg, Med Fac Mannheim, Inst Pharmacol & Toxicol, D-68167 Mannheim, Germany. Maastricht Univ, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands. Natl Canc Inst, Bethesda, MD USA. Tumor Biol Ctr, Dept Vasc Biol & Angiogenesis Res, Freiburg, Germany. RP Kroll, J (reprint author), Univ Heidelberg, Med Fac Mannheim, Joint Res Div Vasc Biol, Theodor Kutzer Ufer 1-3,Bldg 28 Level 0, D-68167 Mannheim, Germany. EM jens_kroll@web.de RI Wieland, Thomas/G-1772-2012; OI Waltenberger, Johannes/0000-0002-2417-9880; Augustin, Hellmut/0000-0002-7173-4242 NR 41 TC 22 Z9 23 U1 0 U2 0 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 APR 27 PY 2007 VL 100 IS 8 BP 1155 EP 1163 DI 10.1161/01.RES.0000265844.56493.ac PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 161JT UT WOS:000246011900009 PM 17395875 ER PT J AU Grubina, R Huang, Z Shiva, S Joshi, MS Azarov, I Basu, S Ringwood, LA Jiang, A Hogg, N Kim-Shapiro, DB Gladwin, MT AF Grubina, Rozalina Huang, Zhi Shiva, Sruti Joshi, Mahesh S. Azarov, Ivan Basu, Swati Ringwood, Lorna A. Jiang, Alice Hogg, Neil Kim-Shapiro, Daniel B. Gladwin, Mark T. TI Concerted nitric oxide formation and release from the simultaneous reactions of nitrite with deoxy- and oxyhemoglobin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BLOOD-FLOW REGULATION; ELECTRON-PARAMAGNETIC-RESONANCE; S-NITROSOHEMOGLOBIN; HYPOXIC CONDITIONS; AUTOCATALYTIC OXIDATION; XANTHINE OXIDOREDUCTASE; ISCHEMIA-REPERFUSION; MEDIATED OXIDATION; HUMAN CIRCULATION; HUMAN HEMOGLOBIN AB Recent studies reveal a novel role for hemoglobin as an allosterically regulated nitrite reductase that may mediate nitric oxide (NO)-dependent signaling along the physiological oxygen gradient. Nitrite reacts with deoxyhemoglobin in an allosteric reaction that generates NO and oxidizes deoxyhemoglobin to methemoglobin. NO then reacts at a nearly diffusion-limited rate with deoxyhemoglobin to form iron-nitrosyl-hemoglobin, which to date has been considered a highly stable adduct and, thus, not a source of bioavailable NO. However, under physiological conditions of partial oxygen saturation, nitrite will also react with oxyhemoglobin, and although this complex autocatalytic reaction has been studied for a century, the interaction of the oxy- and deoxy-reactions and the effects on NO disposition have never been explored. We have now characterized the kinetics of hemoglobin oxidation and NO generation at a range of oxygen partial pressures and found that the deoxy-reaction runs in parallel with and partially inhibits the oxy-reaction. In fact, intermediates in the oxy-reaction oxidize the heme iron of iron nitrosyl hemoglobin, a product of the deoxy-reaction, which releases NO from the iron-nitrosyl. This oxidative denitrosylation is particularly striking during cycles of hemoglobin deoxygenation and oxygenation in the presence of nitrite. These chemistries may contribute to the oxygen-dependent disposition of nitrite in red cells by limiting oxidative inactivation of nitrite by oxyhemoglobin, promoting nitrite reduction to NO by deoxyhemoglobin, and releasing free NO from iron-nitrosyl-hemoglobin. C1 NHLBI, Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Natl Inst Hlth, Res Scholars Program, Bethesda, MD 20814 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. RP Gladwin, MT (reprint author), NHLBI, Vasc Med Branch, Dept Crit Care Med, Ctr Clin,NIH, Bldg 10 CRC,Rm 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov OI Azarov, Ivan/0000-0002-9886-3298 FU Intramural NIH HHS; NHLBI NIH HHS [HL58091, R01 HL058091, R37 HL058091, HL078706] NR 60 TC 104 Z9 104 U1 2 U2 10 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 APR 27 PY 2007 VL 282 IS 17 BP 12916 EP 12927 DI 10.1074/jbc.M700546200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 160LR UT WOS:000245942800063 PM 17322300 ER PT J AU Brister, JR Nossal, NG AF Brister, J. Rodney Nossal, Nancy G. TI Multiple origins of replication contribute to a discontinuous pattern of DNA synthesis across the T4 genome during infection SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE bacteriophage; T4; origins; DNA; replication ID DEFECTIVE PHAGE SYSTEM; ESCHERICHIA-COLI; BACTERIOPHAGE-T4 PROTEINS; IN-VITRO; RECOMBINATION; HELICASE; GENE; POLYMERASE; MUTATIONS; COMPLEX AB Chromosomes provide a template for a number of DNA transactions, including replication and transcription, but the dynamic interplay between these activities is poorly understood at the genomic level. The bacteriophage T4 has long served as a model for the study of DNA replication, transcription, and recombination, and should be an excellent model organism in which to integrate in vitro biochemistry into a chromosomal context. As a first step in characterizing the dynamics of chromosomal transactions during T4 infection, we have employed a unique set of macro array strategies to identify the origins of viral DNA synthesis and monitor the actual accumulation of nascent DNA across the genome in real time. We show that T4 DNA synthesis originates from at least five discrete loci within a single population of infected cells, near oriA, oriC, oriE, oriF, and oriG, the first direct evidence of multiple, active origins within a single population of infected cells. Although early T4 DNA replication is initiated at defined origins, continued synthesis requires viral recombination. The relationship between these two modes of replication during infection has not been well understood, but we observe that the switch between origin and recombination-mediated replication is dependent on the number of infecting viruses. Finally, we demonstrate that the nascent DNAs produced from origin loci are regulated spatially and temporally, leading to the accumulation of multiple, short DNAs near the origins, which are presumably used to prime subsequent recombination-mediated replication. These results provide the foundation for the future characterization of the molecular dynamics that contribute to T4 genome function and evolution and may provide insights into the replication of other multi origin chromosomes. Published by Elsevier Ltd. C1 NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Brister, JR (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jamesbr@niddk.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 49 TC 6 Z9 6 U1 2 U2 5 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 APR 27 PY 2007 VL 368 IS 2 BP 336 EP 348 DI 10.1016/j.jmb.2007.02.008 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 159WD UT WOS:000245897400005 PM 17346743 ER PT J AU Wu, ZB Li, XQ Ericksen, B de Leeuw, E Zou, GZ Zeng, PY Xie, C Li, C Lubkowski, J Lu, WY Lu, WY AF Wu, Zhibin Li, Xiangqun Ericksen, Bryan de Leeuw, Erik Zou, Guozhang Zeng, Pengyun Xie, Cao Li, Chong Lubkowski, Jacek Lu, Wei-Yue Lu, Wuyuan TI Impact of pro segments on the folding and function of human neutrophil alpha-defensins SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE defensin; HNP; pro peptide; native chemical ligation; chaperone ID ANTIMICROBIAL PEPTIDES; LYTIC PROTEASE; MAMMALIAN DEFENSINS; CHEMICAL-SYNTHESIS; DENDRITIC CELLS; PROTEINS; MEMBRANES; BINDING; REGION; DESTABILIZATION AB Human neutrophil alpha-defensins (HNPs) are synthesized in vivo as inactive precursor proteins, i.e. preproHNPs. A series of sequential proteolytic events excise the N-terminal inhibitory pro peptide, leading to defensin maturation and storage in azurophilic granules. The anionic pro peptide, required for correct sub-cellular trafficking and sorting of proHNPs, inhibits the antimicrobial activity of cationic defensins, either inter or intramolecularly, presumably through charge neutralization. To better understand the role of the pro peptide in the folding and functioning of alpha-defensins and/or pro alpha-defensins, we chemically attached the proHNP1 pro peptide or (wt)pro peptide and the following artificial pro segments to the N terminus of HNP1: polyethylene glycol (PEG), Arg(10) (polyR), Ser(10) (polyS), and (cr)pro peptide, a charge-reversing mutant of the pro peptide where Arg/Lys residues were changed to Asp, and Asp/Glu residues to Lys. Comparative in vitro folding suggested that while all artificial pro segments chaperoned defensin folding, with PEG being the most efficient, the pro peptide catalyzed the folding of proHNPs likely through two independent mechanisms: solubilization of and interaction with the C-terminal defensin domain. Further, the N-terminal artificial pro segments dramatically altered the bactericidal activity of HNP1 against both Escherichia coli and Staphylococcus aureus. Surprisingly, "pro peptide and Wtpro peptide showed similar properties with respect to intra-molecular and inter-molecular catalysis of defensin folding as well as ot-defens-in binding, although their binding modes appeared different. Our findings identify a dual chaperone activity of the pro peptide and may shed light on the molecular mechanisms by which pro et-defensins fold in vivo. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Fudan Univ, Sch Pharm, Fudan PharmCo Target Res Ctr, Shanghai 200032, Peoples R China. NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. RP Lu, WY (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM luw@umbi.umd.edu RI Lu, Wuyuan/B-2268-2010; Li, Chong/H-2515-2011; Ericksen, Bryan/F-9047-2012; Lu, Weiyue/E-7938-2010 FU NIAID NIH HHS [AI056264, AI061482, R01 AI061482, R01 AI061482-03, R01 AI072732, R01 AI072732-01, R21 AI056264] NR 56 TC 18 Z9 20 U1 1 U2 6 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 APR 27 PY 2007 VL 368 IS 2 BP 537 EP 549 DI 10.1016/j.jmb.2007.02.040 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 159WD UT WOS:000245897400021 PM 17355880 ER PT J AU Kristiansen, M Deriziotis, P Dimcheff, DE Jackson, GS Ovaa, H Naumann, H Clarke, AR van Leeuwen, FWB Menendez-Benito, V Dantuma, NP Portis, JL Collinge, J Tabrizi, SJ AF Kristiansen, Mark Deriziotis, Pelagia Dimcheff, Derek E. Jackson, Graham S. Ovaa, Huib Naumann, Heike Clarke, Anthony R. van Leeuwen, Fijs W. B. Menendez-Benito, Victoria Dantuma, Nico P. Portis, John L. Collinge, John Tabrizi, Sarah J. TI Disease-associated prion protein oligomers inhibit the 26S proteasome SO MOLECULAR CELL LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; SCRAPIE-INFECTED MICE; NEURODEGENERATIVE DISEASES; UBIQUITIN; SYSTEM; DEGRADATION; PRP; NEUROTOXICITY; IMPAIRMENT; PEPTIDE AB The mechanism of cell death in prion disease is unknown but is associated with the production of a misfolded conformer of the prion protein. We report that disease-associated prion protein specifically inhibits the proteolytic beta subunits of the 26S proteasome. Using reporter substrates, fluorogenic peptides, and an activity probe for the beta subunits, this inhibitory effect was demonstrated in pure 26S proteasome and three different cell lines. By challenge with recombinant prion and other amyloidogenic proteins, we demonstrate that only the prion protein in a normative beta sheet conformation inhibits the 26S proteasome at stoichiometric concentrations. Preincubation with an antibody specific for aggregation intermediates abrogates this inhibition, consistent with an oligomeric species mediating this effect. We also present evidence for a direct relationship between prion neuropathology and impairment of the ubiquitin-proteasome system (UPS) in prion-infected UPS-reporter mice. Together, these data suggest a mechanism for intracellular neurotoxicity mediated by oligomers of misfolded prion protein. C1 UCL, Neurol Inst, Dept Neurodegenerat Dis, London WC1N 3BG, England. UCL, MRC, Prion Unit, London WC1N 3BG, England. NIAID, Lab Persistant Viral Dis, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. Netherlands Canc Inst, Div Cellular Biochem, NL-1066 CX Amsterdam, Netherlands. Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. RP Tabrizi, SJ (reprint author), UCL, Neurol Inst, Dept Neurodegenerat Dis, Queen Sq, London WC1N 3BG, England. EM sarah.tabrizi@prion.ucl.ac.uk RI Derizioti, Pelagia/C-3857-2015; OI Derizioti, Pelagia/0000-0001-5544-8345; Dantuma, Nico/0000-0002-6090-4170; Tabrizi, Sarah/0000-0003-2716-2045; Jackson, Graham/0000-0002-3125-2011; van leeuwen, Fijs/0000-0002-6844-4025; Menendez-Benito, Victoria/0000-0001-5312-3037 FU Intramural NIH HHS; Medical Research Council [G0700877, MC_U123160656, MC_U123170362, MC_U123192748] NR 55 TC 151 Z9 156 U1 0 U2 13 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 APR 27 PY 2007 VL 26 IS 2 BP 175 EP 188 DI 10.1016/j.molcel.2007.04.001 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 162UU UT WOS:000246115800006 PM 17466621 ER PT J AU Martin, W Dagan, T Koonin, EV Dipippo, JL Gogarten, JP Lake, JA AF Martin, William Dagan, Tal Koonin, Eugene V. Dipippo, Jonathan L. Gogarten, J. Peter Lake, James A. TI The evolution of eukaryotes SO SCIENCE LA English DT Letter ID GENES; PHYLOGENY; ORIGIN C1 Univ Dusseldorf, Inst Bot 3, D-40225 Dusseldorf, Germany. