FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Freedman, RA Partridge, AH AF Freedman, Rachel A. Partridge, Ann H. TI Adjuvant therapies for very young women with early stage breast cancer SO BREAST LA English DT Article DE Young women; Breast cancer; Adjuvant therapy; Chemotherapy; Fertility; Premature menopause ID PREMENOPAUSAL PATIENTS; RANDOMIZED-TRIALS; PROGNOSTIC-FACTOR; AGE; SURVIVAL; TAMOXIFEN; CYCLOPHOSPHAMIDE; FLUOROURACIL; CHEMOTHERAPY; METHOTREXATE AB Approximately 16,000-19,000 women aged <= 45 are diagnosed annually with breast cancer in the United States and thousands more are diagnosed worldwide. Compared to older women, young women are more likely to have cancers with aggressive tumor biology and present with higher stage disease, both of which likely lead to their worse outcomes. We review the available evidence for adjuvant systemic therapy as well as treatment considerations for younger women with breast cancer. Although we have begun to appreciate the issues that younger women with breast cancer face, we need a better understanding of how we can optimally prevent disease recurrence while carefully considering their unique physical and emotional needs with regard to diagnosis, treatment, and survivorship. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Freedman, Rachel A.; Partridge, Ann H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Freedman, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rafreedman@partners.org; ahpartridge@partners.org NR 57 TC 6 Z9 6 U1 2 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 3 BP S146 EP S149 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037CA UT WOS:000311077400027 PM 22015283 ER PT J AU Krop, I AF Krop, Ian TI NEW AND FUTURE THERAPIES FOR HER-2+ADVANCED BREAST CANCER SO BREAST LA English DT Meeting Abstract C1 [Krop, Ian] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 4 BP S16 EP S16 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037DM UT WOS:000311082400013 ER PT J AU Lim, E Winer, EP AF Lim, Elgene Winer, Eric P. TI Adjuvant chemotherapy in luminal breast cancers SO BREAST LA English DT Article DE Luminal breast cancer; Adjuvant chemotherapy ID GENE-EXPRESSION; RANDOMIZED-TRIALS; ENDOCRINE THERAPY; PROGNOSTIC VALUE; PREDICTIVE-VALUE; KI67 EXPRESSION; RECEPTOR STATUS; SIGNATURE; TAMOXIFEN; SUBTYPES AB Luminal breast cancers are traditionally considered to comprise of tumors expressing estrogen receptor ( ER) and represent the majority of breast cancers. These tumors are characterized by significant heterogeneity in phenotype, molecular signature, relapse patterns and therapeutic response to endocrine and chemotherapy. Whilst adjuvant endocrine therapy is standard of care in patients with tumors that express either ER and/or progesterone receptor ( PR), the indication for adjuvant chemotherapy is less clear-cut. On average, ER-positive breast tumors derive less benefit from chemotherapy compared to ER-negative tumors, however there is still clearly a subset of patients with ER-positive tumors that are chemosensitive. The basis for the addition of chemotherapy to adjuvant endocrine therapy is usually guided by the clinician's estimation of prognosis and assessment of the endocrine sensitivity of the tumor. The use of chemotherapy in this setting, however, is highly variable. There is tremendous value in identifying subgroups of patients who can expect favorable outcomes with endocrine therapy and who may not require any additional therapy. Similarly, it is equally important, if not more important, to characterize patients with ER-positive disease who will derive a substantial benefit from cytotoxic chemotherapy. In this article, we aim to discuss the utility of current biomarkers used to guide decisions regarding chemotherapy in ER-positive, HER2-negative breast cancers. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lim, Elgene; Winer, Eric P.] Dana Farber Canc Inst, Div Womens Canc, Boston, MA 02115 USA. RP Lim, E (reprint author), Dana Farber Canc Inst, Div Womens Canc, 450 Brookline Ave, Boston, MA 02115 USA. EM elgene_lim@dfci.harvard.edu; eric_winer@dfci.harvard.edu OI Lim, Elgene/0000-0001-8065-8838 FU Genentech FX E.P. Winer: Consultancy: Novartis; Research support: Genentech. E. Lim has no conflict of interest to declare. NR 32 TC 5 Z9 6 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 3 BP S128 EP S131 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037CA UT WOS:000311077400023 PM 22015279 ER PT J AU Mandelblatt, JS Cronin, KA Berry, DA Chang, YJ de Koning, HJ Lee, SJ Plevritis, SK Schechter, CB Stout, NK van Ravesteyn, NT Zelen, M Feuer, EJ AF Mandelblatt, Jeanne S. Cronin, Kathleen A. Berry, Donald A. Chang, Yaojen de Koning, Harry J. Lee, Sandra J. Plevritis, Sylvia K. Schechter, Clyde B. Stout, Natasha K. van Ravesteyn, Nicolien T. Zelen, Marvin Feuer, Eric J. TI Modeling the impact of population screening on breast cancer mortality in the United States SO BREAST LA English DT Article DE Mammography; Screening; Modeling ID SERVICES TASK-FORCE; UPPER AGE LIMIT; RANDOMIZED-TRIALS; OLDER WOMEN; FOLLOW-UP; MAMMOGRAPHY; RECOMMENDATIONS; CHEMOTHERAPY; BENCHMARKS; SURVIVAL AB Objective: Optimal US screening strategies remain controversial. We use six simulation models to evaluate screening outcomes under varying strategies. Methods: The models incorporate common data on incidence, mammography characteristics, and treatment effects. We evaluate varying initiation and cessation ages applied annually or biennially and calculate mammograms, mortality reduction (vs. no screening), false-positives, unnecessary biopsies and over-diagnosis. Results: The lifetime risk of breast cancer death starting at age 40 is 3% and is reduced by screening. Screening biennially maintains 81% (range 67% to 99%) of annual screening benefits with fewer false-positives. Biennial screening from 50-74 reduces the probability of breast cancer death from 3% to 2.3%. Screening annually from 40 to 84 only lowers mortality an additional one-half of one percent to 1.8% but requires substantially more mammograms and yields more false-positives and over-diagnosed cases. Conclusion: Decisions about screening strategy depend on preferences for benefits vs. potential harms and resource considerations. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Mandelblatt, Jeanne S.; Chang, Yaojen] Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Mandelblatt, Jeanne S.; Chang, Yaojen] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Mandelblatt, Jeanne S.; Chang, Yaojen] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Cronin, Kathleen A.; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [de Koning, Harry J.; van Ravesteyn, Nicolien T.] Erasmus MC, Dept Publ Hlth, NL-3015 GE Rotterdam, Netherlands. [Lee, Sandra J.; Zelen, Marvin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Sandra J.; Zelen, Marvin] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Plevritis, Sylvia K.] Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. [Schechter, Clyde B.] Albert Einstein Coll Med, Dept Family & Social Med, Bronx, NY 10461 USA. [Schechter, Clyde B.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Stout, Natasha K.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02215 USA. [Stout, Natasha K.] Harvard Pilgrim Hlth Care, Boston, MA 02215 USA. RP Mandelblatt, JS (reprint author), Lombardi Comprehens Canc Ctr, Canc Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM mandelbj@georgetown.edu FU NCI [RC2CA148577, U01CA086076]; BCSC [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX This work was done under contracts from the Agency for Healthcare Research and Quality (AHRQ) and NCI and grants from the NCI. The NCI provided some data and technical assistance and AHRQ reviewed the manuscript. Model results are the sole responsibility of the investigators.; By NCI cooperative agreement U01 CA152958-01 and NCI Grants RC2CA148577 and U01CA086076. Data collection in the BCSC was supported by NCI-funded BCSC cooperative agreements (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040) and several U.S. state public health departments and cancer registries. CISNET data management and Web site support were provided by Cornerstone Systems Northwest (NCI contract HHSN261200800002C). NR 37 TC 9 Z9 9 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 3 BP S75 EP S81 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037CA UT WOS:000311077400013 PM 22015298 ER PT J AU Robertson, JFR Lindemann, JPO Garnett, S Nicholson, R Kuter, I Gee, J AF Robertson, John F. R. Lindemann, Justin P. O. Garnett, Sally Nicholson, Robert Kuter, Irene Gee, Julia TI FULVESTRANT: ANALYSIS OF TUMOUR BIOMARKER EXPRESSION IN A COMBINED ANALYSIS OF PRE-SURGICAL STUDIES SO BREAST LA English DT Meeting Abstract C1 [Robertson, John F. R.] Univ Nottingham, Div Breast Surg, Nottingham NG7 2RD, England. [Lindemann, Justin P. O.; Garnett, Sally] AstraZeneca, Macclesfield, Cheshire, England. [Nicholson, Robert; Gee, Julia] Cardiff Univ, Welsh Sch Pharm, Tenovus Ctr Canc Res, Cardiff, S Glam, Wales. [Kuter, Irene] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 4 BP S26 EP S26 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037DM UT WOS:000311082400039 ER PT J AU Schoenfeld, JD Harris, JR AF Schoenfeld, Jonathan D. Harris, Jay R. TI Abbreviated course of radiotherapy (RT) for breast cancer SO BREAST LA English DT Article DE Radiation therapy (RT); Hypofractionation; Breast cancer ID HYPOFRACTIONATED RADIATION-THERAPY; INTENSITY-MODULATED RADIOTHERAPY; RANDOMIZED CLINICAL-TRIAL; ACCELERATED WHOLE-BREAST; QUALITY-OF-LIFE; CONSERVING SURGERY; FOLLOW-UP; POSTOPERATIVE RADIOTHERAPY; FRACTIONATION SCHEDULES; BRACHIAL PLEXOPATHY AB The use of RT as a component of breast-conserving therapy or after mastectomy has been proven to reduce the risk of local-regional recurrence (LRR) and to improve long-term breast cancer-specific and overall survival. As has been the common practice in the United States and Continental Europe, the majority of studies that demonstrated these benefits utilized daily radiation doses ranging from 1.8-2 Gray (Gy). However, due to geographic limitations, patient preferences and financial considerations, there have been continued attempts to evaluate the efficacy and toxicity of abbreviated courses of breast RT. Two key factors in these attempts have been: (1) advances in radiobiology allowing for a more precise estimation of equivalent dosing; and (2) advances in the delivery of RT that have resulted in substantially improved dose homogeneity in the target volume. As an alternative to approximately five weeks of daily treatment at 1.8-2 Gy, delivering radiobiologically-equivalent total doses in hypofractionated, abbreviated schedules has been evaluated in five randomized controlled trials, as well as many prospective and retrospective experiences. These studies have generally demonstrated equivalent rates of LRR, disease-free survival and overall survival with the use of hypofractionated regimens. Despite theoretical and historic concerns that hypofractionated regimens could increase damage to normal tissue, the rates of acute and long-term toxicities have generally not been increased in most recent series. Some toxicities, however, may take years to decades to manifest. Questions still remain regarding which patients are appropriate for abbreviated treatment. The majority of patients included in the studies supporting hypofractionated treatment were of older age with early-stage invasive ER+ disease of predominantly lower histological grade. This favorable subset of patients is also the most eligible for other alternative treatment approaches, such as partial-breast irradiation or hormonal therapy alone. Additionally, few to none of the patients included in most studies were treated with mastectomy, lymph node irradiation, a lumpectomy cavity radiation boost, or adjuvant chemotherapy. The existing evidence prompted the American Society for Radiation Oncology (ASTRO) to convene a task force to issue an evidence-based guideline in 2010 delineating the patients for whom an abbreviated radiation course is most supported by the current evidence [Smith et al. 2010, Int J Radiat Oncol Biol Phys]. Ongoing and future studies will further clarify the suitability of a hypofractionated treatment approach for the patient subgroups underrepresented in available trials. Additionally, alternative abbreviated treatment regimens, including those in which treatment is given once weekly and treatments that include an integrated lumpectomy cavity boost, are actively being investigated. Finally, innovative radiation techniques, such as the use of higher energies, prone treatment, and breathing-adapted therapy have further increased the homogeneity of breast irradiation and minimized dose delivered to nearby critical normal structures. Consequently, increasing experience with these techniques may expand the population of patients amenable to hypofractionated therapy. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Harris, Jay R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Harris, Jay R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Schoenfeld, Jonathan D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02215 USA. RP Harris, JR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave,Room D1622, Boston, MA 02215 USA. EM jschoenfeld@lroc.harvard.edu; jharris@lroc.harvard.edu NR 114 TC 8 Z9 8 U1 0 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 3 BP S116 EP S127 PG 12 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037CA UT WOS:000311077400022 PM 22015277 ER PT J AU Winer, EP Lin, NU AF Winer, Eric P. Lin, Nancy U. TI STATE OF THE ART TREATMENT OF TRIPLE NEGATIVE BREAST CANCER SO BREAST LA English DT Meeting Abstract C1 [Winer, Eric P.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Div Womens Canc, Cambridge, MA 02138 USA. [Lin, Nancy U.] Harvard Univ, Dana Farber Brigham & Womens Canc Ctr, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD OCT PY 2011 VL 20 SU 4 BP S16 EP S17 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 037DM UT WOS:000311082400014 ER PT J AU Shin, JM Munson, K Sachs, G AF Shin, Jai Moo Munson, Keith Sachs, George TI Gastric H+,K+-ATPase SO COMPREHENSIVE PHYSIOLOGY LA English DT Article AB The gastric H+, K+-ATPase is responsible for gastric acid secretion. This ATPase is composed of two subunits, the catalytic alpha subunit and the structural beta subunit. The alpha subunit with molecular mass of about 100 kDa has 10 transmembrane domains and is strongly associated with the beta subunit with a single transmembrane segment and a peptide mass of 35 kDa. Its three-dimensional structure is based on homology modeling and site-directed mutagenesis resulting in a proton extrusion and K+ reabsorption model. There are three conserved H3O+-binding sites in the middle of the membrane domain and H3O+ secretion depends on a conformational change involving Lys(791) insertion into the second H3O+ site enclosed by E795, E820, and D824 that allows export of protons at a concentration of 160 mM. K+ countertransport involves binding to this site after the release of protons with retrograde displacement of Lys(791) and then K+ transfer to E343 and exit to the cytoplasm. This ATPase is the major therapeutic target in treatment of acid-related diseases and there are several known luminal inhibitors allowing analysis of the luminal vestibule. One class contains the acid-activated covalent, thiophilic proton pump inhibitors, the most effective of current acid-suppressive drugs. Their binding sites and trypsinolysis allowed identification of all ten transmembrane segments of the ATPase. In addition, various K+-competitive inhibitors of the ATPase are being developed, with the advantage of complete and rapid inhibition of acid secretion independent of pump activity and allowing further refinement of the structure of the luminal vestibule of the E-2 form of this ATPase. (C) 2011 American Physiological Society. Compr Physiol 1: 2141-2153, 2011. C1 [Shin, Jai Moo; Munson, Keith; Sachs, George] Univ Calif Los Angeles, Dept Med Physiol, Los Angeles, CA 90095 USA. [Shin, Jai Moo; Munson, Keith; Sachs, George] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Shin, JM (reprint author), Univ Calif Los Angeles, Dept Med Physiol, Los Angeles, CA 90095 USA. EM jaishin@ucla.edu FU US VA; NIH/NIDDK [DK053642, DK058333] FX This work was supported by US VA Merit Grant, NIH/NIDDK grant numbers DK053642 and DK058333. NR 110 TC 8 Z9 8 U1 1 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD OCT PY 2011 VL 1 IS 4 BP 2141 EP 2153 DI 10.1002/cphy.c110010 PG 13 WC Physiology SC Physiology GA V27SM UT WOS:000208632900018 PM 23733700 ER PT J AU Mimura, T Chang, JH Kim, TI Onguchi, T Kojima, T Sakimoto, T Azar, DT AF Mimura, Tatsuya Chang, Jin-Hong Kim, Tae-im Onguchi, Tatsuya Kojima, Takashi Sakimoto, Tohru Azar, Dimitri T. TI MT1-MMP Cleavage of the Antiangiogenic Proteoglycan Decorin: Role in Corneal Angiogenesis SO CORNEA LA English DT Article DE angiogenesis; cornea; decorin; MT1-MMP AB Purpose: Decorin is a small chondroitin sulfate proteoglycan that inhibits vascular endothelial cell migration and tube formation. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been shown to be an important angiogenic enzyme in the cornea. We evaluated the specific role of MT1-MMP in decorin cleavage in the cornea. Methods: Western blotting was used to evaluate decorin degradation by MT1-MMP. Aortic ring tube formation assays were used to assay the inhibitory effect of decorin and the stimulatory effect of MT1-MMP on vascular endothelial cells in vitro. Corneal micro-pocket assays using basic fibroblast growth factor (bFGF) were used to assess changes in the levels of decorin and MT1-MMP. Results: MT1-MMP cleaves decorin in a time-and concentration-dependent manner in vitro. MT1-MMP levels were upregulated after in vivo bFGF pellet implantation in the cornea, and decorin cleavage products were detected in bFGF-implanted corneas but not in normal corneas. MT1-MMP reduced the inhibitory effects of decorin on aortic ring tube formation in vitro. Conclusion: MT1-MMP may play an essential role in angiogenesis through proteolytic processing of decorin in the cornea. C1 [Mimura, Tatsuya] Univ Tokyo, Dept Ophthalmol, Grad Sch Med, Tokyo 1138655, Japan. [Mimura, Tatsuya] Toranomon Gen Hosp, Dept Ophthalmol, Tokyo, Japan. [Mimura, Tatsuya; Chang, Jin-Hong; Onguchi, Tatsuya; Kojima, Takashi; Azar, Dimitri T.] Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL USA. [Mimura, Tatsuya; Chang, Jin-Hong; Kim, Tae-im; Kojima, Takashi; Sakimoto, Tohru; Azar, Dimitri T.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, Boston, MA USA. RP Mimura, T (reprint author), Univ Tokyo, Dept Ophthalmol, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM mimurat-tky@umin.ac.jp FU National Institutes of Health [EY10101, EY001792, EY14048]; Research to Prevent Blindness (Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago) FX Supported by the National Institutes of Health grants EY10101 and EY001792 (to D. T. A.) and EY14048 to J.-H. Chang and an unrestricted departmental grant from Research to Prevent Blindness (Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago). NR 21 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD OCT PY 2011 VL 30 SU 1 BP S45 EP S49 PG 5 WC Ophthalmology SC Ophthalmology GA V32LC UT WOS:000208951700010 PM 21912230 ER PT J AU Lakhashe, SK Silvestri, G Ruprecht, RM AF Lakhashe, Samir K. Silvestri, Guido Ruprecht, Ruth M. TI No acquisition: A new ambition for HIV vaccine development? SO CURRENT OPINION IN VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLADE C INFECTION; B-CELL RESPONSES; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; PROTECTIVE EFFICACY; IMMUNE-RESPONSES; MONOCLONAL-ANTIBODIES; REPLICATION-COMPETENT; CHALLENGE VIRUSES AB Development of a safe and effective prophylactic HIV-1 vaccine presents unique challenges. The pessimism following the failure of two HIV-1 vaccine concepts in clinical trials, HIV-1 gp120 and an adenovirus-based approach to induce only cellular immune responses, has been replaced by cautious optimism engendered by the RV144 trial outcome, the isolation of several new broadly reactive neutralizing monoclonal antibodies, and recent primate model data indicating prevention of viral acquisition by active or passive immunization. Intense efforts are underway to optimize immunogen design, adjuvants, and the tools for preclinical evaluation of candidate vaccines in primates, where correlates of protection can be examined in detail - as proof-of-concept for clinical trials. C1 [Lakhashe, Samir K.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lakhashe, Samir K.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014 FU NIH [P01 AI048240, R37 AI034266, P01 AI082282, P01 AI054558, R56 AI062515]; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) UCL-VDC (Weiss) [38637]; Center for AIDS Research Immunology Core [P30 AI050409] FX The work described here was supported by NIH grants P01 AI048240, R37 AI034266, P01 AI082282, P01 AI054558, and R56 AI062515. Support was also provided by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) UCL-VDC (Weiss) grant 38637, and by Center for AIDS Research Immunology Core P30 AI050409. NR 76 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD OCT PY 2011 VL 1 IS 4 BP 246 EP 253 DI 10.1016/j.coviro.2011.07.005 PG 8 WC Virology SC Virology GA 051FS UT WOS:000312112200005 PM 22081778 ER PT J AU Forster, S Grimmer, T Miederer, I Henriksen, G Yousefi, BH Graner, P Wester, HJ Forstl, H Kurz, A Dickerson, BC Drzezga, A AF Foerster, S. Grimmer, T. Miederer, I. Henriksen, G. Yousefi, B. H. Graner, P. Wester, H. J. Foerstl, H. Kurz, A. Dickerson, B. C. Drzezga, A. TI Regional expansion of cerebral hypometabolism in AD follows the pattern of amyloid-deposition with temporal delay and is related to healthy functional connectivity networks SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Meeting Abstract C1 [Foerster, S.; Miederer, I.; Henriksen, G.; Yousefi, B. H.; Graner, P.; Wester, H. J.; Drzezga, A.] Univ Munich, Klinikum Rechts Isar, Dept Nucl Med, Munich, Germany. [Grimmer, T.; Foerstl, H.; Kurz, A.] Univ Munich, Dept Psychiat, Klinikum Rechts Isar, D-80539 Munich, Germany. [Dickerson, B. C.] Massachusetts Gen Hosp, Dept Neurol, Massachusetts Alzheimers Dis Res Ctr, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Dickerson, B. C.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD OCT PY 2011 VL 38 SU 2 BP S122 EP S122 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V27NH UT WOS:000208619400107 ER PT J AU Margey, R Selzer, F Quiroz, R Jneid, H Marroquin, OC Mulukutla, SR Laskey, WK Jacobs, AK Maree, AO AF Margey, R. Selzer, F. Quiroz, R. Jneid, H. Marroquin, O. C. Mulukutla, S. R. Laskey, W. K. Jacobs, A. K. Maree, A. O. TI Impact of Renal Insufficiency on Prescription of Discharge Medication and 1 year Outcomes After Percutaneous Coronary Intervention SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Margey, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Quiroz, R.; Jacobs, A. K.; Maree, A. O.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [Selzer, F.; Marroquin, O. C.; Mulukutla, S. R.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Jneid, H.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Jneid, H.] Baylor Coll Med, Houston, TX 77030 USA. [Laskey, W. K.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. RI Marroquin, Oscar/F-2214-2015 OI Marroquin, Oscar/0000-0002-0909-0319 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD OCT PY 2011 VL 180 SU 11 MA 54 BP S400 EP S400 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V27YS UT WOS:000208649100055 ER PT J AU Margey, R Maree, AO Selzer, F Adams, B Patel, N Jneid, H Marroquin, OC Mulukutla, SR Laskey, WK Jacobs, AK AF Margey, R. Maree, A. O. Selzer, F. Adams, B. Patel, N. Jneid, H. Marroquin, O. C. Mulukutla, S. R. Laskey, W. K. Jacobs, A. K. TI Impact of Renal Insufficiency on Bleeding Events in Patients Undergoing Percutaneous Coronary Intervention SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Margey, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Margey, R.] Harvard Univ, Sch Med, Boston, MA USA. [Maree, A. O.; Adams, B.; Patel, N.; Jacobs, A. K.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [Selzer, F.; Marroquin, O. C.; Mulukutla, S. R.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Jneid, H.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Jneid, H.] Baylor Coll Med, Houston, TX 77030 USA. [Laskey, W. K.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. RI Marroquin, Oscar/F-2214-2015 OI Marroquin, Oscar/0000-0002-0909-0319 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD OCT PY 2011 VL 180 SU 11 MA 16 BP S386 EP S386 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V27YS UT WOS:000208649100017 ER PT J AU Margey, R Arzamendi, D Hynes, B Elmariah, S Renfigo-Moreno, P Schainfeld, R Jaff, MR Inglessis, I Palacios, IP AF Margey, R. Arzamendi, D. Hynes, B. Elmariah, S. Renfigo-Moreno, P. Schainfeld, R. Jaff, M. R. Inglessis, I. Palacios, I. P. TI Systemic Embolic Events Other than Stroke or TIA from Paradoxical Embolization via Patent Foramen Ovale SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD OCT PY 2011 VL 180 SU 11 MA 7 BP S383 EP S383 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V27YS UT WOS:000208649100008 ER PT J AU Margey, RJP Sakhuja, R Gandhi, S Rogers, RK Weinberg, I Jaff, MR Schainfeld, R Rosenfield, K AF Margey, R. J. P. Sakhuja, R. Gandhi, S. Rogers, R. K. Weinberg, I Jaff, M. R. Schainfeld, R. Rosenfield, K. TI A Novel Endovenous Approach for Treatment of Massive Central Venous or Pulmonary Arterial Thrombus, Mass, or Vegetation: The AngioVac Suction Cannula and Circuit SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD OCT PY 2011 VL 180 SU 11 MA 12 BP S385 EP S385 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V27YS UT WOS:000208649100013 ER PT J AU Garg, P Misra, S Thakur, JD Song, J AF Garg, Pankaj Misra, Swapna Thakur, Jai Deep Song, Jeremy TI Single incision laparoscopic surgery ovarian cystectomy in large benign ovarian cysts using conventional instruments SO JOURNAL OF MINIMAL ACCESS SURGERY LA English DT Article DE Cystectomy; laparoscopy; ovarian; single incision; single incision laparoscopic surgery AB We describe a technique for the management of large benign ovarian cysts by single incision laparoscopic surgery (SILS) through the umbilicus. The paucity of intra-abdominal working space in large ovarian cysts poses a technical challenge. Moreover, difficult convergence of operating instruments and competition for operating space outside the abdomen during the SILS makes the procedure quite demanding, especially with the conventional instruments. The concept of providing traction by taking sutures from the abdominal wall, as done in SILS laparoscopic cholecystectomy, was applied for SILS cystectomy in large ovarian cysts. Two sutures taken through the abdominal wall and then through the cyst wall provide excellent traction and "hang" the cyst from the abdominal wall, making it convenient to dissect and operate. This technique demonstrates that SILS ovarian cystectomy is feasible, safe and technically unchallenging even in large benign ovarian cysts. C1 [Garg, Pankaj; Misra, Swapna] Fortis Super Special Hosp, Dept Minimal Access Surg & Gynaecol, Mohali, Punjab, India. [Garg, Pankaj] SGHS Hosp, Dept Gen Laparoscop Surg, Mohali, Punjab, India. [Thakur, Jai Deep] Univ Arkansas Med Sci, Dept Gen Surg, Little Rock, AR 72205 USA. [Song, Jeremy] Massachusetts Gen Hosp, Dept Sch Med, Simches Res Ctr, Boston, MA 02114 USA. RP Garg, P (reprint author), 1042,Sect 15, Panchkula, Haryana, India. EM drgargpankaj@yahoo.com NR 5 TC 4 Z9 4 U1 0 U2 0 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0972-9941 J9 J MINIM ACCESS SURG JI J. Minimal Access Surg. PD OCT-DEC PY 2011 VL 7 IS 4 BP 232 EP 235 DI 10.4103/0972-9941.85646 PG 4 WC Surgery SC Surgery GA 009RB UT WOS:000309041800005 PM 22022112 ER PT J AU Pugh, MJV Hanlon, JT Wang, CP Semla, T Burk, M Amuan, ME Lowery, A Good, CB Berlowitz, DR AF Pugh, Mary Jo V. Hanlon, Joseph T. Wang, Chen-Pin Semla, Todd Burk, Muriel Amuan, Megan E. Lowery, Ashlei Good, Chester B. Berlowitz, Dan R. TI Trends in Use of High-Risk Medications for Older Veterans: 2004 to 2006 SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE inappropriate prescribing; quality of care; aged; pharmacoepidemiology ID ELDERLY VETERANS; CLAIMS DATABASE; HEALTH; AFFAIRS; FALLS; DRUG; CARE; NITROFURANTOIN; CRITERIA; PATIENT AB OBJECTIVES: To examine the change in use of high-risk medications for the elderly (HRME), as defined by the National Committee on Quality Assurance's Healthcare Effectiveness Data and Information Set (HEDIS) quality measure (HEDIS HRME), by older outpatient veterans over a 3-year period and to identify risk factors for HEDIS HRME exposure overall and for the most commonly used drug classes. DESIGN: Longitudinal retrospective database analysis. SETTING: Outpatient clinics within the Department of Veterans Affairs (VA). PARTICIPANTS: Veterans aged 65 by October 1, 2003, and who received VA care at least once each year until September 30, 2006. MEASUREMENTS: Rates of use of HEDIS HRME overall and according to specific drug classes each year from fiscal year 2004 (FY04) to FY06. RESULTS: In a cohort of 1,567,467, high-risk medication exposure fell from 13.1% to 12.3% between FY04 and FY06 (P < .001). High-risk antihistamines (e. g., diphenhydramine), opioid analgesics (e. g., propoxyphene), skeletal muscle relaxants (e. g., cyclobenzaprine), psychotropics (e. g., long half-life benzodiazepines), endocrine (e. g., estrogen), and cardiac medications (e. g., short-acting nifedipine) had modest but statistically significant (P < .001) reductions (range -3.8% to -16.0%); nitrofurantoin demonstrated a statistically significant increase (+36.5%; P < .001). Overall HEDIS HRME exposure was more likely for men, Hispanics, those receiving more medications, those with psychiatric comorbidity, and those without prior geriatric care. Exposure was lower for individuals exempt from copayment. Similar associations were seen between ethnicity, polypharmacy, psychiatric comorbidity, access-to-care factors, and use of individual HEDIS HRME classes. CONCLUSION: HEDIS HRME drug exposure decreased slightly in an integrated healthcare system. Risk factors for exposure were not consistent across drug groups. Future studies should examine whether interventions to further reduce HEDIS HRME use improve health outcomes. J Am Geriatr Soc 59:1891-1898, 2011. C1 [Pugh, Mary Jo V.] S Texas Vet Hlth Care Syst 11C6, VERDICT REAP, Vet Evidence Based Res & Implementat Ctr, San Antonio, TX 78023 USA. [Pugh, Mary Jo V.; Wang, Chen-Pin] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Lowery, Ashlei] Univ Texas Hlth Sci Ctr San Antonio, Div Geriatr Gerontol & Palliat Med, San Antonio, TX 78229 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Div Geriatr Med, Dept Pharm & Therapeut, Pittsburgh, PA USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Div Geriatr Med, Pittsburgh, PA 15261 USA. [Good, Chester B.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Hanlon, Joseph T.; Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Hanlon, Joseph T.; Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Semla, Todd; Burk, Muriel] Dept Vet Affairs, Pharm Benefits Management Serv, Hines, IL USA. [Semla, Todd; Burk, Muriel] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Semla, Todd; Burk, Muriel; Berlowitz, Dan R.] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Amuan, Megan E.] Ctr Hlth Qual Outcomes & Econ Res, Dept Vet Affairs, Bedford, MA USA. [Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Pugh, MJV (reprint author), S Texas Vet Hlth Care Syst 11C6, VERDICT REAP, Vet Evidence Based Res & Implementat Ctr, 7400 Merton Minter, San Antonio, TX 78023 USA. EM maryjo.pugh2@va.gov OI Pugh, Mary Jo/0000-0003-4196-7763 FU South Texas Veterans Healthcare System/Audie L. Murphy Division; Veterans Evidence-based Research and Implementation Center; VA Health Services Research and Development Service (HSRD) [DHI-09-237, IIR-06-062, IIR 08-274, SDR-07-042, IIR-05-121, IAF-06-080, IIR-09-335, SHP 08-140, TRX 01-091]; Epilepsy Foundation; Department of Defense CDMRP [09090014]; NIH [R01-NR010828]; VA Health Services Research [IIR-06-062]; National Institute of Aging [R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056]; National Institute of Mental Health [R34 MH082682]; National Institute of Nursing Research [R01NR010135]; Agency for Healthcare Research and Quality [R01HS017695] FX The authors acknowledge and appreciate support from the South Texas Veterans Healthcare System/Audie L. Murphy Division and the Veterans Evidence-based Research and Implementation Center. The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. We acknowledge the contributions of Jeffrey Tabares and Ranjani Davalath in assisting with manuscript preparation.; Dr. Pugh has received research funding from VA Health Services Research and Development Service (HSRD) DHI-09-237 (PI); VA HSRD IIR-06-062 PI, Epilepsy Foundation PI, VA HSRD PPO 09-295 PI, VA HSRD IIR 02-274 PI. Pugh as co-I: VA HSRD IIR 08-274, VA HSRD SDR-07-042, IIR-05-121, IAF-06-080, IIR-09-335, SHP 08-140, TRX 01-091 Department of Defense CDMRP 09090014, NIH R01-NR010828,; This study was supported by a VA Health Services Research grant (IIR-06-062, Dr. Pugh PI). Dr Hanlon is supported by National Institute of Aging grants (R01AG027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056), a National Institute of Mental Health grant (R34 MH082682), a National Institute of Nursing Research grant (R01NR010135), and an Agency for Healthcare Research and Quality grant (R01HS017695). NR 39 TC 14 Z9 15 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2011 VL 59 IS 10 BP 1891 EP 1898 DI 10.1111/j.1532-5415.2011.03559.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 840OE UT WOS:000296449300014 PM 21883108 ER PT J AU Nichols, AJ Evans, CL AF Nichols, Alexander J. Evans, Conor L. TI Video-rate Scanning Confocal Microscopy and Microendoscopy SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Bioengineering; Issue 56; Microscopy; confocal microscopy; microendoscopy; video-rate; fluorescence; scanning; in vivo imaging AB Confocal microscopy has become an invaluable tool in biology and the biomedical sciences, enabling rapid, high-sensitivity, and high-resolution optical sectioning of complex systems. Confocal microscopy is routinely used, for example, to study specific cellular targets(1), monitor dynamics in living cells(2-4), and visualize the three dimensional evolution of entire organisms(5,6). Extensions of confocal imaging systems, such as confocal microendoscopes, allow for high-resolution imaging in vivo(7) and are currently being applied to disease imaging and diagnosis in clinical settings(8,9). Confocal microscopy provides three-dimensional resolution by creating so-called "optical sections" using straightforward geometrical optics. In a standard wide-field microscope, fluorescence generated from a sample is collected by an objective lens and relayed directly to a detector. While acceptable for imaging thin samples, thick samples become blurred by fluorescence generated above and below the objective focal plane. In contrast, confocal microscopy enables virtual, optical sectioning of samples, rejecting out-of-focus light to build high resolution three-dimensional representations of samples. Confocal microscopes achieve this feat by using a confocal aperture in the detection beam path. The fluorescence collected from a sample by the objective is relayed back through the scanning mirrors and through the primary dichroic mirror, a mirror carefully selected to reflect shorter wavelengths such as the laser excitation beam while passing the longer, Stokes-shifted fluorescence emission. This long-wavelength fluorescence signal is then passed to a pair of lenses on either side of a pinhole that is positioned at a plane exactly conjugate with the focal plane of the objective lens. Photons collected from the focal volume of the object are collimated by the objective lens and are focused by the confocal lenses through the pinhole. Fluorescence generated above or below the focal plane will therefore not be collimated properly, and will not pass through the confocal pinhole(1), creating an optical section in which only light from the microscope focus is visible. (Fig 1). Thus the pinhole effectively acts as a virtual aperture in the focal plane, confining the detected emission to only one limited spatial location. Modern commercial confocal microscopes offer users fully automated operation, making formerly complex imaging procedures relatively straightforward and accessible. Despite the flexibility and power of these systems, commercial confocal microscopes are not well suited for all confocal imaging tasks, such as many in vivo imaging applications. Without the ability to create customized imaging systems to meet their needs, important experiments can remain out of reach to many scientists. In this article, we provide a step-by-step method for the complete construction of a custom, video-rate confocal imaging system from basic components. The upright microscope will be constructed using a resonant galvanometric mirror to provide the fast scanning axis, while a standard speed resonant galvanometric mirror will scan the slow axis. To create a precise scanned beam in the objective lens focus, these mirrors will be positioned at the so-called telecentric planes using four relay lenses. Confocal detection will be accomplished using a standard, off-the-shelf photomultiplier tube (PMT), and the images will be captured and displayed using a Matrox framegrabber card and the included software. C1 [Nichols, Alexander J.; Evans, Conor L.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. [Nichols, Alexander J.] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Nichols, Alexander J.; Evans, Conor L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02138 USA. RP Evans, CL (reprint author), Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. EM Evans.Conor@mgh.harvard.edu FU ThorLabs; NSF; National Institutes of Health through the NIH Director's New Innovator Award Program [1 DP2 OD007096-01] FX The authors would like to thank ThorLabs for their support of this project. AJN wishes to acknowledge the support of an NSF Graduate Fellowship.; This work was partially funded by the National Institutes of Health through the NIH Director's New Innovator Award Program, grant number 1 DP2 OD007096-01. Information on the New Innovator Award Program is at http://nihroadmap.nih.gov/newinnovator/. The authors would like to thank Tom Hayes for use of the Harvard Electronics lab. NR 10 TC 1 Z9 1 U1 0 U2 3 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD OCT PY 2011 IS 56 AR UNSP e3252 DI 10.3791/3252 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36PB UT WOS:000209222400032 ER PT J AU Parsons, XH Teng, YD Parsons, JF Snyder, EY Smotrich, DB Moore, DA AF Parsons, Xuejun H. Teng, Yang D. Parsons, James F. Snyder, Evan Y. Smotrich, David B. Moore, Dennis A. TI Efficient Derivation of Human Neuronal Progenitors and Neurons from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Neuroscience; Issue 56; stem cell; human embryonic stem cell; human; neuronal progenitor; neuron; human pluripotent cell; neuronal differentiation; small molecule induction; cell culture; cell therapy AB There is a large unfulfilled need for a clinically-suitable human neuronal cell source for repair or regeneration of the damaged central nervous system (CNS) structure and circuitry in today's healthcare industry. Cell-based therapies hold great promise to restore the lost nerve tissue and function for CNS disorders. However, cell therapies based on CNS-derived neural stem cells have encountered supply restriction and difficulty to use in the clinical setting due to their limited expansion ability in culture and failing plasticity after extensive passaging(1-3). Despite some beneficial outcomes, the CNS-derived human neural stem cells (hNSCs) appear to exert their therapeutic effects primarily by their non-neuronal progenies through producing trophic and neuroprotective molecules to rescue the endogenous cells(1-3). Alternatively, pluripotent human embryonic stem cells (hESCs) proffer cures for a wide range of neurological disorders by supplying the diversity of human neuronal cell types in the developing CNS for regeneration(1,4-7). However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity(7-10). In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic(11-13). To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules(14) (please see a schematic in Fig. 1). Retinoic acid (RA) does not induce neuronal differentiation of undifferentiated hESCs maintained on feeders(1,14). And unlike mouse ESCs, treating hESC-differentiated embryoid bodies (EBs) only slightly increases the low yield of neurons(1,14,15). However, after screening a variety of small molecules and growth factors, we found that such defined conditions rendered retinoic acid (RA) sufficient to induce the specification of neuroectoderm direct from pluripotent hESCs that further progressed to neuroblasts that generated human neuronal progenitors and neurons in the developing CNS with high efficiency (Fig. 2). We defined conditions for induction of neuroblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human neuronal cells across the spectrum of developmental stages for cell-based therapeutics. C1 [Parsons, Xuejun H.; Parsons, James F.; Snyder, Evan Y.; Smotrich, David B.; Moore, Dennis A.] San Diego Regenerat Med Inst, San Diego, CA 92109 USA. [Parsons, Xuejun H.; Parsons, James F.; Snyder, Evan Y.; Smotrich, David B.; Moore, Dennis A.] Xcelthera, San Diego, CA USA. [Teng, Yang D.] Harvard Univ, Sch Med, Dept Neurosurg, Cambridge, MA 02138 USA. [Teng, Yang D.] VA Boston Healthcare Syst, Div SCI Res, Jamaica Plain, MA USA. [Snyder, Evan Y.] Sanford Burnham Med Res Inst, Program Stem Cell & Regenerat Biol, La Jolla, CA USA. [Smotrich, David B.] La Jolla IVF, La Jolla, CA USA. RP Parsons, XH (reprint author), San Diego Regenerat Med Inst, San Diego, CA 92109 USA. EM parsons@SDRMI.org FU National Institute of Health (NIH) grants from National Institute on Aging [NIHK01AG024496]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NIHR21HD056530] FX XHP has been supported by National Institute of Health (NIH) grants from National Institute on Aging (NIHK01AG024496) and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIHR21HD056530). NR 23 TC 2 Z9 2 U1 0 U2 6 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD OCT PY 2011 IS 56 AR UNSP e3273 DI 10.3791/3273 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36PB UT WOS:000209222400036 PM 22064669 ER PT J AU Liu, CF Manning, WG Burgess, JF Hebert, PL Bryson, CL Fortney, J Perkins, M Sharp, ND Maciejewski, ML AF Liu, Chuan-Fen Manning, Willard G. Burgess, James F., Jr. Hebert, Paul L. Bryson, Chris L. Fortney, John Perkins, Mark Sharp, Nancy D. Maciejewski, Matthew L. TI Reliance on Veterans Affairs Outpatient Care by Medicare-eligible Veterans SO MEDICAL CARE LA English DT Article DE outpatient; veteran; Medicare; primary care; specialty care ID HEALTH-CARE; DUAL-USE; VA; SERVICES; VHA; TRANSFORMATION; COVERAGE; ACCESS; SYSTEM AB Objective: To examine longitudinal changes in Medicare-eligible veterans' reliance on the Department of Veterans Affairs (VA) healthcare system for primary and specialty care over 4 years. Methods: We merged VA administrative and Medicare claims data to examine outpatient use during fiscal years (FY) 2001 to 2004 by 15,520 Medicare-eligible veterans who used VA primary care in FY2000. Reliance on VA outpatient care was defined as the proportion of total (VA/Medicare) visits received in VA for primary or specialty care. Results: Of 869,000 primary and specialty care visits in the study period, 39% occurred within VA and 77% were specialty care. Reliance on VA primary care was substantially higher than specialty care (66% vs. 50% in FY2001; P<0.001). Reliance on VA primary and specialty care decreased over time (57% vs. 31% in FY2004; P<0.001). Significant shifts occurred at both extremes of VA reliance. From FY2001 to FY2004, the proportion of patients in the top decile of reliance on VA primary care decreased from 39% to 31%, whereas the proportion in the bottom decile doubled from 8% to 18%. Similarly, the proportion of patients in the top decile of reliance on VA specialty care decreased from 24% to 13%, whereas the proportion in the bottom decile doubled from 22% to 47%. Conclusions: Reliance on VA primary and specialty care among VA primary care patients decreased substantially over time, particularly for specialty care. Increasing use of non-VA services may complicate VA's implementation of patient-centered medical home models and performance measurement. C1 [Liu, Chuan-Fen; Hebert, Paul L.; Bryson, Chris L.; Perkins, Mark; Sharp, Nancy D.] VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, Seattle, WA 98101 USA. [Liu, Chuan-Fen; Hebert, Paul L.; Sharp, Nancy D.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Manning, Willard G.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Burgess, James F., Jr.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Burgess, James F., Jr.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Bryson, Chris L.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Fortney, John] S Cent Mental Hlth Illness Res & Educ & Clin Ctr, Little Rock, AR USA. [Fortney, John] Cent Arkansas Vet Healthcare Syst, HSR&D Ctr Mental Healthcare & Outcomes Res, Little Rock, AR USA. [Fortney, John] Univ Arkansas Med Sci, Dept Psychiat & Behav Sci, Div Hlth Serv Res, Little Rock, AR 72205 USA. [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Maciejewski, Matthew L.] Duke Univ, Med Ctr, Dept Med, Div Gen Internal Med, Durham, NC USA. RP Liu, CF (reprint author), VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM fliu@u.washington.edu OI Burgess, James/0000-0002-6646-7071 FU Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs [IIR 04-292] FX Supported by the Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs, project number IIR 04-292. NR 31 TC 23 Z9 23 U1 2 U2 6 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 OCT PY 2011 VL 49 IS 10 BP 911 EP 917 DI 10.1097/MLR.0b013e31822396c5 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 821EO UT WOS:000294957900006 PM 21685810 ER PT J AU Zhu, JY Stuver, SO Epstein, AM Schneider, EC Weissman, JS Weingart, SN AF Zhu, Junya Stuver, Sherri O. Epstein, Arnold M. Schneider, Eric C. Weissman, Joel S. Weingart, Saul N. TI Can We Rely on Patients' Reports of Adverse Events? SO MEDICAL CARE LA English DT Article DE patient safety; patient surveys; adverse events; complication ID PATIENTS TELL US; HOSPITALIZED-PATIENTS; LIKELIHOOD RATIOS; DRUG EVENTS; MEDICAL PATIENTS; AMBULATORY-CARE; HEALTH-CARE; ERRORS AB Background: Evidence suggests that patients can report a variety of adverse events (AEs) not captured by traditional methods such as a chart review. Little is known, however, about whether patient reports are useful for measuring patient safety. Objectives: To examine the degree to which physician reviewers agreed that patient reports of "negative effects" constituted AEs, and to identify questionnaire items that affected reviewers' judgments. Methods: We surveyed patients discharged from Massachusetts hospitals in 2003 to elicit information about negative effects associated with hospitalization. Physician reviewers judged whether patient-reported negative effects represented AEs, and classified the severity of the event. Likelihood ratios were calculated to assess whether patient responses to questionnaire items affected reviewers' judgments. Results: Of the 2582 patients surveyed, 753 patients reported 1170 negative effects, and 71.2% of these effects were classified as AEs by physician reviewers. Negative effects most likely to be classified as AEs involved newly prescribed medications and changes to previously prescribed medications. Additional information elicited from follow-up survey questions modestly affected reviewers' classification of serious AEs. Negative effects reported by women, younger patients, those reporting better health status, and those not admitted through the emergency department were more likely to be classified as AEs. Conclusions: Many patients were able to identify care-related AEs. Patient responses to questions about the sequelae of the events provided limited additional information for physicians to use in gauging the presence and severity of the event. Patient reports complement other incident-detection methods by providing information that is credible and unavailable from other sources. C1 [Zhu, Junya; Stuver, Sherri O.; Weingart, Saul N.] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02215 USA. [Zhu, Junya] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA 02254 USA. [Epstein, Arnold M.; Schneider, Eric C.; Weissman, Joel S.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Cambridge, MA 02138 USA. [Epstein, Arnold M.; Schneider, Eric C.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Schneider, Eric C.] RAND Boston, Boston, MA USA. [Weissman, Joel S.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Weissman, Joel S.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. RP Zhu, JY (reprint author), Dana Farber Canc Inst, Ctr Patient Safety, 450 Brookline Ave, Boston, MA 02215 USA. EM junya_zhu@dfci.harvard.edu OI Stuver, Sherri/0000-0002-4027-2663; Schneider, Eric/0000-0002-1132-5084 FU Agency for Healthcare Research and Quality [U18 HS11928]; Center for Patient Safety at Dana-Farber Cancer Institute FX Supported by a Cooperative Agreement from the Agency for Healthcare Research and Quality to the Massachusetts Department of Public Health [U18 HS11928], and the Center for Patient Safety at Dana-Farber Cancer Institute. NR 39 TC 27 Z9 27 U1 1 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 OCT PY 2011 VL 49 IS 10 BP 948 EP 955 DI 10.1097/MLR.0b013e31822047a8 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 821EO UT WOS:000294957900011 PM 21642876 ER PT J AU Arora, A Healy, B Hayden, D Ceccarelli, A Tauhid, S Neema, M Bakshi, R AF Arora, A. Healy, B. Hayden, D. Ceccarelli, A. Tauhid, S. Neema, M. Bakshi, R. TI Approaches to normalisation of spinal cord volume: application to multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Brookline, MA USA. Brigham & Womens Hosp, Brookline, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P371 BP S150 EP S150 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300300 ER PT J AU Gavasso, S Maroy, T Gjertsen, BT Anderssen, E Myhr, KM Vedeler, C AF Gavasso, S. Maroy, T. Gjertsen, B. -T. Anderssen, E. Myhr, K. -M. Vedeler, C. TI Monitoring drug response in patients with signalling pathway-specific flow cytometry SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Haukeland Hosp, N-5021 Bergen, Norway. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Gjertsen, Bjorn T/O-1542-2015 OI Gjertsen, Bjorn T/0000-0001-9358-9704 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P545 BP S236 EP S236 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137300474 ER PT J AU Klawiter, EC Jackson, JS Ceccarelli, A Arora, A Bakshi, R Neema, M AF Klawiter, E. C. Jackson, J. S. Ceccarelli, A. Arora, A. Bakshi, R. Neema, M. TI Magnetic resonance imaging correlates of corpus callosum atrophy in multiple sclerosis at 3T SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P834 BP S371 EP S371 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301200 ER PT J AU Xia, Z Liu, Q Keenan, B Berger, C Kaliszewska, A Wood, I Alter, G De Jager, P AF Xia, Z. Liu, Q. Keenan, B. Berger, C. Kaliszewska, A. Wood, I. Alter, G. De Jager, P. TI Cytometric profiling of natural killer cells as a functional screen of genetic variants associated with multiple sclerosis susceptibility SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2011 VL 17 SU 10 MA P764 BP S339 EP S339 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V35GA UT WOS:000209137301130 ER PT J AU Wolf, EJ Miller, MW Brown, TA AF Wolf, Erika J. Miller, Mark W. Brown, Timothy A. TI The Structure of Personality Disorders in Individuals With Posttraumatic Stress Disorder SO PERSONALITY DISORDERS-THEORY RESEARCH AND TREATMENT LA English DT Article DE personality disorder; internalizing; externalizing; boundary disturbances; posttraumatic stress disorder ID COMMON PSYCHOPATHOLOGICAL SYNDROMES; COMORBIDITY SURVEY REPLICATION; PROPOSED META-STRUCTURE; DSM-IV; MENTAL-DISORDERS; COMBAT VETERANS; PSYCHOMETRIC PROPERTIES; GENETIC-STRUCTURE; PTSD CHECKLIST; FIT INDEXES AB Research on the structure of personality disorders (PDs) has relied primarily on exploratory analyses to evaluate trait-based models of the factors underlying the covariation of these disorders. This study used confirmatory factor analysis to evaluate whether a model that included both PD traits and a general personality dysfunction factor would account for the comorbidity of the PDs better than a trait-only model. It also examined if the internalizing/externalizing model of psychopathology, developed previously through research on the structure of Axis I disorders, might similarly account for the covariation of the Axis II disorders in a sample of 245 veterans and nonveterans with posttraumatic stress disorder. Results indicated that the best fitting model was a modified bifactor structure composed of nine lower-order common factors. These factors indexed pathology ranging from aggression to dependency, with the correlations among them accounted for by higher-order Internalizing and Externalizing factors. Further, a general factor, reflecting a construct that we termed boundary disturbance, accounted for additional variance and covariance across nearly all the indicators. The Internalizing, Externalizing, and Boundary Disturbance factors evidenced differential associations with trauma-related covariates. These findings suggest continuity in the underlying structure of psychopathology across DSM-IV Axes I and II and provide empirical evidence of a pervasive, core disturbance in the boundary between self and other across the PDs. C1 [Wolf, Erika J.; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Wolf, Erika J.; Brown, Timothy A.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Wolf, EJ (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-4,150 S Huntington Ave, Boston, MA 02130 USA. EM erika.wolf@va.gov RI Schueter, nicos/A-3625-2014; Miller, Mark/G-7322-2011; OI Miller, Mark/0000-0001-6393-8563; Wolf, Erika/0000-0003-2666-2435 FU CSRD VA [I01 CX000431]; NIMH NIH HHS [5F31MH074267, F31 MH074267] NR 51 TC 10 Z9 10 U1 2 U2 4 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1949-2715 EI 1949-2723 J9 PERSONAL DISORD JI Personal. Disord. PD OCT PY 2011 VL 2 IS 4 BP 261 EP 278 DI 10.1037/a0023168 PG 18 WC Psychology, Clinical SC Psychology GA 051ZG UT WOS:000312166900002 PM 22448802 ER PT J AU Baker, AM Haeri, S Camargo, CA Stuebe, AM Boggess, KA AF Baker, Arthur M. Haeri, Sina Camargo, Carlos A., Jr. Stuebe, Alison M. Boggess, Kim A. TI A Nested Case-Control Study of First-Trimester Maternal Vitamin D Status and Risk for Spontaneous Preterm Birth SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE Preterm birth; vitamin D; 25-hydroxyvitamin D ID D DEFICIENCY; 25-HYDROXYVITAMIN-D; PREECLAMPSIA; MORTALITY; PREVENTION; DELIVERY; OUTCOMES; DISEASE AB We assessed if first-trimester vitamin D deficiency is more prevalent in women who experienced a spontaneous preterm birth compared with women who delivered at term. We conducted a nested case-control study of pregnant women who had previously given blood for first-trimester combined screening for trisomy 21 and subsequently delivered at a tertiary hospital between November 2004 and July 2009. From an overall cohort of 4225 women, 40 cases of spontaneous preterm birth (>= 23 (0)/7 and <= 34 (6)/7 weeks) were matched by race/ethnicity with 120 women delivering at term (>= 37 (0)/7 weeks) with uncomplicated pregnancies. Banked maternal serum was used to measure maternal 25-hydroxyvitamin D [25(OH)D]. The prevalence of first-trimester maternal vitamin D deficiency [25(OH)D < 50 nmol/L] was comparable among women who subsequently delivered preterm compared with controls (7.5% versus 6.7%, p = 0.90). The median 25(OH)D level for all subjects was 89 nmol/L (interquartile range, 73 to 106 nmol/L). Seventy-three percent (117/160) of the cohort had sufficient vitamin D levels [25(OH)D >= 75 nmol/L]. In a cohort of pregnant women with mostly sufficient levels of first-trimester serum 25(OH)D, vitamin D deficiency was not associated with spontaneous preterm birth. C1 [Baker, Arthur M.; Haeri, Sina; Stuebe, Alison M.; Boggess, Kim A.] Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Stuebe, Alison M.] Univ N Carolina, Dept Maternal & Child Hlth, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Ctr D Receptor Activat Res, Boston, MA 02114 USA. RP Baker, AM (reprint author), Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Gillings Sch Global Publ Hlth, 3010 Old Clin Bldg,CB 7516, Chapel Hill, NC 27599 USA. EM abaker2@med.unc.edu FU Bowes/Cefalo Young Researcher Award; Massachusetts General Hospital Center for D-receptor Activation Research FX This research was supported, in part, by the Bowes/Cefalo Young Researcher Award (A.M.B.) and the Massachusetts General Hospital Center for D-receptor Activation Research (C.A.C.). NR 21 TC 33 Z9 34 U1 1 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD OCT PY 2011 VL 28 IS 9 BP 667 EP 671 DI 10.1055/s-0031-1276731 PG 5 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 819SV UT WOS:000294851400001 PM 21500145 ER PT J AU Saund, MS Al Natour, RH Sharma, AM Huang, Q Boosalis, VA Gold, JS AF Saund, Mandeep S. Al Natour, Riad H. Sharma, Ashish M. Huang, Qin Boosalis, Valia A. Gold, Jason S. TI Tumor Size and Depth Predict Rate of Lymph Node Metastasis and Utilization of Lymph Node Sampling in Surgically Managed Gastric Carcinoids SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SMALL-CELL; STOMACH; CANCER; GUIDELINES AB Background. Radical resection with regional lymphadenectomy is recommended for all sporadic gastric carcinoids. Local resection, however, is accepted for some carcinoids from other gastrointestinal sites (i.e., appendix and rectum). We sought to examine the relation of tumor size and depth to lymph node metastasis to determine whether gastric carcinoids can be selected for endoscopic resection. We also sought to quantify the utilization of lymph node sampling. Methods. 984 patients with localized gastric carcinoids who underwent cancer-directed surgery between 1983 and 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) registry database. Results. Tumor size and depth predicted probability of lymph node metastasis. Lymph node metastasis was not seen in intraepithelial (IE) tumors < 2 cm. Of tumors < 1 cm invading into the lamina propria or submucosa (LP/SM), 3.4% had lymph node metastasis. Excluding IE tumors < 2 cm and LP/SM tumors < 1 cm, all other subgroups based on size and depth had rates of lymph node metastasis a parts per thousand yen 8%. Tumor size and depth predicted probability of lymph node sampling. Overall, only 21% of tumors had lymph node sampling. Excluding IE tumors < 2 cm and LP/SM tumors < 1 cm, only 43% of tumors had lymph node sampling. Conclusions. Tumor size and depth predict lymph node metastasis for gastric carcinoids. Endoscopic resection may be appropriate for intraepithelial (IE) tumors < 2 cm and perhaps tumors < 1 cm invading into the lamina propria or submucosa. Lymph node sampling is underused for gastric carcinoids at high risk for lymph node metastasis. C1 [Saund, Mandeep S.; Al Natour, Riad H.; Gold, Jason S.] VA Boston Healthcare Syst, Surg Serv, W Roxbury, MA 02132 USA. [Saund, Mandeep S.; Al Natour, Riad H.; Huang, Qin; Gold, Jason S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Huang, Qin] VA Boston Healthcare Syst, Pathol Serv, W Roxbury, MA USA. [Sharma, Ashish M.; Boosalis, Valia A.] VA Boston Healthcare Syst, Med Serv, W Roxbury, MA USA. [Sharma, Ashish M.; Boosalis, Valia A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Saund, MS (reprint author), VA Boston Healthcare Syst, Surg Serv, W Roxbury, MA 02132 USA. EM jgold4@partners.org RI Gold, Jason/O-5112-2014 OI Gold, Jason/0000-0002-2925-4755 NR 20 TC 17 Z9 19 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2011 VL 18 IS 10 BP 2826 EP 2832 DI 10.1245/s10434-011-1652-0 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 819JG UT WOS:000294820600017 PM 21455598 ER PT J AU Toi, M Winer, EP Inamoto, T Benson, JR Forbes, JF Mitsumori, M Robertson, JFR Sasano, H von Minckwitz, G Yamauchi, A Klimberg, VS AF Toi, Masakazu Winer, Eric P. Inamoto, Takashi Benson, John R. Forbes, John F. Mitsumori, Michihide Robertson, John F. R. Sasano, Hironobu von Minckwitz, Gunter Yamauchi, Akira Klimberg, V. Suzanne TI Identifying Gaps in the Locoregional Management of Early Breast Cancer: Highlights from the Kyoto Consensus Conference SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SENTINEL NODE BIOPSY; CARCINOMA-IN-SITU; POSTMASTECTOMY RADIATION IMPROVES; RANDOMIZED CONTROLLED-TRIAL; SURGICAL ADJUVANT BREAST; LYMPH-NODE; NEOADJUVANT CHEMOTHERAPY; PROGESTERONE-RECEPTOR; CONSERVING TREATMENT; ESTROGEN-RECEPTOR AB A consensus conference was held to investigate issues related to the local management of early breast cancer. Here, we highlight the major topics discussed at the conference and propose ideas for future studies. Regarding axillary management, we examined three major issues. First, we discussed whether the use of axillary reverse mapping could clarify the lymphatic system of breast and whether the ipsilateral arm might help avoid lymphedema. Second, the use of an indocyanine green fluorescent navigation system was discussed for intraoperative lymphatic mapping. These new issues should be examined further in practice. Finally, some agreement was reached on the importance of "four-node diagnosis" to aid in the diagnostic accuracy of sentinel nodes. Regarding breast treatment, there was general agreement that the clinical value of surgical margins in predicting local failure was dependent on the tumor's intrinsic biology and subtypes. For patients treated with preoperative chemotherapy, less extensive excision may be feasible in those who respond to systemic therapy in an acceptable manner. Most trials of preoperative chemotherapy lack outcome data on local recurrence. Therefore, there is a need for such data for overview analysis. We also agreed that radiation after mastectomy may be beneficial in node-positive cases where more than four nodes are involved. Throughout the discussions for both invasive and noninvasive disease, the investigation of nomograms was justified for major issues in the decision-making process, such as the presence or absence of microinvasion and the involvement of nonsentinel nodes in sentinel node-positive patients. C1 [Toi, Masakazu] Kyoto Univ, Grad Sch Med, Dept Surg, Sakyo Ku, Kyoto, Japan. [Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. [Inamoto, Takashi; Yamauchi, Akira] Kitano Hosp, Dept Breast Surg, Osaka, Japan. [Benson, John R.] Univ Cambridge, Cambridge, England. [Benson, John R.] Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England. [Forbes, John F.] Univ Newcastle, Dept Surg Oncol, Newcastle, NSW 2300, Australia. [Mitsumori, Michihide] Kyoto Univ, Grad Sch Med, Dept Radiat Oncol & Image Appl Therapy, Kyoto, Japan. [Robertson, John F. R.] Univ Nottingham, Div Breast Surg, Professorial Surg Unit, Nottingham NG7 2RD, England. [Sasano, Hironobu] Tohoku Univ, Sch Med, Dept Pathol, Sendai, Miyagi 980, Japan. [von Minckwitz, Gunter] Goethe Univ Frankfurt, Dept Gynecol & Obstet, Frankfurt, Germany. [Klimberg, V. Suzanne] Univ Arkansas Med Sci, Rockefeller Canc Inst, Div Breast Surg Oncol, Little Rock, AR 72205 USA. RP Toi, M (reprint author), Kyoto Univ, Grad Sch Med, Dept Surg, Sakyo Ku, Kyoto, Japan. EM toi@kuhp.kyoto-u.ac.jp FU Kyoto University Foundation FX We thank Dr. Masahiro Hiraoka, Chairman of the Department of Radiation Oncology and Image-applied Therapy at Kyoto University, the executive advisor to this project. We are also grateful to Dr. Fabrizio Michelassi, Chairman of the Department of Surgery at New York Presbyterian Hospital, Weill Cornell Medical Center, for providing guidance regarding the consensus questionnaire. We thank the Kyoto University Foundation for their generous donation of funds. The conference was part of a program, "Raising Proficient Oncologists,'' run by the Japanese Ministry of Education, Culture, Sports, Science, and Technology. We acknowledge the kind support of the Japan Breast Cancer Society. We express sincere thanks to the doctors who completed the consensus questionnaire. We are grateful to Dr. Hiroshi Ishiguro for his valuable help and scientific advice. We also thank Ms. Aya Morotomi, Mr. David Graham, Ms. Mihoko Yamamoto, Ms. Nastajia Burke, Ms. Chisa Takano, and Ms. Nobuko Yagi for their invaluable support. Moderators: S. K. Apple (University of California, Los Angeles), J. R. Benson (Addenbrooke's Hospital and University of Cambridge, Cambridge), W. C. Chow (UNIMED Medical Institute/Hong Kong University, Hong Kong), J. F. Forbes (The University of Newcastle, Newcastle), M. Golshan (Dana-Farber Cancer Institute, Brigham & Women's Cancer Center, Boston), T. Inamoto (Kitano Hospital, Osaka), V. S. Klimberg (University of Arkansas for Medical Sciences, Arkansas), M. Mitsumori (Kyoto University, Kyoto), S. Noguchi (Osaka University, Osaka), J. F. R. Robertson (The University of Nottingham, Nottingham), D. H. Roukos (University of Ioannina, Ioannina), H. Sasano (Tohoku University, Sendai), E. A. Strom (The University of Texas M. D. Anderson Cancer Center, Houston), M. Toi (Kyoto University, Kyoto), G. Von Minckwitz (The Centre for Gynecology and Obstetrics at the University of Frankfurt, Frankfurt), E. P. Winer (Dana-Farber Cancer Institute, Brigham & Women's Cancer Center, Boston), and A. Yamauchi (Kitano Hospital, Osaka). Discussants and organizers: S. Akashi-Tanaka (National Cancer Center Hospital, Tokyo), R. Arriagada (Karolinska institute, Stockholm/ Institut Gustave-Roussy, Paris), J. Chen (Cancer Hospital of Fudan University, Shanghai), S. C. Chen (Chang Gung University, Taoyuan), S. W. Ha (Seoul National University Hospital, Seoul), S. Han (Inje University Sanggye Paik Hospital, Kyungnam), C. S. Huang and T. Ikeda (Teikyo University, Tokyo), S. Imoto (Kyorin University, Tokyo), H. Inaji (Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka), T. Iwase (The Cancer Institute Hospital of JFCR, Tokyo), H. Iwata (Aichi Cancer Center, Nagoya), R. V. Jakesz (University of Vienna, Vienna), H. Jinno (Keio University, Tokyo), H. Kawabata (Toranomon Hospital, Tokyo), T. Kinoshita (National Cancer Center Hospital, Tokyo), T. Kitai (Nara Social Insurance Hospital, Nara), N. Kohno (Tokyo Medical University, Tokyo), I. E. Krop (Dana-Farber Cancer Institute, Brigham and Women's Cancer Center, Boston), I. Kunkler (University of Edinburgh, Edinburgh), J. Kurebayashi (Kawasaki Medical University, Kurashiki), K. Kuroi (Tokyo Metropolitan Cancer and Infectious Disease Center, Tokyo), E. S. Lee (Korea University Anam-Hospital, Seoul), S. J. Lee (Yeungnam University, Gyeongsan), N. Masuda (Osaka National Hospital, Osaka), Y. Mikami (Kyoto University, Kyoto), S. Nakamura (St. Luke's International Hospital, Tokyo), D. Y. Noh (Seoul National University, Seoul), S. Ohno (National Kyushu Cancer Center, Fukuoka), N. S.; Paik (Konkuk University Medical Center Seoul), M. D. Pegram (University of Miami, Miller School of Medicine, Miami), T. Saeki (Saitama Medical University, Saitama), M. Shafir (Mount Sinai Hospital and School of Medicine, New York), H. Takei (Saitama Cancer Center, Saitama), H. Sonoo (Kawasaki Medical School Hospital, Kurashiki), T. Sugie (Kyoto University, Kyoto), M. Takada (Kyoto University, Kyoto), Y. Tanaka (Kyoto University, Kyoto), T. Ueno (Kyoto University, Kyoto), T. Varughese (Lakeshore Hospital and Research Centre, Cochin), and K. Yamagami (Shinko Hospital, Kobe). NR 52 TC 5 Z9 5 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2011 VL 18 IS 10 BP 2885 EP 2892 DI 10.1245/s10434-011-1666-7 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 819JG UT WOS:000294820600025 PM 21431404 ER PT J AU Adler, JT Chen, H Schaefer, S Sippel, RS AF Adler, Joel T. Chen, Herbert Schaefer, Sarah Sippel, Rebecca S. TI What is the Added Benefit of Cervical Ultrasound to Tc-99m-Sestamibi Scanning in Primary Hyperparathyroidism? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID MINIMALLY INVASIVE PARATHYROIDECTOMY; SESTAMIBI-SPECT LOCALIZATION; SURGEON-PERFORMED ULTRASOUND; QUALITY-OF-LIFE; RADIOGUIDED PARATHYROIDECTOMY; HYPERPLASTIC GLANDS; BLOCK ANESTHESIA; HORMONE ASSAY; COMBINATION; ADENOMA AB Background. Minimally invasive parathyroidectomy for primary hyperparathyroidism depends on accurate preoperative imaging, which is traditionally accomplished by Tc-99m-sestamibi scanning. Cervical ultrasound is gaining in use, but it is unclear how much information it adds to the routine use of Tc-99m-sestamibi scans. Methods. A prospectively maintained database of patients undergoing parathyroidectomy for primary hyperparathyroidism was queried, and the utility of cervical ultrasound in preoperative planning was analyzed. Results. Between July 2002 and November 2009, 310 patients with primary hyperparathyroidism underwent both Tc-99m-sestamibi and ultrasound imaging. Ultrasound added new information to Tc-99m-sestamibi in 43 patients (14%) by finding either the correct enlarged gland (n = 40, 88%) or additional enlarged glands (n = 5, 12%). Ultrasound correctly localized glands in 38 of 85 (45%) patients with a negative Tc-99m-sestamibi, allowing for a minimally invasive parathyroidectomy in those patients. However, in the 206 patients (66%) who had a 1-gland positive Tc-99m-sestamibi, ultrasound only added information for 8 patients (4%). When compared with radiology-performed ultrasound, surgeon-performed ultrasound was successful in localizing additional glands in 27 (15%) versus 17 patients (10%) (P < 0.001). Conclusions. Ultrasound led to additional localization information in 14% of patients, although this benefit was less in patients with a clearly positive 1-gland Tc-99m-sestamibi scan. Cervical ultrasound provides added benefit to Tc-99m-sestamibi scanning in patients with primary hyperparathyroidism, but its greatest utility is when performed by a surgeon in patients with a negative Tc-99m-sestamibi scan. C1 [Adler, Joel T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Chen, Herbert; Schaefer, Sarah; Sippel, Rebecca S.] Univ Wisconsin, Dept Surg, Madison, WI USA. RP Adler, JT (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM sippel@surgery.wisc.edu OI Adler, Joel/0000-0001-8190-3444 NR 21 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2011 VL 18 IS 10 BP 2907 EP 2911 DI 10.1245/s10434-011-1724-1 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 819JG UT WOS:000294820600028 PM 21509629 ER PT J AU McCann, CK Growdon, WB Munro, EG Del Carmen, MG Boruta, DM Schorge, JO Goodman, A AF McCann, Christopher K. Growdon, Whitfield B. Munro, Elizabeth G. Del Carmen, Marcela G. Boruta, David M. Schorge, John O. Goodman, Annekathryn TI Prognostic Significance of Splenectomy as Part of Initial Cytoreductive Surgery in Ovarian Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LYMPH-NODE DISSECTION; GYNECOLOGIC-ONCOLOGY-GROUP; PROXIMAL GASTRIC-CANCER; IV EPITHELIAL OVARIAN; DISTAL PANCREATECTOMY; STAGE-III; SURGICAL CYTOREDUCTION; FALLOPIAN-TUBE; CARCINOMA; SURVIVAL AB Purpose. We sought to examine how splenectomy as part of up-front cytoreductive surgery in ovarian cancer influences the postoperative course and affects survival. Methods. We reviewed cases of ovarian cancer diagnosed at Massachusetts General Hospital from 1994 to 2008 and found 44 patients who had a splenectomy as part of their up-front cytoreductive surgery. These were compared to 171 patients who did not undergo splenectomy. We evaluated age at diagnosis, estimated blood loss, percentage of patients whose disease was optimally cytoreduced (< 1 cm), reason for splenectomy (oncologic vs. surgical), length of stay, time to first chemotherapy treatment, and survival. Results. In the splenectomy cohort, the mean age at diagnosis was 64 (44-83) years. A total of 37 of 44 (84%) patients were optimally cytoreduced. Mean estimated blood loss was 1326 ml. The purpose of splenectomy was to accomplish an optimal cytoreduction (oncologic) in 82% of cases. Median length of stay was 13 (6-76) days. Median time to first chemotherapy was 13.5 (5-54) days. The median disease-free interval and overall survival of the splenectomy cohort were 8 and 30 months, respectively. The median overall survival for patients whose disease was optimally cytoreduced in the splenectomy cohort compared to the no-splenectomy group was 30 and 45 months (P < 0.045), respectively. Conclusions. The addition of splenectomy to up-front cytoreductive surgery was feasible and safe. However, it appears to carry with it a shortened survival that is unrelated to postoperative morbidity. Our data raise the questions that splenectomy is needed for optimal cytoreduction in more biologically aggressive disease and that splenectomy may be an independent prognostic factor related to depressed immune function. C1 [McCann, Christopher K.; Growdon, Whitfield B.; Munro, Elizabeth G.; Del Carmen, Marcela G.; Boruta, David M.; Schorge, John O.; Goodman, Annekathryn] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. RP McCann, CK (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. EM cmccann3@partners.org NR 36 TC 11 Z9 11 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2011 VL 18 IS 10 BP 2912 EP 2918 DI 10.1245/s10434-011-1661-z PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 819JG UT WOS:000294820600029 PM 21424880 ER PT J AU Lovely, RS Yang, Q Massaro, JM Wang, J D'Agostino, RB O'Donnell, CJ Shannon, J Farrell, DH AF Lovely, Rehana S. Yang, Qiong Massaro, Joseph M. Wang, Jing D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Shannon, Jackilen Farrell, David H. TI Assessment of Genetic Determinants of the Association of gamma ' Fibrinogen in Relation to Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary heart disease; epidemiology; fibrin; gene mutations; risk factors ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; ISCHEMIC-STROKE; SPLICE VARIANT; CHAIN; RISK; FIBRINOLYSIS; POPULATION; RATIO AB Objective-gamma ' fibrinogen is a newly emerging biomarker that is associated with cardiovascular disease (CVD). However, the genetic determinants of gamma ' fibrinogen levels are unknown. We therefore conducted a genome-wide association study on 3042 participants from the Framingham Heart Study Offspring Cohort. Methods and Results-A genome-wide association study with 2.5 million single-nucleotide polymorphisms (SNPs) was carried out for gamma ' fibrinogen levels from the cycle 7 examination. Fifty-four SNPs in or near the fibrinogen gene locus demonstrated genome-wide significance (P<5.0x10(-8)) for association with gamma ' fibrinogen levels. The top-signal SNP was rs7681423 (P=9.97x10(-110)) in the fibrinogen gene locus near FGG, which encodes the gamma chain. Conditional on the top SNP, the only other SNP that remained genome-wide significant was rs1049636. Associations between SNPs, gamma ' fibrinogen levels, and prevalent CVD events were examined using multiple logistic regression. gamma ' fibrinogen levels were associated with prevalent CVD (P=0.02), although the top 2 SNPs associated with gamma ' fibrinogen levels were not associated with CVD. These findings contrast those for total fibrinogen levels, which are associated with different genetic loci, particularly FGB, which encodes the B beta chain. Conclusion-gamma ' fibrinogen is associated with prevalent CVD and with SNPs exclusively in and near the fibrinogen gene locus. (Arterioscler Thromb Vasc Biol. 2011;31:2345-2352.) C1 [Farrell, David H.] Oregon Hlth & Sci Univ, Sch Med, Dept Med, Div Cardiovasc Med, Portland, OR 97239 USA. [Lovely, Rehana S.] Missouri State Univ, Dept Biomed Sci, Springfield, MO USA. [Yang, Qiong; Massaro, Joseph M.; Wang, Jing] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Shannon, Jackilen] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97239 USA. RP Farrell, DH (reprint author), Oregon Hlth & Sci Univ, Sch Med, Dept Med, Div Cardiovasc Med, MQ280,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM farrelld@ohsu.edu RI Yang, Qiong/G-5438-2014; OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association [0865486G]; National Heart, Lung, and Blood Institute; National Institutes of Health [R21-HL-75006, R21-HL-097298]; Office of Naval Research [N000140610411] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195); American Heart Association Grant 0865486G (to R. S. L.); National Heart, Lung, and Blood Institute, National Institutes of Health, Grants R21-HL-75006 and R21-HL-097298 (to D. H. F.); and Office of Naval Research Grant N000140610411 (to D.H.F.). NR 30 TC 19 Z9 19 U1 0 U2 5 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 OCT PY 2011 VL 31 IS 10 BP 2345 EP U399 DI 10.1161/ATVBAHA.111.232710 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 819QK UT WOS:000294843700024 PM 21757653 ER PT J AU Wang, JM Zeng, YS Wu, JL Li, Y Teng, YD AF Wang, Jun-Mei Zeng, Yuan-Shan Wu, Jin-Lang Li, Yan Teng, Yang D. TI Cograft of neural stem cells and schwann cells overexpressing TrkC and neurotrophin-3 respectively after rat spinal cord transection SO BIOMATERIALS LA English DT Article DE Spinal cord injury; Neurotrophin-3; TrkC; Schwann cells; Neural stem cells; Transection ID RECOMBINANT ADENOVIRUS VECTOR; AXONAL REGENERATION; FUNCTIONAL RECOVERY; TRANSPLANTATION THERAPY; EXCITATORY SYNAPSES; GROWTH-FACTOR; INJURY; PROMOTES; NEURONS; BDNF AB Effectively bridging the lesion gap is still an unmet demand for spinal cord repair. In the present study, we tested our hypothesis if cograft of Schwann cells (SCs) and neural stem cells (NSCs) with genetically enhanced expression of neurotrophin-3 (NT-3) and its high affinity receptor TrkC, respectively, could strengthen neural repair through increased NSC survival and neuronal differentiation at the epicenter after complete T10 spinal cord transection in adult rats. Transplantation of NT-3-SCs + TrkC-NSCs in Gelfoam (1 x 10(6)/implant/rat; n = 10) into the lesion gap immediately following injury results in significantly improved relay of the cortical motor evoked potential (CMEP) and cortical somatosensory evoked potential (CSEP) as well as ameliorated hindlimb deficits, relative to controls (treated with LacZ-SCs + LacZ-NSCs, NT-3-SCs + NSCs, NSCs alone, or lesion only; n = 10/group). Further analyses demonstrate that NT-3-SCs + TrkC-NSCs cografting augments levels of neuronal differentiation of NSCs, synaptogenesis (including inhibitory/type II-like synapses) and myelin formation of SCs, in addition to neuroprotection and outgrowth of serotonergic fibers in the lesioned spinal cord. Compared with controls, the treated spinal cords also show elevated expression of laminin, a pro-neurogenic factor, and decreased presence of chondroitin sulfate proteoglycans, major inhibitors of axonal growth and neuroplasticity. Together, our data suggests that coimplantation of neurologically compatible cells with compensatorily overexpressed therapeutic genes may constitute a valuable approach to study, and/or develop therapies for spinal cord injury (SCI). Published by Elsevier Ltd. C1 [Wang, Jun-Mei; Zeng, Yuan-Shan; Li, Yan] Sun Yat Sen Univ, Div Neurosci, Dept Histol & Embryol, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China. [Zeng, Yuan-Shan] Sun Yat Sen Univ, Minist Educ, Key Lab Stem Cells & Tissue Engn, Guangzhou 510080, Guangdong, Peoples R China. [Zeng, Yuan-Shan] Sun Yat Sen Univ, Inst Spinal Cord Injury, Guangzhou 510120, Guangdong, Peoples R China. [Wu, Jin-Lang] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Electron Microscope, Guangzhou 510080, Guangdong, Peoples R China. [Wang, Jun-Mei; Teng, Yang D.] Harvard Univ, Sch Med, Div SCI Res, Dept Neurosurg,VA Boston Healthcare Syst, Boston, MA 02115 USA. [Wang, Jun-Mei; Teng, Yang D.] Harvard Univ, Sch Med, Div SCI Res, Dept Phys Med & Rehabil,VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Zeng, YS (reprint author), Sun Yat Sen Univ, Div Neurosci, Dept Histol & Embryol, Zhongshan Sch Med, 74 Zhongshan 2nd Rd, Guangzhou 510080, Guangdong, Peoples R China. EM zengysh@mail.sysu.edu.cn; yang_teng@hms.harvard.edu FU Chinese National Natural Science Foundation [30270700, 30771143]; Social Developmental Foundation of Guangdong Province [2003C33808]; Guangdong Province Natural Science Foundation [07117373]; HeadNorth Project (La Jolla, CA, USA); United States Department of Veteran Affairs; U.S. Department of Defense, OMIT, NIH; State of Massachusetts; HeadNorth Project; VA; DoD; CIMIT; NIH FX Research work at the lab of Y.S.Z. was supported by the Chinese National Natural Science Foundation (30270700, 30771143), the Social Developmental Foundation of Guangdong Province (2003C33808), and the Guangdong Province Natural Science Foundation (07117373). HeadNorth Project (La Jolla, CA, USA) sponsored J.M.W.'s research at Teng Labs. Teng Labs are additionally supported by the United States Department of Veteran Affairs (Rehabilitation Research and Development Grant; Biomedical and Laboratory Research and Development Grant to Y.D.T.), U.S. Department of Defense, OMIT, NIH, and the State of Massachusetts.; Y.S.Z. thanks all the grant sponsors for their support to work done in his lab. Y.D.T. and J.M.W. gratefully acknowledge the instrumental role of Dr. Evan Y. Snyder in orchestrating research projects sponsored by HeadNorth Project. Y.D.T. wants to thank VA, DoD, CIMIT, NIH, and the State of Massachusetts for their grant support to research projects performed in his labs. NR 65 TC 33 Z9 42 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD OCT PY 2011 VL 32 IS 30 BP 7454 EP 7468 DI 10.1016/j.biomaterials.2011.06.036 PG 15 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 819LW UT WOS:000294829300017 PM 21783247 ER PT J AU Jeong, JY Silver, M Parnes, A Nikiforow, S Berliner, N Vanasse, GJ AF Jeong, Jee-Yeong Silver, Matthew Parnes, Aric Nikiforow, Sarah Berliner, Nancy Vanasse, Gary J. TI Resveratrol ameliorates TNF alpha-mediated suppression of erythropoiesis in human CD34(+) cells via modulation of NF-kappa B signalling SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE erythropoiesis; anaemia; NF-kappa B; resveratrol; TNF alpha ID TRANSCRIPTION FACTOR GATA-1; NECROSIS-FACTOR-ALPHA; ERYTHROID-DIFFERENTIATION; GENE-EXPRESSION; PROINFLAMMATORY STATE; HEMATOPOIETIC-CELLS; INFLAMMATION; ANEMIA; AGE; APOPTOSIS AB Overexpression of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF alpha), has been implicated in the pathogenesis of anaemia of inflammation. TNF alpha suppresses erythroid colony formation via both direct and indirect effects on haematopoietic progenitors, often involving activation of nuclear factor (NF-kappa B signalling resulting in downregulation of transcription factors critical for erythropoiesis. There is a dearth of effective and safe therapies for many patients with inflammatory anaemia. Resveratrol is a flavanol found in red wine grapes that possesses potent anti-inflammatory properties, but studies of its impact on human erythropoiesis have proven contradictory. We investigated whether resveratrol ameliorates TNF alpha-mediated suppression of erythropoiesis in human CD34(+) haematopoietic progenitors. We found that resveratrol partially reverses the erythroid suppressive effects of TNF alpha, leading to significant recovery in burst forming unit-erythroid colony formation in human CD34(+) cells. CD34(+) cells preincubated with resveratrol for 72 h in the presence of TNF alpha inhibited NF-kappa B activation via decreased NF-kappa B nuclear localization without altering total NF-kappa B protein levels and independent of I kappa B degradation. Resveratrol also significantly restored the baseline expression of erythroid transcription factors NFE2 and the GATA1/GATA2 ratio in CD34(+) cells treated with TNF alpha. In conclusion, resveratrol may inhibit TNF alpha-mediated NF-kappa B activation and promote erythropoiesis in primary human CD34(+) cells. C1 [Vanasse, Gary J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Haematol,Dept Med, Boston, MA 02115 USA. [Nikiforow, Sarah] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Vanasse, GJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Haematol,Dept Med, 75 Francis St,Karp 5-216, Boston, MA 02115 USA. EM gvanasse@partners.org FU National Institutes of Health [RO1AG29154] FX This work was supported by National Institutes of Health Grant RO1AG29154 (N.B.). NR 37 TC 6 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2011 VL 155 IS 1 BP 93 EP 101 DI 10.1111/j.1365-2141.2011.08800.x PG 9 WC Hematology SC Hematology GA 820QE UT WOS:000294919700009 PM 21762122 ER PT J AU Eyler, LT Prom-Wormley, E Panizzon, MS Kaup, AR Fennema-Notestine, C Neale, MC Jernigan, TL Fischl, B Franz, CE Lyons, MJ Grant, M Stevens, A Pacheco, J Perry, ME Schmitt, JE Seidman, LJ Thermenos, HW Tsuang, MT Chen, CH Thompson, WK Jak, A Dale, AM Kremen, WS AF Eyler, Lisa T. Prom-Wormley, Elizabeth Panizzon, Matthew S. Kaup, Allison R. Fennema-Notestine, Christine Neale, Michael C. Jernigan, Terry L. Fischl, Bruce Franz, Carol E. Lyons, Michael J. Grant, Michael Stevens, Allison Pacheco, Jennifer Perry, Michele E. Schmitt, J. Eric Seidman, Larry J. Thermenos, Heidi W. Tsuang, Ming T. Chen, Chi-Hua Thompson, Wesley K. Jak, Amy Dale, Anders M. Kremen, William S. TI Genetic and Environmental Contributions to Regional Cortical Surface Area in Humans: A Magnetic Resonance Imaging Twin Study SO CEREBRAL CORTEX LA English DT Article DE cortex; cortical thickness; heritability ID HUMAN CEREBRAL-CORTEX; VIETNAM ERA TWIN; MONOZYGOTIC TWINS; BRAIN; EVOLUTION; THICKNESS; SYSTEM; MRI; HERITABILITY; EXPANSION AB Cortical surface area measures appear to be functionally relevant and distinct in etiology, development, and behavioral correlates compared with other size characteristics, such as cortical thickness. Little is known about genetic and environmental influences on individual differences in regional surface area in humans. Using a large sample of adult twins, we determined relative contributions of genes and environment on variations in regional cortical surface area as measured by magnetic resonance imaging before and after adjustment for genetic and environmental influences shared with total cortical surface area. We found high heritability for total surface area and, before adjustment, moderate heritability for regional surface areas. Compared with other lobes, heritability was higher for frontal lobe and lower for medial temporal lobe. After adjustment for total surface area, regionally specific genetic influences were substantially reduced, although still significant in most regions. Unlike other lobes, left frontal heritability remained high after adjustment. Thus, global and regionally specific genetic factors both influence cortical surface areas. These findings are broadly consistent with results from animal studies regarding the evolution and development of cortical patterning and may guide future research into specific environmental and genetic determinants of variation among humans in the surface area of particular regions. C1 [Eyler, Lisa T.; Panizzon, Matthew S.; Kaup, Allison R.; Fennema-Notestine, Christine; Jernigan, Terry L.; Franz, Carol E.; Perry, Michele E.; Tsuang, Ming T.; Chen, Chi-Hua; Thompson, Wesley K.; Jak, Amy; Kremen, William S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Eyler, Lisa T.] VA San Diego Healthcare Syst, Mental Illness Res Educ & Clin Ctr, San Diego, CA 92161 USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23219 USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23219 USA. [Kaup, Allison R.] Univ Calif San Diego, San Diego State Univ, Joint Doctoral Program Clin Psychol, San Diego, CA 92182 USA. [Jernigan, Terry L.; Perry, Michele E.