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Univ Connecticut, Storrs, CT 06269 USA. Univ Calif Los Angeles, Inst Mol Biol, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Dept Human Genet, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Natl Aeronaut & Space Adm Astrobiol Inst, Los Angeles, CA 90095 USA. RP Martin, W (reprint author), Univ Dusseldorf, Inst Bot 3, D-40225 Dusseldorf, Germany. RI Martin, William/C-5680-2008; Martin, William /O-5446-2015 OI Martin, William /0000-0003-1478-6449 NR 14 TC 21 Z9 22 U1 1 U2 6 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 APR 27 PY 2007 VL 316 IS 5824 BP 542 EP 543 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 160ZC UT WOS:000245983100019 PM 17463271 ER PT J AU Koizumi, S Shigemoto-Mogami, Y Nasu-Tada, K Shinozaki, Y Ohsawa, K Tsuda, M Joshi, BV Jacobson, KA Kohsaka, S Inoue, K AF Koizumi, Schuichi Shigemoto-Mogami, Yukari Nasu-Tada, Kaoru Shinozaki, Yoichi Ohsawa, Keiko Tsuda, Makoto Joshi, Bhalchandra V. Jacobson, Kenneth A. Kohsaka, Shinichi Inoue, Kazuhide TI UDP acting at P2Y(6) receptors is a mediator of microglial phagocytosis SO NATURE LA English DT Article ID NUCLEOTIDE RECEPTOR; APOPTOTIC CELLS; IN-VIVO; RELEASE; ATP; INVOLVEMENT; CHEMOTAXIS; ACTIVATION; MIGRATION; CLONING AB Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated(1,2) or injured(3,4), extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro(5,6) and in vivo(3,4), a previously unrecognized mechanism underlying microglial chemotaxis(5,6); in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y(6) receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y(6)-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y(6) receptors that colocalized with activated microglia were observed. Thus, the P2Y(6) receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia. C1 Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Mol & Syst Pharmacol, Fukuoka 8128582, Japan. Natl Inst Hlth Sci, Div Pharmacol, Setagaya Ku, Tokyo 1588501, Japan. Univ Yamanashi, Interdisciplinary Grad Sch Med & Engn, Dept Pharmacol, Yamanashi 4093893, Japan. Natl Inst Neurosci, Dept Neurochem, Tokyo 1878502, Japan. NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Inoue, K (reprint author), Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Mol & Syst Pharmacol, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM inoue@phar.kyushu-u.ac.jp RI Jacobson, Kenneth/A-1530-2009; Shinozaki, Youichi/E-8594-2010 OI Jacobson, Kenneth/0000-0001-8104-1493; Shinozaki, Youichi/0000-0002-6448-1304 FU Intramural NIH HHS [Z01 DK031116-20] NR 28 TC 327 Z9 344 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 26 PY 2007 VL 446 IS 7139 BP 1091 EP 1095 DI 10.1038/nature05704 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 160NU UT WOS:000245950400052 PM 17410128 ER PT J AU Pruszczyk, P Kostera-Pruszczyk, A Shatunov, A Goudeau, B Draminska, A Takeda, K Sambuughin, N Vicart, P Strelkov, SV Goldfarb, LG Kaminska, A AF Pruszczyk, Piotr Kostera-Pruszczyk, Anna Shatunov, Alexey Goudeau, Bertrand Draminska, Agnieszka Takeda, Kazuyo Sambuughin, Nyamkhishig Vicart, Patrick Strelkov, Sergei V. Goldfarb, Lev G. Kaminska, Anna TI Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE cardiomyopathy; heart failure; arrhythmia; desmin mutation ID DILATED CARDIOMYOPATHY; INTERMEDIATE-FILAMENTS; SKELETAL MYOPATHY; COILED COILS; ROD DOMAIN; GENE; ARCHITECTURE; ASSOCIATION; MECHANISM; HEART AB Background: According to the predominant view, desmin mutations cause dilated cardiomyopathy (DCM). We evaluated a family with restrictive cardiomyopathy (RCM) associated with a novel desmin mutation and reviewed recent reports regarding the frequency of RCM in patients with desmin myopathy. Methods: Cardiovascular examination was performed in three affected and five at-risk members of a family from Poland, histopathologic study of skeletal muscle biopsy was done in a single patient, and functional analysis of mutant desmin protein was carried out in cultured cells. Results: Cardiovascular assessment led to the diagnosis of RCM in affected family members. Histopathological study of skeletal muscle biopsy revealed features characteristic of desmin myopathy. A novel desmin E413K mutation was identified in each affected family member, but not unrelated controls. The pathogenicity of the E413K mutation was confirmed in transfected cell cultures showing inability of mutant desmin to form a cellular filamentous network or support a pre-existing network formed by other intermediate filaments. Three-dimensional modeling and electrostatic calculations indicated that the E413K mutation located in a functionally unique domain of desmin molecule potentially disrupts intramolecular interactions. Analysis of previously reported observations indicates that RCM in desminopathy patients may be as frequent as DCM. Conclusions: A novel E413K mutation in desmin caused autosomal dominant RCM rather than DCM. The location of the E413K mutation at a highly conserved end of the a-helical rod domain may be related to the phenotypic differences from the previously described DCM-associated desmin mutations. Functional and structural analyses of mutant desmin allowed to identify likely pathogenic mechanisms. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NINDS, NIH, Bethesda, MD 20892 USA. Med Univ Warsaw, Dept Internal Med Hypertens & Angiol, Warsaw, Poland. Med Univ Warsaw, Dept Neurol, Warsaw, Poland. Med Univ Warsaw, Dept Internal Med & Cardiol, Warsaw, Poland. RP Goldfarb, LG (reprint author), NINDS, NIH, Room 4S06,5625 Fishers Lane,MSC 9404, Bethesda, MD 20892 USA. EM GoldfarbL@ninds.nih.gov RI Shatunov, Aleksey/E-6946-2011; Strelkov, Sergei/G-7425-2014 FU Intramural NIH HHS NR 33 TC 30 Z9 34 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD APR 25 PY 2007 VL 117 IS 2 BP 244 EP 253 DI 10.1016/j.ijcard.2006.05.019 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 161VN UT WOS:000246044700017 PM 16890305 ER PT J AU Muller, KM AF Muller, Kai-Markus TI Acquiring visual object expertise: Reorganization in the ventral path SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID REPRESENTATIONS; RECOGNITION; CORTEX C1 NIMH, Unit Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. Int Max Planck Res Sch, Grad Sch Neural & Behav Sci, D-72074 Tubingen, Germany. RP Muller, KM (reprint author), NIMH, Unit Cognit Neurophysiol & Imaging, 49 Convent Dr,Room B2J-45,Mail Stop Code 4400, Bethesda, MD 20892 USA. EM muellerkm@mail.nih.gov FU Intramural NIH HHS NR 7 TC 0 Z9 0 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 APR 25 PY 2007 VL 27 IS 17 BP 4497 EP 4498 DI 10.1523/JNEUROSCI.0634-07.2007 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 165HB UT WOS:000246293900002 PM 17460062 ER PT J AU Stark, KD Lim, SY Salem, N AF Stark, Ken D. Lim, Sun-Young Salem, Norman, Jr. TI Docosahexaenoic acid and n-6 docosapentaenoic acid supplementation alter rat skeletal muscle fatty acid composition SO LIPIDS IN HEALTH AND DISEASE LA English DT Article ID HORMONE REPLACEMENT THERAPY; ACYL COMPOSITION; PROFILE; PHOSPHOLIPIDS; DEFICIENCY; METABOLISM; HUMANS; LIPIDS; WOMEN; MITOCHONDRIA AB Background: Docosahexaenoic acid (22:6n-3, DHA) and n-6 docosapentaenoic acid (22:5n-6, DPAn-6) are highly unsaturated fatty acids (HUFA, >= 20 carbons, >= 3 double bonds) that differ by a single carbon-carbon double bond at the Delta 19 position. Membrane 22:6n-3 may support skeletal muscle function through optimal ion pump activity of sarcoplasmic reticulum and electron transport in the mitochondria. Typically n-3 fatty acid deficient feeding trials utilize linoleic acid (18:2n-6, LA) as a comparison group, possibly introducing a lower level of HUFA in addition to n-3 fatty acid deficiency. The use of 22:5n-6 as a dietary control is ideal for determining specific requirements for 22:6n-3 in various physiological processes. The incorporation of dietary 22:5n-6 into rat skeletal muscles has not been demonstrated previously. A one generation, artificial rearing model was utilized to supply 22:6n-3 and/or 22:5n-6 to rats from d2 after birth to adulthood. An n-3 fatty acid deficient, artificial milk with 18:2n-6 was supplemented with 22:6n-3 and/or 22:5n-6 resulting in four artificially reared (AR) dietary groups; AR-LA, AR-DHA, AR-DPAn-6, AR-DHA+ DPAn-6. A dam reared group (DAM) was included as an additional control. Animals were sacrificed at 15 wks and soleus, white gastrocnemius and red gastrocnemius muscles were collected for fatty acid analyses. Results: In all muscles of the DAM group, the concentration of 22:5n-6 was significantly lower than 22:6n-3 concentrations. While 22:5n-6 was elevated in the AR-LA group and the AR-DPAn-6 group, 20:4n-6 tended to be higher in the AR-LA muscles and not in the AR-DPAn-6 muscles. The AR-DHA+ DPAn-6 had a slight, but non-significant increase in 22:5n-6 content. In the red gastrocnemius of the AR-DPAn-6 group, 22:5n-6 levels (8.1 +/- 2.8 wt.%) did not reciprocally replace the 22:6n-3 levels observed in AR-DHA reared rats (12.2 +/- 2.3 wt.%) suggesting a specific preference/requirement for 22:6n-3 in red gastrocnemius. Conclusion: Dietary 22:5n-6 is incorporated into skeletal muscles and appears to largely compete with 22:6n-3 for incorporation into lipids. In contrast, 18:2n-6 feeding tends to result in elevations of 20:4n-6 and restrained increases of 22:5n-6. As such, 22:5n-6 dietary comparison groups may be useful in elucidating specific requirements for 22:6n-3 to support optimal health and disease prevention. C1 Univ Waterloo, Lab Nutr & Nutraceut Res, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. Korea Maritime Univ, Div Marine Environm & Biosci, Pusan 606791, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Stark, KD (reprint author), Univ Waterloo, Lab Nutr & Nutraceut Res, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. EM kstark@uwaterloo.ca; sylim@hhu.ac.kr; nsalem@niaaa.nih.gov RI Wilkinson, Stuart/C-2802-2013; Stark, Ken/I-1347-2016 OI Stark, Ken/0000-0001-7828-4072 FU Intramural NIH HHS NR 41 TC 17 Z9 17 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD APR 25 PY 2007 VL 6 AR 13 DI 10.1186/1476-511X-6-13 PG 11 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 182GD UT WOS:000247492200001 PM 17459159 ER PT J AU Hanada, K Tanaka, Y Mizokami, M Gojobori, T Alter, HJ AF Hanada, Kousuke Tanaka, Yasuhito Mizokami, Masashi Gojobori, Takashi Alter, Harvey J. TI A reduction in selective immune pressure during the course of chronic hepatitis C correlates with diminished biochemical evidence of hepatic inflammation SO VIROLOGY LA English DT Article DE HCV; RNA virus; evolution; positive selection; immune response; selective pressure; persistent infection; E2; alanine aminotransferase (ALT) ID AMINO-ACID SITES; VIRUS-INFECTION; SEQUENCE VARIATION; NON-A; EVOLUTION; NEUTRALIZATION; TRANSFUSION; NUCLEOTIDE; VARIANTS; ANTIBODY AB It is considered that selection pressure exerted by the host immune response during early HCV infection might influence the outcome of that infection particularly as it relates to persistence or clearance of the agent. However, it is unclear whether positive selection pressure plays a role in determining the severity of hepatitis C during the course of persistent HCV infection. To address the evolutionary mechanism by which HCV escapes from the host immune response and to assess the relationship between viral evolution and hepatic inflammation, we determined 57 sequences (3-5 serial samples per patient) from 5 individuals with persistent HCV infection of genotype la who were under long-term follow-up ranging from 15.6 to 21.6 years. We applied a novel method to estimate serial alternations of selective pressure against the HCV enveloped region and compared this to fluctuation in transaminase level over time. Positive selection pressure was reduced over time postinfection, as evidenced by a reduction in nonsynonymous substitutions in the later phase of infection. Furthermore, serum transaminase, as a measure of inflammatory necrosis of hepatocytes, was reduced in parallel with decreased positive selection pressure. These results suggest that during persistent HCV infection, the virus faces diminished immune pressure over time, either from mutation to an immune resistant sequence or from immunologic exhaustion, and that this diminished immune attack is reflected in diminished inflammatory activity. This observation may be applicable to other viruses characterized by a slow rate of disease progression. (c) 2006 Elsevier Inc. All rights reserved. C1 Nagoya City Univ, Grad Sch Med Sci, Dept Clin Mol Informat Med, Mizuho Ku, Nagoya, Aichi 4678601, Japan. Natl Inst Genet, Mishima, Shizuoka 411, Japan. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Tanaka, Y (reprint author), Nagoya City Univ, Grad Sch Med Sci, Dept Clin Mol Informat Med, Mizuho Ku, Nagoya, Aichi 4678601, Japan. EM ytanaka@med.nagoya-cu.ac.jp NR 30 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD APR 25 PY 2007 VL 361 IS 1 BP 27 EP 33 DI 10.1016/j.virol.2006.10.041 PG 7 WC Virology SC Virology GA 161UQ UT WOS:000246042300004 PM 17174372 ER PT J AU Kalaydjian, A Zandi, PP Swartz, KL Eaton, WW Lyketsos, C AF Kalaydjian, A. Zandi, P. P. Swartz, K. L. Eaton, W. W. Lyketsos, C. TI How migraines impact cognitive function - Findings from the Baltimore ECA SO NEUROLOGY LA English DT Article ID AREA FOLLOW-UP; UNITED-STATES; DECLINE; HEADACHE; BRAIN; RISK; METAANALYSIS; IMPAIRMENT; HISTORY; PEOPLE AB Objective: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. Methods: The data were from Waves III ( 1993 through 1996) and IV ( 2004 through 2005) of the Baltimore Epidemiologic Catchment Area Study. Migraine headaches were diagnosed according to modified criteria of the International Headache Society. Scores on the immediate and delayed recall tests and the Mini-Mental State Examination (MMSE) were compared for migraineurs ( n = 204) vs nonmigraineurs ( n = 1,244). The longitudinal association between migraine and cognitive changes was assessed by generalized estimating equations. Results: Migraineurs scored lower on tests of immediate and delayed memory at baseline, but declined by less over time than nonmigraineurs. These associations were specific to migraineurs with aura, who declined by 1.26 ( p < 0.01) and 1.47 ( p < 0.01) words less on the immediate and delayed recall tests over the 12 years of follow-up. The effects of migraine, specifically with aura, on the MMSE were restricted to those older than 50 years. Among those younger than 50 years, migraineurs with aura declined at the same rate on the MMSE as nonmigraineurs. However, among those older than 50 years, migraineurs with aura declined by 0.99 points ( p < 0.01) less over the follow-up. Conclusions: Migraineurs, specifically those with aura, exhibited less decline on cognitive tests over time vs nonmigraineurs. For the Mini-Mental State Examination, these effects were only apparent among those who were older than 50 years. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. Johns Hopkins Univ Hosp, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. RP Kalaydjian, A (reprint author), NIMH, Sect Dev Genet Epidemiol, 35 Convent Dr,1A-108, Bethesda, MD 20892 USA. EM akalaydj@jhsph.edu NR 35 TC 33 Z9 36 U1 3 U2 39 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 24 PY 2007 VL 68 IS 17 BP 1417 EP 1424 DI 10.1212/01.wnl.0000268250.10171.b3 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 160DL UT WOS:000245919400014 PM 17452587 ER PT J AU Cobar, EA Khaliullin, RZ Bergman, RG Head-Gordon, M AF Cobar, Erika A. Khaliullin, Rustam Z. Bergman, Robert G. Head-Gordon, Martin TI Theoretical study of the rhenium-alkane interaction in transition metal-alkane sigma-complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE binding energy; C-H activation; DFT calculations; manganese ID PLESSET CORRELATION-ENERGY; DENSITY-FUNCTIONAL THEORY; H BOND ACTIVATION; REDUCTIVE ELIMINATION; POLARIZATION FUNCTIONS; ORGANOMETALLIC ALKANE; OXIDATIVE ADDITION; NMR-SPECTROSCOPY; PROGRAM PACKAGE; LOW-TEMPERATURE AB Metal-alkane binding energies have been calculated for [CpRe(CO)(2)](alkane) and [(CO)(2)M(C(5)H(4))C C(C(5)H(4))M(CO)(2)](alkane), where M = Re or Mn. Calculated binding energies were found to increase with the number of metal-alkane interaction sites. In all cases examined, the manganese-alkane binding energies were predicted to be significantly lower than those for the analogous rhenium-alkane complexes. The metal (Mn or Re)-alkane interaction was predicted to be primarily one of charge transfer, both from the alkane to the metal complex (70-80% of total charge transfer) and from the metal complex to the alkane (20-30% of the total charge transfer). C1 Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. NHLBI, Lab Computat Biol, Computat Biophys Sect, NIH, Bethesda, MD 20892 USA. Lawrence Berkeley Natl Lab, Chim Sci Div, Berkeley, CA 94720 USA. RP Bergman, RG (reprint author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. EM rbergman@berkeley.edu RI Khaliullin, Rustam/B-2672-2009 OI Khaliullin, Rustam/0000-0002-9073-6753 FU Intramural NIH HHS NR 63 TC 41 Z9 41 U1 5 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 24 PY 2007 VL 104 IS 17 BP 6963 EP 6968 DI 10.1073/pnas.0610295104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 161OK UT WOS:000246024700017 PM 17442751 ER PT J AU Grigorenko, BL Rogov, AV Topol, IA Burt, SK Martinez, HM Nemukhin, AV AF Grigorenko, Bella L. Rogov, Alexander V. Topol, Igor A. Burt, Stanley K. Martinez, Hugo M. Nemukhin, Alexander V. TI Mechanism of the myosin catalyzed hydrolysis of ATP as rationalized by molecular modeling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ATP hydrolysis; enzymatic catalysis; energy profile; quantum mechanics and molecular mechanics simulations ID SALT-BRIDGE; AB-INITIO; ADENOSINE-TRIPHOSPHATASE; FUNCTIONAL TRANSITIONS; GUANOSINE TRIPHOSPHATE; QM/MM SIMULATIONS; OXYGEN-EXCHANGE; RAS; POTENTIALS; PROTEINS AB The intrinsic chemical reaction of adenosine triphosphate (ATP) hydrolysis catalyzed by myosin is modeled by using a combined quantum mechanics and molecular mechanics (QM/MM) methodology that achieves a near ab initio representation of the entire model. Starting with coordinates derived from the heavy atoms of the crystal structure (Protein Data Bank ID code 1VOM) in which myosin is bound to the ATP analog ADP-VO4-, a minimum-energy path is found for the transformation ATP + H2O -> ADP + P-i that is characterized by two distinct events: (t) a low activation-energy cleavage of the P-gamma-O-beta gamma bond and separation of the gamma-phosphate from ADP and (h) the formation of the inorganic phosphate as a consequence of proton transfers mediated by two water molecules and assisted by the Glu-459-Arg-238 salt bridge of the protein. The minimum-energy model of the enzyme-substrate complex features a stable hydrogen-bonding network in which the lytic water is positioned favorably for a nucleophilic attack of the ATP gamma-phosphate and for the transfer of a proton to stably bound second water. In addition, the P-gamma-O-beta gamma bond has become significantly longer than in the unbound state of the ATP and thus is predisposed to cleavage. The modeled transformation is viewed as the part of the overall hydrolysis reaction occurring in the closed enzyme pocket after ATP is bound tightly to myosin and before conformational changes preceding release of inorganic phosphate. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, SAIC Frederick, Advanced Biomed Comp Ctr, Ft Detrick, MD 21702 USA. Computat Biol Consulting, Santa Rosa, CA 95405 USA. RP Nemukhin, AV (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. EM nemukhin@ncisgi.ncifcrf.gov RI Nemukhin, Alexander/P-9662-2015 FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 33 TC 42 Z9 45 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 24 PY 2007 VL 104 IS 17 BP 7057 EP 7061 DI 10.1073/pnas.0701727104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 161OK UT WOS:000246024700033 PM 17438284 ER PT J AU Sekine, H Ferreira, RC Pan-Hammarstrom, Q Graham, RR Ziemba, B de Vries, SS Liu, JB Hippen, K Koeuth, T Ortmann, W Iwahori, A Elliott, MK Offer, S Skon, C Du, LK Novitzke, J Lee, AT Zhao, NX Tompkins, JD Altshuler, D Gregersen, PK Cunningham-Rundles, C Harris, RS Her, C Nelson, DL Hammarstrom, L Gilkeson, GS Behrens, TW AF Sekine, Hideharu Ferreira, Ricardo C. Pan-Hammarstrom, Qiang Graham, Robert R. Ziemba, Beth de Vries, Sandra S. Liu, Jiabin Hippen, Keli Koeuth, Thearith Ortmann, Ward Iwahori, Akiko Elliott, Margaret K. Offer, Steven Skon, Cara Du, Likun Novitzke, Jill Lee, Annette T. Zhao, Nianxi Tompkins, Joshua D. Altshuler, David Gregersen, Peter K. Cunningham-Rundles, Charlotte Harris, Reuben S. Her, Chengtao Nelson, David L. Hammarstrom, Lennart Gilkeson, Gary S. Behrens, Timothy W. TI Role for Msh5 in the regulation of Ig class switch recombination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoglobulin subclass deficiency; mismatch repair; Msh4 ID COMMON VARIABLE IMMUNODEFICIENCY; MAJOR HISTOCOMPATIBILITY COMPLEX; MISMATCH REPAIR PROTEINS; DEFICIENCY; MEIOSIS; IMMUNOGLOBULIN; MICE; SEQUENCES; SUSCEPTIBILITY; CHROMOSOMES AB Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic H-2(b/b) MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2(b) haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway. C1 Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Karolinska Univ Hosp, SE-14186 Huddinge, Sweden. Med Univ S Carolina, Charleston, SC 29425 USA. Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. MIT, Cambridge, MA 02142 USA. Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. Feinstein Inst Med Res, Manhasset, NY 11030 USA. Washington State Univ, Pullman, WA 99164 USA. Mt Sinai Sch Med, New York, NY 10029 USA. NCI, Bethesda, MD 20892 USA. RP Behrens, TW (reprint author), Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. EM behrens.tim@gene.com RI Altshuler, David/A-4476-2009; Offer, Steven/A-7461-2013 OI Altshuler, David/0000-0002-7250-4107; FU NIAID NIH HHS [U19 AI 067152, U19 AI067152]; NIAMS NIH HHS [AR 043274, R01 AR043274] NR 37 TC 95 Z9 100 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 24 PY 2007 VL 104 IS 17 BP 7193 EP 7198 DI 10.1073/pnas.0700815104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 161OK UT WOS:000246024700056 PM 17409188 ER PT J AU Gulick, RM Lalama, CM Ribaudo, HJ Shikuma, CM Schackman, BR Schouten, J Squires, KE Koletar, SL Pilcher, CD Reichman, RC Klingman, KL Kuritzkes, DR AF Gulick, Roy M. Lalama, Christina M. Ribaudo, Heather J. Shikuma, Cecilia M. Schackman, Bruce R. Schouten, Jeffrey Squires, Kathleen E. Koletar, Susan L. Pilcher, Christopher D. Reichman, Richard C. Klingman, Karin L. Kuritzkes, Daniel R. TI Intensification of a triple-nucleoside regimen with tenofovir or efavirenz in HIV-1-infected patients with virological suppression SO AIDS LA English DT Article; Proceedings Paper CT 13th Conference on Retroviruses and Opportunistic Infections CY FEB 05-09, 2006 CL Denver, CO DE abacavir; antiretroviral therapy; efavirenz; lamivudine; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; quadruple nucleosides; tenofovir; zidovudine ID IMMUNODEFICIENCY-VIRUS-INFECTION; ABACAVIR/LAMIVUDINE/ZIDOVUDINE PLUS TENOFOVIR; ANTIRETROVIRAL DRUG-RESISTANCE; SOCIETY-USA PANEL; HIV-1 INFECTION; OPEN-LABEL; PROTEASE INHIBITORS; EQUIVALENCE TRIAL; INITIAL TREATMENT; LAMIVUDINE AB Objective: To compare a quadruple-nucleoside with an efavirenz-containing regimen for treatment of HIV-1 infection. Design: A randomized, open-label study of the AIDS Clinical Trials Group (ACTG). Methods: Subjects receiving zidovudine/lamivudine/abacavir on ACTG 5095 with HIV-1 RNA less than 200 copies/ml were randomly assigned to intensify either with tenofovir or efavirenz. Subjects were followed for time to treatment failure, defined as either virological failure or treatment discontinuation. Analyses were intent-to-treat. Results: One hundred and seventy subjects (21% women; 56% non-white) entered the study. At baseline, 95 and 73% had HIV-1-RNA levels less than 200 and 50 copies/ml, respectively; the median CD4 cell count was 453 cells/mu l. Over a median 79 weeks follow-up, 165 (97%) completed the study, three (2%) discontinued, and two (1%) died. Treatment failure occurred in 31 subjects: 18 (21%) (quadruple nucleosides) and 13 (151%) (efavirenz-containing regimen); however the failure-time curves crossed and demonstrated a non-constant treatment effect over time, characterized by more early treatment failures on the efavirenz-containing regimen and more late treatment failures on the four-nucleoside regimen. HIV-1 RNA remained suppressed in more than 88%, of subjects to less than 200 copies/ml and in more than 78% to less than 50 copies/ml at weeks 24, 48, and 72, without differences by treatment arm. There were no significant differences between the regimens in CD4 cell increases, time to new grade 3/4 adverse events, or adherence. Conclusion: The safety, tolerability, and efficacy of the four-nucleoside regimen were not significantly different from the efavirenz-containing regimen. These pilot data support further investigation of the quadruple-nucleoside regimen. (c) 2007 Lippincott Williams & Wilkins. C1 Cornell Univ, Weill Med Coll, New York, NY 10021 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Hawaii, Honolulu, HI 96822 USA. Univ Washington, Seattle, WA 98195 USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Rochester, Rochester, NY USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Gulick, RM (reprint author), Cornell Univ, Weill Med Coll, Box 566,525 E 68th St, New York, NY 10021 USA. EM rgulick@med.cornell.edu FU NCRR NIH HHS [RR 00044, RR 00046, RR 00047, RR 00052, RR 00865, RR 02635]; NIAID NIH HHS [AI 27668, AI 01781, AI 25859, AI 25868, AI 25879, AI 25897, AI 25903, AI 25915, AI 25924, AI 27658-61, AI 27664, AI 27670, AI 27673, AI 27675, AI 27767, AI 28697, AI 32775, AI 32782, AI 34832, AI 38855, AI 38858, AI 39156, AI 42848, AI 42851, AI 46339, AI 46381, AI 46386, AI 50410, AI 51966] NR 30 TC 16 Z9 16 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 APR 23 PY 2007 VL 21 IS 7 BP 813 EP 823 DI 10.1097/QAD.0b013e32805e8753 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 163MC UT WOS:000246162900004 PM 17415036 ER PT J AU Gray, RH Li, XB Kigozi, G Serwadda, D Nalugoda, F Watya, S Reynolds, SJ Wawer, M AF Gray, Ronald H. Li, Xianbin Kigozi, Godfrey Serwadda, David Nalugoda, Fred Watya, Stephen Reynolds, Steven J. Wawer, Maria TI The impact of male circumcision on HIV incidence and cost per infection prevented: a stochastic simulation model from Rakai, Uganda SO AIDS LA English DT Article DE male circumcision; HIV incidence; cost per infection; Uganda ID ANTIRETROVIRAL THERAPY; RURAL UGANDA; RISK; TRANSMISSION; COHORT; AGE AB Objectives: To estimate the impact of male circumcision on HIV incidence, the number of procedures per HIV infection averted, and costs per infection averted. Methods: A stochastic simulation model with empirically derived parameters from a cohort in Rakai, Uganda was used to estimate HIV incidence, assuming that male circumcision reduced the risks of HIV acquisition with rate ratios (RR) ranging from 0.3 to 0.6 in men, their female partners, and in both sexes combined, with circumcision coverage 0-100%. The reproductive number (R-0) was also estimated. The number of HIV infections averted per circumcision was estimated from the incident cases in the absence of surgery minus the projected number of incident cases over 10 years following circumcision. The cost per procedure ($69.00) was used to estimate the cost per HIV infection averted. Results: Baseline HIV incidence was 1.2/100 person-years. Male circumcision could markedly reduce HIV incidence in this population, particularly if there was preventative efficacy in both sexes. Under many scenarios, with RR <= 0.5, circumcision could reduce R-0 to < 1.0 and potentially abort the epidemic. The number of surgeries per infection averted over 10 years was 19-58, and the costs per infection averted was $1269-3911, depending on the efficacy of circumcision for either or both sexes, assuming 75% service coverage. However, behavioral disinhibition could offset any benefits of circumcision. Conclusion: Male circumcision could have substantial impact on the HIV epidemic and provide a cost-effective prevention strategy if benefits are not countered by behavioral disinhibition. (c) 2007 Lippincott Williams & Wilkins. C1 Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NIH, Baltimore, MD USA. Uganda Virus Res Inst, Rakai Hlth Sci Program, Entebbe, Uganda. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. Makerere Univ, Dept Urol, Kampala, Uganda. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Suite E 4321,615 N Wolfe St, Baltimore, MD 21205 USA. EM rgray@jhsph.edu NR 22 TC 77 Z9 78 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD APR 23 PY 2007 VL 21 IS 7 BP 845 EP 850 DI 10.1097/QAD.0b013e3280187544 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 163MC UT WOS:000246162900007 PM 17415039 ER PT J AU Hilmer, SN Mager, DE Simonsick, EM Cao, Y Ling, SM Windham, BG Harris, TB Hanlon, JT Rubin, SM Shorr, RI Bauer, DC Abernethy, DR AF Hilmer, Sarah N. Mager, Donald E. Simonsick, Eleanor M. Cao, Ying Ling, Shari M. Windham, B. Gwen Harris, Tamara B. Hanlon, Joseph T. Rubin, Susan M. Shorr, Ronald I. Bauer, Douglas C. Abernethy, Darrell R. TI A drug burden index to define the functional burden of medications in older people SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID NURSING-HOME RESIDENTS; COGNITIVE FUNCTION; BENZODIAZEPINE USE; BODY-COMPOSITION; ELDERLY-PEOPLE; HIP FRACTURE; RISK-FACTORS; COMMUNITY; HEALTH; ADULTS AB Background: Older people carry a high burden of illness for which medications are indicated, along with increased risk of adverse drug reactions. We developed an index to determine drug burden based on pharmacologic principles. We evaluated the relationship of this index to physical and cognitive performance apart from disease indication. Methods: Data from the Health, Aging, and Body Composition Study on 3075 well-functioning community-dwelling persons aged 70 to 79 years were analyzed by multiple linear regression to assess the cross-sectional association of drug burden index with a validated composite continuous measure for physical function, and with the Digit Symbol Substitution Test for cognitive performance. Results: Use of anticholinergic and sedative medications was associated with poorer physical performance score (anticholinergic exposure, 2.08 vs 2.21, P<.001; sedative exposure, 2.09 vs 2.19, P<.001) and cognitive performance on the Digit Symbol Substitution Test (anticholinergic exposure, 34.5 vs 35.5, P=.045; sedative exposure, 34.0 vs 35.5, P=.01). Associations were strengthened when exposure was calculated by principles of dose response. An increase of 1 U in drug burden index was associated with a deficit of 0.15 point (P<.001) on the physical function scale and 1.5 points (P=.01) on the Digit Symbol Substitution Test. These values were more than 3 times those associated with a single comorbid illness. Conclusions: The drug burden index demonstrates that anticholinergic and sedative drug exposure is associated with poorer function in community-dwelling older people. This pharmacologic approach provides a useful evidence-based tool for assessing the functional effect of exposure to medications in this population. C1 NIA, Gerontol Res Ctr, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Div Clin Pharmacol, Baltimore, MD USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN 37996 USA. RP Abernethy, DR (reprint author), NIA, Gerontol Res Ctr, Lab Clin Invest, Intramural Res Program, 5600 nathan Shock Dr, Baltimore, MD 21224 USA. EM abernethyd@grc.nia.nih.gov OI Hilmer, Sarah/0000-0002-5970-1501 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 46 TC 161 Z9 165 U1 9 U2 20 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 23 PY 2007 VL 167 IS 8 BP 781 EP 787 DI 10.1001/archinte.167.8.781 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 159YF UT WOS:000245903100006 PM 17452540 ER PT J AU Savill, NJ Shaw, DJ Deardon, R Tildesley, MJ Keeling, MJ Woolhouse, MEJ Brooks, SP Grenfell, BT AF Savill, Nicholas J. Shaw, Darren J. Deardon, Rob Tildesley, Michael J. Keeling, Matthew J. Woolhouse, Mark E. J. Brooks, Stephen P. Grenfell, Bryan T. TI Effect of data quality on estimates of farm infectiousness trends in the UK 2001 foot-and-mouth disease epidemic SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE foot-and-mouth disease; mathematical model; epidemiology ID GREAT-BRITAIN; CONTROL POLICIES; IMPACT; TRANSMISSION; STRATEGIES; LANDSCAPE; SPREAD AB Most of the mathematical models that were developed to study the UK 2001 foot-and-mouth disease epidemic assumed that the infectiousness of infected premises was constant over their infectious periods. However, there is some controversy over whether this assumption is appropriate. Uncertainty about which farm infected which in 2001 means that the only method to determine if there were trends in farm infectiousness is the fitting of mechanistic mathematical models to the epidemic data. The parameter values that are estimated using this technique, however, may be influenced by missing and inaccurate data. In particular to the UK 2001 epidemic, this includes unreported infectives, inaccurate farm infection dates and unknown farm latent periods. Here, we show that such data degradation prevents successful determination of trends in farm infectiousness. C1 Univ Edinburgh, Ctr Infect Dis, Edinburgh EH9 3JT, Midlothian, Scotland. Univ Edinburgh, RDSVS, Easter Bush Vet Ctr, Roslin EH25 9RG, Midlothian, Scotland. Cambridge Infect Dis Consortium, Dept Vet Med, Cambridge CB3 0ES, England. Univ Warwick, Dept Biol Sci, Ecol & Epidemiol Grp, Coventry CV4 7AL, W Midlands, England. Univ Cambridge, Ctr Math Sci, Star Lab, Cambridge CB3 0WB, England. Penn State Univ, Ctr Infect Dis Dynam, Dept Entomol & Biol, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Savill, NJ (reprint author), Univ Edinburgh, Ctr Infect Dis, Kings Bldg,W Mains Rd, Edinburgh EH9 3JT, Midlothian, Scotland. EM nick.savill@ed.ac.uk RI Tildesley, Michael/B-6559-2008; Keeling, Matt/J-9280-2012; OI Keeling, Matt/0000-0003-4639-4765 FU Wellcome Trust NR 13 TC 10 Z9 11 U1 0 U2 10 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD APR 22 PY 2007 VL 4 IS 13 BP 235 EP 241 DI 10.1098/rsif.2006.0178 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 162EF UT WOS:000246068900006 PM 17251150 ER PT J AU Warach, S Chalela, JA AF Warach, Steven Chalela, Julio A. TI MRI versus CT in acute stroke - Reply SO LANCET LA English DT Letter C1 NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Rm B1D733,MSC 1063, Bethesda, MD 20892 USA. EM warachs@ninds.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD APR 21 PY 2007 VL 369 IS 9570 BP 1342 EP 1342 DI 10.1016/S0140-6736(07)60622-9 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 159HL UT WOS:000245856100016 ER PT J AU Armando, I Volpi, S Aguilera, G Saavedra, JM AF Armando, Ines Volpi, Simona Aguilera, Greti Saavedra, Juan M. TI Angiotensin II AT(1) receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress SO BRAIN RESEARCH LA English DT Article DE renin-angiotensin system; hypothalamic-pituitary-adrenal axis; paraventricular nucleus; brain angiotensin II receptor; stress ID PITUITARY-ADRENAL AXIS; SPONTANEOUSLY HYPERTENSIVE-RATS; PARAVENTRICULAR NUCLEUS; MESSENGER-RNA; ADRENOCORTICOTROPIN SECRETION; DIFFERENTIAL REGULATION; REGULATORY MECHANISMS; SUBFORNICAL ORGAN; GENE-EXPRESSION; HORMONE NEURONS AB Sustained pretreatment with angiotensin II AT(1) receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT(1) receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT(1) receptor antagonist, 0.5 mg/ kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT(1) receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. in rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT(1) receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT(1) receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT(1) receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT(1) receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT(1) receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions. (c) 2007 Elsevier B.V. All rights reserved. C1 NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, Div Intramural Res Programs, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov FU Intramural NIH HHS [Z01 MH002762-11, Z99 MH999999] NR 51 TC 45 Z9 48 U1 0 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 APR 20 PY 2007 VL 1142 BP 92 EP 99 DI 10.1016/j.brainres.2007.01.037 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 158IL UT WOS:000245785000011 PM 17306778 ER PT J AU Collins, FS Finnell, RH Rossant, J Wurst, W AF Collins, Francis S. Finnell, Richard H. Rossant, Janet Wurst, Wolfgang TI A new partner for The International Knockout Mouse Consortium SO CELL LA English DT Letter C1 NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Texas Inst Genom Med, Houston, TX 77030 USA. Hosp Sick Children, Program Dev Biol, Toronto, ON M5G 1X8, Canada. GSF Natl Res Ctr Environm & Hlth, Inst Dev Genet, D-85764 Neuherberg, Germany. RP Collins, FS (reprint author), NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. EM francisc@mail.nih.gov NR 1 TC 53 Z9 56 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD APR 20 PY 2007 VL 129 IS 2 BP 235 EP 235 DI 10.1016/j.cell.2007.04.007 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 167TI UT WOS:000246474600007 PM 17448981 ER PT J AU Blumenthal, R Dimitrov, DS AF Blumenthal, Robert Dimitrov, Dimiter S. TI Targeting the sticky fingers of HIV-1 SO CELL LA English DT Editorial Material ID INHIBITION; INFECTION; PEPTIDE; FUSION; ENTRY; GP41 AB Although human blood plasma contains molecules that inhibit the activity of HIV-1, their identity is largely unknown. Winch et al. (2007) now identify a peptide corresponding to a portion of alpha 1-antitrypsin that potently inhibits entry of HIV-1 into host cells by binding to a hydrophobic segment of the viral envelope glycoprotein gp41. C1 NCI Frederick, Ctr Canc Res Nanobiol Program, NIH, Ft Detrick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI Frederick, Ctr Canc Res Nanobiol Program, NIH, Ft Detrick, MD 21702 USA. EM blumen@helix.nih.gov FU Intramural NIH HHS NR 8 TC 14 Z9 15 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD APR 20 PY 2007 VL 129 IS 2 BP 243 EP 245 DI 10.1016/j.cell.2007.04.005 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 167TI UT WOS:000246474600011 PM 17448985 ER PT J AU Novoselov, SV Kryukov, GV Xu, XM Carlson, BA Hatfield, DL Gladyshev, VN AF Novoselov, Sergey V. Kryukov, Gregory V. Xu, Xue-Ming Carlson, Bradley A. Hatfield, Dolph L. Gladyshev, Vadim N. TI Selenoprotein H is a nucleolar thioredoxin-like protein with a unique expression pattern SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SELENOCYSTEINE TRANSFER-RNAS; EUKARYOTIC SECIS ELEMENTS; GENE-EXPRESSION; MAMMALIAN SELENOPROTEIN; GLUTATHIONE-PEROXIDASE; UGA CODONS; INSERTION; BINDING; MUSCLE; FORM AB The human selenoproteome consists of 25 known selenoproteins, but functions of many of these proteins are not known. Selenoprotein H ( SelH) is a recently discovered 14-kDa mammalian protein with no sequence homology to functionally characterized proteins. By sensitive sequence and structure analyses, we identified SelH as a thioredoxin fold-like protein in which a conserved CXXU motif ( cysteine separated by two other residues from selenocysteine) corresponds to the CXXC motif in thioredoxins. These data suggest a redox function of SelH. Indeed, a recombinant SelH shows significant glutathione peroxidase