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Fennema-Notestine, Christine; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Fischl, Bruce; Stevens, Allison; Pacheco, Jennifer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Fischl, Bruce; Stevens, Allison; Pacheco, Jennifer] Massachusetts Gen Hosp, Boston, MA 02129 USA. [Lyons, Michael J.; Grant, Michael] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Seidman, Larry J.; Thermenos, Heidi W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tsuang, Ming T.; Kremen, William S.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Tsuang, Ming T.] Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02215 USA. [Tsuang, Ming T.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Tsuang, Ming T.; Kremen, William S.] VA San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA 92161 USA. [Tsuang, Ming T.; Jak, Amy] VA San Diego Healthcare Syst, Psychol Serv, San Diego, CA 92161 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Eyler, LT (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr,Mail Code 9151B, La Jolla, CA 92093 USA. EM lteyler@ucsd.edu OI Prom-Wormley, Elizabeth/0000-0001-9230-9723; Lyons, Michael/0000-0001-6516-9219; Fennema-Notestine, Christine/0000-0002-6527-6361 FU National Institutes of Health (NIH) National Institute on Aging [U24 RR021382, R01 AG18386, R01 AG18384, R01 AG22381, R01 AG 22982]; National Institute for Mental Health [T32 MH20030]; National Institute for Drug Abuse [R01 DA18673]; VA Desert Pacific Mental Illness Research Education and Clinical Center; Ellison Medical Foundation; US Department of Veterans Affairs FX National Institutes of Health (NIH) National Institute on Aging (U24 RR021382, R01 AG18386, R01 AG18384, R01 AG22381, and R01 AG 22982); National Institute for Mental Health (T32 MH20030); National Institute for Drug Abuse (R01 DA18673); and VA Desert Pacific Mental Illness Research Education and Clinical Center. Additional support was provided in part by the National Center for Research Resources (P41-RR14075 and the NCRR BIRN Morphometric Project BIRN002, U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01 EB006758), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01), as well The Autism and Dyslexia Project funded by the Ellison Medical Foundation. The US Department of Veterans Affairs has provided support for the development and maintenance of the VET Registry. NR 42 TC 44 Z9 44 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD OCT PY 2011 VL 21 IS 10 BP 2313 EP 2321 DI 10.1093/cercor/bhr013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 819ES UT WOS:000294808800012 PM 21378112 ER PT J AU Conner, PS Hyun, J Wells, BO Anema, I Goral, M Monereau-Merry, MM Rubino, D Kuckuk, R Obler, LK AF Conner, Peggy S. Hyun, Jungmoon Wells, Barbara O'Connor Anema, Inge Goral, Mira Monereau-Merry, Marie-Michelle Rubino, Daniel Kuckuk, Raija Obler, Loraine K. TI Age-related differences in idiom production in adulthood SO CLINICAL LINGUISTICS & PHONETICS LA English DT Article DE idioms; older adults; age-related language changes; retrieval ID THE-TONGUE EXPERIENCES; LEXICAL ACCESS; WORD RETRIEVAL; PROPER-NAMES; OLDER-ADULTS; SPEECH PRODUCTION; LIFE-SPAN; TIP; MEMORY; YOUNG AB To investigate whether idiom production was vulnerable to age-related difficulties, we asked 40 younger (ages 18-30) and 40 older healthy adults (ages 60-85) to produce idiomatic expressions in a story-completion task. Younger adults produced significantly more correct idiom responses (73%) than did older adults (60%). When older adults generated partially correct responses, they were less likely than younger participants to eventually produce the complete target idiom (old: 32%; young: 70%); first-word cues after initial failure to retrieve an idiom resulted in more correct idioms for older (24%) than younger (15%) participants. Correlations between age and idiom correctness were positive for the young group and negative for the older group, suggesting mastery of familiar idioms continues into adulthood. Within each group, scores on the Boston Naming Test correlated with performance on the idiom task. Findings for retrieving idiomatic expressions are thus similar to those for retrieving lexical items. C1 [Conner, Peggy S.; Hyun, Jungmoon; Wells, Barbara O'Connor; Goral, Mira; Monereau-Merry, Marie-Michelle; Kuckuk, Raija; Obler, Loraine K.] CUNY, Grad Ctr, Program Speech Language Hearing Sci, New York, NY 10016 USA. [Hyun, Jungmoon; Obler, Loraine K.] VA Boston Healthcare Syst, Boston, MA USA. [Anema, Inge] State Univ New York New Paltz, New Paltz, NY USA. [Goral, Mira] CUNY, Lehman Coll, Bronx, NY USA. [Rubino, Daniel] New York Presbyterian Hosp, Weil Cornell Med Coll, Ctr Sleep Med, New York, NY USA. [Kuckuk, Raija] Univ Freiburg, Deutsch Seminar 1, Freiburg, Germany. RP Conner, PS (reprint author), CUNY, Grad Ctr, Program Speech Language Hearing Sci, 365 5th Ave, New York, NY 10016 USA. EM psconner@gmail.com FU NIA NIH HHS [R01 AG014345, R01-AG 14345] NR 50 TC 3 Z9 3 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0269-9206 J9 CLIN LINGUIST PHONET JI Clin. Linguist. Phon. PD OCT PY 2011 VL 25 IS 10 BP 899 EP 912 DI 10.3109/02699206.2011.584136 PG 14 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 819LH UT WOS:000294826700006 PM 21728830 ER PT J AU Yoo, WJ Kim, YJ Menezes, NM Cheon, JE Jaramillo, D AF Yoo, Won Joon Kim, Young-Jo Menezes, Nina M. Cheon, Jung-Eun Jaramillo, Diego TI Diffusion-weighted MRI Reveals Epiphyseal and Metaphyseal Abnormalities in Legg-Calv,-Perthes Disease: A Pilot Study SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CALVE-PERTHES-DISEASE; TERM-FOLLOW-UP; BONE-MARROW; NATURAL-HISTORY; CLASSIFICATION; SCINTIGRAPHY; DISORDERS; DIAGNOSIS; PERFUSION; SKELETON AB Background Legg-Calv,-Perthes disease (LCP) is thought to be associated with ischemic events in the femoral head. However, the types and patterns of reperfusion after these ischemic events are unclear. Purposes We therefore determined whether (1) there would be any age-related diffusion changes; (2) diffusion-weighted MR imaging would reveal ischemic damage; and (3) diffusion changes are correlated with prognostic MR findings in patients with LCP. Methods We prospectively performed conventional, perfusion, and diffusion-weighted MR imaging studies in 17 children with unilateral LCP. We then measured the apparent diffusion coefficient (ADC) values in the epiphysis and the metaphysis, and compared them with those of the contralateral normal side. Based on perfusion MR imaging, we assessed reperfusion to the epiphysis as either periphyseal or transphyseal. We studied T2-signal intensity changes in the metaphysis and the presence of focal physeal irregularity. We correlated diffusion changes with reperfusion to the epiphysis, T2-signal intensity change, and focal physeal irregularity. Results Normal diffusion decreased with age. In LCP hips, epiphyseal diffusion increased early and remained elevated through the healing stage. Six of the 17 patients who had a metaphyseal ADC greater than 50% over the normal side had 13 times greater odds of having an association with transphyseal reperfusion to the epiphysis. The increase of metaphyseal ADC also was associated with an increased T2-signal intensity in the metaphysis and presence of focal physeal irregularity. Conclusions Diffusion-weighted MR imaging can be used as a complimentary modality to evaluate ischemic tissue damage with a potential prognostic value in patients with LCP. C1 [Kim, Young-Jo] Childrens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Yoo, Won Joon] Seoul Natl Univ, Childrens Hosp, Dept Orthopaed Surg, Seoul, South Korea. [Yoo, Won Joon] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Kim, Young-Jo; Jaramillo, Diego] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Menezes, Nina M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Menezes, Nina M.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA USA. [Cheon, Jung-Eun] Seoul Natl Univ, Childrens Hosp, Dept Radiol, Seoul, South Korea. [Jaramillo, Diego] Massachusetts Gen Hosp, Dept Radiol, Div Pediat Radiol, Boston, MA 02114 USA. [Jaramillo, Diego] Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. RP Kim, YJ (reprint author), Childrens Hosp, Dept Orthopaed Surg, 300 Longwood Ave, Boston, MA 02115 USA. EM young-jo.kim@childrens.harvard.edu RI Cheon, Jung-Eun/J-5684-2012; Yoo, Wonjoon/J-5552-2012 NR 31 TC 15 Z9 16 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2011 VL 469 IS 10 BP 2881 EP 2888 DI 10.1007/s11999-011-1931-x PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 819KA UT WOS:000294822600024 PM 21660596 ER PT J AU Pratchett, LC Daly, K Bierer, LM Yehuda, R AF Pratchett, Laura C. Daly, Kelly Bierer, Linda M. Yehuda, Rachel TI New approaches to combining pharmacotherapy and psychotherapy for posttraumatic stress disorder SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE evidence-based psychotherapy; pharmacologic augmentation of psychotherapy; pharmacotherapy; posttraumatic stress disorder; treatment ID RANDOMIZED CONTROLLED-TRIAL; EYE-MOVEMENT DESENSITIZATION; COGNITIVE-BEHAVIOR-THERAPY; REALITY EXPOSURE THERAPY; VIETNAM COMBAT VETERANS; BRIEF ECLECTIC PSYCHOTHERAPY; AFRICAN REFUGEE SETTLEMENT; PLACEBO-CONTROLLED TRIAL; SOCIAL ANXIETY DISORDER; CHILDHOOD SEXUAL-ABUSE AB Introduction: Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments. Areas covered: A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad - although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission. Expert opinion: So far, the mental health field has tended to focus on either biological or psychological targets. We propose that maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Exciting new developments reflecting this perspective include psychopharmacologic augmentation strategies that enhance the mechanisms of psychotherapy. C1 [Pratchett, Laura C.; Bierer, Linda M.; Yehuda, Rachel] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Daly, Kelly] Bronx Vet Med Res Fdn, Traumat Stress Studies Div, Bronx, NY 10468 USA. [Pratchett, Laura C.; Bierer, Linda M.; Yehuda, Rachel] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Pratchett, LC (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. EM Laura.pratchett@va.gov NR 195 TC 17 Z9 18 U1 12 U2 30 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD OCT PY 2011 VL 12 IS 15 BP 2339 EP 2354 DI 10.1517/14656566.2011.604030 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 820MC UT WOS:000294909000006 PM 21819273 ER PT J AU Gonzalez, JS Batchelder, AW Psaros, C Safren, SA AF Gonzalez, Jeffrey S. Batchelder, Abigail W. Psaros, Christina Safren, Steven A. TI Depression and HIV/AIDS Treatment Nonadherence: A Review and Meta-analysis SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adherence; compliance; depression; HIV/AIDS; meta-analysis ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; POSTTRAUMATIC-STRESS-DISORDER; HIV-INFECTED INDIVIDUALS; MULTICENTER AIDS COHORT; MEDICATION ADHERENCE; VIRAL LOAD; SOCIAL SUPPORT; MENTAL-HEALTH; PSYCHOSOCIAL FACTORS AB We meta-analyzed the relationship between depression and HIV medication nonadherence to calculate the overall effect size and examine potential moderators. Overall, across 95 independent samples, depression was significantly (P < 0.0001) associated with nonadherence (r = 0.19; 95% confidence interval = 0.14 to 0.25). Studies evaluating medication adherence via interview found significantly larger effects than those using self-administered questionnaires. Studies measuring adherence along a continuum found significantly stronger effects than studies comparing dichotomies. Effect size was not significantly related to other aspects of adherence or depression measurement, assessment interval (ie, cross-sectional vs. longitudinal), sex, IV drug use, sexual orientation, or study location. The relationship between depression and HIV treatment nonadherence is consistent across samples and over time, is not limited to those with clinical depression, and is not inflated by self-report bias. Our results suggest that interventions aimed at reducing depressive symptom severity, even at subclinical levels, should be a behavioral research priority. C1 [Gonzalez, Jeffrey S.] Albert Einstein Coll Med, Ferkauf Grad Sch Psychol, Dept Med, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.; Batchelder, Abigail W.] Yeshiva Univ, Dept Med, Ferkauf Grad Sch Psychol, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.; Batchelder, Abigail W.] Yeshiva Univ, Dept Epidemiol & Populat Hlth, Ferkauf Grad Sch Psychol, Bronx, NY 10461 USA. [Gonzalez, Jeffrey S.; Psaros, Christina; Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Psaros, Christina; Safren, Steven A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Gonzalez, JS (reprint author), Albert Einstein Coll Med, Ferkauf Grad Sch Psychol, Dept Med, 1300 Morris Pk Ave,Rousso Bldg, Bronx, NY 10461 USA. EM jeffrey.gonzalez@einstein.yu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), DK [020541]; [DA018603]; [MH084757] FX Funding for investigator time was supported by grants DA018603 and MH084757 awarded to Dr S.A.S. Dr J.S.G. is supported in part by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), DK 020541. NR 69 TC 187 Z9 188 U1 15 U2 54 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2011 VL 58 IS 2 BP 181 EP 187 DI 10.1097/QAI.0B013E31822D490A PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 821AL UT WOS:000294947100021 PM 21857529 ER PT J AU Whitton, JP Polley, DB AF Whitton, Jonathon P. Polley, Daniel B. TI Evaluating the Perceptual and Pathophysiological Consequences of Auditory Deprivation in Early Postnatal Life: A Comparison of Basic and Clinical Studies SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Review DE otitis media; conductive hearing loss; auditory deprivation; development; plasticity; auditory cortex; binaural; dichotic; language; hearing; listening; amblyopia; visual cortex; experience; neural circuit ID CONDUCTIVE HEARING-LOSS; 1ST 3 YEARS; PERSISTENT OTITIS-MEDIA; MASKING LEVEL DIFFERENCES; BRAIN-STEM-RESPONSE; DEVELOPMENTAL OUTCOMES; TYMPANOSTOMY TUBES; BINAURAL HEARING; EARLY-CHILDHOOD; LANGUAGE-DEVELOPMENT AB Decades of clinical and basic research in visual system development have shown that degraded or imbalanced visual inputs can induce a long-lasting visual impairment called amblyopia. In the auditory domain, it is well established that inducing a conductive hearing loss (CHL) in young laboratory animals is associated with a panoply of central auditory system irregularities, ranging from cellular morphology to behavior. Human auditory deprivation, in the form of otitis media (OM), is tremendously common in young children, yet the evidence linking a history of OM to long-lasting auditory processing impairments has been equivocal for decades. Here, we review the apparent discrepancies in the clinical and basic auditory literature and provide a meta-analysis to show that the evidence for human amblyaudia, the auditory analog of amblyopia, is considerably more compelling than is generally believed. We argue that a major cause for this discrepancy is the fact that most clinical studies attempt to link central auditory deficits to a history of middle ear pathology, when the primary risk factor for brain-based developmental impairments such as amblyopia and amblyaudia is whether the afferent sensory signal is degraded during critical periods of brain development. Accordingly, clinical studies that target the subset of children with a history of OM that is also accompanied by elevated hearing thresholds consistently identify perceptual and physiological deficits that can endure for years after peripheral hearing is audiometrically normal, in keeping with the animal studies on CHL. These studies suggest that infants with OM severe enough to cause degraded afferent signal transmission (e.g., CHL) are particularly at risk to develop lasting central auditory impairments. We propose some practical guidelines to identify at-risk infants and test for the positive expression of amblyaudia in older children. C1 [Whitton, Jonathon P.; Polley, Daniel B.] MIT, Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. [Whitton, Jonathon P.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Whitton, JP (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. EM jpwhit05@mit.edu OI Polley, Daniel/0000-0002-5120-2409 FU NIDCD NIH HHS [R01 DC009836] NR 97 TC 32 Z9 33 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2011 VL 12 IS 5 BP 535 EP 547 DI 10.1007/s10162-011-0271-6 PG 13 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 820MK UT WOS:000294909800001 PM 21607783 ER PT J AU Amatuzzi, M Liberman, MC Northrop, C AF Amatuzzi, Monica Liberman, M. Charles Northrop, Clarinda TI Selective Inner Hair Cell Loss in Prematurity: A Temporal Bone Study of Infants from a Neonatal Intensive Care Unit SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE auditory neuropathy; deafness; cochlea; histopathology ID AUDITORY NEUROPATHY; CARBOPLATIN; CHILDREN; HEARING; NERVE; RISK; DEGENERATION; OTOTOXICITY; EXOCYTOSIS; OTOFERLIN AB Premature birth is a well-known risk factor for sensorineural hearing loss in general and auditory neuropathy in particular. However, relatively little is known about the underlying causes, in part because there are so few relevant histopathological studies. Here, we report on the analysis of hair cell loss patterns in 54 temporal bones from premature infants and a control group of 46 bones from full-term infants, all of whom spent time in the neonatal intensive care unit at the Hospital de Nios in San Jose, Costa Rica, between 1977 and 1993. The prevalence of significant hair cell loss was higher in the preterm group than the full-term group (41% vs. 28%, respectively). The most striking finding was the frequency of selective inner hair cell loss, an extremely rare histopathological pattern, in the preterm vs. the full-term babies (27% vs. 3%, respectively). The findings suggest that a common cause of non-genetic auditory neuropathy is selective loss of inner hair cells rather than primary damage to the cochlear nerve. C1 [Liberman, M. Charles; Northrop, Clarinda] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Amatuzzi, Monica] Univ Sao Paulo, Dept Otorhinolaryngol, Sao Paulo, Brazil. [Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Northrop, Clarinda] Temporal Bone Fdn, Boston, MA USA. RP Liberman, MC (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM charles_liberman@meei.harvard.edu FU NIH [R01 DC0188, P30 DC5029]; Temporal Bone Foundation FX This work was supported by NIH Grants: R01 DC0188 (MCL and P30 DC5029 (MCL) and from a grant from the Temporal Bone Foundation. We are grateful to Prof. Jorge Pizza from the Pathology Department of the Hospital de Ninos in San Jose, Costa Rica, for granting access to obtain material for this research. NR 35 TC 12 Z9 16 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2011 VL 12 IS 5 BP 595 EP 604 DI 10.1007/s10162-011-0273-4 PG 10 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 820MK UT WOS:000294909800005 PM 21674215 ER PT J AU Lin, HW Furman, AC Kujawa, SG Liberman, MC AF Lin, Harrison W. Furman, Adam C. Kujawa, Sharon G. Liberman, M. Charles TI Primary Neural Degeneration in the Guinea Pig Cochlea After Reversible Noise-Induced Threshold Shift SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE acoustic injury; excitotoxicity; inner ear ID AUDITORY-NERVE FIBERS; INDUCED HEARING-LOSS; INNER HAIR-CELLS; MAMMALIAN COCHLEA; CAT; EXCITOTOXICITY; TRAUMA; REPAIR; SYNAPSES; NEURONS AB Recent work in mouse showed that acoustic overexposure can produce a rapid and irreversible loss of cochlear nerve peripheral terminals on inner hair cells (IHCs) and a slow degeneration of spiral ganglion cells, despite full recovery of cochlear thresholds and no loss of inner or outer hair cells (Kujawa and Liberman, J Neurosci 29:14077-14085, 2009). This contrasts with earlier ultrastructural work in guinea pig suggesting that acute noise-induced neural degeneration is followed by full regeneration of cochlear nerve terminals in the IHC area (Puel et al., Neuroreport 9:2109-2114, 1998; Pujol and Puel, Ann N Y Acad Sci 884:249-254, 1999). Here, we show that the same patterns of primary neural degeneration reported for mouse are also seen in the noise-exposed guinea pig, when IHC synapses and cochlear nerve terminals are counted 1 week post-exposure in confocal images from immunostained whole mounts and that the same slow degeneration of spiral ganglion cells occurs despite no loss of IHCs and apparent recovery of cochlear thresholds. The data cast doubt on prior claims that there is significant neural regeneration and synaptogenesis in the adult cochlea and suggest that denervation of the inner hair cell is an important sequela of "reversible" noise-induced hearing loss, which likely applies to the human ear as well. C1 [Lin, Harrison W.; Furman, Adam C.; Kujawa, Sharon G.; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Lin, Harrison W.; Kujawa, Sharon G.; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kujawa, Sharon G.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Furman, Adam C.; Kujawa, Sharon G.; Liberman, M. Charles] Harvard MIT, Program Speech & Hearing Biosci & Technol, Cambridge, MA USA. RP Liberman, MC (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM charles_liberman@meei.harvard.edu FU National Institute on Deafness and other Communication Disorders [R01 DC0188, R01 DC8577, T32 DC0038, P30 DC5029] FX This work was supported by grants from the National Institute on Deafness and other Communication Disorders: R01 DC0188, R01 DC8577, T32 DC0038, and P30 DC5029. NR 34 TC 163 Z9 167 U1 7 U2 49 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD OCT PY 2011 VL 12 IS 5 BP 605 EP 616 DI 10.1007/s10162-011-0277-0 PG 12 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 820MK UT WOS:000294909800006 PM 21688060 ER PT J AU Favorov, A Lvovs, D Speier, W Parmigiani, G Ochs, MF AF Favorov, Alexander Lvovs, Dmitrijs Speier, William Parmigiani, Giovanni Ochs, Michael F. TI OnionTree XML: A Format to Exchange Gene-Related Probabilities SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Letter ID MICROARRAY DATA; HUMAN GENOME; SYSTEMS BIOLOGY; IDENTIFICATION; BIOCONDUCTOR; PREDICTION; SEQUENCES; SOFTWARE; LANGUAGE; MODELS C1 [Favorov, Alexander; Speier, William; Ochs, Michael F.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Favorov, Alexander; Lvovs, Dmitrijs] Russian Federat Res Inst Genet & Select Ind Micro, Ctr Sci, Bioinformat Lab, Moscow 117545, Russia. [Favorov, Alexander] RAS, Vavilov Inst Gen Genet, Moscow 119991, Russia. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Favorov, A (reprint author), Sidney Kimmel Comprehens Canc Ctr, 550 North Broadway,Suite 1103, Baltimore, MD 21205 USA. EM favorov@sensi.org FU NCI NIH HHS [P30 CA006973]; NLM NIH HHS [R03 LM008932, LM008932] NR 32 TC 0 Z9 0 U1 0 U2 1 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD OCT PY 2011 VL 29 IS 2 BP 417 EP 423 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 820CV UT WOS:000294884000016 PM 21875159 ER PT J AU Hoeppner, BB Kelly, JF Urbanoski, KA Slaymaker, V AF Hoeppner, Bettina B. Kelly, John F. Urbanoski, Karen A. Slaymaker, Valerie TI Comparative utility of a single-item versus multiple-item measure of self-efficacy in predicting relapse among young adults SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Self-efficacy; Substance use relapse; Young adults; Psychometrics ID JOB-SATISFACTION; ALCOHOL; BEHAVIOR; CONSTRUCTS; MOTIVATION; VALIDITY; SMOKING; SCALES; MODEL AB Single-item measures of psychological experiences are often viewed as psychometrically suspect. The purpose of this study was to evaluate the validity and utility of a single-item measure of self-efficacy in a clinical sample of treatment-seeking young adults. Inpatient young adults (N = 303, age = 18-24, 26% female) were assessed at intake to residential treatment, end of treatment, and at 1, 3, and 6 months following discharge. The single-item measure of self-efficacy consistently correlated positively with a well-established 20-item measure of self-efficacy and negatively with temptation scores from the same scale, demonstrating convergent and discriminant validity. It also consistently predicted relapse to substance use at 1-, 3-, and 6-month assessments postdischarge, even after controlling for other predictors of relapse (e.g., controlled environment), whereas global or subscale scores of the 20-item scale did not. Based on these findings, we encourage the use of this single-item measure of self-efficacy in research and clinical practice. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hoeppner, Bettina B.; Kelly, John F.; Urbanoski, Karen A.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Slaymaker, Valerie] Hazelden Fdn Butler Ctr Res, Ctr City, MN 55012 USA. RP Hoeppner, BB (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. EM bhoeppner@partners.org; jkelly11@partners.org; kurbanoski@partners.org; VSlaymaker@Hazelden.org OI Urbanoski, Karen/0000-0001-7287-7176 FU NIAAA NIH HHS [R21 AA018185, R21 AA018185-01A2, R21AA018185]; NIDA NIH HHS [K01 DA027097, K01 DA027097-02, K01DA027097, L30 DA025511, L30 DA025511-02] NR 33 TC 43 Z9 44 U1 5 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2011 VL 41 IS 3 BP 305 EP 312 DI 10.1016/j.jsat.2011.04.005 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 821NQ UT WOS:000294982100012 PM 21700411 ER PT J AU Spina, JR Glassman, PA Simon, B Lanto, A Lee, M Cunningham, F Good, CB AF Spina, Jeffrey R. Glassman, Peter A. Simon, Barbara Lanto, Andrew Lee, Martin Cunningham, Francesca Good, Chester B. TI Potential Safety Gaps in Order Entry and Automated Drug Alerts A Nationwide Survey of VA Physician Self-Reported Practices With Computerized Order Entry SO MEDICAL CARE LA English DT Article DE medication safety; clinical decision support systems; drug interactions; medication errors; attitude of health personnel ID CLINICAL DECISION-SUPPORT; PRIMARY-CARE; MEDICATION SAFETY; AMBULATORY-CARE AB Objective: Understanding provider perceptions of and experiences with order entry and order checks (drug alerts) in an electronic prescribing system may help improve medication safety technology. Design: Cross-sectional, national survey of Veterans Administration physicians practicing in various specialties. Measurement: Thirty-five question instrument was divided into 4 content domains. Response options included dichotomous, numeric, multiple choices, and Likert-like scales. Statistical methods included logistic regression. Results: The adjusted response rate was 1543 of 3588 (43%). Almost all providers (90%) felt that the VA electronic prescribing system, including its order checks, improved prescribing safety to some degree. Most respondents (72%) reported that they always or almost always document outside medications in a clinic note, although only 44% always or almost always entered outside medications in the non-VA medication data field. Most physicians (88%) who encountered serious allergic or adverse drug reactions reported either notifying a pharmacist or entering the information in the allergies/adverse reactions field. Generalists and physicians with higher numbers of prescriptions were more likely to enter relevant data into the electronic medical record (or notify a pharmacist, in the case of adverse reactions). In addition, 48% of providers described critical drug-drug interaction alerts as very useful; medical specialists found these less useful, whereas surgical specialists found these more useful when compared with generalists. Limitations: Survey was conducted within a single healthcare system. Conclusion: Computerized provider order entry and related order checks are perceived to improve prescribing safety; however, provider entry of some relevant information into the appropriate electronic fields may not be optimal. C1 [Spina, Jeffrey R.; Glassman, Peter A.; Simon, Barbara; Lanto, Andrew; Lee, Martin] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Spina, Jeffrey R.; Glassman, Peter A.; Lee, Martin] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Glassman, Peter A.; Simon, Barbara; Lanto, Andrew; Lee, Martin] VA HSR&D Ctr Study Healthcare Provider Behav, Hines, IL USA. [Glassman, Peter A.; Cunningham, Francesca; Good, Chester B.] VA Ctr Medicat Safety, Hines, IL USA. [Lee, Martin] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Cunningham, Francesca] VA Pharm Benefits Management Serv, Hines, IL USA. [Good, Chester B.] Pittsburgh VA Med Ctr, Pittsburgh, PA USA. RP Spina, JR (reprint author), 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Jeffrey.Spina@va.gov NR 23 TC 6 Z9 6 U1 3 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 OCT PY 2011 VL 49 IS 10 BP 904 EP 910 DI 10.1097/MLR.0b013e318222a6f5 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 821EO UT WOS:000294957900005 PM 21666510 ER PT J AU Lee, JM Rhee, K O'Grady, MJ Basu, A Winn, A John, P Meltzer, DO Kollman, C Laffel, LM Lawrence, JM Tamborlane, WV Wysocki, T Xing, DY Huang, ES AF Lee, Joyce M. Rhee, Kirsten O'Grady, Michael J. Basu, Anirban Winn, Aaron John, Priya Meltzer, David O. Kollman, Craig Laffel, Lori M. Lawrence, Jean M. Tamborlane, William V. Wysocki, Tim Xing, Dongyuan Huang, Elbert S. CA JDRF Continuous Glucose Monitoring TI Health Utilities for Children and Adults With Type 1 Diabetes SO MEDICAL CARE LA English DT Article DE diabetes; health utilities; quality of life ID QUALITY-OF-LIFE; LONG-TERM COMPLICATIONS; INTENSIVE TREATMENT; PREFERENCES; MELLITUS; INDEX; POPULATION; OUTCOMES; PATIENT; CARE AB Objective: We studied health utilities in patients with type 1 diabetes to understand potential differences in health utilities as function of age, type of respondent (self report vs. proxy report), and method of assessment (direct vs. indirect). Research Design and Methods: We elicited self-reported health utilities for adults (n = 213) and children (n = 238) with type 1 diabetes, and by parent proxy report (n = 223) for overall quality of life [Health Utilities Index (HUI) Mark 3 and experienced time-trade-off (TTO) questions] and hypothetical complication states (TTO questions). Results: Mean health utilities for overall quality of life (QOL) ranged from 0.81 to 0.91. Children had significantly higher overall QOL compared with adults (0.89 vs. 0.85, P<0.01) by HUI, but had no significant difference in QOL by TTO. There were no significant differences in QOL between child self report and parent proxy report. Utilities were higher for HUI versus TTO for parent proxy report (P<0.01) but not for adult or child self report. Utilities for hypothetical complication states were lower than for current QOL. Values were lower for stroke (0.34 to 0.53), end stage renal disease (0.47 to 0.55), and blindness (0.52 to 0.69) than for amputation (0.73 to 0.82) and angina (0.74 to 0.80). Complication utilities for parent proxy report were higher compared with adult self report for most hypothetical complication states. Conclusions: Individuals with type 1 diabetes with few complications report a relatively high QOL; however, future end stage complications are rated as having a significant impact on QOL. Differences in utilities by age, self report versus proxy report, and method raise important questions about whose utilities should be used in economic analyses. C1 [Lee, Joyce M.] Univ Michigan, Pediat Endocrinol & Hlth Serv Res, Child Hlth Evaluat & Res Unit, Ann Arbor, MI 48109 USA. [Lee, Joyce M.] Univ Michigan, Child Hlth Evaluat & Res CHEAR Unit, Ann Arbor, MI 48109 USA. [Rhee, Kirsten] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [O'Grady, Michael J.] Univ Chicago, Natl Opin Res Ctr, Chicago, IL 60637 USA. [Basu, Anirban] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Winn, Aaron] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. [John, Priya; Meltzer, David O.; Huang, Elbert S.] Univ Chicago, Sect Hosp Med, Chicago, IL 60637 USA. [Kollman, Craig; Xing, Dongyuan] Jaeb Ctr Hlth Res, Tampa, FL USA. [Laffel, Lori M.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Lawrence, Jean M.] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA USA. [Tamborlane, William V.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Wysocki, Tim] Nemours Childrens Clin, Jacksonville, FL USA. RP Lee, JM (reprint author), Univ Michigan, Pediat Endocrinol & Hlth Serv Res, Child Hlth Evaluat & Res Unit, 300 NIB,Room 6E18,Campus Box 5456, Ann Arbor, MI 48109 USA. EM joyclee@umich.edu RI Meltzer, David/C-2926-2009 OI Meltzer, David/0000-0003-2790-7393 FU NIDDK NIH HHS [K08 DK082386, K08 DK082386-02, P30 DK092949] NR 32 TC 12 Z9 12 U1 2 U2 6 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 OCT PY 2011 VL 49 IS 10 BP 924 EP 931 DI 10.1097/MLR.0b013e318216592c PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 821EO UT WOS:000294957900008 PM 21544001 ER PT J AU Kautz, SA Bowden, MG Clark, DJ Neptune, RR AF Kautz, Steven A. Bowden, Mark G. Clark, David J. Neptune, Richard R. TI Comparison of Motor Control Deficits During Treadmill and Overground Walking Poststroke SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE walking; stroke; motor control; treadmill; overground ID GROUND REACTION FORCES; MUSCLE SYNERGIES; GAIT PATTERN; LOCOMOTION; STROKE; SPEED; COORDINATION; HEMIPARESIS; PERFORMANCE AB Background. Force-sensing split-belt treadmills (TMs) provide an alternative to the conventional overground (OG) setting and allow new avenues for analyzing the biomechanics and motor control of walking. However, walking control may differ on a TM compared with walking OG. Objective. To compare spatiotemporal, kinematic, and EMG-based measures of motor control between TM and OG walking at self-selected and fastest comfortable speeds in persons with poststroke hemiparesis. Methods. Individuals with chronic hemiparesis (56) and similarly aged healthy individuals (17) walked over an instrumented walkway and on an instrumented split-belt TM; 16 channels of EMG recorded bilateral muscle activity, and a 12-camera motion capture system collected bilateral 3D kinematics. The authors applied a nonnegative matrix factorization (NNMF) algorithm to examine the underlying patterns of motor control. Results. Self-selected walking patterns differed on the TM versus OG in controls: speed decreased, stride length decreased, stance percentage increased, and double-support percentage increased. Poststroke, responses were similar, but cadence also decreased, and step length asymmetry increased. Kinematic patterns were similar except those associated with slower walking speeds. NNMF demonstrated similar EMG variance in the 2 environments. Conclusion. Persons, both healthy and poststroke, walk with different gait parameters on the TM. Although measures of motor control were mostly similar between the 2 environments, the TM induced step length asymmetry in 30% of participants (60% of whom took longer paretic steps). TM walking, therefore, is a valid method for detecting motor control deficits. C1 [Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Kautz, Steven A.; Bowden, Mark G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Clark, David J.] Malcom Randall VA Med Ctr, Brain Rehabil Res Ctr, Gainesville, FL USA. [Neptune, Richard R.] Univ Texas Austin, Austin, TX 78712 USA. RP Kautz, SA (reprint author), Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. EM kautz@musc.edu RI Clark, David/A-4916-2013; OI Kautz, Steven/0000-0003-3151-8235 FU NIH [R01 HD46820]; VA Rehabilitation R&D Center of Excellence [F2182C]; Office of Research and Development, Rehabilitation R & D Service, Department of Veterans Affairs (VA); Malcom Randall VA Medical Center, Gainesville, FL FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by NIH R01 HD46820 and VA Rehabilitation R&D Center of Excellence Grant F2182C. This material is the result of work supported in part by the Office of Research and Development, Rehabilitation R & D Service, Department of Veterans Affairs (VA), and the Malcom Randall VA Medical Center, Gainesville, FL. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, National Institute of Child Health and Human Development (NICHHD), or VA. NR 30 TC 32 Z9 33 U1 0 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD OCT PY 2011 VL 25 IS 8 BP 756 EP 764 DI 10.1177/1545968311407515 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 820ID UT WOS:000294898000008 PM 21636831 ER PT J AU Francis, HW Makary, C Halpin, C Crane, BT Merchant, SN AF Francis, Howard W. Makary, Chadi Halpin, Christopher Crane, Benjamin T. Merchant, Saumil N. TI Temporal Bone Findings in a Case of Susac's Syndrome SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Otopathology; Sensorineural hearing loss; Susac's syndrome; Temporal bone histopathology ID CLINICAL-IMPLICATIONS; MICROEMBOLISM; COCHLEA; SPEECH; ARTERY AB Objective: To describe the histopathologic findings in the temporal bones of a patient with Susac's syndrome (SS). Background: The key clinical features of SS consist of symptoms of encephalopathy, visual defects due to occlusion of branches of the retinal artery, and sensorineural hearing loss. The otopathology in SS has not been described. Materials and Methods: A 51-year-old woman was hospitalized with severe headache, rapidly progressive encephalopathy, and bilateral low-frequency sensorineural hearing loss. Magnetic resonance imaging showed lesions of the corpus callosum. Fluorescein angiography of the eyes showed focal areas of irregular retinal artery caliber and leakage from small vessels. SS was diagnosed. She died of a pulmonary embolus 1 month after onset of symptoms. Both temporal bones were prepared in celloidin and examined using light microscopy. Results: Findings were nearly identical in both temporal bones. The apical halves of both cochleae showed widespread atrophy of structures of the cochlear duct (inner and outer hair cells, tectorial membranes, striae vasculares, spiral ligaments, and spiral limbi). The apical parts of both cochleae also showed apparent occlusion of capillaries within the stria vascularis and related areas of the cochlear duct. Cochlear neurons were present in normal numbers. There was no endolymphatic hydrops. The vestibular sense organs were normal for age. Conclusion: This first reported otopathologic case of SS with hearing loss showed atrophy and degeneration involving the apical halves of the cochlear duct without inflammation or infection. The findings were consistent with capillary occlusion as being responsible for the atrophy. C1 [Makary, Chadi; Halpin, Christopher; Merchant, Saumil N.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Makary, Chadi; Halpin, Christopher; Merchant, Saumil N.] Harvard Univ, Sch Med, Boston, MA USA. [Francis, Howard W.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Crane, Benjamin T.] Univ Rochester, Rochester, NY USA. RP Merchant, SN (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM saumil_merchant@meei.harvard.edu FU National Institutes of Health [U24 DC011943] FX This work was supported by National Institutes of Health grant U24 DC011943. NR 17 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2011 VL 32 IS 8 BP 1198 EP 1204 DI 10.1097/MAO.0b013e31822e9665 PG 7 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 821BD UT WOS:000294948900006 PM 21897318 ER PT J AU McCall, AA McKenna, MJ Merchant, SN Curtin, HD Lee, DJ AF McCall, Andrew A. McKenna, Michael J. Merchant, Saumil N. Curtin, Hugh D. Lee, Daniel J. TI Superior Canal Dehiscence Syndrome Associated With the Superior Petrosal Sinus in Pediatric and Adult Patients SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Adult; Canal plugging; Dizziness; Pediatric; Superior canal dehiscence; Superior petrosal sinus; Vascular; Vertigo ID EVOKED MYOGENIC POTENTIALS; INNER-EAR; COMPUTED-TOMOGRAPHY; SYMPTOMS; HEARING; VERTIGO; REPAIR AB Objective: To determine whether pediatric and adult patients with superior canal dehiscence (SCD) at the superior petrosal sinus (SPS) develop superior canal dehiscence syndrome (SCDS). Study Design: Retrospective review. Setting: Tertiary care academic medical center. Patients: Pediatric and adult patients with SPS-associated SCD were identified from a database of 131 patients with SCD based on high-resolution temporal bone computed tomography. Intervention: One pediatric patient experienced incapacitating exercise-induced vertigo, and this patient's superior semicircular canal defect was plugged via a transmastoid approach. The 11 remaining patients were managed by observation. Main Outcome Measure: Clinical symptoms and signs, audiologic testing, vestibular evoked myogenic potentials, and radiologic data. Results: Twelve patients, aged 15 to 84 years, with SCD caused by the SPS contacting the superior semicircular canal were identified. The most characteristic clinical feature in this population (5/12) was dizziness related to exercise and exertion. Bilateral SCD was observed in 3 patients. Eleven patients did not have severe symptoms and were managed conservatively. One patient, aged 15, required surgical intervention for incapacitating vertigo and experienced relief of symptoms with reversal of diagnostic indicators postoperatively. This is the first reported surgical repair of SCDS in a pediatric patient. Conclusion: This is the first series of patients who have SCDS due to contact of the SPS with the superior semicircular canal. Exercise and exertion-related symptoms are common in patients who have SCD owing to this cause. Transmastoid superior canal plugging is feasible and successful in treating SCDS in the pediatric patient. C1 [McCall, Andrew A.; McKenna, Michael J.; Merchant, Saumil N.; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [McCall, Andrew A.; McKenna, Michael J.; Merchant, Saumil N.; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Curtin, Hugh D.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Curtin, Hugh D.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu NR 29 TC 16 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2011 VL 32 IS 8 BP 1312 EP 1319 DI 10.1097/MAO.0b013e31822e5b0a PG 8 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 821BD UT WOS:000294948900025 PM 21918420 ER PT J AU Szmulewicz, DJ Merchant, SN Halmagyi, GM AF Szmulewicz, David J. Merchant, Saumil N. Halmagyi, Gabor Michael TI Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome: A Histopathologic Case Report SO OTOLOGY & NEUROTOLOGY LA English DT Editorial Material C1 [Szmulewicz, David J.] Alfred Hosp, Dept Neurosci, Prahran, Vic, Australia. [Merchant, Saumil N.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Halmagyi, Gabor Michael] Royal Prince Alfred Hosp, Dept Neurol, Camperdown, NSW, Australia. RP Szmulewicz, DJ (reprint author), Alfred Hosp, Dept Neurosci, Prahran, Vic, Australia. EM dsz@me.com FU NIDCD NIH HHS [U24 DC008559, U24 DC008559-04] NR 5 TC 12 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD OCT PY 2011 VL 32 IS 8 BP E63 EP E65 DI 10.1097/MAO.0b013e318210b719 PG 3 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 821BD UT WOS:000294948900004 PM 21451431 ER PT J AU Zou, L Feng, Y Zhang, M Li, Y Chao, W AF Zou, Lin Feng, Yan Zhang, Ming Li, Yan Chao, Wei TI NONHEMATOPOIETIC TOLL-LIKE RECEPTOR 2 CONTRIBUTES TO NEUTROPHIL AND CARDIAC FUNCTION IMPAIRMENT DURING POLYMICROBIAL SEPSIS SO SHOCK LA English DT Article DE Sepsis; phagocytosis; cytokine; innate immunity; toll-like receptors; cardiac dysfunction ID PEPTIDOGLYCAN-ASSOCIATED LIPOPROTEIN; MYOCARDIAL DYSFUNCTION; UNITED-STATES; SURVIVAL; MICE; INJURY; MYD88; RECOGNITION; TLR4; LIPOPOLYSACCHARIDE AB Toll-like receptor 2 (TLR2) has been implicated in neutrophil and cardiac dysfunction during sepsis. Here we tested the hypothesis that nonhematopoietic (parenchymal) and hematopoietic TLR2 play distinct roles in sepsis pathogenesis. To achieve this, we generated two groups of chimeric mice with TLR2 deletions either in nonhematopoietic cells (knockout [KO] mice with wildtype [WT] bone marrow [BM]) or in BM cells (WT mice with KOBM). Polymicrobial sepsis was created by cecal ligation and puncture (CLP). Neutrophil functions, cytokine production, and bacterial clearance were investigated following CLP or sham procedures. Cardiac contractile function was measured in a Langendorff apparatus. Intracellular reactive oxygen species (ROS) were measured using redoxsensitive dye and flow cytometry. Cecal ligation and puncture mice had markedly increased peritoneal neutrophil recruitment compared with the shamoperated mice. Toll-like receptor 2 KO mice, regardless their TLR2 phenotypes (WT vs. KO) in their BM-derived hematopoietic cells, had markedly increased neutrophil migration as well as phagocytosis and reduced cytokine productions compared with TLR2 WT mice following polymicrobial peritonitis. These changes in the chimeric TLR2 KO mice were associated with enhanced blood bacterial clearance and markedly improved cardiac contractile function. Moreover, CLP induced a robust ROS production in the peritoneal leukocytes isolated from WT mice but not from TLR2 KO mice. Taken together, these data indicate that TLR2, particularly that of nonhematopoietic cells, plays a major role in sepsis pathogenesis by impairing neutrophil migratory and phagocytic function, promoting cytokine production, and mediating cardiac contractile dysfunction during polymicrobial sepsis. Toll-like receptor 2 also mediates critical ROS production during polymicrobial sepsis. C1 [Zou, Lin; Feng, Yan; Zhang, Ming; Li, Yan; Chao, Wei] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. RP Chao, W (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 13th St,Room 4-212, Charlestown, MA 02129 USA. EM wchao@partners.org RI Feng, Yan/H-5808-2012 FU National Institutes of Health [GM-080906]; American Heart Association [0755890T] FX This work was supported by National Institutes of Health grant GM-080906 and American Heart Association grant 0755890T. NR 44 TC 18 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD OCT PY 2011 VL 36 IS 4 BP 370 EP 380 DI 10.1097/SHK.0b013e3182279868 PG 11 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 821CF UT WOS:000294951700009 PM 21701420 ER PT J AU Sharpless, BA Barber, JP AF Sharpless, Brian A. Barber, Jacques P. TI Lifetime prevalence rates of sleep paralysis: A systematic review SO SLEEP MEDICINE REVIEWS LA English DT Review DE Sleep paralysis; Isolated sleep paralysis; Anxiety; Fear; Parasomnia; Prevalence ID CHILDHOOD SEXUAL-ABUSE; GENERAL-POPULATION; MEDICAL-STUDENTS; PANIC DISORDER; COLLEGE-STUDENTS; HALLUCINATIONS; SYMPTOMATOLOGY; KANASHIBARI; OUTPATIENTS; FREQUENCY AB Objective: To determine lifetime prevalence rates of sleep paralysis. Data sources: Keyword term searches using "sleep paralysis", "isolated sleep paralysis", or "parasomnia not otherwise specified" were conducted using MEDLINE (1950-present) and PsychINFO (1872-present). English and Spanish language abstracts were reviewed, as were reference lists of identified articles. Study selection: Thirty five studies that reported lifetime sleep paralysis rates and described both the assessment procedures and sample utilized were selected. Data extraction: Weighted percentages were calculated for each study and, when possible, for each reported subsample. Data synthesis: Aggregating across studies (total N = 36,533), 7.6% of the general population, 28.3% of students, and 31.9% of psychiatric patients experienced at least one episode of sleep paralysis. Of the psychiatric patients with panic disorder, 34.6% reported lifetime sleep paralysis. Results also suggested that minorities experience lifetime sleep paralysis at higher rates than Caucasians. Conclusions: Sleep paralysis is relatively common in the general population and more frequent in students and psychiatric patients. Given these prevalence rates, sleep paralysis should be assessed more regularly and uniformly in order to determine its impact on individual functioning and better articulate its relation to psychiatric and other medical conditions. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Sharpless, Brian A.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Barber, Jacques P.] Univ Penn, Ctr Psychotherapy Res, Dept Psychiat, Philadelphia, PA 19104 USA. [Barber, Jacques P.] Univ Philadelphia, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Sharpless, BA (reprint author), Penn State Univ, Dept Psychol, 317 Moore Bldg, University Pk, PA 16802 USA. EM bas171@psu.edu; barberj@mail.med.upenn.edu FU NIMH [R01 MH 070664] FX We would like to thank the authors who responded to our emails with additional clarifications on their published studies as well as the anonymous reviewers. This work was supported in part by a grant (NIMH R01 MH 070664) held by Jacques P. Barber. NR 49 TC 22 Z9 23 U1 3 U2 28 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 J9 SLEEP MED REV JI Sleep Med. Rev. PD OCT PY 2011 VL 15 IS 5 BP 311 EP 315 DI 10.1016/j.smrv.2011.01.007 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 820YL UT WOS:000294941900005 PM 21571556 ER PT J AU Adluri, RS Thirunavukkarasu, M Dunna, NR Zhan, LJ Oriowo, B Takeda, K Sanchez, JA Otani, H Maulik, G Fong, GH Maulik, N AF Adluri, Ram Sudheer Thirunavukkarasu, Mahesh Dunna, Nageswara Rao Zhan, Lijun Oriowo, Babatunde Takeda, Kotaro Sanchez, Juan A. Otani, Hajime Maulik, Gautam Fong, Guo-Hua Maulik, Nilanjana TI Disruption of Hypoxia-Inducible Transcription Factor-Prolyl Hydroxylase Domain-1 (PHD-1(-/-)) Attenuates Ex Vivo Myocardial Ischemia/Reperfusion Injury Through Hypoxia-Inducible Factor-1 alpha Transcription Factor and Its Target Genes in Mice SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; FACTOR-I; INDUCED APOPTOSIS; OXYGEN SENSORS; FACTOR-ALPHA; ANGIOGENESIS; INHIBITION; RAT AB Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1-3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1(-/-)) could facilitate HIF-1 alpha-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1(-/-) mice were randomized into WT time-matched control (TMC), PHD-1(-/-) TMC (PHD1TMC), WT I/R, and PHD-1(-/-) I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2h of reperfusion. TMC hearts were perfused for 2h 30 min without ischemia. Decreased infarct size (35% +/- 0.6% vs. 49% +/- 0.4%) and apoptotic cardiomyocytes (106 +/- 13 vs. 233 +/- 21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1 alpha was significantly increased in PHD1IR compared to WTIR. mRNA expression of beta-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared withWTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1 alpha and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of beta-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1 alpha/beta-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway. Antioxid. Redox Signal. 15, 1789-1797. C1 [Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao; Zhan, Lijun; Oriowo, Babatunde; Maulik, Nilanjana] Univ Connecticut, Sch Med, Mol Cardiol & Angiogenesis Lab, Dept Surg, Farmington, CT 06032 USA. [Oriowo, Babatunde; Sanchez, Juan A.] St Marys Hosp, Dept Surg, Waterbury, CT USA. [Takeda, Kotaro; Fong, Guo-Hua] Univ Connecticut, Sch Med, Dept Cell Biol, Farmington, CT 06032 USA. [Otani, Hajime] Kansai Med Univ, Dept Thorac & Cardiovasc Surg 2, Moriguchi, Osaka 570, Japan. [Maulik, Gautam] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Maulik, N (reprint author), Univ Connecticut, Sch Med, Mol Cardiol & Angiogenesis Lab, Dept Surg, 263 Farmington Ave, Farmington, CT 06032 USA. EM nmaulik@neuron.uchc.edu RI Sanchez, Juan/I-1936-2016 OI Sanchez, Juan/0000-0002-6789-3208 FU [HL-85804]; [5R01EY019721] FX This study was supported by the grant HL-85804 (N. Maulik) and also 5R01EY019721 (G.-H. Fong). NR 39 TC 28 Z9 30 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2011 VL 15 IS 7 BP 1789 EP 1797 DI 10.1089/ars.2010.3769 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 818QY UT WOS:000294770900004 PM 21083501 ER PT J AU Yao, JK Reddy, R AF Yao, Jeffrey K. Reddy, Ravinder TI Oxidative Stress in Schizophrenia: Pathogenetic and Therapeutic Implications SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Editorial Material ID SYSTEM; BRAIN; ABNORMALITIES AB Over a century, a wide-ranging variety of pathophysiological models and causal hypotheses have been conceptualized for schizophrenia. One among these is the role for free radical-mediated pathology in schizophrenia, indicating impaired antioxidant defense system (AODS) and presence of oxidative stress in patients with schizophrenia. For the past two decades, the whole investigative domain of AODS and oxidative stress has broadened to include the wider AODS components, direct central nervous system assays of AODS, chemical imaging studies, proteomics, genetics of AODS, and, of importance to sufferers of schizophrenia, antioxidant therapeutics. These are some of the perspectives that are reviewed by several articles in this Forum. Overall, there has been growing recognition of the importance of oxidative stress in the pathophysiology of schizophrenia and in treatment-related side effects. The totality of the evidence from biochemistry, metabolomics, proteomics, genetics, and in vivo brain imaging points to the presence of multifarious abnormalities in the AODS and redox signaling in schizophrenia. Antioxid. Redox Signal. 15, 1999-2002. C1 [Yao, Jeffrey K.; Reddy, Ravinder] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA 15206 USA. [Yao, Jeffrey K.; Reddy, Ravinder] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Med Res Serv, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM jkyao@pitt.edu FU NIMH NIH HHS [MH58141] NR 33 TC 38 Z9 39 U1 1 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2011 VL 15 IS 7 BP 1999 EP 2002 DI 10.1089/ars.2010.3646 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 818QY UT WOS:000294770900016 PM 21194354 ER PT J AU Yao, JK Keshavan, MS AF Yao, Jeffrey K. Keshavan, Matcheri S. TI Antioxidants, Redox Signaling, and Pathophysiology in Schizophrenia: An Integrative View SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID NITRIC-OXIDE SYNTHASE; POLYUNSATURATED FATTY-ACIDS; MAGNETIC-RESONANCE-SPECTROSCOPY; SERUM URIC-ACID; MEMBRANE PHOSPHOLIPID-METABOLISM; PERFORMANCE LIQUID-CHROMATOGRAPHY; SUPEROXIDE-DISMUTASE ACTIVITY; LIPID-PEROXIDATION PRODUCTS; NEVER-MEDICATED 1ST-EPISODE; MULTIPLE-SCLEROSIS PATIENTS AB Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches. Antioxid. Redox Signal. 15, 2011-2035. C1 [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. [Yao, Jeffrey K.; Keshavan, Matcheri S.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Keshavan, Matcheri S.] Harvard Univ, Boston, MA 02115 USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst 151U H, Med Res Serv, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM jkyao@pitt.edu FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Biomedical Laboratory RD; VA Pittsburgh Healthcare System; National Institute of Health [MH58141, MH45203] FX This material is based upon work supported in part by the grants from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R&D (Merit Reviews and Senior Research Career Scientist Award), VA Pittsburgh Healthcare System, and National Institute of Health [MH58141 (J.K.Y.), and MH45203 (M.S.K.)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. The contents of this article do not represent the views of the Department of Veterans Affairs or the U.S. Government. NR 308 TC 101 Z9 103 U1 3 U2 23 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2011 VL 15 IS 7 BP 2011 EP 2035 DI 10.1089/ars.2010.3603 PG 25 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 818QY UT WOS:000294770900018 PM 21126177 ER PT J AU Reddy, R Reddy, R AF Reddy, Ravinder Reddy, Rajiv TI Antioxidant Therapeutics for Schizophrenia SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID VITAMIN-E TREATMENT; POLYUNSATURATED FATTY-ACIDS; TERM TARDIVE-DYSKINESIA; LIPID-PEROXIDATION; OXIDATIVE STRESS; ATYPICAL ANTIPSYCHOTICS; OPEN-LABEL; SUPPLEMENTATION; OMEGA-3-FATTY-ACIDS; METAANALYSIS AB Pharmaceutical treatment for millions worldwide who have schizophrenia is limited to a handful of antipsychotics. Despite the proven efficacy of these drugs, the overall outcome for schizophrenia remains suboptimal. Thus, alternative treatment options are urgently needed. One possible approach may be antioxidant therapy. The extant evidence for the role of oxidative stress in the pathophysiology of schizophrenia offers a hypothesis-derived therapeutic approach in the form of antioxidants. Vitamins C and E, for example, are suitable for human clinical trials because they are readily available, inexpensive, and relatively safe. Research into the therapeutic use of antioxidants in schizophrenia can be grouped into two main clusters: for psychopathology and for side effects. Of these studies, some have been carefully conducted, but majority are open label. Use of antioxidants for treatment-related side effects has been more extensively investigated. The totality of the evidence to date suggests that specific antioxidants, such as N-acetyl cysteine, may offer tangible benefits for the clinical syndrome of schizophrenia, and vitamin E may offer salutary effects on glycemic effects of antipsychotics. However, a great deal of fundamental clinical research remains to be done before antioxidants can be routinely used therapeutically for schizophrenia and treatment-related complications. Antioxid. Redox Signal. 15, 2047-2055. C1 [Reddy, Ravinder] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Reddy, Ravinder] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Reddy, Rajiv] Univ Toledo, Sch Med, Toledo, OH 43606 USA. RP Reddy, R (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM reddyr@upmc.edu NR 55 TC 17 Z9 17 U1 1 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2011 VL 15 IS 7 BP 2047 EP + DI 10.1089/ars.2010.3571 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 818QY UT WOS:000294770900020 PM 20977337 ER PT J AU Marzia, M Guaiquil, V Horne, WC Blobel, CP Baron, R Chiusaroli, R AF Marzia, Marilena Guaiquil, Victor Horne, William C. Blobel, Carl P. Baron, Roland Chiusaroli, Riccardo TI Lack of ADAM15 in mice is associated with increased osteoblast function and bone mass SO BIOLOGICAL CHEMISTRY LA English DT Article DE ADAM15; beta-catenin; disintegrin; metalloprotease; osteoblast; skeletal homeostasis ID N-CADHERIN; METALLOPROTEASE-DISINTEGRINS; CELL-ADHESION; EXPRESSION; ACTIVATION; CLEAVAGE; BETA; PHOSPHORYLATION; DIFFERENTIATION; PHENOTYPE AB The ADAMs (a disintegrin and metalloprotease) contribute to various biological functions including the development of tissues by taking part in cell-cell and cell-matrix interactions. We previously found that ADAM15 is prominently expressed in osteoblasts and to a lesser extent in osteoclasts. The aim of this study was to investigate a possible function of ADAM15 in bone. Adult ADAM15(-/-) mice displayed an increase in bone volume and thickness with an increase in the number and activity of osteoblasts, whereas osteoclasts were apparently unaffected. We found an increase in proliferation, alkaline phosphatase (ALP) staining and nodule deposition, and mineralization in cultures of ADAM15(-/-) osteoblasts compared to wild-type osteoblasts. We also observed an increase in beta-catenin immunoreactivity in the nucleus of ADAM15(-/-) osteoblasts compared to wild-type, whereas beta-catenin in the membrane/cytoplasm compartment appeared to undergo increased degradation. Furthermore, cyclin D1 and c-Jun, known downstream targets of beta-catenin and effectors of cell activation, were found up-regulated in absence of ADAM15. This study indicates that ADAM15 is required for normal skeletal homeostasis and that its absence causes increased nuclear translocation of beta-catenin in osteoblasts leading to increased osteoblast proliferation and function, which results in higher trabecular and cortical bone mass. C1 [Marzia, Marilena; Baron, Roland; Chiusaroli, Riccardo] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02115 USA. [Marzia, Marilena; Baron, Roland; Chiusaroli, Riccardo] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Marzia, Marilena; Horne, William C.; Baron, Roland; Chiusaroli, Riccardo] Yale Univ, Sch Med, Dept Orthoped & Rehabil, New Haven, CT 06510 USA. [Horne, William C.; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Guaiquil, Victor; Blobel, Carl P.] Cornell Univ, Arthrit & Tissue Degenerat Program, Hosp Special Surg, New York, NY 10021 USA. [Chiusaroli, Riccardo] Rottapharm R&D, Preclin Pharmacol Pharmacol & Toxicol Dept, I-20052 Monza, Italy. RP Chiusaroli, R (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02115 USA. EM riccardo.chiusaroli@rottapharm.com FU National Institutes of Health [ADE-04724, RO1 GM58668]; Rottapharm S.p.A. (Monza, Italy) FX This work was funded by ADE-04724 (to R. B.) from the National Institutes of Health, RO1 GM58668 (to C. P. B.) from National Institutes of Health grant, and by a grant from Rottapharm S.p.A. (Monza, Italy). However, the Rottapharm group as a corporate entity had no role in the conduct of the study; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 34 TC 6 Z9 6 U1 0 U2 3 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD OCT PY 2011 VL 392 IS 10 BP 877 EP 885 DI 10.1515/BC.2011.080 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 816NU UT WOS:000294609900005 PM 21801086 ER PT J AU Chernigovskaya, E Atochin, D Yamova, L Huang, P Glazova, M AF Chernigovskaya, E. Atochin, D. Yamova, L. Huang, P. Glazova, M. TI Immunohistochemical expression of Bcl-2, p53 and caspase-9 in hypothalamus magnocellular centers of nNOS knockout mice following water deprivation SO BIOTECHNIC & HISTOCHEMISTRY LA English DT Article DE apoptosis regulator proteins; hypothalamus; magnocellular neurons; nitric oxide synthase; water deprivation ID NITRIC-OXIDE SYNTHASE; CELL-DEATH; PARAVENTRICULAR NUCLEUS; NERVOUS-SYSTEM; NEURONS; RAT; VASOPRESSIN; BRAIN; MECHANISMS; PITUITARY AB We studied the interactions between apoptosis regulator proteins (Bcl-2, p53 and caspase-9) and neuronal nitric oxide in vasopressinergic magnocellular centers of the hypothalamus using neuronal nitric oxide synthase (nNOS) gene knockout mice. nNOS gene deletion resulted in accumulation of Bcl-2, p53 and caspase-9 in the paraventricular (PVN) and supraoptic (SON) nuclei in controls. Dehydration increased the levels of all three apoptosis regulator proteins studied in nuclei of wild type mice. In the hypothalamus magnocellular centers of nNOS knockout mice, however, expression of Bcl-2, p53 and caspase-9 was unchanged after dehydration. The number of magnocellular neurons did not change in the SON and PVN of nNOS deficient mice compared to wild type, and after dehydration, cell death was not observed in either nucleus of wild type or knockout mice despite activation of apoptosis regulator protein expression. Thus, we demonstrated that gene disruption of nNOS prevents activation of Bcl-2, p53 and caspase-9 expression during water deprivation, and that nNOS deficiency did not affect survival of magnocellular neurons of the hypothalamus. C1 [Chernigovskaya, E.; Atochin, D.; Yamova, L.; Glazova, M.] Russian Acad Sci, IM Sechenov Evolut Physiol & Biochem Inst, St Petersburg 194223, Russia. [Atochin, D.; Huang, P.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Glazova, M (reprint author), Russian Acad Sci, IM Sechenov Evolut Physiol & Biochem Inst, 44 Thorez Pr, St Petersburg 194223, Russia. EM mglazova@hotmail.com RI Atochin, Dmitriy/Q-3150-2016; Glazova, Margarita/Q-8597-2016 OI Glazova, Margarita/0000-0001-6617-3404 FU PHS [NS33335]; American Heart Association [0835344N]; Russian Foundation for Fundamental Research [RFBR 08-04-00028-a] FX This work was supported by PHS NS33335 to PLH, American Heart Association Scientist Development Grant 0835344N to DNA, and RFBR 08-04-00028-a from the Russian Foundation for Fundamental Research. NR 33 TC 2 Z9 3 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1052-0295 J9 BIOTECH HISTOCHEM JI Biotech. Histochem. PD OCT PY 2011 VL 86 IS 5 BP 333 EP 339 DI 10.3109/10520295.2010.501706 PG 7 WC Biotechnology & Applied Microbiology; Cell Biology SC Biotechnology & Applied Microbiology; Cell Biology GA 818UT UT WOS:000294782000005 PM 20662604 ER PT J AU Wang, YN Lee, K Pai, S Ledoux, WR AF Wang, Y. N. Lee, K. Pai, S. Ledoux, W. R. TI Histomorphometric comparison after fixation with formaldehyde or glyoxal SO BIOTECHNIC & HISTOCHEMISTRY LA English DT Article DE formaldehyde; glyoxal; heel pad; plantar soft tissue; stereology; structural properties ID STEREOLOGICAL METHODS; VERTICAL SECTIONS; TISSUE-SECTIONS; SURFACE-AREA; SPECIMENS; THICKNESS; HISTOLOGY; BIOLOGY; SKIN AB Formaldehyde has long been the fixative of choice for histological examination of tissue. The use of alternatives to formaldehyde has grown, however, owing to the serious hazards associated with its use. Companies have striven to maintain the morphological characteristics of formaldehyde-fixed tissue when developing alternatives. Glyoxal-based fixatives now are among the most popular formaldehyde alternatives. Although there are many studies that compare staining quality and immunoreactivity, there have been no studies that quantify possible structural differences. Histomorphometric analysis commonly is used to evaluate diseased tissue. We compared fixation with formaldehyde and glyoxal with regard to the histomorphological properties of plantar foot tissue using a combination of stereological methods and quantitative morphology. We measured skin thickness, interdigitation index, elastic septa thickness, and adipocyte area and diameter. No significant differences were observed between formaldehyde and glyoxal fixation for any feature measured. The glyoxal-based fixative used therefore is a suitable fixative for structural evaluation of plantar soft tissue. Measurements obtained from the glyoxal-fixed tissue can be combined with data obtained from formalin-fixed for analysis. C1 [Wang, Y. N.; Lee, K.; Pai, S.; Ledoux, W. R.] Univ Washington, VA Puget Sound Hlth Care Syst, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Dept Vet Affairs, Seattle, WA 98195 USA. [Wang, Y. N.] Univ Washington, Appl Phys Lab, Seattle, WA 98195 USA. [Pai, S.; Ledoux, W. R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Ledoux, W. R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA Puget Sound, Ms 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@u.washington.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU NIH [R01DK75633-03, P30DK017047]; Department of Veterans Affairs, RRD Service [A4843C] FX This study was supported by NIH grants R01DK75633-03 and P30DK017047 and the Department of Veterans Affairs, RR&D Service grant A4843C. NR 21 TC 4 Z9 5 U1 0 U2 9 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1052-0295 J9 BIOTECH HISTOCHEM JI Biotech. Histochem. PD OCT PY 2011 VL 86 IS 5 BP 359 EP 365 DI 10.3109/10520295.2010.520275 PG 7 WC Biotechnology & Applied Microbiology; Cell Biology SC Biotechnology & Applied Microbiology; Cell Biology GA 818UT UT WOS:000294782000009 PM 20854226 ER PT J AU Misra, D Xie, WL Regan, MM Ross, RW Lee, GS Germain, D Kantoff, PW Oh, WK AF Misra, Dipika Xie, Wanling Regan, Meredith M. Ross, Robert W. Lee, Gwo-shu Germain, Doris Kantoff, Philip W. Oh, William K. TI Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy SO BJU INTERNATIONAL LA English DT Article DE androgen receptor; prostate cancer; androgen deprivation therapy; polymorphisms ID ENDOCRINE THERAPY; GENE; RISK; POLYMORPHISMS; ASSOCIATION; GLUTAMINE; EFFICACY; MEN; AGE AB OBJECTIVES Germline CAG repeat polymorphisms in the androgen receptor (AR-CAG) have been shown to influence the activity of the AR. The purpose of the present study was to determine if AR-CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT). PATIENTS AND METHODS Germline AR-CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival. RESULTS There was no significant correlation between differences in the AR-CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. AR-CAG repeat lengths did not significantly correlate with age, prostate-specific antigen (PSA), Gleason score or clinical stage at diagnosis. In patients with metastatic disease, longer AR-CAG repeat lengths (>23 vs <= 23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P = 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54-1.09). CONCLUSIONS This is the largest published study to date investigating the association of germline AR-CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR-CAG repeat lengths do not predict response to ADT. C1 [Misra, Dipika; Germain, Doris; Oh, William K.] Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA. [Xie, Wanling; Regan, Meredith M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ross, Robert W.; Lee, Gwo-shu; Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Oh, WK (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. EM william.oh@mssm.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 17 TC 6 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD OCT PY 2011 VL 108 IS 7 BP 1086 EP 1091 DI 10.1111/j.1464-410X.2010.10037.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 819WS UT WOS:000294865100010 PM 21410629 ER PT J AU McGinnis, SM Brickhouse, M Pascual, B Dickerson, BC AF McGinnis, Scott M. Brickhouse, Michael Pascual, Belen Dickerson, Bradford C. TI Age-Related Changes in the Thickness of Cortical Zones in Humans SO BRAIN TOPOGRAPHY LA English DT Article DE Magnetic resonance imaging; Morphometry; Cortex; Aging ID HUMAN CEREBRAL-CORTEX; VOXEL-BASED MORPHOMETRY; SURFACE-BASED ANALYSIS; ALZHEIMERS-DISEASE; OLDER-ADULTS; HUMAN BRAIN; COGNITIVE CONTROL; WHITE-MATTER; LIFE-SPAN; REGIONAL DIFFERENCES AB Structural neuroimaging studies have demonstrated that all regions of the cortex are not affected equally by aging, with frontal regions appearing especially susceptible to atrophy. The "last in, first out" hypothesis posits that aging is, in a sense, the inverse of development: late-maturing regions of the brain are preferentially vulnerable to age-related loss of structural integrity. We tested this hypothesis by analyzing age-related changes in regional cortical thickness via three methods: (1) an exploratory linear regression of cortical thickness and age across the entire cortical mantle (2) an analysis of age-related differences in the thickness of zones of cortex defined by functional/cytoarchitectural affiliation (including primary sensory/motor, unimodal association, heteromodal association, and paralimbic zones), and (3) an analysis of age-related differences in the thickness of regions of cortex defined by surface area expansion in the period between birth and early adulthood. Subjects were grouped as young (aged 18-29, n = 138), middle-aged (aged 30-59, n = 80), young-old (aged 60-79, n = 60), and old-old (aged 80+, n = 38). Thinning of the cortex between young and middle-aged adults was greatest in heteromodal association cortex and regions of high postnatal surface area expansion. In contrast, thinning in old-old age was greatest in primary sensory/motor cortices and regions of low postnatal surface area expansion. In sum, these results lead us to propose a sequential "developmental-sensory" model of aging, in which developmental factors influence cortical vulnerability relatively early in the aging process, whereas later-in more advanced stages of aging-factors specific to primary sensory and motor cortices confer vulnerability. This model offers explicitly testable hypotheses and suggests the possibility that normal aging may potentially allow for multiple opportunities for intervention to promote the structural integrity of the cerebral cortex. C1 [McGinnis, Scott M.] Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, Boston, MA 02115 USA. [McGinnis, Scott M.; Brickhouse, Michael; Pascual, Belen; Dickerson, Bradford C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Frontotemporal Dementia Unit, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [McGinnis, Scott M.; Dickerson, Bradford C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Athinoula A Martinos Ctr Biomed Imagi, Boston, MA USA. [McGinnis, Scott M.; Dickerson, Bradford C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Massachusetts Alzheimers Dis Res Ctr, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Brickhouse, Michael; Dickerson, Bradford C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Athinoula A Martinos Ctr Biomed Ima, Boston, MA USA. RP McGinnis, SM (reprint author), Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, 221 Longwood Ave, Boston, MA 02115 USA. EM smmcginnis@partners.org FU NIA [R01-AG29411, R21-AG29840, P50-AG005134]; NCRR [P41-RR14075, U24-RR021382]; Harvard NeuroDiscovery Center; Alzheimer's Association FX This study was supported by grants from the NIA R01-AG29411, R21-AG29840, P50-AG005134, and NCRR P41-RR14075, U24-RR021382, Harvard NeuroDiscovery Center, and the Alzheimer's Association. NR 88 TC 32 Z9 32 U1 1 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 J9 BRAIN TOPOGR JI Brain Topogr. PD OCT PY 2011 VL 24 IS 3-4 SI SI BP 279 EP 291 DI 10.1007/s10548-011-0198-6 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819HC UT WOS:000294815000012 PM 21842406 ER PT J AU Pascual-Leone, A Freitas, C Oberman, L Horvath, JC Halko, M Eldaief, M Bashir, S Vernet, M Shafi, M Westover, B Vahabzadeh-Hagh, AM Rotenberg, A AF Pascual-Leone, Alvaro Freitas, Catarina Oberman, Lindsay Horvath, Jared C. Halko, Mark Eldaief, Mark Bashir, Shahid Vernet, Marine Shafi, Mouhshin Westover, Brandon Vahabzadeh-Hagh, Andrew M. Rotenberg, Alexander TI Characterizing Brain Cortical Plasticity and Network Dynamics Across the Age-Span in Health and Disease with TMS-EEG and TMS-fMRI SO BRAIN TOPOGRAPHY LA English DT Article DE Cortical brain plasticity; Transcranial magnetic stimulation; Electroencephalography; Functional magnetic resonance imaging; Lifespan ID TRANSCRANIAL MAGNETIC STIMULATION; THETA-BURST-STIMULATION; COGNITIVE RESERVE HYPOTHESIS; NEUROTROPHIC FACTOR GENE; LONG-TERM POTENTIATION; HUMAN MOTOR CORTEX; BDNF VAL66MET POLYMORPHISM; GRAPH-THEORETICAL ANALYSIS; TEMPORAL-LOBE EPILEPSY; ALZHEIMERS-DISEASE AB Brain plasticity can be conceptualized as nature's invention to overcome limitations of the genome and adapt to a rapidly changing environment. As such, plasticity is an intrinsic property of the brain across the lifespan. However, mechanisms of plasticity may vary with age. The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) enables clinicians and researchers to directly study local and network cortical plasticity, in humans in vivo, and characterize their changes across the age-span. Parallel, translational studies in animals can provide mechanistic insights. Here, we argue that, for each individual, the efficiency of neuronal plasticity declines throughout the age-span and may do so more or less prominently depending on variable 'starting-points' and different 'slopes of change' defined by genetic, biological, and environmental factors. Furthermore, aberrant, excessive, insufficient, or mistimed plasticity may represent the proximal pathogenic cause of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorders or Alzheimer's disease. C1 [Pascual-Leone, Alvaro; Freitas, Catarina; Oberman, Lindsay; Horvath, Jared C.; Halko, Mark; Eldaief, Mark; Bashir, Shahid; Vernet, Marine; Shafi, Mouhshin; Westover, Brandon; Vahabzadeh-Hagh, Andrew M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Div Cognit Neurol,Dept Neurol,Med Sch, Boston, MA 02215 USA. [Pascual-Leone, Alvaro] Univ Autonoma Barcelona, Inst Univ Neurorehabil Guttmann, E-08193 Barcelona, Spain. [Shafi, Mouhshin; Westover, Brandon] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Partners Neurol Program, Boston, MA 02215 USA. [Vahabzadeh-Hagh, Andrew M.; Rotenberg, Alexander] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Pascual-Leone, A (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Div Cognit Neurol,Dept Neurol,Med Sch, 330 Brookline Ave, Boston, MA 02215 USA. EM apleone@bidmc.harvard.edu RI Bashir, Shahid/E-7212-2014; Halko, Mark/G-8633-2016 OI Halko, Mark/0000-0002-7427-0789 FU National Center for Research Resources: Harvard-Thorndike General Clinical Research Center at BIDMC [NCRR MO1 RR01032]; Harvard Clinical and Translational Science Center [UL1 RR025758]; NIH [K24 RR018875, F32MH080493, 1KL2RR025757-01]; Center for Integration of Medicine and Innovative Technology (CIMIT); Foundation for Science and Technology, Portugal [SFRH/BPD/66846/2009]; European Social Fund; Neuronix; Nexstim FX Work on this study was supported by grants from the National Center for Research Resources: Harvard-Thorndike General Clinical Research Center at BIDMC (NCRR MO1 RR01032) and Harvard Clinical and Translational Science Center (UL1 RR025758), NIH grant K24 RR018875, Center for Integration of Medicine and Innovative Technology (CIMIT), Neuronix and Nexstim to APL. CF was supported by a post-doctoral grant from the Foundation for Science and Technology, Portugal (SFRH/BPD/66846/2009), co-funded by the European Social Fund. LO was supported by NIH fellowship F32MH080493 and 1KL2RR025757-01. APL serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Allied Mind, Neosync, and Novavision, and is an inventor on patents and patent applications related to noninvasive brain stimulation and the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging. NR 136 TC 83 Z9 88 U1 5 U2 58 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0896-0267 EI 1573-6792 J9 BRAIN TOPOGR JI Brain Topogr. PD OCT PY 2011 VL 24 IS 3-4 SI SI BP 302 EP 315 DI 10.1007/s10548-011-0196-8 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 819HC UT WOS:000294815000014 PM 21842407 ER PT J AU Smeets, A Daemen, A Vanden Bempt, I Gevaert, O Claes, B Wildiers, H Drijkoningen, R Van Hummelen, P Lambrechts, D De Moor, B Neven, P Sotiriou, C Vandorpe, T Paridaens, R Christiaens, MR AF Smeets, A. Daemen, A. Vanden Bempt, I. Gevaert, O. Claes, B. Wildiers, H. Drijkoningen, R. Van Hummelen, P. Lambrechts, D. De Moor, B. Neven, P. Sotiriou, C. Vandorpe, T. Paridaens, R. Christiaens, M. R. TI Prediction of lymph node involvement in breast cancer from primary tumor tissue using gene expression profiling and miRNAs SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Microarrays; miRNA; Lymph node; Prediction ID GROWTH-FACTOR RECEPTOR-1; HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; METASTASIS; PROGRESSION; MICROARRAY; CELLS; CLASSIFIERS; SURVIVAL; MARKERS AB The aim of this study was to investigate whether lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tumor. For this purpose, we selected a very homogeneous patient population to minimize heterogeneity in other tumor and patient characteristics. First, we compared gene expression profiles of primary tumor tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix Human U133 Plus 2.0 microarray chip. A model was built by weighted Least-Squares Support Vector Machines and validated on an internal and external dataset. Next, miRNA profiling was performed on a subset of 82 tumors using Human MiRNA-microarray chips (Illumina). Finally, for each miRNA the number of significant inverse correlated targets was determined and compared with 1000 sets of randomly chosen targets. A model based on 241 genes was built (AUC 0.66). The AUC for the internal dataset was 0.646 and 0. 651 for the external datasets. The model includes multiple kinases, apoptosis-related, and zinc ion-binding genes. Integration of the microarray and miRNA data reveals ten miRNAs suppressing lymph node invasion and one miRNA promoting lymph node invasion. Our results provide evidence that measurable differences in gene and miRNA expression exist between node negative and node positive patients and thus that lymph node involvement is not a genetically random process. Moreover, our data suggest a general deregulation of the miRNA machinery that is potentially responsible for lymph node invasion. C1 [Smeets, A.; Wildiers, H.; Neven, P.; Vandorpe, T.; Paridaens, R.; Christiaens, M. R.] Multidisciplinary Breast Ctr Univ Hosp, B-3000 Louvain, Belgium. [Daemen, A.; Gevaert, O.; De Moor, B.] Univ Leuven, Dept Elect Engn, Louvain, Belgium. [Vanden Bempt, I.] Univ Antwerp, Dept Microbiol, B-2020 Antwerp, Belgium. [Gevaert, O.] Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA. [Claes, B.; Lambrechts, D.] VIB, Vesalius Res Ctr, Louvain, Belgium. [Drijkoningen, R.] Jessa Hosp, Dept Pathol, Hasselt, Belgium. [Van Hummelen, P.] Dana Farber Canc Inst, Ctr Canc Genome Discovery CCGD, Boston, MA 02115 USA. [Sotiriou, C.] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. RP Smeets, A (reprint author), Multidisciplinary Breast Ctr Univ Hosp, Herestr 49, B-3000 Louvain, Belgium. EM ann.smeets@uzleuven.be RI Verdrengh, Evelien/H-4571-2012; OI Gevaert, Olivier/0000-0002-9965-5466 FU Research Foundation Flanders (FWO); Pfizer Oncology FX AS is supported by a grant from Research Foundation Flanders (FWO) and Pfizer Oncology. NR 50 TC 16 Z9 17 U1 0 U2 2 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 OCT PY 2011 VL 129 IS 3 BP 767 EP 776 DI 10.1007/s10549-010-1265-5 PG 10 WC Oncology SC Oncology GA 817NK UT WOS:000294680600010 PM 21116709 ER PT J AU Thomenius, M Freel, CD Horn, S Krieser, R Abdelwahid, E Cannon, R Balasundaram, S White, K Kornbluth, S AF Thomenius, M. Freel, C. D. Horn, S. Krieser, R. Abdelwahid, E. Cannon, R. Balasundaram, S. White, K. Kornbluth, S. TI Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; Drosophila; mitochondria; reaper; mitofusins; dMFN ID STRESS-INDUCED APOPTOSIS; CYTOCHROME-C; CASPASE ACTIVATION; MAMMALIAN-CELLS; IAP DEGRADATION; PROTEINS; FISSION; PATHWAY; DOMAIN; BAX AB In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or gamma-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die. Cell Death and Differentiation (2011) 18, 1640-1650; doi:10.1038/cdd.2011.26; published online 8 April 2011 C1 [Thomenius, M.; Freel, C. D.; Horn, S.; Kornbluth, S.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Krieser, R.; Abdelwahid, E.; Cannon, R.; Balasundaram, S.; White, K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Kornbluth, S (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. EM kornb001@mc.duke.edu RI White, Kristin/D-7936-2013 FU NIH [RO1 GM080333, GM55568, GM55568-S1]; MGH Fund for Medical Discovery FX This work was funded by NIH grants RO1 GM080333 (SK), GM55568 (KW), a supplement for collaborative research GM55568-S1 (KW and SAK), and an MGH Fund for Medical Discovery (EA). NR 40 TC 17 Z9 17 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD OCT PY 2011 VL 18 IS 10 BP 1640 EP 1650 DI 10.1038/cdd.2011.26 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 818ND UT WOS:000294757800011 PM 21475305 ER PT J AU Eschler, DC Hasham, A Tomer, Y AF Eschler, Deirdre Cocks Hasham, Alia Tomer, Yaron TI Cutting Edge: The Etiology of Autoimmune Thyroid Diseases SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review DE Thyroid genetics; Autoimmune thyroid disorders epigenetics ID SINGLE-NUCLEOTIDE POLYMORPHISM; CHRONIC HEPATITIS-C; II PEPTIDE-BINDING; GRAVES-DISEASE; INTERFERON-ALPHA; GENETIC SUSCEPTIBILITY; CD40 GENE; THYROGLOBULIN; AMIODARONE; EPIDEMIOLOGY AB Significant progress has been made in our understanding of the mechanisms leading to autoimmune thyroid diseases (AITD). For the first time, we are beginning to unravel these mechanisms at the molecular level. AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune diseases affecting the thyroid. They have a complex etiology that involves genetic and environmental influences. Seven genes have been shown to contribute to the etiology of AITD. The first AITD gene discovered, HLA-DR3, is associated with both GD and HT. More recently, this association was dissected at the molecular level when it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide binding pocket is the specific sequence change causing AITD. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes-thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we summarize the latest findings on disease susceptibility and modulation by environmental factors. C1 [Eschler, Deirdre Cocks; Hasham, Alia; Tomer, Yaron] Mt Sinai Med Ctr, Dept Med, Div Endocrinol, New York, NY 10029 USA. [Tomer, Yaron] James J Peters VA Med Ctr, New York, NY 10029 USA. RP Tomer, Y (reprint author), Mt Sinai Med Ctr, Dept Med, Div Endocrinol, 1 Gustave L Levy Pl,Box 1118, New York, NY 10029 USA. EM Yaron.Tomer@mssm.edu FU NIDDK [DK061659, DK067555, DK073681] FX This work was supported in part by grants DK061659, DK067555, and DK073681 from NIDDK. NR 63 TC 30 Z9 32 U1 2 U2 27 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD OCT PY 2011 VL 41 IS 2 BP 190 EP 197 DI 10.1007/s12016-010-8245-8 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 819KB UT WOS:000294822700008 PM 21234711 ER PT J AU Quesnel, AM McKenna, MJ AF Quesnel, Alicia M. McKenna, Michael J. TI Current strategies in management of intracanalicular vestibular schwannoma SO CURRENT OPINION IN OTOLARYNGOLOGY & HEAD AND NECK SURGERY LA English DT Article DE acoustic neuroma; intracanalicular; management; vestibular schwannoma ID ACOUSTIC NEUROMA SURGERY; TERM HEARING PRESERVATION; GAMMA-KNIFE RADIOSURGERY; QUALITY-OF-LIFE; FACIAL-NERVE FUNCTION; MIDDLE FOSSA APPROACH; STEREOTACTIC RADIOSURGERY; RETROSIGMOID APPROACH; CLINICAL ARTICLE; CONSERVATIVE MANAGEMENT AB Purpose of review The current practitioner is more often managing intracanalicular vestibular schwannomas than in the past, as improved imaging and heightened awareness leads to earlier diagnosis of these tumors. The role of observation, microsurgery, and radiation treatment in the management of intracanalicular tumors continues to evolve. The goal of this article is to evaluate and summarize recent literature pertaining to the management of intracanalicular vestibular schwannomas. Recent findings Watchful waiting is an important management option for patients with minimal symptoms. The literature on the natural history of small vestibular schwannomas continues to expand, with particular emphasis on the expected hearing outcomes. Microsurgical techniques also focus on hearing preservation. Presence of fundal fluid and good or normal hearing preoperatively are positive predictors of hearing preservation after surgery. Long-term follow-up after radiation therapy for vestibular schwannomas continues to demonstrate excellent tumor control rates, although hearing preservation rates are modest. Summary Multiple factors, including status of hearing, presence of vestibular symptoms, patient age, medical comorbidities, institutional outcomes, and patient preferences, help determine the management strategy for patients with an intracanalicular vestibular schwannoma. C1 [Quesnel, Alicia M.; McKenna, Michael J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Quesnel, Alicia M.; McKenna, Michael J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP McKenna, MJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM michael_mckenna@meei.harvard.edu NR 62 TC 10 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9508 EI 1531-6998 J9 CURR OPIN OTOLARYNGO JI Curr. Opin. Otolaryngol. Head Neck Surg. PD OCT PY 2011 VL 19 IS 5 BP 335 EP 340 DI 10.1097/MOO.0b013e32834a3fa7 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 817MQ UT WOS:000294678100003 PM 22552696 ER PT J AU Majithia, AR Jablonski, KA McAteer, JB Mather, KJ Goldberg, RB Kahn, SE Florez, JC AF Majithia, A. R. Jablonski, K. A. McAteer, J. B. Mather, K. J. Goldberg, R. B. Kahn, S. E. Florez, J. C. CA DPP Res Grp TI Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program SO DIABETOLOGIA LA English DT Article DE Diabetes Prevention Program; Genetic association; Proinsulin; Single nucleotide polymorphisms; SLC30A8; Zinc transporter ID GENOME-WIDE ASSOCIATION; INSULIN-RELEASE; TYPE-2; PREDICT; VARIANT; LOCI AB Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions. We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention. We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype x treatment interactions at 1 year. In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year. C1 [Florez, J. C.] George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, Rockville, MD 20852 USA. [Majithia, A. R.; McAteer, J. B.; Florez, J. C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Majithia, A. R.; McAteer, J. B.; Florez, J. C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Majithia, A. R.; McAteer, J. B.; Florez, J. C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Majithia, A. R.; Florez, J. C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Goldberg, R. B.] Univ Miami, Leonard M Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL USA. [Kahn, S. E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, S. E.] Univ Washington, Seattle, WA 98195 USA. RP Florez, JC (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Office of Research on Women's Health; Centers for Disease Control and Prevention; American Diabetes Association; Department of Veterans Affairs; Massachusetts General Hospital; Doris Duke Charitable Foundation; [R01 DK072041] FX The investigators gratefully acknowledge the commitment and dedication of the participants of the DPP. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centres and the Coordinating Center for the design and conduct of the study, and for collection, management, analysis and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources and the Department of Veterans Affairs supported data collection at many of the clinical centres. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Office of Research on Women's Health, the Centers for Disease Control and Prevention and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research programme of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Foods and Quaker Oats donated materials, equipment or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of centres, investigators and staff can be found in the ESM. This work was supported in part by R01 DK072041 to J. C. Florez and K. A. Jablonski. S. E. Kahn is supported in part by the Department of Veterans Affairs. J. C. Florez is supported by a Physician Scientist Development Award by the Massachusetts General Hospital and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. We also thank the late A. F. Moore for his intellectual contribution to the genesis of this project. NR 10 TC 12 Z9 14 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2011 VL 54 IS 10 BP 2570 EP 2574 DI 10.1007/s00125-011-2234-1 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817OF UT WOS:000294683000013 PM 21779873 ER PT J AU Martinez, HG Quinones, MP Jimenez, F Estrada, CA Clark, K Muscogiuri, G Sorice, G Musi, N Reddick, RL Ahuja, SS AF Martinez, H. G. Quinones, M. P. Jimenez, F. Estrada, C. A. Clark, K. Muscogiuri, G. Sorice, G. Musi, N. Reddick, R. L. Ahuja, S. S. TI Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy (+) Apoe (-/-) mouse model of the metabolic syndrome SO DIABETOLOGIA LA English DT Article DE Animal-mouse; Basic science; Cardiac complications; Experimental immunology; KO mice; Metabolic syndrome; Nephropathy ID GLYCOGEN-SYNTHASE KINASE-3; TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; APOLIPOPROTEIN-E; HEPATIC STEATOSIS; SKELETAL-MUSCLE; DENDRITIC CELLS; ADIPOSE-TISSUE; KNOCKOUT MICE; HIGH-FAT AB Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. We generated a model of the metabolic syndrome by backcrossing KKAy (+) with Apoe (-/-) mice (KKAy (+) Apoe (-/-) ) and studied the role of CCR2 in this model system. KKAy (+) Apoe (-/-) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe (-/-) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome. C1 [Martinez, H. G.; Jimenez, F.; Estrada, C. A.; Clark, K.; Muscogiuri, G.; Sorice, G.; Musi, N.; Ahuja, S. S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med MC 7870, San Antonio, TX 78229 USA. [Martinez, H. G.; Jimenez, F.; Ahuja, S. S.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. [Quinones, M. P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Reddick, R. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Ahuja, SS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med MC 7870, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ahuja@uthscsa.edu FU Fraternal Order of Eagles; Veterans' Administration Merit Award; NIH [RO1 AR 052755] FX We thank Y. Patel (Department of Pathology, UTHSCSA) for help with HPLC measurement of creatinine. This work was supported by grants from Fraternal Order of Eagles, a Veterans' Administration Merit Award, and NIH RO1 AR 052755 to S. S. Ahuja. NR 40 TC 8 Z9 8 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2011 VL 54 IS 10 BP 2660 EP 2668 DI 10.1007/s00125-011-2248-8 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817OF UT WOS:000294683000022 PM 21779871 ER PT J AU Patard, JJ Pignot, G Escudier, B Eisen, T Bex, A Sternberg, C Rini, B Roigas, J Choueiri, T Bukowski, R Motzer, R Kirkali, Z Mulders, P Bellmunt, J AF Patard, Jean-Jacques Pignot, Geraldine Escudier, Bernard Eisen, Tim Bex, Axel Sternberg, Cora Rini, Brian Roigas, Jan Choueiri, Toni Bukowski, Ronald Motzer, Robert Kirkali, Ziya Mulders, Peter Bellmunt, Joaquim TI ICUD-EAU International Consultation on Kidney Cancer 2010: Treatment of Metastatic Disease SO EUROPEAN UROLOGY LA English DT Review DE Renal cell carcinoma; First-line; Second-line; Treatment algorithms; VEGF-targeted therapy; mTOR inhibitors ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; SORAFENIB PLUS INTERFERON-ALPHA-2B; COMBINATION TARGETED THERAPY; PULMONARY RESECTION; PROGNOSTIC-FACTORS; ANTITUMOR-ACTIVITY; DOUBLE-BLIND; BEVACIZUMAB; SUNITINIB AB Context: Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC). Objective: This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms. Evidence acquisition: Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature. Evidence synthesis: Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)-targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first-and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed. Conclusions: Increasing clinical evidence is clarifying appropriate first-and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Patard, Jean-Jacques] Univ Paris 11, Bicetre Hosp, Dept Urol, Le Kremlin Bicetre, France. [Pignot, Geraldine] Univ Paris 05, Cochin Hosp, Dept Urol, Paris, France. [Escudier, Bernard] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Eisen, Tim] Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. [Bex, Axel] Netherlands Canc Inst, Div Surg Oncol, Dept Urol, Amsterdam, Netherlands. [Sternberg, Cora] San Camillo Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Rini, Brian; Bukowski, Ronald] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. [Roigas, Jan] Univ Hosp Charite, Dept Urol, Berlin, Germany. [Choueiri, Toni] Dana Farber Canc Inst, Kidney Canc Ctr, Boston, MA 02115 USA. [Motzer, Robert] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, New York, NY 10021 USA. [Kirkali, Ziya] Dokuz Eylul Univ, Sch Med, Izmir, Turkey. [Mulders, Peter] Univ Med Ctr Nijmegen, St Radboud, Netherlands. [Bellmunt, Joaquim] Univ Hosp del Mar, Med Oncol Serv, Barcelona 08003, Spain. RP Patard, JJ (reprint author), Univ Paris 11, Bicetre Hosp, Dept Urol, Le Kremlin Bicetre, France. EM jean-jacques.patard@live.fr; jbellmunt@parcdesalutmar.cat RI Mulders, Peter/H-8076-2014 NR 50 TC 46 Z9 47 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD OCT PY 2011 VL 60 IS 4 BP 684 EP 690 DI 10.1016/j.eururo.2011.06.017 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 812OZ UT WOS:000294304100015 PM 21704448 ER PT J AU Purwaha, P Gu, Y Kelavkar, U Kang, JX Law, B Wu, EX Qian, SY AF Purwaha, Preeti Gu, Yan Kelavkar, Uddhav Kang, Jing X. Law, Benedict Wu, Erxi Qian, Steven Y. TI LC/ESR/MS study of pH-dependent radical generation from 15-LOX-catalyzed DPA peroxidation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE ESR spin trapping; DPA-derived radicals; 15-LOX-catalyzed peroxidation; PC-3-15LOS cellular peroxidation; LC/ESR; LC/MS; LC/MS(2); Free radicals ID CARBON-CENTERED RADICALS; POLYUNSATURATED FATTY-ACIDS; LIPOXYGENASE-CATALYZED PEROXIDATION; DOCOSAPENTAENOIC ACID; EICOSAPENTAENOIC ACID; COLORECTAL-CANCER; TANDEM MS; IN-VITRO; 15-LIPOXYGENASE-1; N-3 AB Docosapentaenoic acid (DPA) is a unique fatty acid that exists in two isomeric forms (n-3 and n-6), which differ in their physiological behaviors. DPA can undergo free radical-mediated peroxidation via lipoxygenase (LOX). 15-LOX, one of the LOX isomers, has received much attention in cancer research because of its very different expression level in normal tissues compared to tumors and some bioactive fatty acid metabolites modulating the tumorigenic pathways in cancer. However, the mechanism linking 15-LOX, DPA metabolites, and their bioactivities is still unclear, and the free radicals generated in DPA peroxidation have never been characterized. In this study, we have studied radicals formed from both soybean and human cellular (PC3-15LOS cells) 15-LOX-catalyzed peroxidation of DPAs at various pH's using a combination of LC/ESR/MS with the spin trapping technique. We observed a total of three carbon-centered radicals formed in 15-LOX-DPA (n-3) stemming from its 7-, 17-, and 20-hydroperoxides, whereas only one formed from 17-hydroperoxide in DPA (n-6). A change in the reaction pH from 8.5 (15-LOX enzyme optimum) to 7.4 (physiological) and to 6.5 (tumor, acidic) not only decreased the total radical formation but also altered the preferred site of oxygenation. This pH-dependent alteration of radical formation and oxygenation pattern may have significant implications and provide a basis for our ongoing investigations of LOXs as well as fatty acids in cancer biology. Published by Elsevier Inc. C1 [Purwaha, Preeti; Gu, Yan; Law, Benedict; Wu, Erxi; Qian, Steven Y.] N Dakota State Univ, Dept Pharmaceut Sci, Coll Pharm Nursing & Allied Sci, Fargo, ND 58105 USA. [Kelavkar, Uddhav] Mem Hlth Univ Med Ctr, Dept Lab Oncol, Savannah, GA 31404 USA. [Kelavkar, Uddhav] Mercer Univ, Sch Med, Div Basic Med Sci, Savannah, GA 31404 USA. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Qian, SY (reprint author), N Dakota State Univ, Dept Pharmaceut Sci, Coll Pharm Nursing & Allied Sci, Fargo, ND 58105 USA. EM steven.qian@ndsu.edu FU NIH [K22ES-012978, R15CA140833, P20 RR015566, P20 RR020151] FX This work was supported by NIH Grants K22ES-012978, R15CA140833, and P20 RR015566 (S.Q.) and P20 RR020151 (E.W.). NR 31 TC 6 Z9 7 U1 0 U2 2 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 OCT 1 PY 2011 VL 51 IS 7 BP 1461 EP 1470 DI 10.1016/j.freeradbiomed.2011.07.001 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 818GV UT WOS:000294740700019 PM 21807091 ER PT J AU Halpern, SD Kohn, R Dornbrand-Lo, A Metkus, T Asch, DA Volpp, KG AF Halpern, Scott D. Kohn, Rachel Dornbrand-Lo, Aaron Metkus, Thomas Asch, David A. Volpp, Kevin G. TI Lottery-Based versus Fixed Incentives to Increase Clinicians' Response to Surveys SO HEALTH SERVICES RESEARCH LA English DT Article DE Incentives; response rate; surveys; lottery; behavioral economics ID RANDOMIZED-TRIAL; MAIL SURVEYS; PHYSICIAN RESPONSE; COST-EFFECTIVENESS; RATES; CASH; QUESTIONNAIRES; 5-DOLLAR; PAY AB Objective. To compare the effects of lottery-based and fixed incentives on clinicians' response to surveys. Data Sources. Three randomized trials with fixed payments and actuarially equivalent lotteries. Study Design. Trial 1 compared a low-probability/high-payout lottery, a high-probability/low-payout lottery, and no incentive. Trial 2 compared a moderate-probability/moderate-payout lottery with an unconditional fixed payment (payment sent with questionnaire). Trial 3 compared a moderate-probability/moderate-payout lottery with a conditional fixed payment (payment promised following response). Principal Findings. Neither the low-probability nor high-probability lotteries improved response compared with no incentive. Unconditional fixed payments produced significantly greater response than actuarially equivalent lotteries, but conditional fixed payments did not. Conclusions. Lottery-based incentives do not improve clinicians' response rates compared with no incentives, and they are inferior to unconditional fixed payments. C1 [Halpern, Scott D.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Halpern, Scott D.; Asch, David A.; Volpp, Kevin G.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Halpern, Scott D.; Dornbrand-Lo, Aaron; Asch, David A.; Volpp, Kevin G.] Univ Penn, Sch Med, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, Philadelphia, PA 19104 USA. [Halpern, Scott D.; Kohn, Rachel; Asch, David A.] Univ Penn, Sch Med, Ctr Bioeth, Philadelphia, PA 19104 USA. [Metkus, Thomas] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Asch, David A.; Volpp, Kevin G.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Halpern, SD (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 723 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM shalpern@exchange.upenn.edu OI Asch, David/0000-0002-7970-286X FU Greenwall Foundation; Leonard Davis Institute of Health Economics Center for Health Incentives; University of Pennsylvania FX Incentives used in this study came from funds provided by a Greenwall Foundation Faculty Scholar Award in Bioethics (SDH), the Leonard Davis Institute of Health Economics Center for Health Incentives (KGV), and the University of Pennsylvania Medical Education Research Fund (SDH). None of these sponsors were involved in the preparation of the manuscript or in the decision to submit the manuscript for publication. NR 27 TC 13 Z9 13 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD OCT PY 2011 VL 46 IS 5 BP 1663 EP 1674 DI 10.1111/j.1475-6773.2011.01264.x PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 818GN UT WOS:000294739800018 PM 21492159 ER PT J AU Weiner, RB Hutter, AM Wang, F Kim, JH Wood, MJ Wang, TJ Picard, MH Baggish, AL AF Weiner, Rory B. Hutter, Adolph M. Wang, Francis Kim, Jonathan H. Wood, Malissa J. Wang, Thomas J. Picard, Michael H. Baggish, Aaron L. TI Performance of the 2010 European Society of Cardiology criteria for ECG interpretation in athletes SO HEART LA English DT Article ID SUDDEN CARDIAC DEATH; HYPERTROPHIC CARDIOMYOPATHY; LAUSANNE RECOMMENDATIONS; CARDIOVASCULAR-DISEASE; PERICARDIAL DISEASES; EXERCISE PHYSIOLOGY; OF-CARDIOLOGY; WORKING GROUP; ELECTROCARDIOGRAPHY; REHABILITATION AB Background The European Society of Cardiology (ESC) recently published revised criteria for ECG interpretation in the athlete. Objective To examine the performance of the 2010 ESC ECG criteria in a population of athletes undergoing preparticipation cardiovascular disease screening. Methods University athletes (n=508) underwent routine medical history/physical examination and ECG before athletic participation. Transthoracic echocardiography (TTE) was also performed on each participant to detect or exclude cardiac findings with relevance to sport participation. Screening test statistics were calculated to determine the performance of the 2010 ESC criteria, and the performance of the 2010 criteria was compared with the 2005 criteria. Results Application of the 2010 ESC criteria, compared with the 2005 criteria, reduced the number of participants with abnormal ECG findings from 83/508 (16.3%) to 49/508 (9.6%). The reduction in the number of abnormal ECGs was driven by the reclassification of participants with isolated QRS voltage criteria for left ventricular hypertrophy from abnormal to normal. Of the 49 participants with abnormal ECGs, 14/49 (29%) had a single ECG abnormality and 35/49 (71%) had two or more abnormalities. The use of the 2010 criteria was associated with improved specificity (reduction in the false positive rate) and preserved sensitivity when compared with the 2005 criteria. Conclusion Application of the 2010 ESC criteria for ECG interpretation in the athlete improves the accuracy of an ECG-inclusive preparticipation screening strategy by reducing the rate of false positive ECGs. C1 [Weiner, Rory B.; Hutter, Adolph M.; Kim, Jonathan H.; Wood, Malissa J.; Wang, Thomas J.; Picard, Michael H.; Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wang, Francis] Harvard Univ, Univ Hlth Serv, Cambridge, MA 02138 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 25 TC 56 Z9 56 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD OCT PY 2011 VL 97 IS 19 BP 1573 EP 1577 DI 10.1136/hrt.2011.227330 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 817JH UT WOS:000294667700008 PM 21602522 ER PT J AU Schumacher, FR Berndt, SI Siddiq, A Jacobs, KB Wang, ZM Lindstrom, S Stevens, VL Chen, C Mondul, AM Travis, RC Stram, DO Eeles, RA Easton, DF Giles, G Hopper, JL Neal, DE Hamdy, FC Donovan, JL Muir, K Al Olama, AA Kote-Jarai, Z Guy, M Severi, G Gronberg, H Isaacs, WB Karlsson, R Wiklund, F Xu, JF Allen, NE Andriole, GL Barricarte, A Boeing, H Bueno-de-Mesquita, HB Crawford, ED Diver, WR Gonzalez, CA Gaziano, JM Giovannucci, EL Johansson, M Le Marchand, L Ma, J Sieri, S Stattin, P Stampfer, MJ Tjonneland, A Vineis, P Virtamo, J Vogel, U Weinstein, SJ Yeager, M Thun, MJ Kolonel, LN Henderson, BE Albanes, D Hayes, RB Feigelson, HS Riboli, E Hunter, DJ Chanock, SJ Haiman, CA Kraft, P AF Schumacher, Fredrick R. Berndt, Sonja I. Siddiq, Afshan Jacobs, Kevin B. Wang, Zhaoming Lindstrom, Sara Stevens, Victoria L. Chen, Constance Mondul, Alison M. Travis, Ruth C. Stram, Daniel O. Eeles, Rosalind A. Easton, Douglas F. Giles, Graham Hopper, John L. Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Kenneth Al Olama, Ali Amin Kote-Jarai, Zsofia Guy, Michelle Severi, Gianluca Gronberg, Henrik Isaacs, William B. Karlsson, Robert Wiklund, Fredrik Xu, Jianfeng Allen, Naomi E. Andriole, Gerald L. Barricarte, Aurelio Boeing, Heiner Bueno-de-Mesquita, H. Bas Crawford, E. David Diver, W. Ryan Gonzalez, Carlos A. Gaziano, J. Michael Giovannucci, Edward L. Johansson, Mattias Le Marchand, Loic Ma, Jing Sieri, Sabina Stattin, Par Stampfer, Meir J. Tjonneland, Anne Vineis, Paolo Virtamo, Jarmo Vogel, Ulla Weinstein, Stephanie J. Yeager, Meredith Thun, Michael J. Kolonel, Laurence N. Henderson, Brian E. Albanes, Demetrius Hayes, Richard B. Feigelson, Heather Spencer Riboli, Elio Hunter, David J. Chanock, Stephen J. Haiman, Christopher A. Kraft, Peter TI Genome-wide association study identifies new prostate cancer susceptibility loci SO HUMAN MOLECULAR GENETICS LA English DT Article ID RISK-ASSOCIATED LOCI; AGGRESSIVENESS LOCI; SEQUENCE VARIANTS; COMMON VARIANT; MULTIPLE LOCI; SCAN; GENE; 8Q24; REPLICATION; SURVIVAL AB Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade >= 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P = 4.3 x 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P = 8.6 x 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P = 0.72 and P = 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes. C1 [Lindstrom, Sara; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Stram, Daniel O.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Berndt, Sonja I.; Jacobs, Kevin B.; Wang, Zhaoming; Mondul, Alison M.; Weinstein, Stephanie J.; Yeager, Meredith; Albanes, Demetrius; Hayes, Richard B.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London, England. [Jacobs, Kevin B.; Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Lindstrom, Sara; Chen, Constance; Giovannucci, Edward L.; Stampfer, Meir J.; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Stevens, Victoria L.; Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Travis, Ruth C.; Allen, Naomi E.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Travis, Ruth C.; Allen, Naomi E.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Eeles, Rosalind A.; Kote-Jarai, Zsofia; Guy, Michelle] Inst Canc Res, Oncogenet Team, Sutton, Surrey, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Dept Publ Hlth, Cambridge, England. [Easton, Douglas F.; Al Olama, Ali Amin] Univ Cambridge, Dept Primary Care, Cambridge, England. [Easton, Douglas F.; Neal, David E.] Univ Cambridge, Dept Oncol, Cambridge, England. [Giles, Graham; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Hopper, John L.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic, Australia. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Muir, Kenneth] Univ Warwick, Hlth Sci Res Inst, Coventry CV4 7AL, W Midlands, England. [Gronberg, Henrik; Karlsson, Robert; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Isaacs, William B.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Winston Salem, NC USA. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Boeing, Heiner] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Crawford, E. David] Univ Colorado, Aurora, CO USA. [Gonzalez, Carlos A.] Catalan Inst Oncol ICO IDIBELL RETICC RD06 0020, Unit Nutr Environm & Canc, Barcelona, Spain. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, VA Cooperat Studies Programs, Boston, MA USA. [Gaziano, J. Michael; Ma, Jing; Stampfer, Meir J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Johansson, Mattias] Int Agcy Res Canc, F-69372 Lyon, France. [Johansson, Mattias; Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Ma, Jing; Stampfer, Meir J.] Channing Labs, Boston, MA USA. [Sieri, Sabina] Fdn IRCCS Ist Nazl Tumori, Nutr Epidemiol Unit, Milan, Italy. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Vogel, Ulla] Natl Res Ctr Working Environm, Copenhagen, Denmark. [Vogel, Ulla] Tech Univ Denmark, Natl Food Inst, Soborg, Denmark. [Hayes, Richard B.] NYU, Dept Environm Med, Inst Canc, Div Epidemiol,Langone Med Ctr, New York, NY 10016 USA. [Feigelson, Heather Spencer] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. RP Kraft, P (reprint author), Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Gonzalez, Carlos A/O-4651-2014; Albanes, Demetrius/B-9749-2015; Sieri, Sabina/K-4667-2016; Vogel, Ulla/I-5048-2012; OI Karlsson, Robert/0000-0002-8949-2587; Gonzalez, Carlos A/0000-0003-2822-9715; Sieri, Sabina/0000-0001-5201-172X; Vogel, Ulla/0000-0001-6807-1524; Eeles, Rosalind/0000-0002-3698-6241; Neal, David/0000-0002-6033-5086; Hayes, Richard/0000-0002-0918-661X; Mondul, Alison/0000-0002-8843-1416; Giles, Graham/0000-0003-4946-9099 FU U.S. National Institutes of Health, National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics); Cancer Research UK [C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, C522/A8649]; Institute of Cancer Research and The Everyman Campaign; Prostate Cancer Research Foundation; Prostate Research Campaign UK; National Cancer Research Network UK; National Cancer Research Institute (NCRI) UK; NIHR Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; National Health and Medical Research Council, Australia [209057, 251533, 450104, 390130]; VicHealth; Cancer Council Victoria; Cancer Council Queensland; Whitten Foundation; Tattersall's; Health Technology Assessment Programme [96/20/06, 96/20/99]; Department of Health, England; Medical Research Council of England [G0500966, ID 75466]; NCRI, UK; Southwest National Health Service Research and Development; USA Dept of Defense [W81XWH-04-1-0280]; Yorkshire Cancer Research and Cancer Research UK; NCRI; NIHR; Swedish Research Council [K2010-70X-20430-04-3, 70867901]; Swedish Cancer Foundation [09-0677]; Hedlund Foundation; Soderberg Foundation; Enqvist Foundation; Stockholm County Council; National Cancer Institute [CA112517, CA133009] FX The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to M.J.T., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). This work was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135, and C16913/A6835. We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. We also acknowledge grant support from The National Health and Medical Research Council, Australia (209057, 251533, 450104, 390130), VicHealth, The Cancer Council Victoria, Cancer Council Queensland, The Whitten Foundation, and Tattersall's. The ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, England; Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK. The epidemiological data for ProtecT were generated though funding from the Southwest National Health Service Research and Development. DNA extraction in ProtecT was supported by USA Dept of Defense award W81XWH-04-1-0280, Yorkshire Cancer Research and Cancer Research UK. The bio-repository from ProtecT is supported by the NCRI (ProMPT) study and the Cambridge BMRC grant from NIHR. Financial support for CAPS was provided through a grant from the Swedish Research Council (grant no K2010-70X-20430-04-3 and 70867901), the Swedish Cancer Foundation (grant no 09-0677), the Hedlund Foundation, Soderberg Foundation, Enqvist Foundation, ALF funds from the Stockholm County Council. W.B.I. was supported by National Cancer Institute grants CA112517 and CA133009. NR 41 TC 93 Z9 94 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 1 PY 2011 VL 20 IS 19 BP 3867 EP 3875 DI 10.1093/hmg/ddr295 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 819FE UT WOS:000294810000014 PM 21743057 ER PT J AU Holgerson, PL Harnevik, L Hernell, O Tanner, ACR Johansson, I AF Holgerson, P. Lif Harnevik, L. Hernell, O. Tanner, A. C. R. Johansson, I. TI Mode of Birth Delivery Affects Oral Microbiota in Infants SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE newborn; Caesarian section; vaginal delivery; bacterial taxa; HOMIM; Slackia exigua ID INTESTINAL MICROBIOTA; GUT MICROBIOTA; ROOT CARIES; MICROFLORA; CHILDREN; IDENTIFICATION; PERIODONTITIS; ACQUISITION; MICROARRAY; PROFILES AB Establishment of the microbiota of the gut has been shown to differ between infants delivered by Caesarian section (C-section) and those delivered vaginally. The aim of the present study was to compare the oral microbiota in infants delivered by these different routes. The oral biofilm was assayed by the Human Oral Microbe Identification Microarray (HOMIM) in healthy three-month-old infants, 38 infants born by C-section, and 25 infants delivered vaginally. Among over 300 bacterial taxa targeted by the HOMIM microarray, Slackia exigua was detected only in infants delivered by C-section. Further, significantly more bacterial taxa were detected in the infants delivered vaginally (79 species/species clusters) compared with infants delivered by C-section (54 species/species clusters). Multivariate modeling revealed a strong model that separated the microbiota of C-section and vaginally delivered infants into two distinct colonization patterns. In conclusion, our study indicated differences in the oral microbiota in infants due to mode of delivery, with vaginally delivered infants having a higher number of taxa detected by the HOMIM microarray. C1 [Holgerson, P. Lif; Harnevik, L.; Johansson, I.] Umea Univ, Dept Odontol, Cariol Sect, S-90187 Umea, Sweden. [Hernell, O.] Umea Univ, Dept Clin Sci, Pediat Sect, S-90187 Umea, Sweden. [Tanner, A. C. R.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Tanner, A. C. R.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Holgerson, PL (reprint author), Umea Univ, Dept Odontol, Cariol Sect, S-90187 Umea, Sweden. EM pernilla.lif@odont.umu.se FU Vasterbotten County Council (TUA/FoU); Swedish Patent Revenue Foundation; Public Health Service [DE-015847]; National Institute of Dental and Craniofacial Research, USA; Henning and Johan Throne-Holst's Foundation FX The present study was supported by grants from Vasterbotten County Council (TUA/FoU) and The Swedish Patent Revenue Foundation, and by a Public Health Service Grant DE-015847 (AT) from the National Institute of Dental and Craniofacial Research, USA, and by Henning and Johan Throne-Holst's Foundation (PL). Dr. Conny Wikstrom, Umetrics, Sweden, is acknowledged for expertise support in PLS-DA. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 30 TC 23 Z9 23 U1 1 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD OCT PY 2011 VL 90 IS 10 BP 1183 EP 1188 DI 10.1177/0022034511418973 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 819PF UT WOS:000294838200006 ER PT J AU Liguori, M Meier, DS Hildenbrand, P Healy, BC Chitnis, T Baruch, NF Khoury, SJ Weiner, HL Bakshi, R Barkhof, F Guttmann, CRG AF Liguori, Maria Meier, Dominik S. Hildenbrand, Peter Healy, Brian C. Chitnis, Tanuja Baruch, Natalie F. Khoury, Samia J. Weiner, Howard L. Bakshi, Rohit Barkhof, Frederik Guttmann, Charles R. G. TI One year activity on subtraction MRI predicts subsequent 4 year activity and progression in multiple sclerosis SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID DIAGNOSTIC-CRITERIA; DISEASE-ACTIVITY; LESION BURDEN; DISABILITY; TRIALS; IMAGES; IMPAIRMENT; PATHOLOGY; PATTERNS; THERAPY AB Objective To investigate the predictive value of 1 year subtraction MRI (sMRI) on activity and progression over the next 4 years in early phase multiple sclerosis (MS). To compare sensitivity of sMRI and contrast enhanced MRI towards disease activity. Methods The study was performed on 127 MS patients with brain MRI within 5 years of symptom onset (y0), after 1 year (y1) and after 5 years (y5). Measures of clinical (Expanded Disability Status Scale, relapse rate) and conventional MRI outcomes (brain parenchyma fraction (BPF); T2 lesion volume (T2LV); contrast enhancing lesions (CEL)) were available at all time points. sMRI was obtained from y1-y0, y5-y1 and y5-y0 image pairs and the number of new, enlarged, resolved and regressed lesions was counted. Results One year lesion change measured by sMRI predicted sMRI lesion change (p<0.0001), BPF and T2LV (p<0.05) changes, as well as clinical relapse rate (p<0.02) in the subsequent 4 years. sMRI measures were retained in stepwise predictive models that included other candidate MRI predictors. Active lesions on sMRI over a 1, 4 or 5 year interval provided a more sensitive assessment of disease activity than number of CEL at y0, y1 and/or y5: 83%, 93% and 90% of patients without CEL showed sMRI activity during the y1-y0, y5-y1, and y5-y0 intervals. Conclusions sMRI is a feasible and sensitive tool for detecting MS activity and may provide an alternative to contrast enhanced MRI in clinical practice, particularly in cases where CEL are not available or inconclusive. Furthermore, sMRI metrics combined with conventional MRI outcomes (CEL, T2LV, BPF) can increase the prediction of longer term MRI activity and progression. C1 [Liguori, Maria; Meier, Dominik S.; Hildenbrand, Peter; Guttmann, Charles R. G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging,Dept Radiol, Boston, MA 02115 USA. [Liguori, Maria; Meier, Dominik S.; Hildenbrand, Peter; Guttmann, Charles R. G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging,Dept Neurol, Boston, MA 02115 USA. [Liguori, Maria] CNR, Inst Neurol Sci, Mangone, Italy. [Hildenbrand, Peter] Lahey Clin Fdn, Dept Radiol, Neuroradiol Div, Burlington, MA USA. [Healy, Brian C.; Chitnis, Tanuja; Baruch, Natalie F.; Khoury, Samia J.; Weiner, Howard L.; Bakshi, Rohit] Harvard Univ, Brigham & Womens Hosp, Sch Med, Partners MS Ctr,Dept Neurol, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Bakshi, Rohit] Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Neuroimaging Res,Dept Neurol, Boston, MA 02115 USA. [Barkhof, Frederik] Vrije Univ Amsterdam Med Ctr, Dept Radiol, MS Ctr Amsterdam, Amsterdam, Netherlands. RP Guttmann, CRG (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging,Dept Radiol, 221 Longwood Ave,RF 396, Boston, MA 02115 USA. EM guttmann@bwh.harvard.edu RI Liguori, Maria/D-4390-2016; OI Liguori, Maria/0000-0003-4338-0392; khoury, samia/0000-0003-3198-6063 NR 40 TC 8 Z9 8 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD OCT PY 2011 VL 82 IS 10 BP 1125 EP 1131 DI 10.1136/jnnp.2011.242115 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 818EF UT WOS:000294733400015 PM 21429902 ER PT J AU Kearney, CJ Lee, JY Padera, RF Hsu, HP Spector, M AF Kearney, Cathal J. Lee, Ji Yoo Padera, Robert F. Hsu, Hu-Ping Spector, Myron TI Extracorporeal Shock Wave-Induced Proliferation of Periosteal Cells SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE shock waves; cambium cell proliferation; tissue engineering; rodent; immunohistochemistry ID SMOOTH-MUSCLE ACTIN; BONE-FORMATION; OSTEOGENESIS; EXPRESSION; CARTILAGE; DIFFERENTIATION; CHONDROGENESIS; FEMUR AB The cambium cells of the periosteum are an important cell source for select tissue engineering/regenerative medicine applications due to their osteogenic and chondrogenic potential. However, the cambium layer is only 2-5 cells thick, which complicates its harvest, and the low cell number limits its suitability for certain applications. Extracorporeal shock waves (ESWs) have been reported to cause periosteal osteogenesis following cambium layer thickening. This study quantified the proliferation of cambium cells in the femur and tibia of adult rats following ESW treatment at two different energy flux densities. Four days after application of ESWs, there was a significant (3- to 6-fold) increase in cambium layer thickness and cell number. Proliferation was seen with an energy flux density as low as 0.15 mJ/mm(2). The tibial cambium cells were more proliferative than those of the femur, with the cells closest to the ESW source proliferating the most. Within the thickened periosteum, alpha-smooth muscle actin and von Willebrand Factor expression were upregulated, suggesting a vascular role in ESW osteogenesis. Bone formation was seen within the stimulated periosteum at day 4. We propose that non-invasive ESWs can be used to rapidly stimulate cambium cell proliferation, providing a larger cell population for use as a progenitor cell source for tissue engineering applications, than can normally be provided by periosteum. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:1536-1543, 2011 C1 [Kearney, Cathal J.; Padera, Robert F.; Spector, Myron] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Kearney, Cathal J.; Lee, Ji Yoo; Hsu, Hu-Ping; Spector, Myron] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Padera, Robert F.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hsu, Hu-Ping; Spector, Myron] Harvard Univ, Sch Med, Brigham & Womens Hosp, Orthopaed Res Lab, Boston, MA 02115 USA. RP Spector, M (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM mspector@rics.bwh.harvard.edu OI Kearney, Cathal/0000-0002-9514-6517 FU Department of Veterans Affairs; SANUWAVE Health, Inc.; NICHD FX The authors would like to acknowledge the Department of Veterans Affairs and SANUWAVE Health, Inc. for funding and supplies, respectively, for this project. The collagen II monoclonal antibody developed by Rikard Holmdahl/Kristofer Rubin was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA. NR 24 TC 6 Z9 6 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD OCT PY 2011 VL 29 IS 10 BP 1536 EP 1543 DI 10.1002/jor.21346 PG 8 WC Orthopedics SC Orthopedics GA 816IV UT WOS:000294592800013 PM 21448986 ER PT J AU Rutgers, KS van Remoortere, A van Buchem, MA Verrips, CT Greenberg, SM Bacskai, BJ Frosch, MP van Duinen, SG Maat-Schieman, ML van der Maarel, SM AF Rutgers, Kim S. van Remoortere, Alexandra van Buchem, Mark A. Verrips, C. Theo Greenberg, Steven M. Bacskai, Brian J. Frosch, Matthew P. van Duinen, Sjoerd G. Maat-Schieman, Marion L. van der Maarel, Silvere M. TI Differential recognition of vascular and parenchymal beta amyloid deposition SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Amyloid beta; Antibody; Histochemistry; Imaging; Immunoreactivity ID HEREDITARY CEREBRAL-HEMORRHAGE; DOMAIN ANTIBODY FRAGMENTS; ALZHEIMERS-DISEASE; DUTCH TYPE; A-BETA; ANGIOPATHY; SECRETION; LIBRARIES; DEMENTIA; FIBRILS AB By phage display, llama-derived heavy chain antibody fragments were selected from non-immune and immune libraries and tested for their affinity and specificity for beta amyloid by phage-ELISA, immunohistochemistry and surface plasmon resonance. We identified eight distinct heavy chain antibody fragments specific for beta amyloid. While three of them recognized vascular and parenchymal beta amyloid deposits, the remaining five heavy chain antibody fragments recognized vascular beta amyloid specifically, failing to bind to parenchymal beta amyloid. These heavy chain antibody fragments, selected from different libraries, demonstrated differential affinity for different epitopes when used for immunohistochemistry. These observations indicate that the llama heavy chain antibody fragments are the first immunologic probes with the ability to differentiate between parenchymal and vascular beta amyloid aggregates. This indicates that vascular and parenchymal beta amyloid deposits are heterogeneous in epitope presence/availability. The properties of these heavy chain antibody fragments make them potential candidates for use in in vivo differential diagnosis of Alzheimer disease and cerebral amyloid angiopathy. Continued use and characterization of these reagents will be necessary to fully understand the performance of these immunoreagents. (C) 2009 Elsevier Inc. All rights reserved. C1 [Rutgers, Kim S.; van der Maarel, Silvere M.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2333 ZA Leiden, Netherlands. [van Remoortere, Alexandra] Leiden Univ, Dept Parasitol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [van Buchem, Mark A.] Leiden Univ, Dept Radiol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Verrips, C. Theo] Univ Utrecht, Dept Mol Cell Biol, NL-3584 CH Utrecht, Netherlands. [Greenberg, Steven M.; Bacskai, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Charlestown, MA USA. [van Duinen, Sjoerd G.] Leiden Univ, Dept Pathol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [van Duinen, Sjoerd G.; Maat-Schieman, Marion L.] Leiden Univ, Dept Neurol, Med Ctr, NL-2333 ZA Leiden, Netherlands. RP van der Maarel, SM (reprint author), Leiden Univ, Dept Human Genet, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. EM maarel@lumc.nl FU IOP Genomics Senter [IGE05005]; National Institutes of Health (NIH) [AG021084, AG005134]; Centre for Medical Systems Biology within the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) FX We would like to thank Finnbogi R. Thormodsson, Ph.D., Faculty of Medicine, University of Iceland, Reykjavik, for providing cryosections of HCHWA-I patients and Ingrid Hegeman-Kleinn for technical assistance. We also would like to thank Kim Retera, Ph.D., VU Medical Center, Amsterdam, for Biacore analysis support. This work was supported by grants from the IOP Genomics Senter [IGE05005], the National Institutes of Health (NIH AG021084 and AG005134) and by the Centre for Medical Systems Biology within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). NR 30 TC 10 Z9 11 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD OCT PY 2011 VL 32 IS 10 BP 1774 EP 1783 DI 10.1016/j.neurobiolaging.2009.11.012 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 815SZ UT WOS:000294551000005 PM 20015576 ER PT J AU Costanza, A Weber, K Gandy, S Bouras, C Hof, PR Giannakopoulos, P Canuto, A AF Costanza, A. Weber, K. Gandy, S. Bouras, C. Hof, P. R. Giannakopoulos, P. Canuto, A. TI Contact sport-related chronic traumatic encephalopathy in the elderly: clinical expression and structural substrates SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Review DE Alzheimer's disease; boxing; chronic traumatic encephalopathy; contact sports; frontotemporal dementia; traumatic brain injuries ID AMYOTROPHIC-LATERAL-SCLEROSIS; BETA-AMYLOID PROTEIN; NEUROFIBRILLARY TANGLE DISTRIBUTION; REPETITIVE HEAD-INJURY; BRAIN-INJURY; ALZHEIMERS-DISEASE; DEMENTIA-PUGILISTICA; PARKINSONISM-DEMENTIA; PROFESSIONAL BOXERS; COGNITIVE IMPAIRMENT AB Professional boxers and other contact sport athletes are exposed to repetitive brain trauma that may affect motor functions, cognitive performance, emotional regulation and social awareness. The term of chronic traumatic encephalopathy (CTE) was recently introduced to regroup a wide spectrum of symptoms such as cerebellar, pyramidal and extrapyramidal syndromes, impairments in orientation, memory, language, attention, information processing and frontal executive functions, as well as personality changes and behavioural and psychiatric symptoms. Magnetic resonance imaging usually reveals hippocampal and vermis atrophy, a cavum septum pellucidum, signs of diffuse axonal injury, pituitary gland atrophy, dilated perivascular spaces and periventricular white matter disease. Given the partial overlapping of the clinical expression, epidemiology and pathogenesis of CTE and Alzheimer's disease (AD), as well as the close association between traumatic brain injuries (TBIs) and neurofibrillary tangle formation, a mixed pathology promoted by pathogenetic cascades resulting in either CTE or AD has been postulated. Molecular studies suggested that TBIs increase the neurotoxicity of the TAR DNA-binding protein 43 (TDP-43) that is a key pathological marker of ubiquitin-positive forms of frontotemporal dementia (FTLD-TDP) associated or not with motor neurone disease/amyotrophic lateral sclerosis (ALS). Similar patterns of immunoreactivity for TDP-43 in CTE, FTLD-TDP and ALS as well as epidemiological correlations support the presence of common pathogenetic mechanisms. The present review provides a critical update of the evolution of the concept of CTE with reference to its neuropathological definition together with an in-depth discussion of the differential diagnosis between this entity, AD and frontotemporal dementia. C1 [Giannakopoulos, P.] Univ Hosp, Dept Psychiat, CH-1225 Geneva, Switzerland. [Giannakopoulos, P.] Univ Geneva, Fac Med, CH-1225 Geneva, Switzerland. [Costanza, A.; Weber, K.; Bouras, C.; Canuto, A.] Univ Geneva, Sch Med, Dept Psychiat, CH-1225 Geneva, Switzerland. [Giannakopoulos, P.] Hosp CHUV, Div Old Age Psychiat, Dept Psychiat, Lausanne, Switzerland. [Gandy, S.] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Gandy, S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Gandy, S.; Hof, P. R.] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY USA. [Gandy, S.] James J Peters VA Med Ctr, Bronx, NY USA. [Hof, P. R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. RP Giannakopoulos, P (reprint author), Univ Hosp, Dept Psychiat, CH-1225 Geneva, Switzerland. EM panteleimon.giannakopoulos@unige.ch FU NIH [AG02219, AG05138] FX We thank all the technical staff members of the Division of Neuropsychiatry of the University of Geneva Hospitals for expert assistance. This work was supported in part by NIH grants AG02219 and AG05138 (P.R.H., S.G.). NR 151 TC 44 Z9 44 U1 1 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0305-1846 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD OCT PY 2011 VL 37 IS 6 BP 570 EP 584 DI 10.1111/j.1365-2990.2011.01186.x PG 15 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 819KZ UT WOS:000294825300001 PM 21696410 ER PT J AU Teich, AF Hedley-Whyte, ET Goldman, JE AF Teich, A. F. Hedley-Whyte, E. T. Goldman, J. E. TI 'Pontinization' of the medulla: two clinical case studies SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Letter ID PONTINE GRAY; NUCLEI; RAT; MIGRATION; BRAIN C1 [Teich, A. F.; Goldman, J. E.] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10027 USA. [Teich, A. F.; Goldman, J. E.] New York Presbyterian Hosp, New York, NY USA. [Hedley-Whyte, E. T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol Neuropathol, Boston, MA USA. RP Teich, AF (reprint author), Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10027 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0305-1846 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD OCT PY 2011 VL 37 IS 6 BP 689 EP 693 DI 10.1111/j.1365-2990.2011.01171.x PG 5 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 819KZ UT WOS:000294825300011 PM 21450049 ER PT J AU Hauck, EF Natarajan, SK Ohta, H Ogilvy, CS Hopkins, LN Siddiqui, AH Levy, EI AF Hauck, Erik F. Natarajan, Sabareesh K. Ohta, Hajime Ogilvy, Christopher S. Hopkins, L. Nelson Siddiqui, Adnan H. Levy, Elad I. TI Emergent Endovascular Recanalization for Cervical Internal Carotid Artery Occlusion in Patients Presenting With Acute Stroke SO NEUROSURGERY LA English DT Article DE Carotid occlusion; Carotid stent; Intracranial stenting; Ischemic stroke ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS THROMBOLYSIS AB BACKGROUND: Acute proximal (cervical) internal carotid artery (ICA) occlusion may cause ischemia of an entire hemisphere or no ischemia at all, depending on the presence of intracranial collaterals. OBJECTIVE: To retrospectively analyze the clinical results for emergent endovascular carotid recanalization in patients with acute proximal (cervical) ICA occlusion and to assess predictors of recanalization and clinical, neurological, and functional outcome. METHODS: Emergent endovascular revascularization was attempted in 22 patients presenting with acute stroke secondary to complete cervical ICA occlusion. Patients with pseudo-occlusion were excluded. Recanalization was assessed with the Thrombolysis in Myocardial Ischemia (TIMI) system: grade 0 (no flow) to grade 3 (normal flow). RESULTS: The median age of the patients was 65 years; mean admission National Institutes of Health Stroke Scale (NIHSS) score was 14. Recanalization (TIMI grade 2/3) occurred in 17 patients (77.3%). Ten patients (45.5%) demonstrated significant clinical improvement during hospitalization (NIHSS improved >= 4 points). Fifty percent of patients had good outcomes (modified Rankin Scale <= 2) after a median follow-up of 3 months. Patient age <70 years and successful recanalization (TIMI grade 2/3) predicted a good outcome (P <= .01). Presence of atrial fibrillation, admission NIHSS score >= 20, and complete ICA occlusion at all levels (cervical, petrocavernous, and intracranial) were associated with poor outcomes (P <= .05). Patients with complete cervical ICA occlusion but partial distal preservation of the vessel were most likely to benefit from the intervention (recanalization in 88.2%; good outcome in 64.7%). CONCLUSION: Attempts at emergent endovascular carotid recanalization for acute stroke are encouraged, particularly in younger patients with partial distal preservation of the ICA. C1 [Hauck, Erik F.; Natarajan, Sabareesh K.; Ohta, Hajime; Ogilvy, Christopher S.; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Neurosurg, Buffalo, NY 14260 USA. [Hauck, Erik F.; Natarajan, Sabareesh K.; Ohta, Hajime; Ogilvy, Christopher S.; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Toshiba Stroke Res Ctr, Buffalo, NY 14260 USA. [Natarajan, Sabareesh K.; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Radiol, Buffalo, NY 14260 USA. [Hauck, Erik F.; Natarajan, Sabareesh K.; Ohta, Hajime; Ogilvy, Christopher S.; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] Millard Fillmore Gates Hosp, Dept Neurosurg, Buffalo, NY USA. [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. RP Levy, EI (reprint author), SUNY Buffalo, Millard Fillmore Gates Hosp, 3 Gates Circle, Buffalo, NY 14209 USA. EM elevy@ubns.com FU Toshiba; Boston Scientific; Codman Shurtleff, Inc; ev3/Covidien Vascular Therapies; Abbott Vascular; National Institutes of Health [NINDS 1R01NS064592-01A1]; University at Buffalo FX Dr Hopkins receives grant/research support from Toshiba; serves as a consultant to Abbott, Boston Scientific, Cordis, Micrus, and W. L. Gore; holds a financial interest in AccessClosure, Augmenix, Boston Scientific,* Claret Medical Inc., Micrus, and Valor Medical; has a board/trustee/officer position with AccessClosure, Claret Medical Inc., and Micrus (until September, 2010); belongs to the Abbott Vascular speakers' bureau; and receives honoraria from Bard, Boston Scientific, Cordis, Memorial Healthcare System, Complete Conference Management, SCAI, and Cleveland Clinic. Dr Levy receives research grant support (principal investigator, Stent-Assisted Recanalization in Acute Ischemic Stroke), other research support (devices), and honoraria from Boston Scientific and research support from Codman & Shurtleff, Inc and ev3/Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc; serves as a consultant for Codman & Shurtleff, Inc, ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. Dr Ogilvy serves as a consultant to Mizuoho America Inc. Dr Siddiqui has received research grants from the National Institutes of Health (coinvestigator, NINDS 1R01NS064592-01A1, Hemodynamic Induction of Pathologic Remodeling Leading to Intracranial Aneurysms) and the University at Buffalo (Research Development Award); holds financial interests in Hotspur, Intratech Medical, StimSox, and Valor Medical; serves as a consultant to Codman & Shurtleff, Inc, Concentric Medical, ev3/Covidien Vascular Therapies, GuidePoint Global Consulting, and Penumbra; belongs on the speakers' bureaus of Codman & Shurtleff, Inc and Genentech; serves on an advisory board for Codman & Shurtleff; and has received honoraria from American Association of Neurological Surgeons' courses, an Emergency Medicine Conference, Genentech, and Neocure Group LLC and from Abbott Vascular, and Codman & Shurtleff, Inc. for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. NR 22 TC 20 Z9 21 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD OCT PY 2011 VL 69 IS 4 BP 899 EP 907 DI 10.1227/NEU.0b013e31821cfa52 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 817OV UT WOS:000294684600063 PM 21499144 ER PT J AU Lopez-Olivo, MA Landon, GC Siff, SJ Edelstein, D Pak, C Kallen, MA Stanley, M Zhang, H Robinson, KC Suarez-Almazor, ME AF Lopez-Olivo, Maria A. Landon, Glenn C. Siff, Sherwin J. Edelstein, David Pak, Chong Kallen, Michael A. Stanley, Melinda Zhang, Hong Robinson, Kausha C. Suarez-Almazor, Maria E. TI Psychosocial determinants of outcomes in knee replacement SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID QUALITY-OF-LIFE; TOTAL JOINT ARTHROPLASTY; SHORT-TERM RECOVERY; TOTAL HIP; FUNCTIONAL OUTCOMES; SELF-EFFICACY; SURGERY; OSTEOARTHRITIS; PAIN; POPULATION AB Objective To identify potential psychosocial and educational barriers to clinical success following knee replacement. Patients and Methods The authors evaluated 241 patients undergoing total knee replacement, preoperatively and 6 months after surgery. Outcomes included the Western Ontario McMaster (WOMAC) scale and the Knee Society rating system (KSRS). Independent variables included: the medical outcome study-social support scale; depression, anxiety and stress scale; brief COPE inventory; health locus of control; arthritis self-efficacy scale and the life orientation test-revised. Multiple regression models evaluated associations of baseline demographic and psychosocial variables with outcomes at 6 months, controlling for body mass index, comorbidities and baseline outcome scores. Results Patients' mean age was 65 +/- 9 years; 65% were women. Most patients improved outcomes after surgery. Several psychosocial variables were associated with outcomes. Regression analyses indicated lower education, less tangible support, depression, less problem-solving coping, more dysfunctional coping, lower internal locus of control were associated with worse WOMAC scores (R 2 contribution of psychosocial variables for pain 0.07; for function, 0.14). Older age, lower education, depression and less problem-solving coping were associated with poorer total KSRS scores (R 2 contribution of psychosocial variables to total KSRS model 0.09). Psychosocial variables as a set contributed from 25% to 74% of total explained variance across the models tested. Conclusion Patients' level of education, tangible support, depression, problem-solving coping, dysfunctional coping and internal locus of control were associated with pain and functional outcomes after knee replacement. The findings suggest that, in addition to medical management, perioperative psychosocial evaluation and intervention are crucial in enhancing knee replacement outcomes. C1 [Suarez-Almazor, Maria E.] Univ Texas MD Anderson Canc Ctr, Unit 1467, Houston, TX 77030 USA. [Landon, Glenn C.; Siff, Sherwin J.; Edelstein, David] St Lukes Episcopal Hlth Syst, Houston, TX USA. [Stanley, Melinda] Dept Vet Affairs Med Ctr, Houston VA HSR&D Ctr Excellence, Hlth Serv Res & Dev Serv, Houston, TX USA. [Stanley, Melinda] Baylor Coll Med, Houston, TX 77030 USA. [Stanley, Melinda] VA S Cent Mental Illness Res, Educ & Clin Ctr, N Little Rock, AR USA. RP Suarez-Almazor, ME (reprint author), Univ Texas MD Anderson Canc Ctr, Unit 1467, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM msalmazor@mdanderson.org FU National Institute for Arthritis, Musculoskeletal and Skin Disorders (NIAMS) [R01 AR48662]; Agency for Healthcare Research and Quality; VA HSR&D Houston Center of Excellence [HFP-90-020] FX This study was supported by a grant from the National Institute for Arthritis, Musculoskeletal and Skin Disorders (NIAMS; R01 AR48662). MES-A is the recipient of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders. She is also the Director of the Houston Center for Education and Research on Therapeutics, funded by the Agency for Healthcare Research and Quality. It was also partly supported by the VA HSR&D Houston Center of Excellence (HFP-90-020). The views expressed are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs/Baylor College of Medicine. MES-A has received honoraria from Zimmer as a speaker at the 2010 Summit on Musculoskeletal Health Disparities. NR 47 TC 47 Z9 47 U1 1 U2 16 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2011 VL 70 IS 10 BP 1775 EP 1781 DI 10.1136/ard.2010.146423 PG 7 WC Rheumatology SC Rheumatology GA 814XX UT WOS:000294491600013 PM 21791452 ER PT J AU Chen, YB Driscoll, JP McAfee, SL Spitzer, TR Rosenberg, ES Sanders, R Moss, RB Fang, F Marty, FM AF Chen, Yi-Bin Driscoll, Jessica P. McAfee, Steven L. Spitzer, Thomas R. Rosenberg, Eric S. Sanders, Rebecca Moss, Ronald B. Fang, Fang Marty, Francisco M. TI Treatment of Parainfluenza 3 Infection With DAS181 in a Patient After Allogeneic Stem Cell Transplantation SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID RESPIRATORY VIRUS-INFECTIONS; SIALIDASE FUSION PROTEIN; RECIPIENTS; DIAGNOSIS; THERAPY AB Parainfluenza virus (PIV) can cause significant morbidity after allogeneic stem cell transplantation (SCT). We report the first use of inhaled DAS181 for PIV in an allogeneic SCT recipient. Symptoms, oxygenation, and pulmonary function tests improved. Nasopharyngeal samples showed a reduction in viral load. DAS181 should be systematically evaluated for severe PIV infection. C1 [Chen, Yi-Bin; Driscoll, Jessica P.; McAfee, Steven L.; Spitzer, Thomas R.] Massachusetts Gen Hosp, Bone Marrow Transplant Unit, Boston, MA 02114 USA. [Rosenberg, Eric S.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Sanders, Rebecca; Moss, Ronald B.; Fang, Fang] NexBio, San Diego, CA USA. [Marty, Francisco M.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Marty, Francisco M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Bone Marrow Transplant Unit, Cox 108,55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org NR 12 TC 27 Z9 27 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD OCT 1 PY 2011 VL 53 IS 7 BP E77 EP E80 DI 10.1093/cid/cir501 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 815AJ UT WOS:000294498200005 PM 21880586 ER PT J AU Spain, R Bourdette, D AF Spain, Rebecca Bourdette, Dennis TI The Radiologically Isolated Syndrome: Look (Again) Before You Treat SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Multiple sclerosis/diagnosis; Multiple sclerosis/therapy; Magnetic resonance imaging; Incidental findings; Brain/pathology; Disease progression; Radiologically isolated syndrome ID UNSUSPECTED MULTIPLE-SCLEROSIS; CLINICALLY ISOLATED SYNDROMES; DIAGNOSTIC-CRITERIA; FOLLOW-UP; DEMYELINATING LESIONS; INTERNATIONAL PANEL; PREDICT CONVERSION; MRI CRITERIA; DEFINITE; MS AB The advent and wide use of magnetic resonance brain imaging has led to in the unexpected detection of lesions that appear typical of multiple sclerosis (MS) in otherwise asymptomatic patients. Several cohorts of patients with the "radiologically isolated syndrome (RIS)" have been studied mainly retrospectively, and a proportion of them do go on to have clinical symptoms of MS. This has led to the not infrequent clinical conundrum of whether or not to treat patients with MRI lesions suggestive of MS, given the knowledge that MS disease-modifying therapies work best when given early in the disease course. However, the decision to proactively treat patients with RIS is countered by the increasing risks associated with MS disease-modifying therapies as well as the uncertain prognostic outcome of RIS. This review will highlight what is and is not known about the long-term outcomes of RIS and present recommendations for clinicians when faced with this challenging situation. C1 [Spain, Rebecca] Portland VA Med Ctr, Neurol Serv, Portland, OR 97239 USA. [Spain, Rebecca; Bourdette, Dennis] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. RP Spain, R (reprint author), Portland VA Med Ctr, Neurol Serv, Mail Code CR120,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM spainr@ohsu.edu FU Department of Veterans Affairs Rehabilitation Research & Development Service FX We thank Bronwyn Hamilton, MD, for sharing information about the prevalence of RIS among patients undergoing MRI for headache at Oregon Health & Science University. Dr. Spain has a Career Development Award from the Department of Veterans Affairs Rehabilitation Research & Development Service. NR 46 TC 10 Z9 12 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD OCT PY 2011 VL 11 IS 5 BP 498 EP 506 DI 10.1007/s11910-011-0213-z PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 814PH UT WOS:000294468700006 PM 21748263 ER PT J AU Cameron, MH Wagner, JM AF Cameron, Michelle H. Wagner, Joanne M. TI Gait Abnormalities in Multiple Sclerosis: Pathogenesis, Evaluation, and Advances in Treatment SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE 4-Aminopyridine; Accidental falls; Botulinum toxin; Electric stimulation; Gait; Multiple sclerosis; Rehabilitation; Gait abnormalities ID FUNCTIONAL ELECTRICAL-STIMULATION; LEG CYCLING EXERCISE; WALKING PERFORMANCE; RANDOMIZED-TRIAL; 6-MINUTE WALK; DOUBLE-BLIND; SPASTICITY; PEOPLE; COMPOSITE; CAPACITY AB Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by episodic decline in various neurologic functions. Gait dysfunction in MS is distinguished by decreased gait speed, walking endurance, step length, cadence and joint motion, as well as increased metabolic cost of walking and increased variability of gait. Standardized clinical, timed, and patient-based measures can identify MS patients with gait dysfunction, and observational gait analysis, instrumented walkways, or three-dimensional gait analysis can help determine which problem underlies their gait dysfunction to help direct effective treatment. Exercise may ameliorate all types of gait dysfunction. In addition, gait dysfunction due to weakness may be alleviated by orthoses or functional electrical stimulation; gait dysfunction due to spasticity may be relieved by oral, intrathecal, or intramuscular medications. Assistive devices and balance training may reduce gait dysfunction from imbalance, and dalfampridine may accelerate gait in people with MS who walk slowly. C1 [Cameron, Michelle H.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Cameron, Michelle H.] Portland VA Med Ctr, Portland, OR USA. [Wagner, Joanne M.] St Louis Univ, Dept Phys Therapy & Athlet Training, St Louis, MO 63104 USA. RP Cameron, MH (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,CR120, Portland, OR 97239 USA. EM cameromi@ohsu.edu; jwagne34@slu.edu FU Acorda; Rehabilitation Research & Development Service, Department of Veterans Affairs FX M.H. Cameron: has been a consultant for Innovative Neurotronics; has received grant support from Acorda; and has received a career development award from the Rehabilitation Research & Development Service, Department of Veterans Affairs; J.M. Wagner: none. NR 50 TC 31 Z9 31 U1 2 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD OCT PY 2011 VL 11 IS 5 BP 507 EP 515 DI 10.1007/s11910-011-0214-y PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 814PH UT WOS:000294468700007 PM 21779953 ER PT J AU Milanesi, A Brent, GA AF Milanesi, Anna Brent, Gregory A. TI Management of hypothyroidism in pregnancy SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Article DE hypothyroidism; pregnancy; thyroxine therapy ID MATERNAL THYROID-FUNCTION; IN-VITRO FERTILIZATION; SUBCLINICAL HYPOTHYROIDISM; SELENIUM SUPPLEMENTATION; LEVOTHYROXINE TREATMENT; IODINE DEFICIENCY; AUTOIMMUNE-THYROIDITIS; HORMONE CONCENTRATIONS; STIMULATING HORMONE; REFERENCE INTERVALS AB Purpose of review Examine recent studies on the assessment of thyroid status in pregnancy, approach to thyroid testing, the spectrum of hypothyroidism in pregnancy, and strategies for thyroid replacement in women with known hypothyroidism. Recent findings Trimester-specific references range for thyroid-stimulating hormone (TSH) and free thyroxine in pregnancy must take into account iodine and thyroid autoantibody status, race, BMI, as well as other factors. Thyroid testing of only those pregnant women at increased risk for thyroid disease, case finding, will miss 30-80% of women with thyroid disease. Subclinical hypothyroidism is associated with an increasing number of adverse effects including infertility, miscarriage, preterm delivery, and breech presentation at birth. Many pregnant women with known hypothyroidism have an out-of-range TSH at the time of confirmed pregnancy. A variety of strategies are effective at keeping serum TSH normal during pregnancy including preconception increase in thyroxine, increase in thyroxine dose at the time pregnancy is confirmed, or making adjustments based on serum TSH monitoring. Summary Evaluation of thyroid status in pregnancy requires an understanding of pregnancy-associated changes in thyroid function tests and how they vary by trimester. The spectrum of hypothyroidism in pregnancy includes isolated thyroid peroxidase antibody positivity, isolated hypothyroxinemia, subclinical and overt hypothyroidism. These patterns, in some situations, may be related to iodine status, selenium status, or underlying thyroid disease. There are a variety of approaches to management of thyroxine replacement in known hypothyroid women at the time of pregnancy that are all effective at maintaining a normal range during pregnancy. C1 [Milanesi, Anna; Brent, Gregory A.] VA Greater Los Angeles Healthcare Syst, Endocrinol & Diabet Div, Dept Med, Los Angeles, CA USA. [Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. RP Brent, GA (reprint author), 111 VA Greater Los Angeles Healthcare Syst, Dept Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM gbrent@ucla.edu FU VA Merit Review funds; Cedars Sinai Clinical Scholars Program FX G.A. Brent is supported by VA Merit Review funds. A. Milanesi is supported by the Cedars Sinai Clinical Scholars Program. NR 54 TC 8 Z9 10 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD OCT PY 2011 VL 18 IS 5 BP 304 EP 309 DI 10.1097/MED.0b013e32834a91d1 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 814KD UT WOS:000294448700004 PM 21841481 ER PT J AU LaRocque, RC Jentes, ES AF LaRocque, Regina C. Jentes, Emily S. TI Health recommendations for international travel: a review of the evidence base of travel medicine SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE evidence-based medicine; international travel; travel medicine ID RABIES POSTEXPOSURE PROPHYLAXIS; 4-DOSE VACCINE SCHEDULE; ILL RETURNED TRAVELERS; MALARIA CHEMOPROPHYLAXIS; IMMUNIZATION PRACTICES; ADVISORY-COMMITTEE; DIARRHEA; CHILDREN; TRIAL; SURVEILLANCE AB Purpose of review International travel is increasing, including travel to countries with emerging economies. Travel may pose health risks for the individual and contribute to the global spread of infectious diseases. The specialty of travel medicine is aimed at minimizing health risks associated with international travel. The field has emerged in the past 25 years, and the evidence base supporting its clinical practice is growing. This review will describe the evidence base underlying travel medicine, highlight recently updated travel medicine guidelines, and outline future research priorities. Recent findings Recommendations for a number of common vaccines for travelers have been updated recently. More sophisticated detection methods are leading to the identification of a wider spectrum of pathogens associated with travelers' diarrhea, and antibiotic resistance is increasingly being identified. New treatment options for malaria are available, and a fifth Plasmodium species causing disease in humans has been identified. Summary An evidence base for the practice of travel medicine is emerging. Expert opinion and consensus guidelines continue to play an important role in supporting clinical practice. C1 [LaRocque, Regina C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [LaRocque, Regina C.] Harvard Univ, Sch Med, Boston, MA USA. [Jentes, Emily S.] Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Atlanta, GA USA. RP LaRocque, RC (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Gray Jackson 520,55 Fruit St, Boston, MA 02114 USA. EM rclarocque@partners.org FU US Centers for Disease Control and Prevention [U19CI000514] FX R.C.L.R. is supported by funding from the US Centers for Disease Control and Prevention (U19CI000514). The authors are grateful to Dr Edward T. Ryan and Dr Phyllis Kozarsky for critical reading of the manuscript and to Robert Citorik for assistance with the figures. NR 48 TC 5 Z9 5 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD OCT PY 2011 VL 24 IS 5 BP 403 EP 409 DI 10.1097/QCO.0b013e32834a1aef PG 7 WC Infectious Diseases SC Infectious Diseases GA 814UD UT WOS:000294481800001 PM 21788892 ER PT J AU Charles, RC Ryan, ET AF Charles, Richelle C. Ryan, Edward T. TI Cholera in the 21st century SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE cholera; diarrhea; outbreak; vaccine; Vibrio cholerae ID VIBRIO-CHOLERAE; FIELD TRIAL; FOLLOW-UP; EL-TOR; BANGLADESH; INFECTION; EPIDEMIC; HAITI; TRANSMISSION; VACCINES AB Purpose of review This review will focus on recent advances in our understanding of biologic and environmental factors that shape current cholera outbreaks, advances in our understanding of host-pathogen interactions during cholera, and recent evolution of current treatment and cholera prevention strategies. Recent findings New research studies have improved our understanding of a number of dynamic factors that shape the ecology of Vibrio cholerae and influence its transmission, including the role of lytic bacteriophage, biofilm formation, a hyperinfectious state of human-passaged V. cholerae, and the impact of severe weather events. Provision of safe water and improved sanitation continue to be the mainstays of preventing cholera transmission; however, the role of cholera vaccination as a control measure in both endemic and epidemic settings is evolving. Recent advances in our understanding of long-lived protective immunity after natural infection may aid in the global efforts to control cholera. Summary Improved understanding of factors associated with protective immunity and dynamic factors associated with cholera outbreaks may lead to improved control and prevention strategies for cholera. C1 [Charles, Richelle C.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Charles, Richelle C.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM etryan@partners.org FU National Institute of Allergy and Infectious Diseases [AI077883, AI058935, AI089721]; MGH FX This work was supported by National Institute of Allergy and Infectious Diseases [AI077883 (ETR), AI058935 (ETR), AI089721 (RCC)] and a MGH Physician-Scientist Development Award (RCC). NR 61 TC 34 Z9 35 U1 8 U2 50 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD OCT PY 2011 VL 24 IS 5 BP 472 EP 477 DI 10.1097/QCO.0b013e32834a88af PG 6 WC Infectious Diseases SC Infectious Diseases GA 814UD UT WOS:000294481800011 PM 21799407 ER PT J AU Hammerness, PG Surman, CBH Chilton, A AF Hammerness, Paul G. Surman, Craig B. H. Chilton, Ashley TI Adult Attention-Deficit/Hyperactivity Disorder Treatment and Cardiovascular Implications SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE ADHD; Treatment; Adult; Medication; Stimulant; Cardiovascular ID DEFICIT-HYPERACTIVITY DISORDER; EXECUTIVE FUNCTION IMPAIRMENTS; PLACEBO-CONTROLLED TRIAL; RESTING HEART-RATE; REPORT SCALE ASRS; LONG-TERM; LISDEXAMFETAMINE DIMESYLATE; OROS METHYLPHENIDATE; EXTENDED-RELEASE; DOUBLE-BLIND AB Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder afflicting adults worldwide. This article is an update on the evidence supporting medications for adult ADHD, with particular emphasis on cardiovascular implications. Relevant clinical literature was sought using PubMed searches, with an emphasis on new reports from April 2009 to April 2011. This review describes the efficacy and general tolerability of stimulant and nonstimulant medications for adults with ADHD as seen in contemporary clinical trials. Cardiovascular response to medications for ADHD is primarily seen in heart rate and blood pressure elevations, while less is known about the etiology of rare cardiovascular events or long-term sequelae. Further research is indicated to delineate clinical and functional outcomes for adults with ADHD, as well as long-term safety of medication treatment. C1 [Hammerness, Paul G.; Surman, Craig B. H.; Chilton, Ashley] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Cambridge, MA 02138 USA. [Hammerness, Paul G.; Surman, Craig B. H.; Chilton, Ashley] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hammerness, PG (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, 185 Alewife Brook Pkwy,Suite 2000, Cambridge, MA 02138 USA. EM phammerness@partners.org FU National Institutes of Health; Hilda and Preston Davis Foundation; Cephalon; Eli Lilly and Company; ElMindA; GlaxoSmithKline; Johnson Johnson; McNeil; Merck Co.; New River Pharmaceuticals; Novartis; Ortho-McNeil-Janssen Pharmaceuticals; Pfizer; Shire; Takeda Pharmaceuticals North America; McNeil Pharmaceutical FX Dr. Surman has received research support from the National Institutes of Health and the Hilda and Preston Davis Foundation.; During the past 2 years, Dr. Hammerness has served on an advisory board for Shire; has received honoraria from Shire and Ortho-McNeil-Janssen Pharmaceuticals; and has received grant support from Cephalon, Eli Lilly and Company, ElMindA, GlaxoSmithKline, Johnson & Johnson, McNeil, Merck & Co., New River Pharmaceuticals, Novartis, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, Shire, and Takeda Pharmaceuticals North America.; Dr. Surman has served as a consultant for Shire and McNeil Pharmaceutical and received research support from Shire, Takeda Pharmaceuticals North America, and McNeil Pharmaceutical. NR 48 TC 11 Z9 11 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2011 VL 13 IS 5 BP 357 EP 363 DI 10.1007/s11920-011-0213-3 PG 7 WC Psychiatry SC Psychiatry GA 815CR UT WOS:000294504200008 PM 21698412 ER PT J AU Oliva, EM Maisel, NC Gordon, AJ Harris, AHS AF Oliva, Elizabeth M. Maisel, Natalya C. Gordon, Adam J. Harris, Alex H. S. TI Barriers to Use of Pharmacotherapy for Addiction Disorders and How to Overcome Them SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Pharmacotherapy; Pharmacologic interventions; Addiction; Substance dependence; Medication-assisted treatment; Substance abuse treatment; Alcohol; Opioids; Barriers; Facilitators ID SUBSTANCE-ABUSE TREATMENT; RANDOMIZED CONTROLLED-TRIALS; PSYCHIATRY WFSBP GUIDELINES; OPIOID-DEPENDENT PATIENTS; ALCOHOL-USE DISORDERS; BUPRENORPHINE TREATMENT; MAINTENANCE THERAPY; PRIMARY-CARE; TREATMENT ORGANIZATIONS; SUBSTITUTION TREATMENT AB Substance use disorders are highly prevalent, debilitating conditions for which effective pharmacotherapies exist with a broad evidence base, yet pharmacotherapy for the treatment of addiction disorders is underutilized. The goals of this review are to describe the barriers that may contribute to poor adoption and utilization of pharmacotherapy for alcohol and opioid dependence at the system, provider, and patient level and to discuss ways to overcome those barriers. Multifaceted efforts directed at all three levels may be needed to speed pharmacotherapy adoption. More research is needed to help us better understand barriers from patients' perspectives. Strategies to promote adoption of pharmacotherapy for addiction disorders should be modified to fit the needs of the practice, system, and individual patients. Pharmacotherapy is a valuable tool in the clinical armamentarium of addiction treatment; thus, overcoming barriers to implementation may improve clinical and social outcomes. C1 [Oliva, Elizabeth M.; Maisel, Natalya C.; Harris, Alex H. S.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Mental Hlth Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. [Gordon, Adam J.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA USA. RP Oliva, EM (reprint author), VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, 795 Willow Rd,Mailcode 152 MPD, Menlo Pk, CA 94025 USA. EM elizabeth.oliva@va.gov; natalya.maisel@va.gov; adam.gordon@va.gov; alexander.harris2@va.gov FU NIMH NIH HHS [R25 MH080916] NR 76 TC 26 Z9 26 U1 4 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD OCT PY 2011 VL 13 IS 5 BP 374 EP 381 DI 10.1007/s11920-011-0222-2 PG 8 WC Psychiatry SC Psychiatry GA 815CR UT WOS:000294504200010 PM 21773951 ER PT J AU Moscariello, A Takx, RAP Schoepf, UJ Renker, M Zwerner, PL O'Brien, TX Allmendinger, T Vogt, S Schmidt, B Savino, G Fink, C Bonomo, L Henzler, T AF Moscariello, Antonio Takx, Richard A. P. Schoepf, U. Joseph Renker, Matthias Zwerner, Peter L. O'Brien, Terrence X. Allmendinger, Thomas Vogt, Sebastian Schmidt, Bernhard Savino, Giancarlo Fink, Christian Bonomo, Lorenzo Henzler, Thomas TI Coronary CT angiography: image quality, diagnostic accuracy, and potential for radiation dose reduction using a novel iterative image reconstruction technique-comparison with traditional filtered back projection SO EUROPEAN RADIOLOGY LA English DT Article DE Iterative reconstruction; Coronary CT angiography; Image noise; Radiation dose; Image quality ID DUAL-SOURCE CT; SPIRAL COMPUTED-TOMOGRAPHY; ARTERY-DISEASE; TEMPORAL-RESOLUTION; CARDIAC CT; PERFORMANCE; NOISE; CHEST; METAANALYSIS AB Objectives To compare image noise, image quality and diagnostic accuracy of coronary CT angiography (cCTA) using a novel iterative reconstruction algorithm versus traditional filtered back projection (FBP) and to estimate the potential for radiation dose savings. Methods Sixty five consecutive patients (48 men; 59.3 +/- 7.7 years) prospectively underwent cCTA and coronary catheter angiography (CCA). Full radiation dose data, using all projections, were reconstructed with FBP. To simulate image acquisition at half the radiation dose, 50% of the projections were discarded from the raw data. The resulting half-dose data were reconstructed with sinogram-affirmed iterative reconstruction (SAFIRE). Full-dose FBP and half-dose iterative reconstructions were compared with regard to image noise and image quality, and their respective accuracy for stenosis detection was compared against CCA. Results Compared with full-dose FBP, half-dose iterative reconstructions showed significantly (p = 0.001 - p = 0.025) lower image noise and slightly higher image quality. Iterative reconstruction improved the accuracy of stenosis detection compared with FBP (per-patient: accuracy 96.9% vs. 93.8%, sensitivity 100% vs. 100%, specificity 94.6% vs. 89.2%, NPV 100% vs. 100%, PPV 93.3% vs. 87.5%). Conclusions Iterative reconstruction significantly reduces image noise without loss of diagnostic information and holds the potential for substantial radiation dose reduction from cCTA. C1 [Moscariello, Antonio; Takx, Richard A. P.; Schoepf, U. Joseph; Renker, Matthias; Zwerner, Peter L.; O'Brien, Terrence X.; Fink, Christian; Henzler, Thomas] Med Univ S Carolina, Heart & Vasc Ctr, Charleston, SC 29425 USA. [Moscariello, Antonio; Savino, Giancarlo; Bonomo, Lorenzo] Univ Cattolica Sacro Cuore, Dept Bioimaging & Radiol Sci, A Gemelli Hosp, I-00168 Rome, Italy. [Takx, Richard A. P.] Maastricht Univ Med Ctr, Dept Radiol, Maastricht, Netherlands. [O'Brien, Terrence X.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Allmendinger, Thomas; Schmidt, Bernhard] Siemens AG, Healthcare Sect, Forchheim, Germany. [Vogt, Sebastian] Siemens Med Solut USA, Malvern, PA USA. [Fink, Christian; Henzler, Thomas] Univ Heidelberg, Inst Clin Radiol & Nucl Med, Univ Med Ctr Mannheim, Med Fac Mannheim, Heidelberg, Germany. RP Schoepf, UJ (reprint author), Med Univ S Carolina, Heart & Vasc Ctr, Ashley River Tower,25 Courtenay Dr, Charleston, SC 29425 USA. EM schoepf@musc.edu FU Bayer-Schering; Bracco; General Electric, Medrad; Siemens; Department of Veterans Affairs FX UJS is a consultant for and receives research support from Bayer-Schering, Bracco, General Electric, Medrad, and Siemens. TA, SV, and BS are employees of Siemens Healthcare. The other authors have no conflict of interest to disclose.; This study was supported in part by the Research and Development Program of the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 36 TC 156 Z9 194 U1 1 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD OCT PY 2011 VL 21 IS 10 BP 2130 EP 2138 DI 10.1007/s00330-011-2164-9 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 814QD UT WOS:000294471100013 PM 21611758 ER PT J AU Macco, R Pelizzoni, I Arbel-Ornath, M Codazzi, F Zacchetti, D Bacskai, BJ Grohovaz, F AF Macco, R. Pelizzoni, I Arbel-Ornath, M. Codazzi, F. Zacchetti, D. Bacskai, B. J. Grohovaz, F. TI ASTROCYTIC RESPONSE TO OXIDATIVE STRESS: EVIDENCES FROM IN VITRO AND IN VIVO STUDIES SO GLIA LA English DT Meeting Abstract DE Astrocyte activation; Oxidative stress; In vivo two-photon microscopy C1 [Macco, R.; Pelizzoni, I; Codazzi, F.; Zacchetti, D.; Grohovaz, F.] Ist Sci San Raffaele, Div Neurosci, I-20132 Milan, Italy. [Arbel-Ornath, M.; Bacskai, B. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Arbel-Ornath, M.; Bacskai, B. J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S77 EP S77 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900299 ER PT J AU Vitte, J Chareyre, F Chareyre, B Bonne, NX Stemmer-Rachamimov, A Giovannini, M AF Vitte, J. Chareyre, F. Chareyre, B. Bonne, N. X. Stemmer-Rachamimov, A. Giovannini, M. TI SNF5 INACTIVATION IN P0 PERMISSIVE CELLS INITIATES FORMATION OF PERIPHERAL NERVE SHEATH TUMORS (PNST) WITH RHABDOID FEATURES SO GLIA LA English DT Meeting Abstract DE SMARCB1/Snf5/Ini1; Peripheral Nerve Sheath Tumors; Olfactory Ensheathing Cells C1 [Vitte, J.; Chareyre, F.; Chareyre, B.; Bonne, N. X.; Giovannini, M.] Ctr Neural Tumor Res, House Res Inst, Los Angeles, CA USA. [Stemmer-Rachamimov, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stemmer-Rachamimov, A.] Harvard Univ, Sch Med, Mol Neurooncol & Pathol Dept, Boston, MA USA. RI Vitte, Jeremie/B-9874-2017 OI Vitte, Jeremie/0000-0002-2567-7988 NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S97 EP S97 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900381 ER PT J AU Wegener, A Kerninon, C Deboux, C Maire, C Wegner, M Oumesmar, BN AF Wegener, A. Kerninon, C. Deboux, C. Maire, C. Wegner, M. Oumesmar, Nait B. TI FUNCTION OF THE B-HLH TRANSCRIPTION FACTOR OLIG2 IN OLIGODENDROCYTE DIFFERENTIATION SO GLIA LA English DT Meeting Abstract DE multiple sclerosis; OLIG2; oligodendrocyte differentiation C1 [Wegener, A.; Kerninon, C.; Deboux, C.; Oumesmar, Nait B.] Univ Paris 06, INSERM, Cellular & Mol Approaches Myelin Repair U975, F-75013 Paris, France. [Maire, C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Maire, C.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Wegner, M.] Inst Biochem, Erlangen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-1491 J9 GLIA JI Glia PD OCT PY 2011 VL 59 SU 1 BP S49 EP S49 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 811CF UT WOS:000294178900188 ER PT J AU Carter, EA Bonab, AA Goverman, J Paul, K Yerxa, J Tompkins, RG Fischman, AJ AF Carter, Edward A. Bonab, Ali A. Goverman, Jeremy Paul, Kasie Yerxa, John Tompkins, Ronald G. Fischman, Alan J. TI Evaluation of the antioxidant peptide SS31 for treatment of burn-induced insulin resistance SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE burn-injury; trauma; insulin-resistance; glucose-tolerance cold-stress; anti-oxidant oxidative stress; brown adipose tissue; oral glucose tolerance tests; mu PET; (18)FDG; SS31; SS20; reactive oxygen species ID OBESE ZUCKER RATS; ALPHA-LIPOIC ACID; OXIDATIVE STRESS; SKELETAL-MUSCLE; REPERFUSION INJURY; GLUCOSE-TRANSPORT; ADIPOSE-TISSUE; REDOX STATE; KINASE-B; CELL AB After severe burn injury and other major traumas, glucose tolerance tests demonstrate delayed glucose disposal. This 'diabetes of injury' could be explained by insulin deficiency, and several studies have shown that soon after trauma (ebb phase) insulin concentrations are reduced in the face of hyperglycemia. After resuscitation of trauma patients (flow phase), p-cell responsiveness normalizes and plasma insulin levels are appropriate or even higher than expected, however, glucose intolerance and hyperglycemia persist. In the acute care setting, several approaches have been used for treating insulin resistance, including insulin infusion, propranolol and glucagon-like-peptide-1 (GLP-1). Recently, it was demonstrated that a tetrapeptide with antioxidant properties D-Arg-Dmt-Lys-Phe-NH2 (SS31), but not its inactive analogue Phe-D-Arg-Phe-Lys-NH2 (SS20) attenuates insulin resistance in mice maintained on a high fat diet. In this report the effects of SS31 and SS20 on burn-induced insulin resistance was studied in mice. Oral glucose tolerance tests (OGTT) were performed in 4 groups of 6 mice with thermal injury with or without pre-treatment with SS31 or SS20 and sham controls. In addition, biodistribution of (18)FDG was measured in burned mice with and without SS31 treatment and shams (subsets of these animals were also studied by mu PET). For comparison purposes, groups of 6 cold-stressed mice with and without SS31 treatment were also studied. The results of these studies demonstrate that SS31 but not SS20 ameliorated burn-induced insulin resistance. In addition, SS31 treatment resulted in marked reduction in the increased (18)FDG uptake by brown adipose tissue (BAT) in burned but not cold-stressed animals; suggesting that the stressors act by different mechanisms. Overall, these studies confirmed that SS31 can be used to reverse burn-induced insulin resistance and provide a firm pre-clinical basis for future clinical trials of SS31 for the treatment of insulin resistance in patients with burn injury. C1 [Carter, Edward A.; Bonab, Ali A.; Goverman, Jeremy; Paul, Kasie; Yerxa, John; Tompkins, Ronald G.; Fischman, Alan J.] Shriners Hosp Children, Boston, MA 02114 USA. [Goverman, Jeremy; Paul, Kasie; Yerxa, John; Tompkins, Ronald G.; Fischman, Alan J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Carter, Edward A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Bonab, Ali A.] Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. [Carter, Edward A.; Bonab, Ali A.; Goverman, Jeremy; Tompkins, Ronald G.; Fischman, Alan J.] Harvard Univ, Sch Med, Boston, MA USA. RP Fischman, AJ (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM aajjff@gmail.com RI Yerxa, John/E-7252-2017 OI Yerxa, John/0000-0002-5283-3069 FU National Institutes of Health [2P50 GM21700-27A]; Shriners Hospitals for Children FX This study was supported in part by grants from the National Institutes of Health (2P50 GM21700-27A) and the Shriners Hospitals for Children. NR 50 TC 7 Z9 8 U1 0 U2 7 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD OCT PY 2011 VL 28 IS 4 BP 589 EP 594 DI 10.3892/ijmm.2011.752 PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 815NS UT WOS:000294532900016 PM 21805045 ER PT J AU Hwang, SJ Suh, MJ Yoon, JH Kim, MR Ryu, KS Nam, SW Donahoe, PK MacLaughlin, DT Kim, JH AF Hwang, Seong Jin Suh, Min Jung Yoon, Joo Hee Kim, Mee Ran Ryu, Ki Sung Nam, Suk Woo Donahoe, Patricia K. MacLaughlin, David T. Kim, Jang Heub TI Identification of characteristic molecular signature of Mullerian inhibiting substance in human HPV-related cervical cancer cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Mullerian inhibiting substance; anti-Mullerian hormone; Mullerian inhibiting substance type II receptor; CaSki cell line; DNA microarray; cell cycle ID HUMAN OVARIAN-CANCER; GENE-EXPRESSION; IN-VIVO; HEPATOCELLULAR-CARCINOMA; DEPENDENT KINASES; II RECEPTOR; GROWTH; HORMONE; PATHWAY; FAMILY AB Mullerian inhibiting substance (MIS), also known as anti-Mullerian hormone (AMH), is a member of the transforming growth factor-beta (TGF-beta) superfamily that plays an important role in the mesenchymal-epithelial interaction, cell growth and proliferation, extracellular matrix production and tissue remodeling. Previously, we demonstrated that MIS suppressed ovarian cancer cell growth and suggested large-scale genetic elements that could be responsible for anti-neoplastic effects of MIS on ovarian cancer cells. In this study, we demonstrated the expression of MIS type II receptor (MISRII) in the human papillomavirus (HPV)-16-related cervical cancer cell lines CaSki and Si Ha, and a non-HPV-related cervical cancer cell line, C33A. We also showed that MIS inhibited growth of cervical cancer cells, and induced cellular apoptosis of C33A. In addition, we identified a characteristic molecular signature of MIS in CaSki cells by using whole genome expression analysis. Of the 1,690 genes that showed significant expression changes by MIS, 21 genes were related to cell cycle; 13 genes to apoptosis; and 52 genes to the cancer pathway. On performing a search for cell cycle pathways in the KEGG pathway database, several gene expressions at the G(1)/S checkpoint were found. In particular, the expression of p16 and p107 increased and that of E2F2 and E2F3 decreased at an early stage, whereas the expression of E2F4 and E2F5 decreased at a later stage after MIS treatment. These data suggest that MIS produces activity against HPV16-related cervical cancers in vitro, and MIS may also be an effective targeted therapy for HPV16-related cervical cancer. Genetic data obtained here could be useful in determining the treatment strategy of MISR-expressing cervical tumors in the future. C1 [Hwang, Seong Jin; Suh, Min Jung; Yoon, Joo Hee; Kim, Mee Ran; Ryu, Ki Sung; Kim, Jang Heub] Catholic Univ Korea, Coll Med, Dept Obstet & Gynecol, Seoul 137701, South Korea. [Nam, Suk Woo] Catholic Univ Korea, Coll Med, Microdissect Genom Res Inst, Dept Pathol, Seoul 137701, South Korea. [Donahoe, Patricia K.; MacLaughlin, David T.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Donahoe, Patricia K.; MacLaughlin, David T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kim, JH (reprint author), Catholic Univ Korea, Coll Med, Dept Obstet & Gynecol, 505 Banpo Dong, Seoul 137701, South Korea. EM janghkim@catholic.ac.kr NR 28 TC 7 Z9 9 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD OCT PY 2011 VL 39 IS 4 BP 811 EP 820 DI 10.3892/ijo.2011.1042 PG 10 WC Oncology SC Oncology GA 815NU UT WOS:000294533100007 PM 21573503 ER PT J AU Pedrelli, P Iovieno, N Vitali, M Tedeschini, E Bentley, KH Papakostas, GI AF Pedrelli, Paola Iovieno, Nadia Vitali, Mario Tedeschini, Enrico Bentley, Kate H. Papakostas, George I. TI Treatment of Major Depressive Disorder and Dysthymic Disorder With Antidepressants in Patients With Comorbid Opiate Use Disorders Enrolled in Methadone Maintenance Therapy A Meta-Analysis SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antidepressant; placebo; major depressive disorder; opiate-use disorders; methadone maintenance therapy ID 2.5-YEAR FOLLOW-UP; EXCLUSION CRITERIA; CLINICAL-TRIALS; SUBSTANCE USE; DIAGNOSTIC CRITERIA; MAINTAINED PATIENTS; DEPENDENT PATIENTS; TREATMENT-SEEKING; EXCHANGE PROGRAM; PLACEBO-RESPONSE AB Depression and opiate-use disorders (abuse, dependence) often co-occur, each condition complicating the course and outcome of the other. It has been recommended that clinicians prescribe antidepressant therapy for mood symptoms in patients with active substance-use disorders, but whether antidepressants are effective in this specific population is not entirely clear. Therefore, the aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder (DD) with comorbid opiate-use disorders currently in methadone maintenance treatment (MMT). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the treatment of MDD/DD in patients with comorbid opiate-use disorders currently in MMT. The search was limited to articles published between January 1, 1980, and June 30, 2010 (inclusive). Four manuscripts were found eligible for inclusion in our analysis (n = 317 patients). We found no statistically significant difference in response rates between antidepressant and placebo therapy in trials of MDD/DD patients with comorbid opiate-use disorders currently in MMT (risk ratio for response, 1.182; 95% CI: 0.822-1.700; P = 0.366). These results show no difference in the depressive outcome of patients with comorbid opiate-use disorders on MMT whether they are on medication or placebo. Future studies examining the effectiveness of antidepressants while controlling for several variables such as psychosocial treatment and assessing the specific classes of antidepressants are needed. C1 [Pedrelli, Paola; Iovieno, Nadia; Vitali, Mario; Tedeschini, Enrico; Bentley, Kate H.; Papakostas, George I.] Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Iovieno, Nadia] Univ Pisa, Dept Psychiat, Pisa, Italy. [Vitali, Mario] Univ Roma La Sapienza, Dept Psychiat, Rome, Italy. [Tedeschini, Enrico] Univ Modena & Reggio Emilia, Dept Psychiat, Modena, Italy. RP Pedrelli, P (reprint author), Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, 1 Bowdoin Sq, Boston, MA 02114 USA. EM ppedrelli@partners.org RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 FU Bristol-Myers Squibb Company; Forest Pharmaceuticals; National Institute of Mental Health FX Drs Pedrelli, Iovieno, Vitali, and Tedeschini and Ms Bentley report no competing interests. Dr Papakostas has served as a consultant for AstraZeneca PLC, Bristol-Myers Squibb Company, Eli Lilly Company, GlaxoSmithKline, Evotec AG, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc, Pierre Fabre Laboratories, Shire Pharmaceuticals, and Wyeth, Inc; has received honoraria from AstraZeneca PLC, Bristol-Myers Squibb Company, Eli Lilly Company, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Shire Pharmaceuticals, Titan Pharmaceuticals, and Wyeth Inc; has received research support from Bristol-Myers Squibb Company, Forest Pharmaceuticals, and the National Institute of Mental Health; and has served on the speakers' bureau for Bristol-Myers Squibb Company and Pfizer, Inc. NR 40 TC 9 Z9 9 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2011 VL 31 IS 5 BP 582 EP 586 DI 10.1097/JCP.0b013e31822c0adf PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 814OU UT WOS:000294467300007 PM 21869696 ER PT J AU Evins, AE Pachas, G Mischoulon, D Urbanoski, K Carlini, S Sousa, J Bentley, K Rigotti, NA Nino-Gomez, J Loebl, T Janes, AC Kaufman, MJ Fava, M AF Evins, A. Eden Pachas, Gladys Mischoulon, David Urbanoski, Karen Carlini, Sara Sousa, Jessica Bentley, Kate Rigotti, Nancy A. Nino-Gomez, Johanna Loebl, Tsafrir Janes, Amy C. Kaufman, Marc J. Fava, Maurizio TI A Double-Blind, Placebo-Controlled Trial of the NMDA Glycine Site Antagonist, GW468816, for Prevention of Relapse to Smoking in Females SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE nicotine; smoking cessation; NMDA; glutamate; relapse prevention; glycine ID SUSTAINED-RELEASE BUPROPION; RANDOMIZED CONTROLLED-TRIAL; INDUCED DOPAMINE RELEASE; RECEPTOR PARTIAL AGONIST; VENTRAL TEGMENTAL AREA; PHYSICAL-DEPENDENCE; NUCLEUS-ACCUMBENS; GLUTAMATE RECEPTORS; MK-801 DIZOCILPINE; CHRONIC NICOTINE AB Relapse to smoking is common after initial abstinence with pharmacotherapy and behavioral support and represents a major clinical challenge. Although mechanisms underlying relapse to smoking have not been elucidated, preclinical studies suggest that glutamate receptors may be involved. We sought to test a selective antagonist of the glycine coagonist site on the glutamate N-methyl-D-aspartate receptor, GW468816, for prevention of relapse in recently abstinent smokers. To do so, we enrolled 264 healthy female smokers in an open 8-week smoking cessation intervention with behavioral therapy and a standard dose of transdermal nicotine replacement therapy with taper and additional gum or lozenge as needed for nicotine withdrawal symptoms. Ninety-eight participants achieved 7-day point prevalence abstinence and were randomized into a 5-week double-blind, placebo-controlled, relapse-prevention trial of GW468816 (200 mg/d) and then followed for 60 days after randomization. There was no effect of treatment on abstinence rates at the end of treatment (chi(2) [1, n = 96] = 0.168, P = 0.838), on the rates of relapse (chi(2) [1, n = 98] = 0.031, P = 1.000) or lapse (chi(2) [1, n = 62] = 0.802, P = 0.423), or on time to relapse (chi(2) [1, n = 98) = 0.001, P = 0.972). No significant relationships were detected between plasma GW468816 concentrations and abstinence, time to relapse, or self-reported craving. In conclusion, despite promising preclinical data that support the use of a selective NMDA glycine site antagonist for prevention of relapse to smoking, we observed no effect of GW468816 on relapse or lapse rates, time to relapse, or craving compared to placebo. C1 [Evins, A. Eden] Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, Boston, MA 02114 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Janes, Amy C.; Kaufman, Marc J.] McLean Hosp, Belmont, MA 02178 USA. RP Evins, AE (reprint author), Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, 60 Staniford St, Boston, MA 02114 USA. EM a_eden_evins@hms.harvard.edu RI Janes, Amy/A-5322-2013; OI Janes, Amy/0000-0002-3749-5006; Urbanoski, Karen/0000-0001-7287-7176 FU National Institute of Health [U01DA019378]; GlaxoSmithKline; Abbott Laboratories; Alkermes, Inc; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc; Bristol-Myers Squibb; Cephalon, Inc; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc; Euthymics Bioscience, Inc; Forest Pharmaceuticals, Inc; Ganeden Biotech, Inc; Icon Clinical Research; i3 Innovus/Ingenix; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; NARSAD; NCCAM; NIDA; NIMH; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc; Pharmavite(R) LLC; Photothera; Roche; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc; Synthelabo; Wyeth-Ayerst Pharmaceuticals, Inc; Transcept Pharmaceuticals, Inc; Vanda Pharmaceuticals, Inc.; Pfizer; Janssen; Nordic Naturals; Ganeden; Nabi Biopharmaceuticals FX This study was funded by National Institute of Health grant U01DA019378 and by research product and grant support from GlaxoSmithKline (Drs Evins, Kaufman, and Fava).; Dr Fava has received research support from: Abbott Laboratories; Alkermes, Inc; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc; Bristol-Myers Squibb; Cephalon, Inc; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc; Euthymics Bioscience, Inc; Forest Pharmaceuticals, Inc; Ganeden Biotech, Inc; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; NARSAD; NCCAM; NIDA; NIMH; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc; Pharmavite (R) LLC; Photothera; Roche; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc; Synthelabo; Wyeth-Ayerst Pharmaceuticals, Inc; Transcept Pharmaceuticals, Inc; and Vanda Pharmaceuticals, Inc.; Dr Evins has received research support from Pfizer, Janssen, GSK, and Aspect Medical Systems, and honoraria from Pfizer, Janssen, GSK and Boehringer Ingelheim. Dr Mischoulon has received research support from Nordic Naturals, and Ganeden; royalties from Back Bay Scientific and Lippincott Williams & Wilkins; and honoraria from Pamlab, Nordic Naturals, and Reed Medical Education. Dr Rigotti has received research grant support from Pfizer and Nabi Biopharmaceuticals and is an unpaid consultant for Pfizer and Free and Clear. Drs Pachas, Janes, Urbanoski, Nino-Gomez, Loebl and Ms Carlini, Sousa, and Bentley have none to disclose. NR 49 TC 5 Z9 5 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2011 VL 31 IS 5 BP 597 EP 602 DI 10.1097/JCP.0b013e31822bb390 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 814OU UT WOS:000294467300010 PM 21869693 ER PT J AU Borba, CPC Fan, X Copeland, PM Paiva, A Freudenreich, O Henderson, DC AF Borba, Christina P. C. Fan, Xiaoduo Copeland, Paul M. Paiva, Alexander Freudenreich, Oliver Henderson, David C. TI Placebo-Controlled Pilot Study of Ramelteon for Adiposity and Lipids in Patients With Schizophrenia SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE ramelteon; schizophrenia; obesity; insulin resistance; glucose metabolism ID FATTY-ACID-METABOLISM; GLUCOSE-TOLERANCE; INSULIN SENSITIVITY; VISCERAL ADIPOSITY; MELATONIN; SCALE; CHOLESTEROL; OLANZAPINE; DENSITY; QUALITY AB Objective: Few interventions have been successful to prevent or reverse the medical complications associated with antipsychotic agents in the schizophrenia population. In particular, no single agent can correct multiple metabolic abnormalities such as insulin resistance, hyperlipidemia, inflammation, obesity, and fat distribution. We now report a randomized placebo-controlled pilot study to examine the effects of ramelteon on obesity and metabolic disturbances among subjects with schizophrenia. Methods: A double-blind, placebo-controlled, 8-week pilot trial was conducted, adding ramelteon 8 mg/d to stable outpatients with schizophrenia. Vital signs and anthropometric measurements, including height, weight, waist circumference, and body fat were assessed, and laboratory assays were tracked to monitor changes in metabolic markers. Results: Twenty-five subjects were randomly assigned to treatment with study drug or placebo, and 20 subjects were included in the final analysis. Ramelteon did not improve anthropometric measurements, glucose metabolism, and inflammatory markers. There was, however, a significant decrease in total cholesterol and ratio of cholesterol to high-density lipoprotein in the ramelteon group. Although the standard anthropometric measures did not show significant change, the dual-energy x-ray absorptiometry scan showed a trend toward reduction in fat in the abdominal and trunk areas with a moderate effect size. Conclusions: Although ramelteon decreased cholesterol, treatment may have to be longer than 8 weeks and with a higher dose for maximal effect of ramelteon for body fat and lipid changes. Future studies are needed for patients with schizophrenia with a larger sample size to fully understand ramelteon's effects on abdominal adiposity and lipids. C1 [Borba, Christina P. C.; Fan, Xiaoduo; Paiva, Alexander; Freudenreich, Oliver; Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Borba, Christina P. C.; Fan, Xiaoduo; Copeland, Paul M.; Freudenreich, Oliver; Henderson, David C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Copeland, Paul M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Borba, CPC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. EM cborba@partners.org FU Takeda Pharmaceuticals North America, Inc; Harvard Clinical and Translational Science Center, National Center for Research Resources [M01-RR-01066, 1 UL1 RR025758-01] FX This study was funded by Takeda Pharmaceuticals North America, Inc, and supported by grant M01-RR-01066 and grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. NR 30 TC 16 Z9 16 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2011 VL 31 IS 5 BP 653 EP 658 DI 10.1097/JCP.0b013e31822bb573 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 814OU UT WOS:000294467300018 PM 21869685 ER PT J AU Mani, N Caiola, E Fortuna, RJ AF Mani, Nandini Caiola, Enrico Fortuna, Robert J. TI The Influence of Social Networks on Patients' Attitudes Toward Type II Diabetes SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Primary care; Disease management; Diabetes; Social network; Health outcomes ID GLYCEMIC CONTROL; PERCEIVED RISK; FAMILY; MELLITUS; ADULTS; WOMEN AB Social networks are increasingly recognized as important determinants of many chronic diseases, yet little data exist regarding the influence of social networks on diabetes. We surveyed diabetic patients to determine how social networks affect their overall level of concern regarding diabetes and its complications. We adapted a previously published instrument and surveyed 240 diabetic patients at two primary care practices. Patients recorded the number of family and friends who had diabetes and rated their level of concern about diabetes on a scale of 0% (no concern) to 100% (extremely concerned). Our primary outcome variable was patients' level of concern (< 75% or a parts per thousand yen75%). We developed logistic regression models to determine the effect of disease burden in patients' social networks on expressed level of concern about diabetes. We received 154 surveys (64% response rate). We found that for each additional family member with diabetes, patients expressed a greater level of concern about diabetes (AOR 1.5; 95% CI 1.2-2.0) and its potential complications (AOR 1.4; 95% CI 1.1-1.7). Similarly, patients with an increased number of friends with diabetes expressed greater concern about diabetes (AOR 1.5; 95% CI 1.2-1.9) and its complications (AOR 1.3; 95% CI 1.1-1.7). Patients with a higher prevalence of diabetes within their social networks expressed greater concern about diabetes and diabetic complications. Determining disease burden within patients' social networks may allow physicians to better understand patients' perspectives on their disease and ultimately help them achieve meaningful behavioral change. C1 [Mani, Nandini] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Revere, MA 02151 USA. [Mani, Nandini] MGH Revere Hlth Care Ctr, Revere, MA 02151 USA. [Caiola, Enrico; Fortuna, Robert J.] Univ Rochester, Sch Med & Dent, Ctr Primary Care, Culver Med Grp, Rochester, NY 14609 USA. RP Mani, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 300 Ocean Ave, Revere, MA 02151 USA. EM nmani1@partners.org; Enrico_Caiola@urmc.rochester.edu; Robert_Fortuna@urmc.rochester.edu NR 12 TC 2 Z9 2 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 J9 J COMMUN HEALTH JI J. Community Health PD OCT PY 2011 VL 36 IS 5 BP 728 EP 732 DI 10.1007/s10900-011-9366-6 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 812MS UT WOS:000294298200006 PM 21298473 ER PT J AU Prerau, MJ Eden, UT AF Prerau, Michael J. Eden, Uri T. TI A General Likelihood Framework for Characterizing the Time Course of Neural Activity SO NEURAL COMPUTATION LA English DT Article ID SPIKE TRAIN DATA; CROSS-VALIDATION; NONPARAMETRIC REGRESSION; NEURONS; KERNEL; PATTERNS; INFORMATION; HIPPOCAMPUS; PREDICTION; DISCHARGE AB We develop a general likelihood-based framework for use in the estimation of neural firing rates, which is designed to choose the temporal smoothing parameters that maximize the likelihood of missing data. This general framework is algorithm-independent and thus can be applied to a multitude of established methods for firing rate or conditional intensity estimation. As a simple example of the use of the general framework, we apply it to the peristimulus time histogram and kernel smoother, the methods most widely used for firing rate estimation in the electrophysiological literature and practice. In doing so, we illustrate how the use of the framework can employ the general point process likelihood as a principled cost function and can provide substantial improvements in estimation accuracy for even the most basic of rate estimation algorithms. In particular, the resultant kernel smoother is simple to implement, efficient to compute, and can accurately determine the bandwidth of a given rate process from individual spike trains. We perform a simulation study to illustrate how the likelihood framework enables the kernel smoother to pick the bandwidth parameter that best predicts missing data, and we show applications to real experimental spike train data. Additionally, we discuss how the general likelihood framework may be used in conjunction with more sophisticated methods for firing rate and conditional intensity estimation and suggest possible applications. C1 [Prerau, Michael J.; Eden, Uri T.] Boston Univ, Grad Program Neurosci, Boston, MA 02215 USA. [Eden, Uri T.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Prerau, MJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. EM prerau@nmr.mgh.harvard.edu; tzvi@bu.edu FU National Science Foundation [IIS-0643995] FX This work was supported by the National Science Foundation under grant number IIS-0643995. We thank Paul Lipton and Howard Eichenbaum for the use of the experimental data. NR 44 TC 3 Z9 3 U1 1 U2 2 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD OCT PY 2011 VL 23 IS 10 BP 2537 EP 2566 PG 30 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA 815SR UT WOS:000294549600004 PM 21732865 ER PT J AU Ghomi, RH Bredella, MA Thomas, BJ Miller, KK Torriani, M AF Ghomi, Reza Hosseini Bredella, Miriam A. Thomas, Bijoy J. Miller, Karen K. Torriani, Martin TI Modular MR-compatible lower leg exercise device for whole-body scanners SO SKELETAL RADIOLOGY LA English DT Article DE Exercise; Ergometer; MR-compatible ID IN-VIVO MRS; CALF MUSCLE; ERGOMETER AB To develop a modular MR-compatible lower leg exercise device for muscle testing using a clinical 3 T MR scanner. An exercise device to provide isotonic resistance to plantar- or dorsiflexion was constructed from nonferrous materials and designed for easy setup and use in a clinical environment. Validation tests were performed during dynamic MR acquisitions. For this purpose, the device was tested on the posterior lower leg musculature of five subjects during 3 min of exercise at 30% of maximum voluntary plantarflexion during 31-phosphorus MR spectroscopy (P-31-MRS). Measures of muscle phosphocreatine (PCr), inorganic phosphate (Pi), and pH were obtained before, during, and after the exercise protocol. At the end of exercise regimen, muscle PCr showed a 28% decrease from resting levels (to 21.8 +/- 3.9 from 30.4 +/- 3.0 mM) and the average PCr recovery rate was 35.3 +/- 8.3 s. Muscle Pi concentrations increased 123% (to 14.6 +/- 4.7 from 6.5 +/- 3.3 mM) and pH decreased 1.5% (to 7.06 +/- 0.14 from 7.17 +/- 0.07) from resting levels. The described MR-compatible lower leg exercise was an effective tool for data acquisition during dynamic MR acquisitions of the calf muscles. The modular design allows for adaptation to other whole-body MR scanners and incorporation of custom-built mechanical or electronic interfaces and can be used for any MR protocol requiring dynamic evaluation of calf muscles. C1 [Ghomi, Reza Hosseini; Bredella, Miriam A.; Thomas, Bijoy J.; Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ghomi, Reza Hosseini; Bredella, Miriam A.; Thomas, Bijoy J.; Miller, Karen K.; Torriani, Martin] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@hms.harvard.edu OI Hosseini Ghomi, Reza/0000-0003-4369-8237 FU National Institutes of Health [RO1 HL-077674, UL1 RR025758, K23 RR-23090] FX This work was supported in part by National Institutes of Health Grants RO1 HL-077674, UL1 RR025758, and K23 RR-23090. NR 17 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 EI 1432-2161 J9 SKELETAL RADIOL JI Skeletal Radiol. PD OCT PY 2011 VL 40 IS 10 BP 1349 EP 1354 DI 10.1007/s00256-011-1098-2 PG 6 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 813DH UT WOS:000294346500013 ER PT J AU Antonescu, CR Zhang, L Nielsen, GP Rosenberg, AE Dal Cin, P Fletcher, CDM AF Antonescu, Cristina R. Zhang, Lei Nielsen, G. Petur Rosenberg, Andrew E. Dal Cin, Paola Fletcher, Christopher D. M. TI Consistent t(1;10) with Rearrangements of TGFBR3 and MGEA5 in Both Myxoinflammatory Fibroblastic Sarcoma and Hemosiderotic Fibrolipomatous Tumor SO GENES CHROMOSOMES & CANCER LA English DT Article ID RING CHROMOSOMES; SOFT-TISSUE; GROWTH; LESION; CELLS; GENE AB Despite their shared predilection for superficial soft tissue of distal extremities and frequent local recurrences, myxoinflammatory fibroblastic sarcoma (MIFS) and hemosiderotic fibrolipomatous tumor (HFLT) have distinct morphologic appearances. Recent studies have identified an identical t(1; 10)(p22; q24) in five cases of MIFS and two of HFLT, as well as common amplifications on 3p11-12. To investigate further their potential relationship and to determine the incidence of t(1; 10) in a larger cohort, we subjected seven MIFS, 14 HFLT, and three cases with mixed morphology, to molecular and cytogenetic analysis. Fluorescence in situ hybridization (FISH) analysis for rearrangements of TGFBR3 on 1p22 and of MGEA5 on 10q24 was performed in all cases, whereas the status of VGLL3 gene amplification on 3p12.1 was investigated in 12 cases. Conventional karyotyping was performed in one HFLT and two cases with mixed MIFS/HFLT histology. Overall 83% of cases showed rearrangements in both TGFBR3 and MGEA5. All three cases with mixed features of MIFS and HFLT were positive. Cytogenetic analysis performed in three cases confirmed an unbalanced der(10) t(1; 10)(p22; q24). VGLL3 gene amplification was noted in 10/12 cases of both histologies. The high incidence of t(1; 10) in MIFS and HFLT reinforces a shared pathogenetic relationship. Furthermore, the co-existence of both components either synchronously or metachronously in a primary or subsequent recurrence, suggest either different morphologic variants or different levels of tumor progression of a single biologic entity. FISH analysis for TGFBR3 and MGEA5 rearrangements can be applied as a reliable diagnostic molecular test when confronted with limited material or a challenging diagnosis. (C) 2011 Wiley-Liss, Inc. C1 [Antonescu, Cristina R.; Zhang, Lei] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Nielsen, G. Petur; Rosenberg, Andrew E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dal Cin, Paola; Fletcher, Christopher D. M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Antonescu, CR (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM antonesc@mskcc.org; cfletcher@partners.org FU [PO1 CA047179-15A2]; [P50 CA140146-01] FX Supported by: PO1 CA047179-15A2 (CRA), P50 CA140146-01 (CRA). NR 22 TC 41 Z9 44 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD OCT PY 2011 VL 50 IS 10 BP 757 EP 764 DI 10.1002/gcc.20897 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 811BQ UT WOS:000294177300001 PM 21717526 ER PT J AU Fang, A Asnaani, A Gutner, C Cook, C Wilhelm, S Hofmann, SG AF Fang, Angela Asnaani, Anu Gutner, Cassidy Cook, Courtney Wilhelm, Sabine Hofmann, Stefan G. TI Rejection sensitivity mediates the relationship between social anxiety and body dysmorphic concerns SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Dysmorphic concern; Social anxiety; Rejection sensitivity ID PSYCHOMETRIC PROPERTIES; SELF-REPORT; DSM-V; DISORDER; PREVALENCE; SCALE AB The goal of this study was to examine the role of rejection sensitivity in the relationship between social anxiety and body dysmorphic concerns. To test our hypothesis that rejection sensitivity mediates the link between social anxiety and body dysmorphic concerns, we administered self-report questionnaires to 209 student volunteers. Consistent with our prediction, rejection sensitivity partially mediated the relationship between social anxiety symptoms and body dysmorphic concerns. The implications of the overlap between these constructs are discussed. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Hofmann, Stefan G.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Wilhelm, Sabine] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hofmann, SG (reprint author), Boston Univ, Dept Psychol, 648 Beacon St,6th Floor, Boston, MA 02215 USA. EM shofmann@bu.edu RI Hofmann, Stefan/B-8769-2014 OI Hofmann, Stefan/0000-0002-3548-9681 FU NIMH NIH HHS [R01 MH078308, R01 MH078308-04] NR 30 TC 16 Z9 16 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD OCT PY 2011 VL 25 IS 7 BP 946 EP 949 DI 10.1016/j.janxdis.2011.06.001 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 810CH UT WOS:000294102500013 PM 21741203 ER PT J AU Yoo, JJ Bichara, DA Zhao, X Randolph, MA Gill, TJ AF Yoo, Jeong Joon Bichara, David A. Zhao, Xing Randolph, Mark A. Gill, Thomas J. TI Implant-assisted meniscal repair in vivo using a chondrocyte-seeded flexible PLGA scaffold SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE meniscal tear; meniscal healing; articular chondrocytes; PLGA mesh ID VICRYL MESH; LIGAMENT AUGMENTATION; MECHANICAL-PROPERTIES; ENGINEERED CARTILAGE; FOLLOW-UP; TISSUE; MENISCECTOMY; KNEE; RECONSTRUCTION; PROLIFERATION AB A cell-based engineered construct can be used for healing of intractable meniscal lesions. Our aims were to assess the culture conditions (static versus dynamic oscillation) and the healing capacity of the chondrocyte-seeded flexible implants in a heterotopic mouse model. Swine articular chondrocytes were labeled with PKH 26 or DiI dye and seeded onto a flexible PLGA scaffold using dynamic oscillating conditions for 24 h. Half of cell-seeded scaffolds were cultured in the same dynamic conditions, while the remaining scaffolds were cultured statically. After 7 days, scaffolds were placed between swine meniscal discs and were implanted subcutaneously in nude mice for 6 weeks. Additional constructs for assessing in vivo cell tracking were implanted for 12 weeks. Live/dead assays demonstrated labeled chondrocytes attached throughout the scaffold in both culture conditions. DNA measurements showed no significant difference between the culture conditions. A continuous fibro-cartilaginous healing tissue was observed between meniscal discs in all 12 dynamically cultured constructs and 9 of 11 statically cultured ones. There was no evidence of meniscal healing using acellular scaffold as well as in meniscal constructs lacking an implant. Both PKH 26- and DiI-labeled cells were identified along the healing interface. We conclude the chondrocyte-seeded flexible PLGA implants induce healing of meniscal discs in nude mice. Culture conditions after seeding have no apparent effects on healing. (C) 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 99A: 102-108, 2011. C1 [Yoo, Jeong Joon; Bichara, David A.; Zhao, Xing; Randolph, Mark A.; Gill, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Lab Musculoskeletal Tissue En, Boston, MA USA. [Yoo, Jeong Joon] Seoul Natl Univ, Coll Med, Dept Orthopaed Surg, Seoul, South Korea. [Randolph, Mark A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Plast Surg Res Lab,Div Plast Surg, Boston, MA USA. RP Randolph, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Lab Musculoskeletal Tissue En, Boston, MA USA. EM marandolph@partners.org RI Yoo, Jeong Joon/J-5553-2012 FU Musculoskeletal Transplantation Foundation FX Contract grant sponsor: The Musculoskeletal Transplantation Foundation NR 34 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1549-3296 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD OCT PY 2011 VL 99A IS 1 BP 102 EP 108 DI 10.1002/jbm.a.33168 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 811VG UT WOS:000294243600012 PM 21800420 ER PT J AU Mahon, MJ AF Mahon, Matthew J. TI Apical membrane segregation of phosphatidylinositol-4,5-bisphosphate influences parathyroid hormone 1 receptor compartmental signaling and localization via direct regulation of ezrin in LLC-PK1 cells SO CELLULAR SIGNALLING LA English DT Article DE Ezrin; Parathyroid hormone; Parathyroid hormone receptor; Phosphatidylinositol-4.5-bisphosphate; Phospholipase; LLC-PK1 ID EZRIN/RADIXIN/MOESIN ERM PROTEINS; CARBOXYL-TERMINAL REGION; PHOSPHOLIPASE-C-BETA; ACTIN-BINDING-SITE; PLASMA-MEMBRANE; 4-PHOSPHATE 5-KINASE; PHOSPHATE-TRANSPORT; KIDNEY-CELLS; DOMAIN; ASSOCIATION AB The parathyroid hormone 1 receptor (PTH1R), a primary regulator of mineral ion homeostasis, is expressed on both the apical and basolateral membranes of kidney proximal tubules and in the LLC-PK1 kidney cell line. In LLC-PK1 cells, apical PTH1R subpopulations are far more effective at signaling via phospholipase (PLC) than basolateral counterparts, revealing the presence of compartmental signaling. Apical PTH1R localization is dependent upon direct interactions with ezrin, an actin-membrane cross-linking scaffold protein. Ezrin undergoes an activation process that is dependent upon phosphorylation and binding to phosphatidylinositol-4,5-bisphosphate (PIP2), a lipid that is selectively concentrated to apical surfaces of polarized epithelia. Consistently, the intracellular probe for PIP2, GFP-PLC delta 1-PH, localizes to the apical membranes of LLC-PK1 cells, directly overlapping ezrin and PTH1R expression. Activation of the apical PTH1R shifts the GFP-PLC delta 1-PH probe from the apical membrane to the cytosol and basolateral membranes, reflecting domain-specific activation of PLC and hydrolysis of PIP2. This compartmental signaling is likely due to the polarized localization of PIP2, the substrate for PLC. PIP2 degradation using a membrane-directed phosphatase shifts ezrin localization to the cytosol and induces ezrin de-phosphorylation, processes consistent with inactivation. PIP2 degradation also shifts PTH1R expression from brush border microvilli to basolateral membranes and markedly blunts PTH-elicited activation of the MAPK pathway. Transient expression of ezrin in HEK293 cells shifts PTH1R expression from the plasma membrane to microvilli-like surface projections that also contain PIP2. As a result, ezrin enhances PTH mediated activation of the PLC pathway in this cell model with increasing total receptor surface expression. Collectively, these findings demonstrate that the apical segregation of PIP2 to the apical domains not only promotes the activation of ezrin and the subsequent formation of the PTH1R containing scaffold, but also ensures the presence of ample substrate for propagating the PLC pathway. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mahon, Matthew J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Mahon, Matthew J.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. RP Mahon, MJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Their 10, Boston, MA 02114 USA. EM mahon@helix.mgh.harvard.edu FU NIH [P01 DK073911] FX This study was funded by a program project grant from the NIH (P01 DK073911) to Dr. John Potts. Thanks to Dr. Tamas Balla and Monique Arpin for providing invaluable reagents. NR 54 TC 1 Z9 1 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2011 VL 23 IS 10 BP 1659 EP 1668 DI 10.1016/j.cellsig.2011.05.020 PG 10 WC Cell Biology SC Cell Biology GA 809FW UT WOS:000294038200018 PM 21672629 ER PT J AU Schapira, L Schutt, R AF Schapira, Lidia Schutt, Russell TI Training Community Health Workers About Cancer Clinical Trials SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Cancer; Clinical trials; Disparities; Community health workers ID BREAST-CANCER; MEDICAL-RESEARCH; PARTICIPATION; POPULATIONS; CARE; RECRUITMENT; DISPARITIES; VOLUNTEERS; KNOWLEDGE; AMERICANS AB Innovative projects to reduce disparities in cancer treatment and research include partnerships between academic and community cancer centers, patient navigation programs and strategies to promote community awareness, education and engagement. A 4 h training program about cancer clinical trials was developed through a needs assessment and in collaboration with community health workers who served as consultants and a larger advisory board comprised of community health workers, educators and clinical trialists. This program was delivered first as a collaboration between a phsycian who is experienced in the conduct of clinical research and two community health workers, and subsequently by the community health workers alone. We report on four workshops attended by a total of 61 community health workers recruited from Boston-area hospitals, community health centers and outreach programs. Support for and knowledge of clinical trials was measured in a pretest and post-test, which also included a satisfaction rating. Participants had a range of prior experience with clinical trials in the context of their personal and professional experience. Mean accuracy of knowledge about clinical trials increased from 72 to 84%, support for clinical trials improved considerably, and satisfaction with the training experience was high. Knowledge gaps and low levels of support for cancer clinical trials among community health workers can be improved with a short training program delivered by other community health workers. Further research is needed to identify the impact of this training on accrual to cancer clinical trials. C1 [Schapira, Lidia] Massachusetts Gen Hosp, Boston, MA 02214 USA. [Schutt, Russell] Univ Massachusetts, Dept Sociol, Boston, MA 02125 USA. RP Schapira, L (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02214 USA. EM lschapira@partners.org FU NCI NIH HHS [1U56CA118641-01] NR 37 TC 5 Z9 5 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD OCT PY 2011 VL 13 IS 5 BP 891 EP 898 DI 10.1007/s10903-010-9432-7 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 806ZN UT WOS:000293857400012 PM 21181445 ER PT J AU Kelly, JF Hoeppner, BB Urbanoski, KA Slaymaker, V AF Kelly, John F. Hoeppner, Bettina B. Urbanoski, Karen A. Slaymaker, Valerie TI Predicting relapse among young adults: Psychometric validation of the advanced warning of relapse (AWARE) scale SO ADDICTIVE BEHAVIORS LA English DT Article DE Substance use relapse; Young adults; Psychometrics ID ALCOHOL DEPENDENCE; FIT INDEXES; NUMBER; ABUSE; ADOLESCENTS; COMPONENTS; RECOVERY; DURATION; SIGNS AB Objective: Failure to maintain abstinence despite incurring severe harm is perhaps the key defining feature of addiction. Relapse prevention strategies have been developed to attenuate this propensity to relapse, but predicting who will, and who will not, relapse has stymied attempts to more efficiently tailor treatments according to relapse risk profile. Here we examine the psychometric properties of a promising relapse risk measure-the Advance WArning of RElapse (AWARE) scale (Miller & Harris, 2000) in an understudied but clinically important sample of young adults. Method: Inpatient youth (N = 303: Ages 18-24; 26% female) completed the AWARE scale and the Brief Symptom Inventory-18 (BSI) at the end of residential treatment, and at 1-, 3-, and 6-months following discharge. Internal and convergent validity was tested for each of these four timepoints using confirmatory factor analysis and correlations (with BSI scores). Predictive validity was tested for relapse 1, 3, and 6 months following discharge, as was incremental utility, where AWARE scores were used as predictors of any substance use while controlling for treatment entry substance use severity and having spent time in a controlled environment following treatment. Results: Confirmatory factor analysis revealed a single, internally consistent, 25-item factor that demonstrated convergent validity and predicted subsequent relapse alone and when controlling for other important relapse risk predictors. Conclusions: The AWARE scale may be a useful and efficient clinical tool for assessing short-term relapse risk among young people and, thus, could serve to enhance the effectiveness of relapse prevention efforts. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kelly, John F.; Hoeppner, Bettina B.; Urbanoski, Karen A.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Slaymaker, Valerie] Hazelden Fdn, Butler Ctr Res, Ctr City, MN 55012 USA. RP Kelly, JF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, 60 Staniford St, Boston, MA 02114 USA. EM jkelly11@partners.org; bhoeppner@partners.org; kurbanoski@partners.org; VSlaymaker@Hazelden.org OI Urbanoski, Karen/0000-0001-7287-7176 FU NIAAA [1R21AA018185-01A2]; NIDA [1K01DA027097-01A1] FX This work was supported by the NIAAA Grant Number # 1R21AA018185-01A2 and NIDA Grant Number #1K01DA027097-01A1. NIH had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 34 TC 4 Z9 4 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD OCT PY 2011 VL 36 IS 10 BP 987 EP 993 DI 10.1016/j.addbeh.2011.05.013 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 801ZZ UT WOS:000293480400006 PM 21700396 ER PT J AU Genkinger, JM Spiegelman, D Anderson, KE Bernstein, L van den Brandt, PA Calle, EE English, DR Folsom, AR Freudenheim, JL Fuchs, CS Giles, GG Giovannucci, E Horn-Ross, PL Larsson, SC Leitzmann, M Mannisto, S Marshall, JR Miller, AB Patel, AV Rohan, TE Stolzenberg-Solomon, RZ Verhage, BAJ Virtamo, J Willcox, BJ Wolk, A Ziegler, RG Smith-Warner, SA AF Genkinger, Jeanine M. Spiegelman, Donna Anderson, Kristin E. Bernstein, Leslie van den Brandt, Piet A. Calle, Eugenia E. English, Dallas R. Folsom, Aaron R. Freudenheim, Jo L. Fuchs, Charles S. Giles, Graham G. Giovannucci, Edward Horn-Ross, Pamela L. Larsson, Susanna C. Leitzmann, Michael Mannisto, Satu Marshall, James R. Miller, Anthony B. Patel, Alpa V. Rohan, Thomas E. Stolzenberg-Solomon, Rachael Z. Verhage, Bas A. J. Virtamo, Jarmo Willcox, Bradley J. Wolk, Alicja Ziegler, Regina G. Smith-Warner, Stephanie A. TI A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; anthropometry; pooled analysis; deceased ID BODY-MASS INDEX; LARGE US COHORT; PHYSICAL-ACTIVITY; ALCOHOL-CONSUMPTION; UNITED-STATES; GLYCEMIC INDEX; OBESITY; WEIGHT; HEIGHT; WOMEN AB Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2), pancreatic cancer risk was 47% higher (95% CI:23-75%) among obese (BMI >= 30 kg/m(2)) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI >= 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2)). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2)) and not obese at baseline (BMI < 30 kg/m(2)), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI >= 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer. C1 [Genkinger, Jeanine M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Spiegelman, Donna; Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Anderson, Kristin E.; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, Kristin E.; Folsom, Aaron R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA 91010 USA. [van den Brandt, Piet A.; Verhage, Bas A. J.] Maastricht Univ, Dept Epidemiol, Sch Oncol & Dev Biol GROW, Maastricht, Netherlands. [Calle, Eugenia E.; Patel, Alpa V.] Amer Canc Soc, Atlanta, GA 30329 USA. [English, Dallas R.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [English, Dallas R.; Giles, Graham G.] Univ Melbourne, Melbourne, Vic, Australia. [Freudenheim, Jo L.; Marshall, James R.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Fuchs, Charles S.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, Charles S.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward; Smith-Warner, Stephanie A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Horn-Ross, Pamela L.] No Calif Canc Ctr, Fremont, CA USA. [Larsson, Susanna C.; Wolk, Alicja] Karolinska Inst, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. [Leitzmann, Michael; Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Leitzmann, Michael] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Mannisto, Satu; Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Willcox, Bradley J.] Univ Hawaii, John A Burns Sch Med, Manoa, HI USA. [Willcox, Bradley J.] Okinawa Res Ctr Longev Sci, Okinawa, Japan. [Willcox, Bradley J.] Pacific Hlth Res Inst, Honolulu, HI USA. [Willcox, Bradley J.] Queens Med Ctr, Honolulu, HI USA. [Ziegler, Regina G.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Genkinger, JM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St, New York, NY 10032 USA. EM jg3081@columbia.edu RI Larsson, Susanna/F-6065-2015; OI Larsson, Susanna/0000-0003-0118-0341; Mannisto, Satu/0000-0002-8668-3046; Giles, Graham/0000-0003-4946-9099; English, Dallas/0000-0001-7828-8188 FU National Institutes of Health [CA098566, CA55075] FX Grant sponsor: National Institutes of Health; Grant numbers: CA098566 and CA55075 NR 44 TC 70 Z9 71 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2011 VL 129 IS 7 BP 1708 EP 1717 DI 10.1002/ijc.25794 PG 10 WC Oncology SC Oncology GA 798XX UT WOS:000293246600017 PM 21105029 ER PT J AU Evers, K Noens, I Steyaert, J Wagemans, J AF Evers, Kris Noens, Ilse Steyaert, Jean Wagemans, Johan TI Combining strengths and weaknesses in visual perception of children with an autism spectrum disorder: Perceptual matching of facial expressions SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism spectrum disorder (ASD); Matching; Facial emotional expressions; Compensation strategy; Weak central coherence; Enhanced perceptual functioning ID PERVASIVE DEVELOPMENTAL DISORDERS; FACE PROCESSING SKILLS; WEAK CENTRAL COHERENCE; ASPERGER-SYNDROME; EMOTION RECOGNITION; PEOPLE; FIXATION; DEFICITS; MIND; INDIVIDUALS AB Background: Children with an autism spectrum disorder (ASD) are known to have an atypical visual perception, with deficits in automatic Gestalt formation and an enhanced processing of visual details. In addition, they are sometimes found to have difficulties in emotion processing. Methods: In three experiments, we investigated whether 7-to-11-year old children with ASD were showing superiorities or deficits in matching tasks that required focusing on faces with an emotional expression. Throughout these experiments, we increased the complexity of the stimuli and tasks demands. Results and conclusions: In matching faces with emotional expressions, children with ASD were not able to show superior processing of details in any of the three experiments. They were able to compensate their inferior processing of emotions in some of the experiments (e.g., by using a slower, more sequential processing style). However, when stimulus complexity (e.g., dynamic facial expressions) or task demands (e.g., extracting and remembering the relevant stimulus dimension) increased, they were no longer able to do so, and they did show performance deficits. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Evers, Kris; Wagemans, Johan] Univ Leuven KU Leuven, Expt Psychol Lab, B-3000 Louvain, Belgium. [Evers, Kris; Steyaert, Jean] Univ Leuven KU Leuven, Dept Neurosci, B-3000 Louvain, Belgium. [Noens, Ilse] Univ Leuven KU Leuven, Ctr Parenting & Special Educ, B-3000 Louvain, Belgium. [Noens, Ilse] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Steyaert, Jean] Univ Hosp Maastricht, Maastricht, Netherlands. RP Wagemans, J (reprint author), Univ Leuven KU Leuven, Expt Psychol Lab, Tiensestr 102,Bus 3711, B-3000 Louvain, Belgium. EM johan.wagemans@psy.kuleuven.be RI Steyaert, Jean/B-5326-2015 OI Steyaert, Jean/0000-0003-2512-4694 NR 67 TC 10 Z9 11 U1 5 U2 32 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD OCT-DEC PY 2011 VL 5 IS 4 BP 1327 EP 1342 DI 10.1016/j.rasd.2011.01.004 PG 16 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 785NL UT WOS:000292235600006 ER PT J AU Van Eylen, L Boets, B Steyaert, J Evers, K Wagemans, J Noens, I AF Van Eylen, Lien Boets, Bart Steyaert, Jean Evers, Kris Wagemans, Johan Noens, Ilse TI Cognitive flexibility in autism spectrum disorder: Explaining the inconsistencies? SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism spectrum disorders; Cognitive flexibility; Task-switching; Wisconsin Card Sorting Task; Disengagement; Task instructions ID HIGH-FUNCTIONING AUTISM; CARD SORTING TEST; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; EXECUTIVE FUNCTION; CENTRAL COHERENCE; YOUNG-CHILDREN; PERFORMANCE; DEFICITS; TASK; SET AB The Wisconsin Card Sorting Task (WCST) is the only cognitive flexibility task that has consistently shown deficits in individuals with an autism spectrum disorder (ASD). As this is the only task characterized by limited explicit task instructions and a high degree of disengagement required to perform the switch, we hypothesized that cognitive flexibility deficits of individuals with ASD might only become apparent in situations fulfilling these requirements. However, the WCST involves various additional cognitive processes besides switching, making it uncertain whether difficulties are indeed due to cognitive flexibility impairments. The aim of this study was to investigate whether individuals with ASD show cognitive flexibility impairments on a more controlled task-switching variant of the WCST, still fulfilling both requirements. We therefore developed such a task and administered it to 40 high-functioning children with ASD and 40 age- and IQ- matched typically developing controls. As predicted, individuals with ASD made more perseveration errors and had a significantly higher switch cost than typically developing controls, but they performed equally well on the control measures. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Van Eylen, Lien; Noens, Ilse] Katholieke Univ Leuven, Parenting & Special Educ Res Grp, Louvain, Belgium. [Van Eylen, Lien; Evers, Kris; Wagemans, Johan] Katholieke Univ Leuven, Expt Psychol Lab, Louvain, Belgium. [Noens, Ilse] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Steyaert, Jean] Univ Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands. RP Van Eylen, L (reprint author), Univ Hosp Leuven, Dept Child Psychiat, Herestr 49,Box 7003, B-3000 Louvain, Belgium. EM Lien.VanEylen@ped.kuleuven.be RI Steyaert, Jean/B-5326-2015 OI Steyaert, Jean/0000-0003-2512-4694 NR 57 TC 27 Z9 28 U1 9 U2 53 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD OCT-DEC PY 2011 VL 5 IS 4 BP 1390 EP 1401 DI 10.1016/j.rasd.2011.01.025 PG 12 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 785NL UT WOS:000292235600013 ER PT J AU Lin, HW Silver, AL Cunnane, ME Sadow, PM Kieff, DA AF Lin, Harrison W. Silver, Amanda L. Cunnane, Mary E. Sadow, Peter M. Kieff, David A. TI Lateral dermoid cyst of the floor of mouth: Unusual radiologic and pathologic findings SO AURIS NASUS LARYNX LA English DT Article DE Dermoid; Neck mass; Neoplasm; Head and neck imaging; Head and neck pathology ID MASSES AB A lateral dermoid cyst is a rare lesion of the floor of mouth, with only 12 cases reported in the literature. We describe the case of a 60-year-old man with a slowly enlarging mass in the submandibular region. Magnetic resonance imaging demonstrated a lesion containing multiple uniformly rounded foci, creating a "sack-of-marbles" appearance. Needle aspirations showed atypical findings, and the mass was excised. Histopathology revealed a cyst containing a keratinizing stratified squamous epithelial lining with apocrine and eccrine glands. These findings were diagnostic of a dermoid cyst, which should be considered in the differential diagnosis of any midline or lateral cervical lesion. (c) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Lin, Harrison W.; Silver, Amanda L.; Kieff, David A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Cunnane, Mary E.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lin, Harrison W.; Silver, Amanda L.; Kieff, David A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Cunnane, Mary E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lin, HW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM harrison_lin@meei.harvard.edu NR 8 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0385-8146 J9 AURIS NASUS LARYNX JI Auris Nasus Larynx PD OCT PY 2011 VL 38 IS 5 BP 650 EP 653 DI 10.1016/j.anl.2011.01.002 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 762HG UT WOS:000290465200017 PM 21334151 ER PT J AU Kang, JH Wiggs, JL Haines, J Abdrabou, W Pasquale, LR AF Kang, Jae Hee Wiggs, Janey L. Haines, Jonathan Abdrabou, Wael Pasquale, Louis R. TI Reproductive factors and NOS3 variant interactions in primary open-angle glaucoma SO MOLECULAR VISION LA English DT Article ID HORMONE REPLACEMENT THERAPY; OXIDE SYNTHASE GENE; HUMOR OUTFLOW FACILITY; MESHWORK CELL-VOLUME; NITRIC-OXIDE; INTRAOCULAR-PRESSURE; TRABECULAR MESHWORK; RELAXING FACTOR; BLOOD-FLOW; VITREOUS CONCENTRATION AB Purpose: To investigate whether associations with the nitric oxide synthase gene (NOS3) variants and risk of primary open-angle glaucoma (POAG) depend on female reproductive factors. Methods: Two functional and two tagging single nucleotide polymorphisms (SNPs; T-786C: rs2070744, Glu298Asp: rs1799983, rs7830, and rs3918188) were evaluated in a nested case-control study from the Nurses' Health Study (women followed 1980 - 2002). Participants were aged >= 40 years and Caucasian, who were followed biennially with update information on reproductive factors. We included 374 Nurses' Health Study (NHS) cases and 1,085 controls, matched on age and eye exam at the matched cases' diagnosis dates. Relative risks (RRs) were estimated using multivariable conditional logistic regression. Results: Among women with age at menarche <13 years, compared with the CC homozygotes of the rs3918188 tagging SNP, the wild-type AA homozygotes were at significantly reduced risk of POAG (RR=0.31, 95% CI=0.16, 0.59); however, for women with age at menarche >= 13 years, the SNP was not associated with POAG (p-interaction=0.0007). Among parous women with 3+ children, carriers of the minor variant (T) allele of the functional Glu298Asp SNP were at increased risk, while among parous women with 1-2 children, they were not (p-interaction=0.003). No significant interactions between NOS3 SNPs and oral contraceptive use in POAG were detected. Conclusions: These data provide further support for the notion that NOS3 genotype - female reproductive health interactions are important in POAG pathogenesis. C1 [Wiggs, Janey L.; Abdrabou, Wael; Pasquale, Louis R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Kang, Jae Hee; Pasquale, Louis R.] Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02114 USA. [Kang, Jae Hee; Pasquale, Louis R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Haines, Jonathan] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. RP Pasquale, LR (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM Louis_Pasquale@meei.harvard.edu RI Haines, Jonathan/C-3374-2012 FU National Institutes of Health [CA87969, CA49449, CA055075, EY09611, HL35464, EY015473]; Wyeth Pharmaceuticals; Research to Prevent Blindness; Harvard Glaucoma Center of Excellence; Margolis Foundation FX This work was supported by grants CA87969, CA49449, CA055075, EY09611, HL35464, and EY015473 from the National Institutes of Health. Jae Hee Kang has received research funding (2008-2009) from Wyeth Pharmaceuticals. Louis R. Pasquale is also supported by a Research to Prevent Blindness Physician Scientist award in New York City. This work is also supported by the Harvard Glaucoma Center of Excellence (L. R. P., J.L.W.) and by the Margolis Foundation (L. R. P.). The authors have no proprietary or commercial interest in any materials discussed in this paper. We are indebted to the participants and staff of the Nurses' Health Study. NR 46 TC 9 Z9 9 U1 0 U2 1 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 30 PY 2011 VL 17 IS 275 BP 2544 EP 2551 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 833MT UT WOS:000295890300001 PM 22025889 ER PT J AU Lochner, C Stein, DJ Woods, D Pauls, DL Franklin, ME Loerke, EH Keuthen, NJ AF Lochner, Christine Stein, Dan J. Woods, Douglas Pauls, David L. Franklin, Martin E. Loerke, Elizabeth H. Keuthen, Nancy J. TI The validity of DSM-IV-TR criteria B and C of hair-pulling disorder (trichotillomania): Evidence from a clinical study SO PSYCHIATRY RESEARCH LA English DT Article DE Trichotillomania; Diagnostic criteria; DSM; Hair-pulling ID MGH HAIRPULLING SCALE; PHENOMENOLOGY; IMPAIRMENT; DISABILITY AB In both DSM-IV-TR and the ICD-10, hair-pulling disorder (trichotillomania, or TTM) is described as hair-pulling, with a rising urge or tension prior to pulling or when attempting to resist, and pleasure, relief or gratification during or after pulling. However, it has been questioned whether all patients with hair-pulling experience these other phenomena, and whether they occur with all pulling episodes. The objective of this study was to examine the DSM-IV-TR requirement of criteria B and C for a diagnosis of TTM in a sample of people with hair-pulling. A multi-site sample of adults with hair-pulling who met both DSM-IV-TR diagnostic criteria B and C (n=82.89.13%) were compared to those who failed to satisfy both B and C (n=10, 10.87%) on a number of clinical variables. There were no differences in hair-pulling severity, levels of comorbid depressive and anxiety symptoms, number of comorbid body-focused repetitive behaviors, or impairment between those patients who did and did not meet criteria B and C. Our study does not provide convincing support for the inclusion of the current diagnostic criteria B and C for TTM in DSM-5. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Lochner, Christine; Stein, Dan J.] Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7505 Tygerberg, South Africa. [Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Health, ZA-7925 Cape Town, South Africa. [Woods, Douglas] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Pauls, David L.; Loerke, Elizabeth H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA. [Pauls, David L.; Loerke, Elizabeth H.; Keuthen, Nancy J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Franklin, Martin E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Lochner, C (reprint author), POB 19063, ZA-7505 Tygerberg, South Africa. EM cl2@sun.ac.za RI Citations, TLC SAB/C-4006-2011; Stein, Dan/A-1752-2008 OI Stein, Dan/0000-0001-7218-7810 NR 22 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD SEP 30 PY 2011 VL 189 IS 2 BP 276 EP 280 DI 10.1016/j.psychres.2011.07.022 PG 5 WC Psychiatry SC Psychiatry GA 831RG UT WOS:000295748200020 PM 21813182 ER PT J AU Zhu, H Shyh-Chang, N Segre, AV Shinoda, G Shah, SP Einhorn, WS Takeuchi, A Engreitz, JM Hagan, JP Kharas, MG Urbach, A Thornton, JE Triboulet, R Gregory, RI Altshuler, D Daley, GQ AF Zhu, Hao Shyh-Chang, Ng Segre, Ayellet V. Shinoda, Gen Shah, Samar P. Einhorn, William S. Takeuchi, Ayumu Engreitz, Jesse M. Hagan, John P. Kharas, Michael G. Urbach, Achia Thornton, James E. Triboulet, Robinson Gregory, Richard I. Altshuler, David Daley, George Q. CA DIAGRAM Consortium MAGIC Investigators TI The Lin28/let-7 Axis Regulates Glucose Metabolism SO CELL LA English DT Article ID LET-7 MICRORNA FAMILY; HUMAN HEPATOCELLULAR-CARCINOMA; CAENORHABDITIS-ELEGANS; PROMOTES TRANSFORMATION; INSULIN-RESISTANCE; TRANSGENIC MICE; MESSENGER-RNA; STEM-CELLS; LIN-28; LIN28 AB The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, them TOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. C1 [Zhu, Hao; Shyh-Chang, Ng; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Daley, George Q.] Childrens Hosp, Stem Cell Transplantat Program, Stem Cell Program, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Zhu, Hao; Shyh-Chang, Ng; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA USA. [Zhu, Hao] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Zhu, Hao; Einhorn, William S.; Kharas, Michael G.; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Segre, Ayellet V.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Diabet Unit, Dept Med, Boston, MA 02114 USA. [Segre, Ayellet V.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Segre, Ayellet V.; Altshuler, David] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Engreitz, Jesse M.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Shyh-Chang, Ng; Hagan, John P.; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Hagan, John P.] Ohio State Univ, Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Daley, George Q.] Howard Hughes Med Inst, Boston, MA USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA USA. RP Daley, GQ (reprint author), Childrens Hosp, Stem Cell Transplantat Program, Stem Cell Program, Div Pediat Hematol Oncol, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Segre, Ayellet/E-9800-2010; Rudan, Igor/I-1467-2012; Singleton, Andrew/C-3010-2009; Colaus, PsyColaus/K-6607-2013; Altshuler, David/A-4476-2009; Palmer, Lyle/K-3196-2014; Boehm, Bernhard/F-8750-2015; Naitza, Silvia/D-5620-2017; Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Kyvik, Kirsten /K-5680-2016; Visvikis-Siest, Sophie/H-2324-2014; OI Rudan, Igor/0000-0001-6993-6884; Altshuler, David/0000-0002-7250-4107; Palmer, Lyle/0000-0002-1628-3055; Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Kyvik, Kirsten /0000-0003-2981-0245; Visvikis-Siest, Sophie/0000-0001-8104-8425; Jorgensen, Torben/0000-0001-9453-2830; Hagan, John/0000-0003-0295-4898; Kaprio, Jaakko/0000-0002-3716-2455; de Geus, Eco/0000-0001-6022-2666; Pichler, Irene/0000-0001-8251-0757; Magi, Reedik/0000-0002-2964-6011; Willems van Dijk, Ko/0000-0002-2172-7394; Zhu, Hao/0000-0002-8417-9698; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Kivimaki, Mika/0000-0002-4699-5627; Shyh-Chang, Ng/0000-0003-3138-9525; Zeggini, Eleftheria/0000-0003-4238-659X; Seedorf, Udo/0000-0003-4652-5358; Hide, Winston/0000-0002-8621-3271; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838 FU US NIH; Graduate Training in Cancer Research Grant; American Cancer Society; Agency for Science, Technology and Research, Singapore; NIH NIDDK; American Diabetes Association; National Human Genome Research Institute (NHGRI); US National Institute of General Medical Sciences (NIGMS); Burroughs Wellcome Fund; Leukemia and Lymphoma Society FX We thank John Powers, Harith Rajagopalan, Jason Locasale, Abdel Saci, Akash Patnaik, Charles Kaufman, Christian Mosimann and Lewis Cantley for invaluable discussions and advice, Roderick Bronson and the Harvard Medical School Rodent Histopathology Core for mouse tissue pathology, and the Harvard Neurobehavior Laboratory for CLAMS experiments. This work was supported by grants from the US NIH to G. Q. D., a Graduate Training in Cancer Research Grant and a American Cancer Society Postdoctoral Fellowship to H.Z., the NSS Scholarship from the Agency for Science, Technology and Research, Singapore for N.S.C, an NIH NIDDK Diseases Career Development Award to M. G. K, and an American Diabetes Association Postdoctoral Fellowship for A. V. S. J.M.E. was supported by the National Human Genome Research Institute (NHGRI). R. I. G. was supported by US National Institute of General Medical Sciences (NIGMS) and is a Pew Research Scholar. D. A. is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. G. Q. D. is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. H.Z. and N.S.C designed and performed the experiments, and wrote the manuscript. A. V. S. and D. A. performed bioinformatic analysis on let-7 targets in GWAS. G. S. and S. P. S. performed expression analysis, metabolic assays and mouse husbandry. G. S., W. S. E. and A. T. generated the mouse strains. J.E.T, R. T. and R. I. G. assisted with the luciferase assays. J.P.H., R. I. G., G. S., and A. T generated the conditional knockout mice. M. G. K. helped to design the experiments. G. Q. D. designed and supervised experiments, and wrote the manuscript. The authors declare no competing financial interests. NR 55 TC 320 Z9 338 U1 4 U2 85 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 30 PY 2011 VL 147 IS 1 BP 81 EP 94 DI 10.1016/j.cell.2011.08.033 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827AJ UT WOS:000295396700017 PM 21962509 ER PT J AU Chiarle, R Zhang, Y Frock, RL Lewis, SM Molinie, B Ho, YJ Myers, DR Choi, VW Compagno, M Malkin, DJ Neuberg, D Monti, S Giallourakis, CC Gostissa, M Alt, FW AF Chiarle, Roberto Zhang, Yu Frock, Richard L. Lewis, Susanna M. Molinie, Benoit Ho, Yu-Jui Myers, Darienne R. Choi, Vivian W. Compagno, Mara Malkin, Daniel J. Neuberg, Donna Monti, Stefano Giallourakis, Cosmas C. Gostissa, Monica Alt, Frederick W. TI Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells SO CELL LA English DT Article ID END-JOINING PATHWAY; CLASS SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; DNA BREAKS; C-MYC; HYPERMUTATION; LYMPHOCYTES; CANCER; IDENTIFICATION; TRANSCRIPTION AB Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics. C1 [Chiarle, Roberto; Zhang, Yu; Frock, Richard L.; Lewis, Susanna M.; Ho, Yu-Jui; Myers, Darienne R.; Choi, Vivian W.; Compagno, Mara; Malkin, Daniel J.; Gostissa, Monica; Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Chiarle, Roberto; Zhang, Yu; Frock, Richard L.; Lewis, Susanna M.; Ho, Yu-Jui; Myers, Darienne R.; Choi, Vivian W.; Compagno, Mara; Malkin, Daniel J.; Gostissa, Monica; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chiarle, Roberto; Zhang, Yu; Frock, Richard L.; Lewis, Susanna M.; Ho, Yu-Jui; Myers, Darienne R.; Choi, Vivian W.; Compagno, Mara; Malkin, Daniel J.; Gostissa, Monica; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Chiarle, Roberto; Compagno, Mara] Univ Turin, Dept Biomed Sci & Human Oncol, I-10126 Turin, Italy. [Chiarle, Roberto; Compagno, Mara] Univ Turin, CERMS, I-10126 Turin, Italy. [Molinie, Benoit; Giallourakis, Cosmas C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Neuberg, Donna] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Monti, Stefano] 5 Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA. [Monti, Stefano] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02118 USA. RP Zhang, Y (reprint author), Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. EM zhang@idi.harvard.edu; cgiallourakis@partners.org; gostissa@idi.harvard.edu; alt@enders.tch.harvard.edu OI Monti, Stefano/0000-0002-9376-0660; CHIARLE, Roberto/0000-0003-1564-8531; Frock, Richard/0000-0001-6963-4931 FU NIH [5P01CA92625, AI070837, 5T32CA070083-13]; Leukemia and Lymphoma Society of America (LLS); AIRC [ERC-2009-StG, 242965]; V Foundation; CRI postdoctoral fellowship FX We thank Barry Sleckman for providing unpublished information about circular PCR translocation cloning of RAG-generated DSBs. This work was supported by NIH grant 5P01CA92625 and a Leukemia and Lymphoma Society of America (LLS) SCOR grant to F. W. A., grants from AIRC and grant FP7 ERC-2009-StG (Proposal No. 242965-"Lunely'') to R. C., an NIH KO8 grant AI070837 to C. C. G., and a V Foundation Scholar award to M. G. Y.Z. was supported by CRI postdoctoral fellowship and R. L. F. by NIH training grant 5T32CA070083-13. F. W. A. is an Investigator of the Howard Hughes Medical Institute. F. W. A. is a member of the scientific advisory board of Cellectis Pharmaceuticals. NR 46 TC 186 Z9 190 U1 4 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 30 PY 2011 VL 147 IS 1 BP 107 EP 119 DI 10.1016/j.cell.2011.07.049 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 827AJ UT WOS:000295396700019 PM 21962511 ER PT J AU Archuleta, TL Du, YQ English, CA Lory, S Lesser, C Ohi, MD Ohi, R Spiller, BW AF Archuleta, Tara L. Du, Yaqing English, Chauca A. Lory, Stephen Lesser, Cammie Ohi, Melanie D. Ohi, Ryoma Spiller, Benjamin W. TI The Chlamydia Effector Chlamydial Outer Protein N (CopN) Sequesters Tubulin and Prevents Microtubule Assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID III SECRETION TRANSLOCATOR; STATHMIN-LIKE DOMAIN; HOST-CELLS; IN-VITRO; DYNAMIC INSTABILITY; BACTERIAL INVASION; TRACHOMATIS; POLYMERIZATION; CHAPERONES; SHIGELLA AB Chlamydia species are obligate intracellular pathogens that utilize a type three secretion system to manipulate host cell processes. Genetic manipulations are currently not possible in Chlamydia, necessitating study of effector proteins in heterologous expression systems and severely complicating efforts to relate molecular strategies used by Chlamydia to the biochemical activities of effector proteins. CopN is a chlamydial type three secretion effector that is essential for virulence. Heterologous expression of CopN in cells results in loss of microtubule spindles and metaphase plate formation and causes mitotic arrest. CopN is a multidomain protein with similarity to type three secretion system "plug" proteins from other organisms but has functionally diverged such that it also functions as an effector protein. Weshow that CopN binds directly to alpha beta-tubulin but not to microtubules (MTs). Furthermore, CopN inhibits tubulin polymerization by sequestering free alpha beta-tubulin, similar to one of the mechanisms utilized by stathmin. Although CopN and stathmin share no detectable sequence identity, both influence MT formation by sequestration of alpha beta-tubulin. CopN displaces stathmin from preformed stathmin-tubulin complexes, indicating that the proteins bind overlapping sites on tubulin. CopN is the first bacterial effector shown to disrupt MT formation directly. This recognition affords a mechanistic understanding of a strategy Chlamydia species use to manipulate the host cell cycle. C1 [Archuleta, Tara L.; Spiller, Benjamin W.] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA. [Archuleta, Tara L.] Vanderbilt Univ, Div Chem & Phys Biol, Sch Med, Nashville, TN 37232 USA. [Du, Yaqing; English, Chauca A.; Ohi, Melanie D.; Ohi, Ryoma] Vanderbilt Univ, Dept Cell & Dev Biol, Sch Med, Nashville, TN 37232 USA. [Spiller, Benjamin W.] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA. [Lory, Stephen; Lesser, Cammie] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Lesser, Cammie] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Spiller, BW (reprint author), Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA. EM benjamin.spiller@vanderbilt.edu FU National Institutes of Health [5T90 DA022873]; National Center for Research Resources [UL1RR024975-01, DK058404] FX This work was supported, in whole or in part, by National Institutes of Health Grant UL1RR024975-01 from the National Center for Research Resources and Grant DK058404 (to B. W. S.) and Grant NIH 5T90 DA022873 (to T. L. A.). NR 64 TC 22 Z9 22 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 30 PY 2011 VL 286 IS 39 BP 33992 EP 33998 DI 10.1074/jbc.M111.258426 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 823WW UT WOS:000295159200031 PM 21841198 ER PT J AU Avsar, KB Stoeckel, LE Bolding, MS White, DM Tagamets, MA Holcomb, HH Lahti, AC AF Avsar, Kathy Burton Stoeckel, Luke Edward Bolding, Mark Steven White, David Matthew Tagamets, Malle Anne Holcomb, Henry Hilliard Lahti, Adrienne Carol TI Aberrant visual circuitry associated with normal spatial match-to-sample accuracy in schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE fMRI; Anterior cingulate cortex; Visual perception; Working memory; Dorsolateral prefrontal cortex ID DORSOLATERAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; WORKING-MEMORY TASK; EVENT-RELATED FMRI; 1ST-EPISODE SCHIZOPHRENIA; PHYSIOLOGICAL DYSFUNCTION; TALAIRACH ATLAS; STROOP TASK; BRAIN; PERFORMANCE AB A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging ( fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Avsar, Kathy Burton; Bolding, Mark Steven; White, David Matthew; Lahti, Adrienne Carol] Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA. [Avsar, Kathy Burton] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Stoeckel, Luke Edward] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bolding, Mark Steven] Univ Alabama Birmingham, Dept Vis Sci, Birmingham, AL 35294 USA. [Tagamets, Malle Anne; Holcomb, Henry Hilliard] Univ Maryland, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21247 USA. RP Lahti, AC (reprint author), Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, SC 501,1530 3rd Ave S, Birmingham, AL 35294 USA. EM alahti@uab.edu OI White, David/0000-0002-6372-5311 FU National Alliance for Research on Schizophrenia and Depression (NARSAD) FX This work was supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD), Independent Investigator Award to A. C. Lahti. We want to thank all the volunteers with schizophrenia and their families who so gracefully took part in this project and the staff of the Maryland Psychiatric Research Center at the University of Maryland. We also want to thank Alan Francis for his assistance on data preprocessing. NR 65 TC 1 Z9 1 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD SEP 30 PY 2011 VL 193 IS 3 BP 138 EP 143 DI 10.1016/j.pscychresns.2011.03.008 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 822TV UT WOS:000295073400002 PM 21782395 ER PT J AU Epstein, J Perez, DL Ervin, K Pan, H Kocsis, JH Butler, T Stern, E Silbersweig, DA AF Epstein, Jane Perez, David Lewis Ervin, Kate Pan, Hong Kocsis, James Howard Butler, Tracy Stern, Emily Silbersweig, David Alan TI Failure to segregate emotional processing from cognitive sensorimotor processing in major depression SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE fMRI; Ventral striatum; Functional connectivity; Principal component analysis; Default mode network; Neuroimaging ID DEFAULT-MODE NETWORK; FUNCTIONAL CONNECTIVITY; MOOD DISORDERS; PREFRONTAL CORTEX; CINGULATE CORTEX; BRAIN-FUNCTION; FMRI; MEMORY; SELF; ABNORMALITIES AB Most functional neuroimaging studies of major depressive disorder (MDD) employ univariate methods of statistical analysis to localize abnormalities of neural activity. Less has been done to investigate functional relations between these regions, or with regions not usually implicated in depression. Examination of intraneuronal and interneural network relations is important for the advancement of emerging network models for MDD. Principal component analysis (PCA), a multivariate statistical method, was used to examine differences in functional connectivity between 10 unmedicated patients with MDD and 12 healthy subjects engaged in a positive word viewing task. In healthy subjects, principal component (PC) 1 (33% variance) revealed functional connectivity of task-specific sensory, linguistic, and motor regions, along with functional anticorrelations in the default mode network; PC2 (10% variance) displayed functional connectivity of areas involved in emotional processing. This segregation of functions did not occur in the depressed group, where regions involved in emotional functions appeared in PC1 (34% variance) co-varying with those involved in linguistic, motor, and default mode network processing. The lack of segregation of emotional processing from cognitive and sensorimotor functions may represent a systems level neural substrate for a core phenomenon of depression: the interconnection of affective disturbance with experience, cognition, and behavior. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Epstein, Jane; Ervin, Kate; Silbersweig, David Alan] Harvard Univ, Sch Med, Dept Psychiat, Brigham & Womens Hosp, Boston, MA 02115 USA. [Pan, Hong; Stern, Emily] Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Perez, David Lewis] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Kocsis, James Howard; Butler, Tracy] Weill Cornell Med Coll, Dept Psychiat, New York Presbyterian Hosp, New York, NY 10065 USA. [Perez, David Lewis] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Epstein, J (reprint author), Brigham & Womens Hosp, Funct Neuroimaging Lab, Dept Psychiat, 824 Boylston St, Chestnut Hill, MA 02467 USA. EM janeepsteinmd@gmail.com RI Stern, Emily/E-6035-2011 FU National Alliance for Research on Schizophrenia and Depression; Pritzker Network for the Study of Depression; New York Community Trust FX The authors thank the following individuals for their assistance: Jude Allen (subject recruitment and characterization, study coordination, and data management), Susie de Rubertis and Elizabeth Levitan (subject recruitment and characterization), Hong Gu (development of imaging sequence), Josefino Borja (MRI technologist) and Eva Catenaccio (figure design). This work was supported by the National Alliance for Research on Schizophrenia and Depression, the Pritzker Network for the Study of Depression, and the DeWitt Wallace Fund of the New York Community Trust. All co-authors report no conflicts of interest. NR 50 TC 11 Z9 11 U1 3 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD SEP 30 PY 2011 VL 193 IS 3 BP 144 EP 150 DI 10.1016/j.pscychresns.2011.01.012 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 822TV UT WOS:000295073400003 PM 21764265 ER PT J AU Letai, A AF Letai, Anthony TI Targeting Bcl-2 in CLL: cui bono? SO BLOOD LA English DT Editorial Material ID INHIBITOR; FAMILY AB Antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies. In this issue of Blood, Al-harbi et al describe a way to combine mRNA expression data from several Bcl-2 family members into a tool that predicts in vitro sensitivity of CLL cells to ABT-737, a small molecule Bcl-2 antagonist.(1) C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 6 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 29 PY 2011 VL 118 IS 13 BP 3453 EP 3454 DI 10.1182/blood-2011-08-370346 PG 4 WC Hematology SC Hematology GA 826MW UT WOS:000295359300007 PM 21960677 ER PT J AU Smith, MR Neuberg, D Flinn, IW Grever, MR Lazarus, HM Rowe, JM Dewald, G Bennett, JM Paietta, EM Byrd, JC Hussein, MA Appelbaum, FR Larson, RA Litzow, MR Tallman, MS AF Smith, Mitchell R. Neuberg, Donna Flinn, Ian W. Grever, Michael R. Lazarus, Hillard M. Rowe, Jacob M. Dewald, Gordon Bennett, John M. Paietta, Elisabeth M. Byrd, John C. Hussein, Mohamad A. Appelbaum, Frederick R. Larson, Richard A. Litzow, Mark R. Tallman, Martin S. TI Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997 SO BLOOD LA English DT Article ID PHASE-III TRIAL; RITUXIMAB; REGIMEN AB Chemotherapy-related myeloid neoplasia (t-MN) is a significant late toxicity concern after cancer therapy. In the randomized intergroup phase 3 E2997 trial, initial therapy of chronic lymphocytic leukemia with fludarabine plus cyclophosphamide (FC) compared with fludarabine alone yielded higher complete and overall response rates and longer progression-free, but not overall, survival. Here, we report t-MN incidence in 278 patients enrolled in E2997 with a median 6.4-year follow-up. Thirteen cases (4.7%) of t-MN occurred at a median of 5 years from initial therapy for chronic lymphocytic leukemia, 9 after FC and 4 after fludarabine alone. By cumulative incidence methodology, rates of t-MN at 7 years were 8.2% after FC and 4.6% after fludarabine alone (P = .09). Seven of the 9 cases of t-MN after FC occurred without additional therapy. Abnormalities involving chromosomes 5 or 7 were found in 10 cases, which suggests alkylator involvement. These data suggest that FC may induce more t-MN than fludarabine alone. (Blood. 2011;118(13):3525-3527) C1 [Smith, Mitchell R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Neuberg, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Flinn, Ian W.] Sarah Cannon Res Inst, Nashville, TN USA. [Grever, Michael R.; Byrd, John C.] Ohio State Univ, Columbus, OH 43210 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Dewald, Gordon; Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Bennett, John M.] Univ Rochester, Ctr Canc, Rochester, NY USA. [Paietta, Elisabeth M.] Montefiore Med Ctr, North Div, Bronx, NY 10467 USA. [Hussein, Mohamad A.] Univ S Florida, Tampa, FL USA. [Appelbaum, Frederick R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Larson, Richard A.] Univ Chicago, Chicago, IL 60637 USA. [Tallman, Martin S.] Northwestern Univ, Sch Med, Chicago, IL USA. RP Smith, MR (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM m_smith@fccc.edu OI Larson, Richard/0000-0001-9168-3203; Smith, Mitchell/0000-0003-1428-8765 FU Public Health Service [CA23318, CA66636, CA21115, CA27525, CA14548, CA16116, CA77658, CA04919, CA38926, CA13650, CA17145, CA11083, CA14958, CA032291, CA031946]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grants CA23318, CA66636, CA21115, CA27525, CA14548, CA16116, CA77658, CA04919, CA38926, CA13650, CA17145, CA11083, CA14958, CA032291, and CA031946; and by grants from the National Cancer Institute, the National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 12 TC 20 Z9 21 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 29 PY 2011 VL 118 IS 13 BP 3525 EP 3527 DI 10.1182/blood-2011-03-342485 PG 3 WC Hematology SC Hematology GA 826MW UT WOS:000295359300018 PM 21803850 ER PT J AU Shaknovich, R Cerchietti, L Tsikitas, L Kormaksson, M De, S Figueroa, ME Ballon, G Yang, SN Weinhold, N Reimers, M Clozel, T Luttrop, K Ekstrom, TJ Frank, J Vasanthakumar, A Godley, LA Michor, F Elemento, O Melnick, A AF Shaknovich, Rita Cerchietti, Leandro Tsikitas, Lucas Kormaksson, Matthias De, Subhajyoti Figueroa, Maria E. Ballon, Gianna Yang, Shao Ning Weinhold, Nils Reimers, Mark Clozel, Thomas Luttrop, Karin Ekstrom, Tomas J. Frank, Jared Vasanthakumar, Aparna Godley, Lucy A. Michor, Franziska Elemento, Olivier Melnick, Ari TI DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation SO BLOOD LA English DT Article ID SOMATIC HYPERMUTATION; CYTOSINE METHYLATION; DEAMINASE AID; DNMT1; ASSAY; TARGETS; CANCER; GENE; HYPERMETHYLATION; LYMPHOMAGENESIS AB The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair. (Blood. 2011;118(13):3559-3569) C1 [Shaknovich, Rita; Cerchietti, Leandro; Tsikitas, Lucas; Figueroa, Maria E.; Yang, Shao Ning; Clozel, Thomas; Frank, Jared; Melnick, Ari] Weill Cornell Med Coll, Div Hematol Oncol, Dept Med, New York, NY 10065 USA. [Shaknovich, Rita; Ballon, Gianna] Weill Cornell Med Coll, Dept Pathol, Div Immunopathol, New York, NY 10065 USA. [Kormaksson, Matthias] Weill Cornell Med Coll, Div Biostat & Epidemiol, Dept Publ Hlth, New York, NY 10065 USA. [De, Subhajyoti; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [De, Subhajyoti] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Weinhold, Nils] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Reimers, Mark] Virginia Commonwealth Univ, Dept Biostat, Sch Med, Richmond, VA USA. [Luttrop, Karin; Ekstrom, Tomas J.] Karolinska Inst, Lab Med Epigenet, Dept Clin Neurosci, Stockholm, Sweden. [Vasanthakumar, Aparna; Godley, Lucy A.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Elemento, Olivier] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10065 USA. RP Melnick, A (reprint author), Weill Cornell Med Coll, Div Hematol Oncol, Dept Med, 1300 York Ave, New York, NY 10065 USA. EM amm2014@med.cornell.edu OI Cerchietti, Leandro/0000-0003-0608-1350 FU Leukemia & Lymphoma Society [LLS 6304-11]; Leukemia & Lymphoma Society SCOR [LLS 7017-09]; Chemotherapy Foundation; Burroughs Wellcome Clinical Translational Scientist Award; HFSP; Swedish Cancer Society.; [K08 CA127353]; [CA129831]; [CA129831-03S1]; [R01CA138234]; [U54CA143798] FX This research was supported by K08 CA127353 (R.S.), Leukemia & Lymphoma Society Translational Research Program Award LLS 6304-11 (R.S.), and Leukemia & Lymphoma Society SCOR LLS 7017-09 (A.M.). A.M. is also supported by the Chemotherapy Foundation, a Leukemia & Lymphoma Society Scholar Award, and a Burroughs Wellcome Clinical Translational Scientist Award. L.A.G. is supported by CA129831 and CA129831-03S1. F.M. is supported by R01CA138234 and U54CA143798. S. D. is a recipient of an HFSP fellowship. T.J.E. and K.L. were supported by the Swedish Cancer Society. NR 45 TC 49 Z9 50 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 29 PY 2011 VL 118 IS 13 BP 3559 EP 3569 DI 10.1182/blood-2011-06-357996 PG 11 WC Hematology SC Hematology GA 826MW UT WOS:000295359300022 PM 21828137 ER PT J AU Nilsson, RJA Balaj, L Hulleman, E van Rijn, S Pegtel, DM Walraven, M Widmark, A Gerritsen, WR Verheul, HM Vandertop, WP Noske, DP Skog, J Wurdinger, T AF Nilsson, R. Jonas A. Balaj, Leonora Hulleman, Esther van Rijn, Sjoerd Pegtel, D. Michiel Walraven, Maudy Widmark, Anders Gerritsen, Winald R. Verheul, Henk M. Vandertop, W. Peter Noske, David P. Skog, Johan Wurdinger, Thomas TI Blood platelets contain tumor-derived RNA biomarkers SO BLOOD LA English DT Article ID LUNG-CANCER; GENE-EXPRESSION; PROSTATE-CANCER; GROWTH-FACTOR; ANGIOGENESIS; MICROVESICLES; EXOSOMES; PLASMA; THROMBOSPONDIN-1; DIAGNOSTICS AB Diagnostic platforms providing biomarkers that are highly predictive for diagnosing, monitoring, and stratifying cancer patients are key instruments in the development of personalized medicine. We demonstrate that tumor cells transfer (mutant) RNA into blood platelets in vitro and in vivo, and show that blood platelets isolated from glioma and prostate cancer patients contain the cancer-associated RNA biomarkers EGFRvIII and PCA3, respectively. In addition, gene-expression profiling revealed a distinct RNA signature in platelets from glioma patients compared with normal control subjects. Because platelets are easily accessible and isolated, they may form an attractive platform for the companion diagnostics of cancer. (Blood. 2011; 118(13):3680-3683) C1 [Nilsson, R. Jonas A.; Balaj, Leonora; Hulleman, Esther; van Rijn, Sjoerd; Noske, David P.; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp, NL-1081 HV Amsterdam, Netherlands. [Nilsson, R. Jonas A.; Balaj, Leonora; Hulleman, Esther; van Rijn, Sjoerd; Vandertop, W. Peter; Noske, David P.; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Dept Neurosurg, NL-1081 HV Amsterdam, Netherlands. [Nilsson, R. Jonas A.; Widmark, Anders] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Balaj, Leonora; Skog, Johan; Wurdinger, Thomas] Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Boston, MA 02114 USA. [Balaj, Leonora; Skog, Johan; Wurdinger, Thomas] Harvard Univ, Sch Med, Boston, MA USA. [Hulleman, Esther] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Dept Pediat Oncol, NL-1081 HV Amsterdam, Netherlands. [Pegtel, D. Michiel] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. [Walraven, Maudy; Gerritsen, Winald R.; Verheul, Henk M.] Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. RP Wurdinger, T (reprint author), Vrije Univ Amsterdam Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM t.wurdinger@vumc.nl RI Gerritsen, W.R./H-8031-2014; Pegtel, Dirk/M-8393-2015 OI Pegtel, Dirk/0000-0002-7357-4406 FU Lion's Cancer Research Foundation; Umea University (Sweden); Stichting Translational Research CCA/VU University Medical Center; Swedish Research Council; NWO-VIDI FX This work was supported by Lion's Cancer Research Foundation, Umea University (Sweden); Stichting Translational Research CCA/VU University Medical Center, Swedish Research Council (R.J.A.N.); and NWO-VIDI (T.W.). NR 33 TC 42 Z9 42 U1 3 U2 13 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 SEP 29 PY 2011 VL 118 IS 13 BP 3680 EP 3683 DI 10.1182/blood-2011-03-344408 PG 4 WC Hematology SC Hematology GA 826MW UT WOS:000295359300034 PM 21832279 ER PT J AU Woo, AJ Kim, J Xu, J Huang, H Cantor, AB AF Woo, Andrew J. Kim, Jonghwan Xu, Jian Huang, Hui Cantor, Alan B. TI Role of ZBP-89 in human globin gene regulation and erythroid differentiation SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; LOCUS-CONTROL REGION; MODEL-BASED ANALYSIS; KRUPPEL-LIKE FACTOR; BINDING-PROTEIN; FETAL-HEMOGLOBIN; GAMMA-GLOBIN; FACTOR EKLF; FACTOR SP1; EXPRESSION AB The molecular mechanisms underlying erythroid-specific gene regulation remain incompletely understood. Closely spaced binding sites for GATA, NF-E2/maf, and CACCC interacting transcription factors play functionally important roles in globin and other erythroid-specific gene expression. We and others recently identified the CACCC-binding transcription factor ZBP-89 as a novel GATA-1 and NF-E2/mafK interacting partner. Here, we examined the role of ZBP-89 in human globin gene regulation and erythroid maturation using a primary CD34(+) cell ex vivo differentiation system. We show that ZBP-89 protein levels rise dramatically during human erythroid differentiation and that ZBP-89 occupies key cis-regulatory elements within the globin and other erythroid gene loci. ZBP-89 binding correlates strongly with RNA Pol II occupancy, active histone marks, and high-level gene expression. ZBP-89 physically associates with the histone acetyltransferases p300 and Gcn5/Trrap, and occupies common sites with Gcn5 within the human globin loci. Lentiviral short hair-pin RNAs knockdown of ZBP-89 results in reduced Gcn5 occupancy, decreased acetylated histone 3 levels, lower globin and erythroid-specific gene expression, and impaired erythroid maturation. Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation. (Blood. 2011; 118(13):3684-3693) C1 [Woo, Andrew J.; Kim, Jonghwan; Xu, Jian; Huang, Hui; Cantor, Alan B.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Woo, Andrew J.; Kim, Jonghwan; Xu, Jian; Huang, Hui; Cantor, Alan B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cantor, AB (reprint author), Childrens Hosp Boston, Div Pediat Hematol Oncol, 300 Longwood Ave,Karp 7, Boston, MA 02115 USA. EM alan.cantor@childrens.harvard.edu FU National Institutes of Health [P01 HL32262-25] FX A.B.C. is supported by the National Institutes of Health (grant P01 HL32262-25). NR 50 TC 10 Z9 10 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 SEP 29 PY 2011 VL 118 IS 13 BP 3684 EP 3693 DI 10.1182/blood-2011-03-341446 PG 10 WC Hematology SC Hematology GA 826MW UT WOS:000295359300035 PM 21828133 ER PT J AU Fuchs, TA Bhandari, AA Wagner, DD AF Fuchs, Tobias A. Bhandari, Ashish A. Wagner, Denisa D. TI Histones induce rapid and profound thrombocytopenia in mice SO BLOOD LA English DT Article ID PLATELET-AGGREGATION; HEPARIN; BLOOD; COAGULATION; THROMBOSIS; BINDING; SEPSIS; TRAPS AB Histones are released from dying cells and contribute to antimicrobial defense during infection. However, extracellular histones are a double-edged sword because they also damage host tissue and may cause death. We studied the interactions of histones with platelets. Histones bound to platelets, induced calcium influx, and recruited plasma adhesion proteins such as fibrinogen to induce platelet aggregation. Hereby fibrinogen crosslinked histone-bearing platelets and triggered microaggregation. Fibrinogen interactions with alpha IIb beta 3 integrins were not required for this process but were necessary for the formation of large platelet aggregates. Infused histones associated with platelets in vivo and caused a profound thrombocytopenia within minutes after administration. Mice lacking platelets or alpha IIb beta 3 integrins were protected from histone-induced death but not from histone-induced tissue damage. Heparin, at high concentrations, prevented histone interactions with platelets and protected mice from histone-induced thrombocytopenia, tissue damage, and death. Heparin and histones are evolutionary maintained. Histones may combine microbicidal with prothrombotic properties to fight invading microbes and maintain hemostasis after injury. Heparin may provide an innate counter mechanism to neutralize histones and diminish collateral tissue damage. (Blood. 2011; 118(13):3708-3714) C1 [Fuchs, Tobias A.; Bhandari, Ashish A.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Fuchs, Tobias A.; Bhandari, Ashish A.; Wagner, Denisa D.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Fuchs, Tobias A.