activity. In addition, SelH has a conserved RKRK motif in the N-terminal sequence. We cloned wild-type and cysteine mutant forms of SelH either upstream or downstream of green fluorescent protein ( GFP) and localized this fusion protein to the nucleus in transfected mammalian cells, whereas mutations in the RKRK motif resulted in the cytosolic protein. Interestingly, the full-length SelH-GFP fusion protein localized specifically to nucleoli, whereas the N-terminal sequence of SelH fused to GFP had a diffuse nucleoplasm location. Northern blot analyses revealed low expression levels of SelH mRNA in various mouse tissues, but it was elevated in the early stages of embryonic development. In addition, SelH mRNA was overexpressed in human prostate cancer LNCaP and mouse lung cancer LCC1 cells. Down-regulation of SelH by RNA interference made LCC1 cells more sensitive to hydrogen peroxide but not to other peroxides tested. Overall, these data establish SelH as a novel nucleolar oxidoreductase and suggest that some functions in this compartment are regulated by redox and dependent on the trace element selenium. C1 Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Kryukov, Gregory/A-9592-2008; Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU Intramural NIH HHS; NIGMS NIH HHS [GM061603] NR 70 TC 61 Z9 65 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 20 PY 2007 VL 282 IS 16 BP 11960 EP 11968 DI 10.1074/jbc.M701605200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 160LK UT WOS:000245941900039 PM 17337453 ER PT J AU Hait, NC Bellamy, A Milstien, S Kordula, T Spiegel, S AF Hait, Nitai C. Bellamy, Andrea Milstien, Sheldon Kordula, Tomasz Spiegel, Sarah TI Sphingosine kinase type 2 activation by ERK-mediated phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNOMODULATORY DRUG FTY720; PLASMA-MEMBRANE; GROWTH-FACTOR; FUNCTIONAL-CHARACTERIZATION; DEPENDENT TRANSLOCATION; CELL-PROLIFERATION; MOLECULAR-CLONING; BINDING SITE; PROTEIN; SPHINGOSINE-1-PHOSPHATE AB Sphingosine 1-phosphate ( S1P), a potent lipid mediator, is a ligand for a family of five G protein-coupled receptors ( S1P1-5) that have been shown to regulate a variety of biological responses important for cancer progression. The cellular level of S1P is low and tightly regulated in a spatio-temporal manner through its synthesis catalyzed by two sphingosine kinases, denoted SphK1 and SphK2. Many stimuli activate and translocate SphK1 to the plasma membrane by mechanisms that are dependent on its phosphorylation. Much less is known about activation of SphK2. Here we demonstrate that epidermal growth factor ( EGF) as well as the protein kinase C activator, phorbol ester, induce rapid phosphorylation of hSphK2 which was markedly reduced by inhibition of MEK1/ERK pathway. Down-regulation of ERK1 blocked EGF-induced phosphorylation of SphK2. Recombinant ERK1 phosphorylated hSphK2 in vitro and increased its enzymatic activity. ERK1 also was found to be in a complex with hSphK2 in vivo. Site-directed mutagenesis indicated that hSphK2 is phosphorylated on Ser-351 and Thr-578 by ERK1 and that phosphorylation of these residues is important for EGF-stimulated migration of MDA-MB-453 cells. These studies provide the first clues to the mechanism of agonist-mediated SphK2 activation and enhance understanding of the regulation of SphK2 activity by phosphorylation and its role in movement of human breast cancer cells toward EGF. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, 1101 E Marshall St,2-011 Sanger Hall,Box 980614, Richmond, VA 23298 USA. EM sspiegel@vcu.edu FU Intramural NIH HHS; NCI NIH HHS [R01CA61774]; NIGMS NIH HHS [R37GM043880] NR 40 TC 76 Z9 78 U1 0 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 APR 20 PY 2007 VL 282 IS 16 BP 12058 EP 12065 DI 10.1074/jbc.M609559200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 160LK UT WOS:000245941900048 PM 17311928 ER PT J AU Ong, HL Liu, XB Tsaneva-Atanasova, K Singh, BB Bandyopadhyay, BC Swaim, WD Russell, JT Hegde, RS Sherman, A Ambudkar, IS AF Ong, Hwei Ling Liu, Xibao Tsaneva-Atanasova, Krasimira Singh, Brij B. Bandyopadhyay, Bidhan C. Swaim, William D. Russell, James T. Hegde, Ramanujan S. Sherman, Arthur Ambudkar, Indu S. TI Relocalization of STIM1 for activation of store-operated Ca2+ entry is determined by the depletion of subplasma membrane endoplasmic reticulum Ca2+ store SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMA-MEMBRANE; CHANNEL FUNCTION; CRAC CHANNELS; CALCIUM-ENTRY; GLAND CELLS; INFLUX; SENSOR; DYNAMICS; RELEASE; ORAI1 AB STIM1 (stromal interacting molecule 1), an endoplasmic reticulum (ER) protein that controls store-operated Ca2+ entry (SOCE), redistributes into punctae at the cell periphery after store depletion. This redistribution is suggested to have a causal role in activation of SOCE. However, whether peripheral STIM1 punctae that are involved in regulation of SOCE are determined by depletion of peripheral or more internal ER has not yet been demonstrated. Here we show that Ca2+ depletion in subplasma membrane ER is sufficient for peripheral redistribution of STIM1 and activation of SOCE. 1 mu M thapsigargin (Tg) induced substantial depletion of intracellular Ca2+ stores and rapidly activated SOCE. In comparison, 1 nM Tg induced slower, about 60 - 70% less Ca2+ depletion but similar SOCE. SOCE was confirmed by measuring I-SOC in addition to Ca2+, Mn2+, and Ba2+ entry. Importantly, 1 nM Tg caused redistribution of STIM1 only in the ER-plasma membrane junction, whereas 1 mu M Tg caused a relatively global relocalization of STIM1 in the cell. During the time taken for STIM1 relocalization and SOCE activation, 1 nM Bodipy-fluorescein Tg primarily labeled the subplasma membrane region, whereas 1 mu M Tg labeled the entire cell. The localization of Tg in the subplasma membrane region was associated with depletion of ER in this region and activation of SOCE. Together, these data suggest that peripheral STIM1 relocalization that is causal in regulation of SOCE is determined by the status of [Ca2+] in the ER in close proximity to the plasma membrane. Thus, the mechanism involved in regulation of SOCE is contained within the ER-plasma membrane junctional region. C1 NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58203 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N-113,10 Ctr Dr, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov RI Tsaneva-Atanasova, Krasimira/A-7153-2011; OI Hegde, Ramanujan/0000-0001-8338-852X; Singh, Brij/0000-0003-0535-5997; Tsaneva-Atanasova, Krasimira/0000-0002-6294-7051 FU NCRR NIH HHS [P20 RR017699, P20 RR017699-077011]; NIDCR NIH HHS [R01 DE017102-01A1, R01 DE017102, R01 DE017102-02, R01 DE017102-03] NR 42 TC 41 Z9 41 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 APR 20 PY 2007 VL 282 IS 16 BP 12176 EP 12185 DI 10.1074/jbc.M609435200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 160LK UT WOS:000245941900060 PM 17298947 ER PT J AU Hodgson, DC Gilbert, ES Dores, GAM Schonfeld, SJ Lynch, CF Storm, H Hall, P Langmark, F Pukkala, E Andersson, M Kaijser, M Joensuu, H Foss, SD Travis, LB AF Hodgson, David C. Gilbert, Ethel S. Dores, Grac A. M. Schonfeld, Sara J. Lynch, Charles F. Storm, Hans Hall, Per Langmark, Froydis Pukkala, Eero Andersson, Michael Kaijser, Magnus Joensuu, Heikki Foss, Sophie D. Travis, Lois B. TI Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INVOLVED-FIELD RADIOTHERAPY; 2ND MALIGNANCY; BREAST-CANCER; LUNG-CANCER; FOLLOW-UP; RADIATION-THERAPY; YOUNG-WOMEN; DISEASE; CHEMOTHERAPY; MESOTHELIOMA AB Purpose Hodgkin's lymphoma (HL) survivors are known to be at substantially increased risk of solid cancers (SC). However, no investigation has used multivariate modeling to estimate the relative risk (RR), excess absolute risk (EAR), and cumulative incidence for specific attained ages and ages at HL diagnosis. Patients and Methods We identified 18,862 5-year HL survivors from 13 population-based cancer registries in North America and Europe. Poisson regression was used to evaluate the effects of age at diagnosis, attained age, latency, sex, treatment, and year of diagnosis on the RR and EAR of SC. Results Among 1,490 identified SC, 850 were estimated to be in excess. For most cancer sites, both RR and EAR decreased with age at HL diagnosis and showed strong dependencies on attained age. For a patient diagnosed at age 30 years and survived to >= 40 years, modeled risks were significantly elevated for cancers of the breast (RR = 6.1), other supradiaphragmatic sites (RR = 6.0), and infradiaphragmatic sites (RR = 3.7); the largest RR (20-fold) was observed for malignant mesothelioma. Thirty- year cumulative risks of SC for men and women diagnosed at 30 years were 18% and 26%, respectively, compared with 7% and 9%, respectively, in the general population. For young HL patients, risks of breast and colorectal cancers were elevated 10 to 25 years before the age when routine screening would be recommended in the general population. Conclusion Multivariable modeling demonstrates for the first time temporal changes in SC risk not evident in unadjusted analyses, and can facilitate the development of individualized risk assessment and the creation of screening strategies for early detection. C1 Princess Margaret Hosp, Dept Radiat Oncol, Univ Hlth Network, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Iowa, Iowa City, IA USA. Danish Canc Soc, Copenhagen, Denmark. Karolinska Inst, Stockholm, Sweden. Norwegian Radium Hosp, Norwegian Canc Registry, Oslo, Norway. Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, FIN-00170 Helsinki, Finland. Univ Helsinki, Cent Hosp, Helsinki, Finland. RP Hodgson, DC (reprint author), Princess Margaret Hosp, Dept Radiat Oncol, Univ Hlth Network, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM David.Hodgson@rmp.uhn.on.ca OI Storm, Hans/0000-0001-7223-8198; Joensuu, Heikki/0000-0003-0281-2507 FU Intramural NIH HHS NR 38 TC 164 Z9 170 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2007 VL 25 IS 12 BP 1489 EP 1497 DI 10.1200/JCO.2006.09.0936 PG 9 WC Oncology SC Oncology GA 160DO UT WOS:000245920300008 PM 17372278 ER PT J AU Paz-Priel, I Long, L Helman, LJ Mackall, CL Wayne, AS AF Paz-Priel, Ido Long, Lauren Helman, Lee J. Mackall, Crystal L. Wayne, Alan S. TI Thromboembolic events in children and young adults with pediatric sarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 05-08, 2004 CL New Orleans, LA SP Amer Soc Clin Oncol ID ACUTE LYMPHOBLASTIC-LEUKEMIA; L-ASPARAGINASE THERAPY; DEEP-VEIN THROMBOSIS; IDIOPATHIC VENOUS THROMBOEMBOLISM; PROTHROMBOTIC RISK-FACTORS; ANTICARDIOLIPIN ANTIBODIES; PULMONARY-EMBOLISM; ANTIPHOSPHOLIPID ANTIBODIES; CLINICAL-SIGNIFICANCE; CANCER-PATIENTS AB Purpose Adults with malignancy are at increased risk for venous thromboembolic events (TEs). However, data in children and young adults with cancer are limited. Patients and Methods To determine the risk and clinical features of TEs in children and young adults with sarcoma, we reviewed records on 122 consecutive patients with sarcoma treated from October 1980 to July 2002. Results Twenty-three TEs were diagnosed in 19 of 122 (16%; 95% CI, 10% to 23%) patients. Prevalence by diagnosis was Ewing sarcoma, eight of 61 (13%); osteosarcoma, two of 20 (10%); rhabdomyosarcoma, four of 26 (15%); and other sarcomas, five of 15 (33%). TEs developed in 23% of patients with metastases at presentation versus 10% with localized disease (odds ratio, 2.59; 95% CI, 0.9 to 7.1; P < .06). Fifty-three percent of patients with thrombosis had a clot at presentation. A lupus anticoagulant was detected in four of five evaluated patients. There was a single fatality due to pulmonary embolism. Patients who were diagnosed with cancer after 1993 had a higher rate of TE (7% v 23%; P < .015). Of the 23 events, 43% were asymptomatic. Main sites of thromboses were deep veins of the extremities (10 of 23; 43%), pulmonary embolism (five of 23; 22%), and the inferior vena cava (four of 23; 17%). TEs were associated with tumor compression in eight of 23 (35%) and with venous catheters in three of 23 (13%). Conclusion Thromboembolism is common in pediatric patients with sarcomas. Thromboses are detected frequently around the time of oncologic presentation, may be asymptomatic, and seem to be associated with a higher disease burden. Children and young adults with sarcoma should be monitored closely for thrombosis. C1 Johns Hopkins Univ Hosp, Div Pediat Oncol, Baltimore, MD 21287 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Paz-Priel, I (reprint author), Johns Hopkins Univ Hosp, Div Pediat Oncol, Bunting Blaustein Canc Res Bldg,Room 2M52,1650 Or, Baltimore, MD 21287 USA. EM ipazpri1@jhmi.edu FU Intramural NIH HHS NR 51 TC 31 Z9 32 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2007 VL 25 IS 12 BP 1519 EP 1524 DI 10.1200/JCO.2006.06.9930 PG 6 WC Oncology SC Oncology GA 160DO UT WOS:000245920300012 PM 17442994 ER PT J AU Chen, CI Kouroukis, CT White, D Voralia, M Stadtmauer, E Stewart, AK Wright, JJ Powers, J Walsh, W Eisenhauer, E AF Chen, Christine I. Kouroukis, C. Tom White, Darrell Voralia, Michael Stadtmauer, Edward Stewart, A. Keith Wright, John J. Powers, Jean Walsh, Wendy Eisenhauer, Elizabeth