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Fuchs, TA (reprint author), Immune Dis Inst, 3 Blackfan Cir,3rd Fl, Boston, MA 02115 USA. EM fuchs@idi.harvard.edu; wagner@idi.harvard.edu RI Fuchs, Tobias/F-1189-2013 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [P01 HL056949]; Deutsche Forschungsgemeinschaft, Germany [FU 742/1-1] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant P01 HL056949, D. D. W.) and a fellowship from the Deutsche Forschungsgemeinschaft, Germany (FU 742/1-1, T.A. F.). NR 26 TC 116 Z9 117 U1 0 U2 6 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 SEP 29 PY 2011 VL 118 IS 13 BP 3708 EP 3714 DI 10.1182/blood-2011-01-332676 PG 7 WC Hematology SC Hematology GA 826MW UT WOS:000295359300038 PM 21700775 ER PT J AU Yang, YP Wang, H Yu, H Yeap, BY Liang, TT Wang, GJ Cheng, T Yang, YG AF Yang, Yanping Wang, Hui Yu, Hui Yeap, Beow Yong Liang, Tingting Wang, Guanjun Cheng, Tao Yang, Yong-Guang TI IFN-gamma promotes graft-versus-leukemia effects without directly interacting with leukemia cells in mice after allogeneic hematopoietic cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CD8(+) T-CELLS; HOST-DISEASE; INTERFERON-GAMMA; NOTCH; INHIBITION; CHIMERAS; GVHD AB The ability of IFN-gamma to enhance graft-versus-leukemia (GVL) activity without direct interaction with leukemia cells was examined by comparing GVL effects against IFN-gamma receptor-deficient (GRKO) leukemia between wild-type (WT) and IFN-gamma-deficient (GKO) allogeneic hematopoietic cell transplantation (allo-HCT). We established a primary IFN-gamma-unresponsive T-cell leukemia model using virally-transduced GRKO B6 mouse bone marrow cells overexpressing Notch1. We first assessed GVL effects in lethally-irradiated B6 mice receiving CD4-depleted allo-HCT from WT or GKO BALB/c donors. Administration of CD4(+) cell-depleted allo-HCT from WT, but not GKO, BALB/c donors mediated significant GVL effects against GRKO leukemia. Similar results were obtained in preestablished allogeneic chimeras receiving delayed donor lymphocyte infusion (DLI). Although both WT and GKO DLI achieved significant anti-tumor responses, the former was markedly stronger than the latter. These data indicate that IFN-gamma is capable of promoting GVL effects via mechanisms independent of its interaction with leukemia cells. (Blood. 2011; 118(13):3721-3724) C1 [Wang, Hui; Liang, Tingting; Yang, Yong-Guang] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA. [Yang, Yanping; Liang, Tingting; Wang, Guanjun] Jilin Univ, Bethune Hosp 1, Changchun 130023, Jilin, Peoples R China. [Yang, Yanping; Wang, Hui; Liang, Tingting; Yang, Yong-Guang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Yu, Hui; Cheng, Tao] Univ Pittsburgh, Sch Med, Inst Canc, Canc Stem Cell Program,Dept Radiat Oncol, Pittsburgh, PA USA. [Yeap, Beow Yong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Cheng, Tao] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin, Peoples R China. [Cheng, Tao] Chinese Acad Med Sci, Ctr Stem Cell Med, Tianjin, Peoples R China. RP Yang, YG (reprint author), Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, 630 W 168th St,Mail Box 127, New York, NY 10032 USA. EM guanjunwang2006@163.com; yy2324@columbia.edu FU National Institutes of Health [5P01CA111519-020002, RC1 HL100117]; NSFC [81090410, 30825017, 2011CB964800]; Ministry of Health of China; China Scholarship Council; Leukemia & Lymphoma Society FX This work was supported by grants from the National Institutes of Health (5P01CA111519-020002 and RC1 HL100117 to Y.G.Y.), NSFC (81090410, 30825017 and 2011CB964800 to T. C.), and the Ministry of Health of China (a Key Clinical Program 2010 to GW). Y.Y. and T. L. are partially supported by awards from the China Scholarship Council. T. C. is a recipient of the scholar award from the Leukemia & Lymphoma Society. NR 22 TC 4 Z9 5 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 29 PY 2011 VL 118 IS 13 BP 3721 EP 3724 DI 10.1182/blood-2010-05-283887 PG 4 WC Hematology SC Hematology GA 826MW UT WOS:000295359300040 PM 21835954 ER PT J AU Seton, M AF Seton, Margaret TI Providing for Those Who Have Too Little SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Seton, M (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 29 PY 2011 VL 365 IS 13 BP 1169 EP 1171 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 825YO UT WOS:000295318400003 PM 21991890 ER PT J AU Cunningham, J Harisinghani, MG Taheri, D AF Cunningham, John Harisinghani, Mukesh G. Taheri, Diana TI Case 30-2011: A 62-Year-Old Woman with Renal Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYSTEMIC-SCLEROSIS; SCLERODERMA; CRISIS; CLASSIFICATION; SUBSETS; DRUGS C1 [Cunningham, John] Royal Free & Univ Coll London, Sch Med, Ctr Nephrol, London, England. [Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Taheri, Diana] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Harisinghani, Mukesh G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Taheri, Diana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cunningham, J (reprint author), Royal Free & Univ Coll London, Sch Med, Ctr Nephrol, London, England. FU Harvard Medical School Department of Continuing Education, Boston; Abbott; Amgen; Ineos; Shire; Leo; Genzyme; Fresenius FX Presented at the Internal Medicine Comprehensive Review and Update 2010; course director, Ravi Thadhani, M. D., Massachusetts General Hospital; sponsored by the Harvard Medical School Department of Continuing Education, Boston.; Dr. Cunningham reports receiving consulting fees from Abbott, Amgen, Ineos, Shire, Leo, Genzyme, and Fresenius; grant support from Amgen and Abbott; and payment for the development of educational presentations, including service on speakers' bureaus, from Amgen, Fresenius, Shire, and Abbott. No other potential conflict of interest relevant to this article was reported. NR 16 TC 0 Z9 0 U1 1 U2 2 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 SEP 29 PY 2011 VL 365 IS 13 BP 1234 EP 1244 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 825YO UT WOS:000295318400013 ER PT J AU Overmoyer, BA Lee, JM Younger, J AF Overmoyer, Beth A. Lee, Janie M. Younger, Jerry TI Case 17-2011: A Woman with a Mass in the Breast and Overlying Skin Changes REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID CANCER; MRI C1 [Overmoyer, Beth A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Janie M.; Younger, Jerry] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Overmoyer, BA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 29 PY 2011 VL 365 IS 13 BP 1260 EP 1260 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 825YO UT WOS:000295318400028 ER PT J AU Geng, EH Hunt, PW Diero, LO Kimaiyo, S Somi, GR Okong, P Bangsberg, DR Bwana, MB Cohen, CR Otieno, JA Wabwire, D Elul, B Nash, D Easterbrook, PJ Braitstein, P Musick, BS Martin, JN Yiannoutsos, CT Wools-Kaloustian, K AF Geng, Elvin H. Hunt, Peter W. Diero, Lameck O. Kimaiyo, Sylvester Somi, Geofrey R. Okong, Pius Bangsberg, David R. Bwana, Mwebesa B. Cohen, Craig R. Otieno, Juliana A. Wabwire, Deo Elul, Batya Nash, Denis Easterbrook, Philippa J. Braitstein, Paula Musick, Beverly S. Martin, Jeffrey N. Yiannoutsos, Constantin T. Wools-Kaloustian, Kara TI Trends in the clinical characteristics of HIV-infected patients initiating antiretroviral therapy in Kenya, Uganda and Tanzania between 2002 and 2009 SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article ID SUB-SAHARAN AFRICA; MULTILEVEL ANALYSIS; EARLY MORTALITY; PROGRAM; ADULTS; TUBERCULOSIS; RIFAMPICIN; SURVIVAL; DISEASE AB Background: East Africa has experienced a rapid expansion in access to antiretroviral therapy (ART) for HIV-infected patients. Regionally representative socio-demographic, laboratory and clinical characteristics of patients accessing ART over time and across sites have not been well described. Methods: We conducted a cross-sectional analysis of characteristics of HIV-infected adults initiating ART between 2002 and 2009 in Kenya, Uganda and Tanzania and in the International Epidemiologic Databases to Evaluate AIDS Consortium. Characteristics associated with advanced disease (defined as either a CD4 cell count level of less than 50 cells/mm(3) or a WHO Stage 4 condition) at the time of ART initiation and use of stavudine (D4T) or nevirapine (NVP) were identified using a log-link Poisson model with robust standard errors. Results: Among 48, 658 patients (69% from Kenya, 22% from Uganda and 9% from Tanzania) accessing ART at 30 clinic sites, the median age at the time of ART initiation was 37 years (IQR: 31-43) and 65% were women. Pretherapy CD4 counts rose from 87 cells/mm(3) (IQR: 26-161) in 2002-03 to 154 cells/mm(3) (IQR: 71-233) in 2008-09 (p < 0.001). Accessing ART at advanced disease peaked at 35% in 2005-06 and fell to 27% in 2008-09. D4T use in the initial regimen fell from a peak of 88% in 2004-05 to 59% in 2008-09, and a greater extent of decline was observed in Uganda than in Kenya and Tanzania. Self-pay for ART peaked at 18% in 2003, but fell to less than 1% by 2005. In multivariable analyses, accessing ART at advanced immunosuppression was associated with male sex, women without a history of treatment for prevention of mother to child transmission (both as compared with women with such a history) and younger age after adjusting for year of ART initiation and country of residence. Receipt of D4T in the initial regimen was associated with female sex, earlier year of ART initiation, higher WHO stage, and lower CD4 levels at ART initiation and the absence of co-prevalent tuberculosis. Conclusions: Public health ART services in east Africa have improved over time, but the fraction of patients accessing ART with advanced immunosuppression is still high, men consistently access ART with more advanced disease, and D4T continues to be common in most settings. Strategies to facilitate access to ART, overcome barriers among men and reduce D4T use are needed. C1 [Geng, Elvin H.; Hunt, Peter W.; Cohen, Craig R.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA. [Braitstein, Paula; Musick, Beverly S.; Yiannoutsos, Constantin T.; Wools-Kaloustian, Kara] Indiana Univ, Dept Med, Indianapolis, IN USA. [Bangsberg, David R.; Bwana, Mwebesa B.] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Somi, Geofrey R.] Natl AIDS Control Program, Dar Es Salaam, Tanzania. [Easterbrook, Philippa J.] Infect Dis Inst, Kampala, Uganda. [Diero, Lameck O.; Kimaiyo, Sylvester] Moi Univ, Dept Med, Eldoret, Kenya. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Global Hlth, Boston, MA USA. [Okong, Pius] St Francis Hosp, Kampala, Uganda. [Wabwire, Deo] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Otieno, Juliana A.] Kisumu MTCT Plus Initiat, Kisumu, Kenya. [Elul, Batya; Nash, Denis] Int Ctr AIDS Care & Treatment Programs, New York, NY USA. RP Geng, EH (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, 995 Potrero Ave, San Francisco, CA 94143 USA. EM genge@php.ucsf.edu FU National Institutes of Health [K23 AI084544, U01 AI069911, P30 AI027763]; United States President's Emergency Plan for AIDS Relief (PEPFAR) FX This study received financial support from the National Institutes of Health (K23 AI084544, U01 AI069911, P30 AI027763) and the United States President's Emergency Plan for AIDS Relief (PEPFAR). All authors are members of the East Africa International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortium. NR 25 TC 24 Z9 24 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD SEP 28 PY 2011 VL 14 AR 46 DI 10.1186/1758-2652-14-46 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GU UT WOS:000296354300001 PM 21955541 ER PT J AU Majumder, S Richardson, A Strong, R Oddo, S AF Majumder, Smita Richardson, Arlan Strong, Randy Oddo, Salvatore TI Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits SO PLOS ONE LA English DT Article ID EXACERBATES TAU PATHOLOGY; P70 S6 KINASE; ALZHEIMERS-DISEASE; A-BETA; LIFE-SPAN; AMYLOID-BETA; MOUSE MODEL; IN-VIVO; SIGNALING PATHWAY; TRANSGENIC MODEL AB Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-beta (A beta). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble A beta and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression. C1 [Majumder, Smita; Oddo, Salvatore] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Majumder, Smita; Richardson, Arlan; Strong, Randy; Oddo, Salvatore] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Richardson, Arlan] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Richardson, Arlan; Strong, Randy] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Richardson, Arlan; Strong, Randy] S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX USA. RP Majumder, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. EM oddo@uthscsa.edu FU National Institute on Aging (NIA) [K99/R00AG29729-4, R01AG037637]; William and Ella Owens Medical Research Foundation; [RC2AG036613] FX This work was supported by National Institute on Aging (NIA) grant awards K99/R00AG29729-4 and R01AG037637 (Oddo, Principal Investigator), RC2AG036613 (Richardson, Principal Investigator, Strong and Oddo, Project Co-leaders), and by an award from the William and Ella Owens Medical Research Foundation to S.O. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 95 TC 127 Z9 133 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2011 VL 6 IS 9 AR e25416 DI 10.1371/journal.pone.0025416 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834CT UT WOS:000295936900063 PM 21980451 ER PT J AU Roffman, JL Nitenson, AZ Agam, Y Isom, M Friedman, JS Dyckman, KA Brohawn, DG Smoller, JW Goff, DC Manoach, DS AF Roffman, Joshua L. Nitenson, Adam Z. Agam, Yigal Isom, Marlisa Friedman, Jesse S. Dyckman, Kara A. Brohawn, David G. Smoller, Jordan W. Goff, Donald C. Manoach, Dara S. TI A Hypomethylating Variant of MTHFR, 677C > T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals SO PLOS ONE LA English DT Article ID HUMAN CEREBRAL-CORTEX; METHYLENETETRAHYDROFOLATE REDUCTASE; ANTERIOR CINGULATE; EXECUTIVE FUNCTION; DNA-METHYLATION; COMMON MUTATION; POLYMORPHISMS; PERFORMANCE; DISORDERS; NEURONS AB Background: Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%. Methodology/Principal Findings: Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele. Conclusions/Significance: These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene. C1 [Roffman, Joshua L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Roffman, JL (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM jroffman@partners.org FU National Institute of Mental Health [5R01MH067720]; Howard Hughes Medical Institute FX This paper was funded by the National Institute of Mental Health (5R01MH067720) to DSM. and a Howard Hughes Medical Institute Physician-Scientist Early Career Award to JLR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 15 Z9 16 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2011 VL 6 IS 9 AR e25253 DI 10.1371/journal.pone.0025253 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834CT UT WOS:000295936900040 PM 21980405 ER PT J AU Soulieres, I Dawson, M Gernsbacher, MA Mottron, L AF Soulieres, Isabelle Dawson, Michelle Gernsbacher, Morton Ann Mottron, Laurent TI The Level and Nature of Autistic Intelligence II: What about Asperger Syndrome? SO PLOS ONE LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; SPECTRUM DISORDERS; FLUID INTELLIGENCE; CHILDREN; PERSPECTIVE; ABILITY; IQ; INDIVIDUALS; PERFORMANCE; PERCEPTION AB A distinctively uneven profile of intelligence is a feature of the autistic spectrum. Within the spectrum, Asperger individuals differ from autistics in their early speech development and in being less likely to be characterized by visuospatial peaks. While different specific strengths characterize different autistic spectrum subgroups, all such peaks of ability have been interpreted as deficits: isolated, aberrant, and irreconcilable with real human intelligence. This view has recently been challenged by findings of autistic strengths in performance on Raven's Progressive Matrices (RPM), an important marker of general and fluid intelligence. We investigated whether these findings extend to Asperger syndrome, an autistic spectrum subgroup characterized by verbal peaks of ability, and whether the cognitive mechanisms underlying autistic and Asperger RPM performance differ. Thirty-two Asperger adults displayed a significant advantage on RPM over Wechsler Full-Scale and Performance scores relative to their typical controls, while in 25 Asperger children an RPM advantage was found over Wechsler Performance scores only. As previously found with autistics, Asperger children and adults achieved RPM scores at a level reflecting their Wechsler peaks of ability. Therefore, strengths in RPM performance span the autistic spectrum and imply a common mechanism advantageously applied to different facets of cognition. Autistic spectrum intelligence is atypical, but also genuine, general, and underestimated. C1 [Soulieres, Isabelle; Dawson, Michelle; Mottron, Laurent] Univ Montreal, Ctr Excellence Troubles Envahissants Dev, Montreal, PQ, Canada. [Soulieres, Isabelle] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Gernsbacher, Morton Ann] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. RP Soulieres, I (reprint author), Univ Montreal, Ctr Excellence Troubles Envahissants Dev, Montreal, PQ, Canada. EM isabelle@nmr.mgh.harvard.edu FU Canadian Institutes for Health Research (CIHR) [MOP-84243] FX This work was supported by a grant from Canadian Institutes for Health Research (CIHR; grant MOP-84243) to LM and a postdoctoral award from CIHR to IS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 23 Z9 23 U1 12 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2011 VL 6 IS 9 AR e25372 DI 10.1371/journal.pone.0025372 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834CT UT WOS:000295936900056 PM 21991394 ER PT J AU Weisberg, E Ray, A Nelson, E Adamia, S Barrett, R Sattler, M Zhang, CS Daley, JF Frank, D Fox, E Griffin, JD AF Weisberg, Ellen Ray, Arghya Nelson, Erik Adamia, Sophia Barrett, Rosemary Sattler, Martin Zhang, Chengsheng Daley, John F. Frank, David Fox, Edward Griffin, James D. TI Reversible Resistance Induced by FLT3 Inhibition: A Novel Resistance Mechanism in Mutant FLT3-Expressing Cells SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; ACTIVATING MUTATION; POINT MUTATIONS; IN-VITRO; CONSTITUTIVE ACTIVATION; CLINICAL RESISTANCE; THERAPEUTIC TARGET AB Objectives: Clinical responses achieved with FLT3 kinase inhibitors in acute myeloid leukemia (AML) are typically transient and partial. Thus, there is a need for identification of molecular mechanisms of clinical resistance to these drugs. In response, we characterized MOLM13 AML cell lines made resistant to two structurally-independent FLT3 inhibitors. Methods: MOLM13 cells were made drug resistant via prolonged exposure to midostaurin and HG-7-85-01, respectively. Cell proliferation was determined by Trypan blue exclusion. Protein expression was assessed by immunoblotting, immunoprecipitation, and flow cytometry. Cycloheximide was used to determine protein half-life. RT-PCR was performed to determine FLT3 mRNA levels, and FISH analysis was performed to determine FLT3 gene expression. Results and Conclusions: We found that MOLM13 cells readily developed cross-resistance when exposed to either midostaurin or HG-7-85-01. Resistance in both lines was associated with dramatically elevated levels of cell surface FLT3 and elevated levels of phosphor-MAPK, but not phospho-STAT5. The increase in FLT3-ITD expression was at least in part due to reduced turnover of the receptor, with prolonged half-life. Importantly, the drug-resistant phenotype could be rapidly reversed upon withdrawal of either inhibitor. Consistent with this phenotype, no significant evidence of FLT3 gene amplification, kinase domain mutations, or elevated levels of mRNA was observed, suggesting that protein turnover may be part of an auto-regulatory pathway initiated by FLT3 kinase activity. Interestingly, FLT3 inhibitor resistance also correlated with resistance to cytosine arabinoside. Over-expression of FLT3 protein in response to kinase inhibitors may be part of a novel mechanism that could contribute to clinical resistance. C1 [Weisberg, Ellen; Ray, Arghya; Nelson, Erik; Adamia, Sophia; Barrett, Rosemary; Sattler, Martin; Frank, David; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. [Zhang, Chengsheng] Dana Farber Canc Inst, Cytogenet Core Facil, Boston, MA 02115 USA. [Daley, John F.] Dana Farber Canc Inst, Hematol Neoplasia Flow Cytometry Facil, Boston, MA 02115 USA. [Fox, Edward] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02115 USA. RP Weisberg, E (reprint author), Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. EM ellen_weisberg@dfci.harvard.edu FU National Institutes of Health (NIH) [CA66996, CA134660-03] FX JDG is supported by National Institutes of Health (NIH) grant CA66996 and MS is supported by NIH grant CA134660-03. JDG has a financial interest with Novartis Pharma AG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 13 Z9 13 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2011 VL 6 IS 9 AR e25351 DI 10.1371/journal.pone.0025351 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834CT UT WOS:000295936900054 PM 21980431 ER PT J AU Nasr, S Liu, N Devaney, KJ Yue, XM Rajimehr, R Ungerleider, LG Tootell, RBH AF Nasr, Shahin Liu, Ning Devaney, Kathryn J. Yue, Xiaomin Rajimehr, Reza Ungerleider, Leslie G. Tootell, Roger B. H. TI Scene-Selective Cortical Regions in Human and Nonhuman Primates SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HUMAN VISUAL-CORTEX; FUSIFORM FACE AREA; PARAHIPPOCAMPAL PLACE AREA; HUMAN EXTRASTRIATE CORTEX; INFERIOR TEMPORAL CORTEX; FUNCTIONAL MRI; CEREBRAL-CORTEX; VISUOTOPIC ORGANIZATION; RETROSPLENIAL CORTEX; OBJECT PERCEPTION AB fMRI studies have revealed three scene-selective regions in human visual cortex [the parahippocampal place area (PPA), transverse occipital sulcus (TOS), and retrosplenial cortex (RSC)], which have been linked to higher-order functions such as navigation, scene perception/recognition, and contextual association. Here, we document corresponding (presumptively homologous) scene-selective regions in the awake macaque monkey, based on direct comparison to human maps, using identical stimuli and largely overlapping fMRI procedures. In humans, our results showed that the three scene-selective regions are centered near-but distinct from-the gyri/sulci for which they were originally named. In addition, all these regions are located within or adjacent to known retinotopic areas. Human RSC and PPA are located adjacent to the peripheral representation of primary and secondary visual cortex, respectively. Human TOS is located immediately anterior/ventral to retinotopic area V3A, within retinotopic regions LO-1, V3B, and/or V7. Mirroring the arrangement of human regions fusiform face area (FFA) and PPA (which are adjacent to each other in cortex), the presumptive monkey homolog of human PPA is located adjacent to the monkey homolog of human FFA, near the posterior superior temporal sulcus. Monkey TOS includes the region predicted from the human maps (macaque V4d), extending into retinotopically defined V3A. A possible monkey homolog of human RSC lies in the medial bank, near peripheral V1. Overall, our findings suggest a homologous neural architecture for scene-selective regions in visual cortex of humans and nonhuman primates, analogous to the face-selective regions demonstrated earlier in these two species. C1 [Nasr, Shahin; Devaney, Kathryn J.; Yue, Xiaomin; Rajimehr, Reza; Tootell, Roger B. H.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Liu, Ning; Ungerleider, Leslie G.; Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu FU NIH [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; NCRR; MIND Institute [1S10RR023401, 1S10RR019, 1S10RR023043]; NIMH FX This work was supported by NIH Grants R01 MH67529 and R01 EY017081 ( R. B. H. T.), the Martinos Center for Biomedical Imaging, the NCRR, the MIND Institute, Shared Instrumentation Grants 1S10RR023401, 1S10RR019, and 1S10RR023043, and the NIMH Intramural Research Program. NR 89 TC 81 Z9 82 U1 0 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 28 PY 2011 VL 31 IS 39 BP 13771 EP 13785 DI 10.1523/JNEUROSCI.2792-11.2011 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 826OP UT WOS:000295363800010 PM 21957240 ER PT J AU Syed, Z Stultz, CM Scirica, BM Guttag, JV AF Syed, Zeeshan Stultz, Collin M. Scirica, Benjamin M. Guttag, John V. TI Computationally Generated Cardiac Biomarkers for Risk Stratification After Acute Coronary Syndrome SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; ACUTE MYOCARDIAL-INFARCTION; SCIENTIFIC STATEMENT; CLINICAL CARDIOLOGY; RANDOMIZED-TRIALS; TIME-SERIES; DEATH; STRATEGIES; THERAPY; DISEASE AB The existing tools for estimating the risk of death in patients after they experience acute coronary syndrome are commonly based on echocardiography and clinical risk scores (for example, the TIMI risk score). These identify a small group of high-risk patients who account for only a minority of the deaths that occur in patients after acute coronary syndrome. Here, we investigated the use of three computationally generated cardiac biomarkers for risk stratification in this population: morphologic variability (MV), symbolic mismatch (SM), and heart rate motifs (HRM). We derived these biomarkers from time-series analyses of continuous electrocardiographic data collected from patients in the TIMI-DISPERSE2 clinical trial through machine learning and data mining methods designed to extract information that is difficult to visualize directly in these data. We evaluated these biomarkers in a blinded, prespecified, and fully automated study on more than 4500 patients in the MERLIN-TIMI36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36) clinical trial. Our results showed a strong association between all three computationally generated cardiac biomarkers and cardiovascular death in the MERLIN-TIMI36 trial over a 2-year period after acute coronary syndrome. Moreover, the information in each of these biomarkers was independent of the information in the others and independent of the information provided by existing clinical risk scores, electrocardiographic metrics, and echocardiography. The addition of MV, SM, and HRM to existing metrics significantly improved model discrimination, as well as the precision and recall of prediction rules based on left ventricular ejection fraction. These biomarkers can be extracted from data that are routinely captured from patients with acute coronary syndrome and will allow for more accurate risk stratification and potentially for better patient treatment. C1 [Syed, Zeeshan] Univ Michigan, Ann Arbor, MI 48109 USA. [Stultz, Collin M.; Scirica, Benjamin M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Stultz, Collin M.; Guttag, John V.] MIT, Cambridge, MA 02139 USA. [Scirica, Benjamin M.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Syed, Z (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. EM zhs@umich.edu FU National Science Foundation; American Heart Association; Center for Integration of Medicine and Innovative Technology; Quanta Computer; Harvard-MIT Division of Health Sciences and Technology; AstraZeneca LLC; CV Therapeutics (now Gilead Sciences); Brigham and Women's Hospital FX Supported by the National Science Foundation, the American Heart Association, the Center for Integration of Medicine and Innovative Technology, Quanta Computer, and the Harvard-MIT Division of Health Sciences and Technology. The TIMI-DISPERSE2 trial was supported by AstraZeneca LLC. The MERLIN-TIMI36 trial was supported by CV Therapeutics (now Gilead Sciences).; B.M.S. has received research support via Brigham and Women's Hospital from Gilead Sciences and served as a paid consultant. The other authors declare that they have no competing interests. The Massachusetts Institute of Technology has submitted a patent application for the use of the MV analysis with Z.S., C. M. S., and J.V.G. listed as inventors. NR 38 TC 4 Z9 4 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 28 PY 2011 VL 3 IS 102 AR 102ra95 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 826AH UT WOS:000295323200006 PM 21957173 ER PT J AU Soremekun, OA Brown, DFM Pines, JM AF Soremekun, Olan A. Brown, David F. M. Pines, Jesse M. TI Ambulance Diversion and Survival Among Patients With Acute Myocardial Infarction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ASSOCIATION C1 [Soremekun, Olan A.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Brown, David F. M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Pines, Jesse M.] George Washington Univ, Dept Emergency Med, Washington, DC USA. RP Soremekun, OA (reprint author), Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. EM olanrewaju.soremekun@uphs.upenn.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 28 PY 2011 VL 306 IS 12 BP 1324 EP 1325 DI 10.1001/jama.2011.1352 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 825FQ UT WOS:000295257000014 PM 21954474 ER PT J AU Barry, MJ Meleth, S Lee, JY Kreder, KJ Avins, AL Nickel, JC Roehrborn, CG Crawford, ED Foster, HE Kaplan, SA McCullough, A Andriole, GL Naslund, MJ Williams, OD Kusek, JW Meyers, CM Betz, JM Cantor, A McVary, KT AF Barry, Michael J. Meleth, Sreelatha Lee, Jeannette Y. Kreder, Karl J. Avins, Andrew L. Nickel, J. Curtis Roehrborn, Claus G. Crawford, E. David Foster, Harris E., Jr. Kaplan, Steven A. McCullough, Andrew Andriole, Gerald L. Naslund, Michael J. Williams, O. Dale Kusek, John W. Meyers, Catherine M. Betz, Joseph M. Cantor, Alan McVary, Kevin T. CA Complementary Alternative Med Urol TI Effect of Increasing Doses of Saw Palmetto Extract on Lower Urinary Tract Symptoms A Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; CLINICAL-RESEARCH; HEALTH-STATUS; IMPACT INDEX; SCALE; MEN; QUESTIONNAIRE; PHYTOTHERAPY; DYSFUNCTION; VALIDATION AB Context Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). Objective To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. Design, Setting, and Participants A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. Interventions One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. Main Outcome Measures Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, post-void residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. Results Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -0.36) with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P=.91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. Conclusion Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. C1 [Barry, Michael J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meleth, Sreelatha; Williams, O. Dale; Cantor, Alan] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [Kreder, Karl J.] Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. [Avins, Andrew L.] No Calif Kaiser Permanente, Div Res, Oakland, CA USA. [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON, Canada. [Roehrborn, Claus G.] Univ Texas SW Med Ctr Dallas, Dept Urol, Dallas, TX 75390 USA. [Crawford, E. David] Univ Colorado, Sect Urol Oncol, Denver, CO 80202 USA. [Foster, Harris E., Jr.] Yale Univ, Sch Med, Urol Sect, New Haven, CT USA. [Kaplan, Steven A.] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [McCullough, Andrew] NYU, Urol Associates, New York, NY USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Naslund, Michael J.] Univ Maryland, Maryland Prostate Ctr, Baltimore, MD 21201 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. [Meyers, Catherine M.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [McVary, Kevin T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM mbarry@partners.org FU GlaxoSmithKline; Pfizer; Watson; Astellas; Ferring; Taris; Triton; Farr Labs; Trillium; Cernelle; Johnson Johnson; Amgen; Bayer; Caris; France Foundation; GenProbe; Steba Biotech; Ortho-Clinical Diagnostics; Ferring Pharmaceuticals; Lilly/ICOS; Allergan; National Institute of Diabetes and Digestive and Kidney Diseases; Watson Pharm; Neotract; National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, U01 DK63788]; National Center for Complementary and Alternative Medicine; Office of Dietary Supplements, NIH FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Barry reported serving on the board of and receiving salary support as president of the not-for-profit (501[3]c) Foundation for Informed Medical Decision Making (http://www.fimdm.org), which develops content for patient education programs. The foundation has an arrangement with a for-profit company, Health Dialog, to coproduce and market these programs to health care organizations. Dr Lee reported that funds were paid to her institution for consultancy to Merck. Dr Nickel reported receiving consultation funds from GlaxoSmithKline, Pfizer, Watson, Astellas, Ferring, Taris, Triton, Farr Labs, Trillium, Cernelle, and Johnson & Johnson; having provided expert testimony for GlaxoSmithKline; and having received payment for development of educational presentations from the Canadian Urological Association. Dr Crawford reported receiving payment for lectures from Ferring Pharmaceuticals and GlaxoSmithKline. Dr Andriole reported receiving consultation funds from Amgen, Bayer, Caris, France Foundation, GenProbe, GlaxoSmithKline, Steba Biotech, Ortho-Clinical Diagnostics, and Ferring Pharmaceuticals; having received royalties from Up to Date; receiving payment for development of educational presentations from Amgen; having stock and/or stock options in Envisioneering Medical, Viking Medical, Augmenix, and Cambridge Endo; and receiving travel, accommodations, and meeting expenses from Amgen, Augmenix, Bayer, Cambridge Endo, Caris, France Foundation, GenProbe, Myriad Genetics, Steba Biotech, and Ortho Clinical Diagnostics. Dr Naslund reported receiving payment for lectures from GlaxoSmithKline and sanofi-aventis, as well as payment for development of educational presentations for France Foundation. Dr McVary reported receiving consultancy funds from Lilly/ICOS, Allergan, National Institute of Diabetes and Digestive and Kidney Diseases, Watson Pharm, and Neotract, as well as payment for lectures from GlaxoSmithKline. No other disclosures were reported.; This study was funded by cooperative agreements U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, and U01 DK63788 from the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. Support was also provided by the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, NIH. Saw palmetto fruit extract and matching placebo were donated by Rottapharm/Madaus, Cologne, Germany. This study was conducted under an Investigational New Drug Application from the US Food and Drug Administration. NR 28 TC 55 Z9 55 U1 1 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 28 PY 2011 VL 306 IS 12 BP 1344 EP 1351 DI 10.1001/jama.2011.1364 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 825FQ UT WOS:000295257000023 PM 21954478 ER PT J AU Maher, AR Maglione, M Bagley, S Suttorp, M Hu, JH Ewing, B Wang, Z Timmer, M Sultzer, D Shekelle, PG AF Maher, Alicia Ruelaz Maglione, Margaret Bagley, Steven Suttorp, Marika Hu, Jian-Hui Ewing, Brett Wang, Zhen Timmer, Martha Sultzer, David Shekelle, Paul G. TI Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in Adults A Systematic Review and Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID OBSESSIVE-COMPULSIVE DISORDER; PLACEBO-CONTROLLED-TRIAL; SEROTONIN REUPTAKE INHIBITORS; GENERALIZED ANXIETY DISORDER; CONTROLLED CLINICAL-TRIAL; NURSING-HOME RESIDENTS; FUMARATE QUETIAPINE XR; DOUBLE-BLIND TRIAL; A-DOUBLE-BLIND; ALZHEIMERS-DISEASE AB Context Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder. Objective To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration. Data Sources and Study Selection Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events. Data Extraction Independent article review and study quality assessment by 2 investigators. Data Synthesis Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH]=87), stroke (NNH=53 for risperidone), extrapyramidal symptoms (NNH=10 for olanzapine; NNH=20 for risperidone), and urinary tract symptoms (NNH range=16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms. Conclusions Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common. JAMA. 2011;306(12):1359-1369 C1 [Maher, Alicia Ruelaz; Maglione, Margaret; Suttorp, Marika; Hu, Jian-Hui; Ewing, Brett; Wang, Zhen; Timmer, Martha; Shekelle, Paul G.] So Calif Evidence Based Practice Ctr, RAND Hlth, Santa Monica, CA 90401 USA. [Bagley, Steven] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Sultzer, David; Shekelle, Paul G.] W Los Angeles VA Med Ctr, Los Angeles, CA USA. [Sultzer, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Maher, AR (reprint author), So Calif Evidence Based Practice Ctr, RAND Hlth, 1776 Main St, Santa Monica, CA 90401 USA. EM Alicia.Ruelaz@cshs.org RI Wang, Zhen/D-5991-2013 OI Wang, Zhen/0000-0002-9368-6149 FU Eli Lilly; RAND Corporation; Agency for Healthcare Research and Quality [HHSA2902007100621]; Department of Veterans Affairs FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sultzer reported that he received research support for an Alzheimer disease study from Eli Lilly (no direct or indirect salary was paid to him) and consulting fees from RAND Corporation for his work as member of a technical expert panel for the Agency for Healthcare Research and Quality that performed the initial analysis. No other disclosures were reported.; This article is based on research conducted by the Southern California Evidence-Based Practice Center under contract HHSA2902007100621 with the Agency for Healthcare Research and Quality. This work was commissioned by the Agency for Healthcare Research and Quality as an update to an earlier report. Drs Sultzer and Shekelle are also supported by the Department of Veterans Affairs. NR 99 TC 191 Z9 199 U1 9 U2 37 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 28 PY 2011 VL 306 IS 12 BP 1359 EP 1369 DI 10.1001/jama.2011.1360 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 825FQ UT WOS:000295257000025 PM 21954480 ER PT J AU Murphy, RM Shah, RV Malhotra, R Pappagianopoulos, PP Hough, SS Systrom, DM Semigran, MJ Lewis, GD AF Murphy, Ryan M. Shah, Ravi V. Malhotra, Rajeev Pappagianopoulos, Paul P. Hough, Stacyann S. Systrom, David M. Semigran, Marc J. Lewis, Gregory D. TI Exercise Oscillatory Ventilation in Systolic Heart Failure An Indicator of Impaired Hemodynamic Response to Exercise SO CIRCULATION LA English DT Article DE congestive heart failure; exercise testing; heart failure; ventilation ID CHEYNE-STOKES RESPIRATION; IDIOPATHIC DILATED CARDIOMYOPATHY; CARDIAC TRANSPLANTATION; WEDGE PRESSURE; SLEEP; MORTALITY; MECHANISM; SECONDARY; HYPERVENTILATION; CHEMOSENSITIVITY AB Background-Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. Methods and Results-Fifty-six patients with systolic HF (mean +/- SEM age, 59 +/- 2 years; left ventricular ejection fraction, 30 +/- 1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF + EOV) patients and in none of the control subjects. The HF + EOV group did not differ from the HF patients without EOV (HF - EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not PaCO(2) or PaO(2). Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L.min(-1).m(-2) decrement in CI; 95% confidence interval, 1.14-1.70; P=0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length (R=-0.71) and amplitude (R=-0.60; both P<0.001). In 11 HF + EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. Conclusion-Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. C1 [Lewis, Gregory D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Med, Heart Failure & Cardiac Transplantat Unit,Cardiol, Boston, MA 02114 USA. [Pappagianopoulos, Paul P.; Hough, Stacyann S.; Systrom, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Lewis, GD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Med, Heart Failure & Cardiac Transplantat Unit,Cardiol, Bigelow 800,Fruit St, Boston, MA 02114 USA. EM glewis@partners.org OI Systrom, David/0000-0002-9610-6330; Malhotra, Rajeev/0000-0003-0120-4630 FU National Heart, Lung, and Blood Institute [NIH-K23HL091106]; National Heart, Lung, and Blood Institute Heart Failure Network [U01-HL084877]; American Heart Association [11POST000002]; Heart Failure Research Innovation Fund FX We gratefully acknowledge support from the National Heart, Lung, and Blood Institute (NIH-K23HL091106, Dr Lewis); the National Heart, Lung, and Blood Institute Heart Failure Network training grant (U01-HL084877, to Drs Shah and Lewis); the American Heart Association Post-Doctoral Fellowship Award (11POST000002, to Dr Shah); and the Heart Failure Research Innovation Fund (to R. M. Murphy and Dr Lewis). NR 45 TC 38 Z9 39 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 27 PY 2011 VL 124 IS 13 BP 1442 EP U196 DI 10.1161/CIRCULATIONAHA.111.024141 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 824QV UT WOS:000295218000017 PM 21875912 ER PT J AU Goldstein, JA Chinnaiyan, KM Abidov, A Achenbach, S Berman, DS Hayes, SW Hoffmann, U Lesser, JR Mikati, IA O'Neil, BJ Shaw, LJ Shen, MYH Valeti, US Raff, GL AF Goldstein, James A. Chinnaiyan, Kavitha M. Abidov, Aiden Achenbach, Stephan Berman, Daniel S. Hayes, Sean W. Hoffmann, Udo Lesser, John R. Mikati, Issam A. O'Neil, Brian J. Shaw, Leslee J. Shen, Michael Y. H. Valeti, Uma S. Raff, Gilbert L. CA CT-STAT Investigators TI The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute chest pain; coronary computed tomography; cost of care; diagnostic effectiveness; emergency department ID CARDIOVASCULAR-MAGNETIC-RESONANCE; AMERICAN-HEART-ASSOCIATION; RANDOMIZED CONTROLLED-TRIAL; APPROPRIATE USE CRITERIA; EMERGENCY-DEPARTMENT; NUCLEAR-CARDIOLOGY; TASK-FORCE; UNSTABLE ANGINA; ARTERY-DISEASE; COMPREHENSIVE STRATEGY AB Objectives The purpose of this study was to compare the efficiency, cost, and safety of a diagnostic strategy employing early coronary computed tomographic angiography (CCTA) to a strategy employing rest-stress myocardial perfusion imaging (MPI) in the evaluation of acute low-risk chest pain. Background In the United States, >8 million patients require emergency department evaluation for acute chest pain annually at an estimated diagnostic cost of >$10 billion. Methods This multicenter, randomized clinical trial in 16 emergency departments ran between June 2007 and November 2008. Patients were randomly allocated to CCTA (n = 361) or MPI (n = 338) as the index noninvasive test. The primary outcome was time to diagnosis; the secondary outcomes were emergency department costs of care and safety, defined as freedom from major adverse cardiac events in patients with normal index tests, including 6-month follow-up. Results The CCTA resulted in a 54% reduction in time to diagnosis compared with MPI (median 2.9 h [25th to 75th percentile: 2.1 to 4.0 h] vs. 6.3 h [25th to 75th percentile: 4.2 to 19.0 h], p < 0.0001). Costs of care were 38% lower compared with standard (median $2,137 [25th to 75th percentile: $1,660 to $3,077] vs. $3,458 [25th to 75th percentile: $2,900 to $4,297], p < 0.0001). The diagnostic strategies had no difference in major adverse cardiac events after normal index testing (0.8% in the CCTA arm vs. 0.4% in the MPI arm, p = 0.29). Conclusions In emergency department acute, low-risk chest pain patients, the use of CCTA results in more rapid and cost-efficient safe diagnosis than rest-stress MPI. Further studies comparing CCTA to other diagnostic strategies are needed to optimize evaluation of specific patient subsets. (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment [CT-STAT]; NCT00468325) (J Am Coll Cardiol 2011; 58: 1414-22) (C) 2011 by the American College of Cardiology Foundation C1 [Goldstein, James A.; Chinnaiyan, Kavitha M.; Raff, Gilbert L.] William Beaumont Hosp, Div Cardiol, Royal Oak, MI 48073 USA. [Abidov, Aiden] Univ Arizona, Div Cardiol, Tucson, AZ USA. [Achenbach, Stephan] Univ Giessen, Dept Cardiol, Giessen, Germany. [Berman, Daniel S.; Hayes, Sean W.] Cedars Sinai Med Ctr, Dept Imaging, Los Angeles, CA 90048 USA. [Berman, Daniel S.; Hayes, Sean W.] Cedars Sinai Med Ctr, Dept Cardiol, Los Angeles, CA 90048 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Lesser, John R.] Minneapolis Heart Inst, Minneapolis, MN USA. [Mikati, Issam A.] Northwestern Univ, Div Cardiol, Sch Med, Chicago, IL USA. [O'Neil, Brian J.] Wayne State Univ, Sch Med, Dept Emergency Med, Detroit, MI USA. [Shaw, Leslee J.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Shen, Michael Y. H.] Cleveland Clin Florida, Div Cardiol, Ft Lauderdale, FL USA. [Valeti, Uma S.] Univ Minnesota, Minneapolis, MN USA. RP Raff, GL (reprint author), William Beaumont Hosp, Div Cardiol, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM graff@beaumont.edu FU Bayer Pharmaceuticals; Sarver Heart Center; Siemens FX From the *Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan; dagger Division of Cardiology, University of Arizona, Tucson, Arizona; double dagger Department of Cardiology, University of Giessen, Giessen, Germany; Departments of Imaging and Cardiology, Cedars-Sinai Medical Center, Los Angeles, California; parallel to Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Minneapolis Heart Institute, Minneapolis, Minnesota; #Division of Cardiology, Northwestern University Medical School, Chicago, Illinois; **Department of Emergency Medicine, Wayne State University Medical School, Detroit, Michigan; dagger dagger Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; double dagger double dagger Division of Cardiology, Cleveland Clinic Florida, Fort Lauderdale, Florida; and the University of Minnesota, Minneapolis, Minnesota. This study was funded by a research grant from Bayer Pharmaceuticals. Bayer Pharmaceuticals did not design, conduct, analyze, or interpret this study, nor did it prepare or review this manuscript. Dr. Abidov has served on the Speakers' Bureau of Astellas Pharma and has received grant support from Sarver Heart Center. Drs. Achenbach and Lesser have received research grants and speaker honoraria from Siemens. Dr. O'Neil is on the Speakers' Bureau of Bristol Myers-Squibb and Sanofi-Aventis; and is an unpaid consultant for Heartscape and ZOLL Circulation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 45 TC 209 Z9 214 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 27 PY 2011 VL 58 IS 14 BP 1414 EP 1422 DI 10.1016/j.jacc.2011.03.068 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 824PH UT WOS:000295213900003 PM 21939822 ER PT J AU Camargo, CA AF Camargo, Carlos A., Jr. TI Vitamin D and Cardiovascular Disease Time for Large Randomized Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE heart failure; mineral metabolism; myocardial infarction; parathyroid hormone; vitamin D ID SERUM 25-HYDROXYVITAMIN D; HEART-FAILURE; D DEFICIENCY; MORTALITY; METAANALYSIS; SUPPLEMENTS; PREVENTION C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Camargo, CA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org NR 18 TC 7 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 27 PY 2011 VL 58 IS 14 BP 1442 EP 1444 DI 10.1016/j.jacc.2011.06.037 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 824PH UT WOS:000295213900007 PM 21939826 ER PT J AU Kapoor, JR Kapoor, R Hellkamp, AS Hernandez, AF Heidenreich, PA Fonarow, GC AF Kapoor, John R. Kapoor, Roger Hellkamp, Anne S. Hernandez, Adrian F. Heidenreich, Paul A. Fonarow, Gregg C. TI Payment Source, Quality of Care, and Outcomes in Patients Hospitalized With Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE outcomes; payment source; quality ID INITIATE LIFESAVING TREATMENT; ORGANIZED PROGRAM; OPTIMIZE-HF; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; CLINICAL-OUTCOMES AB Objectives The aim of this study was to analyze the relationship between payment source and quality of care and outcomes in heart failure (HF). Background HF is a major cause of morbidity and mortality. There is a lack of studies assessing the association of payment source with HF quality of care and outcomes. Methods A total of 99,508 HF admissions from 244 sites between January 2005 and September 2009 were analyzed. Patients were grouped on the basis of payer status (private/health maintenance organization, no insurance, Medicare, or Medicaid) with private/health maintenance organization as the reference group. Results The no-insurance group was less likely to receive evidence-based beta-blockers (adjusted odds ratio [OR]: 0.73; 95% confidence interval [CI]: 0.62 to 0.86), implantable cardioverter-defibrillator (OR: 0.59; 95% CI: 0.50 to 0.70), or anticoagulation for atrial fibrillation (OR: 0.73; 95% CI: 0.61 to 0.87). Similarly, the Medicaid group was less likely to receive evidence-based beta-blockers (OR: 0.86; 95% CI: 0.78 to 0.95) or implantable cardioverter-defibrillators (OR: 0.86; 95% CI: 0.78 to 0.96). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers were prescribed less frequently in the Medicare group (OR: 0.89; 95% CI: 0.81 to 0.98). The Medicare, Medicaid, and no-insurance groups had longer hospital stays. Higher adjusted rates of in-hospital mortality were seen in patients with Medicaid (OR: 1.22; 95% CI: 1.06 to 1.41) and in patients with reduced systolic function with no insurance. Conclusions Decreased quality of care and outcomes for patients with HF were observed in the no-insurance, Medicaid, and Medicare groups compared with the private/health maintenance organization group. (J Am Coll Cardiol 2011; 58:1465-71) (C) 2011 by the American College of Cardiology Foundation C1 [Kapoor, John R.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60031 USA. [Kapoor, Roger] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hellkamp, Anne S.; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Heidenreich, Paul A.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Kapoor, JR (reprint author), Univ Chicago, Pritzker Sch Med, 5841 S Maryland Ave, Chicago, IL 60031 USA. EM doctorjrk@gmail.com RI Hernandez, Adrian F./A-7818-2016 OI Heidenreich, Paul/0000-0001-7730-8490; Hernandez, Adrian F./0000-0003-3387-9616 FU Medtronic; Ortho-McNeil; AHA Pharmaceutical Roundtable; GlaxoSmithKline; Johnson Johnson; Proventys; Amylin Pharmaceuticals; National Heart, Lung, and Blood Institute FX From the *University of Chicago Pritzker School of Medicine, Chicago, Illinois; dagger Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts; double dagger Duke Clinical Research Institute, Durham, North Carolina; Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and the parallel to Ahmanson-UCLA Cardiomyopathy Center, Los Angeles, California. The Get With the Guidelines Heart Failure (GWTG-HF) program is provided by the American Heart Association (AHA). The GWTG-HF program is currently supported in part by Medtronic, Ortho-McNeil, and the AHA Pharmaceutical Roundtable. GWTG-HF has been funded in the past through support from GlaxoSmithKline. Dr. Hernandez has received research support from Johnson & Johnson, Proventys, and Amylin Pharmaceuticals. Dr. Heidenreich has received grant support from Medtronic. Dr. Fonarow has received research support from the National Heart, Lung, and Blood Institute (significant), is a consultant for Novartis (significant) and Scios (modest), and has received an honorarium from Medtronic (modest). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 14 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 27 PY 2011 VL 58 IS 14 BP 1465 EP 1471 DI 10.1016/j.jacc.2011.06.034 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 824PH UT WOS:000295213900011 PM 21939830 ER PT J AU Van den Stock, J Tamietto, M Sorger, B Pichon, S Grezes, J de Gelder, B AF Van den Stock, Jan Tamietto, Marco Sorger, Bettina Pichon, Swann Grezes, Julie de Gelder, Beatrice TI Cortico-subcortical visual, somatosensory, and motor activations for perceiving dynamic whole-body emotional expressions with and without striate cortex (V1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE blindsight; body expressions; consciousness ID NON-CONSCIOUS RECOGNITION; FACIAL EXPRESSIONS; AFFECTIVE BLINDSIGHT; AMYGDALA RESPONSES; BODILY EXPRESSIONS; MACAQUE MONKEY; AREA-MT; BRAIN; THREAT; FEAR AB Patients with striate cortex damage and clinical blindness retain the ability to process certain visual properties of stimuli that they are not aware of seeing. Here we investigated the neural correlates of residual visual perception for dynamic whole-body emotional actions. Angry and neutral emotional whole-body actions were presented in the intact and blind visual hemifield of a cortically blind patient with unilateral destruction of striate cortex. Comparisons of angry vs. neutral actions performed separately in the blind and intact visual hemifield showed in both cases increased activation in primary somatosensory, motor, and premotor cortices. Activations selective for intact hemifield presentation of angry compared with neutral actions were located subcortically in the right lateral geniculate nucleus and cortically in the superior temporal sulcus, prefrontal cortex, precuneus, and intraparietal sulcus. Activations specific for blind hemifield presentation of angry compared with neutral actions were found in the bilateral superior colliculus, pulvinar nucleus of the thalamus, amygdala, and right fusiform gyrus. Direct comparison of emotional modulation in the blind vs. intact visual hemifield revealed selective activity in the right superior colliculus and bilateral pulvinar for angry expressions, thereby showing a selective involvement of these subcortical structures in nonconscious visual emotion perception. C1 [Van den Stock, Jan; Tamietto, Marco; de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [Van den Stock, Jan; de Gelder, Beatrice] Katholieke Univ Leuven, Brain & Emot Lab Leuven, Dept Neurosci, B-3000 Louvain, Belgium. [Tamietto, Marco] Univ Turin, Dept Psychol, I-10123 Turin, Italy. [Sorger, Bettina] Maastricht Univ, Dept Neuropsychol, NL-6200 MD Maastricht, Netherlands. [Pichon, Swann] Univ Geneva, Lab Behav Neurol & Imaging Cognit, Dept Neurosci, Sch Med, CH-1211 Geneva, Switzerland. [Grezes, Julie] Ecole Normale Super, Cognit Neurosci Lab, Inst Natl Sante & Rech Med, Dept Cognit Studies,U960, F-75005 Paris, France. [de Gelder, Beatrice] Harvard Univ, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP de Gelder, B (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. EM degelder@nmr.mgh.harvard.edu RI Van den Stock, Jan/F-1906-2014; pichon, swann/M-2966-2014; Grezes, Julie/E-5060-2016; OI Van den Stock, Jan/0000-0001-5756-3195; pichon, swann/0000-0001-5697-702X; Tamietto, Marco/0000-0002-8815-8499 FU European Commission [FP6-2005-NEST-Path, Imp 043403-COBOL]; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Netherlands Organization for Scientific Research Postdoctoral Veni [451-07-032]; Fondazione Carlo Molo, Turin, Italy FX B.d.G., S.P., and J.G. were supported by European Commission Communication with Emotional Body Language (COBOL) Grant FP6-2005-NEST-Path Imp 043403-COBOL. J.V.d.S. is a postdoctoral researcher supported by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. M. T. was supported by Netherlands Organization for Scientific Research Postdoctoral Veni Grant 451-07-032 and partly by the Fondazione Carlo Molo, Turin, Italy. NR 61 TC 48 Z9 48 U1 3 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2011 VL 108 IS 39 BP 16188 EP 16193 DI 10.1073/pnas.1107214108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300019 PM 21911384 ER PT J AU Baliram, R Latif, R Berkowitz, J Frid, S Colaianni, G Sun, L Zaidi, M Davies, TF AF Baliram, Ramkumarie Latif, Rauf Berkowitz, Joshua Frid, Simon Colaianni, Graziana Sun, Li Zaidi, Mone Davies, Terry F. TI Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BONE-MARROW-CELLS; RECOMBINANT TSH; PKC-DELTA; IN-VITRO; RECEPTOR; PATHWAY; OSTEOPROTEGERIN; DIFFERENTIATION; EXPRESSION; WOMEN AB We have shown that the anterior pituitary hormone, thyroid-stimulating hormone (TSH), can bypass the thyroid to exert a direct protective effect on the skeleton. Thus, we have suggested that a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels. Earlier mouse genetic, cell-based, and clinical studies together have established that TSH inhibits osteoclastic bone resorption. However, the direct influence of TSH on the osteoblast has remained unclear. Here, we have used a model system developed from murine ES cells, induced to form mature mineralizing osteoblasts, and show that TSH stimulates osteoblast differentiation primarily through the activation of protein kinase C delta and the up-regulation of the noncanonical Wnt components frizzled and Wnt5a. We predict that a TSH-induced, fast-forward short loop in bone marrow permits Wnt5a production, which, in addition to enhancing osteoblast differentiation, also stimulates osteoprotegerin secretion to attenuate bone resorption by neighboring osteoclasts. We surmise that this loop should uncouple bone formation from bone resorption with a net increase in bone mass, which is what has been observed upon injecting TSH. C1 [Baliram, Ramkumarie; Latif, Rauf; Berkowitz, Joshua; Frid, Simon; Davies, Terry F.] Mt Sinai Sch Med, Thyroid Res Lab, New York, NY 10029 USA. [Colaianni, Graziana; Sun, Li; Zaidi, Mone; Davies, Terry F.] Mt Sinai Sch Med, Mt Sinai Bone Program, New York, NY 10029 USA. [Colaianni, Graziana; Sun, Li; Zaidi, Mone; Davies, Terry F.] James J Peters VA Med Ctr, New York, NY 10029 USA. RP Davies, TF (reprint author), Mt Sinai Sch Med, Thyroid Res Lab, New York, NY 10029 USA. EM terry.davies@mssm.edu OI Colaianni, Graziana/0000-0001-8501-5399 FU National Institutes of Health [DK080459, DK069713, DK052464, AG40132, DK70526]; David Owen Segal Endowment; VA Merit Review Program FX This work was supported in part by National Institutes of Health Grants DK080459 (M.Z., L. S., and T. F. D.), DK069713 and DK052464 (T. F. D.), AG40132 and DK70526 (M.Z.), the David Owen Segal Endowment, and the VA Merit Review Program (T. F. D.). NR 29 TC 18 Z9 19 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2011 VL 108 IS 39 BP 16277 EP 16282 DI 10.1073/pnas.1110286108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300034 PM 21911383 ER PT J AU Huang, YT Lin, XH Liu, Y Chirieac, LR McGovern, R Wain, J Heist, R Skaug, V Zienolddiny, S Haugen, A Su, L Fox, EA Wong, KK Christiani, DC AF Huang, Yen-Tsung Lin, Xihong Liu, Yan Chirieac, Lucian R. McGovern, Ray Wain, John Heist, Rebecca Skaug, Vidar Zienolddiny, Shanbeh Haugen, Aage Su, Li Fox, Edward A. Wong, Kwok-Kin Christiani, David C. TI Cigarette smoking increases copy number alterations in nonsmall-cell lung cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor genome; multimarker analyses ID GROWTH-FACTOR-I; BINDING PROTEIN-3; PLASMA-LEVELS; RISK; GENOME; IGF; ADENOCARCINOMA; POLYMORPHISM; EXPOSURE AB Cigarette smoking has been a well-established risk factor of lung cancer for decades. How smoking contributes to tumorigenesis in the lung remains not fully understood. Here we report the results of a genome-wide study of DNA copy number and smoking pack-years in a large collection of nonsmall-cell lung cancer (NSCLC) tumors. Genome-wide analyses of DNA copy number and pack-years of cigarette smoking were performed on 264 NSCLC tumors, which were divided into discovery and validation sets. The copy number-smoking associations were investigated in three scales: whole-genome, chromosome/arm, and focal regions. We found that heavy cigarette smokers (>60 pack-years) have significantly more copy number gains than non-or light smokers (<= 60 pack-years) (P = 2.46 x 10(-4)), especially in 8q and 12q. Copy number losses tend to occur away from genes in non/light smokers (P = 5.15 x 10(-5)) but not in heavy smokers (P = 0.52). Focal copy number analyses showed that there are strong associations of copy number and cigarette smoking pack-years in 12q23 (P = 9.69 x 10(-10)) where IGF1 (insulin-like growth factor 1) is located. All of the above analyses were tested in the discovery set and confirmed in the validation set. DNA double-strand break assays using human bronchial epithelial cell lines treated with cigarette smoke condensate were also performed, and indicated that cigarette smoke condensate leads to genome instability in human bronchial epithelial cells. We conclude that cigarette smoking leads to more copy number alterations, which may be mediated by the genome instability. C1 [Huang, Yen-Tsung; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Huang, Yen-Tsung; Lin, Xihong; McGovern, Ray] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Heist, Rebecca; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Liu, Yan; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fox, Edward A.] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02115 USA. [Chirieac, Lucian R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wain, John; Heist, Rebecca] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Wain, John] Massachusetts Gen Hosp, Thorac Surg Unit, Boston, MA 02114 USA. [Christiani, David C.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Skaug, Vidar; Zienolddiny, Shanbeh; Haugen, Aage] Natl Inst Occupat Hlth, Dept Biol & Chem Working Environm, N-0033 Oslo, Norway. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu RI Huang, Yen-Tsung/I-1003-2014; Zienolddiny, Shanbeh/O-7392-2015; OI wong, kwok kin/0000-0001-6323-235X FU National Institutes of Health [CA076404, CA134294, CA092824, CA074386, CA090578, CA122794, CA140594, CA141576]; Raymond P. Lavietes Foundation; Norwegian Cancer Society FX We thank the participants of the Molecular and Genetic Analysis of Lung Cancer Study; Dr. Cheng Li for his advice on data preprocessing; the Harvard School of Public Health Lung Cancer Study Group: Dr. Kofi Asomaning, Dr. Eugene Mark, Dr. Matthew Kulke, Dr. Wei Zhou, Dr. Geoffrey Liu, Marcia Chertok, Andrea Shafer, Lauren Cassidy, Maureen Convery, and Salvatore Mucci; Drs. Panos Fidias and Bruce A. Chabner and the physicians and surgeons of the Massachusetts General Hospital Cancer Center; and Dr. Lodve Stangeland for recruiting patients. This study is supported by National Institutes of Health Grants CA076404 and CA134294 (to Y.-T. H. and X. L.); National Institutes of Health Grants CA092824, CA074386, and CA090578 (to D. C. C.) and CA122794, CA140594, and CA141576 (to K. K. W.); the Raymond P. Lavietes Foundation (D. C. C.); and the Norwegian Cancer Society (A. H.). NR 29 TC 25 Z9 25 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2011 VL 108 IS 39 BP 16345 EP 16350 DI 10.1073/pnas.1102769108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300046 PM 21911369 ER PT J AU Gutierrez, A Snyder, EL Marino-Enriquez, A Zhang, YX Sioletic, S Kozakewich, E Grebliunaite, R Ou, WB Sicinska, E Raut, CP Demetri, GD Perez-Atayde, AR Wagner, AJ Fletcher, JA Fletcher, CDM Look, AT AF Gutierrez, Alejandro Snyder, Eric L. Marino-Enriquez, Adrian Zhang, Yi-Xiang Sioletic, Stefano Kozakewich, Elena Grebliunaite, Ruta Ou, Wen-bin Sicinska, Ewa Raut, Chandrajit P. Demetri, George D. Perez-Atayde, Antonio R. Wagner, Andrew J. Fletcher, Jonathan A. Fletcher, Christopher D. M. Look, A. Thomas TI Aberrant AKT activation drives well-differentiated liposarcoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MDM2 AMPLIFICATION; TISSUE TUMORS; EXPRESSION; MUTATION; PATHWAY; PLAYS; MTOR AB Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma. C1 [Gutierrez, Alejandro; Kozakewich, Elena; Grebliunaite, Ruta; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Snyder, Eric L.; Sicinska, Ewa] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Snyder, Eric L.; Sicinska, Ewa] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [Snyder, Eric L.; Zhang, Yi-Xiang; Sioletic, Stefano; Sicinska, Ewa; Demetri, George D.; Wagner, Andrew J.] Dana Farber Canc Inst, Ludwig Ctr Dana Farber, Harvard Canc Ctr, Boston, MA 02215 USA. [Zhang, Yi-Xiang; Sioletic, Stefano; Raut, Chandrajit P.; Demetri, George D.; Wagner, Andrew J.; Fletcher, Jonathan A.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02215 USA. [Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Perez-Atayde, Antonio R.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Snyder, Eric L.; Marino-Enriquez, Adrian; Ou, Wen-bin; Fletcher, Jonathan A.; Fletcher, Christopher D. M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Raut, Chandrajit P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Snyder, Eric L.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Gutierrez, A (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Alejandro_Gutierrez@dfci.harvard.edu; thomas_look@dfci.harvard.edu OI Gutierrez, Alejandro/0000-0002-0249-9007 FU Novartis; Roche/Genentech; Pfizer; Exelixis; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Institutes of Health), Harvard University [UL1 RR 025758]; Ludwig Center at Dana-Farber/Harvard Cancer Center; Harvard Medical School; National Institutes of Health [1K08CA133103]; Fundacion Alfonso Martin Escudero FX C.P.R. is a consultant for Novartis and participates in clinical trials of Novartis. G.D.D. is a consultant for Novartis, Pfizer, Ariad, Johnson & Johnson, PharmaMar, Genentech, Infinity Pharmaceuticals, EMD-Serono, Glaxo Smith Kline, Amgen, Daiichi-Sankyo, ArQule, Enzon, Millenium/Takeda; is a member of the scientific advisory board of Plexxikon, ZioPharm, Nereus, N-of-One, and Kolltan Pharmaceuticals; and participates in clinical trials of Novartis, Pfizer, Ariad, Johnson & Johnson, PharmaMar, and Infinity Pharmaceuticals. A.J.W. is a consultant for Novartis, Roche/Genentech, Sanofi, Pfizer, EMD-Serono, and participates in clinical trials supported by Novartis, Roche/Genentech, Pfizer, and Exelixis.; We thank G. Molind and L. Zhang for zebrafish husbandry, J. Testa for the myristoylated mouse Akt2 transgene used in these studies, and D. E. Fisher for the SU-CCS-1 cell line. This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers), as well as the Ludwig Center at Dana-Farber/Harvard Cancer Center and Harvard Medical School; A. G. is supported by National Institutes of Health Grant 1K08CA133103 and is a scholar of the American Society of Hematology-Amos Medical Faculty Development program; and A. M.-E. is supported by Fundacion Alfonso Martin Escudero. NR 26 TC 26 Z9 26 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 27 PY 2011 VL 108 IS 39 BP 16386 EP 16391 DI 10.1073/pnas.1106127108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FB UT WOS:000295255300053 PM 21930930 ER PT J AU Vallabhajosyula, P Tena, A Yamada, K Sachs, DH AF Vallabhajosyula, Prashanth Tena, Aseda Yamada, Kazuhiko Sachs, David H. TI Signal Joint T-Cell Receptor Excision Circle Assay in Miniature Swine SO TRANSPLANTATION LA English DT Article DE T-cell receptor excision circle; Signal joint TREC; Pig; T cell ID MISMATCHED RENAL-ALLOGRAFTS; RECENT THYMIC EMIGRANTS; HIV-INFECTION; TRANSPLANTATION TOLERANCE; PERIPHERAL-BLOOD; ANTIRETROVIRAL THERAPY; IMMUNE RECONSTITUTION; STABLE INDUCTION; OUTPUT; AGE AB Objective: Assays for T cell receptor excision circles (TREC) have been utilized in human, primate, and mouse models as a measure of thymic activity, but no comparable assay has been described in artiodactyls. We describe the development of the porcine signal joint (sj) TREC assay, and provide a likely reason for previous difficulties in its identification in artiodactyls. Design and Methods: Utilizing the homology between the known genomic sequences in sjTREC in human and mouse, polymerase chain reaction (PCR) primers were derived for the putative porcine sjTREC. Primers from the psi J alpha side of the sjTREC were derived from the known porcine sequence. Results: The sjTREC in two artiodactyls, swine and sheep, was identified using forward primers from the psi J alpha region, and reverse primers from the putative delta-rec region. Unlike in the detection of primate TRECs, initially the use of similar primers close to the delta-rec failed to yield the sjTREC product. Marching about 800 basepairs into delta-rec, primers derived from a homology region between human and mouse led to the detection of sjTREC. Comparing sjTREC amongst the species revealed highest homology between the two artiodactyls. A quantitative PCR (QPCR) assay of porcine sjTREC was also developed. Conclusion: Identification and analysis of the sjTREC sequences in two artiodactyls suggested why previous attempts at cloning the pig TREC using known sjTREC sequences were unsuccessful. The development of the porcine signal joint TREC assay should enable a more direct quantification of thymic activity in porcine models of transplant biology. C1 [Sachs, David H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr,Dept Surg, Boston, MA 02129 USA. [Vallabhajosyula, Prashanth] Hosp Univ Penn, Dept Surg, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. RP Sachs, DH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr,Dept Surg, Bldg 149,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu FU American College of Surgeons; American Society of Transplant Surgeons; Roche Scientific Research Fellowship; Ruth L. Kirschstein National Research Scholarship [F32 AI066699-02] FX This work was supported by the American College of Surgeons Fellowship, American Society of Transplant Surgeons, Roche Scientific Research Fellowship, Ruth L. Kirschstein National Research Scholarship Award (5 F32 AI066699-02) (P.V.). NR 41 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 27 PY 2011 VL 92 IS 6 BP 634 EP 640 DI 10.1097/TP.0b013e31822b9287 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 818NE UT WOS:000294757900007 PM 21822172 ER PT J AU Nishimura, H Scalea, J Wang, ZR Shimizu, A Moran, S Gillon, B Sachs, DH Yamada, K AF Nishimura, Hiroaki Scalea, Joseph Wang, Zhirui Shimizu, Akira Moran, Shannon Gillon, Bradford Sachs, David H. Yamada, Kazuhiko TI First Experience With the Use of a Recombinant CD3 Immunotoxin as Induction Therapy in Pig-to-Primate Xenotransplantation: The Effect of T-Cell Depletion on Outcome SO TRANSPLANTATION LA English DT Article DE GalT-KO; Renal graft; Thymokidney; T-cell depletion; Xenotransplantation; Large animal model ID THYMIC TRANSPLANTATION; XENOGRAFT REJECTION; NUCLEAR TRANSFER; MINIATURE SWINE; BABOON MODEL; TOLERANCE; MACROPHAGE; BARRIER AB Background. We have previously reported life-supporting kidney xenograft-survival greater than 80 days using a steroid-free antithymocyte globulin (ATG)-based induction regimen (ATG regimen) in a GalT-KO pig-to-baboon thymokidney (TK) model. We evaluated two induction regimens, a newly developed anti-monkey CD3 recombinant immunotoxin (anti-CD3 rIT) and an anti-human CD2 antibody (LoCD2), by assessing T-cell depletion (TCD) and graft survival. Methods. Four baboons received anti-CD3 rIT; the time course of TCD was studied in two animals and the other two received GalT-KO TK transplants. Two additional baboons underwent GalT-KO TK transplantation after treatment with LoCD2. All other treatments were identical to previous TCD studies with ATG. TCD was assessed by flow-cytometry; renal function was evaluated by serum creatinine and histology. Results. Baboons that received the anti-CD3 rIT died from pneumonia or cardiac failure on days 15 and 23. Both animals in the rIT group died with functioning grafts. Thymokidney grafts from baboons treated with the LoCD2 regimen were rejected by day 14. TCD levels in baboons receiving the anti-CD3 rIT regimen were 150 to 250 cells/mu L for at least 14 days, whereas baboons receiving the LoCD2 recovered to more than 300 cells/mu L by day 7. Conclusions. The newly developed anti-CD3 rIT could be a useful TCD agent in baboons. However, optimal dosage, treatment duration, and bioactivity must be studied to avoid side effects. A LoCD2-based regimen was not effective for preventing xenogeneic rejection. Optimal TCD levels less than 250/mu L during the induction period seem to be important for success of xeno-thymokidney transplantation. C1 [Yamada, Kazuhiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med,MGH East, Transplantat Biol Res Ctr,Organ Transplantat Tole, Boston, MA 02129 USA. RP Yamada, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,MGH East, Transplantat Biol Res Ctr,Organ Transplantat Tole, Bldg 149-9014,13th St, Boston, MA 02129 USA. EM kaz.yamada@tbrc.mgh.harvard.edu FU NIH [5PO1-A145897, 19209043 A] FX This work was supported by NIH Program Project 5PO1-A145897 (Project 1), RPrEP Core, and DF/HCC, and Grant-in-aid for 19209043 A. NR 22 TC 12 Z9 12 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 27 PY 2011 VL 92 IS 6 BP 641 EP 647 DI 10.1097/TP.0b013e31822b92a5 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 818NE UT WOS:000294757900008 PM 21822171 ER PT J AU Yeh, H Kitchens, WH Elias, N Kelsey, PB Markmann, JF Hertl, M AF Yeh, Heidi Kitchens, William H. Elias, Nahel Kelsey, Peter B. Markmann, James F. Hertl, Martin TI Hyperlipidemia due to Biliary Stricture After Living-Donor Liver Transplantation SO TRANSPLANTATION LA English DT Letter ID CIRRHOSIS C1 [Yeh, Heidi; Kitchens, William H.; Elias, Nahel; Markmann, James F.; Hertl, Martin] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. [Kelsey, Peter B.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Yeh, H (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Transplantat, White Bldg 516,55 Fruit St, Boston, MA 02114 USA. EM hyeh@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 27 PY 2011 VL 92 IS 6 BP E29 EP E30 DI 10.1097/TP.0b013e31822d095d PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 818NE UT WOS:000294757900002 PM 21909017 ER PT J AU Roper, J Richardson, MP Wang, WV Richard, LG Chen, W Coffee, EM Sinnamon, MJ Lee, L Chen, PC Bronson, RT Martin, ES Hung, KE AF Roper, Jatin Richardson, Michael P. Wang, Wei Vivian Richard, Larissa Georgeon Chen, Wei Coffee, Erin M. Sinnamon, Mark J. Lee, Lydia Chen, Peng-Chieh Bronson, Roderick T. Martin, Eric S. Hung, Kenneth E. TI The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Induces Tumor Regression in a Genetically Engineered Mouse Model of PIK3CA Wild-Type Colorectal Cancer SO PLOS ONE LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; RENAL-CELL CARCINOMA; RAPAMYCIN INHIBITOR; MAMMALIAN TARGET; SIGNALING PATHWAYS; ANTITUMOR-ACTIVITY; MTORC1 PATHWAY; COLON-CANCER; PI3K; GROWTH AB Purpose: To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC). Experimental Design: PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM) model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined. Results: In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC50 = 9.0-14.3 nM). Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01) vs. a 43% decrease (p = 0.008) in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003), no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013). Conclusions: These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC. C1 [Roper, Jatin; Richardson, Michael P.; Wang, Wei Vivian; Chen, Wei; Coffee, Erin M.; Sinnamon, Mark J.; Lee, Lydia; Hung, Kenneth E.] Tufts Med Ctr, Dept Med, Div Gastroenterol, Boston, MA USA. [Richard, Larissa Georgeon; Chen, Peng-Chieh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. [Bronson, Roderick T.; Martin, Eric S.] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Roper, J (reprint author), Tufts Med Ctr, Dept Med, Div Gastroenterol, Boston, MA USA. EM khung@tuftsmedicalcenter.org OI Roper, Jatin/0000-0002-8851-1352 FU National Cancer Institute [2U01CA084301]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [5K08DK7803325, R03DK088014, T32-DK07542] FX This study was supported by grants from the National Cancer Institute (2U01CA084301) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)(5K08DK7803325, R03DK088014, and T32-DK07542). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 50 Z9 55 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 26 PY 2011 VL 6 IS 9 AR e25132 DI 10.1371/journal.pone.0025132 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834BK UT WOS:000295932100020 PM 21966435 ER PT J AU Yeung, A Hails, K Chang, T Trinh, NH Fava, M AF Yeung, Albert Hails, Kate Chang, Trina Trinh, Nhi-Ha Fava, Maurizio TI A study of the effectiveness of telepsychiatry-based culturally sensitive collaborative treatment of depressed Chinese Americans SO BMC PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; PRIMARY-CARE; DSM-IV; INTERVENTION; VALIDATION; OUTCOMES; MINI AB Background: Chinese American patients with Major Depressive Disorder (MDD) tend to underutilize mental health services and are more likely to seek help in primary care settings than from mental health specialists. Our team has reported that Culturally Sensitive Collaborative Treatment (CSCT) is effective in improving recognition and treatment engagement of depressed Chinese Americans in primary care. The current study builds on this prior research by incorporating telemedicine technology into the CSCT model. Methods/Design: We propose a randomized controlled trial to evaluate the acceptability and effectiveness of a telepsychiatry-based culturally sensitive collaborative treatment (T-CSCT) intervention targeted toward Chinese Americans. Patients meeting the study's eligibility criteria will receive either treatment as usual or the intervention under investigation. The six-month intervention involves: 1) an initial psychiatric interview using a culturally sensitive protocol via videoconference; 2) eight scheduled phone visits with a care manager assigned to the patient, who will monitor the patient's progress, as well as medication side effects and dosage if applicable; and 3) collaboration between the patient's PCP, psychiatrist, and care manager. Outcome measures include depressive symptom severity as well as patient and PCP satisfaction with the telepsychiatry-based care management service. Discussion: The study investigates the T-CSCT model, which we believe will increase the feasibility and practicality of the CSCT model by adopting telemedicine technology. We anticipate that this model will expand access to culturally competent psychiatrists fluent in patients' native languages to improve treatment of depressed minority patients in primary care settings. C1 [Yeung, Albert; Hails, Kate; Chang, Trina; Trinh, Nhi-Ha; Fava, Maurizio] Massachusetts Gen Hosp, Depress & Clin Res Program, Boston, MA 02114 USA. RP Yeung, A (reprint author), Massachusetts Gen Hosp, Depress & Clin Res Program, Boston, MA 02114 USA. EM ayeung@partners.org FU National Institute of Mental Health [R01 MH079831]; AstraZeneca; CeNeRx; Euthymics; Forest; GlaxoSmithKline; Johnson Johnson; Pfizer; Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; Icon Clinical Research; i3 Innovus; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; NARSAD; NCCAM; NIDA; NIMH; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmavite(Register trademark) LLC; Photothera; Roche; RCT Logic, LLC; SanofiAventis US LLC; Shire; Solvay Pharmaceuticals, Inc; Synthelabo; Wyeth-Ayerst Laboratories FX This project is supported by a grant (R01 MH079831) from the National Institute of Mental Health.; Dr. Chang has received research funding from AstraZeneca, CeNeRx, Euthymics, Forest, GlaxoSmithKline, Johnson & Johnson, and Pfizer.; Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Icon Clinical Research; i3 Innovus; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; NARSAD; NCCAM; NIDA; NIMH; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmavite (R) LLC; Photothera; Roche; RCT Logic, LLC; SanofiAventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories NR 24 TC 15 Z9 15 U1 5 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD SEP 26 PY 2011 VL 11 AR 154 DI 10.1186/1471-244X-11-154 PG 8 WC Psychiatry SC Psychiatry GA 832GA UT WOS:000295790000001 PM 21943315 ER PT J AU Goroll, AH AF Goroll, Allan H. TI When It Comes to Primary Care, More May Be More SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID HYPERTENSION; FUTURE C1 [Goroll, Allan H.] Harvard Univ, Sch Med, Boston, MA 02493 USA. [Goroll, Allan H.] Massachusetts Gen Hosp, Med Serv, Boston, MA 02493 USA. RP Goroll, AH (reprint author), Harvard Univ, Sch Med, 15 Parkman St,Ste 645, Boston, MA 02493 USA. EM ahgoroll@partners.org NR 10 TC 3 Z9 3 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 26 PY 2011 VL 171 IS 17 BP 1550 EP 1551 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 824RY UT WOS:000295221000006 PM 21949162 ER PT J AU Zhang, YT Zhou, L Gellad, W AF Zhang, Yuting Zhou, Lei Gellad, Walid TI The True Cost of Discounted Medication Programs reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Zhang, Yuting; Zhou, Lei] Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Gellad, Walid] Univ Pittsburgh, Sch Med, Div Gen Med, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Gellad, Walid] RAND Corp, Pittsburgh, PA USA. RP Zhang, YT (reprint author), Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, 130 De Soto St,Crabtree Hall A664, Pittsburgh, PA 15261 USA. EM ytzhang@pitt.edu OI Zhang, Yuting/0000-0002-6460-6779 NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 26 PY 2011 VL 171 IS 17 BP 1595 EP 1596 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 824RY UT WOS:000295221000025 ER PT J AU Mendelson, T Meltzer, M Campbell, EG Caplan, AL Kirkpatrick, JN AF Mendelson, Todd Meltzer, Michele Campbell, Eric G. Caplan, Arthur L. Kirkpatrick, James N. TI The Proactive Management of "Relationship With Industry" by ACC/AHA in the Creation of Our Cardiovascular Clinical Practice Guidelines reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Kirkpatrick, James N.] Univ Penn, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Mendelson, Todd] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Mendelson, Todd; Caplan, Arthur L.; Kirkpatrick, James N.] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Meltzer, Michele] Thomas Jefferson Univ, Dept Med, Div Rheumatol, Philadelphia, PA 19107 USA. [Campbell, Eric G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mongan Inst Hlth Policy, Boston, MA USA. RP Kirkpatrick, JN (reprint author), Univ Penn, Dept Med, Div Cardiovasc Med, 3400 Spruce St,9014 Gates, Philadelphia, PA 19104 USA. EM james.kirkpatrick@uphs.upenn.edu NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 26 PY 2011 VL 171 IS 17 BP 1599 EP 1600 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 824RY UT WOS:000295221000031 ER PT J AU Casarett, D Richardson, D Smith, D Johnson, M AF Casarett, David Richardson, Diane Smith, Dawn Johnson, Megan TI Palliative Care Units: The Best Option for the Most Distressed reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Casarett, David] Univ Penn, Perelman Sch Med, Div Geriatr Med, Philadelphia, PA 19104 USA. [Richardson, Diane; Smith, Dawn; Johnson, Megan] Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Casarett, D (reprint author), Univ Penn, Perelman Sch Med, Div Geriatr Med, 3615 Chestnut St, Philadelphia, PA 19104 USA. EM casarett@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 26 PY 2011 VL 171 IS 17 BP 1601 EP 1602 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 824RY UT WOS:000295221000036 ER PT J AU Xiao, JJ Jing, ZC Ellinor, PT Liang, DD Zhang, H Liu, Y Chen, XL Pan, L Lyon, R Liu, Y Peng, LY Liang, XQ Sun, YF Popescu, LM Condorelli, G Chen, YH AF Xiao, Junjie Jing, Zhi-Cheng Ellinor, Patrick T. Liang, Dandan Zhang, Hong Liu, Ying Chen, Xiaoli Pan, Lei Lyon, Robert Liu, Yi Peng, Lu-Ying Liang, Xingqun Sun, Yunfu Popescu, Laurentiu M. Condorelli, Gianluigi Chen, Yi-Han TI MicroRNA-134 as a potential plasma biomarker for the diagnosis of acute pulmonary embolism SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; CIRCULATING MICRORNAS; COMPUTED-TOMOGRAPHY; HEART-FAILURE; CARDIOVASCULAR-DISEASES; CANCER; MORTALITY; CARCINOMA; MARKER AB Background: Acute pulmonary embolism (APE) remains a diagnostic challenge due to a variable clinical presentation and the lack of a reliable screening tool. MicroRNAs (miRNAs) regulate gene expression in a wide range of pathophysiologic processes. Circulating miRNAs are emerging biomarkers in heart failure, type 2 diabetes and other disease states; however, using plasma miRNAs as biomarkers for the diagnosis of APE is still unknown. Methods: Thirty-two APE patients, 32 healthy controls, and 22 non-APE patients (reported dyspnea, chest pain, or cough) were enrolled in this study. The TaqMan miRNA microarray was used to identify dysregulated miRNAs in the plasma of APE patients. The TaqMan-based miRNA quantitative real-time reverse transcription polymerase chain reactions were used to validate the dysregulated miRNAs. The receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the miRNA identified as the candidate biomarker. Results: Plasma miRNA-134 (miR-134) level was significantly higher in the APE patients than in the healthy controls or non-APE patients. The ROC curve showed that plasma miR-134 was a specific diagnostic predictor of APE with an area under the curve of 0.833 (95% confidence interval, 0.737 to 0.929; P < 0.001). Conclusions: Our findings indicated that plasma miR-134 could be an important biomarker for the diagnosis of APE. Because of this finding, large-scale investigations are urgently needed to pave the way from basic research to clinical utilization. C1 [Xiao, Junjie; Liang, Dandan; Zhang, Hong; Liu, Ying; Chen, Xiaoli; Pan, Lei; Liu, Yi; Peng, Lu-Ying; Liang, Xingqun; Sun, Yunfu; Chen, Yi-Han] Tongji Univ, Minist Educ, China E Hosp, Key Lab Arrhythmias,Sch Med, Shanghai 200092, Peoples R China. [Xiao, Junjie; Liang, Dandan; Zhang, Hong; Liu, Ying; Liu, Yi; Peng, Lu-Ying; Chen, Yi-Han] Tongji Univ, Inst Med Genet, Shanghai 200092, Peoples R China. [Jing, Zhi-Cheng] Tongji Univ, Shanghai Pulm Hosp, Dept Pulm Circulat, Shanghai 200092, Peoples R China. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lyon, Robert; Condorelli, Gianluigi] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Popescu, Laurentiu M.] Carol Davila Univ Med & Pharm, Dept Cellular & Mol Med, Bucharest, Romania. RP Chen, YH (reprint author), Tongji Univ, Minist Educ, China E Hosp, Key Lab Arrhythmias,Sch Med, Shanghai 200092, Peoples R China. EM yihanchen@tongji.edu.cn OI Condorelli, Gianluigi/0000-0003-0481-6843 FU "973" Program Fund of China [2007CB512100, 2011CB504006]; Ministry of Education, China; Science and Techonology Commission of Shanghai Municipality [10JC1414700]; Key Laboratory of Arrhythmias, Ministry of Education, China (East Hospital, Tongji University School of Medicine); National Institutes of Health [R01HL104156, R21DA027021, R01HL092577] FX This work was supported by the "973" Program Fund of China (2007CB512100 and 2011CB504006); the Yangtze Scholars Program Fund by the Ministry of Education, China; the Program Fund for Innovative Research Teams by the Ministry of Education, China; the Major Project Fund of Science and Techonology Commission of Shanghai Municipality (10JC1414700) (all to Y.-H.C.); the Youth Fund of the Key Laboratory of Arrhythmias, Ministry of Education, China (East Hospital, Tongji University School of Medicine) (to DDL and HZ); and National Institutes of Health grants (R01HL104156, R21DA027021, R01HL092577, to P.T.E). NR 34 TC 40 Z9 43 U1 1 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD SEP 24 PY 2011 VL 9 AR 159 DI 10.1186/1479-5876-9-159 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 832RR UT WOS:000295825000001 PM 21943159 ER PT J AU Jost, S Quillay, H Reardon, J Peterson, E Simmons, RP Parry, BA Bryant, NNP Binder, WD Altfeld, M AF Jost, Stephanie Quillay, Heloise Reardon, Jeff Peterson, Eric Simmons, Rachel P. Parry, Blair A. Bryant, Nancy N. P. Binder, William D. Altfeld, Marcus TI Changes in Cytokine Levels and NK Cell Activation Associated with Influenza SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; ACUTE RESPIRATORY SYNDROME; ACUTE HIV-1 INFECTION; VIRUS-INFECTION; T-CELLS; HUMORAL IMMUNITY; DENDRITIC CELLS; UNITED-STATES; A VIRUS; RESPONSES AB Several studies have highlighted the important role played by murine natural killer (NK) cells in the control of influenza infection. However, human NK cell responses in acute influenza infection, including infection with the 2009 pandemic H1N1 influenza virus, are poorly documented. Here, we examined changes in NK cell phenotype and function and plasma cytokine levels associated with influenza infection and vaccination. We show that absolute numbers of peripheral blood NK cells, and particularly those of CD56(bright) NK cells, decreased upon acute influenza infection while this NK cell subset expanded following intramuscular influenza vaccination. NK cells exposed to influenza antigens were activated, with higher proportions of NK cells expressing CD69 in study subjects infected with seasonal influenza strains. Vaccination led to increased levels of CD25+ NK cells, and notably CD56(bright) CD25+ NK cells, whereas decreased amounts of this subset were present in the peripheral blood of influenza infected individuals, and predominantly in study subjects infected with the 2009 pandemic H1N1 influenza virus. Finally, acute influenza infection was associated with low plasma concentrations of inflammatory cytokines, including IFN-gamma, MIP-1 beta, IL-2 and IL-15, and high levels of the anti-inflammatory cytokines IL-10 and IL-1ra. Altogether, these data suggest a role for the CD56(bright) NK cell subset in the response to influenza, potentially involving their recruitment to infected tissues and a local production and/or uptake of inflammatory cytokines. C1 [Jost, Stephanie; Quillay, Heloise; Reardon, Jeff; Peterson, Eric; Simmons, Rachel P.; Altfeld, Marcus] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst Massachusetts Gen Hosp,Massachusetts I, Boston, MA 02215 USA. [Parry, Blair A.; Binder, William D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Bryant, Nancy N. P.] Massachusetts Gen Hosp, Massachusetts Gen Hosp Med Walk Clin, Boston, MA 02114 USA. RP Jost, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst Massachusetts Gen Hosp,Massachusetts I, Boston, MA 02215 USA. EM maltfeld@partners.org OI Simmons, Rachel/0000-0003-2498-7965 FU Doris Duke Charitable Foundation; Philip T. and Susan M. Ragon Foundation; Swiss National Science Foundation [PBELP3-122872]; Massachusetts General Hospital Executive Committee FX This work was supported by the Doris Duke Charitable Foundation (MA; http://www.ddcf.org/) and the Philip T. and Susan M. Ragon Foundation (MA; http://www.ragoninstitute.org). SJ was supported by the Swiss National Science Foundation (PBELP3-122872; http://www.snf.ch) and the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 27 Z9 28 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2011 VL 6 IS 9 AR e25060 DI 10.1371/journal.pone.0025060 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IZ UT WOS:000295267100019 PM 21966414 ER PT J AU Ladeira, A Fregni, F Campanha, C Valasek, CA De Ridder, D Brunoni, AR Boggio, PS AF Ladeira, Andrea Fregni, Felipe Campanha, Camila Valasek, Claudia Aparecida De Ridder, Dirk Brunoni, Andre Russwsky Boggio, Paulo Sergio TI Polarity-Dependent Transcranial Direct Current Stimulation Effects on Central Auditory Processing SO PLOS ONE LA English DT Article ID MOTOR CORTEX; PHOSPHENE THRESHOLDS; PREFRONTAL CORTEX; DC STIMULATION; PURE-TONES; MODULATION; LOUDNESS; HUMANS; MEMORY; FACILITATION AB Given the polarity dependent effects of transcranial direct current stimulation (tDCS) in facilitating or inhibiting neuronal processing, and tDCS effects on pitch perception, we tested the effects of tDCS on temporal aspects of auditory processing. We aimed to change baseline activity of the auditory cortex using tDCS as to modulate temporal aspects of auditory processing in healthy subjects without hearing impairment. Eleven subjects received 2mA bilateral anodal, cathodal and sham tDCS over auditory cortex in a randomized and counterbalanced order. Subjects were evaluated by the Random Gap Detection Test (RGDT), a test measuring temporal processing abilities in the auditory domain, before and during the stimulation. Statistical analysis revealed a significant interaction effect of time vs. tDCS condition for 4000 Hz and for clicks. Post-hoc tests showed significant differences according to stimulation polarity on RGDT performance: anodal improved 22.5% and cathodal decreased 54.5% subjects' performance, as compared to baseline. For clicks, anodal also increased performance in 29.4% when compared to baseline. tDCS presented polarity-dependent effects on the activity of the auditory cortex, which results in a positive or negative impact in a temporal resolution task performance. These results encourage further studies exploring tDCS in central auditory processing disorders. C1 [Ladeira, Andrea; Campanha, Camila; Valasek, Claudia Aparecida; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Social & Cognit Neurosci Lab, Sao Paulo, Brazil. [Ladeira, Andrea; Campanha, Camila; Valasek, Claudia Aparecida; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Dev Disorders Program, Ctr Hlth & Biol Sci, Sao Paulo, Brazil. [Fregni, Felipe] Spaulding Rehabil Hosp, Lab Neuromodulat, Boston, MA USA. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Fregni, Felipe] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [De Ridder, Dirk] Univ Antwerp Hosp, BRAI2N TRI, Antwerp, Belgium. [De Ridder, Dirk] Univ Antwerp Hosp, Dept Neurosurg, Antwerp, Belgium. [Brunoni, Andre Russwsky] Univ Sao Paulo, Inst Psicol, Nucleo Neurociencias & Comportamento, Sao Paulo, Brazil. RP Ladeira, A (reprint author), Univ Prebiteriana Mackenzie, Social & Cognit Neurosci Lab, Sao Paulo, Brazil. EM boggio@mackenzie.br RI Boggio, Paulo/K-6272-2012; Brunoni, Andre/H-8394-2012 OI Boggio, Paulo/0000-0002-6109-0447; Brunoni, Andre/0000-0002-6310-3571 FU MackPesquisa; CNPq [305718/2009-6]; FAPESP FX This work was supported by MackPesquisa. PSB is supported by a CNPq researcher grant (305718/2009-6). AL was supported by a Master grant (MackPesquisa). CC is supported by a PhD grant (FAPESP). CAV is supported by a Master grant (FAPESP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 33 Z9 33 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 23 PY 2011 VL 6 IS 9 AR e25399 DI 10.1371/journal.pone.0025399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IZ UT WOS:000295267100055 PM 21966519 ER PT J AU Tzatsos, A Paskaleva, P Lymperi, S Contino, G Stoykova, S Chen, Z Wong, KK Bardeesy, N AF Tzatsos, Alexandros Paskaleva, Polina Lymperi, Stephania Contino, Gianmarco Stoykova, Svetlana Chen, Zhao Wong, Kwok-Kin Bardeesy, Nabeel TI Lysine-specific Demethylase 2B (KDM2B)-let-7-Enhancer of Zester Homolog 2 (EZH2) Pathway Regulates Cell Cycle Progression and Senescence in Primary Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYCOMB GROUP; TUMOR-SUPPRESSOR; SKELETAL-MUSCLE; NASOPHARYNGEAL CARCINOMA; EMBRYONIC FIBROBLASTS; MICRORNA EXPRESSION; PROTEIN EZH2; SELF-RENEWAL; STEM-CELLS; P16(INK4A) AB Sustained expression of the histone demethylase, KDM2B (Ndy1/FBXL10/JHDM1B), bypasses cellular senescence in primary mouse embryonic fibroblasts (MEFs). Here, we show that KDM2B is a conserved regulator of lifespan in multiple primary cell types and defines a program in which this chromatin-modifying enzyme counteracts the senescence-associated down-regulation of the EZH2 histone methyltransferase. Senescence in MEFs epigenetically silences KDM2B and induces the tumor suppressor miRNAs let-7b and miR-101, which target EZH2. Forced expression of KDM2B promotes immortalization by silencing these miRNAs through locus-specific histone H3 K36me2 demethylation, leading to EZH2 up-regulation. Overexpression of let-7b down-regulates EZH2, induces premature senescence, and counteracts immortalization of MEFs driven by KDM2B. The KDM2B-let-7-EZH2 pathway also contributes to the proliferation of immortal Ink4a/Arf null fibroblasts suggesting that, beyond its anti-senescence role in primary cells, this histone-modifying enzyme functions more broadly in the regulation of cellular proliferation. C1 [Tzatsos, Alexandros; Paskaleva, Polina; Contino, Gianmarco; Stoykova, Svetlana; Bardeesy, Nabeel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lymperi, Stephania] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Chen, Zhao; Wong, Kwok-Kin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Zhao; Wong, Kwok-Kin] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Tzatsos, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, CPZN4216,185 Cambridge St, Boston, MA 02114 USA. EM atzatsos@partners.org; nelbardeesy@partners.org OI Contino, Gianmarco/0000-0001-5874-0405; wong, kwok kin/0000-0001-6323-235X FU National Institutes of Health, NCI/Harvard GI SPORE [P50 CA127003, R01 CA133557-01]; Waxman Foundation; Andrew Warshaw Institute; Nestora fund FX This work was supported by a National Institutes of Health, NCI/Harvard GI SPORE Grant (P50 CA127003 and R01 CA133557-01). This work was also supported by grants from the Waxman Foundation, the Andrew Warshaw Institute (to N. B.), and from the Nestora fund (to A. T.). NR 38 TC 46 Z9 46 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 23 PY 2011 VL 286 IS 38 BP 33061 EP 33069 DI 10.1074/jbc.M111.257667 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 821IR UT WOS:000294968800025 PM 21757686 ER PT J AU Xiang, XJ Huang, W Haile, CN Kosten, TA AF Xiang, Xiaojun Huang, Wen Haile, Colin N. Kosten, Therese A. TI Hippocampal GluR1 associates with behavior in the elevated plus maze and shows sex differences SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE CREB; AMPA; Anxiety; Female; Rat ID ELEMENT-BINDING PROTEIN; ANXIETY-RELATED BEHAVIOR; ESTROUS-CYCLE; FEMALE RATS; AMPA RECEPTORS; DEFICIENT MICE; CA1 REGION; IN-VIVO; CREB; MEMORY AB The hippocampus is involved in anxiety as well as spatial memory formation and is sexually dimorphic. Female rats typically show less anxiety in elevated plus maze procedure (EPM), a standard animal model of anxiety. Many intracellular proteins, including alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 and the cyclic AMP response element-binding protein (CREB), in hippocampus contribute to memory formation. However, less is known about the roles for hippocampal GluR1 and CREB in anxiety. We examined behavior in EPM in male and female rats and obtained hippocampal tissue samples to determine levels of GluR1 and CREB with western blots. EPM results showed that female rats exhibited less anxiety-like behaviors than male rats. Further, behaviors in EPM were significantly correlated with hippocampal GluR1 levels, but not with CREB. Yet, both proteins showed sex differences with lower levels in female rats. These data not only suggest some potential bases for sex differences in behaviors to which the hippocampus contributes but demonstrate that there is a strong association between hippocampal GluR1 levels and anxiety as assessed with EPM. (C) 2011 Elsevier B.V. All rights reserved. C1 [Xiang, Xiaojun; Huang, Wen; Haile, Colin N.; Kosten, Therese A.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Xiang, Xiaojun; Huang, Wen; Haile, Colin N.; Kosten, Therese A.] Michael E Debakey Vet Adm Med Ctr, Houston, TX 77030 USA. [Xiang, Xiaojun] Cent S Univ, Mental Hlth Inst, Xiangya Hosp 2, Changsha, Hunan, Peoples R China. RP Kosten, TA (reprint author), Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM tkosten@bcm.edu OI Haile, Colin/0000-0001-8293-7291 FU National Institute on Drug Abuse [DA 020117]; Chinese government FX This research was supported by a National Institute on Drug Abuse grant to TAK (DA 020117). XX was supported by a fellowship from the Chinese government. We thank Dr. Alicia Walf for her expert guidance in the elevated plus maze procedure and its analysis. NR 44 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD SEP 23 PY 2011 VL 222 IS 2 BP 326 EP 331 DI 10.1016/j.bbr.2011.03.068 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 780ED UT WOS:000291836400008 PM 21497621 ER PT J AU Chakraborty, N Menze, MA Malsam, J Aksan, A Hand, SC Toner, M AF Chakraborty, Nilay Menze, Michael A. Malsam, Jason Aksan, Alptekin Hand, Steven C. Toner, Mehmet TI Cryopreservation of Spin-Dried Mammalian Cells SO PLOS ONE LA English DT Article ID VITRIFICATION SOLUTIONS; DESICCATION TOLERANCE; TREHALOSE SOLUTIONS; STEM-CELLS; LIPOSOMES; PRESERVATION; TEMPERATURES; KINETICS; DROPLETS; EMBRYOS AB This study reports an alternative approach to achieve vitrification where cells are pre-desiccated prior to cooling to cryogenic temperatures for storage. Chinese Hamster Ovary (CHO) cells suspended in a trehalose solution were rapidly and uniformly desiccated to a low moisture content (<0.12 g of water per g of dry weight) using a spin-drying technique. Trehalose was also introduced into the cells using a high-capacity trehalose transporter (TRET1). Fourier Transform Infrared Spectroscopy (FTIR) was used to examine the uniformity of water concentration distribution in the spin-dried samples. 62% of the cells were shown to survive spin-drying in the presence of trehalose following immediate rehydration. The spin-dried samples were stored in liquid nitrogen (LN(2)) at a vitrified state. It was shown that following re-warming to room temperature and re-hydration with a fully complemented cell culture medium, 51% of the spin-dried and vitrified cells survived and demonstrated normal growth characteristics. Spin-drying is a novel strategy that can be used to improve cryopreservation outcome by promoting rapid vitrification. C1 [Chakraborty, Nilay; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Chakraborty, Nilay; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, BioMEMS Resource Ctr, Boston, MA USA. [Chakraborty, Nilay; Toner, Mehmet] Shriners Hosp Children, Boston, MA USA. [Menze, Michael A.] Eastern Illinois Univ, Dept Biol Sci, Charleston, IL 61920 USA. [Malsam, Jason; Aksan, Alptekin] Univ Minnesota, Dept Mech Engn, Biostabilizat Lab, Minneapolis, MN 55455 USA. [Hand, Steven C.] Louisiana State Univ, Dept Biol Sci, Div Cellular Dev & Integrat Biol, Baton Rouge, LA 70803 USA. RP Chakraborty, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. EM chakraborty.nilay@mgh.harvard.edu RI Chakraborty, Nilay/C-3118-2009; Aksan, Alptekin/C-1579-2014; OI Aksan, Alptekin/0000-0001-9891-1715; Menze, Michael/0000-0003-1072-5462 FU National Institutes of Health [2 RO1 DK046270-14A1, 5 R01 GM086886]; Biopreservation Core Resource, University of Minnesota, Minneapolis, Minnesota FX This work was supported by National Institutes of Health (www.NIH.gov) grants 2 RO1 DK046270-14A1 and 5 R01 GM086886. The authors would like to thank the Biopreservation Core Resource, University of Minnesota, Minneapolis, Minnesota 55455 for providing necessary funding for the Fourier Transform Infrared Spectroscopy Studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 6 Z9 6 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e24916 DI 10.1371/journal.pone.0024916 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100030 PM 21966385 ER PT J AU Coleman, JJ Ghosh, S Okoli, I Mylonakis, E AF Coleman, Jeffrey J. Ghosh, Suman Okoli, Ikechukwu Mylonakis, Eleftherios TI Antifungal Activity of Microbial Secondary Metabolites SO PLOS ONE LA English DT Article ID BIOSYNTHETIC GENE-CLUSTER; CYTOCHROME BC(1) COMPLEX; ASPERGILLUS-FUMIGATUS; CANDIDA-ALBICANS; CAENORHABDITIS-ELEGANS; GLIOTOXIN PRODUCTION; FUSARIUM-OXYSPORUM; ILICICOLIN-H; IN-VITRO; IDENTIFICATION AB Secondary metabolites are well known for their ability to impede other microorganisms. Reanalysis of a screen of natural products using the Caenorhabditis elegans-Candida albicans infection model identified twelve microbial secondary metabolites capable of conferring an increase in survival to infected nematodes. In this screen, the two compound treatments conferring the highest survival rates were members of the epipolythiodioxopiperazine (ETP) family of fungal secondary metabolites, acetylgliotoxin and a derivative of hyalodendrin. The abundance of fungal secondary metabolites indentified in this screen prompted further studies investigating the interaction between opportunistic pathogenic fungi and Aspergillus fumigatus, because of the ability of the fungus to produce a plethora of secondary metabolites, including the well studied ETP gliotoxin. We found that cell-free supernatant of A. fumigatus was able to inhibit the growth of Candida albicans through the production of a secreted product. Comparative studies between a wild-type and an A. fumigatus Delta gliP strain unable to synthesize gliotoxin demonstrate that this secondary metabolite is the major factor responsible for the inhibition. Although toxic to organisms, gliotoxin conferred an increase in survival to C. albicans-infected C. elegans in a dose dependent manner. As A. fumigatus produces gliotoxin in vivo, we propose that in addition to being a virulence factor, gliotoxin may also provide an advantage to A. fumigatus when infecting a host that harbors other opportunistic fungi. C1 [Coleman, Jeffrey J.; Ghosh, Suman; Okoli, Ikechukwu; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Harvard Med Sch, Div Infect Dis, Boston, MA 02114 USA. RP Coleman, JJ (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Div Infect Dis, Boston, MA 02114 USA. EM emylonakis@partners.org RI Ghosh, Suman/F-3453-2013; Coleman, Jeffrey/E-2981-2015; OI Coleman, Jeffrey/0000-0001-8579-1996 FU National Institutes of Health [AI075286, AI070569, AI07061] FX This work was supported by the National Institutes of Health trough, an R01 award (AI075286), and an R21 award (AI070569) to EM, and a T32 (AI07061) to JJC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 22 Z9 24 U1 0 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e25321 DI 10.1371/journal.pone.0025321 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100087 PM 21966496 ER PT J AU Izar, B Rai, A Raghuram, K Rotruck, J Carpenter, J AF Izar, Benjamin Rai, Ansaar Raghuram, Karthikram Rotruck, Jill Carpenter, Jeffrey TI Comparison of Devices Used for Stent-Assisted Coiling of Intracranial Aneurysms SO PLOS ONE LA English DT Article ID SINGLE-CENTER EXPERIENCE; WIDE-NECKED ANEURYSMS; SELF-EXPANDING STENT; CEREBRAL ANEURYSMS; NEUROFORM STENT; ENTERPRISE STENT; FOLLOW-UP; ENDOVASCULAR OCCLUSION; MIDTERM; EMBOLIZATION AB Introduction: Two self-expandable stents, the Neuroform and the Enterprise stent, are widely used for stent-assisted coiling (SAC) of complex shaped intracranial aneurysms. However, comparative knowledge about technical feasibility, peri-and post-procedural morbidity and mortality, packing densities as well as follow-up data is limited. Material and Methods: We conducted a retrospective study to investigate differences in aneurysms stented with the Enterprise or Neuroform stents. Angiographic follow-up (mean 19.42 months) was available in 72.6% (61/84) of aneurysms treated with stent-assisted coiling. We further sought to compare stent-assisted coiling to a matched patient population with aneurysms treated by conventional coil embolization. Results: The stenting success rate of the Enterprise was higher compared to the Neuroform stent (46/48 and 42/51, respectively). In 5 of 9 cases in which the Neuroform stent was not navigable to the landing zone, we successfully deployed an Enterprise stent instead. Eventually, 42 aneurysms were coiled after stenting in each group. We observed no significant differences in peri-procedural complication rate, post-procedural hospital stay, packing density, recurrence rate or number of in-stent stenosis. Strikingly, 36.1% of followed aneurysms in the SAC group showed progressive occlusion on angiographic follow-up imaging. The packing density was significantly higher in aneurysms treated by SAC as compared to conventionally coiled aneurysms, while recanalization rate was significantly lower in the SAC group. Conclusion: The procedural success rate is higher using the Enterprise, but otherwise both stents exhibited similar characteristics. Lower recurrence frequency and complication rates comparable to conventional coil embolization emphasize the importance of stent-assisted coiling in the treatment of complex aneurysms. Progressive occlusion on angiographic follow-up was a distinct and frequent observation in the SAC group and may in part be due to flow diversion. C1 [Izar, Benjamin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Rai, Ansaar; Raghuram, Karthikram; Carpenter, Jeffrey] W Virginia Univ, Dept Radiol, Morgantown, WV 26506 USA. [Rotruck, Jill] W Virginia Univ, Sch Med, Morgantown, WV 26506 USA. RP Izar, B (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM jcarpenter@hsc.wvu.edu NR 24 TC 33 Z9 36 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e24875 DI 10.1371/journal.pone.0024875 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100023 PM 21966374 ER PT J AU Mantopoulos, D Murakami, Y Comander, J Thanos, A Roh, M Miller, JW Vavvas, DG AF Mantopoulos, Dimosthenis Murakami, Yusuke Comander, Jason Thanos, Aristomenis Roh, Miin Miller, Joan W. Vavvas, Demetrios G. TI Tauroursodeoxycholic Acid (TUDCA) Protects Photoreceptors from Cell Death after Experimental Retinal Detachment SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; BILE-ACID; INDUCED APOPTOSIS; RAT HEPATOCYTES; HUNTINGTONS-DISEASE; EXPERIMENTAL-MODEL; DEGENERATION; ACTIVATION; NECROSIS; CYTOLYSIS AB Background: Detachment of photoreceptors from the underlying retinal pigment epithelium is seen in various retinal disorders such as retinal detachment and age-related macular degeneration and leads to loss of photoreceptors and vision. Pharmacologic inhibition of photoreceptor cell death may prevent this outcome. This study tests whether systemic administration of tauroursodeoxycholic acid (TUDCA) can protect photoreceptors from cell death after experimental retinal detachment in rodents. Methodology/Principal Findings: Retinal detachment was created in rats by subretinal injection of hyaluronic acid. The animals were treated daily with vehicle or TUDCA (500 mg/kg). TUNEL staining was used to evaluate cell death. Photoreceptor loss was evaluated by measuring the relative thickness of the outer nuclear layer (ONL). Macrophage recruitment, oxidative stress, cytokine levels, and caspase levels were also quantified. Three days after detachment, TUDCA decreased the number of TUNEL-positive cells compared to vehicle (651 +/- 68/mm(2) vs. 1314 +/- 68/mm(2), P = 0.001) and prevented the reduction of ONL thickness ratio (0.84 +/- 0.03 vs. 0.65 +/- 0.03, P = 0.002). Similar results were obtained after 5 days of retinal detachment. Macrophage recruitment and expression levels of TNF-a and MCP-1 after retinal detachment were not affected by TUDCA treatment, whereas increases in activity of caspases 3 and 9 as well as carbonyl-protein adducts were almost completely inhibited by TUDCA treatment. Conclusions/Significance: Systemic administration of TUDCA preserved photoreceptors after retinal detachment, and was associated with decreased oxidative stress and caspase activity. TUDCA may be used as a novel therapeutic agent for preventing vision loss in diseases that are characterized by photoreceptor detachment. C1 [Mantopoulos, Dimosthenis; Murakami, Yusuke; Comander, Jason; Thanos, Aristomenis; Roh, Miin; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA USA. RP Mantopoulos, D (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA USA. EM vavvas@meei.harvard.edu OI Comander, Jason/0000-0002-4257-7145; Vavvas, Demetrios/0000-0002-8622-6478 FU Research to Prevent Blindness Foundation; Lions Eye Research Fund; Onassis Foundation; National Eye Institute [EY014104]; Yeatts Family Fund FX The Research to Prevent Blindness Foundation, the Lions Eye Research Fund (D. G. V.), the Onassis Foundation (D. G. V.), National Eye Institute Grant EY014104 (Massachusetts Eye and Ear Infirmary core grant), and Yeatts Family Fund (D. G. V. and J.W.M). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 28 Z9 29 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e24245 DI 10.1371/journal.pone.0024245 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100006 PM 21961034 ER PT J AU Wan, Q Kerr, C Pritchett, D Hamalainen, M Moore, C Jones, S AF Wan, Qian Kerr, Catherine Pritchett, Dominique Haemaelaeinen, Matti Moore, Christopher Jones, Stephanie TI Dynamics of Dynamics within a Single Data Acquisition Session: Variation in Neocortical Alpha Oscillations in Human MEG SO PLOS ONE LA English DT Article ID PRIMARY SOMATOSENSORY CORTEX; VISUOSPATIAL ATTENTION; OCCIPITAL CORTEX; EVOKED-RESPONSES; MU RHYTHM; MODULATION; EEG; SYNCHRONIZATION; FLUCTUATIONS; PERFORMANCE AB Background: Behavioral paradigms applied during human recordings in electro- and magneto-encephalography (EEG and MEG) typically require 1-2 hours of data collection. Over this time scale, the natural fluctuations in brain state or rapid learning effects could impact measured signals, but are seldom analyzed. Methods and Findings: We investigated within-session dynamics of neocortical alpha (7-14 Hz) rhythms and their allocation with cued-attention using MEG recorded from primary somatosensory neocortex (SI) in humans. We found that there were significant and systematic changes across a single similar to 1 hour recording session in several dimensions, including increased alpha power, increased differentiation in attention-induced alpha allocation, increased distinction in immediate time-locked post-cue evoked responses in SI to different visual cues, and enhanced power in the immediate cue-locked alpha band frequency response. Further, comparison of two commonly used baseline methods showed that conclusions on the evolution of alpha dynamics across a session were dependent on the normalization method used. Conclusions: These findings are important not only as they relate to studies of oscillations in SI, they also provide a robust example of the type of dynamic changes in brain measures within a single session that are overlooked in most human brain imaging/recording studies. C1 [Wan, Qian; Pritchett, Dominique; Moore, Christopher] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Wan, Qian; Kerr, Catherine] Harvard Univ, Harvard Osher Res Ctr, Sch Med, Boston, MA 02115 USA. [Haemaelaeinen, Matti; Jones, Stephanie] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Wan, Q (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM srjones@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; OI Pritchett, Dominique/0000-0003-1187-1162 FU National Institutes of Health (NIH) [P41RR14075, K25MH072941, K01AT003459, 1RO1-NS045130-01, T32GM007484]; National Science Foundation (NSF) [0316933]; Osher Institute; Athinoula A. Martinos Center for Biomedical Imaging; McGovern Institute for Brain Research FX This work was supported by the National Institutes of Health (NIH): P41RR14075, K25MH072941, K01AT003459, 1RO1-NS045130-01, T32GM007484, the National Science Foundation (NSF): 0316933, and the Osher Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors wish to thank Athinoula A. Martinos Center for Biomedical Imaging, the McGovern Institute for Brain Research, the Osher Institute, National Institute of Health, and the National Science Foundation for their support of this research. NR 35 TC 4 Z9 4 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2011 VL 6 IS 9 AR e24941 DI 10.1371/journal.pone.0024941 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825IJ UT WOS:000295265100033 PM 21966388 ER PT J AU Liong, M Tassa, C Shaw, SY Lee, H Weissleder, R AF Liong, Monty Tassa, Carlos Shaw, Stanley Y. Lee, Hakho Weissleder, Ralph TI Multiplexed Magnetic Labeling Amplification Using Oligonucleotide Hybridization SO ADVANCED MATERIALS LA English DT Article ID CIRCULATING TUMOR-CELLS; PROTEIN; NANOPARTICLES; CANCER AB Multiplexed Magnetic Labeling Amplification Using Oligonucleotide Hybridization Oligonucleotide hybridization was used as a cell-labeling method to significantly amplify the loading of magnetic probes onto target cells. The method utilized short oligonucleotides as the binding agents between antibodies and superparamagnetic iron oxide. This method not only enabled multiplexed analysis, but also allowed detection of multiple markers on a single sample containing only scant cell numbers. C1 [Liong, Monty; Tassa, Carlos; Shaw, Stanley Y.; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Ctr Syst Biol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. RP Lee, H (reprint author), Harvard Univ, Ctr Syst Biol, Massachusetts Gen Hosp, Sch Med, 185 Cambridge St, Boston, MA 02114 USA. EM hlee@mgh.harvard.edu; rweissleder@mgh.harvard.edu FU National Institute of Health [R01-EB004626, U54-CA119349]; TPEN [HHSN268201000044C] FX We thank S. S. Agasti, M. Fernandez-Suarez, R. Mazitschek, T. Reiner, and H. Shao for helpful discussions; I. Bagayev, A. Chudnovskiy, V. Cortez-Retamozo, and A. Newton for assistance in cell experiments; N. Sergeyev for providing the cross-linked iron oxide particles; and Y. Fisher-Jeffes for reviewing the manuscript. This work was supported in part by National Institute of Health Grants R01-EB004626, U54-CA119349, and TPEN contract (HHSN268201000044C). NR 20 TC 15 Z9 15 U1 2 U2 31 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0935-9648 J9 ADV MATER JI Adv. Mater. PD SEP 22 PY 2011 VL 23 IS 36 BP H254 EP + DI 10.1002/adma.201101401 PG 5 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 824VC UT WOS:000295229300004 PM 21780311 ER PT J AU Reeves, RK Rajakumar, PA Evans, TI Connole, M Gillis, J Wong, FE Kuzmichev, YV Carville, A Johnson, RP AF Reeves, R. Keith Rajakumar, Premeela A. Evans, Tristan I. Connole, Michelle Gillis, Jacqueline Wong, Fay E. Kuzmichev, Yury V. Carville, Angela Johnson, R. Paul TI Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44(+) mucosal NK cells during SIV infection SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; SIMIAN IMMUNODEFICIENCY VIRUS; SECONDARY LYMPHOID-TISSUE; ROR-GAMMA-T; RHESUS MACAQUES; HIV-1 INFECTION; NKP46(+) CELLS; I INTERFERON; HLA-B; DIFFERENTIATION AB Natural killer (NK) cells are classically viewed as effector cells that kill virus-infected and neoplastic cells, but recent studies have identified a rare mucosal NK-cell subpopulation secreting the TH17 cytokine IL-22. Here, we report identification of 2 distinct lineages of mucosal NK cells characterized as NKG2A(+)NFIL3(+)RORC(-) and NKp44(+)NFIL3(+)RORC(+). NKG2A(+) NK cells were systemically distributed, cytotoxic, and secreted IFN-gamma, whereas NKp44(+) NK cells were mucosae-restricted, noncytotoxic, and produced IL-22 and IL-17. During SIV infection, NKp44(+) NK cells became apoptotic, were depleted, and had an altered functional profile characterized by decreased IL-17 secretion; increased IFN-gamma secretion; and, surprisingly, increased potential for cytotoxicity. NKp44(+) NK cells showed no evidence of direct SIV infection; rather, depletion and altered function were associated with SIV-induced up-regulation of inflammatory mediators in the gut, including indoleamine 2,3-dioxygenase 1. Furthermore, treatment of NKp44(+) NK cells with indoleamine 2,3-dioxygenase 1 catabolites in vitro ablated IL-17 production in a dose-dependent manner, whereas other NK-cell functions were unaffected. Thus lentiviral infection both depletes and modifies the functional repertoire of mucosal NK cells involved in the maintenance of gut integrity, a finding that highlights the plasticity of this rare mucosal NK-cell population. (Blood. 2011;118(12):3321-3330) C1 [Reeves, R. Keith; Rajakumar, Premeela A.; Evans, Tristan I.; Connole, Michelle; Gillis, Jacqueline; Wong, Fay E.; Kuzmichev, Yury V.; Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Carville, Angela] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Primate Med, Southborough, MA 01772 USA. [Johnson, R. Paul] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Johnson, R. Paul] Harvard Univ, Boston, MA 02115 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Johnson, RP (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, 1 Pine Hill Dr, Southborough, MA 01772 USA. EM paul_johnson@hms.harvard.edu FU National Institutes of Health [AI071306, AI090735, RR00168]; Center for HIV/AIDS Vaccine Immunology/HIV Vaccine Trials Network [U19 AI 067854-04] FX This work was supported through National Institutes of Health grants AI071306, AI090735, and RR00168, and Center for HIV/AIDS Vaccine Immunology/HIV Vaccine Trials Network Early Career Investigator award U19 AI 067854-04 to R.K.R. NR 50 TC 52 Z9 52 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 22 PY 2011 VL 118 IS 12 BP 3321 EP 3330 DI 10.1182/blood-2011-04-347260 PG 10 WC Hematology SC Hematology GA 823KK UT WOS:000295120900019 PM 21791421 ER PT J AU Faraday, N Yanek, LR Yang, XP Mathias, R Herrera-Galeano, JE Suktitipat, B Qayyum, R Johnson, AD Chen, MH Tofler, GH Ruczinski, I Friedman, AD Gylfason, A Thorsteinsdottir, U Bray, PF O'Donnell, CJ Becker, DM Becker, LC AF Faraday, Nauder Yanek, Lisa R. Yang, Xiao Ping Mathias, Rasika Herrera-Galeano, J. Enrique Suktitipat, Bhoom Qayyum, Rehan Johnson, Andrew D. Chen, Ming-Huei Tofler, Geoffrey H. Ruczinski, Ingo Friedman, Alan D. Gylfason, Arnaldur Thorsteinsdottir, Unnur Bray, Paul F. O'Donnell, Christopher J. Becker, Diane M. Becker, Lewis C. TI Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; ASPIRIN RESISTANCE; CARDIOVASCULAR EVENTS; AGGREGATION; HERITABILITY; METAANALYSIS; ACTIVATION; PATHWAYS; HISTORY; DISEASE AB Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for <= 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 x 10(-8)) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 x 10(-27)) and in an independent sample of 2755 persons of European descent (P = 1.64 x 10(-5)). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 x 10(-6)) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the Gallele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype. (Blood. 2011;118(12):3367-3375) C1 [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Yanek, Lisa R.; Yang, Xiao Ping; Mathias, Rasika; Herrera-Galeano, J. Enrique; Suktitipat, Bhoom; Qayyum, Rehan; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, GeneSTAR Res Program, Dept Med, Baltimore, MD 21205 USA. [Johnson, Andrew D.; Chen, Ming-Huei; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Friedman, Alan D.] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Baltimore, MD USA. [Gylfason, Arnaldur; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Bray, Paul F.] Thomas Jefferson Sch Med, Dept Med, Div Hematol, Philadelphia, PA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. RP Faraday, N (reprint author), Johns Hopkins Univ Hosp, 298 Meyer Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. EM nfaraday@jhmi.edu RI Johnson, Andrew/G-6520-2013; OI Qayyum, Rehan/0000-0003-3086-8014; Suktitipat, Bhoom/0000-0001-8034-7757 FU National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI [U01 HL72518]; STAMPEED consortia [R01 HL087698-01]; Johns Hopkins General Clinical Research Center; National Center for Research Resources [M01-RR000052]; NHLBI [N01-HC-25195]; Affymetrix Inc [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine; Boston Medical Center; [R01-HL-48157] FX This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia and by grant R01-HL-48157. A portion of this work was supported by resources of the Johns Hopkins General Clinical Research Center, funded through the National Center for Research Resources (grant M01-RR000052). This work was also supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 20 TC 32 Z9 34 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 22 PY 2011 VL 118 IS 12 BP 3367 EP 3375 DI 10.1182/blood-2010-11-320788 PG 9 WC Hematology SC Hematology GA 823KK UT WOS:000295120900025 PM 21791418 ER PT J AU Guo, CG Yoon, HS Franklin, A Jain, S Ebert, A Cheng, HL Hansen, E Despo, O Bossen, C Vettermann, C Bates, JG Richards, N Myers, D Patel, H Gallagher, M Schlissel, MS Murre, C Busslinger, M Giallourakis, CC Alt, FW AF Guo, Chunguang Yoon, Hye Suk Franklin, Andrew Jain, Suvi Ebert, Anja Cheng, Hwei-Ling Hansen, Erica Despo, Orion Bossen, Claudia Vettermann, Christian Bates, Jamie G. Richards, Nicholas Myers, Darienne Patel, Harin Gallagher, Michael Schlissel, Mark S. Murre, Cornelis Busslinger, Meinrad Giallourakis, Cosmas C. Alt, Frederick W. TI CTCF-binding elements mediate control of V(D)J recombination SO NATURE LA English DT Article ID B-CELL DEVELOPMENT; HEAVY-CHAIN LOCUS; VH GENE SEGMENTS; IGH LOCUS; REGULATORY ELEMENTS; INTRONIC ENHANCER; ANTISENSE TRANSCRIPTION; LYMPHOCYTE DEVELOPMENT; NUCLEAR-ORGANIZATION; REGION AB Immunoglobulin heavy chain (IgH) variable region exons are assembled from V-H, D and J(H) gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the V-H and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D-H-proximal V-H gene segments and promoting rearrangement of distal V-H segments. IGCR1 maintains ordered and lineage-specific V-H(D)J(H) recombination by suppressing V-H joining to D segments not joined to J(H) segments, and V-H to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V-H-to-DJ(H) recombination. Our studies elucidate a long-sought Igh V(D) J recombination control region and indicate a new role for the generally expressed CTCF protein. C1 [Guo, Chunguang; Yoon, Hye Suk; Franklin, Andrew; Jain, Suvi; Cheng, Hwei-Ling; Hansen, Erica; Despo, Orion; Richards, Nicholas; Myers, Darienne; Patel, Harin; Gallagher, Michael; Giallourakis, Cosmas C.; Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Boston, MA 02115 USA. [Guo, Chunguang; Yoon, Hye Suk; Franklin, Andrew; Jain, Suvi; Cheng, Hwei-Ling; Hansen, Erica; Despo, Orion; Richards, Nicholas; Myers, Darienne; Patel, Harin; Gallagher, Michael; Giallourakis, Cosmas C.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ebert, Anja; Busslinger, Meinrad] Res Inst Mol Pathol, A-1030 Vienna, Austria. [Bossen, Claudia; Murre, Cornelis] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Vettermann, Christian; Bates, Jamie G.; Schlissel, Mark S.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Giallourakis, Cosmas C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM cgiallourakis@partners.org; alt@enders.tch.harvard.edu RI Busslinger, Meinrad/J-1249-2016 OI Busslinger, Meinrad/0000-0002-9111-9351 FU NIH [RO1 AI20047, RO1 HL48702, RO1 AI40227, CA054198-20, K08 AI070839]; Austrian GEN-AU initiative; Boehringer Ingelheim; Cancer Research Institute; Marie Curie Fellowship; EMBO FX We thank Y. Fujiwara and P.-Y. Huang for generating chimaeric mice. This work was supported by NIH grants RO1 AI20047 (to F. W. A.), RO1 HL48702 and AI40227 (to M. S. S.), CA054198-20 (to C. M.) and K08 AI070839 (to C. C. G.). M. B. was supported by the Austrian GEN-AU initiative and Boehringer Ingelheim. C. G. is supported by an Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute. C. V. is supported by a Marie Curie Fellowship. C. B. is supported by an EMBO fellowship. F. W. A. is an Investigator of the Howard Hughes Medical Institute. NR 53 TC 113 Z9 117 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 22 PY 2011 VL 477 IS 7365 BP 424 EP U182 DI 10.1038/nature10495 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822WH UT WOS:000295080500032 PM 21909113 ER PT J AU Choi, JH Banks, AS Kamenecka, TM Busby, SA Chalmers, MJ Kumar, N Kuruvilla, DS Shin, YS He, YJ Bruning, JB Marciano, DP Cameron, MD Laznik, D Jurczak, MJ Schurer, SC Vidovic, D Shulman, GI Spiegelman, BM Griffin, PR AF Choi, Jang Hyun Banks, Alexander S. Kamenecka, Theodore M. Busby, Scott A. Chalmers, Michael J. Kumar, Naresh Kuruvilla, Dana S. Shin, Youseung He, Yuanjun Bruning, John B. Marciano, David P. Cameron, Michael D. Laznik, Dina Jurczak, Michael J. Schuerer, Stephan C. Vidovic, Dusica Shulman, Gerald I. Spiegelman, Bruce M. Griffin, Patrick R. TI Antidiabetic actions of a non-agonist PPAR gamma ligand blocking Cdk5-mediated phosphorylation SO NATURE LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; ADIPOCYTE DIFFERENTIATION; SKELETAL-MUSCLE; ROSIGLITAZONE; EXPRESSION; OBESITY; POTENT; THIAZOLIDINEDIONE; PPAR-GAMMA-2; MODULATORS AB PPAR gamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone(1). These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPAR gamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPAR gamma by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPAR gamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPAR gamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPAR gamma. C1 [Choi, Jang Hyun; Banks, Alexander S.; Laznik, Dina; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Choi, Jang Hyun; Banks, Alexander S.; Laznik, Dina; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA. [Choi, Jang Hyun; Banks, Alexander S.; Laznik, Dina; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kamenecka, Theodore M.; Shin, Youseung; He, Yuanjun; Cameron, Michael D.; Griffin, Patrick R.] Scripps Res Inst, Translat Res Inst, Jupiter, FL 33458 USA. [Busby, Scott A.; Chalmers, Michael J.; Kumar, Naresh; Kuruvilla, Dana S.; Marciano, David P.; Cameron, Michael D.; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Kamenecka, Theodore M.; Cameron, Michael D.; Griffin, Patrick R.] Scripps Res Inst, SRMSC, Jupiter, FL 33458 USA. [Bruning, John B.] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. [Jurczak, Michael J.; Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Internal Med, New Haven, CT 06510 USA. [Jurczak, Michael J.; Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Schuerer, Stephan C.; Vidovic, Dusica] Univ Miami, Ctr Computat Sci, Miami, FL 33136 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu; pgriffin@scripps.edu RI Choi, Jang Hyun/B-3055-2012; Banks, Alexander/B-4832-2012 OI Banks, Alexander/0000-0003-1787-6925 FU National Institutes of Health (NIH), National Institute of Mental Health [U54-MH074404]; National Institute of General Medical Sciences [R01-GM084041]; National Institute of Diabetes and Digestive and Kidney Diseases [1RC4DK090861]; NIH [DK31405] FX We are grateful for support from S. Novick for assistance in the HDX studies and from R. D. Garcia-Ordonez in protein production and mutagenesis. We are grateful for support from B. Pascal and S. Willis for software analysing the HDX data. We are grateful to R. Gupta and P. Cohen for their critical comments on the manuscript. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Mental Health (grant U54-MH074404, H. Rosen principal investigator), the National Institute of General Medical Sciences (grant R01-GM084041, P. R. G.) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant 1RC4DK090861, B. M. S.). This work also supported by NIH DK31405 to B.M.S. NR 28 TC 200 Z9 208 U1 4 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 22 PY 2011 VL 477 IS 7365 BP 477 EP U131 DI 10.1038/nature10383 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822WH UT WOS:000295080500043 PM 21892191 ER PT J AU Raje, NS Steele, DJR Lawrimore, TM Johri, AM Sohani, AR AF Raje, Noopur S. Steele, David J. R. Lawrimore, Tara M. Johri, Amer M. Sohani, Aliyah R. TI Case 29-2011: A 66-Year-Old Woman with Cardiac and Renal Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; PLASMA-EXCHANGE; AL AMYLOIDOSIS; DEXAMETHASONE; BORTEZOMIB; THERAPY; CHEMOTHERAPY; NEPHROPATHY; IMPROVEMENT; CRITERIA C1 [Raje, Noopur S.] Dept Med, Div Hematol Oncol, Boston, MA 02101 USA. [Steele, David J. R.] Dept Med, Div Nephrol, Boston, MA USA. [Johri, Amer M.] Dept Med, Div Cardiol, Boston, MA USA. [Lawrimore, Tara M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Raje, Noopur S.; Steele, David J. R.; Johri, Amer M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lawrimore, Tara M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. RP Raje, NS (reprint author), Dept Med, Div Hematol Oncol, Boston, MA 02101 USA. NR 30 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 22 PY 2011 VL 365 IS 12 BP 1129 EP 1138 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 822WR UT WOS:000295081600013 PM 21992126 ER PT J AU Lencer, WI von Andrian, UH AF Lencer, Wayne I. von Andrian, Ulrich H. TI Eliciting Mucosal Immunity SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DENDRITIC CELLS C1 [Lencer, Wayne I.] Harvard Univ, Sch Med, Childrens Hosp, Dept Med, Boston, MA 02115 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Lencer, WI (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Dept Med, Boston, MA 02115 USA. RI von Andrian, Ulrich/A-5775-2008 FU NIDDK NIH HHS [P30 DK034854, R01 DK048106, R37 DK048106] NR 7 TC 4 Z9 5 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 22 PY 2011 VL 365 IS 12 BP 1151 EP 1153 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 822WR UT WOS:000295081600017 PM 21992128 ER PT J AU Calabro, FJ Soto-Faraco, S Vaina, LM AF Calabro, F. J. Soto-Faraco, S. Vaina, L. M. TI Acoustic facilitation of object movement detection during self-motion SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE flow parsing; visual search; multisensory perception; visual motion; auditory motion ID VISUAL-SEARCH; SENSORY MODALITIES; RETINAL MOTION; AUDIOVISUAL INTEGRATION; AUDITORY MOTION; PERCEPTION; VISION; INFORMATION; PARALLEL; CAPTURE AB In humans, as well as most animal species, perception of object motion is critical to successful interaction with the surrounding environment. Yet, as the observer also moves, the retinal projections of the various motion components add to each other and extracting accurate object motion becomes computationally challenging. Recent psychophysical studies have demonstrated that observers use a flow-parsing mechanism to estimate and subtract self-motion from the optic flow field. We investigated whether concurrent acoustic cues for motion can facilitate visual flow parsing, thereby enhancing the detection of moving objects during simulated self-motion. Participants identified an object (the target) that moved either forward or backward within a visual scene containing nine identical textured objects simulating forward observer translation. We found that spatially co-localized, directionally congruent, moving auditory stimuli enhanced object motion detection. Interestingly, subjects who performed poorly on the visual-only task benefited more from the addition of moving auditory stimuli. When auditory stimuli were not co-localized to the visual target, improvements in detection rates were weak. Taken together, these results suggest that parsing object motion from self-motion-induced optic flow can operate on multisensory object representations. C1 [Calabro, F. J.; Vaina, L. M.] Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA. [Soto-Faraco, S.] Univ Pompeu Fabra, ICREA, Barcelona, Spain. [Soto-Faraco, S.] Univ Pompeu Fabra, Dept Tecnol Informacio & Comunicac, Barcelona, Spain. [Vaina, L. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02215 USA. [Vaina, L. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02215 USA. RP Vaina, LM (reprint author), Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA. EM vaina@bu.edu RI Brain and Cognition, Center/H-5448-2011; Consolider Ingenio 2010, BRAINGLOT/D-1235-2009; SOTO-FARACO, SALVADOR/B-8400-2011; OI SOTO-FARACO, SALVADOR/0000-0002-4799-3762; Calabro, Finnegan/0000-0002-8092-3942 FU NIH [RO1NS064100]; Ministerio de Ciencia e Innovacion [PSI2010-15426, CSD2007-00012]; Comissionat per a Universitats i Recerca del DIUE [SRG2009-092]; European Research Council [StG-2010 263145]; Sound Field Laboratory at Sargent College, Boston University [P30 DC04663] FX L.M.V. and F.J.C. were supported by NIH grant RO1NS064100 to L.M.V. S.S.F. was supported by grants from the Ministerio de Ciencia e Innovacion (PSI2010-15426 and CSD2007-00012), by the Comissionat per a Universitats i Recerca del DIUE (SRG2009-092) and by the European Research Council (StG-2010 263145).; We thank Gerald Kidd and Chris Mason for their helpful suggestions and for generously making available to us the resources of the Sound Field Laboratory at Sargent College, Boston University, supported by grant P30 DC04663. We also thank Franco Rupcich, Benvy Caldwell and Megan Menard for helping with psychophysical data collection and subject recruitment, and Leonardo Sassi for developing and implementing a preliminary version of the object motion task. NR 52 TC 15 Z9 15 U1 4 U2 9 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD SEP 22 PY 2011 VL 278 IS 1719 BP 2840 EP 2847 DI 10.1098/rspb.2010.2757 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 805NG UT WOS:000293733600019 PM 21307050 ER PT J AU Zamakhchari, M Wei, GX Dewhirst, F Lee, J Schuppan, D Oppenheim, FG Helmerhorst, EJ AF Zamakhchari, Maram Wei, Guoxian Dewhirst, Floyd Lee, Jaeseop Schuppan, Detlef Oppenheim, Frank G. Helmerhorst, Eva J. TI Identification of Rothia Bacteria as Gluten-Degrading Natural Colonizers of the Upper Gastro-Intestinal Tract SO PLOS ONE LA English DT Article ID COMBINATION ENZYME THERAPY; CELIAC-DISEASE; TISSUE TRANSGLUTAMINASE; GLIADIN PEPTIDES; PROLYL-ENDOPEPTIDASE; T-CELLS; SP-NOV; SPRUE; ENDOPROTEASE; MICROBIOME AB Background: Gluten proteins, prominent constituents of barley, wheat and rye, cause celiac disease in genetically predisposed subjects. Gluten is notoriously difficult to digest by mammalian proteolytic enzymes and the protease-resistant domains contain multiple immunogenic epitopes. The aim of this study was to identify novel sources of gluten-digesting microbial enzymes from the upper gastro-intestinal tract with the potential to neutralize gluten epitopes. Methodology/Principal Findings: Oral microorganisms with gluten-degrading capacity were obtained by a selective plating strategy using gluten agar. Microbial speciations were carried out by 16S rDNA gene sequencing. Enzyme activities were assessed using gliadin-derived enzymatic substrates, gliadins in solution, gliadin zymography, and 33-mer alpha-gliadin and 26-mer gamma-gliadin immunogenic peptides. Fragments of the gliadin peptides were separated by RP-HPLC and structurally characterized by mass spectrometry. Strains with high activity towards gluten were typed as Rothia mucilaginosa and Rothia aeria. Gliadins (250 mu g/ml) added to Rothia cell suspensions (OD(620) 1.2) were degraded by 50% after similar to 30 min of incubation. Importantly, the 33-mer and 26-mer immunogenic peptides were also cleaved, primarily C-terminal to Xaa-Pro-Gln (XPQ) and Xaa-Pro-Tyr (XPY). The major gliadin-degrading enzymes produced by the Rothia strains were similar to 70-75 kDa in size, and the enzyme expressed by Rothia aeria was active over a wide pH range (pH 3-10). Conclusion/Significance: While the human digestive enzyme system lacks the capacity to cleave immunogenic gluten, such activities are naturally present in the oral microbial enzyme repertoire. The identified bacteria may be exploited for physiologic degradation of harmful gluten peptides. C1 [Zamakhchari, Maram; Wei, Guoxian; Lee, Jaeseop; Oppenheim, Frank G.; Helmerhorst, Eva J.] Boston Univ, Dept Periodontol & Oral Biol, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. [Dewhirst, Floyd] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Schuppan, Detlef] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Gastroenterol, Sch Med, Boston, MA 02215 USA. [Schuppan, Detlef] Johannes Gutenberg Univ Mainz, Div Mol & Translat Med, Mainz, Germany. RP Zamakhchari, M (reprint author), Boston Univ, Dept Periodontol & Oral Biol, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. EM helmer@bu.edu OI Wei, Guoxian/0000-0001-5115-3697; Helmerhorst, Eva/0000-0002-4803-3018 FU National Institutes of Health [DE016937, DK073254, AI078385, DE05672, DE7652, AI087803, DE18132] FX This study was supported by grants from the National Institutes of Health: DE016937 (FD), DK073254 (DS), AI078385 (DS) DE05672 (FO) and DE7652 (FO) AI087803 (EJH), DE18132 (EJH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 26 Z9 26 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 21 PY 2011 VL 6 IS 9 AR e24455 DI 10.1371/journal.pone.0024455 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825HM UT WOS:000295262100010 PM 21957450 ER PT J AU Maleki, N Becerra, L Nutile, L Pendse, G Brawn, J Bigal, M Burstein, R Borsook, D AF Maleki, Nasim Becerra, Lino Nutile, Lauren Pendse, Gautam Brawn, Jennifer Bigal, Marcelo Burstein, Rami Borsook, David TI Migraine attacks the Basal Ganglia SO MOLECULAR PAIN LA English DT Article DE Headache; Pain; Migraine; fMRI; Functional Connectivity; Morphometry; Gray Matter Volume; Basal Ganglia ID HUMAN BRAIN; CENTRAL SENSITIZATION; PREFRONTAL CORTEX; THERMAL STIMULI; CEREBRAL-CORTEX; CNS ACTIVATION; SPINY NEURONS; PAIN; HEADACHE; THALAMUS AB Background: With time, episodes of migraine headache afflict patients with increased frequency, longer duration and more intense pain. While episodic migraine may be defined as 1-14 attacks per month, there are no clear-cut phases defined, and those patients with low frequency may progress to high frequency episodic migraine and the latter may progress into chronic daily headache (> 15 attacks per month). The pathophysiology of this progression is completely unknown. Attempting to unravel this phenomenon, we used high field (human) brain imaging to compare functional responses, functional connectivity and brain morphology in patients whose migraine episodes did not progress (LF) to a matched (gender, age, age of onset and type of medication) group of patients whose migraine episodes progressed (HF). Results: In comparison to LF patients, responses to pain in HF patients were significantly lower in the caudate, putamen and pallidum. Paradoxically, associated with these lower responses in HF patients, gray matter volume of the right and left caudate nuclei were significantly larger than in the LF patients. Functional connectivity analysis revealed additional differences between the two groups in regard to response to pain. Conclusions: Supported by current understanding of basal ganglia role in pain processing, the findings suggest a significant role of the basal ganglia in the pathophysiology of the episodic migraine. C1 [Becerra, Lino; Nutile, Lauren; Pendse, Gautam; Borsook, David] Harvard Univ, Sch Med, Dept Psychiat, PAIN Grp,Brain Imaging Ctr,McLean Hosp, Belmont, MA 02478 USA. [Maleki, Nasim; Brawn, Jennifer] Harvard Univ, Sch Med, Dept Radiol, Childrens Hosp Boston, Boston, MA 02115 USA. [Becerra, Lino] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Becerra, Lino] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. [Bigal, Marcelo] Merck & Co Inc, Merck Investigator Studies Program, N Wales, PA 19454 USA. [Bigal, Marcelo] Merck & Co Inc, Sci Educ Grp, Merck Res Labs, N Wales, PA 19454 USA. [Bigal, Marcelo; Borsook, David] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA. [Burstein, Rami] Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Borsook, D (reprint author), Harvard Univ, Sch Med, Dept Psychiat, PAIN Grp,Brain Imaging Ctr,McLean Hosp, Belmont, MA 02478 USA. EM dborsook@partners.org FU NIH [K24 NS064050, R01 NS056195]; Merck and Co. FX The work was supported in by grants from NIH (K24 NS064050 (NINDS) and R01 NS056195 (NINDS) to DB) (data collection) and an Investigator Initiated Grant from Merck and Co. (Data Analysis). NR 89 TC 57 Z9 60 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD SEP 21 PY 2011 VL 7 AR 71 DI 10.1186/1744-8069-7-71 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 832UD UT WOS:000295833000001 PM 21936901 ER PT J AU Ramos, OV Torterolo, P Lim, V Chase, MH Sampogna, S Yamuy, J AF Ramos, Oscar V. Torterolo, Pablo Lim, Vincent Chase, Michael H. Sampogna, Sharon Yamuy, Jack TI The role of mesopontine NGF in sleep and wakefulness SO BRAIN RESEARCH LA English DT Article DE Neurotrophin; Brainstem; Reticular formation; LDT; PPT; Immunohistochemistry ID NERVE GROWTH-FACTOR; PEDUNCULOPONTINE TEGMENTAL NUCLEI; INDUCED ACTIVE SLEEP; EYE-MOVEMENT SLEEP; NEUROTROPHIN-LIKE IMMUNOREACTIVITY; PONTINE RETICULAR-FORMATION; RAT SYMPATHETIC NEURONS; REM-SLEEP; CHOLINE-ACETYLTRANSFERASE; BRAIN-STEM AB The microinjection of nerve growth factor (NGF) into the cat pontine tegmentum rapidly induces rapid eye movement (REM) sleep. To determine if NGF is involved in naturally-occurring REM sleep, we examined whether it is present in mesopontine cholinergic structures that promote the initiation of REM sleep, and whether the blockade of NGF production in these structures suppresses REM sleep. We found that cholinergic neurons in the cat dorso-lateral mesopontine tegmentum exhibited NGF-like immunoreactivity. In addition, the microinjection of an oligodeoxyribonucleotide (OD) directed against cat NGF mRNA into this region resulted in a reduction in the time spent in REM sleep in conjunction with an increase in the time spent in wakefulness. Sleep and wakefulness returned to baseline conditions 2 to 5 days after antisense OD administration. The preceding antisense OD-induced effects occurred in conjunction with the suppression of NGF-like immunoreactivity within the site of antisense OD injection. These data support the hypothesis that NGF is involved in the modulation of naturally-occurring sleep and wakefulness. (C) 2011 Elsevier B.V. All rights reserved. C1 [Yamuy, Jack] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Ramos, Oscar V.; Lim, Vincent; Chase, Michael H.; Sampogna, Sharon] Websci Int, Los Angeles, CA 90024 USA. [Chase, Michael H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. [Torterolo, Pablo] Univ Republica, Fac Med, Dept Fisiol, Montevideo, Uruguay. RP Yamuy, J (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. EM jyamuy@ucla.edu FU USPHS [MH59284] FX Supported by USPHS grant MH59284. The authors thank Trent Wenzel for his excellent technical assistance. NR 64 TC 1 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 21 PY 2011 VL 1413 BP 9 EP 23 DI 10.1016/j.brainres.2011.06.066 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 825QM UT WOS:000295297200002 PM 21840513 ER PT J AU Scarcelli, G Kim, P Yun, SH AF Scarcelli, Giuliano Kim, Pilhan Yun, Seok Hyun TI In Vivo Measurement of Age-Related Stiffening in the Crystalline Lens by Brillouin Optical Microscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID EYE LENS; ELASTIC PROPERTIES; REFRACTIVE-INDEX; LIGHT-SCATTERING; NUCLEAR CATARACT; BOVINE LENS; PRESBYOPIA; STIFFNESS; TRANSPARENCY; BIOMECHANICS AB The biophysical and biomechanical properties of the crystalline lens (e.g., viscoelasticity) have long been implicated in accommodation and vision problems, such as presbyopia and cataracts. However, it has been difficult to measure such parameters noninvasively. Here, we used in vivo Brillouin optical microscopy to characterize material acoustic properties at GHz frequency and measure the longitudinal elastic moduli of lenses. We obtained three-dimensional elasticity maps of the lenses in live mice, which showed biomechanical heterogeneity in the cortex and nucleus of the lens with high spatial resolution. An in vivo longitudinal study of mice over a period of 2 months revealed a marked age-related stiffening of the lens nucleus. We found remarkably good correlation (log-log linear) between the Brillouin elastic modulus and the Young's modulus measured by conventional mechanical techniques at low frequencies (similar to 1 Hz). Our results suggest that Brillouin microscopy is potentially useful for basic and animal research and clinical ophthalmology. C1 [Scarcelli, Giuliano; Kim, Pilhan; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Scarcelli, Giuliano; Kim, Pilhan; Yun, Seok Hyun] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Yun, Seok Hyun] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA USA. RP Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM syun@hms.harvard.edu RI Kim, Pilhan/C-1836-2011; OI Kim, Pilhan/0000-0001-8388-1840; scarcelli, giuliano/0000-0002-1736-077X FU National Institutes of Health [R2 1EB008472]; National Science of Foundation [CBET-0853773]; Department of Defense [FA9550-04-1-0079]; Center for Integration of Medical Innovation and Technology; Milton Foundation; Tosteson Fellowship FX This work was supported by grants from the National Institutes of Health (R2 1EB008472), National Science of Foundation (CBET-0853773), Department of Defense (FA9550-04-1-0079), Center for Integration of Medical Innovation and Technology, and Milton Foundation. G.S received financial support from the Tosteson Fellowship. NR 42 TC 41 Z9 42 U1 2 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP 21 PY 2011 VL 101 IS 6 BP 1539 EP 1545 DI 10.1016/j.bpj.2011.08.008 PG 7 WC Biophysics SC Biophysics GA 824JD UT WOS:000295197300029 PM 21943436 ER PT J AU McCarthy, DM Zhang, X Darnell, SB Sangrey, GR Yanagawa, Y Sadri-Vakili, G Bhide, PG AF McCarthy, Deirdre M. Zhang, Xuan Darnell, Shayna B. Sangrey, Gavin R. Yanagawa, Yuchio Sadri-Vakili, Ghazaleh Bhide, Pradeep G. TI Cocaine Alters BDNF Expression and Neuronal Migration in the Embryonic Mouse Forebrain SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; CELL-CYCLE EXIT; PRENATAL COCAINE; CEREBRAL-CORTEX; CORTICAL-NEURONS; INTERNEURON MIGRATION; DEVELOPING NEOCORTEX; PROTEIN EXPRESSION; BASAL FOREBRAIN; D-3 RECEPTOR AB Prenatal cocaine exposure impairs brain development and produces lasting alterations in cognitive function. In a prenatal cocaine exposure mouse model, we found that tangential migration of GABA neurons from the basal to the dorsal forebrain and radial neuron migration within the dorsal forebrain were significantly decreased during the embryonic period. The decrease in the tangential migration occurred early in gestation and normalized by late gestation, despite ongoing cocaine exposure. The decrease in radial migration was associated with altered laminar positioning of neurons in the medial prefrontal cortex. The cocaine exposure led to transient decreases in the expression of Tbr2 and Tbr1, transcription factors associated with intermediate progenitor cells and newborn neurons of the dorsal forebrain, respectively, although neurogenesis was not significantly altered. Since cocaine can modulate brain derived neurotrophic factor (BDNF) expression in the mature brain, we examined whether cocaine can alter BDNF expression in the embryonic brain. We found a transient decrease in BDNF protein expression in the cocaine-exposed embryonic forebrain early in gestation. By late gestation, the BDNF expression recovered to control levels, despite ongoing cocaine exposure. In basal forebrain explants from cocaine-exposed embryos, cell migration was significantly decreased, corroborating the in vivo data on tangential GABA neuron migration. Since BDNF can influence tangential neuronal migration, we added BDNF to the culture medium and observed increased cell migration. Our data suggest that cocaine can alter tangential and radial neuronal migration as well as BDNF expression in the embryonic brain and that decreased BDNF may mediate cocaine's effects on neuronal migration. C1 [McCarthy, Deirdre M.; Zhang, Xuan; Bhide, Pradeep G.] Harvard Univ, Dept Neurol, MassGen Inst Neurodegenerat Dis, Sch Med, Charlestown, MA 02129 USA. [Darnell, Shayna B.; Sangrey, Gavin R.; Sadri-Vakili, Ghazaleh] Harvard Univ, NeuroEpigenetcis Lab, MassGen Inst Neurodegenerat Dis, Sch Med, Charlestown, MA 02129 USA. [Darnell, Shayna B.; Sangrey, Gavin R.; Sadri-Vakili, Ghazaleh] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Yanagawa, Yuchio] Gunma Univ, Grad Sch Med, Gunma 3718511, Japan. RP Bhide, PG (reprint author), Florida State Univ, Coll Med, 1115 W Call St, Tallahassee, FL 32306 USA. EM Pradeep.Bhide@med.fsu.edu OI Bhide, Pradeep/0000-0003-4236-9415 FU U.S. Public Health Service [RO1DA020796, P30NS045776, R01DA022339] FX This work was supported by U.S. Public Health Service Grants RO1DA020796, P30NS045776, and R01DA022339. We are grateful to Igor Bagayev for expert assistance with confocal microscopy and to the staff of the Massachusetts General Hospital's Center for Comparative Medicine for expert assistance with mouse colony management and drug administration. NR 65 TC 19 Z9 21 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 21 PY 2011 VL 31 IS 38 BP 13400 EP 13411 DI 10.1523/JNEUROSCI.2944-11.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 822XG UT WOS:000295083300006 PM 21940433 ER PT J AU Schierberl, K Hao, J Tropea, TF Ra, S Giordano, TP Xu, QH Garraway, SM Hofmann, F Moosmang, S Striessnig, J Inturrisi, CE Rajadhyaksha, AM AF Schierberl, Kathryn Hao, Jin Tropea, Thomas F. Ra, Stephen Giordano, Thomas P. Xu, Qinghao Garraway, Sandra M. Hofmann, Franz Moosmang, Sven Striessnig, Joerg Inturrisi, Charles E. Rajadhyaksha, Anjali M. TI Ca(v)1.2 L-Type Ca2+ Channels Mediate Cocaine-Induced GluA1 Trafficking in the Nucleus Accumbens, a Long-Term Adaptation Dependent on Ventral Tegmental Area Ca(v)1.3 Channels SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-II; INDUCED BEHAVIORAL SENSITIZATION; EVOKED SYNAPTIC PLASTICITY; AMPA RECEPTOR PLASTICITY; CORD DORSAL-HORN; CALCIUM-CHANNELS; CREB PHOSPHORYLATION; GLUR1 PHOSPHORYLATION; SURFACE EXPRESSION; GLUTAMATE-RECEPTOR AB AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization, we have examined phosphorylation of GluA1 at key residues serine 845 (S845) and S831, as well as GluA1 cell surface levels in the nucleus accumbens (NAc) of cocaine-preexposed mice and the role of brain-specific Ca(v)1.2 and Ca(v)1.3 L-type Ca2+ channels (LTCCs), therein. We found higher basal levels of S845 phospho-GluA1 (P-GluA1) and cell surface GluA1 in the NAc following protracted withdrawal from cocaine exposure, changes that occur independently of LTCCs. In contrast, we found that a cocaine challenge that elicits expression of the cocaine-sensitized response increases S831 P-GluA1 that further increases surface GluA1 beyond the higher basal levels. Intra-NAc pharmacological manipulations indicate that the Ca(v)1.2-activated CaM kinase II (CaMKII) mediates cocaine-induced increase in S831 P-GluA1 and that both Ca(v)1.2-activated CaMKII and extracellular signal-regulated kinase 2 (ERK2) mediate the increase in GluA1 cell surface levels specific to the sensitized response. Experiments using adenoassociated viral vectors expressing Ca(v)1.3 and ERK2 siRNA further indicate that recruitment of the Cav1.2 pathway in the NAc is dependent on ventral tegmental area Ca(v)1.3 LTCCs and ERK2. Together, these results identify candidate pathways that mediate cocaine-induced AMPAR plasticity in the NAc and provide a mechanism linking LTCCs and GluA1 plasticity to cocaine-induced persistent behavioral changes. C1 [Schierberl, Kathryn; Xu, Qinghao; Inturrisi, Charles E.; Rajadhyaksha, Anjali M.] Weill Cornell Med Coll, Grad Program Neurosci, New York, NY 10065 USA. [Hao, Jin; Tropea, Thomas F.; Ra, Stephen; Giordano, Thomas P.; Rajadhyaksha, Anjali M.] Weill Cornell Med Coll, Dept Pediat, Div Pediat Neurol, New York, NY 10065 USA. [Garraway, Sandra M.; Inturrisi, Charles E.] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Giordano, Thomas P.; Rajadhyaksha, Anjali M.] Harvard Univ, Martinos Ctr Biomed Engn, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. [Hofmann, Franz] Tech Univ Munich, Res Grp 923, D-80802 Munich, Germany. [Moosmang, Sven] Tech Univ Munich, Inst Pharmacol, D-80802 Munich, Germany. [Striessnig, Joerg] Inst Pharm Pharmacol & Toxicol, A-6020 Innsbruck, Austria. RP Rajadhyaksha, AM (reprint author), Weill Cornell Med Coll, Grad Program Neurosci, 1300 York Ave,Box 91, New York, NY 10065 USA. EM amr2011@med.cornell.edu RI Inturrisi, Charles/E-7365-2013 FU NIDA [K01 DA14057, R21 DA023686, DA007274-19, DA001457, DA000198, DA005130]; Austrian Science Fund [P20670]; Deutsche Forschungsgemeinschaft FX This work was supported by NIDA Grants K01 DA14057 (A.M.R.), R21 DA023686 (A.M.R.), and DA007274-19 (K.S.), Austrian Science Fund P20670 (J.S.), Deutsche Forschungsgemeinschaft (F.H., S.M.), and NIDA Grants DA001457, DA000198, and DA005130 (C.E.I.). We thank Michael J. Glass, Andrew A. Pieper, and Anni S. Lee for their helpful suggestions in manuscript preparation and Barry A. Kosofsky for useful discussions. NR 82 TC 36 Z9 37 U1 2 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 21 PY 2011 VL 31 IS 38 BP 13562 EP 13575 DI 10.1523/JNEUROSCI.2315-11.2011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 822XG UT WOS:000295083300020 PM 21940447 ER PT J AU Devor, A Sakadzic, S Saisan, PA Yaseen, MA Roussakis, E Srinivasan, VJ Vinogradov, SA Rosen, BR Buxton, RB Dale, AM Boas, DA AF Devor, Anna Sakadzic, Sava Saisan, Payam A. Yaseen, Mohammad A. Roussakis, Emmanuel Srinivasan, Vivek J. Vinogradov, Sergei A. Rosen, Bruce R. Buxton, Richard B. Dale, Anders M. Boas, David A. TI "Overshoot" of O-2 Is Required to Maintain Baseline Tissue Oxygenation at Locations Distal to Blood Vessels SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SOMATOSENSORY CORTEX; OXIDATIVE-METABOLISM; 2-PHOTON MICROSCOPY; PARTIAL-PRESSURE; CEREBRAL-CORTEX; FLOW; TENSION; STIMULATION; ACTIVATION; PHOSPHORESCENCE AB In vivo imaging of cerebral tissue oxygenation is important in defining healthy physiology and pathological departures associated with cerebral disease. We used a recently developed two-photon microscopy method, based on a novel phosphorescent nanoprobe, to image tissue oxygenation in the rat primary sensory cortex in response to sensory stimulation. Our measurements showed that a stimulus-evoked increase in tissue pO(2) depended on the baseline pO(2) level. In particular, during sustained stimulation, the steady-state pO(2) at low-baseline locations remained at the baseline, despite large pO(2) increases elsewhere. In contrast to the steady state, where pO(2) never decreased below the baseline, transient decreases occurred during the "initial dip" and "poststimulus undershoot." These results suggest that the increase in blood oxygenation during the hemodynamic response, which has been perceived as a paradox, may serve to prevent a sustained oxygenation drop at tissue locations that are remote from the vascular feeding sources. C1 [Devor, Anna; Saisan, Payam A.; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna; Buxton, Richard B.; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Devor, Anna; Sakadzic, Sava; Yaseen, Mohammad A.; Srinivasan, Vivek J.; Rosen, Bruce R.; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02114 USA. [Roussakis, Emmanuel; Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. RP Devor, A (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. EM adevor@ucsd.edu FU NINDS [NS051188, NS057198, NS057476, NS055104]; NIBIB [EB00790, EB009118, EB2066, EB007279] FX We gratefully acknowledge support from NINDS (Grants NS051188 and NS057198 to A. D., NS057476 and NS055104 to D. A. B.) and NIBIB (Grants EB00790 to A. M. D., EB009118 to A. D., EB2066 to B. R. R., and EB007279 to S. A. V.). NR 32 TC 60 Z9 61 U1 2 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 21 PY 2011 VL 31 IS 38 BP 13676 EP 13681 DI 10.1523/JNEUROSCI.1968-11.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 822XG UT WOS:000295083300031 PM 21940458 ER PT J AU Alemozaffar, M Regan, MM Cooperberg, MR Wei, JT Michalski, JM Sandler, HM Hembroff, L Sadetsky, N Saigal, CS Litwin, MS Klein, E Kibel, AS Hamstra, DA Pisters, LL Kuban, DA Kaplan, ID Wood, DP Ciezki, J Dunn, RL Carroll, PR Sanda, MG AF Alemozaffar, Mehrdad Regan, Meredith M. Cooperberg, Matthew R. Wei, John T. Michalski, Jeff M. Sandler, Howard M. Hembroff, Larry Sadetsky, Natalia Saigal, Christopher S. Litwin, Mark S. Klein, Eric Kibel, Adam S. Hamstra, Daniel A. Pisters, Louis L. Kuban, Deborah A. Kaplan, Irving D. Wood, David P. Ciezki, Jay Dunn, Rodney L. Carroll, Peter R. Sanda, Martin G. TI Prediction of Erectile Function Following Treatment for Prostate Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; RADICAL RETROPUBIC PROSTATECTOMY; EXTERNAL-BEAM RADIOTHERAPY; SEXUAL FUNCTION; INDEX COMPOSITE; UNITED-STATES; OUTCOMES; SURVIVORS; THERAPY; URINARY AB Context Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking. Objective To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. Design Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N=1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n=1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort. Main Outcome Measures Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment. Results Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%-52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%-56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74-0.80] for prostatectomy; 0.87 [95% CI, 0.80-0.94] for external radiotherapy; and 0.90 [95% CI, 0.85-0.95] for brachytherapy). Conclusion Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. JAMA. 2011;306(11):1205-1214 www.jama.com C1 [Alemozaffar, Mehrdad; Sanda, Martin G.] Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02215 USA. [Kaplan, Irving D.] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Regan, Meredith M.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Regan, Meredith M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Cooperberg, Matthew R.; Sadetsky, Natalia; Carroll, Peter R.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Wei, John T.; Wood, David P.] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI USA. [Hamstra, Daniel A.] Univ Michigan, Dept Radiat Oncol, Sch Med, Ann Arbor, MI 48109 USA. [Dunn, Rodney L.] Univ Michigan, Sch Med, Dept Biostat Core, Ann Arbor, MI USA. [Michalski, Jeff M.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. [Kibel, Adam S.] Washington Univ, Dept Surg, St Louis, MO USA. [Sandler, Howard M.] Cedars Sinai Med Ctr, Dept Radiat Oncol, Los Angeles, CA 90048 USA. [Hembroff, Larry] Michigan State Univ, Off Survey Res, Inst Publ Policy & Social Res, E Lansing, MI 48824 USA. [Saigal, Christopher S.; Litwin, Mark S.] UCLA Ctr Hlth Sci, Dept Urol, Los Angeles, CA USA. [Litwin, Mark S.] UCLA Ctr Hlth Sci, Dept Hlth Serv, Los Angeles, CA USA. [Klein, Eric] Cleveland Clin Hosp, Glickman Urol & Kidney Inst, Cleveland, OH USA. [Ciezki, Jay] Cleveland Clin Hosp, Dept Radiat Oncol, Cleveland, OH USA. [Pisters, Louis L.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Kuban, Deborah A.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Sanda, MG (reprint author), Beth Israel Deaconess Med Ctr, Div Urol, 330 Brookline Ave,Rabb 440, Boston, MA 02215 USA. EM msanda@bidmc.harvard.edu RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; Wei, John/E-8967-2012 FU National Institutes of Health (NIH) [R01 CA 95662, 1RC1CA146596]; Takeda; Abbott; Amgen; sanofi-aventis; Dendreon; Radiation Oncology Institute FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. None of the coauthors have been compensated specifically for work related to this manuscript other than having received research support from the National Institutes of Health (NIH) to cover costs of conducting the study. Dr Cooperberg reported serving as a consultant for Denreon and Ortho-Centocor and receiving payment for lectures from Takeda, Abbott, and Amgen. Dr Wei reported serving as a consultant for Envisioneering Inc and sanofi-aventis; serving as an expert witness for Genprobe; serving as a proctor for American Medical Systems; and receiving research funding from sanofi-aventis. Dr Michaliski reported making donations to charity in lieu of honoraria for his role as a board member for Elekta Inc, Augmenix Inc, and Viewray. Dr Sandler reported serving as a consultant for Varian, Calypso Medical, Millennium-Takeda, and Centocor-Ortho Biotech. Dr Kibel reported serving as a consultant for Myraid, Caris, Dendreon, sanofi-aventis, Cougar, and Ferring; receiving payment for lectures from Dendreon; and holding stock in Myriad. Dr Kuban serving as a consultant for Ferring Pharmaceuticals and bioTheranostics and as a lecturer supported by the Radiation Oncology Institute. Dr Wood reported serving as a consultant for Intuitive Surgical and holding stock in that company. Dr Carroll reported receiving an institutional research grant from Abbott. Dr Sanda reported receiving a lecture honnorarium from Eli Lily. No other authors reported financial disclosures.; The study was supported by NIH grants R01 CA 95662 and 1RC1CA146596 NR 40 TC 126 Z9 131 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 21 PY 2011 VL 306 IS 11 BP 1205 EP 1214 DI 10.1001/jama.2011.1333 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 822HB UT WOS:000295033500021 PM 21934053 ER PT J AU Barry, MJ AF Barry, Michael J. TI Helping Patients Make Better Personal Health Decisions The Promise of Patient-Centered Outcomes Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Barry, Michael J.] Massachusetts Gen Hosp, Div Gen Med, Med Practices Evaluat Ctr, Boston, MA 02114 USA. [Barry, Michael J.] Harvard Univ, Sch Med, Boston, MA USA. [Barry, Michael J.] Fdn Informed Med Decis Making, Boston, MA USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Div Gen Med, Med Practices Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM mbarry@partners.org NR 10 TC 11 Z9 11 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 21 PY 2011 VL 306 IS 11 BP 1258 EP 1259 DI 10.1001/jama.2011.1363 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 822HB UT WOS:000295033500030 PM 21934062 ER PT J AU Li, XH Zhang, D Liu, B AF Li, Xinhua Zhang, Da Liu, Bob TI A practical approach to estimate the weighted CT dose index over an infinite integration length SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; DOSIMETRY; PROFILES; CTDI100 AB The CT scanner-displayed radiation dose information is based on CT dose index (CTDI) over an integration length of 100 mm (CTDI(100)), which is lower than the CTDI over an infinite integration length (CTDI(infinity)). In an adult or a pediatric body CT scan, the limiting equilibrium dose can be established near the central scan plane, and CTDI(infinity) more closely indicates the accumulated dose than CTDI(100). The aim of this study was to (a) evaluate CTDI efficiencies, epsilon (CTDI(100)) = CTDI(100)/CTDI(infinity), for a multi-detector CT (MDCT) scanner, (b) examine the dependences of epsilon (CTDI(100)) on kV, beam width, phantom diameter, phantom length and position in phantom and (c) investigate how to estimate CTDI(infinity) based on the CT scanner-displayed information. We performed a comprehensive Geant4-based simulation study of a clinical CT scanner, and calculated epsilon (CTDI(100)) for a range of parameters. The results were compared with the epsilon (CTDI(100)) data of previous studies. Differences in the epsilon (CTDI(100)) values of these studies were assessed. A broad analysis of the epsilon (CTDI(100)) variations with the above-mentioned parameters was presented. Based on the results, we proposed a practical approach to obtain the weighted CTDI(infinity) using the CT scanner-displayed information. A reference combination of 120 kV and a beam width close to 20 mm can be selected to determine the efficiencies of the weighted CTDI by using either phantom measurements or computer simulations. The results can be applied to estimate the weighted CTDI(infinity) for 80-140 kV and the beam widths within 40 mm. Errors in the weighted CTDI(infinity) due to the variations of kV and beam width can be 5% or less for the MDCT scanners. C1 [Li, Xinhua; Zhang, Da; Liu, Bob] Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, Boston, MA 02114 USA. RP Liu, B (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Diagnost Imaging Phys, Boston, MA 02114 USA. EM bliu7@bics.bwh.harvard.edu NR 26 TC 15 Z9 15 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2011 VL 56 IS 18 BP 5789 EP 5803 DI 10.1088/0031-9155/56/18/002 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 818WT UT WOS:000294787300004 PM 21846935 ER PT J AU Gu, SX Gupta, R Kyprianou, I AF Gu, Songxiang Gupta, Rajiv Kyprianou, Iacovos TI Computational high-resolution heart phantoms for medical imaging and dosimetry simulations SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CARDIAC MR; LEFT-VENTRICLE; SEGMENTATION; MODELS; IMAGES; DISEASE AB Cardiovascular disease in general and coronary artery disease (CAD) in particular, are the leading cause of death worldwide. They are principally diagnosed using either invasive percutaneous transluminal coronary angiograms or non-invasive computed tomography angiograms (CTA). Minimally invasive therapies for CAD such as angioplasty and stenting are rendered under fluoroscopic guidance. Both invasive and non-invasive imaging modalities employ ionizing radiation and there is concern for deterministic and stochastic effects of radiation. Accurate simulation to optimize image quality with minimal radiation dose requires detailed, gender-specific anthropomorphic phantoms with anatomically correct heart and associated vasculature. Such phantoms are currently unavailable. This paper describes an open source heart phantom development platform based on a graphical user interface. Using this platform, we have developed seven high-resolution cardiac/coronary artery phantoms for imaging and dosimetry from seven high-quality CTA datasets. To extract a phantom from a coronary CTA, the relationship between the intensity distribution of the myocardium, the ventricles and the coronary arteries is identified via histogram analysis of the CTA images. By further refining the segmentation using anatomy-specific criteria such as vesselness, connectivity criteria required by the coronary tree and image operations such as active contours, we are able to capture excellent detail within our phantoms. For example, in one of the female heart phantoms, as many as 100 coronary artery branches could be identified. Triangular meshes are fitted to segmented high-resolution CTA data. We have also developed a visualization tool for adding stenotic lesions to the coronaries. The male and female heart phantoms generated so far have been cross-registered and entered in the mesh-based Virtual Family of phantoms with matched age/gender information. Any phantom in this family, along with user-defined stenoses, can be used to obtain clinically realistic projection images with the Monte Carlo code penMesh for optimizing imaging and dosimetry. C1 [Gu, Songxiang; Kyprianou, Iacovos] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Gupta, Rajiv] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gu, SX (reprint author), US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. EM songxiang.gu@fda.hhs.gov; rgupta1@partners.org; iacovos.kyprianou@fda.hhs.gov FU FDA; National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health; Food and Drug Administration Office of Women's Health FX Dr Songxiang Gu was supported in part by a grant from the FDA Critical Path. Dr Kyprianou's research was supported in part by the National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health and by the Food and Drug Administration Office of Women's Health. Special gratitude is expressed for the help and recommendations of Dr Rongping Zeng, Dr Aldo Badano, Dr Kyle Myers, Dr Andreu Badal-Soler, Dr Camille Vidal and Mr Samir Abboud. NR 46 TC 8 Z9 8 U1 1 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2011 VL 56 IS 18 BP 5845 EP 5864 DI 10.1088/0031-9155/56/18/005 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 818WT UT WOS:000294787300007 PM 21852725 ER PT J AU Shima, K Morikawa, T Yamauchi, M Kuchiba, A Imamura, Y Liao, XY Meyerhardt, JA Fuchs, CS Ogino, S AF Shima, Kaori Morikawa, Teppei Yamauchi, Mai Kuchiba, Aya Imamura, Yu Liao, Xiaoyun Meyerhardt, Jeffrey A. Fuchs, Charles S. Ogino, Shuji TI TGFBR2 and BAX Mononucleotide Tract Mutations, Microsatellite Instability, and Prognosis in 1072 Colorectal Cancers SO PLOS ONE LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; POPULATION-BASED SAMPLE; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; III COLON-CANCER; DNA METHYLATION; LINE-1 HYPOMETHYLATION; ADJUVANT CHEMOTHERAPY; KRAS MUTATION; BRAF MUTATION; BETA RECEPTOR AB Background: Mononucleotide tracts in the coding regions of the TGFBR2 and BAX genes are commonly mutated in microsatellite instability-high (MSI-high) colon cancers. The receptor TGFBR2 plays an important role in the TGFB1 (transforming growth factor-beta, TGF-beta) signaling pathway, and BAX plays a key role in apoptosis. However, a role of TGFBR2 or BAX mononucleotide mutation in colorectal cancer as a prognostic biomarker remains uncertain. Methodology/Principal Findings: We utilized a database of 1072 rectal and colon cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusted for clinical, pathological and molecular features including the CpG island methylator phenotype (CIMP), LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. MSI-high was observed in 15% (162/1072) of all colorectal cancers. TGFBR2 and BAX mononucleotide mutations were detected in 74% (117/159) and 30% (48/158) of MSI-high tumors, respectively. In Kaplan-Meier analysis as well as univariate and multivariate Cox regression analyses, compared to microsatellite stable (MSS)/MSI-low cases, MSI-high cases were associated with superior colorectal cancer-specific survival [adjusted HR, 0.34; 95% confidence interval (CI), 0.20-0.57] regardless of TGFBR2 or BAX mutation status. Among MSI-high tumors, TGFBR2 mononucleotide mutation was associated with CIMP-high independent of other variables [multivariate odds ratio, 3.57; 95% CI, 1.66-7.66; p = 0.0011]. Conclusions: TGFBR2 or BAX mononucleotide mutations are not associated with the patient survival outcome in MSI-high colorectal cancer. Our data do not support those mutations as prognostic biomarkers (beyond MSI) in colorectal carcinoma. C1 [Shima, Kaori; Morikawa, Teppei; Yamauchi, Mai; Kuchiba, Aya; Imamura, Yu; Liao, Xiaoyun; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shima, Kaori; Morikawa, Teppei; Yamauchi, Mai; Kuchiba, Aya; Imamura, Yu; Liao, Xiaoyun; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Shima, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU United States National Institutes of Health (NIH) [P01CA87969, P01CA55075, P50CA127003, K07CA122826, R01CA151993]; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance FX This work was supported by United States National Institutes of Health (NIH) grants P01CA87969 (to SE Hankinson), P01CA55075 (to WC Willett), P50CA127003 (to CSF), K07CA122826 (to SO) and R01CA151993 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 15 Z9 15 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 20 PY 2011 VL 6 IS 9 AR e25062 DI 10.1371/journal.pone.0025062 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825GY UT WOS:000295260400043 PM 21949851 ER PT J AU Lo Re, V Teal, V Localio, AR Amorosa, VK Kaplan, DE Gross, R AF Lo Re, Vincent, III Teal, Valerie Localio, A. Russell Amorosa, Valerianna K. Kaplan, David E. Gross, Robert TI Relationship Between Adherence to Hepatitis C Virus Therapy and Virologic Outcomes SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID INTERFERON-ALPHA-2B PLUS RIBAVIRIN; INITIATED ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; PEGINTERFERON ALPHA-2A; COMBINATION THERAPY; SUSTAINED RESPONSE; PHARMACY RECORDS; VIRAL LOAD; INFECTION; COMPLICATIONS AB Background: Adherence to therapy with pegylated interferon and ribavirin for hepatitis C virus (HCV) infection has been incompletely examined. Objective: To evaluate the relationship between adherence to HCV therapy and early and sustained virologic response, assess changes in adherence over time, and examine risk factors for nonadherence. Design: Retrospective cohort study. Setting: National Veterans Affairs Hepatitis C Clinical Case Registry. Patients: 5706 HCV-infected patients (genotypes 1, 2, 3, or 4) with at least 1 prescription for both pegylated interferon and ribavirin between 2003 and 2006 and HCV RNA results before and after treatment initiation. Measurements: Adherence was calculated over 12-week intervals by using pharmacy refill data. End points included early virologic response (decrease of >= 2 log(10) HCV RNA at 12 weeks) and sustained virologic response (undetectable HCV RNA 24 weeks after the end of treatment). Results: Early virologic response increased with higher levels of adherence to ribavirin therapy over the initial 12 weeks (patients with HCV genotype 1 or 4, 25 of 68 [37%] with <= 40% adherence vs. 1367 of 2187 [63%] with 91% to 100% adherence [P < 0.001]; patients with HCV genotype 2 or 3, 12 of 18 [67%] with <= 40% adherence vs. 651 of 713 [91%] with 91% to 100% adherence [P < 0.001]). Among patients with HCV genotype 1 or 4, sustained response increased with higher adherence to ribavirin therapy over the second, third, and fourth 12-week intervals. Results were similar for adherence to interferon therapy. Mean adherence to therapy with interferon and ribavirin decreased by 3.4 and 6.6 percentage points per 12-week interval, respectively (P for trend < 0.001 for each drug). Patients who received growth factors or thyroid medications during treatment had higher mean adherence to antiviral therapy. Limitation: This was an observational study without standardized timing for outcome measurements. Conclusion: Early and sustained virologic responses increased with higher levels of adherence to interferon and ribavirin therapy. Adherence to therapy with both antivirals decreased over time, but more so for ribavirin. C1 [Lo Re, Vincent, III] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Lo Re, V (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 836 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM vincentl@mail.med.upenn.edu RI Lo Re, Vincent/N-7817-2015; OI Teal, Valerie/0000-0001-7116-5353 FU Department of Veterans Affairs; National Institutes of Health [K01 AI070001]; Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics [HS10399] FX This material is based on work supported in part by the Department of Veterans Affairs. The contents do not represent the views of the Department of Veterans Affairs or the U.S. Government.; By grant K01 AI070001 from the National Institutes of Health (Dr. Lo Re), grant HS10399 from the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics cooperative agreement (Drs. Lo Re, Localio, and Gross), and a Department of Veterans Affairs Competitive Pilot Project Fund grant (Drs. Lo Re and Amorosa). NR 37 TC 27 Z9 27 U1 0 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 20 PY 2011 VL 155 IS 6 BP 353 EP U46 DI 10.7326/0003-4819-155-6-201109200-00003 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 822HA UT WOS:000295033400014 PM 21930852 ER PT J AU Chou, R Arora, B Dana, T Fu, RW Walker, M Humphrey, L AF Chou, Roger Arora, Bhaskar Dana, Tracy Fu, Rongwei Walker, Miranda Humphrey, Linda TI Screening Asymptomatic Adults With Resting or Exercise Electrocardiography: A Review of the Evidence for the US Preventive Services Task Force SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; LEFT-VENTRICULAR HYPERTROPHY; FACTOR INTERVENTION TRIAL; ST-SEGMENT DEPRESSION; ALL-CAUSE MORTALITY; APPARENTLY HEALTHY-MEN; CARDIOVASCULAR RISK-FACTORS; SILENT-MYOCARDIAL-ISCHEMIA; T-WAVE ABNORMALITIES AB Background: Coronary heart disease is the leading cause of death in adults. Screening for abnormalities by using resting or exercise electrocardiography (ECG) might help identify persons who would benefit from interventions to reduce cardiovascular risk. Purpose: To update the 2004 U. S. Preventive Services Task Force evidence review on screening for resting or exercise ECG abnormalities in asymptomatic adults. Data Sources: MEDLINE (2002 through January 2011), the Cochrane Library database (through the fourth quarter of 2010), and reference lists. Study Selection: Randomized, controlled trials and prospective cohort studies. Data Extraction: Investigators abstracted details about the study population, study design, data analysis, follow-up, and results and assessed quality by using predefined criteria. Data Synthesis: No study evaluated clinical outcomes or use of risk-reducing therapies after screening versus no screening. No study estimated how accurately resting or exercise electrocardiography classified participants into high-, intermediate-, or low-risk groups, compared with traditional risk factor assessment alone. Sixty-three prospective cohort studies evaluated abnormalities on resting or exercise ECG as predictors of cardiovascular events after adjustment for traditional risk factors. Abnormalities on resting ECG (ST-segment or T-wave abnormalities, left ventricular hypertrophy, bundle branch block, or left-axis deviation) or exercise ECG (ST-segment depression with exercise, chronotropic incompetence, abnormal heart rate recovery, or decreased exercise capacity) were associated with increased risk (pooled hazard ratio estimates, 1.4 to 2.1). Evidence on harms was limited, but direct harms seemed minimal (for resting ECG) or small (for exercise ECG). No study estimated harms from subsequent testing or interventions, although rates of angiography after exercise ECG ranged from 0.6% to 2.9%. Limitations: Only English-language studies were included. Statistical heterogeneity was present in several of the pooled analyses. Conclusion: Abnormalities on resting or exercise ECG are associated with an increased risk for subsequent cardiovascular events after adjustment for traditional risk factors, but the clinical implications of these findings are unclear. C1 [Chou, Roger] Oregon Hlth & Sci Univ, Oregon Evidence Based Practice Ctr, Mailcode BICC, Portland, OR 97239 USA. Portland VA Med Ctr, Portland, OR USA. RP Chou, R (reprint author), Oregon Hlth & Sci Univ, Oregon Evidence Based Practice Ctr, Mailcode BICC, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM chour@ohsu.edu FU Agency for Healthcare Research and Quality [HHSA-290-2007-10057-I-EPC3] FX By contract number HHSA-290-2007-10057-I-EPC3, Task Order No. 3, from the Agency for Healthcare Research and Quality. NR 100 TC 63 Z9 63 U1 1 U2 8 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 20 PY 2011 VL 155 IS 6 BP 375 EP U74 DI 10.7326/0003-4819-155-6-201109200-00006 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 822HA UT WOS:000295033400017 PM 21930855 ER PT J AU Jewell, CM Lopez, SCB Irvine, DJ AF Jewell, Christopher M. Lopez, Sandra C. Bustamante Irvine, Darrell J. TI In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTITUMORAL IMMUNITY; TLR LIGANDS; T-CELLS; ANTIGEN; RESPONSES; MICROSPHERES; SIZE; IMMUNOTHERAPY; PHAGOCYTOSIS; IMMUNIZATION AB Recent studies have demonstrated a simple, potentially universal strategy to enhance vaccine potency, via intralymph node (i.LN) injection. To date, intranodal immunization studies have focused on the delivery of unadjuvanted vaccines (e. g., naked DNA, peptide, or protein). We hypothesized that combining i.LN vaccination with controlled release biomaterials permitting sustained dosing of molecular adjuvants to the local tissue microenvironment would further enhance this promising vaccination strategy. To test this idea, we encapsulated the Toll-like receptor-3 ligand poly(inosiniccytidylic acid) (polyIC) in biodegradable poly(lactide-co-glycolide) microparticles (MPs) designed to remain extracellular and release polyIC in the LN over several days. Intranodal injection of MPs increased persistence of polyIC in LNs compared to the same dose of soluble polyIC or polyIC formulated in nanoparticles, leading to increased accumulation of Toll-like receptor agonist in LN-resident antigen presenting cells and more enduring dendritic cell activation. Intralymph node injection of ovalbumin mixed with polyIC-releasing MPs enhanced the humoral response and expanded ovalbumin-specific T cells to frequencies as high as 18% among all CD8(+) cells following a single injection (8.2-fold greater than the same vaccine given i.m.), a response that could not be matched by antigen mixed with polyIC-loaded nanoparticles or a 10-fold greater dose of soluble polyIC. Thus, i.LN immunization with slow release-formulated adjuvants may be a broadly applicable strategy to enhance therapeutic or prophylactic vaccines. C1 [Jewell, Christopher M.; Lopez, Sandra C. Bustamante; Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Jewell, Christopher M.; Lopez, Sandra C. Bustamante; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Jewell, Christopher M.; Irvine, Darrell J.