TI Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: A phase II study of the National Cancer Institute of Canada Clinical Trials Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID PROTEASOME INHIBITOR BORTEZOMIB; NON-HODGKINS-LYMPHOMA; MANTLE-CELL LYMPHOMA; INTERNATIONAL WORKSHOP; REFRACTORY MYELOMA; RESPONSE CRITERIA; FLUDARABINE; MULTICENTER; RITUXIMAB; THERAPY AB Purpose To evaluate the efficacy and toxicity of single-agent bortezomib in Waldenstrom's macroglobulinemia (WM). Patients and Methods Symptomatic WM patients, untreated or previously treated, received bortezomib 1.3 mg/m(2) intravenously days 1, 4, 8, and 11 on a 21-day cycle until two cycles past complete response (CR), stable disease (SD) attained, progression (PD), or unacceptable toxicity. Responses were based on both paraprotein levels and bidimensional disease measurements. Results Twenty-seven patients were enrolled. A median of six cycles ( range, two to 39) of bortezomib were administered. Twenty-one patients had a decrease in immunoglobulin M (IgM) of at least 25%, with 12 patients (44%) reaching at least 50% IgM reduction. Using both IgM and bidimensional criteria, responses included seven partial responses (PRs; 26%), 19 SDs (70%), and one PD (4%). Total response rate was 26%. IgM reductions were prompt, with nodal responses lagging. Hemoglobin levels increased by at least 10 g/L in 18 patients (66%). Most nonhematologic toxicities were grade 1 to 2, but 20 patients (74%) developed new or worsening peripheral neuropathy (five patients with grade 3, no grade 4), a common cause for dose reduction. Onset of neuropathy was within two to four cycles and reversible in the majority. Hematologic toxicities included grade 3 to 4 thrombocytopenia in eight patients (29.6%) and neutropenia in five (19%). Toxicity led to treatment discontinuation in 12 patients (44%), most commonly because of neuropathy. Conclusion Bortezomib has efficacy in WM, but neurotoxicity can be dose limiting. The slower response in nodal disease may require prolonged therapy, perhaps with a less intensive dosing schedule to avoid early discontinuation because of toxicity. Future studies of bortezomib in combination with other agents are warranted. C1 Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. Queen Elizabeth II Hlth Sci Ctr, Halifax, NS, Canada. Saskatoon Canc Ctr, Saskatoon, SK, Canada. Eastern Cooperat Oncol Grp, Philadelphia, PA USA. NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Chen, CI (reprint author), Princess Margaret Hosp, 610 Univ Ave,Suite 5-220, Toronto, ON M5G 2M9, Canada. EM christine.chen@uhn.on.ca NR 28 TC 110 Z9 116 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2007 VL 25 IS 12 BP 1570 EP 1575 DI 10.1200/JCO.2006.07.8659 PG 6 WC Oncology SC Oncology GA 160DO UT WOS:000245920300019 PM 17353550 ER PT J AU Pyrski, M Koo, JH Polumuri, SK Ruknudin, AM Margolis, JW Schulze, DH Margolis, FL AF Pyrski, Martina Koo, Jae Hyung Polumuri, Swamy K. Ruknudin, Abdul M. Margolis, Joyce W. Schulze, Dan H. Margolis, Frank L. TI Sodium/calcium exchanger expression in the mouse and rat olfactory systems SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE olfaction; Ca2+-clearance; signal transduction; NCX ID SODIUM-CALCIUM EXCHANGER; ALTERNATIVELY SPLICED ISOFORMS; PUTATIVE PHEROMONE RECEPTORS; NUCLEOTIDE-GATED CHANNELS; MARKER PROTEIN OMP; NA+/CA2+ EXCHANGER; NA+-CA2+ EXCHANGER; MOLECULAR-CLONING; FUNCTIONAL EXPRESSION; SENSORY NEURONS AB Sodium/calcium (Na+/Ca2+) exchangers are membrane transport systems that regulate Ca2+-homeostasis in many eukaryotic cells. In olfactory and vomeronasal sensory neurons ligand-induced olfactory signal transduction is associated with influx and elevation of intracellular Ca2+, [Ca2+](i). While much effort has been devoted to the characterization of Ca2+-related excitation and adaptation events of olfactory chemosensory neurons (OSNs), much less is known about mechanisms that return [Ca2+](i) to the resting state. To identify proteins participating in the poststimulus Ca2+-clearance of mouse OSNs, we analyzed the expression of three potassium (K+)-independent (NCX1, 2, 3) and three K+-dependent (NCKX1, 2, 3) Na+/Ca2+ exchangers. In situ hybridization showed that mRNAs of all six Na+/Ca2+ exchangers coexist in neurons of the olfactory and vomeronasal systems, and that some are already detectable in the embryo. Of these, NCX1 and NCKX1 represent the most and least abundant mRNAs, respectively. Moreover, immunohistochemistry revealed that the NCX1, 2, and 3 proteins are expressed in nearly all neurons of the olfactory epithelium, the vomeronasal organ, the septal organ of Masera, and the Grueneberg ganglion. These three exchanger proteins display different expression profiles in dendrites, knobs, and plasma membranes of OSNs and in sustentacular cells. Furthermore, we show that NCX1 mRNA in rat olfactory mucosa is expressed as 8 alternative splice variants. This is the first comprehensive analysis of Na+/Ca2+ exchanger expression in the mammalian olfactory system. Our results suggest that Ca2+-extrusion by OSNs utilizes multiple different Na+/ Ca2+ exchangers and that different subtypes are targeted to different subcellular compartments. C1 Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. NIA, Lab Cardiovasc Sci, Gerontol Res Ctr, Baltimore, MD 21224 USA. German Inst Human Nutr, Dept Mol Genet, D-14558 Nuthetal, Germany. Univ Saarland, Inst Physiol, D-66421 Homburg, Germany. RP Margolis, FL (reprint author), Univ Maryland, Dept Anat & Neurobiol, Sch Med, HSF 2,S203,20 Penn St, Baltimore, MD 21201 USA. EM fmargoli@umaryland.edu FU NHLBI NIH HHS [HL-62521]; NIA NIH HHS [AG-020823]; NIDCD NIH HHS [R01 DC003112, DC-03112, DC-00347] NR 93 TC 27 Z9 27 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD APR 20 PY 2007 VL 501 IS 6 BP 944 EP 958 DI 10.1002/cne.21290 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 147AF UT WOS:000244975100010 PM 17311327 ER PT J AU Jacewicz, A Makiela, K Kierzek, A Drake, JW Bebenek, A AF Jacewicz, Agata Makiela, Karolina Kierzek, Andrzej Drake, John W. Bebenek, Anna TI The roles of Tyr391 and Tyr619 in RB69 DNA polymerase replication fidelity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA replication; replication fidelity; bacteriophage RB69; DNA polymerase; proofreading ID I KLENOW FRAGMENT; REVERSE-TRANSCRIPTASE; SYNTHESIS ERRORS; ACTIVE-SITE; BACTERIOPHAGE-T4; MUTATIONS; PROCESSIVITY; MISALIGNMENT; MECHANISM; CRYSTAL AB In the family-B DNA polymerase of bacteriophage RB69, the conserved aromatic palm-subdomain residues Tyr391 and Tyr619 interact with the last primer-template base-pair. Tyr619 interacts via a water-mediated hydrogen bond with the phosphate of the terminal primer nucleotide. The main-chain amide of Tyr391 interacts with the corresponding template nucleotide. A hydrogen bond has been postulated between Tyr391 and the hydroxyl group of Tyr567, a residue that plays a key role in base discrimination. This hydrogen bond may be crucial for forcing an infrequent Tyr567 rotamer conformation and, when the bond is removed, may influence fidelity. We investigated the roles of these residues in replication fidelity in vivo employing phage T4 rII reversion assays and an rI forward assay. Tyr391 was replaced by Phe, Met and Ala, and Tyr619 by Phe. The Y391A mutant, reported previously to decrease polymerase affinity for incoming nucleotides, was unable to support DNA replication in vivo, so we used an in vitro fidelity assay. Tyr391F/M replacements affect fidelity only slightly, implying that the bond with Tyr567 is not essential for fidelity. The Y391A enzyme has no mutator phenotype in vitro. The Y619F mutant displays a complex profile of impacts on fidelity but has almost the same mutational spectrum as the parental enzyme. The Y619F mutant displays reduced DNA binding, processivity, and exonuclease activity on single-stranded DNA and double-stranded DNA substrates. The Y619F substitution would disrupt the hydrogen bond network at the primer terminus and may affect the alignment of the 3' primer terminus at the polymerase active site, slowing chemistry and overall DNA synthesis. (c) 2007 Elsevier Ltd. All rights reserved. C1 Polish Acad Sci, Inst Biochem & Biophys, PL-02114 Warsaw, Poland. Univ Surrey, Sch Biomed & Mol Sci, Guildford GU2 7XH, Surrey, England. NIEHS, Res Triangle Pk, NC 27709 USA. RP Bebenek, A (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, PL-02114 Warsaw, Poland. EM aniab@ibb.waw.pl RI Makiela-Dzbenska, Karolina/E-6751-2016; OI Kierzek, Andrzej/0000-0002-2605-9057 FU FIC NIH HHS [R01 TW006626, R01 TW006626-01, R01 TW006626-02, R01 TW006626-03, R01 TW006626-03S1, TW006626]; Intramural NIH HHS [Z01 ES061054-10] NR 32 TC 12 Z9 12 U1 1 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 APR 20 PY 2007 VL 368 IS 1 BP 18 EP 29 DI 10.1016/j.jmb.2007.01.067 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 156TJ UT WOS:000245672500003 PM 17321543 ER PT J AU Blaszczyk, J Li, Y Gan, JH Yan, HG Ji, XH AF Blaszczyk, Jaroslaw Li, Yue Gan, Jianhua Yan, Honggao Ji, Xinhua TI Structural basis for the aldolase and epirnerase activities of Staphylococcus aureus dihydroneopterin aldolase SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE aldolase; dihydroneopterin aldolase; dihydroneopterin; dihydromonapterin; pterin ID CRYSTAL-STRUCTURE; 7,8-DIHYDRONEOPTERIN ALDOLASE; BIOSYNTHESIS; MOLSCRIPT; MECHANISM AB Dihydroneopterin aldolase (DHNA) catalyzes the conversion of 7,8dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and the epimerization of DHNP to 7,8-dihydromonopterin (DHMP). Although crystal structures of the enzyme from several microorganisms have been reported, no structural information is available about the critical interactions between DHNA and the trihydroxypropyl moiety of the substrate, which undergoes bond cleavage and formation. Here, we present the structures of Staphylocoecus aureus DHNA (SaDHNA) in complex with neopterin (NP, an analog of DHNP) and with monapterin (MP, an analog of DHMP), filling the gap in the structural analysis of the enzyme. In combination with previously reported SaDHNA structures in its ligand-free form (PDB entry IDHN) and in complex with HP (PDB entry 2DHN), four snapshots for the catalytic center assembly along the reaction pathway can be derived, advancing our knowledge about the molecular mechanism of SaDHNA-catalyzed reactions. An additional step appears to be necessary for the epimerization of DHMP to DHNP. Three active site residues (E22, K100, and Y54) function coordinately during catalysis: together, they organize the catalytic center assembly, and individually, each plays a central role at different stages of the catalytic cycle. (c) 2007 Elsevier Ltd. All rights reserved. C1 Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Yan, HG (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM yanh@msu.edu; jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC010326-06]; NIGMS NIH HHS [GM51901] NR 22 TC 7 Z9 8 U1 1 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 APR 20 PY 2007 VL 368 IS 1 BP 161 EP 169 DI 10.1016/j.jmb.2007.02.009 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 156TJ UT WOS:000245672500014 PM 17331536 ER PT J AU Sebat, J Lakshmi, B Malhotra, D Troge, J Lese-Martin, C Walsh, T Yamrom, B Yoon, S Krasnitz, A Kendall, J Leotta, A Pai, D Zhang, R Lee, YH Hicks, J Spence, SJ Lee, AT Puura, K Lehtimaki, T Ledbetter, D Gregersen, PK Bregman, J Sutcliffe, JS Jobanputra, V Chung, W Warburton, D King, MC Skuse, D Geschwind, DH Gilliam, TC Ye, K Wigler, M AF Sebat, Jonathan Lakshmi, B. Malhotra, Dheeraj Troge, Jennifer Lese-Martin, Christa Walsh, Tom Yamrom, Boris Yoon, Seungtai Krasnitz, Alex Kendall, Jude Leotta, Anthony Pai, Deepa Zhang, Ray Lee, Yoon-Ha Hicks, James Spence, Sarah J. Lee, Annette T. Puura, Kaija Lehtimaeki, Terho Ledbetter, David Gregersen, Peter K. Bregman, Joel Sutcliffe, James S. Jobanputra, Vaidehi Chung, Wendy Warburton, Dorothy King, Mary-Claire Skuse, David Geschwind, Daniel H. Gilliam, T. Conrad Ye, Kenny Wigler, Michael TI Strong association of de novo copy number mutations with autism SO SCIENCE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; COMMON FRAGILE SITES; SPECTRUM DISORDERS; GENE; DELETIONS; POLYMORPHISM; RETARDATION AB We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism ( P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. Univ Washington, Dept Med & Genome Sci, Seattle, WA 98195 USA. NIMH, Pediat & Neurodev Psychiat Branch, NIH, Bethesda, MD 20892 USA. N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA. Univ Tampere, Sch Med, Dept Child Psychiat, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Clin Chem, FIN-33521 Tampere, Finland. N Shore Long Isl Jewish Hlth Syst, Fay J Lindner Ctr Autism & Dev Disorders, Bethpage, NY 11714 USA. Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN 37232 USA. Columbia Univ, Dept Genet & Dev, New York, NY 10027 USA. Columbia Univ, Dept Pediat, New York, NY 10027 USA. UCL, Inst Child Hlth, Behav & Brain Sci Unit, London WC1N 1EH, England. Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Program Neurogenet,Interdept Program Neurosci, Los Angeles, CA 90095 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. RP Wigler, M (reprint author), Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. EM sebat@cshl.edu; wigler@cshl.edu RI Sutcliffe, James/C-1348-2012; OI Sutcliffe, James/0000-0001-5200-6007; Sebat, Jonathan/0000-0002-9087-526X; Walsh, Tom/0000-0002-8875-0310; Wigler, Michael/0000-0003-4396-1971 FU NIMH NIH HHS [MH076431, MH61009, MH64547, R01 MH061009, R01 MH064547, R01 MH076431, R01 MH076431-01] NR 30 TC 1448 Z9 1505 U1 30 U2 214 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 APR 20 PY 2007 VL 316 IS 5823 BP 445 EP 449 DI 10.1126/science.1138659 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158RY UT WOS:000245813400056 PM 17363630 ER PT J AU Tang, GZ Yang, CY Nikolovska-Coleska, Z Guo, J Qiu, S Wang, RX Gao, W Wang, GP Stuckey, J Krajewski, K Jiang, S Roller, PP Wang, SM AF Tang, Guozhi Yang, Chao-Yie Nikolovska-Coleska, Zaneta Guo, Jie Qiu, Su Wang, Renxiao Gao, Wei Wang, Guoping Stuckey, Jeanne Krajewski, Krzysztof Jiang, Sheng Roller, Peter P. Wang, Shaomeng TI Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FAMILY PROTEINS; CELL-DEATH; APOPTOSIS; DISCOVERY; CANCER; REGULATORS; BCL-X(L); LIGANDS; MCL-1 AB We report herein a new class of small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound, 7, binds to Bcl-2, Bcl-xL, and Mcl-1 proteins with K-i of 110, 638, and 150 nM, respectively. Compound 7 is highly effective in induction of cell death in breast cancer cells with high levels of Bcl-2, Bcl-xL, and Mcl-1 proteins and represents a promising lead compound for the design of new anticancer drugs. C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pharmacol & Med Chem, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, 1500 E Med CTr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010; OI Tang, Guozhi/0000-0002-7131-4678 FU NCI NIH HHS [U19 CA113317-010001, U19 CA113317, U19 CA113317-01, U19 CA113317-015118, U19 CA113317-02, U19 CA113317-020001, U19 CA113317-03, U19 CA113317-030001, U19 CA113317-04, U19 CA113317-040001, U19CA113317] NR 23 TC 33 Z9 41 U1 3 U2 11 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 APR 19 PY 2007 VL 50 IS 8 BP 1723 EP 1726 DI 10.1021/jm0614001 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 156FW UT WOS:000245634500001 PM 17378545 ER PT J AU Adachi, H Palaniappan, KK Ivanov, AA Bergman, N Gao, ZG Jacobson, KA AF Adachi, Hayamitsu Palaniappan, Krishnan K. Ivanov, Andrei A. Bergman, Nathaniel Gao, Zhan-Guo Jacobson, Kenneth A. TI Structure-activity relationships of 2,N-6,5 '-substituted adenosine derivatives with potent activity at the A(2B) adenosine receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ADENYLATE-CYCLASE; A(3) RECEPTOR; ANTAGONISTS; CELLS; AFFINITY; AGONISTS; PHARMACOLOGY; EXPRESSION; LIGANDS; MECHANISM AB 2, N-6, and 5'-substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-arylalkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was examined in both binding and cAMP assays and found to be a potent agonist of the human A(2B)AR. Simplification, altered connectivity, and mimicking of the indole ring of 17 failed to maintain A2BAR potency. Introduction of N-6-ethyl or N-6-guanidino substitution, shown to favor A2BAR potency, failed to enhance potency in the 2-( 3-( indolyl)ethyloxy) adenosine series. Indole 5 ''- or 6 ''-halo substitution was favored at the A(2B)AR, but a 5'-N-ethylcarboxyamide did not further enhance potency. 2-(3 ''-(6 ''-Bromoindolyl)ethyloxy)adenosine 28 displayed an A(2B)AR EC50 value of 128 nM, that is, more potent than the parent 17 (299 nM) and similar to 5'-N-ethylcarboxamidoadenosine (140 nM). Compound 28 was a full agonist at A(2B) and A(2A)ARs and a low efficacy partial agonist at A(1) and A(3)ARs. Thus, we have identified and optimized 2-(2-arylethyl) oxo moieties in AR agonists that enhance A(2B)AR potency and selectivity. C1 NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, 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 Intramural NIH HHS [Z01 DK031117-20] NR 46 TC 31 Z9 31 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 19 PY 2007 VL 50 IS 8 BP 1810 EP 1827 DI 10.1021/jm061278q PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 156FW UT WOS:000245634500011 PM 17378544 ER PT J AU Kang, SU Choi, WJ Oishi, S Lee, K Karki, RG Worthy, KM Bindu, LK Nicklaus, MC Fisher, RJ Burke, TR AF Kang, Sang-Uk Choi, Won Jun Oishi, Shinya Lee, Kyeong Karki, Rajeshri G. Worthy, Karen M. Bindu, Lakshman K. Nicklaus, Marc C. Fisher, Robert J. Burke, Terrence R., Jr. TI Examination of acylated 4-aminopiperidine-4-carboxylic acid residues in the phosphotyrosyl+1 position of Grb2 SH2 domain-binding tripeptides SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURES; INHIBITORS; PEPTIDES; MIMETICS; LIGANDS; DESIGN AB A 4-aminopiperidine-4-carboxylic acid residue was placed in the pTyr+1 position of a Grb2 SH2 domain-binding peptide to form a general platform, which was then acylated with a variety of groups to yield a library of compounds designed to explore potential binding interactions, with protein features lying below the beta D strand. The highest affinities were obtained using phenylethyl carbamate and phenylbutyrylamide functionalities. C1 NCI, Canc Res Ctr, Med Chem Lab, NIH, Frederick, MD 21702 USA. Sci Applicat Int Corp, Prot Chem Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Canc Res Ctr, Med Chem Lab, NIH, POB B,Bldg 376 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; Oishi, Shinya/C-1350-2011; OI Oishi, Shinya/0000-0002-2833-2539; Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS NR 14 TC 8 Z9 8 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD APR 19 PY 2007 VL 50 IS 8 BP 1978 EP 1982 DI 10.1021/jm0614073 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 156FW UT WOS:000245634500026 PM 17371004 ER PT J AU Wang, JX Scully, K Zhu, X Cai, L Zhang, J Prefontaine, GG Krones, A Ohgi, KA Zhu, P Garcia-Bassets, I Liu, F Taylor, H Lozach, J Jayes, FL Korach, KS Glass, CK Fu, XD Rosenfeld, MG AF Wang, Jianxun Scully, Kathleen Zhu, Xiaoyan Cai, Ling Zhang, Jie Prefontaine, Gratien G. Krones, Anna Ohgi, Kenneth A. Zhu, Ping Garcia-Bassets, Ivan Liu, Forrest Taylor, Havilah Lozach, Jean Jayes, Friederike L. Korach, Kenneth S. Glass, Christopher K. Fu, Xiang-Dong Rosenfeld, Michael G. TI Opposing LSD1 complexes function in developmental gene activation and repression programmes SO NATURE LA English DT Article ID NOTCH TARGET GENES; LINEAGE DETERMINATION; ANDROGEN-RECEPTOR; ESTROGEN-RECEPTOR; POLYCOMB PROTEIN; PITUITARY-GLAND; EXPRESSION; MICE; GROWTH; TRANSCRIPTION AB Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1 - a component of the CoREST-CtBP co- repressor complex - is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co- activator or co- repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Kruppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co- repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs. C1 Univ Calif San Diego, Howard Hughes Med Inst, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Howard Hughes Med Inst, Sch Med, La Jolla, CA 92093 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Biol, Grad Program, La Jolla, CA 92093 USA. Univ Calif San Diego, Mol Pathol Grad Program, La Jolla, CA 92093 USA. RP Rosenfeld, MG (reprint author), Univ Calif San Diego, Howard Hughes Med Inst, Dept Med, 9500 Gilman Dr,Room 345, La Jolla, CA 92093 USA. EM mrosenfeld@ucsd.edu RI Garcia-Bassets, Ivan/F-5075-2010; OI Korach, Kenneth/0000-0002-7765-418X; Garcia-Bassets, Ivan/0000-0002-6941-9585 NR 50 TC 268 Z9 281 U1 5 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 19 PY 2007 VL 446 IS 7138 BP 882 EP 887 DI 10.1038/nature05671 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 158IR UT WOS:000245785700035 PM 17392792 ER PT J AU Silberberg, SD Li, MF Swartz, KJ AF Silberberg, Shai D. Li, Mufeng Swartz, Kenton J. TI Ivermectin interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels SO NEURON LA English DT Article ID GATED CHLORIDE CHANNEL; CAENORHABDITIS-ELEGANS; ION CHANNELS; DOMAIN; SUBUNIT; MECHANISM; MEMBRANES; RESIDUES; AVERMECTIN-B1A; IDENTIFICATION AB P2X receptors are trimeric cation channels that open in response to binding of extracellular ATP. Each subunit contains a large extracellular ligand binding domain and two flanking transmembrane (TM) helices that form the pore, but the extent of gating motions of the TM helices is unclear. We probed these motions using ivermectin (IM), a macrocyclic lactone that stabilizes the open state of P2X(4) receptor channels. We find that IVM partitions into lipid membranes and that transfer of the TM regions of P2X(4) receptors is sufficient to convey sensitivity to the lactone, suggesting that IVM interacts most favorably with the open conformation of the two TM helices at the protein-lipid interface. Scanning mutagenesis of the two TMs identifies residues that change environment between closed and open states, and substitutions at a subset of these positions weaken IVM binding. The emerging patterns point to widespread rearrangements of the TM helices during opening of P2X receptor channels. C1 NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Silberberg, SD (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM silberbs@ninds.nih.gov; swartzk@ninds.nih.gov RI Li, Mufeng/A-7859-2010 FU Intramural NIH HHS [ZIA NS003018-03] NR 42 TC 79 Z9 79 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 19 PY 2007 VL 54 IS 2 BP 263 EP 274 DI 10.1016/j.neuron.2007.03.020 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 163VF UT WOS:000246190600011 PM 17442247 ER PT J AU Ravdin, PM Cronin, KA Howlader, N Berg, CD Chlebowski, RT Feuer, EJ Edwards, BK Berry, DA AF Ravdin, Peter M. Cronin, Kathleen A. Howlader, Nadia Berg, Christine D. Chlebowski, Rowan T. Feuer, Eric J. Edwards, Brenda K. Berry, Donald A. TI The decrease in breast-cancer incidence in 2003 in the United States. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HORMONE REPLACEMENT THERAPY; WITHDRAWAL; WOMEN AB An initial analysis of data from the National Cancer Institute's Surveillance, Epidemiology, and End Results ( SEER) registries shows that the age-adjusted incidence rate of breast cancer in women in the United States fell sharply ( by 6.7%) in 2003, as compared with the rate in 2002. Data from 2004 showed a leveling off relative to the 2003 rate, with little additional decrease. Regression analysis showed that the decrease began in mid-2002 and had begun to level off by mid-2003. A comparison of incidence rates in 2001 with those in 2004 ( omitting the years in which the incidence was changing) showed that the decrease in annual age-adjusted incidence was 8.6% (95% confidence interval [CI], 6.8 to 10.4). The decrease was evident only in women who were 50 years of age or older and was more evident in cancers that were estrogen-receptor - positive than in those that were estrogen-receptor - negative. The decrease in breast-cancer incidence seems to be temporally related to the first report of the Women's Health Initiative and the ensuing drop in the use of hormone-replacement therapy among postmenopausal women in the United States. The contributions of other causes to the change in incidence seem less likely to have played a major role but have not been excluded. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. RP Ravdin, PM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd, Houston, TX 77030 USA. NR 18 TC 557 Z9 568 U1 0 U2 13 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 APR 19 PY 2007 VL 356 IS 16 BP 1670 EP 1674 DI 10.1056/NEJMsr070105 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 158AB UT WOS:000245762000012 PM 17442911 ER PT J AU Kammula, US Kuntz, EJ Francone, TD Zeng, ZS Shia, J Landmann, RG Paty, PB Weiser, MR AF Kammula, Udal S. Kuntz, Eleanor J. Francone, Todd D. Zeng, Zhaoshi Shia, Jinru Landmann, Ron G. Paty, Philip B. Weiser, Martin R. TI Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome SO CANCER LETTERS LA English DT Article DE colon cancer; c-met; hepatocyte growth factor; scatter factor; HGF; tumor stage; survival; outcome; metastasis; tumor progression ID HUMAN COLORECTAL-CANCER; PAPILLARY RENAL-CARCINOMAS; FACTOR SCATTER FACTOR; TYROSINE KINASE; MONOCLONAL-ANTIBODIES; ANTITUMOR-ACTIVITY; LIVER METASTASES; IN-VIVO; RECEPTOR; EXPRESSION AB Introduction/hypothesis: Over-expression of the c-Met receptor tyrosine kinase has been described in a variety of cancers and implicated in tumor progression. Unlike some solid tumors, current evidence indicates that c-Met activation in colon cancer is unrelated to gene mutation, is ligand dependent, and occurs via a paracrine fashion. We hypothesize that overexpression of the c-Met receptor and its ligand, hepatocyte growth factor (HGF) in the tumor microenvironment is associated with tumor progression and metastases. Methods: Primary tumor c-Met and HGF mRNA expression was analyzed in 60 colon adenocarcinomas. Receptor and ligand expression was analyzed for correlation and association with clinicopathologic features and outcome. Results: Compared to adjacent normal mucosa, 69% and 48% of tumors showed a greater than 2- and greater than 10-fold elevation in c-Met mRNA, respectively. Elevated HGF mRNA was noted in 47% of tumors with 19% having a greater than 10-fold increase. Tumor c-Met expression was correlated with HGF expression, and a cohort of 33 patients could be defined with both low c-Met and HGF expression. Compared with the 27 tumors with either high c-Met or HGF, the cohort with low c-Met and HGF expression had fewer nodal and distant metastases as well as improved overall survival (HR = 2.3, p < 0.05). Conclusion: Evaluation of the c-Met receptor in context of ligand, HGF, allows identification of a metastatic phenotype that correlates with advanced stage and poor survival. c-Met and HGF co-expression in the tumor microenvironment could be useful in the molecular staging of colon cancer and viable therapeutic targets. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. NCI, Surg Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Weiser, MR (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. EM weiser1@mskcc.org OI Shia, Jinru/0000-0002-4351-2511 NR 42 TC 102 Z9 107 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 APR 18 PY 2007 VL 248 IS 2 BP 219 EP 228 DI 10.1016/j.canlet.2006.07.007 PG 10 WC Oncology SC Oncology GA 154SV UT WOS:000245528800007 PM 16945480 ER PT J AU Mbulaiteye, SM Sternberg, LR Nsubuga, MM Anver, MR Mehta, M Biryahwaho, B Kambugu, F Rabkin, CS Biggar, RJ AF Mbulaiteye, Sam M. Sternberg, Lawrence R. Nsubuga, Martin M. Anver, Miriam R. Mehta, Meghna Biryahwaho, Benon Kambugu, Fred Rabkin, Charles S. Biggar, Robert J. TI Absence of Y-chromosome sequences in tumors from African women with AIDS-related Kaposi sarcoma SO CANCER LETTERS LA English DT Article DE Kaposi sarcoma; chimerism; sexual transmission ID HUMAN-HERPESVIRUS-8 INFECTION; HERPESVIRUS AB Kaposi sarcoma (KS) Occurs with relatively high frequency in immunosuppressed transplant recipients and in patients with AIDS. Recently, Italian investigators reported transplant-related KS tumors bearing donor-derived antigens, suggesting possible parenteral transmission of KS as whole cells, i.e., chimeric tumors. To investigate the hypothesis that KS whole cells may also be transmitted into immunocompromised persons via heterosexual acts, we tested nodular KS lesions and matched normal tissue obtained from female patients with AIDS for the presence of the Y-chromosome specific sex determining sequence (SRY). Among 25 unique tumors tested, none was positive for SRY sequence. While our results do not exclude sexual cellular transmission of whole KS cells, they suggest that if it occurs, it is rare. Published by Elsevier Ireland Ltd. C1 NCI, Viral Epidemiol Branch, DCEG, Rockville, MD 20852 USA. SAIC Frederick Inc, Pathol Histotechnol Lab, NCI Frederick, Ft Detrick, MD 21702 USA. Makerere Univ, Sch Med, Kampala, Uganda. Uganda Virus Res Inst, Entebbe, Uganda. RP Mbulaiteye, SM (reprint author), NCI, Viral Epidemiol Branch, DCEG, 6120 Execut Blvd,Execut Pl S Rm 7080, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CO12400] NR 13 TC 2 Z9 2 U1 0 U2 0 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 APR 18 PY 2007 VL 248 IS 2 BP 229 EP 233 DI 10.1016/j.canlet.2006.07.008 PG 5 WC Oncology SC Oncology GA 154SV UT WOS:000245528800008 PM 16934394 ER PT J AU Hong, A Narbonne-Reveau, K Riesgo-Escovar, J Fu, HQ Aladjem, MI Lilly, MA AF Hong, Amy Narbonne-Reveau, Karine Riesgo-Escovar, Juan Fu, Haiqing Aladjem, Mirit I. Lilly, Mary A. TI The cyclin-dependent kinase inhibitor Dacapo promotes replication licensing during Drosophila endocycles SO EMBO JOURNAL LA English DT Article ID CELL-CYCLE; DNA-REPLICATION; S-PHASE; FOLLICLE CELLS; ENDOREDUPLICATION CYCLES; GENOMIC INSTABILITY; EXPRESSION; OOGENESIS; PROTEIN; GENE AB The endocycle is a developmentally programmed variant cell cycle in which cells undergo repeated rounds of DNA replication with no intervening mitosis. In Drosophila, the endocycle is driven by the oscillations of Cyclin E/Cdk2 activity. How the periodicity of Cyclin E/Cdk2 activity is achieved during endocycles is poorly understood. Here, we demonstrate that the p21 cip1/p27 kip1/p57 kip2-like cyclin-dependent kinase inhibitor (CKI), Dacapo (Dap), promotes replication licensing during Drosophila endocycles by reinforcing low Cdk activity during the endocycle Gap-phase. In dap mutants, cells in the endocycle have reduced levels of the licensing factor Double Parked/Cdt1 (Dup/Cdt1), as well as decreased levels of chromatin-bound minichromosome maintenance (MCM2-7) complex. Moreover, mutations in dup/cdt1 dominantly enhance the dap phenotype in several polyploid cell types. Consistent with a reduced ability to complete genomic replication, dap mutants accumulate increased levels of DNA damage during the endocycle S-phase. Finally, genetic interaction studies suggest that dap functions to promote replication licensing in a subset of Drosophila mitotic cycles. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Nacl Autonoma Mexico, Dept Neurobiol Desarrollo & Neurofisiol, Inst Neurobiol, Mexico City 04510, DF, Mexico. NCI, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. RP Lilly, MA (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM mlilly@helix.nih.gov RI Aladjem, Mirit/G-2169-2010; OI Aladjem, Mirit/0000-0002-1875-3110; Lilly, Mary/0000-0003-1564-619X FU Intramural NIH HHS NR 57 TC 34 Z9 34 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD APR 18 PY 2007 VL 26 IS 8 BP 2071 EP 2082 DI 10.1038/sj.emboj.7601648 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FT UT WOS:000245851500008 PM 17380129 ER PT J AU Ling, C Ishiai, M Ali, AM Medhurst, AL Neveling, K Kalb, R Yan, ZJ Xue, YT Oostra, AB Auerbach, AD Hoatlin, ME Schindler, D Joenje, H de Winter, JP Takata, M Meetei, AR Wang, WD AF Ling, Chen Ishiai, Masamichi Ali, Abdullah Mahmood Medhurst, Annette L. Neveling, Kornelia Kalb, Reinhard Yan, Zhijiang Xue, Yutong Oostra, Anneke B. Auerbach, Arleen D. Hoatlin, Maureen E. Schindler, Detlev Joenje, Hans de Winter, Johan P. Takata, Minoru Meetei, Amom Ruhikanta Wang, Weidong TI FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway SO EMBO JOURNAL LA English DT Article DE FAAP100; FANCB; FANCD2; FANCL; Fanconi anemia ID CROSS-LINK REPAIR; HOMOLOGOUS RECOMBINATION; NUCLEAR-COMPLEX; CORE COMPLEX; PROTEIN; MUTATIONS; GENE; FANCG/XRCC9; CANCER; BRCA2 AB The Fanconi anemia ( FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. Here, we report a novel component of this complex, termed FAAP100, which is essential for the stability of the core complex and directly interacts with FANCB and FANCL to form a stable subcomplex. Formation of this subcomplex protects each component from proteolytic degradation and also allows their coregulation by FANCA and FANCM during nuclear localization. Using siRNA depletion and gene knockout techniques, we show that FAAP100-deficient cells display hallmark features of FA cells, including defective FANCD2 monoubiquitination, hypersensitivity to DNA crosslinking agents, and genomic instability. Our study identifies FAAP100 as a new critical component of the FA-BRCA DNA damage response network. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. Kawasaki Med Univ, Dept Immunol & Mol Genet, Kurashiki, Okayama, Japan. Cincinnati Childrens Hosp, Res Fdn, Div Expt Hematol, Cincinnati, OH USA. Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. VU Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. Univ Wurzburg, Dept Human Genet, D-97070 Wurzburg, Germany. Rockefeller Univ, Lab Human Genet & Hematol, New York, NY 10021 USA. Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. Hiroshima Univ, Dept Human Genet, Res Inst Radiat Biol & Med, Hiroshima, Japan. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, 333 Cassell Dr,TRIAD Ctr Room 3000, Baltimore, MD 21224 USA. EM Ruhikanta.Meetei@cchmc.org; wangw@grc.nia.nih.gov RI Ali, Abdullah/C-5292-2011; OI Auerbach, Arleen/0000-0002-6911-8379 FU NCI NIH HHS [CA112775, R01 CA082678, R01 CA112775, R01CA82678]; NHLBI NIH HHS [R37 HL032987, R37HL32987] NR 42 TC 91 Z9 95 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD APR 18 PY 2007 VL 26 IS 8 BP 2104 EP 2114 DI 10.1038/sj.emboj.7601666 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159FT UT WOS:000245851500011 PM 17396147 ER PT J AU Ngo, TTB Peng, T Liang, XJ Akeju, O Pastorino, S Zhang, W Kotliarov, Y Zenklusen, JC Fine, HA Maric, D Wen, PY De Girolami, U Black, PM Wu, WW Shen, RF Jeffries, NO Kang, DW Park, JK AF Ngo, Teri-T B. Peng, Tien Liang, Xing-Jie Akeju, Oluwaseun Pastorino, Sandra Zhang, Wei Kotliarov, Yuri Zenklusen, Jean C. Fine, Howard A. Maric, Dragan Wen, Patrick Y. De Girolami, Umberto Black, Peter McL. Wu, Wells W. Shen, Rong-Fong Jeffries, Neal O. Kang, Dong-Won Park, John K. TI The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHROMOSOME 1P LOSS; PHASE-III TRIAL; OLIGODENDROGLIAL TUMORS; CELL-CYCLE; ANAPLASTIC OLIGODENDROGLIOMAS; MULTISITE PHOSPHORYLATION; GRADE GLIOMAS; IN-VITRO; ARM 1P; SURVIVAL AB Background Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p(+/-)). Patients with 1p(+/-) anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p(+/-) and 1p(+/+) malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. Methods We used a comparative proteomic screen of A172 (1p(+/+)) and U251 (1p(+/+)) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1 p(+/-) and 1 p(+/-) anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Results Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P <.001) and increased recurrence-free survival (P < 001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [Cl] = 0 to 90 months), 17 months (95% Cl = 10.6 to 23.4 months), and 6 months (95% Cl = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin(+/-) tumors was 95 days (95% Cl = 68.7 to 121.3 days) and that of mice with stathmin(+/+) tumors was 64 days (95% Cl = 58.2 to 69.8 days) (difference = 31 days, 95% Cl = 4.1 to 57.9 days; P <.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression. Conclusions Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p(+/-) anaplastic oligodendroglioma tumors. C1 NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD USA. NINDS, Flow Cytometry Facil, NIH, Bethesda, MD USA. NINDS, Off Clin Director, NIH, Bethesda, MD USA. NCI, Neurooncol Branch, Bethesda, MD 20892 USA. Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NHLBI, Proteom Core Facil, NIH, Bethesda, MD 20892 USA. RP Park, JK (reprint author), 35 Convent Dr,MSC 3706, Bethesda, MD 20892 USA. EM parkjk@ninds.nih.gov RI Kotliarov, Yuri/B-6938-2017 FU Intramural NIH HHS NR 49 TC 38 Z9 39 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 APR 18 PY 2007 VL 99 IS 8 BP 639 EP 652 DI 10.1093/jnci/djk135 PG 14 WC Oncology SC Oncology GA 166BN UT WOS:000246352200014 PM 17440165 ER PT J AU Ma, Z Nie, ZZ Luo, RB Casanova, JE Ravichandran, KS AF Ma, Zhong Nie, Zhongzhen Luo, Ruibai Casanova, James E. Ravichandran, Kodi S. TI Regulation of Arf6 and ACAP1 signaling by the PTB-domain-containing adaptor protein GULP SO CURRENT BIOLOGY LA English DT Article ID APOPTOTIC CELLS; ACTIN CYTOSKELETON; EXCHANGE FACTOR; C-ELEGANS; ENGULFMENT; MEMBRANE; CED-6; PROMOTES; HOMOLOG; GAPS AB The GTPase Arf6 regulates multiple cellular processes, including endocytosis, secretion, phagocytosis, cell adhesion, and cell migration [1, 2]. The Arf6-specific GAP ACAP1 is a negative regulator of Arf6-nnediated signaling [3-7]. However, regulation of ACAP1- and Arf6-mediated signaling by other cellular proteins is not well understood. GULP/CED-6 is a phosphotyrosine binding (PTB)-domain-containing adaptor protein linked to engulfment of apoptotic cells [8-13] and to cholesterol homeostasis [114]. Here, we identify a novel role for GULP as a positive regulator of Arf6. Knockdown of GULP decreased cellular Arf6-GTP, whereas GULP overexpression increased cellular Arf6-GTP. At the mechanistic level, GULP influenced Arf6 at four levels. First, GULP bound directly to GDP-bound Arf6 via its PTB domain. Second, GULP associated with the Arf6-GAP ACAP1 at endogenous levels. Third, GULP reversed the Arf6-GTP decrease induced by ACAPI, and countered the ACAP1 -mediated inhibition of cell migration. Fourth, GULP, ACAP1, and GDP-bound Arf6 were part of a tripartite complex, suggesting sequestration of ACAP1 as one mechanism of GULP action. Taken together, these data identify GULP as a modifier of cellular Arf6-GTP through regulation of ACAP1. Because PTB-domain-containing adaptor proteins influence endocytosis and trafficking of membrane proteins and cell migration [15,16], our data support a model wherein PTB-domain-containing adaptor proteins regulate Arf family proteins. C1 Univ Virginia, Carter Ctr Immunol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. Univ Virginia, Dept Cell Biol, Charlottesville, VA 22908 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RP Ravichandran, KS (reprint author), Univ Virginia, Carter Ctr Immunol, Charlottesville, VA 22908 USA. EM ravi@virginia.edu FU NIAID NIH HHS [T32 AI055432]; NIGMS NIH HHS [R01 GM069998, R01 GM069998-03, GM069998] NR 25 TC 15 Z9 18 U1 0 U2 2 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 APR 17 PY 2007 VL 17 IS 8 BP 722 EP 727 DI 10.1016/j.cub.2007.03.014 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 159KG UT WOS:000245864000030 PM 17398097 ER EF