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Jewell, Christopher M.; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Jewell, Christopher M.; Irvine, Darrell J.] Harvard, Charlestown, MA 02129 USA. RP Irvine, DJ (reprint author), MIT, Dept Mat Sci & Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM djirvine@mit.edu FU Ragon Institute of Massachusetts General Hospital; Massachusetts Institute of Technology; Harvard and The Gates Foundation; National Cancer Institute [P30-CA14051] FX This work was supported in part by the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard and The Gates Foundation. C.M.J. is a Ragon Institute Postdoctoral Fellow. D.J.I. is an investigator of the Howard Hughes Medical Institute. Core facilities were supported by Koch Institute Cancer Center Support Grant P30-CA14051 (National Cancer Institute). NR 32 TC 81 Z9 83 U1 6 U2 51 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 20 PY 2011 VL 108 IS 38 BP 15745 EP 15750 DI 10.1073/pnas.1105200108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822FS UT WOS:000295030000023 PM 21896725 ER PT J AU Saylor, PJ Lee, RJ Smith, MR AF Saylor, Philip J. Lee, Richard J. Smith, Matthew R. TI Emerging Therapies to Prevent Skeletal Morbidity in Men With Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ANDROGEN-DEPRIVATION THERAPY; RANDOMIZED CONTROLLED-TRIAL; ORAL SODIUM CLODRONATE; PLACEBO-CONTROLLED TRIAL; BONE-MINERAL DENSITY; DOUBLE-BLIND; ZOLEDRONIC ACID; FRACTURE RISK; SEX STEROIDS; OLDER MEN AB Skeletal morbidity is a prominent burden to men with advanced prostate cancer throughout the natural history of the disease. Bone metastases can cause pain and greatly elevate the risk for fractures and other structural complications. Distinct from the problem of metastases, treatment-related osteoporosis and associated fragility fractures are potential complications of androgen-deprivation therapy. Bone-targeted therapies for prostate cancer have therefore been the focus of considerable research and drug development efforts. The osteoclast is a validated therapeutic target in the management of prostate cancer. Osteoclast inhibition with zoledronic acid (a bisphosphonate) or with denosumab (a monoclonal antibody to RANK ligand) reduces risk for skeletal events in men with castration-resistant prostate cancer metastatic to bone. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density, a surrogate for osteoporotic fracture risk. Denosumab and toremifene (a selective estrogen receptor modulator) have each been shown to reduce osteoporotic fracture risk among men receiving androgen-deprivation therapy. Beta-emitting radiopharmaceuticals reduce pain due to metastatic disease. Investigations involving alpha-emitting radium-223, endothelin-A receptor antagonists atrasentan and zibotentan, proto-oncogene tyrosine-protein kinase (SRC) inhibitor dasatinib, and tyrosine kinase inhibitor cabozantinib (XL184) are ongoing in clinical trials and are also discussed. C1 [Saylor, Philip J.] Massachusetts Gen Hosp, Div Hematol Oncol, Ctr Canc, Boston, MA 02114 USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Ctr Canc, 55 Fruit St,Yawkey 7E, Boston, MA 02114 USA. EM psaylor@partners.org FU Prostate Cancer Foundation; American Society of Clinical Oncology (ASCO) Cancer Foundation; Physician Research Training Award (Prostate Cancer Research Program, Department of Defense); National Institutes of Health [5K24CA121990-02] FX Supported by Young Investigator Awards from the Prostate Cancer Foundation and American Society of Clinical Oncology (ASCO) Cancer Foundation (P. J. S.), by a Physician Research Training Award (Prostate Cancer Research Program, Department of Defense) and a Career Development Award from the ASCO Cancer Foundation (R. J. L.), and by National Institutes of Health K24 Midcareer Investigator Award No. 5K24CA121990-02 and awards from the Prostate Cancer Foundation (M.R.S.). NR 73 TC 38 Z9 38 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 BP 3705 EP 3714 DI 10.1200/JCO.2010.34.4994 PG 10 WC Oncology SC Oncology GA 821CL UT WOS:000294952300016 PM 21860001 ER PT J AU Arnaout, A Leblebjian, H Bartel, S Hassett, MJ AF Arnaout, A. Leblebjian, H. Bartel, S. Hassett, M. J. TI Relative dose intensity (RDI) assessment in an academic center. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Arnaout, A.; Leblebjian, H.; Bartel, S.; Hassett, M. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 139 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600134 PM 27958144 ER PT J AU Arun, B Biswas, S Tankhiwale, N Blackford, AL Gutierrez-Barrera, AM Litton, JK Hortobagy, GN Amos, CI Parmigiani, G AF Arun, B. Biswas, S. Tankhiwale, N. Blackford, A. L. Gutierrez-Barrera, A. M. Litton, J. K. Hortobagy, G. N. Amos, C. I. Parmigiani, G. TI Assessing the added value of breast tumor markers in breast cancer genetic risk prediction model BRCAPRO SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ N Texas, Hlth Sci Ctr, Ft Worth, TX USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 164 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600158 PM 27957957 ER PT J AU Buckley, JM Coopey, S Samphao, S Specht, MC Hughes, KS Gadd, M Taghian, AG Smith, BL AF Buckley, J. M. Coopey, S. Samphao, S. Specht, M. C. Hughes, K. S. Gadd, M. Taghian, A. G. Smith, B. L. TI Recurrence rates and long-term survival in women diagnosed with breast cancer at age 40 and younger SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Buckley, J. M.; Coopey, S.; Samphao, S.; Specht, M. C.; Hughes, K. S.; Gadd, M.; Taghian, A. G.; Smith, B. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 70 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600068 PM 27958096 ER PT J AU Carp, SA Wanyo, C Specht, MC Schapira, L Moy, B Finkelstein, DM Boas, D Isakoff, SJ AF Carp, S. A. Wanyo, C. Specht, M. C. Schapira, L. Moy, B. Finkelstein, D. M. Boas, D. Isakoff, S. J. TI Functional metabolic tomographic optical breast imaging (TOBI) to monitor response to neoadjuvant therapy in breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Charlestown, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 60 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600058 PM 27958134 ER PT J AU Childs, SK Chen, Y Pochebit, S Golshan, M Duggan, MM Wong, JS Harris, JR Bellon, JR AF Childs, S. K. Chen, Y. Pochebit, S. Golshan, M. Duggan, M. M. Wong, J. S. Harris, J. R. Bellon, J. R. TI Surgical margins and the risk of local-regional recurrence (LRR) following mastectomy for early-stage breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Faulkner Hosp, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 95 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600092 PM 27957926 ER PT J AU Hattangadi, JA Taback, N Neville, BA Harris, JR Punglia, RS AF Hattangadi, J. A. Taback, N. Neville, B. A. Harris, J. R. Punglia, R. S. TI Accelerated partial breast irradiation using brachytherapy (APBIb) for breast cancer (bca): Predictors of use and guideline concordance SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 84 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600082 PM 27958075 ER PT J AU Schneider, BP Wang, M Stearns, V Martino, S Jones, VE Perez, EA Saphner, TJ Wolff, AC Sledge, GW Wood, W Davidson, NE Sparano, JA AF Schneider, B. P. Wang, M. Stearns, V. Martino, S. Jones, V. E. Perez, E. A. Saphner, T. J. Wolff, A. C. Sledge, G. W. Wood, W. Davidson, N. E. Sparano, J. A. TI Relationship between taxane-induced neuropathy and clinical outcomes after adjuvant chemotherapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ Sch Med, Indianapolis, IN 46202 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Angeles Clin & Res Inst, Santa Monica, CA USA. North Star Lodge Canc Ctr, Yakima, WA USA. Mayo Clin, Jacksonville, FL 32224 USA. Green Bay Oncol, Green Bay, WI USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 270 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600256 PM 27957989 ER PT J AU Sgroi, D Carney, E Richardson, E Steffel, L Binns, SN Finkelstein, DM Shepherd, LE Kesty, NC Schnabel, C Erlander, MG Ingle, JN Porter, P Paik, S Muss, HB Pritchard, KI Tu, D Goss, PE AF Sgroi, D. Carney, E. Richardson, E. Steffel, L. Binns, S. N. Finkelstein, D. M. Shepherd, L. E. Kesty, N. C. Schnabel, C. Erlander, M. G. Ingle, J. N. Porter, P. Paik, S. Muss, H. B. Pritchard, K. I. Tu, D. Goss, P. E. TI Prediction of late recurrences by breast cancer index in the NCIC CTG MA.17 cohort SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. BioTheranostics Inc, San Diego, CA USA. Mayo Clin, Rochester, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 2 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600003 PM 27958176 ER PT J AU Sperduto, PW Kased, N Roberge, D Shanley, R Chao, ST Bhatt, AK Brown, PD Shih, HA Kirkpatrick, J Gaspar, LE AF Sperduto, P. W. Kased, N. Roberge, D. Shanley, R. Chao, S. T. Bhatt, A. K. Brown, P. D. Shih, H. A. Kirkpatrick, J. Gaspar, L. E. CA Graded Prognostic Assessment TI The effect of tumor subtype on survival and the graded prognostic assessment (GPA) for patients with breast cancer and brain metastases. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Minnesota, Gamma Knife Ctr, Waconia, MN USA. Minneapolis Radiat Oncol, Waconia, MN USA. Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA. McGill Univ, Dept Radiat Oncol, Ctr Hlth, Montreal, PQ H3A 2T5, Canada. Univ Minnesota, Minneapolis, MN USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Wisconsin Hosp, Dept Radiat Oncol, Madison, WI USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Colorado Denver, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 238 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600227 PM 27958084 ER PT J AU Valero, M Dominici, LS Golshan, M AF Valero, M. Dominici, L. S. Golshan, M. TI Use of intraoperative digital specimen mammography to improve operative efficiency. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2011 VL 29 IS 27 SU S MA 138 PG 1 WC Oncology SC Oncology GA V31JT UT WOS:000208880600133 PM 27958142 ER PT J AU Lucero, CA Oda, G Cox, K Maldonado, F Lombardo, J Wojcik, R Holodniy, M AF Lucero, Cynthia A. Oda, Gina Cox, Kenneth Maldonado, Frank Lombardo, Joseph Wojcik, Richard Holodniy, Mark TI Enhanced health event detection and influenza surveillance using a joint Veterans Affairs and Department of Defense biosurveillance application SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID COMMUNITY-BASED EPIDEMICS; SYNDROMIC SURVEILLANCE; OUTBREAK DETECTION; EARLY NOTIFICATION; SYSTEM AB Background: The establishment of robust biosurveillance capabilities is an important component of the U.S. strategy for identifying disease outbreaks, environmental exposures and bioterrorism events. Currently, U.S. Departments of Defense (DoD) and Veterans Affairs (VA) perform biosurveillance independently. This article describes a joint VA/DoD biosurveillance project at North Chicago-VA Medical Center (NC-VAMC). The Naval Health Clinics-Great Lakes facility physically merged with NC-VAMC beginning in 2006 with the full merger completed in October 2010 at which time all DoD care and medical personnel had relocated to the expanded and remodeled NC-VAMC campus and the combined facility was renamed the Lovell Federal Health Care Center (FHCC). The goal of this study was to evaluate disease surveillance using a biosurveillance application which combined data from both populations. Methods: A retrospective analysis of NC-VAMC/Lovell FHCC and other Chicago-area VAMC data was performed using the ESSENCE biosurveillance system, including one infectious disease outbreak (Salmonella/Taste of Chicago-July 2007) and one weather event (Heat Wave-July 2006). Influenza-like-illness (ILI) data from these same facilities was compared with CDC/Illinois Sentinel Provider and Cook County ESSENCE data for 2007-2008. Results: Following consolidation of VA and DoD facilities in North Chicago, median number of visits more than doubled, median patient age dropped and proportion of females rose significantly in comparison with the pre-merger NC-VAMC facility. A high-level gastrointestinal alert was detected in July 2007, but only low-level alerts at other Chicago-area VAMCs. Heat-injury alerts were triggered for the merged facility in June 2006, but not at the other facilities. There was also limited evidence in these events that surveillance of the combined population provided utility above and beyond the VA-only and DoD-only components. Recorded ILI activity for NC-VAMC/Lovell FHCC was more pronounced in the DoD component, likely due to pediatric data in this population. NCVAMC/Lovell FHCC had two weeks of ILI activity exceeding both the Illinois State and East North Central Regional baselines, whereas Hines VAMC had one and Jesse Brown VAMC had zero. Conclusions: Biosurveillance in a joint VA/DoD facility showed potential utility as a tool to improve surveillance and situational awareness in an area with Veteran, active duty and beneficiary populations. Based in part on the results of this pilot demonstration, both agencies have agreed to support the creation of a combined VA/DoD ESSENCE biosurveillance system which is now under development. C1 [Lucero, Cynthia A.; Oda, Gina; Holodniy, Mark] US Dept Vet Affairs, Off Publ Hlth, Off Publ Hlth Surveillance & Res, Palo Alto, CA 94304 USA. [Cox, Kenneth] Armed Forces Hlth Surveillance Ctr, Med Informat Project, Silver Spring, MD 20910 USA. [Cox, Kenneth] Armed Forces Hlth Surveillance Ctr, Special Project, Silver Spring, MD 20910 USA. [Maldonado, Frank] US Dept Vet Affairs, Captain James A Lovell Fed Hlth Care Ctr, N Chicago, IL 60064 USA. [Lombardo, Joseph; Wojcik, Richard] Johns Hopkins Univ, Appl Phys Lab, ESSENCE Grp, Laurel, MD 20723 USA. RP Lucero, CA (reprint author), US Dept Vet Affairs, Off Publ Hlth, Off Publ Hlth Surveillance & Res, 3801 Miranda Ave 132, Palo Alto, CA 94304 USA. EM cynthia.lucero@va.gov NR 37 TC 6 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD SEP 19 PY 2011 VL 11 AR 56 DI 10.1186/1472-6947-11-56 PG 12 WC Medical Informatics SC Medical Informatics GA 832DE UT WOS:000295781100001 PM 21929813 ER PT J AU Merquiol, E Uzi, D Mueller, T Goldenberg, D Nahmias, Y Xavier, RJ Tirosh, B Shibolet, O AF Merquiol, Emmanuelle Uzi, Dotan Mueller, Tobias Goldenberg, Daniel Nahmias, Yaakov Xavier, Ramnik J. Tirosh, Boaz Shibolet, Oren TI HCV Causes Chronic Endoplasmic Reticulum Stress Leading to Adaptation and Interference with the Unfolded Protein Response SO PLOS ONE LA English DT Article ID HEPATITIS-C VIRUS; ER STRESS; SUBGENOMIC REPLICONS; VIRAL REPLICATION; OXIDATIVE STRESS; PHOSPHATASE 2A; CORE PROTEIN; CELL-CULTURE; IN-VITRO; TRANSCRIPTION AB Background: The endoplasmic reticulum (ER) is the cellular site for protein folding. ER stress occurs when protein folding capacity is exceeded. This stress induces a cyto-protective signaling cascades termed the unfolded protein response (UPR) aimed at restoring homeostasis. While acute ER stress is lethal, chronic sub-lethal ER stress causes cells to adapt by attenuation of UPR activation. Hepatitis C virus (HCV), a major human pathogen, was shown to cause ER stress, however it is unclear whether HCV induces chronic ER stress, and if so whether adaptation mechanisms are initiated. We wanted to characterize the kinetics of HCV-induced ER stress during infection and assess adaptation mechanisms and their significance. Methods and Findings: The HuH7.5.1 cellular system and HCV-transgenic (HCV-Tg) mice were used to characterize HCV-induced ER stress/UPR pathway activation and adaptation. HCV induced a wave of acute ER stress peaking 2-5 days post-infection, which rapidly subsided thereafter. UPR pathways were activated including IRE1 and EIF2 alpha phosphorylation, ATF6 cleavage and XBP-1 splicing. Downstream target genes including GADD34, ERdj4, p58ipk, ATF3 and ATF4 were upregulated. CHOP, a UPR regulated protein was activated and translocated to the nucleus. Remarkably, UPR activity did not return to baseline but remained elevated for up to 14 days post infection suggesting that chronic ER stress is induced. At this time, cells adapted to ER stress and were less responsive to further drug-induced ER stress. Similar results were obtained in HCV-Tg mice. Suppression of HCV by Interferon-alpha 2 alpha treatment, restored UPR responsiveness to ER stress tolerant cells. Conclusions: Our study shows, for the first time, that HCV induces adaptation to chronic ER stress which was reversed upon viral suppression. These finding represent a novel viral mechanism to manipulate cellular response pathways. C1 [Merquiol, Emmanuelle; Uzi, Dotan] Hadassah Hebrew Univ, Med Ctr, Div Med, Liver Unit, Jerusalem, Israel. [Tirosh, Boaz] Fac Med, Sch Pharmacol, Inst Drug Res, Jerusalem, Israel. [Mueller, Tobias] Charite, CVK, Med Klin MS Hepatol & Gastroenterol, D-13353 Berlin, Germany. [Goldenberg, Daniel] Hadassah Hebrew Univ, Med Ctr, Goldyne Savad Inst Gene Therapy, Jerusalem, Israel. [Nahmias, Yaakov] Hebrew Univ Jerusalem, Silberman Inst Life Sci, Rachel & Selim Benin Sch Comp Sci & Engn, Ctr Bioengn, Jerusalem, Israel. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Gastroenterol Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA USA. [Shibolet, Oren] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Gastroenterol & Liver Dis, Liver Unit, IL-69978 Tel Aviv, Israel. RP Merquiol, E (reprint author), Hadassah Hebrew Univ, Med Ctr, Div Med, Liver Unit, Jerusalem, Israel. EM orensh@tasmc.health.gov.il RI Nahmias, Yaakov/H-4725-2013; OI Nahmias, Yaakov/0000-0002-6051-616X FU Israel Science Foundation [1668/08, 78/09]; Bi-National Science Foundation [2007083]; Kamea Scientific Foundation of the Israeli Government FX This research was supported by the Morasha Program of Israel Science Foundation (grant No. 1668/08) and the Bi-National Science Foundation (grant No. 2007083) to OS and by the Israel Science Foundation (grant 78/09) to BT. DG is supported by the Kamea Scientific Foundation of the Israeli Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 53 Z9 55 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 19 PY 2011 VL 6 IS 9 AR e24660 DI 10.1371/journal.pone.0024660 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825FZ UT WOS:000295257900027 PM 21949742 ER PT J AU Shi, DL Bedford, NM Cho, HS AF Shi, Donglu Bedford, Nicholas M. Cho, Hoon-Sung TI Engineered Multifunctional Nanocarriers for Cancer Diagnosis and Therapeutics SO SMALL LA English DT Review ID WALLED CARBON NANOTUBES; DIFFUSE OPTICAL TOMOGRAPHY; SEMICONDUCTOR QUANTUM DOTS; CONTROLLED DRUG-RELEASE; IN-VIVO; MAGNETIC NANOPARTICLES; BREAST-CANCER; IRON-OXIDE; PROSTATE-CANCER; MACROMOLECULAR THERAPEUTICS AB This article reviews advances in the design and development of multifunctional carbon-based and/or magnetic nanoparticle systems (or simply 'nanocarriers') for early cancer diagnosis and spatially and temporally controlled therapy. The critical issues in cancer diagnosis and treatment are addressed based on novel nanotechnologies such as real-time in-vivo imaging, drug storage and release, and specific cancer-cell targeting. The implementation of nanocarriers into animal models and the subsequent effectiveness in treating tumors is also reviewed. Recommendations for future research are given. C1 [Shi, Donglu] Tongji Univ, Inst Adv Mat & Nano Biomed, Shanghai 200092, Peoples R China. [Shi, Donglu; Bedford, Nicholas M.] Univ Cincinnati, Dept Chem & Mat Engn, Cincinnati, OH 45221 USA. [Cho, Hoon-Sung] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Cho, Hoon-Sung] Massachusetts Gen Hosp, Ctr Translat Nucl Med & Mol Imaging, Charlestown, MA 02129 USA. RP Shi, DL (reprint author), Tongji Univ, Inst Adv Mat & Nano Biomed, Shanghai 200092, Peoples R China. EM shid@ucmail.uc.edu FU Dayton Area Graduate Studies Institute FX The authors would collectively like to thank Dr. Giovanni Pauletti and Chris Huth (University of Cincinnati) for their critical review and editing of this manuscript. The authors are grateful to Dr. Haiqing Dong for developing the schematic drawing of Figure 1. We would also like to thank Drs. San-Yuan Chen (National Chiao Tung University), Hongjie Dai (Stanford University), Qinghua Lu (Shanghai Jiao Tong University), James F. Rusling (University of Connecticut), Z. John Zhang (Georgia Institute of Technology), and Zhuang Liu (Soochow University) for kindly provides figures for this review. N.M. Bedford would like to acknowledge the financial support from the Dayton Area Graduate Studies Institute. NR 156 TC 55 Z9 58 U1 5 U2 107 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1613-6810 J9 SMALL JI Small PD SEP 19 PY 2011 VL 7 IS 18 BP 2549 EP 2567 DI 10.1002/smll.201100436 PG 19 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 826VB UT WOS:000295382500001 PM 21648074 ER PT J AU Barnitz, RA Chaigne-Delalande, B Bolton, DL Lenardo, MJ AF Barnitz, R. Anthony Chaigne-Delalande, Benjamin Bolton, Diane L. Lenardo, Michael J. TI Exposed Hydrophobic Residues in Human Immunodeficiency Virus Type 1 Vpr Helix-1 Are Important for Cell Cycle Arrest and Cell Death SO PLOS ONE LA English DT Article ID INDUCED G(2) ARREST; HIV-1 VPR; NUCLEAR-LOCALIZATION; VIRION INCORPORATION; PROTEIN VPR; T-CELLS; UBIQUITIN LIGASE; MUTATIONAL ANALYSIS; REGULATORY PROTEIN; ACCESSORY PROTEIN AB The human immunodeficiency virus type 1 (HIV-1) accessory protein viral protein R (Vpr) is a major determinant for virus-induced G2/M cell cycle arrest and cytopathicity. Vpr is thought to perform these functions through the interaction with partner proteins. The NMR structure of Vpr revealed solvent exposed hydrophobic amino acids along helices 1 and 3 of Vpr, which could be putative protein binding domains. We previously showed that the hydrophobic patch along helix-3 was important for G2/M blockade and cytopathicity. Mutations of the exposed hydrophobic residues along helix-1 were found to reduce Vpr-induced cell cycle arrest and cell death as well. The levels of toxicity during virion delivery of Vpr correlated with G2/M arrest. Thus, the exposed hydrophobic amino acids in the amino-terminal helix-1 are important for the cell cycle arrest and cytopathicity functions of Vpr. C1 [Barnitz, R. Anthony; Chaigne-Delalande, Benjamin; Bolton, Diane L.; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Barnitz, R. Anthony; Lenardo, Michael J.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. RP Barnitz, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM lenardo@nih.gov OI Barnitz, Tony/0000-0002-9634-4558; Tripp, Ralph/0000-0002-2924-9956 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2011 VL 6 IS 9 AR e24924 DI 10.1371/journal.pone.0024924 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800049 PM 21949789 ER PT J AU Krajewska, M You, ZR Rong, J Kress, C Huang, XS Yang, JS Kyoda, T Leyva, R Banares, S Hu, Y Sze, CH Whalen, MJ Salmena, L Hakem, R Head, BP Reed, JC Krajewski, S AF Krajewska, Maryla You, Zerong Rong, Juan Kress, Christina Huang, Xianshu Yang, Jinsheng Kyoda, Tiffany Leyva, Ricardo Banares, Steven Hu, Yue Sze, Chia-Hung Whalen, Michael J. Salmena, Leonardo Hakem, Razqallah Head, Brian P. Reed, John C. Krajewski, Stan TI Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity SO PLOS ONE LA English DT Article ID PROGRAMMED CELL-DEATH; FOCAL CEREBRAL-ISCHEMIA; C-JUN; HEAD-INJURY; IN-VITRO; ORGANOTYPIC CULTURES; NERVOUS-SYSTEM; JNK ACTIVATION; APOPTOSIS; MICE AB Background: Acute brain injury is an important health problem. Given the critical position of caspase 8 at the crossroads of cell death pathways, we generated a new viable mouse line (Ncasp8(-/-)), in which the gene encoding caspase 8 was selectively deleted in neurons by cre-lox system. Methodology/Principal Findings: Caspase 8 deletion reduced rates of neuronal cell death in primary neuronal cultures and in whole brain organotypic coronal slice cultures prepared from 4 and 8 month old mice and cultivated up to 14 days in vitro. Treatments of cultures with recombinant murine TNF alpha (100 ng/ml) or TRAIL (250 ng/mL) plus cyclohexamide significantly protected neurons against cell death induced by these apoptosis-inducing ligands. A protective role of caspase 8 deletion in vivo was also demonstrated using a controlled cortical impact (CCI) model of traumatic brain injury (TBI) and seizure-induced brain injury caused by kainic acid (KA). Morphometric analyses were performed using digital imaging in conjunction with image analysis algorithms. By employing virtual images of hundreds of brain sections, we were able to perform quantitative morphometry of histological and immunohistochemical staining data in an unbiased manner. In the TBI model, homozygous deletion of caspase 8 resulted in reduced lesion volumes, improved post-injury motor performance, superior learning and memory retention, decreased apoptosis, diminished proteolytic processing of caspases and caspase substrates, and less neuronal degeneration, compared to wild type, homozygous cre, and caspase 8-floxed control mice. In the KA model, Ncasp8(-/-) mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging. Conclusions: Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma. C1 [Krajewska, Maryla; Rong, Juan; Kress, Christina; Huang, Xianshu; Kyoda, Tiffany; Leyva, Ricardo; Banares, Steven; Sze, Chia-Hung; Reed, John C.; Krajewski, Stan] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [You, Zerong; Yang, Jinsheng; Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA USA. [Hu, Yue; Head, Brian P.] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Hu, Yue] VA San Diego Healthcare Syst, San Diego, CA USA. [Salmena, Leonardo; Hakem, Razqallah] Ontario Canc Inst, Dept Med Biophys, Toronto, ON M4X 1K9, Canada. RP Krajewska, M (reprint author), Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. EM jreed@sanfordburnham.org; stan@sanfordburnham.org FU NIH [NS36821, CA69381]; DoD [W81XWH-08-2-0067, W81XWH-07-1-0569]; VA CDA-2 FX Supported by the NIH grants (NS36821 [SK]; CA69381 [JCR]) and DoD grants (W81XWH-08-2-0067 [SK]; W81XWH-07-1-0569 [JCR]); VA CDA-2 [BPH]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 23 Z9 26 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2011 VL 6 IS 9 AR e24341 DI 10.1371/journal.pone.0024341 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800020 PM 21957448 ER PT J AU Qin, W Bajaj, V Malinowska, I Lu, X MacConaill, L Wu, CL Kwiatkowski, DJ AF Qin, Wei Bajaj, Vineeta Malinowska, Izabela Lu, Xin MacConaill, Laura Wu, Chin-Lee Kwiatkowski, David J. TI Angiomyolipoma Have Common Mutations in TSC2 but No Other Common Genetic Events SO PLOS ONE LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; LYMPHANGIOLEIOMYOMATOSIS; HETEROZYGOSITY; ACTIVATION; NEOPLASMS; FREQUENT; PATHWAY; FUTURE; GROWTH; MTOR AB Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC) and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series. Seven of 8 samples subjected to RT-PCR-cDNA sequencing showed mutations in TSC2; none showed mutations in TSC1 or RHEB. Six of the seven mutations were deletions. We searched for 983 activating and inactivating mutations in 115 genes, and found none in these tumors. Similarly analysis for genomic regions of loss or gain, assessed by Affymetrix SNP6.0 analysis, showed no abnormalities. Loss of heterozygosity in the TSC2 region was commonly seen, except in patients with low frequency TSC2 mutations. We conclude that sporadic renal angiomyolipoma usually have mutations in TSC2, but not TSC1 or RHEB, and have no other common genomic events, among those we searched for. However, chromosomal translocations and gene fusion events were not assessed here. TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most angiomyolipoma. C1 [Qin, Wei; Bajaj, Vineeta; Malinowska, Izabela; Kwiatkowski, David J.] Brigham & Womens Hosp, Dept Med, Translat Med Div, Boston, MA 02115 USA. [Lu, Xin; Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lu, Xin; Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [MacConaill, Laura] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. RP Qin, W (reprint author), Brigham & Womens Hosp, Dept Med, Translat Med Div, 75 Francis St, Boston, MA 02115 USA. EM dk@rics.bwh.harvard.edu RI Malinowska, Izabela/A-4816-2013 FU National Institutes of Health [NIH NCI 1P01CA120964-01A1]; NIH NINDS [4R37NS031535-18] FX This work was funded by National Institutes of Health grants NIH NCI 1P01CA120964-01A1 and NIH NINDS 4R37NS031535-18. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 16 Z9 16 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2011 VL 6 IS 9 AR e24919 DI 10.1371/journal.pone.0024919 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800048 PM 21949787 ER PT J AU Williams, BL Hornig, M Buie, T Bauman, ML Paik, MC Wick, I Bennett, A Jabado, O Hirschberg, DL Lipkin, WI AF Williams, Brent L. Hornig, Mady Buie, Timothy Bauman, Margaret L. Paik, Myunghee Cho Wick, Ivan Bennett, Ashlee Jabado, Omar Hirschberg, David L. Lipkin, W. Ian TI Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances SO PLOS ONE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; ISOMALTASE GENE-EXPRESSION; SPECTRUM DISORDERS; SUCRASE-ISOMALTASE; DIETARY INTERVENTION; MICROBIAL COMMUNITY; COLONIC MICROBIOTA; REGRESSIVE AUTISM; VIRAL-INFECTION; GUT MICROBIOTA AB Gastrointestinal disturbances are commonly reported in children with autism, complicate clinical management, and may contribute to behavioral impairment. Reports of deficiencies in disaccharidase enzymatic activity and of beneficial responses to probiotic and dietary therapies led us to survey gene expression and the mucoepithelial microbiota in intestinal biopsies from children with autism and gastrointestinal disease and children with gastrointestinal disease alone. Ileal transcripts encoding disaccharidases and hexose transporters were deficient in children with autism, indicating impairment of the primary pathway for carbohydrate digestion and transport in enterocytes. Deficient expression of these enzymes and transporters was associated with expression of the intestinal transcription factor, CDX2. Metagenomic analysis of intestinal bacteria revealed compositional dysbiosis manifest as decreases in Bacteroidetes, increases in the ratio of Firmicutes to Bacteroidetes, and increases in Betaproteobacteria. Expression levels of disaccharidases and transporters were associated with the abundance of affected bacterial phylotypes. These results indicate a relationship between human intestinal gene expression and bacterial community structure and may provide insights into the pathophysiology of gastrointestinal disturbances in children with autism. C1 [Williams, Brent L.; Hornig, Mady; Wick, Ivan; Bennett, Ashlee; Jabado, Omar; Hirschberg, David L.; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. [Buie, Timothy] Massachusetts Gen Hosp, Div Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. [Bauman, Margaret L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bauman, Margaret L.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Bauman, Margaret L.] Massachusetts Gen Hosp, LADDERS, Boston, MA 02114 USA. [Bauman, Margaret L.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Paik, Myunghee Cho] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. RP Williams, BL (reprint author), Columbia Univ, Ctr Infect & Immun, New York, NY 10027 USA. EM wil2001@columbia.edu FU National Institutes of Health [NS047537]; Google.org; Department of Defense; Cure Autism Now (CAN) FX This work was supported by National Institutes of Health (NS047537), Google.org, Department of Defense, and Cure Autism Now (CAN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 97 Z9 109 U1 8 U2 39 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 16 PY 2011 VL 6 IS 9 AR e24585 DI 10.1371/journal.pone.0024585 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824BI UT WOS:000295173800029 PM 21949732 ER PT J AU Delmore, JE Issa, GC Lemieux, ME Rahl, PB Shi, JW Jacobs, HM Kastritis, E Gilpatrick, T Paranal, RM Qi, J Chesi, M Schinzel, AC McKeown, MR Heffernan, TP Vakoc, CR Bergsagel, PL Ghobrial, IM Richardson, PG Young, RA Hahn, WC Anderson, KC Kung, AL Bradner, JE Mitsiades, CS AF Delmore, Jake E. Issa, Ghayas C. Lemieux, Madeleine E. Rahl, Peter B. Shi, Junwei Jacobs, Hannah M. Kastritis, Efstathios Gilpatrick, Timothy Paranal, Ronald M. Qi, Jun Chesi, Marta Schinzel, Anna C. McKeown, Michael R. Heffernan, Timothy P. Vakoc, Christopher R. Bergsagel, P. Leif Ghobrial, Irene M. Richardson, Paul G. Young, Richard A. Hahn, William C. Anderson, Kenneth C. Kung, Andrew L. Bradner, James E. Mitsiades, Constantine S. TI BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc SO CELL LA English DT Article ID B-CELL LINE; MULTIPLE-MYELOMA; BCL-2 FAMILY; TRANSCRIPTION FACTORS; TRANSGENIC MICE; SOLID TUMORS; BONE-MARROW; EXPRESSION; CANCER; ACTIVATION AB MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc. C1 [Delmore, Jake E.; Issa, Ghayas C.; Jacobs, Hannah M.; Kastritis, Efstathios; Gilpatrick, Timothy; Paranal, Ronald M.; Qi, Jun; Schinzel, Anna C.; McKeown, Michael R.; Heffernan, Timothy P.; Ghobrial, Irene M.; Richardson, Paul G.; Hahn, William C.; Anderson, Kenneth C.; Bradner, James E.; Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Lemieux, Madeleine E.; Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Lemieux, Madeleine E.; Kung, Andrew L.] Childrens Hosp Boston, Boston, MA 02215 USA. [Rahl, Peter B.; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Shi, Junwei; Vakoc, Christopher R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Chesi, Marta; Bergsagel, P. Leif] Mayo Clin Arizona, Ctr Comprehens Canc, Scottsdale, AZ 85259 USA. [Ghobrial, Irene M.; Richardson, Paul G.; Anderson, Kenneth C.; Bradner, James E.; Mitsiades, Constantine S.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Hahn, William C.] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM james_bradner@dfci.harvard.edu; constantine_mitsiades@dfci.harvard.edu RI Bergsagel, Peter/A-7842-2011; Young, Richard/F-6495-2012; OI Bergsagel, Peter/0000-0003-1523-7388; Young, Richard/0000-0001-8855-8647; Lemieux, Madeleine/0000-0001-6355-8691; Vakoc, Christopher/0000-0002-1158-7180; Kung, Andrew/0000-0002-9091-488X FU Chambers Medical Foundation; Stepanian Fund for Myeloma Research; Richard J. Corman Foundation; American Cancer Society [120272-PF-11-042-01-DMC]; Burroughs-Wellcome Fund; Smith Family Award; Damon-Runyon Cancer Research Foundation; MMRF; [NIH-K08CA128972]; [NIH-R01CA050947]; [NIH-R01HG002668]; [NIH-R01CA46455] FX We are grateful to S. Lowe for sharing unpublished information; A. Azab, D. McMillin, C. Ott, and A. Roccaro for technical support; E. Fox for microarray data; J. Daley and S. Lazo-Kallanian for flow cytometry; the MMRF, MMRC, and Broad Institute for establishing the MM Genomics Portal (http://www.broadinstitute.org/mmgp/). This research was supported by NIH-K08CA128972 (J.E.B.), NIH-R01CA050947 (C.S.M.), NIH-R01HG002668 (R.A.Y.), and NIH-R01CA46455 (R.A.Y.); the Chambers Medical Foundation (P.G.R., C.S.M.); the Stepanian Fund for Myeloma Research (P.G.R., C.S.M.); and the Richard J. Corman Foundation (P.G.R., C.S.M.); an American Cancer Society Postdoctoral Fellowship, 120272-PF-11-042-01-DMC (P.B.R.); the Burroughs-Wellcome Fund, the Smith Family Award, the Damon-Runyon Cancer Research Foundation, and the MMRF (to J.E.B.). NR 63 TC 859 Z9 866 U1 20 U2 144 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 16 PY 2011 VL 146 IS 6 BP 903 EP 916 DI 10.1016/j.cell.2011.08.017 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 825GB UT WOS:000295258100013 PM 21889194 ER PT J AU Wu, XL Zhou, TQ Zhu, J Zhang, BS Georgiev, I Wang, C Chen, XJ Longo, NS Louder, M McKee, K O'Dell, S Perfetto, S Schmidt, SD Shi, W Wu, L Yang, YP Yang, ZY Yang, ZJ Zhang, ZH Bonsignori, M Crump, JA Kapiga, SH Sam, NE Haynes, BF Simek, M Burton, DR Koff, WC Doria-Rose, NA Connors, M Mullikin, JC Nabel, GJ Roederer, M Shapiro, L Kwong, PD Mascola, JR AF Wu, Xueling Zhou, Tongqing Zhu, Jiang Zhang, Baoshan Georgiev, Ivelin Wang, Charlene Chen, Xuejun Longo, Nancy S. Louder, Mark McKee, Krisha O'Dell, Sijy Perfetto, Stephen Schmidt, Stephen D. Shi, Wei Wu, Lan Yang, Yongping Yang, Zhi-Yong Yang, Zhongjia Zhang, Zhenhai Bonsignori, Mattia Crump, John A. Kapiga, Saidi H. Sam, Noel E. Haynes, Barton F. Simek, Melissa Burton, Dennis R. Koff, Wayne C. Doria-Rose, Nicole A. Connors, Mark Mullikin, James C. Nabel, Gary J. Roederer, Mario Shapiro, Lawrence Kwong, Peter D. Mascola, John R. CA NISC Comparative Sequencing Progra TI Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; GP120; BROAD; INDIVIDUALS; SELECTION; BREADTH; EPITOPE; GLYCOPROTEIN; DIVERSITY AB Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development. C1 [Wu, Xueling; Zhou, Tongqing; Zhu, Jiang; Zhang, Baoshan; Georgiev, Ivelin; Wang, Charlene; Chen, Xuejun; Longo, Nancy S.; Louder, Mark; McKee, Krisha; O'Dell, Sijy; Perfetto, Stephen; Schmidt, Stephen D.; Shi, Wei; Wu, Lan; Yang, Yongping; Yang, Zhi-Yong; Yang, Zhongjia; Zhang, Zhenhai; Nabel, Gary J.; Roederer, Mario; Shapiro, Lawrence; Kwong, Peter D.; Mascola, John R.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Crump, John A.] Duke Univ, Med Ctr, Div Infect Dis & Int Hlth, Dept Med, Durham, NC 27710 USA. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Ctr, Moshi, Tanzania. [Crump, John A.; Sam, Noel E.] Tumaini Univ, Kilimanjaro Christian Med Coll, Moshi, Tanzania. [Kapiga, Saidi H.; Sam, Noel E.] Kilimanjaro Reprod Hlth Programme, Moshi, Tanzania. [Simek, Melissa; Koff, Wayne C.] Int AIDS Vaccine Initiat IAVI, New York, NY 10038 USA. [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, Massachusetts Inst Technol & Harvard, Ragon Inst, Cambridge, MA 02129 USA. [Doria-Rose, Nicole A.; Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov RI Schmidt, Stephen/B-5398-2012; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, NIH; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; NIH [AI 5U19 AI 067854-06]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX X.W., T.Z., J.Z., G.J.N., M. R., L. S., P. D. K., and J.R.M. designed research; B.Z., C. W., X. C., M. L., K. M., S.O.D., S. P., S. D. S., W. S., L. W., Y.Y., Z.Y.Y., Z.Y., NISC, and J.M. performed experiments; X. W. isolated and characterized VRC01-like antibodies by RSC3 probe, devised and prepared samples for 454 pyrosequencing, and assisted with functional characterization; T.Z. determined and analyzed structures of VRC-PG04 and VRC03 with gp120 and assisted with functional characterization; J.Z. devised and carried out computational bioinformatics on the antibodyome; M. B., J.A.C, S. H. K, N.E.S., and B. F. H. contributed donor 0219 materials; M. S., D. R. B., and W. C. K contributed Protocol G materials, including donor 74; N.D.R. and M. C. contributed donor 45 materials; X. W., T.Z., J.Z, I. G., N.S.L., Z.Z., L. S., P. D. K., and J. R. M. analyzed the data; and L. S., G.J.N., P. D. K., and J. R. M. wrote the paper, on which all authors commented. We thank J. Almeida and D. Douek for protocols of PBMC cDNA preparation and for helpful discussions; J. Stuckey for assistance with figures; T. Wrin for sequence information on the donor 74 virus; J. Binley, D. Montefiori, L. Morris, and G. Tomaras for donor 0219 serum characterization; and all of the IAVI Protocol G team members and the Protocol G clinical investigators, specifically, G. Miiro, A. Pozniak, D. McPhee, O. Manigart, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L.-G. Bekker, P. Pitisuttithum, R. Paris, J. Serwanga, and S. Allen. We also thank H. Sato, I. Wilson, and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions or comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the National Human Genome Research Institute, NIH; by grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; and by the Center for HIV AIDS Vaccine Immunology grant AI 5U19 AI 067854-06 from NIH. Use of sector 22 (Southeast Region Collaborative Access Team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. Structure factors and coordinates for antibodies VRC03 and VRC-PG04 in complex with HIV-1 gp120 have been deposited with the Protein Data Bank under accession codes 3SE8 and 3SE9, respectively. We have also deposited deep sequencing data for donors 45 and 74 (Appendices 1 to 4) used in this study to National Center for Biotechnology Information Short Reads Archives (SRA) under accession no. SRP006992. Information deposited with GenBank includes the heavy-and light-chain variable region sequences of probe-identified antibodies VRC-PG04 and VRC-PG04b (accession nos. JN159464 to JN159467), VRC-CH30, VRC-CH31, and VRC-CH32 (JN159434 to JN159439), and VRC-CH33 and VRC-CH34 (JN159470 to 159473), as well as the sequences of genomically identified neutralizers: 24 heavy chains from donor 74, 2008 (JN159440 to JN159463), two heavy chains from donor 45, 2008 (JN159474 and JN159475), two light chains from donor 45, 2001 (JN159468 and JN159469), and 1561 unique sequences associated with neutralizing CDR H3 distributions with at least one low divergent member shown in Fig. 6B and fig. S16 (JN157873 to JN159433). NR 37 TC 431 Z9 436 U1 5 U2 79 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 16 PY 2011 VL 333 IS 6049 BP 1593 EP 1602 DI 10.1126/science.1207532 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900034 PM 21835983 ER PT J AU Scheid, JF Mouquet, H Ueberheide, B Diskin, R Klein, F Oliveira, TYK Pietzsch, J Fenyo, D Abadir, A Velinzon, K Hurley, A Myung, S Boulad, F Poignard, P Burton, DR Pereyra, F Ho, DD Walker, BD Seaman, MS Bjorkman, PJ Chait, BT Nussenzweig, MC AF Scheid, Johannes F. Mouquet, Hugo Ueberheide, Beatrix Diskin, Ron Klein, Florian Oliveira, Thiago Y. K. Pietzsch, John Fenyo, David Abadir, Alexander Velinzon, Klara Hurley, Arlene Myung, Sunnie Boulad, Farid Poignard, Pascal Burton, Dennis R. Pereyra, Florencia Ho, David D. Walker, Bruce D. Seaman, Michael S. Bjorkman, Pamela J. Chait, Brian T. Nussenzweig, Michel C. TI Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding SO SCIENCE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; NEUTRALIZING ANTIBODIES; TYPE-1 GP120; ENVELOPE GLYCOPROTEIN; EPITOPE; RECEPTOR; GP41; INDIVIDUALS AB Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike. C1 [Scheid, Johannes F.; Mouquet, Hugo; Klein, Florian; Oliveira, Thiago Y. K.; Pietzsch, John; Abadir, Alexander; Velinzon, Klara; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scheid, Johannes F.] Charite, D-10117 Berlin, Germany. [Ueberheide, Beatrix; Fenyo, David; Myung, Sunnie; Chait, Brian T.] Rockefeller Univ, Lab Mass Spectrometry & Gaseous Ion Chem, New York, NY 10065 USA. [Diskin, Ron; Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Pietzsch, John] Free Univ Berlin, Dept Biol Chem & Pharm, D-14195 Berlin, Germany. [Hurley, Arlene] Rockefeller Univ, Rockefeller Univ Hosp, New York, NY 10065 USA. [Boulad, Farid] Mem Sloan Kettering Canc Ctr, Bone Marrow Transplant Serv, New York, NY 10065 USA. [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Poignard, Pascal] Int AIDS Vaccine Initiat, New York, NY 10028 USA. [Burton, Dennis R.; Pereyra, Florencia; Walker, Bruce D.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02129 USA. [Pereyra, Florencia; Walker, Bruce D.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. [Pereyra, Florencia; Walker, Bruce D.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ho, David D.; Walker, Bruce D.; Bjorkman, Pamela J.; Nussenzweig, Michel C.] Howard Hughes Med Inst, New York, NY 10065 USA. Aaron Diamond AIDS Res Ctr, New York, NY 10065 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@mail.rockefeller.edu RI poignard, pascal/N-6678-2013; Mouquet, Hugo/M-2750-2014; OI Oliveira, Thiago/0000-0002-2654-0879; Ueberheide, Beatrix/0000-0003-2512-0204; Fenyo, David/0000-0001-5049-3825 FU NIH [P01 AI081677, RR00862, RR022220]; Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody-Vaccine Immune Monitoring Consortium [38619s, 38660]; Gordon and Betty Moore Foundation; Stanford Synchrotron Radiation Lightsource; German Research Foundation (Deutsche Forschungsgemeinschaft) [KL 2389/1-1] FX The data reported in this paper are tabulated in the supporting online material, and the coordinates for the 3BNC60 Fab as well as the antibody sequences have been deposited in the Protein Data Bank and the European Molecular Biology Laboratory-European Bioinformatics Institute database [accession codes: 3RPI (3BNC60 coordinates), HE584535 to HE584554 (antibody sequences)]. We thank the HIV-positive donors for their support. We thank M. Jankovic for discussions and help with cloning of HIV envelope constructs; R. Wyatt for the plasmid of YU2-gp140; J. Mascola for the plasmid of 2CC-core and YU2-gp120 mutants; and M. Connors for access to patient NIH45; C. Gaebler, M. Warncke, P. M. Marcovecchio, and H. Gao for help with protein expression; K. Moss for patient coordination. We thank F. McCutchan, G. Shaw, B. Hahn, J. Baalwa, D. Montefiori, F. Gao, M. Thomson, J. Overbaugh, R. Swanstrom, L. Morris, J. Kim, L. Zhang, D. Ellenberger, and C. Williamson for contributing the HIV-1 Envelope plasmids used in our neutralization panel. We thank M. Simek, F. Priddy, and all the study participants and research staff at each of the International AIDS Vaccine Initiative (IAVI) Protocol G project; clinical and site team members; and all of the Protocol G clinical investigators, specifically, G. Miiro, A. Pozniak, D. McPhee, O. Manigart, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L.-G. Bekker, P. Pitisuttithum, R. Paris, J. Serwanga, and S. Allen for samples from one broadly neutralizing serum donor from Protocol G. We thank L. Walker for providing data on the neutralizing specificity of the Protocol G donor. In connection with this work, M.C.N. and J. F. S. have a pending patent application with the U. S. Patent and Trademark Office, patent number U. S. 61/486,960, entitled "Human Immunodeficiency Virus Neutralizing Antibodies and Methods of Use Thereof." The reagents are available with a Materials Transfer Agreement. The work was supported by NIH grants P01 AI081677, RR00862, and RR022220, and by the Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody-Vaccine Immune Monitoring Consortium, grant numbers 38619s and 38660. We thank the Molecular Observatory at Caltech (supported by the Gordon and Betty Moore Foundation) and the Stanford Synchrotron Radiation Lightsource. F. K. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, KL 2389/1-1). M.C.N., P. J. B, and B. D. W. are Howard Hughes Medical Institute Investigators. NR 36 TC 470 Z9 476 U1 6 U2 53 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 16 PY 2011 VL 333 IS 6049 BP 1633 EP 1637 DI 10.1126/science.1207227 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820JE UT WOS:000294900900044 PM 21764753 ER PT J AU Thangasamy, A Rogge, J Krishnegowda, NK Freeman, JW Ammanamanchi, S AF Thangasamy, Amalraj Rogge, Jessica Krishnegowda, Naveen K. Freeman, James W. Ammanamanchi, Sudhakar TI Novel Function of Transcription Factor Nrf2 as an Inhibitor of RON Tyrosine Kinase Receptor-mediated Cancer Cell Invasion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVE STRESS; BREAST-CANCER; ACTIVATION; MICE; SULFORAPHANE; SENSITIVITY; PREVENTION; MUTATIONS AB Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion. RON receptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective genes. Using chromatin immunoprecipitation (ChIP) and site-directed mutagenesis studies of the RON promoter, we identified Nrf2 as a negative regulator of RON gene expression. High Nrf2 and low RON expression was observed in normal mammary tissue whereas high RON and low or undetectable expression of Nrf2 was observed in breast tumors. The Nrf2 inducer sulforaphane (SFN) as well as ectopic Nrf2 expression or knock-down of the Nrf2 negative regulator keap1, which stabilizes Nrf2, inhibited RON expression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a "repressor" and RON kinase as a molecular target of SFN, which mediates the anti-tumor effects of SFN. These results are not limited to breast cancer cells since the Nrf2 inducer SFN stabilized Nrf2 and inhibited RON expression in carcinoma cells from various tumor types. C1 [Thangasamy, Amalraj; Rogge, Jessica; Krishnegowda, Naveen K.; Freeman, James W.; Ammanamanchi, Sudhakar] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol Med Oncol, San Antonio, TX 78229 USA. [Freeman, James W.] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78229 USA. RP Ammanamanchi, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hematol Med Oncol, San Antonio, TX 78229 USA. EM sammanamanchi@hotmail.com FU Veterans Administration FX This work was supported by the Veterans Administration Merit Award (to J. W. F.). NR 20 TC 13 Z9 14 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 16 PY 2011 VL 286 IS 37 BP 32115 EP 32122 DI 10.1074/jbc.M111.245746 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818CK UT WOS:000294726800021 PM 21799005 ER PT J AU Delgado, GA Truesdell, AG Kirchner, RM Zuzek, RW Pomerantsev, EV Gordon, PC Regnante, RA AF Delgado, Gabriel A. Truesdell, Alexander G. Kirchner, Robert M. Zuzek, Ryan W. Pomerantsev, Eugene V. Gordon, Paul C. Regnante, Richard A. TI An Angiographic and Intravascular Ultrasound Study of the Left Anterior Descending Coronary Artery in Takotsubo Cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID APICAL BALLOONING SYNDROME; TAKO-TSUBO CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; ACUTE MYOCARDIAL-INFARCTION; ST-SEGMENT ELEVATION; PLAQUE RUPTURE; FEATURES; DISEASE AB The precise cause of takotsubo cardiomyopathy (TC) remains controversial. Plaque rupture with transient thrombotic occlusion of a transapical left anterior descending coronary artery (LAD) has been advanced as a potential mechanism. To explore this hypothesis, the investigators analyzed data from 11 patients prospectively enrolled in the Rhode Island Takotsubo Cardiomyopathy Registry who underwent coronary angiography and intravascular ultrasound evaluation of the LAD during their initial presentation. Despite the presence of nonobstructive coronary artery disease, no culprit lesion was identified in any patient. Similarly, the course of the LAD failed to account for the characteristic left ventricular apical ballooning seen in TC. In conclusion, an atherosclerotic coronary lesion in the LAD causing an aborted myocardial infarction may not be the primary underlying cause of TC, and nonobstructive coronary artery disease and TC may coexist without a direct causal association. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:888-891) C1 [Delgado, Gabriel A.; Truesdell, Alexander G.; Kirchner, Robert M.; Zuzek, Ryan W.; Gordon, Paul C.; Regnante, Richard A.] Brown Univ, Div Cardiol, Warren Alpert Med Sch, Providence, RI 02912 USA. [Pomerantsev, Eugene V.] Harvard Univ, Cardiac Invas Serv, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Truesdell, AG (reprint author), Brown Univ, Div Cardiol, Warren Alpert Med Sch, Providence, RI 02912 USA. EM atruesdell@lifespan.org FU Abbott Cardiovascular Systems Inc., Santa Clara, California; Accumetrics, Inc., San Diego, California; AstraZeneca, Wilmington, Delaware; Boston Scientific Corporation, Natick, Massachusetts; Bristol-Myers Squibb, New York, New York; Cordis Corporation, a Johnson & Johnson Company, Bridge-water, New Jersey; Hoffman-La Roche, Inc., Nutley, New Jersey; Eli Lilly & Company, Indianapolis, Indiana; MEDRAD, Inc., Warrendale, Pennsylvania; MD Scientific, LLC, Charlotte, North Carolina; Medtronic Vascular, Inc., Santa Rosa, California; Sanofi-Aventis, Malvern, Pennsylvania; Schering Plough Research Institute, a Division of Schering Corporation, Kenilworth, New Jersey; Spectranetics Corporation, Colorado Springs, Colorado FX Dr. Gordon receives grant and research support from Abbott Cardiovascular Systems, Inc., Santa Clara, California; Accumetrics, Inc., San Diego, California; AstraZeneca, Wilmington, Delaware; Boston Scientific Corporation, Natick, Massachusetts; Bristol-Myers Squibb, New York, New York; Cordis Corporation, a Johnson & Johnson Company, Bridge-water, New Jersey; Hoffman-La Roche, Inc., Nutley, New Jersey; Eli Lilly & Company, Indianapolis, Indiana; MEDRAD, Inc., Warrendale, Pennsylvania; MD Scientific, LLC, Charlotte, North Carolina; Medtronic Vascular, Inc., Santa Rosa, California; Sanofi-Aventis, Malvern, Pennsylvania; Schering Plough Research Institute, a Division of Schering Corporation, Kenilworth, New Jersey; and the Spectranetics Corporation, Colorado Springs, Colorado. NR 22 TC 14 Z9 16 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2011 VL 108 IS 6 BP 888 EP 891 DI 10.1016/j.amjcard.2011.05.012 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 826KJ UT WOS:000295352700022 PM 21741604 ER PT J AU Ueland, T Aukrust, P Omdal, TR Damas, JK Endresen, K Ren, F Hysing, J Giugliano, RP AF Ueland, Thor Aukrust, Pal Omdal, Tom Roar Damas, Jan Kristian Endresen, Knut Ren, Fang Hysing, Jan Giugliano, Robert P. TI Effect of eptifibatide on platelet-mediated inflammation in acute coronary syndromes SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Acute coronary syndrome; Platelets; Inflammation; GP IIb/IIIa antagonism ID ANTIPLATELET THERAPY; ATHEROSCLEROSIS; DISEASE C1 [Ueland, Thor; Aukrust, Pal] Univ Oslo, Rikshosp, Oslo Univ Hosp, Internal Med Res Inst, N-0027 Oslo, Norway. [Ueland, Thor; Aukrust, Pal] Univ Oslo, Fac Med, N-0027 Oslo, Norway. [Aukrust, Pal] Univ Oslo, Rikshosp, Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0027 Oslo, Norway. [Endresen, Knut] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Cardiol, N-0027 Oslo, Norway. [Omdal, Tom Roar] Sorlandet Sykehus Arendal, Arendal, Norway. [Damas, Jan Kristian] St Olavs Hosp, Dept Infect Dis, Trondheim, Norway. [Ren, Fang; Giugliano, Robert P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Hysing, Jan] Sykehuset Telemark HF, Skien, Norway. RP Ueland, T (reprint author), Univ Oslo, Rikshosp, Oslo Univ Hosp, Internal Med Res Inst, N-0027 Oslo, Norway. EM thor.ueland@medisin.uio.no NR 9 TC 3 Z9 4 U1 0 U2 2 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 SEP 15 PY 2011 VL 151 IS 3 BP 385 EP 387 DI 10.1016/j.ijcard.2011.06.117 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 824PP UT WOS:000295214700046 PM 21782261 ER PT J AU Harzstark, AL Small, EJ Weinberg, VK Sun, J Ryan, CJ Lin, AM Fong, L Brocks, DR Rosenberg, JE AF Harzstark, Andrea L. Small, Eric J. Weinberg, Vivian K. Sun, Janine Ryan, Charles J. Lin, Amy M. Fong, Lawrence Brocks, Dion R. Rosenberg, Jonathan E. TI A Phase 1 Study of Everolimus and Sorafenib for Metastatic Clear Cell Renal Cell Carcinoma SO CANCER LA English DT Article DE renal cell carcinoma; clear cell; everolimus; sorafenib; mammalian target of rapamycin (mTOR) inhibitor; tyrosine kinase inhibitor; combination therapy ID INTERFERON-ALPHA; III TRIAL; RAPAMYCIN; EFFICACY AB BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma. Cancer 2011;117:4194-200. (C) 2011 American Cancer Society. C1 [Harzstark, Andrea L.; Small, Eric J.; Sun, Janine; Ryan, Charles J.; Lin, Amy M.; Fong, Lawrence] Univ Calif San Francisco, Dept Med, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Brocks, Dion R.] Univ Alberta, Edmonton, AB, Canada. [Rosenberg, Jonathan E.] Dana Farber Canc Inst, Dept Med, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Harzstark, AL (reprint author), Univ Calif San Francisco, Dept Med, Helen Diller Family Comprehens Canc Ctr, 1600 Divisadero St,POB 1711, San Francisco, CA 94143 USA. EM andrea.harzstark@ucsf.edu FU Novartis Oncology; Novartis FX Supported in part by Novartis Oncology. Dr. Ryan has received honoraria from Novartis. Dr. Rosenberg has received research support, consulting fees, and honoraria from Novartis. NR 12 TC 34 Z9 34 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2011 VL 117 IS 18 BP 4194 EP 4200 DI 10.1002/cncr.25931 PG 7 WC Oncology SC Oncology GA 824EU UT WOS:000295186000015 PM 21387258 ER PT J AU Haas, JS Brawarsky, P Iyer, A Fitzmaurice, GM Neville, BA Earle, C AF Haas, Jennifer S. Brawarsky, Phyllis Iyer, Aarthi Fitzmaurice, Garrett M. Neville, Bridget A. Earle, Craig TI Association of Area Sociodemographic Characteristics and Capacity for Treatment With Disparities in Colorectal Cancer Care and Mortality SO CANCER LA English DT Article DE colorectal cancer; disparities; regional variation; treatment ID ADJUVANT CHEMOTHERAPY USE; COLON-CANCER; UNITED-STATES; MEDICARE BENEFICIARIES; REGIONAL-VARIATIONS; RADIATION-THERAPY; SURGEON VOLUME; LUNG-CANCER; POPULATION; BREAST AB BACKGROUND: Disparities in treatment and mortality for colorectal cancer (CRC) may reflect differences in access to specialized care or other characteristics of the area where an individual lives. METHODS: Surveillance, Epidemiology and End Results Program-Medicare data for seniors diagnosed with CRC were linked to area measures of the sociodemographic characteristics and the capacity of surgeons, medical oncologists, and radiation oncologists. Outcomes included receipt of stage-appropriate CRC care and mortality. RESULTS: After adjustment, blacks and Hispanics were less likely than whites to undergo surgery (odds ratio [OR] 0.57, 95% confidence interval (CI) 0.52-0.63 and OR 0.82, 95% CI 0.70-0.95, respectively). Individuals who lived in areas with the highest tertile of surgeon capacity were more likely to undergo resection than those in the lowest, and use of surgery declined as the percentage of blacks in the area increased. Adjustment for the area measures resulted in a modest decline in disparities in care relative to whites (5.3% for black). Blacks also experienced greater all-cause and cancer-specific mortality than whites. Further adjustment for area sociodemographics and surgeon capacity reduced the disparity in mortality between blacks and whites. Although there was a similar black/white disparity in the use of adjuvant chemotherapy, the disparity remained after adjustment for area characteristics, although use of chemotherapy was greater in areas with the greatest capacity of medical oncologists. CONCLUSIONS: Sociodemographic characteristics and measures of the availability of specialized cancer providers in the area in which an individual resides modestly mediated disparities in the receipt of CRC care and mortality, suggesting that other factors may also be important. Cancer 2011;117:4267-76. (C) 2011 American Cancer Society. C1 [Haas, Jennifer S.; Brawarsky, Phyllis; Iyer, Aarthi] Brigham & Womens Hosp, Div Gen Med & Primary Care, Dept Med, Boston, MA 02120 USA. [Haas, Jennifer S.; Brawarsky, Phyllis; Iyer, Aarthi; Fitzmaurice, Garrett M.] Harvard Univ, Sch Med, Boston, MA USA. [Fitzmaurice, Garrett M.] McLean Hosp, Lab Psychiat Biostat, Boston, MA USA. [Neville, Bridget A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Earle, Craig] Canc Care Ontario, Toronto, ON, Canada. [Earle, Craig] Ontario Inst Canc Res, Toronto, ON, Canada. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, Dept Med, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU American Cancer Society [RSGT CPHPS-114979] FX Supported by grants from the American Cancer Society (RSGT CPHPS-114979). NR 31 TC 29 Z9 29 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2011 VL 117 IS 18 BP 4267 EP 4276 DI 10.1002/cncr.26034 PG 10 WC Oncology SC Oncology GA 824EU UT WOS:000295186000023 PM 21413000 ER PT J AU Buss, MK Lessen, DS Sullivan, AM Von Roenn, J Arnold, RM Block, SD AF Buss, Mary K. Lessen, David S. Sullivan, Amy M. Von Roenn, Jamie Arnold, Robert M. Block, Susan D. TI Hematology/Oncology Fellows' Training in Palliative Care SO CANCER LA English DT Article DE palliative care; oncology education and training; pain and symptom management; psychosocial care; communication skills ID OF-LIFE CARE; GLOBAL CORE CURRICULUM; CANCER PAIN MANAGEMENT; MEDICAL ONCOLOGY; NATIONAL-SURVEY; CLINICAL ONCOLOGY; AMERICAN SOCIETY; COMMUNICATION; RECOGNITION; RECOMMENDATIONS AB BACKGROUND: Palliative care is recognized as integral to the practice of oncology, yet many oncologists report inadequate training in critical palliative care domains, such as symptom management, psychosocial care, and communication skills. The authors of this report sought to assess the quantity and quality of palliative care education within oncology fellowships. METHODS: Second-year oncology fellows completed a 104-item survey that was modified and adapted from a national survey of medical students and residents. Items allowed comparison between palliative care and nonpalliative care topics. RESULTS: Of 402 eligible fellows, 63.2% responded (n = 254). Respondents were: 52% men, 62% Caucasian, and 64% US medical school graduates. Twenty-six percent had completed a palliative care rotation. Fellows rated the overall quality of fellowship teaching more highly than teaching on palliative care (3.7 v 3.0 on a 1-5 scale; t=10.2; P < .001). Rates of being observed (81%) and receiving feedback (80%) on an end-of-life communication skill were high. Psychosocial needs of patients received some attention: Fifty-seven percent of fellows reported that they were conveyed as a core competency, but only 32% of fellows received explicit education on assessing and managing depression at the end of life. Fellows rarely reported receiving explicit education on opioid rotation (33%). Fellows scored a median of 2 of 4 items that tested basic palliative care knowledge, and only 23% correctly performed an opioid conversion. CONCLUSIONS: Fellows rated the quality of palliative care education as inferior to overall oncology training and may benefit from more teaching on pain management, psychosocial care, and communication skills. Cancer 2011;117:4304-11. (C) 2077 American Cancer Society C1 [Buss, Mary K.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Palliat Care Consultat Serv, Div Gen Internal Med,Gynecol Med Oncol Prog, Boston, MA 02215 USA. [Buss, Mary K.] Harvard Univ, Sch Med, Boston, MA USA. [Lessen, David S.] SE Florida Hematol Oncol Grp, Ft Lauderdale, FL USA. [Sullivan, Amy M.] Virginia Commonwealth Univ, Sch Med, Dept Social & Behav Sci, Richmond, VA USA. [Von Roenn, Jamie] Northwestern Univ, Div Hematol Oncol, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Von Roenn, Jamie] Feinberg Sch Med, Chicago, IL USA. [Arnold, Robert M.] Univ Pittsburgh Hosp, Inst Doctor Patient Commun, Sect Palliat Care & Med Eth, Pittsburgh, PA USA. [Arnold, Robert M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Block, Susan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Block, Susan D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Buss, MK (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Palliat Care Consultat Serv, Div Gen Internal Med,Gynecol Med Oncol Prog, 330 Brookline Ave,Rose 144, Boston, MA 02215 USA. EM mbuss@bidmc.harvard.edu NR 30 TC 36 Z9 36 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2011 VL 117 IS 18 BP 4304 EP 4311 DI 10.1002/cncr.25952 PG 8 WC Oncology SC Oncology GA 824EU UT WOS:000295186000027 PM 21365618 ER PT J AU Villar, J Cabrera, NE Valladares, F Casula, M Flores, C Blanch, L Quilez, ME Santana-Rodriguez, N Kacmarek, RM Slutsky, AS AF Villar, Jesus Cabrera, Nuria E. Valladares, Francisco Casula, Milena Flores, Carlos Blanch, Lluis Elisa Quilez, Maria Santana-Rodriguez, Norberto Kacmarek, Robert M. Slutsky, Arthur S. TI Activation of the Wnt/beta-Catenin Signaling Pathway by Mechanical Ventilation Is Associated with Ventilator-Induced Pulmonary Fibrosis in Healthy Lungs SO PLOS ONE LA English DT Article ID END-EXPIRATORY PRESSURE; RESPIRATORY-DISTRESS-SYNDROME; GENE-EXPRESSION; PHOSPHOINOSITIDE 3-KINASE; INFLAMMATORY RESPONSES; TIDAL VOLUME; BETA-CATENIN; INJURY MODEL; CELL FACTOR; MICE AB Background: Mechanical ventilation (MV) with high tidal volumes (V(T)) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/beta-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/beta-catenin signaling plays a role during VILI. Methodology/Principal Findings: Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (V(T)) (6 mL/kg) or high V(T) (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total beta-catenin, non-phospho (Ser33/37/Thr41) beta-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) beta-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-V(T) MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) beta-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-V(T) MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) beta-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels. Conclusions/Significance: Our findings demonstrate that the Wnt/beta-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI. C1 [Villar, Jesus; Cabrera, Nuria E.; Valladares, Francisco; Casula, Milena; Flores, Carlos; Blanch, Lluis; Elisa Quilez, Maria] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus; Cabrera, Nuria E.; Casula, Milena; Santana-Rodriguez, Norberto] Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. [Villar, Jesus; Slutsky, Arthur S.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Valladares, Francisco] Univ La Laguna, Dept Anat Pathol & Histol, Tenerife, Spain. [Flores, Carlos] Hosp Univ NS Candelaria, Res Unit, Santa Cruz De Tenerife, Spain. [Blanch, Lluis; Elisa Quilez, Maria] Corp Sanitaria Parc Tauli, Crit Care Ctr, Barcelona, Spain. [Santana-Rodriguez, Norberto] Hosp Univ Dr Negrin, Dept Thorac Surg, Las Palmas Gran Canaria, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesia, Boston, MA 02115 USA. [Slutsky, Arthur S.] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Slutsky, Arthur S.] King Saud Univ, Riyadh, Saudi Arabia. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. EM jesus.villar54@gmail.com FU Ministry of Science, Spain [SAF 2004-06833, PI10/0393] FX This work was supported by grants from the Ministry of Science, Spain (SAF 2004-06833 and PI10/0393). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 33 Z9 36 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 15 PY 2011 VL 6 IS 9 AR e23914 DI 10.1371/journal.pone.0023914 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JR UT WOS:000295041700002 PM 21935365 ER PT J AU Patterson, HC Kraus, M Wang, DH Shahsafaei, A Henderson, JM Seagal, J Otipoby, KL Thai, TH Rajewsky, K AF Patterson, Heide Christine Kraus, Manfred Wang, Donghai Shahsafaei, Aliakbar Henderson, Joel M. Seagal, Jane Otipoby, Kevin L. Thai, To-Ha Rajewsky, Klaus TI Cytoplasmic Iga Serine/Threonines Fine-Tune Ig alpha Tyrosine Phosphorylation and Limit Bone Marrow Plasma Cell Formation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN RECEPTOR COMPLEX; HIGH-AFFINITY RECEPTOR; ACTIVATION MOTIF ITAM; B-LYMPHOCYTE; MICE; PROLIFERATION; RESPONSES; KINASE; BETA; DIFFERENTIATION AB Ig alpha serine 191 and 197 and threonine 203, which are located in proximity of the Ig alpha ITAM, dampen Ig alpha ITAM tyrosine phosphorylation. In this study, we show that mice with targeted mutations of Ig alpha S191, 197, and T203 displayed elevated serum IgG2c and IgG2b concentrations and had elevated numbers of IgG2c- and IgG2b-secreting cells in the bone marrow. BCR-induced Ig alpha tyrosine phosphorylation was slightly increased in splenic B cells. Our results suggest that Ig alpha serine/threonines limit formation of IgG2c- and IgG2b-secreting bone marrow plasma cells, possibly by fine-tuning Ig alpha tyrosine-mediated BCR signaling. The Journal of Immunology, 2011, 187: 2853-2858. C1 [Patterson, Heide Christine; Kraus, Manfred; Wang, Donghai; Seagal, Jane; Otipoby, Kevin L.; Thai, To-Ha; Rajewsky, Klaus] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Patterson, Heide Christine; Kraus, Manfred; Wang, Donghai; Seagal, Jane; Otipoby, Kevin L.; Thai, To-Ha; Rajewsky, Klaus] Immune Dis Inst, Boston, MA 02115 USA. [Patterson, Heide Christine; Shahsafaei, Aliakbar; Henderson, Joel M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kraus, Manfred] Merck Res Labs, Boston, MA 02115 USA. [Wang, Donghai] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Henderson, Joel M.] Boston Univ, Med Ctr, Boston, MA 02118 USA. [Seagal, Jane] Abbott Biores Ctr, Worcester, MA 01605 USA. [Otipoby, Kevin L.] Biogen Idec Inc, Cambridge, MA 02142 USA. [Thai, To-Ha] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Rajewsky, K (reprint author), Childrens Hosp, Program Cellular & Mol Med, 200 Longwood Ave, Boston, MA 02115 USA. EM rajewsky@idi.harvard.edu FU National Institutes of Health [R37 AI054636]; Deutsche Forschungsgemeinschaft; T32 training grant FX This work was supported by the National Institutes of Health (Grant R37 AI054636) and a research fellowship from the Deutsche Forschungsgemeinschaft and T32 training grant (transfusion medicine) (to H. C. P.). NR 35 TC 5 Z9 5 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2011 VL 187 IS 6 BP 2853 EP 2858 DI 10.4049/jimmunol.1101143 PG 6 WC Immunology SC Immunology GA 822HI UT WOS:000295034200003 PM 21841126 ER PT J AU Lu, TX Hartner, J Lim, EJ Fabry, V Mingler, MK Cole, ET Orkin, SH Aronow, BJ Rothenberg, ME AF Lu, Thomas X. Hartner, Jochen Lim, Eun-Jin Fabry, Victoria Mingler, Melissa K. Cole, Eric T. Orkin, Stuart H. Aronow, Bruce J. Rothenberg, Marc E. TI MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12/IFN-gamma Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL ASTHMA; DENDRITIC CELLS; EXPRESSION; GENE; PATHOGENESIS; INFLAMMATION; CYTOKINES; GAMMA; DISSECTION; INNATE AB An altered balance between Th1 and Th2 cytokines is responsible for a variety of immunoinflammatory disorders such as asthma, yet the role of posttranscriptional mechanisms, such as those mediated by microRNAs (miRs), in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. In this study, we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to Ags. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome and significantly increased levels of the Th1 cytokine IFN-gamma. Biological network-based transcriptome analysis of OVA-challenged miR-21(-/-) mice identified an unexpected prominent dysregulation of IL-12/IFN-gamma pathways as the most significantly affected in the lungs, with a key role for miR-21 in IFN-g signaling and T cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation and OVA-challenged CD4(+) T lymphocytes to produce increased IFN-gamma and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 versus Th2 responses, defining a new mechanism for regulating polarized immunoinflammatory responses. The Journal of Immunology, 2011, 187: 3362-3373. C1 [Lu, Thomas X.; Lim, Eun-Jin; Fabry, Victoria; Mingler, Melissa K.; Cole, Eric T.; Rothenberg, Marc E.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Div Allergy & Immunol,Med Ctr, Cincinnati, OH 45229 USA. [Lu, Thomas X.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Grad Program Mol & Dev Biol,Med Ctr, Cincinnati, OH 45229 USA. [Lu, Thomas X.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Phys Scientist Training Program,Med Ctr, Cincinnati, OH 45229 USA. [Hartner, Jochen; Orkin, Stuart H.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hartner, Jochen; Orkin, Stuart H.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Hartner, Jochen; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Aronow, Bruce J.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Div Biomed Informat,Med Ctr, Cincinnati, OH 45229 USA. RP Rothenberg, ME (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp, Div Allergy & Immunol,Med Ctr, 3333 Burnet Ave,ML7028, Cincinnati, OH 45229 USA. EM Rothenberg@cchmc.org FU National Heart, Lung, and Blood Institute [F30HL104892]; Albert J. Ryan Foundation; National Institutes of Health [T32HD046387, R01AI083450]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK049216]; Campaign Urging Research for Eosinophilic Disease; Buckeye Foundation; Food Allergy Project/Food Allergy Initiative FX This work was supported by the Ruth L. Kirschstein National Research Service Award for individual predoctoral M.D./Ph.D. fellows (F30HL104892) from the National Heart, Lung, and Blood Institute (to T.X.L.), the Ryan Fellowship from the Albert J. Ryan Foundation (to T.X.L.), and the Organogenesis Training grant (National Institutes of Health Grant T32HD046387 to T.X.L.). Targeted mice were generated in the Center for Excellence in Molecular Hematology at Children's Hospital Boston, which is supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK049216). Additionally, this work was supported by National Institutes of Health Grant R01AI083450 (to M.E.R.), the Campaign Urging Research for Eosinophilic Disease, the Buckeye Foundation, and the Food Allergy Project/Food Allergy Initiative. NR 40 TC 130 Z9 152 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2011 VL 187 IS 6 BP 3362 EP 3373 DI 10.4049/jimmunol.1101235 PG 12 WC Immunology SC Immunology GA 822HI UT WOS:000295034200056 PM 21849676 ER PT J AU Zhou, F Sikorski, TW Ficarro, SB Webber, JT Marto, JA AF Zhou, Feng Sikorski, Timothy W. Ficarro, Scott B. Webber, James T. Marto, Jarrod A. TI Online Nanoflow Reversed Phase-Strong Anion Exchange-Reversed Phase Liquid Chromatography-Tandem Mass Spectrometry Platform for Efficient and In-Depth Proteome Sequence Analysis of Complex Organisms SO ANALYTICAL CHEMISTRY LA English DT Article ID STRONG CATION-EXCHANGE; LINEAR ION-TRAP; SHOTGUN PROTEOMICS; SACCHAROMYCES-CEREVISIAE; AFFINITY PURIFICATION; POLYACRYLAMIDE-GELS; SIGNALING NETWORKS; YEAST PROTEOME; DYNAMIC-RANGE; STEM-CELLS AB The dynamic range of protein expression in complex organisms coupled with the stochastic nature of discovery-driven tandem mass spectrometry (MS/MS) analysis continues to impede comprehensive sequence analysis and often provides only limited information for low-abundance proteins. High-performance fractionation of proteins or peptides prior to mass spectrometry analysis can mitigate these effects, though achieving an optimal combination of automation, reproducibility, separation peak capacity, and sample yield remains a significant challenge. Here we demonstrate an automated nanoflow 3-D liquid chromatography (LC)-MS/MS platform based on high-pH reversed phase (RP), strong anion exchange (SAX), and low-pH reversed phase (RP) separation stages for analysis of complex proteomes. We observed that RP-SAX-RP outperformed RP-RP for analysis of tryptic peptides derived from Escherichia coli and enabled identification of proteins present at a level of SO copies per cell in Saccharomyces cerevisiae, corresponding to an estimated detection limit of 500 amol, from 40 mu g of total lysate on a low-resolution 3-D ion trap mass spectrometer. A similar study performed on a LTQ:Orbitrap yielded over 4000 unique proteins from 5 mu g of total yeast lysate analyzed in a single, 101 fraction RP-SAX-RP LC-MS/MS acquisition, providing an estimated detection limit of 65 amol for proteins expressed at 50 copies per cell. C1 [Zhou, Feng; Sikorski, Timothy W.; Ficarro, Scott B.; Webber, James T.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Ficarro, Scott B.; Webber, James T.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Zhou, Feng; Sikorski, Timothy W.; Ficarro, Scott B.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave,Smith 1158A, Boston, MA 02215 USA. EM jarrod_marto@dfci.harvard.edu OI Webber, James/0000-0001-8594-9888 FU National Institutes of Health, NHGRI [P50HG004233]; NINDS [P01NS047572] FX The authors thank Eric Smith for assistance with the figures. In addition the authors thank Keith Fadgen, Jim Murphy, and Geoff Gerhardt of Waters Corp. for valuable discussions and technical assistance. Generous support for this work was provided by the Dana-Farber Cancer Institute and the National Institutes of Health, NHGRI (Grant P50HG004233) and NINDS (Grant P01NS047572). NR 71 TC 30 Z9 34 U1 1 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD SEP 15 PY 2011 VL 83 IS 18 BP 6996 EP 7005 DI 10.1021/ac200639v PG 10 WC Chemistry, Analytical SC Chemistry GA 818XM UT WOS:000294790000013 PM 21851055 ER PT J AU Ouillette, P Collins, R Shakhan, S Li, JH Peres, E Kujawski, L Talpaz, M Kaminski, M Li, C Shedden, K Malek, SN AF Ouillette, Peter Collins, Roxane Shakhan, Sajid Li, Jinghui Peres, Edward Kujawski, Lisa Talpaz, Moshe Kaminski, Mark Li, Cheng Shedden, Kerby Malek, Sami N. TI Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID SIGNIFICANT CLINICAL ACTIVITY; ACUTE MYELOGENOUS LEUKEMIA; ACUTE MYELOID-LEUKEMIA; MUTATION STATUS; CLL PATIENTS; CHROMOSOMAL TRANSLOCATIONS; GENETIC-CHARACTERIZATION; TELOMERE DYSFUNCTION; UNIPARENTAL DISOMY; CD38 EXPRESSION AB Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with chronic lymphocytic leukemia (CLL), and FISH-based genomic risk classifications are routinely used in clinical decision making in CLL. One of the known limitations of CLL FISH is the inability to comprehensively interrogate the CLL genome for genomic changes. In an effort at overcoming the existing limitations in CLL genome analysis, we have analyzed high-purity DNA isolated from FACS-sorted CD19(+) cells and paired CD3(+) or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays. Overall, >= 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas >= 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. Subsequently, we have correlated genomic lesion loads (genomic complexity) with the clinical outcome measures time to first therapy and overall survival. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array-based genomic lesion loads at various thresholds, we identify elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival. (Blood. 2011;118(11):3051-3061) C1 [Ouillette, Peter; Collins, Roxane; Shakhan, Sajid; Li, Jinghui; Peres, Edward; Kujawski, Lisa; Talpaz, Moshe; Kaminski, Mark; Malek, Sami N.] Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Li, Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Li, Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Cheng] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shedden, Kerby] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. RP Malek, SN (reprint author), Univ Michigan, Dept Internal Med, Div Hematol & Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM smalek@med.umich.edu FU National Institutes of Health [1R01 CA136537-01]; Leukemia & Lymphoma Society of America; National Institutes of Health through the University of Michigan's Cancer Center [5 P30 CA46592] FX This work was supported by the National Institutes of Health through grant 1R01 CA136537-01 (S.N.M.), by the Translational Research Program of the Leukemia & Lymphoma Society of America (S.N.M.), and in part by the National Institutes of Health through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592). NR 50 TC 59 Z9 59 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 SEP 15 PY 2011 VL 118 IS 11 BP 3051 EP 3061 DI 10.1182/blood-2010-12-327858 PG 11 WC Hematology SC Hematology GA 821DU UT WOS:000294955900022 PM 21795749 ER PT J AU Wilson, AJ Holson, E Wagner, F Zhang, YL Fass, DM Haggarty, SJ Bhaskara, S Hiebert, SW Schreiber, SL Khabele, D AF Wilson, Andrew J. Holson, Edward Wagner, Florence Zhang, Yan-Ling Fass, Daniel M. Haggarty, Stephen J. Bhaskara, Srividya Hiebert, Scott W. Schreiber, Stuart L. Khabele, Dineo TI The DNA damage mark pH2AX differentiates the cytotoxic effects of small molecule HDAC inhibitors in ovarian cancer cells SO CANCER BIOLOGY & THERAPY LA English DT Article DE histone deacetylase inhibitors (HDACi); pH2AX; ovarian cancer ID HISTONE DEACETYLASE INHIBITORS; COLON-CANCER; EPITHELIAL OVARIAN; ANTITUMOR-ACTIVITY; TUMOR-CELLS; GROWTH; BENZAMIDE; APOPTOSIS; POTENT; FK228 AB High grade epithelial ovarian cancers are relatively sensitive to DNA damaging platinum-based chemotherapy, suggesting that the dependencies of ovarian tumors on DNA damage response pathways can be harnessed for therapeutic purposes. Our goal was to determine if the DNA damage mark gamma- H2AX phosphorylation (pH2AX) could be used to identify suitable cytotoxic histone deacetylase inhibitors (HDACi) for ovarian cancer treatment. Nineteen chemically diverse HDACi compounds were tested in 7 ovarian cancer cell lines. Fluorescent, biochemical and cell-based assays were performed to assess DNA damage by induction of pH2AX and to measure cell viability and apoptosis. The relationships between pH2AX and the cellular effects of cell viability and apoptosis were calculated. Selected HDACi were tested in combination with cisplatin and other DNA damaging agents to determine if the HDACi improved upon the effects of the DNA damaging agents. The HDACi compounds induced differing levels of pH2AX expression. High levels of pH2AX in HDACi-treated ovarian cancer cells were tightly associated with decreased cell viability and increased apoptosis. Consequently, a ketone-based HDACi was chosen and found to enhance the effects of cisplatin, even in ovarian cancer cells with extreme resistance to DNA damaging drugs. In conclusion, a fluorescent-based assay for pH2AX can be used to determine cellular responses to HDACi in vitro and may be a useful tool to identify potentially more effective HDACi for the treatment of ovarian cancer. In addition, these results lend support to the inclusion of ketone-derived HDACi compounds for future development. C1 [Wilson, Andrew J.; Khabele, Dineo] Vanderbilt Univ Sch Med, Dept Obstet & Gynecol, Div Gynecol Oncol, Nashville, TN 37203 USA. [Bhaskara, Srividya] Vanderbilt Univ Sch Med, Dept Biochem, Nashville, TN USA. [Hiebert, Scott W.; Khabele, Dineo] Vanderbilt Univ Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Holson, Edward; Wagner, Florence; Zhang, Yan-Ling; Fass, Daniel M.; Haggarty, Stephen J.] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Schreiber, Stuart L.] Harvard Univ, Howard Hughes Med Inst, Chem Biol Program, Broad Inst, Cambridge, MA 02138 USA. RP Khabele, D (reprint author), Vanderbilt Univ Sch Med, Dept Obstet & Gynecol, Div Gynecol Oncol, Nashville, TN 37203 USA. EM dineo.khabele@vanderbilt.edu OI Bhaskara, Srividya/0000-0002-2182-9585; Haggarty, Stephen J./0000-0002-7872-168X FU NIH [1K08CA148887-01, 5P30 CA068485, CA091408 5 U54, 1UL1 RR024975, 5R01DA028301-02] FX NIH grants: 1K08CA148887-01 (D.K.); 5P30 CA068485; CA091408 5 U54; 1UL1 RR024975; and 5R01DA028301-02 (S.J.H.), Stanley Medical Research Institute. The Gynecologic Cancer Foundation and Gloucester Pharmaceuticals (Celgene Corp.) (D.K.). The Vanderbilt immunohistochemistry, Translational Pathology Shared Resource and High-Throughput Screening Cores. The Broad Institute Visiting Faculty Program. NR 48 TC 19 Z9 20 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP 15 PY 2011 VL 12 IS 6 BP 484 EP 493 DI 10.4161/cbt.12.6.15956 PG 10 WC Oncology SC Oncology GA 821DJ UT WOS:000294954700003 PM 21738006 ER PT J AU Mostaghel, EA Marck, BT Plymate, SR Vessella, RL Balk, S Matsumoto, AM Nelson, PS Montgomery, RB AF Mostaghel, Elahe A. Marck, Brett T. Plymate, Stephen R. Vessella, Robert L. Balk, Stephen Matsumoto, Alvin M. Nelson, Peter S. Montgomery, R. Bruce TI Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; CYTOCHROME P450(17-ALPHA); THERAPEUTIC IMPLICATIONS; STEROIDAL INHIBITORS; ANTITUMOR-ACTIVITY; PROGRESSION; ACETATE; DEHYDROGENASE; GROWTH; ANTIANDROGEN AB Purpose: Abiraterone is a potent inhibitor of the steroidogenic enzyme CYP17A1 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The effectiveness of abiraterone in reducing tumor androgens is not known, nor have mechanisms contributing to abiraterone resistance been established. Experimental Design: We treated human CRPC xenografts with abiraterone and measured tumor growth, tissue androgens, androgen receptor (AR) levels, and steroidogenic gene expression versus controls. Results: Abiraterone suppressed serum PSA levels and improved survival in two distinct CRPC xenografts: median survival of LuCaP35CR improved from 17 to 39 days (HR = 3.6, P = 0.0014) and LuCaP23CR from 14 to 24 days (HR = 2.5, P = 0.0048). Abiraterone strongly suppressed tumor androgens, with testosterone (T) decreasing from 0.49 +/- 0.22 to 0.03 +/- 0.01 pg/mg (P < 0.0001), and from 0.69 +/- 0.36 to 0.03 +/- 0.01 pg/mg (P = 0.002) in abiraterone-treated 23CR and 35CR, respectively, with comparable decreases in tissue DHT. Treatment was associated with increased expression of full-length AR (AR(FL)) and truncated AR variants (AR(FL) 2.3-fold, P = 0.008 and AR(del567es) 2.7-fold, P = 0.036 in 23 CR; AR(FL) 3.4-fold, P = 0.001 and AR(V7) 3.1-fold, P = 0.0003 in 35CR), and increased expression of the abiraterone target CYP17A1 (similar to 2.1- fold, P = 0.0001 and P = 0.028 in 23CR and 35CR, respectively) and transcript changes in other enzymes modulating steroid metabolism. Conclusions: These studies indicate that abiraterone reduces CRPC growth via suppression of intratumoral androgens and that resistance to abiraterone may occur through mechanisms that include upregulation of CYP17A1, and/or induction of AR and AR splice variants that confer ligand-independent AR transactivation. Clin Cancer Res; 17(18); 5913-25. (C) 2011 AACR. C1 [Mostaghel, Elahe A.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Mostaghel, Elahe A.; Plymate, Stephen R.; Matsumoto, Alvin M.; Nelson, Peter S.; Montgomery, R. Bruce] Univ Washington, Dept Med, Seattle, WA USA. [Marck, Brett T.; Plymate, Stephen R.; Matsumoto, Alvin M.; Montgomery, R. Bruce] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Vessella, Robert L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Balk, Stephen] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Mostaghel, EA (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D4-100, Seattle, WA 98109 USA. EM emostagh@fhcrc.org FU Cougar Biotechnology; Prostate Cancer Foundation; Damon Runyon Cancer Research Foundation [CI-40-08]; NIH [K23 CA122820, P50 CA97186]; Cancer Center [P30 CA015704]; Veterans Affairs Research Service FX R.B. Montomery received commercial research grant from Cougar Biotechnology. The other authors disclosed no potential conflicts of interest.; Prostate Cancer Foundation (Career Development Award to E.A. Mostaghel and Synergy Award to S. Balk, R.B. Montgomery, and P. S. Nelson); Damon Runyon Cancer Research Foundation (Damon Runyon-Genentech Clinical Investigator Award CI-40-08 to E.A. Mostaghel); NIH [Career Development Award K23 CA122820 to E.A. Mostaghel; Pacific Northwest Prostate Cancer SPORE P50 CA97186 (R.L. Vessella, P. S. Nelson); the Cancer Center Support Grant to Fred Hutchinson Cancer Research Center (P30 CA015704 pilot to R.B. Montgomery)]; and the Veterans Affairs Research Service (S.R. Plymate). NR 42 TC 278 Z9 282 U1 3 U2 21 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 SEP 15 PY 2011 VL 17 IS 18 BP 5913 EP 5925 DI 10.1158/1078-0432.CCR-11-0728 PG 13 WC Oncology SC Oncology GA 821CM UT WOS:000294952400009 PM 21807635 ER PT J AU Kim, SG Veena, MS Basak, SK Han, E Tajima, T Gjertson, DW Starr, J Eidelman, O Pollard, HB Srivastava, M Srivatsan, ES Wang, MB AF Kim, Suejung G. Veena, Mysore S. Basak, Saroj K. Han, Eugene Tajima, Tracey Gjertson, David W. Starr, Joshua Eidelman, Ofer Pollard, Harvey B. Srivastava, Meera Srivatsan, Eri S. Wang, Marilene B. TI Curcumin Treatment Suppresses IKK beta Kinase Activity of Salivary Cells of Patients with Head and Neck Cancer: A Pilot Study SO CLINICAL CANCER RESEARCH LA English DT Article ID FACTOR-KAPPA-B; INDEPENDENT PATHWAY; CARCINOMA; INHIBITION; GROWTH; INTERLEUKIN-6; PROLIFERATION AB Purpose: To determine whether curcumin would inhibit I kappa B kinase beta (IKK beta) kinase activity and suppress expression of proinflammatory cytokines in head and neck squamous cell carcinoma cancer (HNSCC) patients. Experimental Design: Saliva was collected before and after subjects chewed curcumin tablets. Protein was extracted and IKK beta kinase activity measured. Interleukin (IL)-6 and IL-8 levels in the salivary supernatants were measured by ELISA. IL-6, IL-8, and other interleukin were also measured independently with ELISA to confirm the inhibitory effect of curcumin on expression and secretion of salivary cytokines. Results: Curcumin treatment led to a reduction in IKK beta kinase activity in the salivary cells of HNSCC patients ( P < 0.05). Treatment of UM-SCC1 cells with curcumin as well as with post-curcumin salivary supernatant showed a reduction of IKK beta kinase activity. Significant reduction of IL-8 levels ( P < 0.05) was seen in post-curcumin samples from patients with dental caries. Although there was reduced IL-8 expression in 8 of 21 post-curcumin samples of HNSCC patients, the data did not reach statistical significance. Saliva samples from HNSCC patients were also analyzed in a blinded fashion for expression of cytokines. IL-10, IFN-gamma, IL-12p70, and IL-2 clustered together, and granulocyte macrophage colony stimulating factor and TNF-alpha clustered together. Log(10) ratio analysis showed decrease in expression of all nine cytokines in both the salivary supernatant and salivary cells of curcumin-treated samples. Conclusions: Curcumin inhibited IKK beta kinase activity in the saliva of HNSCC patients, and this inhibition correlated with reduced expression of a number of cytokines. IKK beta kinase could be a useful biomarker for detecting the effect of curcumin in head and neck cancer. Clin Cancer Res; 17( 18); 5953-61. (C) 2011 AACR. C1 [Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Gjertson, David W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Kim, Suejung G.; Veena, Mysore S.; Basak, Saroj K.; Han, Eugene; Srivatsan, Eri S.; Wang, Marilene B.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Tajima, Tracey] VA Greater Los Angeles Healthcare Syst, Dept Dent, Los Angeles, CA USA. [Starr, Joshua; Eidelman, Ofer; Pollard, Harvey B.; Srivastava, Meera] Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Starr, Joshua; Eidelman, Ofer; Pollard, Harvey B.; Srivastava, Meera] Uniformed Serv Univ Hlth Sci, Sch Med, Inst Mol Med, Bethesda, MD 20814 USA. RP Wang, MB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, 200 UCLA Med Plaza,Suite 550, Los Angeles, CA 90095 USA. EM mbwang@ucla.edu FU VAGLAHS; West Los Angeles Surgical Education Research Center; UCLA; NIH [R21 CA116826-01]; Veterans Administration, Washington, DC FX The study was supported by funds from VAGLAHS, West Los Angeles Surgical Education Research Center, UCLA Academic Senate grant (M.B. Wang), NIH (R21 CA116826-01 to M. Wang), and Merit grant from the Veterans Administration, Washington, DC (E.S. Srivatsan). NR 20 TC 26 Z9 26 U1 0 U2 5 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 SEP 15 PY 2011 VL 17 IS 18 BP 5953 EP 5961 DI 10.1158/1078-0432.CCR-11-1272 PG 9 WC Oncology SC Oncology GA 821CM UT WOS:000294952400013 PM 21821700 ER PT J AU Yang, XM Turke, AB Qi, J Song, Y Rexer, BN Miller, TW Janne, PA Arteaga, CL Cantley, LC Engelman, JA Asara, JM AF Yang, Xuemei Turke, Alexa B. Qi, Jie Song, Youngchul Rexer, Brent N. Miller, Todd W. Jaenne, Pasi A. Arteaga, Carlos L. Cantley, Lewis C. Engelman, Jeffrey A. Asara, John M. TI Using Tandem Mass Spectrometry in Targeted Mode to Identify Activators of Class IA PI3K in Cancer SO CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITORS; CELL LUNG-CANCER; QUANTITATIVE PROTEOMICS; BREAST-CANCER; ACQUIRED-RESISTANCE; MET AMPLIFICATION; PIK3CA MUTATIONS; PATHWAY; PROTEINS; GROWTH AB Phosphatiditylinositide-3-kinase (PI3K) is activated in some cancers by direct mutation, but it is activated more commonly in cancer by mutation of upstream acting receptor tyrosine kinases (TK). At present, there is no systematic method to determine which TK signaling cascades activate PI3K in certain cancers, despite the likely utility of such information to help guide selection of tyrosine kinase inhibitor (TKI) drug strategies for personalized therapy. Here, we present a quantitative liquid chromatography tandem mass spectrometry approach that identifies upstream activators of PI3K both in vitro and in vivo. Using non-small cell lung carcinoma to illustrate this approach, we show a correct identification of the mechanism of PI3K activation in several models, thereby identifying the most appropriate TKI to downregulate PI3K signaling. This approach also determined the molecular mechanisms and adaptors required for PI3K activation following inhibition of the mTOR kinase TORC1. We further validated the approach in breast cancer cells with mutational activation of PIK3CA, where tandem mass spectrometry detected and quantitatively measured the abundance of a helical domain mutant (E545K) of PIK3CA connected to PI3K activation. Overall, our findings establish a mass spectrometric approach to identify functional interactions that govern PI3K regulation in cancer cells. Using this technique to define the pathways that activate PI3K signaling in a given tumor could help inform clinical decision making by helping guide personalized therapeutic strategies for different patients. Cancer Res; 71(18); 5965-75. (C) 2011 AACR. C1 [Yang, Xuemei; Cantley, Lewis C.; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Turke, Alexa B.; Qi, Jie; Song, Youngchul; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Thorac Canc, Boston, MA 02114 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rexer, Brent N.; Miller, Todd W.; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Asara, JM (reprint author), Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. EM jengelman@partners.org; jasara@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NIH [5P01CA120964-04, K08 CA120060, R01CA137008, R01CA140594, R01-GM41890, P01CA089021, R01CA135257-01, R01CA136851, P50CA98131]; NIH DF/HCC Cancer Center [5P30CA006516-46]; NIH DF/HCC [P50 CA127003]; NCI [P50CA090578]; NIH Vanderbilt-Ingram Cancer Center [P30CA68485]; ACS [CRP-07-234]; Stand Up to Cancer/AACR Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0209] FX The work was supported in part by NIH 5P01CA120964-04 and NIH DF/HCC Cancer Center Support Grant 5P30CA006516-46 (J.M. Asara), NIH K08 CA120060 (J.A. Engelman), R01CA137008 (J.A. Engelman, P. A. Janne), R01CA140594 (J.A. Engelman), NIH DF/HCC Gastrointestinal Cancers SPORE P50 CA127003 (J.A. Engelman and L. C. Cantley), NCI Lung SPORE P50CA090578 (J.A. Engelman, P. A. Janne), NIH R01-GM41890 and P01CA089021 (L. C. Cantley), NIH R01CA135257-01 (P. A. Janne and J.A. Engelman), and NIH R01CA136851 (P. A. Janne). NIH Breast Cancer SPORE P50CA98131, NIH Vanderbilt-Ingram Cancer Center Support Grant P30CA68485, ACS Clinical Research Professorship Grant CRP-07-234 (C. L. Arteaga), and Stand Up to Cancer/AACR Dream Team Translational Cancer Research Grant, grant no. SU2C-AACR-DT0209 (C. L. Arteaga and L. C. Cantley). NR 50 TC 10 Z9 11 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2011 VL 71 IS 18 BP 5965 EP 5975 DI 10.1158/0008-5472.CAN-11-0445 PG 11 WC Oncology SC Oncology GA 819QJ UT WOS:000294843600003 PM 21775521 ER PT J AU Anand, S Wilson, C Hasan, T Maytin, EV AF Anand, Sanjay Wilson, Clara Hasan, Tayyaba Maytin, Edward V. TI Vitamin D3 Enhances the Apoptotic Response of Epithelial Tumors to Aminolevulinate-Based Photodynamic Therapy SO CANCER RESEARCH LA English DT Article ID INDUCED PROTOPORPHYRIN-IX; PROSTATE-CANCER CELLS; NECROSIS-FACTOR-ALPHA; METHYL-AMINOLEVULINATE; IN-VITRO; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; PORPHOBILINOGEN DEAMINASE; ACTINIC KERATOSES; ACID; DIFFERENTIATION AB Photodynamic therapy, mediated by exogenously administered aminolevulinic acid (ALA-PDT), followed by exposure to a laser or broadband light source, is a promising modality for treatment of many types of cancers; however, it remains inadequate to treat large, deep, solid tumors. In this article, we report that calcitriol, the active form of vitamin D3, can be administered before ALA as a nontoxic preconditioning regimen to markedly increase the efficacy of ALA-PDT. Using mouse models of squamous cell skin cancer for preclinical proof of concept, we showed that calcitriol, delivered topically or intraperitoneally, increased tumoral accumulation of the PDT-activated ALA product protoporphyrin-IX (PpIX) up to 10-fold, mainly by altering expression of the porphyrin-synthesis enzymes coproporphyrinogen oxidase (increased) and ferrochelatase (decreased). Calcitriol-pretreated tumors underwent enhanced apoptotic cell death after ALA-based PDT. Mechanistic studies have documented activation of the extrinsic apoptotic pathway, with specific cleavage of caspase-8 and increased production of TNF-alpha in tumors preconditioned by calcitriol treatment before receiving ALA-PDT. Very low doses of calcitriol (0.1-1 mu g/kg body weight) were sufficient to elicit tumor-selective enhancement to ALA-PDT efficacy, rendering toxicity concerns negligible. Our findings define a simple, nontoxic, and highly effective preconditioning regimen to enhance the response of epithelial tumors to ALA-PDT, possibly broadening its clinical applications by selectively enhancing accumulation of photosensitizer PpIX together with TNF-a in tumors. Cancer Res; 71(18); 6040-50. (C) 2011 AACR. C1 [Anand, Sanjay; Maytin, Edward V.] Cleveland Clin, Dept Dermatol, Lerner Res Inst, Cleveland, OH 44195 USA. [Anand, Sanjay; Wilson, Clara; Maytin, Edward V.] Cleveland Clin, Dept Biomed Engn, Lerner Res Inst, Cleveland, OH 44195 USA. [Hasan, Tayyaba; Maytin, Edward V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. RP Maytin, EV (reprint author), Cleveland Clin, Dept Dermatol, Lerner Res Inst, Mailstop ND 20,9500 Euclid Ave, Cleveland, OH 44195 USA. EM maytine@ccf.org FU National Cancer Institute/NIH [P01-CA84203] FX This work was supported by the National Cancer Institute/NIH grant P01-CA84203 (T. Hasan and E.V. Maytin). NR 50 TC 39 Z9 39 U1 0 U2 9 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 SEP 15 PY 2011 VL 71 IS 18 BP 6040 EP 6050 DI 10.1158/0008-5472.CAN-11-0805 PG 11 WC Oncology SC Oncology GA 819QJ UT WOS:000294843600010 PM 21807844 ER PT J AU Sasaki, T Koivunen, J Ogino, A Yanagita, M Nikiforow, S Zheng, W Lathan, C Marcoux, JP Du, JY Okuda, K Capelletti, M Shimamura, T Ercan, D Stumpfova, M Xiao, Y Weremowicz, S Butaney, M Heon, S Wilner, K Christensen, JG Eck, MJ Wong, KK Lindeman, N Gray, NS Rodig, SJ Janne, PA AF Sasaki, Takaaki Koivunen, Jussi Ogino, Atsuko Yanagita, Masahiko Nikiforow, Sarah Zheng, Wei Lathan, Christopher Marcoux, J. Paul Du, Jinyan Okuda, Katsuhiro Capelletti, Marzia Shimamura, Takeshi Ercan, Dalia Stumpfova, Magda Xiao, Yun Weremowicz, Stanislawa Butaney, Mohit Heon, Stephanie Wilner, Keith Christensen, James G. Eck, Michel J. Wong, Kwok-Kin Lindeman, Neal Gray, Nathanael S. Rodig, Scott J. Jaenne, Pasi A. TI A Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase Inhibitors SO CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; ANAPLASTIC LYMPHOMA KINASE; CHRONIC MYELOID-LEUKEMIA; EML4-ALK FUSION GENE; GEFITINIB; AMPLIFICATION; IMATINIB; THERAPY; TUMORS; IDENTIFICATION AB Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients. Cancer Res; 71(18); 6051-60. (C) 2011 AACR. C1 [Sasaki, Takaaki; Koivunen, Jussi; Ogino, Atsuko; Yanagita, Masahiko; Nikiforow, Sarah; Lathan, Christopher; Marcoux, J. Paul; Okuda, Katsuhiro; Capelletti, Marzia; Shimamura, Takeshi; Ercan, Dalia; Stumpfova, Magda; Butaney, Mohit; Heon, Stephanie; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Sasaki, Takaaki; Koivunen, Jussi; Ogino, Atsuko; Yanagita, Masahiko; Nikiforow, Sarah; Lathan, Christopher; Marcoux, J. Paul; Okuda, Katsuhiro; Capelletti, Marzia; Shimamura, Takeshi; Ercan, Dalia; Stumpfova, Magda; Butaney, Mohit; Heon, Stephanie; Wong, Kwok-Kin; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Zheng, Wei; Eck, Michel J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Zheng, Wei; Eck, Michel J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Xiao, Yun; Weremowicz, Stanislawa; Lindeman, Neal; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Nikiforow, Sarah; Lathan, Christopher; Marcoux, J. Paul; Shimamura, Takeshi; Heon, Stephanie; Wong, Kwok-Kin; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Du, Jinyan] Broad Inst, Cambridge, MA USA. [Wilner, Keith; Christensen, James G.] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla, CA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D820,450 Brookline Ave, Boston, MA 02215 USA. EM pjanne@partners.org OI Sasaki, Takaaki/0000-0002-6505-8786; wong, kwok kin/0000-0001-6323-235X FU NIH [R01CA136851, R01CA135257]; Cammarata Family Foundation; NCI [P50CA090578] FX This study was supported by NIH R01CA136851 (N.S. Gray and P. A. Janne), R01CA135257 (P. A. Janne), The Cammarata Family Foundation Research Fund (P. A. Janne), and by the NCI Lung SPORE P50CA090578 (P.A. Janne). NR 31 TC 270 Z9 278 U1 1 U2 25 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 SEP 15 PY 2011 VL 71 IS 18 BP 6051 EP 6060 DI 10.1158/0008-5472.CAN-11-1340 PG 10 WC Oncology SC Oncology GA 819QJ UT WOS:000294843600011 PM 21791641 ER PT J AU Mylonakis, E Muse, VV Mino-Kenudson, M AF Mylonakis, Eleftherios Muse, Victorine V. Mino-Kenudson, Mari TI A Man with Pemphigus Vulgaris and Lung Nodules Cryptococcal infection of the lung and central nervous system SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MENINGITIS; NEOFORMANS; THERAPY; ERA; MANAGEMENT; DIAGNOSIS C1 [Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Muse, Victorine V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mylonakis, Eleftherios] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Muse, Victorine V.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Mylonakis, E (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. FU Harvard Medical School Department of Continuing Education; Astellas; T2 Biosystems; Pfizer; Biomedical Systems FX This case was discussed at the postgraduate course Infectious Diseases of Adults, sponsored by the Harvard Medical School Department of Continuing Education, Course Directors Stephen B. Calderwood, Nesli Basgoz, and Jay A. Fishman.; Dr. Mylonakis reports receiving grant support from Astellas and T2 Biosystems, fees for board membership from Astellas, and lecture fees from Pfizer. Dr. Muse reports receiving consulting fees and lecture fees from Biomedical Systems. No other potential conflict of interest relevant to this article was reported. NR 15 TC 0 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 15 PY 2011 VL 365 IS 11 BP 1043 EP 1050 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 819UR UT WOS:000294857300014 PM 21916643 ER PT J AU Goss, PE Richardson, H AF Goss, Paul E. Richardson, Harriet TI Exemestane for Breast-Cancer Prevention REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID WOMEN C1 [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Richardson, Harriet] NCIC Clin Trials Grp, Kingston, ON, Canada. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM pgoss@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 15 PY 2011 VL 365 IS 11 BP 1057 EP 1058 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819UR UT WOS:000294857300020 ER PT J AU Haspel, RL Cserti-Gazdewich, C Dzik, WH AF Haspel, Richard L. Cserti-Gazdewich, Christine Dzik, Walter H. TI Renal Improvement in Myeloma with Plasma Exchange SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID REMOVAL C1 [Haspel, Richard L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Cserti-Gazdewich, Christine] Univ Hlth Network, Toronto, ON, Canada. [Dzik, Walter H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Haspel, RL (reprint author), Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. EM rhaspel@bidmc.harvard.edu NR 5 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 15 PY 2011 VL 365 IS 11 BP 1061 EP 1062 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819UR UT WOS:000294857300027 PM 21916653 ER PT J AU Branda, JA Linskey, K Kim, YA Steere, AC Ferraro, MJ AF Branda, John A. Linskey, Katy Kim, Yeowon A. Steere, Allen C. Ferraro, Mary Jane TI Two-Tiered Antibody Testing for Lyme Disease With Use of 2 Enzyme Immunoassays, a Whole-Cell Sonicate Enzyme Immunoassay Followed by a VlsE C6 Peptide Enzyme Immunoassay SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; BORRELIA-BURGDORFERI; ANTIGENIC VARIATION; IGG ELISA; DIAGNOSIS; SERODIAGNOSIS AB Background. Lyme disease (LD) antibody testing currently involves a 2-tiered algorithm with a whole-cell sonicate (WCS) enzyme immunoassay (EIA), followed by IgM/IgG Western immunoblots. A single EIA using the C6 peptide of the Borrelia burgdorferi variable-major protein-like sequence expressed lipoprotein provides similar or better sensitivity but less specificity, compared with standard 2-tiered testing. Here, we investigated an alternative 2-tiered strategy, in which the first step remained a WCS EIA, but immunoblotting was replaced by a C6 EIA. Methods. We determined the sensitivity of the 3 testing strategies with use of 91 serum samples from research study patients with LD and 78 serum samples from patients with LD whose samples were submitted to our hospital's clinical laboratory. Specificity was measured using 54 patients with other illnesses and 1246 healthy subjects from areas where the infection is endemic and nonendemic. Results. The 2-EIA algorithm in early LD had similar sensitivity as C6 testing alone, and both strategies had better sensitivity than did standard 2-tiered testing (61% and 64%, respectively, vs 48%; P = .03 and P = .008). For late disease, all 3 strategies had 100% sensitivity. The specificity of the 2-EIA algorithm was equal to that of standard 2-tiered testing, and both 2-tiered strategies were more specific than C6 testing alone (for both, 99.5% vs 98.4%; P = .01). The positive predictive value of the 2-EIA algorithm was 70%, compared with 66% for standard 2-tiered testing and 43% for the C6 EIA alone. Conclusions. The 2-EIA strategy matched the individual strengths of the C6 EIA and Western blotting, without the drawbacks. The 2 EIAs provided sensitivity comparable to that of the C6 EIA but maintained the specificity of standard 2-tiered testing. C1 [Branda, John A.] Massachusetts Gen Hosp, Clin Microbiol Lab, Dept Pathol, Boston, MA 02114 USA. [Branda, John A.; Linskey, Katy; Kim, Yeowon A.; Steere, Allen C.; Ferraro, Mary Jane] Harvard Univ, Sch Med, Boston, MA USA. [Steere, Allen C.; Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Branda, JA (reprint author), Massachusetts Gen Hosp, Clin Microbiol Lab, Dept Pathol, GRB 526, Boston, MA 02114 USA. EM branda.john@mgh.harvard.edu FU CDC [CCU110291]; English, Bonter, Mitchell Foundation; Eshe Fund; Massachusetts General Hospital; Viramed Biotech AG; Diasorin FX This work was supported by the CDC (cooperative agreement CCU110291 to A. C. S.), the English, Bonter, Mitchell Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital (to A. C. S.).; A. C. S. has received a research grant from Viramed Biotech AG in the past, to support an earlier study. J. A. B. has received a research grant from Diasorin, to support a separate study. M. J. F. has been a member of the scientific advisory board at bioMerieux. All other authors report no potential conflicts. NR 21 TC 40 Z9 40 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2011 VL 53 IS 6 BP 541 EP 547 DI 10.1093/cid/cir464 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 813JQ UT WOS:000294363100013 PM 21865190 ER PT J AU Ruel, TD Zanoni, BC Ssewanyana, I Cao, HY Havlir, DV Kamya, M Achan, J Charlebois, ED Feeney, ME AF Ruel, Theodore D. Zanoni, Brian C. Ssewanyana, Isaac Cao, Huyen Havlir, Diane V. Kamya, Moses Achan, Jane Charlebois, Edwin D. Feeney, Margaret E. TI Sex Differences in HIV RNA Level and CD4 Cell Percentage During Childhood SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VIRUS TYPE-1 INFECTION; VIRAL LOAD; GENE-EXPRESSION; CHRONIC HEPATITIS; IMMUNE-RESPONSE; PLASMA HIV; PROGRESSION; ACTIVATION; AIDS; CHILDREN AB Background. HIV-infected women have lower HIV RNA levels and higher CD4-cell counts than do men. This observation has been attributed to the immunomodulatory effects of sex steroid hormones, such as estrogen and progesterone. Limited data exist regarding potential sex differences in HIV RNA level and CD4 parameters among prepubertal children with untreated HIV infection. Methods. We examined the relationship of sex to HIV RNA level and CD4 parameters among 670 perinatally HIV-infected, antiretroviral therapy-naive African children aged < 18 years (median age, 4.8 years) using multivariate linear regression. In a subset of 188 children, we used longitudinal data to compare changes in HIV RNA levels and CD4 percentage over time. Levels of CD4 and CD8 T-cell activation (CD38+HLA-DR+) were also compared between boys and girls. Results. Female children had lower HIV RNA levels (P = .0004) and higher CD4 percentages (P < .0001), compared to male children. Multivariate linear regression demonstrated an independent association of sex with both HIV RNA level and CD4 percentage after controlling for other covariates. Multilevel mixed-effects linear regression analysis of longitudinal HIV RNA level and CD4 parameter data showed that sex differences persisted across all observed ages. Levels of T-cell activation did not differ between the sexes. Conclusions. Significant sex differences in HIV RNA levels and CD4 parameters are present in HIV-infected children before the onset of puberty. These data suggest that intrinsic genetic differences between male and female individuals, unrelated to sex steroid hormone levels, influence HIV RNA level and CD4 parameters in HIV-infected individuals. C1 [Feeney, Margaret E.] Univ Calif San Francisco, Div Expt Med, Dept Med, San Francisco, CA 94110 USA. [Ruel, Theodore D.; Feeney, Margaret E.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94110 USA. [Zanoni, Brian C.; Feeney, Margaret E.] MGH MIT & Harvard, Ragon Inst, Boston, MA USA. [Zanoni, Brian C.; Feeney, Margaret E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zanoni, Brian C.; Feeney, Margaret E.] McCord Hosp, Sinikithemba Clin, Durban, South Africa. [Zanoni, Brian C.; Feeney, Margaret E.] McCord Hosp, Philani Program, Durban, South Africa. [Ssewanyana, Isaac] Joint Clin Res Ctr, Kampala, Uganda. [Kamya, Moses] Makerere Univ, Coll Hlth Sci, Dept Med, Kampala, Uganda. [Achan, Jane] Makerere Univ, Coll Hlth Sci, Dept Paediat, Kampala, Uganda. RP Feeney, ME (reprint author), Univ Calif San Francisco, Div Expt Med, Dept Med, 1001 Potrero Ave,Bldg 3,Rm 525A, San Francisco, CA 94110 USA. EM margaret.feeney@ucsf.edu FU Sullivan Family Foundation; Elizabeth Glaser Pediatric AIDS Foundation; National Institute of Health [A151982, K236045901A2, R01AI068497]; Jewelers for Children Elizabeth Glaser Scientist Award FX This work was supported by the Sullivan Family Foundation (Philani Program), the Elizabeth Glaser Pediatric AIDS Foundation (to M. E. F.), and the National Institute of Health (grants A151982 to D. H., K236045901A2 to T. D. R, and R01AI068497 to M. E. F.). M. E. F. is the recipient of the Jewelers for Children Elizabeth Glaser Scientist Award. NR 36 TC 7 Z9 7 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2011 VL 53 IS 6 BP 592 EP 599 DI 10.1093/cid/cir484 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 813JQ UT WOS:000294363100022 PM 21840929 ER PT J AU Kollef, MH Golan, Y Micek, ST Shorr, AF Restrepo, MI AF Kollef, Marin H. Golan, Yoav Micek, Scott T. Shorr, Andrew F. Restrepo, Marcos I. TI Appraising Contemporary Strategies to Combat Multidrug Resistant Gram-Negative Bacterial Infections-Proceedings and Data From the Gram-Negative Resistance Summit SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VENTILATOR-ASSOCIATED PNEUMONIA; INTENSIVE-CARE-UNIT; COMBINATION ANTIBIOTIC-THERAPY; CRITICALLY-ILL PATIENTS; INADEQUATE ANTIMICROBIAL TREATMENT; BLOOD-STREAM INFECTION; PSEUDOMONAS-AERUGINOSA; DISEASES-SOCIETY; SEPTIC SHOCK; STAPHYLOCOCCUS-AUREUS AB The emerging problem of antibiotic resistance, especially among Gram-negative bacteria (GNB), has become a serious threat to global public health. Very few new antibacterial classes with activity against antibiotic-resistant GNB have been brought to market. Renewed and growing attention to the development of novel compounds targeting antibiotic-resistant GNB, as well as a better understanding of strategies aimed at preventing the spread of resistant bacterial strains and preserving the efficacy of existing antibiotic agents, has occurred. The Gram-Negative Resistance Summit convened national opinion leaders for the purpose of analyzing current literature, epidemiologic trends, clinical trial data, therapeutic options, and treatment guidelines related to the management of antibiotic-resistant GNB infections. After an in-depth analysis, the Summit investigators were surveyed with regard to 4 clinical practice statements. The results then were compared with the same survey completed by 138 infectious disease and critical care physicians and are the basis of this article. C1 [Kollef, Marin H.] Washington Univ, Sch Med, Div Pulm & Crit Care Med, St Louis, MO 63110 USA. [Golan, Yoav] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Micek, Scott T.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Shorr, Andrew F.] Georgetown Univ, Washington, DC USA. [Shorr, Andrew F.] Washington Hosp Ctr, Washington, DC 20010 USA. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Restrepo, Marcos I.] Audie L Murphy Vet Hosp, Div Pulm & Crit Care Med, Dept Med, San Antonio, TX USA. RP Kollef, MH (reprint author), Washington Univ, Sch Med, Div Pulm & Crit Care Med, 660 S Euclid Ave,Campus Box 8052, St Louis, MO 63110 USA. EM mkollef@dom.wustl.edu RI Restrepo, Marcos/H-4442-2014 FU Consensus Medical Communication; Astellas; Sanofi Pasteur; Astrazeneca; Therafan; Forest Laboratories and Novartis; TRIUS; Covidien; BARD; National Heart, Lung, and Blood Institute [K23HL096054]; University of Colorado School of Medicine; Consensus Medical Communications; Ortho-McNeil Janssen Scientific Affairs, LLC.; Merck; Cubist; Pfizer; Johnson Johnson; National Heart, Lung, and Blood Institute; GlaxoSmithKline FX This work was supported by Consensus Medical Communication (consulting fees and travel support to M. H. K., Y. G., S. T. M., M. I. R.; payment for the development of educational presentations to S. T. M.; payment for writing manuscript to all authors); Merck (payment for lectures to M. H. K. and Y. G., manuscript preparation to M. H. K., and consultancy to Y. G.; grant support to Y. G.); Pfizer (Wyeth) (payment for lectures to M. H. K., Y. G., and M. I. R.; payment for manuscript preparation to M. H. K.; payment for consultancies to Y. G. and M. I. R.; grant support to Y. G. and S. T. M.); Astellas (payment for lectures and manuscript preparation to M. H. K., grant support to Y. G.); Sanofi Pasteur and Astrazeneca (payment for lectures and manuscript preparation to M. H. K.); Cubist (grant support to Y. G. and S. T. M.; payment for lectures to Y. G.); Vernco MedEd (payment for the development of educational presentations to S. T. M.); Ortho-McNeil-Janssen (Johnson & Johnson) (payment for board membership and consultancy to M. I. R.; grants to Y. G. and S. T. M.); Therafan (payment for board membership and consultancy to M. I. R.); Forest Laboratories and Novartis (payment for board membership to M. I. R.); TRIUS (payment for consultancy to M. I. R.); Covidien and BARD (payment for lectures to M. I. R.). M. I. R. is supported and his time partially protected by a grant from the National Heart, Lung, and Blood Institute (award no. K23HL096054).; Supplement sponsorship. This article was published as part of a supplement entitled "Appraising Contemporary Strategies to Combat Multidrug Resistant Gram-Negative Bacterial Infections-Proceedings and Data From the Gram-Negative Resistance Summit," jointly sponsored by the University of Colorado School of Medicine and Consensus Medical Communications and is supported by an educational grant from Ortho-McNeil Janssen Scientific Affairs, LLC.; Potential conflicts of interest. Yoav Golan, MD: is on the speakers' bureau for Merck, Pfizer, and Cubist; received grants and/or research support from Merck, Cubist, Pfizer, Astellas, and Johnson & Johnson; is a consultant for Merck, Pfizer, and Cubist. Marin Kollef, MD: is on the speakers' bureau for Merck, Pfizer, Astellas, Sanofi Pasteur, and AstraZeneca. Scott Micek, PharmD: no reported conflicts or financial disclosures. Marcos Restrepo, MD: is on the speakers' bureau for Covidien; received grant and/or research support from the National Heart, Lung, and Blood Institute; is also a consultant for Ortho-McNeil-Janssen (Johnson & Johnson), Forest Laboratories, Novartis, Theravance, and Pfizer (Wyeth). Andrew Shorr, MD: is on the speakers' bureau for Astellas, AstraZeneca, Boehringer Ingleheim, Covidien, and Pfizer; received grants and/or research support from Astellas, GlaxoSmithKline, and Pfizer; is a consultant for Astellas, Bayer, Bard, Cadence Pharmaceuticals, Canyon Pharmaceuticals, Johnson & Johnson, Eli Lilly and Company, Eisai Pharmaceuticals, Forest Laboratories, MedCo, and Theravance. NR 95 TC 34 Z9 35 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2011 VL 53 SU 2 BP S33 EP S55 DI 10.1093/cid/cir475 PG 23 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 813LE UT WOS:000294367300001 PM 21868447 ER PT J AU Kachadourian, R Pugazhenthi, S Velmurugan, K Backos, DS Franklin, CC McCord, JM Day, BJ AF Kachadourian, Remy Pugazhenthi, Subbiah Velmurugan, Kalpana Backos, Donald S. Franklin, Christopher C. McCord, Joe M. Day, Brian J. TI 2 ',5 '-Dihydroxychalcone-induced glutathione is mediated by oxidative stress and kinase signaling pathways SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE ROS; Nrf2; AP-1; MCF-7/AREc32; Metalloporphyrin; Free radicals ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; CANCER RESISTANCE PROTEIN; GLUTAMATE CYSTEINE LIGASE; HAMSTER V79 CELLS; HEME OXYGENASE-1; ANTIOXIDANT RESPONSE; MOLECULAR-MECHANISMS; INDUCED EXPRESSION; ENDOTHELIAL-CELLS; IN-VITRO AB Hydroxychalcones are naturally:occurring compounds that continue to attract considerable interest because of their anti-inflammatory and antiangiogenic properties. They have been reported to inhibit the synthesis of the inducible nitric oxide synthase and to induce the expression of heme oxygenase-1. This study examines the mechanisms by which 2',5'-dihydroxychalcone (2',5'-DHC) induces an increase in cellular glutathione (GSH) levels using a cell line stably expressing a luciferase reporter gene driven by antioxidant-response elements (MCF-7/AREc32). The 2',5'-DHC-induced increase in cellular GSH levels was partially inhibited by the catalytic antioxidant MnTDE-1,3-IP(5+), suggesting that reactive oxygen species (ROS) mediate the antioxidant adaptive response. 2',5'-DHC treatment induced phosphorylation of the c-Jun N-terminal kinase (JNK) pathway, which was also inhibited by MnTDE-1,3-IP(5+). These findings suggest a ROS-dependent activation of the AP-1 transcriptional response. However, whereas 2',5'-DHC triggered the NF-E2-related factor 2 (Nrf2) transcriptional response, cotreatment with MnTDE-1,3-IP(5+) did not decrease 2',5'-DHC-induced Nrf2/ARE activity, showing that this pathway is not dependent on ROS. Moreover, pharmacological inhibitors of mitogen-activated protein kinase (MAPK) pathways showed a role for JNK and p38MAPK in mediating the 2',5'-DHC-induced Nrf2 response. These findings suggest that the 2',5'-DHC-induced increase in GSH levels results from a combination of ROS-dependent and ROS-independent pathways. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kachadourian, Remy; Day, Brian J.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Kachadourian, Remy; Pugazhenthi, Subbiah; McCord, Joe M.; Day, Brian J.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Pugazhenthi, Subbiah; Velmurugan, Kalpana] Denver VA Med Ctr, Denver, CO 80220 USA. [Backos, Donald S.; Franklin, Christopher C.; Day, Brian J.] Univ Colorado Denver, Dept Pharmaceut Sci, Aurora, CO 80045 USA. RP Day, BJ (reprint author), Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. EM dayb@njhealth.org OI Backos, Donald/0000-0001-6735-6210 FU NIH [HL755223, HL84469, ES015678, ES017582]; VA Merit Review [NEUD-004-07F] FX This work was supported by NIH Grants HL755223, HL84469, ES015678, and ES017582 to B.J. Day and VA Merit Review NEUD-004-07F to S. Pugazhenthi. The authors thank Gregory Mahaffey for his help with immunoblotting. Dr. Day is a consultant for and holds equity in Aeolus Pharmaceuticals, which is commercially developing metalloporphyrins as human therapeutic agents. NR 56 TC 10 Z9 11 U1 0 U2 7 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 SEP 15 PY 2011 VL 51 IS 6 BP 1146 EP 1154 DI 10.1016/j.freeradbiomed.2011.05.041 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 813WB UT WOS:000294399800006 PM 21712085 ER PT J AU Yu, Y Bhangale, TR Fagerness, J Ripke, S Thorleifsson, G Tan, PL Souied, EH Richardson, AJ Merriam, JE Buitendijk, GHS Reynolds, R Raychaudhuri, S Chin, KA Sobrin, L Evangelou, E Lee, PH Lee, AY Leveziel, N Zack, DJ Campochiaro, B Campochiaro, P Smith, RT Barile, GR Guymer, RH Hogg, R Chakravarthy, U Robman, LD Gustafsson, O Sigurdsson, H Ortmann, W Behrens, TW Stefansson, K Uitterlinden, AG van Duijn, CM Vingerling, JR Klaver, CCW Allikmets, R Brantley, MA Baird, PN Katsanis, N Thorsteinsdottir, U Ioannidis, JPA Daly, MJ Graham, RR Seddon, JM AF Yu, Yi Bhangale, Tushar R. Fagerness, Jesen Ripke, Stephan Thorleifsson, Gudmar Tan, Perciliz L. Souied, Eric H. Richardson, Andrea J. Merriam, Joanna E. Buitendijk, Gabrielle H. S. Reynolds, Robyn Raychaudhuri, Soumya Chin, Kimberly A. Sobrin, Lucia Evangelou, Evangelos Lee, Phil H. Lee, Aaron Y. Leveziel, Nicolas Zack, Donald J. Campochiaro, Betsy Campochiaro, Peter Smith, R. Theodore Barile, Gaetano R. Guymer, Robyn H. Hogg, Ruth Chakravarthy, Usha Robman, Luba D. Gustafsson, Omar Sigurdsson, Haraldur Ortmann, Ward Behrens, Timothy W. Stefansson, Kari Uitterlinden, Andre G. van Duijn, Cornelia M. Vingerling, Johannes R. Klaver, Caroline C. W. Allikmets, Rando Brantley, Milam A., Jr. Baird, Paul N. Katsanis, Nicholas Thorsteinsdottir, Unnur Ioannidis, John P. A. Daly, Mark J. Graham, Robert R. Seddon, Johanna M. TI Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMPLEMENT FACTOR-H; GENETIC-ASSOCIATION; RISK; SUSCEPTIBILITY; METAANALYSIS; HAPLOTYPE; DISEASE; LOCI; ANGIOGENESIS AB Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 x 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 x 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD. C1 [Yu, Yi; Reynolds, Robyn; Chin, Kimberly A.; Seddon, Johanna M.] Tufts Univ, Sch Med, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Ctr Genet Epidemiol & Modeling, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Ioannidis, John P. A.; Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Tufts Med Ctr, Boston, MA 02111 USA. [Bhangale, Tushar R.] Genentech Inc, Human Genet Grp, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA. [Ortmann, Ward; Behrens, Timothy W.; Graham, Robert R.] Genentech Inc, Human Genet Grp, Immunol & Tissue Growth & Repair Dept, San Francisco, CA 94080 USA. [Fagerness, Jesen; Ripke, Stephan; Raychaudhuri, Soumya; Lee, Phil H.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Fagerness, Jesen; Ripke, Stephan; Raychaudhuri, Soumya; Lee, Phil H.; Daly, Mark J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Thorleifsson, Gudmar; Gustafsson, Omar; Stefansson, Kari; Thorsteinsdottir, Unnur] deCODE Genet, IS-101 Reykjavik, Iceland. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC 27710 USA. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Dept Pediat, Durham, NC 27710 USA. [Souied, Eric H.; Leveziel, Nicolas] Univ Paris Est Creteil, Hop Intercommunal Creteil, Dept Ophthalmol, F-94000 Creteil, France. [Souied, Eric H.; Leveziel, Nicolas] UPEC, Dept Ophthalmol, Fac Med Henri Mondor, Creteil, France. [Richardson, Andrea J.; Guymer, Robyn H.; Robman, Luba D.; Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Merriam, Joanna E.; Smith, R. Theodore; Barile, Gaetano R.; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Buitendijk, Gabrielle H. S.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; van Duijn, Cornelia M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Sobrin, Lucia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Evangelou, Evangelos; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Lee, Aaron Y.; Brantley, Milam A., Jr.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. [Lee, Aaron Y.; Brantley, Milam A., Jr.] Barnes Retina Inst, St Louis, MO 63144 USA. [Zack, Donald J.; Campochiaro, Betsy; Campochiaro, Peter] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA. [Zack, Donald J.; Campochiaro, Betsy; Campochiaro, Peter] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. [Zack, Donald J.; Campochiaro, Betsy] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Mol Biol & Genet, Baltimore, MD 21287 USA. [Zack, Donald J.; Campochiaro, Betsy] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. [Hogg, Ruth; Chakravarthy, Usha] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland. [Sigurdsson, Haraldur] Natl Univ Hosp Reykjavik, Dept Ophthalmol, IS-101 Reykjavik, Iceland. [Sigurdsson, Haraldur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Zack, Donald J.] UPMC, Inst Vis, Paris, France. RP Seddon, JM (reprint author), Tufts Univ, Sch Med, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, 800 Washington St,450, Boston, MA 02111 USA. EM jseddon@tuftsmedicalcenter.org RI du, zhao jiang/F-6229-2011; Ioannidis, John/G-9836-2011; Katsanis, Nicholas/E-1837-2012; Evangelou, Evangelos/C-3033-2013; Klaver, Caroline/A-2013-2016; OI smith, theodore/0000-0002-1693-943X; Katsanis, Nicholas/0000-0002-2480-0171; Hogg, Ruth/0000-0001-9413-2669; Baird, Paul/0000-0002-1305-3502; Zack, Don/0000-0002-7966-1973; Lee, Aaron/0000-0002-7452-1648; Evangelou, Evangelos/0000-0002-5488-2999 FU National Eye Institute; National Institute of Mental Health [R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469, U01 MH79470]; National Institutes of Health, Bethesda, MD, USA [RO1-EY11309, RO1-EY13435, R24-EY017404, P30-EY 001765, K12-EY16335]; Massachusetts Lions Eye Research Fund, Inc.; Research to Prevent Blindness, Inc., New York, NY, USA; Foundation Fighting Blindness, Owing Mills, MD, USA; Macula Vision Research Foundation; Kaplen Foundation; Widgeon Point Charitable Foundation; Alcon Research Institute; Fight for Sight; National Health and Medical Research Council of Australia Centre for Clinical Research Excellence [529923]; Victorian Government; American Macular Degeneration Foundation; Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service; New England Eye Center; Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA FX We thank the participants, their families and numerous ophthalmologists throughout the country who participated in this study, the MIGen study group and the Brigham and Women's Hospital PhenoGenetic Project for providing DNA samples that were used in this study, the AREDS Research Group, and Dr J. Barre, Dr. J. C. Danan and P. Ledudal from the Clinical Researches Functional Unit, CHI Creteil, France. The MMAP dataset used for the analyses described in this manuscript was obtained from the NEI Study of Age-Related Macular Degeneration (NEI-AMD) Database found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000182.v2.p1. Funding support for NEI-AMD was provided by the National Eye Institute. We would like to thank NEI-AMD participants and the NEI-AMD Research Group for their valuable contribution to this research. Funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2. Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA).; We deeply appreciate the support of a generous anonymous donor to the research of J.M.S., without whom the Tufts/MGH genome-wide association study would not have been possible. This research was also supported in part by grants RO1-EY11309, RO1-EY13435, R24-EY017404, P30-EY 001765 and K12-EY16335 from the National Institutes of Health, Bethesda, MD, USA; Massachusetts Lions Eye Research Fund, Inc.; Unrestricted grants and Career Development Award from Research to Prevent Blindness, Inc., New York, NY, USA; Foundation Fighting Blindness, Owing Mills, MD, USA; The Macula Vision Research Foundation; Kaplen Foundation; Widgeon Point Charitable Foundation; the Alcon Research Institute; a Fight for Sight postdoctoral award; the National Health and Medical Research Council of Australia Centre for Clinical Research Excellence No. 529923-Translational Clinical Research in Major Eye Diseases and a Practitioner Fellowship to R. H. G. and Operational Infrastructure Support from the Victorian Government; American Macular Degeneration Foundation; and the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. Funding to pay the Open Access publication charges for this article was provided by the Macular Degeneration Research Fund, Tufts Medical Center. NR 51 TC 129 Z9 130 U1 1 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2011 VL 20 IS 18 BP 3699 EP 3709 DI 10.1093/hmg/ddr270 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 814IP UT WOS:000294442200016 PM 21665990 ER PT J AU Xie, PX Kranzler, HR Krauthammer, M Cosgrove, KP Oslin, D Anton, RF Farrer, LA Picciotto, MR Krystal, JH Zhao, HY Gelernter, J AF Xie, Pingxing Kranzler, Henry R. Krauthammer, Michael Cosgrove, Kelly P. Oslin, David Anton, Raymond F. Farrer, Lindsay A. Picciotto, Marina R. Krystal, John H. Zhao, Hongyu Gelernter, Joel TI Rare Nonsynonymous Variants in Alpha-4 Nicotinic Acetylcholine Receptor Gene Protect Against Nicotine Dependence SO BIOLOGICAL PSYCHIATRY LA English DT Article DE CHRNA4; deep sequencing; imaging genetics; nicotine dependence; nonsynonymous; rare variants ID VENTRAL TEGMENTAL AREA; MULTILOCUS GENOTYPE DATA; GENOMEWIDE LINKAGE SCAN; SMOKING-BEHAVIOR; SEMISTRUCTURED ASSESSMENT; ALCOHOLISM SSADDA; DRUG-DEPENDENCE; SUBUNIT GENE; IN-VIVO; ASSOCIATION AB Background: Several studies report association of alpha-4 nicotinic acetylcholine receptors (encoded by CHRNA4) with nicotine dependence (ND). A meta-analysis of genomewide linkage studies for ND implicated a single chromosomal region, which includes CHRNA4, as genome-wide significant. Methods: After establishing that common variants are unlikely to completely account for this linkage, we investigated the distribution of CHRNA4 rare variants by sequencing the coding exons and flanking intronic regions of CHRNA4 in 209 European American (EA) ND cases and 183 EA control subjects. Because most of the rare variants that we detected (and all nonsynonymous changes) were in Exon 5, we sequenced Exon 5 in an additional 1000 ND cases and 1000 non-ND comparison subjects, both of which included equal numbers of EAs and African Americans. Results: Comparison subjects had a higher frequency of rare nonsynonymous variants in the Exon 5 region (encoding the large intercellular loop of the alpha 4 subunit; Fisher's Exact Test p = .009; association test p = .009, odds ratio = .43; weighted-sum method p = .014), indicating a protective effect against ND. Considering data from the two stages combined and only nonsynonymous variants predicted to alter protein function, the association was stronger (Fisher's Exact Test p = .005; association test p = .008, odds ratio = .29; weighted-sum method p = .005). Single-photon emission computed tomography imaging results were consistent with functionality. Conclusions: CHRNA4 functional rare variants may reduce ND risk. This is the first demonstration that rare functional variants at a candidate locus protect against substance dependence to our knowledge, suggesting a novel mechanism of substance dependence heritability that is potentially of general importance. C1 [Xie, Pingxing; Zhao, Hongyu; Gelernter, Joel] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Cosgrove, Kelly P.; Picciotto, Marina R.; Krystal, John H.; Gelernter, Joel] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Krauthammer, Michael] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Xie, Pingxing; Cosgrove, Kelly P.; Krystal, John H.; Gelernter, Joel] VA Connecticut Healthcare Ctr, West Haven, CT USA. [Kranzler, Henry R.; Oslin, David] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Anton, Raymond F.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Anton, Raymond F.] Med Univ S Carolina, Dept Psychiat, Ctr Alcohol & Drug Programs, Charleston, SC 29425 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol & Biostat, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Med, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Genet & Genom, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. RP Gelernter, J (reprint author), Yale Univ, Sch Med, Dept Psychiat, Div Human Genet Psychiat, 950 Campbell Ave, West Haven, CT 06516 USA. EM joel.gelernter@yale.edu RI Picciotto, Marina/F-8747-2012; Cosgrove, Kelly/J-7004-2013; OI Picciotto, Marina/0000-0002-4404-1280; Farrer, Lindsay/0000-0001-5533-4225 FU National Institute of Health [R01 DA12690, R01 DA12849, R01 AA11330, R01 AA017535, K01 DA020651, R01 DA015577, 2P50-AA012870, K05 AA017435, R01 DA030976]; Vetrans Affairs (VA) VISN1 MIRECC; VA Alcohol Research Center; Clinical Neuroscience Division of the VA National Center for Posttraumatic Stress Disorder; Alkermes; GlaxoSmithKline; Gilead; Merck; ACNP Alcohol Clinical Trials Initiative (ACTIVE); Janssen Research Foundation FX This study was supported by National Institute of Health Grant Nos. R01 DA12690, R01 DA12849, R01 AA11330, R01 AA017535, K01 DA020651, R01 DA015577, 2P50-AA012870, K05 AA017435, R01 DA030976 and the Vetrans Affairs (VA) VISN1 MIRECC, VA Alcohol Research Center, and the Clinical Neuroscience Division of the VA National Center for Posttraumatic Stress Disorder. Ann Marie Lacobelle provided technical assistance. We thank the individuals and families participating in this work and the interviewers at all the participating sites for collecting the data.; Dr. Kranzler has received consulting fees from Alkermes, GlaxoSmithKline, and Gilead and research support from Merck. Dr. Anton reports being a consultant for Eli Lilly, GlaxoSmithKline, and Alkermes for the past 2 years. Drs. Kranzler and Anton also report associations with Eli Lilly, Merck, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson; these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and they receive support from ACTIVE. Dr. Picciotto has received an honorarium from Targacept. Dr. Krystal reports serving as a scientific consultant and/or on the scientific advisory board to the following companies: Aisling Capital, AstraZeneca Pharmaceuticals, Brintnall & Nicolini, Easton Associates, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Lundbeck Research USA, Medivation, Merz Pharmaceuticals, MK Medical Communications, F. Hoffmann-La Roche, SK Holdings Co., Takeda Industries, Teva Pharmaceutical Industries, Abbott Laboratories, Bristol-Myers Squibb, Eisai, Eli Lilly and Co, Lohocla Research Corporation, Naurex and Pfizer Pharmaceuticals. Dr. Krystal holds less than US$ 150 in exercisable warrant options with Tetragenex Pharmaceuticals, is the principal investigator of a multicenter study in which Janssen Research Foundation has provided drug and some financial support to the Department of Veterans Affairs, and is a cosponsor for two patents under review for glutamatergic agents targeting the treatment of depression, including one that involves the antide-pressant effects of ketamine. The other authors report no biomedical financial interests or potential conflicts of interest. NR 49 TC 33 Z9 33 U1 1 U2 9 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 SEP 15 PY 2011 VL 70 IS 6 BP 528 EP 536 DI 10.1016/j.biopsych.2011.04.017 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 810UX UT WOS:000294154100007 PM 21683344 ER PT J AU Cardenas, VA Durazzo, TC Gazdzinski, S Mon, A Studholme, C Meyerhoff, DJ AF Cardenas, Valerie A. Durazzo, Timothy C. Gazdzinski, Stefan Mon, Anderson Studholme, Colin Meyerhoff, Dieter J. TI Brain Morphology at Entry into Treatment for Alcohol Dependence Is Related to Relapse Propensity SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Abstinence; deformation morphometry; longitudinal; relapse ID CHRONIC CIGARETTE-SMOKING; CONSUMPTION FOLLOWING TREATMENT; SUBSTANCE USE DISORDERS; ORBITOFRONTAL CORTEX; PROBLEM DRINKING; ADDICTION; DRUG; INDIVIDUALS; MORPHOMETRY; PREDICTORS AB Background: We examined whether any differences in brain volumes at entry into alcohol dependence treatment differentiate subsequent Abstainers from Relapsers. Methods: Individuals in alcohol dependence treatment (n = 75) underwent magnetic resonance imaging approximately 6 +/- 4 days after their last alcoholic drink, and 40 age-matched nonsmoking light drinkers (LD) were studied as control subjects. At follow-up 7.8 +/- 2.6 months later, 23 alcoholics (31%) had abstained from drinking and 52 (69%) had relapsed. Deformation morphometry compared Relapsers, Abstainers, and LD. Results: Compared with LD, future Abstainers had smaller brain tissue volumes in the left amygdala, hippocampal head, and entorhinal cortex and bilaterally in the thalamus and adjacent subcortical white matter (WM) and had larger volume in the left lateral orbitofrontal region. Compared with LD, future Relapsers had smaller brain tissue volumes in the right middle temporal, occipital, and superior frontal WM. Compared with future Abstainers, future Relapsers had smaller tissue volumes primarily in bilateral orbitofrontal cortex and surrounding WM. Results were virtually unaffected after controlling for common comorbidities. Conclusions: At entry into alcohol dependence treatment, the brain tructure of future Relapsers differs from that of future Abstainers. Future Relapsers have smaller brain volumes in regions of the mesocorticolimbic reward system that are critically involved in impulse control, emotional regulation, craving, and evaluation and anticipation of stimulus salience and hedonics. Structural abnormalities of this circuitry might confer greater risk for resumption of hazardous drinking after treatment and might contribute to the definition of a neurobiological relapse risk profile in alcohol dependence. C1 [Cardenas, Valerie A.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94121 USA. [Cardenas, Valerie A.; Durazzo, Timothy C.; Gazdzinski, Stefan; Mon, Anderson; Studholme, Colin; Meyerhoff, Dieter J.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. RP Cardenas, VA (reprint author), San Francisco VA Med Ctr, 4150 Clement St,114M, San Francisco, CA 94121 USA. EM valerie.cardenas-nicolson@ucsf.edu FU National Institutes of Health [R01AA10788, K08DA24136, R03EB008136, P01AA11493, P41RR023953] FX This material is the result of work supported by National Institutes of Health [R01AA10788, K08DA24136, R03EB008136, P01AA11493, P41RR023953], which were administered by the Northern California Institute for Research and Education, and with resources and the use of facilities of the Veterans Affairs Medical Center, San Francisco, California. We thank Mary Rebecca Young, Bill Clift, Jeanne Eichenbaum, and Drs. Peter Banys and Ellen Herbst of the Veterans Administration Substance Abuse Day Hospital and Dr. David Pating, Karen Moise, and their colleagues at the Kaiser Permanente Chemical Dependency Recovery Program in San Francisco for their valuable assistance in recruiting participants. We also wish to extend our gratitude to the study participants, who made this research possible. NR 43 TC 33 Z9 33 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2011 VL 70 IS 6 BP 561 EP 567 DI 10.1016/j.biopsych.2011.04.003 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 810UX UT WOS:000294154100011 PM 21601177 ER PT J AU Kuralay, F Campuzano, S Haake, DA Wang, J AF Kuralay, Filiz Campuzano, Susana Haake, David A. Wang, Joseph TI Highly sensitive disposable nucleic acid biosensors for direct bioelectronic detection in raw biological samples SO TALANTA LA English DT Article DE Screen-printed gold electrodes; Dithiols; Self-assembled monolayer; DNA hybridization; Raw samples ID SELF-ASSEMBLED MONOLAYERS; PRINTED GOLD ELECTRODES; ELECTROCHEMICAL IMPEDANCE SPECTROSCOPY; CARBON ELECTRODES; DNA MONOLAYERS; HYBRIDIZATION; MERCAPTOHEXANOL; AMPLIFICATION; GENOSENSOR; SURFACES AB The development of rapid, low-cost and reliable diagnostic methods is crucial for the identification and treatment of many diseases. Screen-printed gold electrodes (Au/SPEs), coated with a ternary monolayer interface, involving hexanedithiol (HDT), a specific thiolated capture probe (SHCP), and 6-mercapto-1 hexanol (MCH) (SHCP/HDT/MCH) are shown here to offer direct and sensitive detection of nucleic acid hybridization events in untreated raw biological samples (serum, urine and crude bacterial lysate solutions). The composition of the ternary monolayer was modified and tailored to the surface of the Au/SPE. The resulting SHCP/HDT/MCH monolayer has demonstrated to be extremely useful for enhancing the performance of disposable nucleic acid sensors based on screen-printed electrodes. Compared to common SHCP/MCH binary interfaces, the new ternary self-assembled monolayer (SAM) resulted in a 10-fold improvement in the signal (S)-to-noise (N) ratio (S/N) for 1 nM target DNA. The SHCP/HDT/MCH-modified Au/SPEs allowed the direct quantification of the target DNA down to 25 pM (0.25 fmol) and 100 pM (1 fmol) in undiluted/untreated serum and urine samples, respectively, and of 16S rRNA Escherichia coli (E. con) corresponding to 3000 CFU mu L-1 in raw cell lysate samples. The new SAM-coated screen-printed electrodes also displayed favorable non-fouling properties after a 24 h exposure to raw human serum and urine samples, offering great promise as cost-effective nucleic acid sensors for a wide range of decentralized genetic tests. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kuralay, Filiz; Campuzano, Susana; Wang, Joseph] Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA. [Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Wang, J (reprint author), Univ Calif San Diego, Dept Nanoengn, La Jolla, CA 92093 USA. EM josephwang@ucsd.edu RI Campuzano Ruiz, Susana/C-6448-2011; Wang, Joseph/C-6175-2011 FU National Institutes of Health [U01 AI075565]; Scientific and Technical Council of Turkey (TUBITAK); Programa Becas Complutense del Amo FX Financial support from the National Institutes of Health (Award U01 AI075565) is gratefully acknowledged. FK and SC acknowledge fellowships from The Scientific and Technical Council of Turkey (TUBITAK) and Programa Becas Complutense del Amo (2010-2011), respectively. The authors would like to acknowledge S. Marx and C. Halford for their assistance. NR 42 TC 25 Z9 26 U1 5 U2 47 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0039-9140 EI 1873-3573 J9 TALANTA JI Talanta PD SEP 15 PY 2011 VL 85 IS 3 BP 1330 EP 1337 DI 10.1016/j.talanta.2011.06.012 PG 8 WC Chemistry, Analytical SC Chemistry GA 809YO UT WOS:000294092800018 PM 21807191 ER PT J AU Ontoria, JM Bufi, LL Torrisi, C Bresciani, A Giomini, C Rowley, M Serafini, S Bin, H Hao, W Steinkuhler, C Jones, P AF Ontoria, Jesus M. Bufi, Laura Llauger Torrisi, Caterina Bresciani, Alberto Giomini, Claudia Rowley, Michael Serafini, Sergio Bin, Hu Hao, Wu Steinkuehler, Christian Jones, Philip TI Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Hedgehog pathway; Smoothened antagonist; Hedgehog inhibitor ID SMALL-MOLECULE INHIBITORS; SIGNALING PATHWAY; CANCER; CYCLOPAMINE AB The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Ontoria, Jesus M.; Bufi, Laura Llauger; Torrisi, Caterina; Bresciani, Alberto; Giomini, Claudia; Rowley, Michael; Serafini, Sergio; Steinkuehler, Christian; Jones, Philip] IRBM, Merck Res Labs Rome, I-00040 Rome, Italy. [Bin, Hu; Hao, Wu] WuXi AppTec Co Ltd, Shanghai 200131, Peoples R China. RP Jones, P (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 450 Brookline Ave, Boston, MA 02115 USA. EM philip_jones@dfci.harvard.edu NR 20 TC 17 Z9 18 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2011 VL 21 IS 18 BP 5274 EP 5282 DI 10.1016/j.bmcl.2011.07.031 PG 9 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 809KB UT WOS:000294051800031 PM 21803580 ER PT J AU Muraglia, E Ontoria, JM Branca, D Dessole, G Bresciani, A Fonsi, M Giuliano, C Bufi, LL Monteagudo, E Palumbi, MC Torrisi, C Rowley, M Steinkuhler, C Jones, P AF Muraglia, Ester Ontoria, Jesus M. Branca, Danila Dessole, Gabriella Bresciani, Alberto Fonsi, Massimiliano Giuliano, Claudio Bufi, Laura Llauger Monteagudo, Edith Palumbi, Maria Cecilia Torrisi, Caterina Rowley, Michael Steinkuehler, Christian Jones, Philip TI N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Hedgehog pathway; Smoothened antagonist; Hedgehog inhibitor ID HEDGEHOG SIGNALING PATHWAY; INHIBITION; METABOLISM; CANCER; CYCLOPAMINE; DISCOVERY; DOGS AB Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[ 3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl] piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Muraglia, Ester; Ontoria, Jesus M.; Branca, Danila; Dessole, Gabriella; Bresciani, Alberto; Fonsi, Massimiliano; Giuliano, Claudio; Bufi, Laura Llauger; Monteagudo, Edith; Palumbi, Maria Cecilia; Torrisi, Caterina; Rowley, Michael; Steinkuehler, Christian; Jones, Philip] IRBM, Merck Res Labs Rome, I-00040 Rome, Italy. RP Jones, P (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, 450 Brookline Ave, Boston, MA 02115 USA. EM philip_jones@dfci.harvard.edu NR 22 TC 14 Z9 15 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2011 VL 21 IS 18 BP 5283 EP 5288 DI 10.1016/j.bmcl.2011.07.030 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 809KB UT WOS:000294051800032 PM 21802943 ER PT J AU Carpenter, D Joffe, S AF Carpenter, Daniel Joffe, Steven TI Information Disclosure and the Physician Payments Sunshine Act Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Carpenter, Daniel] Harvard Univ, Dept Govt, Cambridge, MA 02138 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Carpenter, D (reprint author), Harvard Univ, Dept Govt, Cambridge, MA 02138 USA. EM dcarpenter@gov.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 14 PY 2011 VL 306 IS 10 BP 1087 EP 1088 DI 10.1001/jama.2011.1299 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819DS UT WOS:000294806200020 ER PT J AU Michelena, HI Khanna, AD Mahoney, D Margaryan, E Topilsky, Y Suri, RM Eidem, B Edwards, WD Sundt, TM Enriquez-Sarano, M AF Michelena, Hector I. Khanna, Amber D. Mahoney, Douglas Margaryan, Edit Topilsky, Yan Suri, Rakesh M. Eidem, Ben Edwards, William D. Sundt, Thoralf M., III Enriquez-Sarano, Maurice TI Incidence of Aortic Complications in Patients With Bicuspid Aortic Valves SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ASCENDING AORTA; INTERNATIONAL REGISTRY; EJECTION FRACTION; DISSECTION IRAD; MARFAN-SYNDROME; HEART-DISEASE; RISK-FACTORS; ECHOCARDIOGRAPHY; ANEURYSMS; DILATATION AB Context Bicuspid aortic valve (BAV), the most common congenital heart defect, has been thought to cause frequent and severe aortic complications; however, long-term, population-based data are lacking. Objective To determine the incidence of aortic complications in patients with BAV in a community cohort and in the general population. Design, Setting, and Participants In this retrospective cohort study, we conducted comprehensive assessment of aortic complications of patients with BAV living in a population-based setting in Olmsted County, Minnesota. We analyzed long-term follow-up of a cohort of all Olmsted County residents diagnosed with definite BAV by echocardiography from 1980 to 1999 and searched for aortic complications of patients whose bicuspid valves had gone undiagnosed. The last year of follow-up was 2008-2009. Main Outcome Measure Thoracic aortic dissection, ascending aortic aneurysm, and aortic surgery. Results The cohort included 416 consecutive patients with definite BAV diagnosed by echocardiography, mean (SD) follow-up of 16 (7) years (6530 patient-years). Aortic dissection occurred in 2 of 416 patients; incidence of 3.1 (95% CI, 0.5-9.5) cases per 10 000 patient-years, age-adjusted relative-risk 8.4 (95% CI, 2.1-33.5; P=.003) compared with the county's general population. Aortic dissection incidences for patients 50 years or older at baseline and bearers of aortic aneurysms at baseline were 17.4 (95% CI, 2.9-53.6) and 44.9(95% CI, 7.5-138.5) cases per 10 000 patient-years, respectively. Comprehensive search for aortic dissections in undiagnosed bicuspid valves revealed 2 additional patients, allowing estimation of aortic dissection incidence in bicuspid valve patients irrespective of diagnosis status (1.5; 95% CI, 0.4-3.8 cases per 10 000 patient-years), which was similar to the diagnosed cohort. Of 384 patients without baseline aneurysms, 49 developed aneurysms at follow-up, incidence of 84.9 (95% CI, 63.3-110.9) cases per 10 000 patient-years and an age-adjusted relative risk 86.2 (95% CI, 65.1-114; P<.001 compared with the general population). The 25-year rate of aortic surgery was 25% (95% CI, 17.2%-32.8%). Conclusions In the population of patients with BAV, the incidence of aortic dissection over a mean of 16 years of follow-up was low but significantly higher than in the general population. JAMA. 2011;306(10):1104-1113 www.jama.com C1 [Michelena, Hector I.; Khanna, Amber D.; Margaryan, Edit; Topilsky, Yan; Eidem, Ben; Enriquez-Sarano, Maurice] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Mahoney, Douglas] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Suri, Rakesh M.] Mayo Clin, Div Cardiovasc Surg, Rochester, MN 55905 USA. [Edwards, William D.] Mayo Clin, Div Anat Pathol, Rochester, MN 55905 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. RP Michelena, HI (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 1st St SW, Rochester, MN 55905 USA. EM michelena.hector@mayo.edu FU Department of Internal Medicine of the Mayo Clinic, Rochester, Minnesot; Division of Cardiovascular Diseases of the Mayo Clinic FX Partially funded by a faculty development grant awarded to Dr Michelena by the Department of Internal Medicine of the Mayo Clinic, Rochester, Minnesot. The Division of Cardiovascular Diseases of the Mayo Clinic supported the costs of survey creation and mailings, as well as statistical analysis costs. NR 40 TC 166 Z9 169 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 14 PY 2011 VL 306 IS 10 BP 1104 EP 1112 DI 10.1001/jama.2011.1286 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 819DS UT WOS:000294806200024 PM 21917581 ER PT J AU Fredman, G Oh, SF Ayilavarapu, S Hasturk, H Serhan, CN Van Dyke, TE AF Fredman, Gabrielle Oh, Sungwhan F. Ayilavarapu, Srinivas Hasturk, Hatice Serhan, Charles N. Van Dyke, Thomas E. TI Impaired Phagocytosis in Localized Aggressive Periodontitis: Rescue by Resolvin E1 SO PLOS ONE LA English DT Article ID ATHEROSCLEROTIC CARDIOVASCULAR-DISEASE; EDITORS CONSENSUS PERIODONTITIS; JOURNAL-OF-CARDIOLOGY; LIPID MEDIATORS; PORPHYROMONAS-GINGIVALIS; JUVENILE PERIODONTITIS; INFLAMMATORY RESPONSE; SUPEROXIDE PRODUCTION; ARACHIDONIC-ACID; TISSUE-DAMAGE AB Resolution of inflammation is an active temporally orchestrated process demonstrated by the biosynthesis of novel proresolving mediators. Dysregulation of resolution pathways may underlie prevalent human inflammatory diseases such as cardiovascular diseases and periodontitis. Localized Aggressive Periodontitis (LAP) is an early onset, rapidly progressing form of inflammatory periodontal disease. Here, we report increased surface P-selectin on circulating LAP platelets, and elevated integrin (CD18) surface expression on neutrophils and monocytes compared to healthy, asymptomatic controls. Significantly more platelet-neutrophil and platelet-monocyte aggregates were identified in circulating whole blood of LAP patients compared with asymptomatic controls. LAP whole blood generates increased pro-inflammatory LTB4 with addition of divalent cation ionophore A23187 (5 mu M) and significantly less, 15-HETE, 12-HETE, 14-HDHA, and lipoxin A(4). Macrophages from LAP subjects exhibit reduced phagocytosis. The pro-resolving lipid mediator, Resolvin E1 (0.1-100 nM), rescues the impaired phagocytic activity in LAP macrophages. These abnormalities suggest compromised resolution pathways, which may contribute to persistent inflammation resulting in establishment of a chronic inflammatory lesion and periodontal disease progression. C1 [Fredman, Gabrielle; Ayilavarapu, Srinivas; Hasturk, Hatice; Van Dyke, Thomas E.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. [Fredman, Gabrielle; Oh, Sungwhan F.; Serhan, Charles N.] Harvard Univ, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Med, Ctr Expt Therapeut & Reperfus Injury,Sch Med, Boston, MA 02115 USA. RP Fredman, G (reprint author), Forsyth Inst, Dept Periodontol, Cambridge, MA USA. EM tvandyke@forsyth.org FU National Institutes of Health [DE-019938, DE-015566, GM38765] FX This study was supported in part by National Institutes of Health Grants DE-019938 (C.N. Serhan and T.E. Van Dyke), DE-015566 (T.E. Van Dyke) and GM38765 (C.N. Serhan). No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 47 Z9 46 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 14 PY 2011 VL 6 IS 9 AR e24422 DI 10.1371/journal.pone.0024422 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JC UT WOS:000295039700021 PM 21935407 ER PT J AU Thurber, GM Weissleder, R AF Thurber, Greg Michael Weissleder, Ralph TI A Systems Approach for Tumor Pharmacokinetics SO PLOS ONE LA English DT Article ID METASTATIC COLORECTAL-CANCER; SOLID TUMORS; MODELING ANALYSIS; BLOOD-FLOW; MONOCLONAL-ANTIBODIES; OXYGEN-TRANSPORT; DRUG DISCOVERY; NORMAL-TISSUES; IN-VIVO; DELIVERY AB Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design. C1 [Thurber, Greg Michael; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02115 USA. RP Thurber, GM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02115 USA. EM gthurber@alum.mit.edu; rweissleder@mgh.harvard.edu OI Thurber, Greg/0000-0001-7570-2080 FU National Institutes of Health (NIH) [T32 CA079443] FX Funding was provided by National Institutes of Health (NIH) grant T32 CA079443. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 40 Z9 40 U1 5 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 14 PY 2011 VL 6 IS 9 AR e24696 DI 10.1371/journal.pone.0024696 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JC UT WOS:000295039700036 PM 21935441 ER PT J AU Venkatesh, AK Geisler, BP Chambers, JJG Baugh, CW Bohan, JS Schuur, JD AF Venkatesh, Arjun K. Geisler, Benjamin P. Chambers, Jennifer J. Gibson Baugh, Christopher W. Bohan, J. Stephen Schuur, Jeremiah D. TI Use of Observation Care in US Emergency Departments, 2001 to 2008 SO PLOS ONE LA English DT Article ID OBSERVATION UNITS; STATES AB Background: Observation care is a core component of emergency care delivery, yet, the prevalence of emergency department (ED) observation units (OUs) and use of observation care after ED visits is unknown. Our objective was to describe the 1) prevalence of OUs in United States (US) hospitals, 2) clinical conditions most frequently evaluated with observation, and 3) patient and hospital characteristics associated with use of observation. Methods: Retrospective analysis of the proportion of hospitals with dedicated OUs and patient disposition after ED visit (discharge, inpatient admission or observation evaluation) using the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2001 to 2008. NHAMCS is an annual, national probability sample of ED visits to US hospitals conducted by the Center for Disease Control and Prevention. Logistic regression was used to assess hospital-level predictors of OU presence and polytomous logistic regression was used for patient-level predictors of visit disposition, each adjusted for multi-level sampling data. OU analysis was limited to 2007-2008. Results: In 2007-2008, 34.1% of all EDs had a dedicated OU, of which 56.1% were under ED administrative control (EDOU). Between 2001 and 2008, ED visits resulting in a disposition to observation increased from 642,000 (0.60% of ED visits) to 2,318,000 (1.87%, p < .05). Chest pain was the most common reason for ED visit resulting in observation and the most common observation discharge diagnosis (19.1% and 17.1% of observation evaluations, respectively). In hospital-level adjusted analysis, hospital ownership status (non-profit or government), non-teaching status, and longer ED length of visit (>3.6 h) were predictive of OU presence. After patient-level adjustment, EDOU presence was associated with increased disposition to observation (OR 2.19). Conclusions: One-third of US hospitals have dedicated OUs and observation care is increasingly used for a range of clinical conditions. Further research is warranted to understand the quality, cost and efficiency of observation care. C1 [Venkatesh, Arjun K.] Brigham & Womens Hosp Massachusetts Gen Hosp Harv, Boston, MA USA. [Geisler, Benjamin P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Chambers, Jennifer J. Gibson] Univ New England, Coll Osteopath Med, Biddeford, ME USA. [Baugh, Christopher W.; Bohan, J. Stephen; Schuur, Jeremiah D.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Baugh, Christopher W.; Bohan, J. Stephen; Schuur, Jeremiah D.] Harvard Univ, Sch Med, Div Emergency Med, Boston, MA USA. RP Venkatesh, AK (reprint author), Brigham & Womens Hosp Massachusetts Gen Hosp Harv, Boston, MA USA. EM akvenkatesh@partners.org RI Geisler, Benjamin/A-9244-2010 OI Geisler, Benjamin/0000-0003-1704-6067 FU NCRR NIH HHS [UL1 RR 025758, UL1 RR025758] NR 26 TC 35 Z9 35 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 14 PY 2011 VL 6 IS 9 AR e24326 DI 10.1371/journal.pone.0024326 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822JC UT WOS:000295039700017 PM 21935398 ER PT J AU Williams, KW Sohn, JW Donato, J Lee, CE Zhao, JJ Elmquist, JK Elias, CF AF Williams, Kevin W. Sohn, Jong-Woo Donato, Jose, Jr. Lee, Charlotte E. Zhao, Jean J. Elmquist, Joel K. Elias, Carol F. TI The Acute Effects of Leptin Require PI3K Signaling in the Hypothalamic Ventral Premammillary Nucleus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROOPIOMELANOCORTIN NEURONS; ARCUATE NUCLEUS; ENERGY-BALANCE; LUTEINIZING-HORMONE; RECOMBINANT LEPTIN; RAPID INHIBITION; POMC NEURONS; FEMALE MICE; RAT-BRAIN; RECEPTOR AB Evidence suggests that the role played by the adipocyte-derived hormone leptin in female reproductive physiology is mediated in part by neurons located within the ventral premammillary nucleus (PMV). Leptin activates PMV neurons; however, the intracellular signaling pathway and channel(s) involved remain undefined. Notably, leptin's excitatory and inhibitory effects within hypothalamic and brainstem nuclei share the intracellular signaling cascade phosphoinositide 3 kinase (PI3K). Therefore, we assessed whether PI3K signaling is required for the acute effect of leptin to alter cellular activity of PMV neurons that express leptin receptors (LepR PMV neurons). Leptin caused a rapid depolarization in the majority of LepR PMV neurons in patch-clamp recordings of hypothalamic slices, while a subset of LepR PMV neurons were hyperpolarized in response to leptin. Data were obtained from both male and female mice and results demonstrate that the acute effect of leptin on LepR PMV neurons was identical for both sexes. Pharmacological inhibition of PI3K prevented the acute leptin-induced change in neuronal activity of LepR PMV neurons, indicating a PI3K-dependent mechanism of leptin action. Similarly, mice with genetically disrupted PI3K signaling in LepR PMV neurons failed to alter cellular activity in response to leptin. Moreover, the leptin-induced depolarization was dependent on a putative TRPC channel. In contrast, the leptin-induced-hyperpolarization required the activation of a putative Katp channel. Collectively, these results suggest that PI3K signaling in LepR PMV neurons is essential for leptin-induced alteration in cellular activity, and these data may suggest a cellular correlate in which leptin contributes to the initiation of reproductive development. C1 [Williams, Kevin W.; Sohn, Jong-Woo; Donato, Jose, Jr.; Lee, Charlotte E.; Elmquist, Joel K.; Elias, Carol F.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Elmquist, Joel K.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. RP Williams, KW (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Kevin.Williams@UTSouthwestern.edu RI Sohn, Jong Woo/D-6700-2014; Donato, Jose Jr./A-9662-2010; OI Donato, Jose Jr./0000-0002-6183-3861; Elias, Carol F/0000-0001-9878-9203 FU NIH [HD061539, K01DK087780, R01DK53301, R01MH61583, R01DK088423, RL1DK081185, PL1 DK081182, UL1RR024923]; University of Texas Southwestern Medical Center at Dallas; American Diabetes Association [7-07-MN-17] FX This work was supported by NIH Grant HD061539 and Regent's Scholar Research Award (University of Texas Southwestern Medical Center at Dallas) grants (to C. F. E.), American Diabetes Association Grant 7-07-MN-17 (to J.-W.S.), NIH Grant K01DK087780 (to K. W. W.), and NIH Grants R01DK53301, R01MH61583, R01DK088423, and RL1DK081185 (to J.K.E.). This work was also supported by NIH Grants PL1 DK081182 and UL1RR024923. NR 61 TC 29 Z9 30 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 14 PY 2011 VL 31 IS 37 BP 13147 EP 13156 DI 10.1523/JNEUROSCI.2602-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 819QA UT WOS:000294841900014 PM 21917798 ER PT J AU Bogdan, R Santesso, DL Fagerness, J Perlis, RH Pizzagalli, DA AF Bogdan, Ryan Santesso, Diane L. Fagerness, Jesen Perlis, Roy H. Pizzagalli, Diego A. TI Corticotropin-Releasing Hormone Receptor Type 1 (CRHR1) Genetic Variation and Stress Interact to Influence Reward Learning SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EVENT-RELATED POTENTIALS; HEDONIC CAPACITY; PERCEIVED STRESS; EXTERNAL INFORMATION; ANTERIOR CINGULATE; SIGNAL-DETECTION; DOPAMINE; DEPRESSION; REINFORCEMENT; ANXIETY AB Stress is a general risk factor for psychopathology, but the mechanisms underlying this relationship remain largely unknown. Animal studies and limited human research suggest that stress can induce anhedonic behavior. Moreover, emerging data indicate that genetic variation within the corticotropin-releasing hormone type 1 receptor gene (CRHR1) at rs12938031 may promote psychopathology, particularly in the context of stress. Using an intermediate phenotypic neurogenetics approach, we assessed how stress and CRHR1 genetic variation (rs12938031) influence reward learning, an important component of anhedonia. Psychiatrically healthy female participants (n = 75) completed a probabilistic reward learning task during stress and no-stress conditions while 128-channel event-related potentials were recorded. Fifty-six participants were also genotyped across CRHR1. Response bias, an individual's ability to modulate behavior as a function of reward, was the primary behavioral variable of interest. The feedback-related positivity (FRP) in response to reward feedback was used as a neural index of reward learning. Relative to the no-stress condition, acute stress was associated with blunted response bias as well as a smaller and delayed FRP (indicative of disrupted reward learning) and reduced anterior cingulate and orbitofrontal cortex activation to reward. Critically, rs12938031 interacted with stress to influence reward learning: both behaviorally and neurally, A homozygotes showed stress-induced reward learning abnormalities. These findings indicate that acute, uncontrollable stressors reduce participants' ability to modulate behavior as a function of reward, and that such effects are modulated by CRHR1 genotype. Homozygosity for the A allele at rs12938031 may increase risk for psychopathology via stress-induced reward learning deficits. C1 [Pizzagalli, Diego A.] McLean Hosp, Ctr Depress Anxiety & Stress Res, Belmont, MA 02478 USA. [Pizzagalli, Diego A.] McLean Hosp, Neuroimaging Ctr, Belmont, MA 02478 USA. [Pizzagalli, Diego A.] Harvard Univ, Sch Med, Belmont, MA 02478 USA. [Bogdan, Ryan; Santesso, Diane L.; Pizzagalli, Diego A.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Fagerness, Jesen; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Perlis, Roy H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Pizzagalli, DA (reprint author), McLean Hosp, Ctr Depress Anxiety & Stress Res, 115 Mill St, Belmont, MA 02478 USA. EM dap@mclean.harvard.edu OI Bogdan, Ryan/0000-0002-1430-1045 FU Harvard University; NIMH [R01 MH68376, R21 MH078979]; National Alliance for Research on Schizophrenia and Depression Independent Investigator Award; ANT North America Inc.; AstraZeneca; Bristol-Myers Squibb; Eli Lilly and Company; GlaxoSmithKline; Pfizer; Proteus FX This work was supported by Sackler Scholar in Psychobiology (Harvard University) and Mind, Brain, and Behavior (Harvard University) grants awarded to R. B., and by NIMH Grants R01 MH68376 and R21 MH078979, Merck Awards for Genome-Related Research (Harvard University), Talley Fund (Harvard University) grants, and a 2008 National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (D. A. P.). We thank Brian Galloway, Miles Nugent, Avram Holmes, Yuliya Nikolova, Sara Rubenstein, Courtney Bagge, Scott Coffey, and Yan Emily Yuan for their assistance. Parts of this paper have been presented previously at the 22nd Annual Meeting of the Society for Research in Psychopathology (September 2008; Pittsburgh, PA), the 23rd Annual Meeting of the Society for Research in Psychopathology (September 2009; Minneapolis, MN), and the 49th Annual Meeting of the Society for Psychophysiological Research (October 2009; Berlin, Germany).; D.A.P. has received consulting fees from ANT North America Inc. (Advanced Neuro Technology) and AstraZeneca, and honoraria from AstraZeneca. R. H. P. has received honoraria and speaker's or consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Pfizer, and Proteus. R. H. P. is a major stockholder in Concordant Rater Systems, LLC. R. B., D. L. S., and J.F. declare no competing financial interests. NR 60 TC 32 Z9 33 U1 3 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 14 PY 2011 VL 31 IS 37 BP 13246 EP 13254 DI 10.1523/JNEUROSCI.2661-11.2011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 819QA UT WOS:000294841900023 PM 21917807 ER PT J AU Suri, P Miyakoshi, A Hunter, DJ Jarvik, JG Rainville, J Guermazi, A Li, L Katz, JN AF Suri, Pradeep Miyakoshi, Asako Hunter, David J. Jarvik, Jeffrey G. Rainville, James Guermazi, Ali Li, Ling Katz, Jeffrey N. TI Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE degenerative cascade; degeneration; disk; facet joint; arthritis; lumbar; spine ID FACET JOINT OSTEOARTHRITIS; LOW-BACK-PAIN; DISC DEGENERATION; CORONARY-ARTERY; VARIABILITY; PROGRESSION; DISEASE; DESIGN; COHORT AB Background-: Prior studies that have concluded that disk degeneration uniformly precedes facet degeneration have been based on convenience samples of individuals with low back pain. We conducted a study to examine whether the view that spinal degeneration begins with the anterior spinal structures is supported by epidemiologic observations of degeneration in a community-based population. Methods-: 361 participants from the Framingham Heart Study were included in this study. The prevalences of anterior vertebral structure degeneration (disk height loss) and posterior vertebral structure degeneration (facet joint osteoarthritis) were characterized by CT imaging. The cohort was divided into the structural subgroups of participants with 1) no degeneration, 2) isolated anterior degeneration (without posterior degeneration), 3) combined anterior and posterior degeneration, and 4) isolated posterior degeneration (without anterior structure degeneration). We determined the prevalence of each degeneration pattern by age group < 45, 45-54, 55-64, >= 65. In multivariate analyses we examined the association between disk height loss and the response variable of facet joint osteoarthritis, while adjusting for age, sex, BMI, and smoking. Results-: As the prevalence of the no degeneration and isolated anterior degeneration patterns decreased with increasing age group, the prevalence of the combined anterior/posterior degeneration pattern increased. 22% of individuals demonstrated isolated posterior degeneration, without an increase in prevalence by age group. Isolated posterior degeneration was most common at the L5-S1 and L4-L5 spinal levels. In multivariate analyses, disk height loss was independently associated with facet joint osteoarthritis, as were increased age (years), female sex, and increased BMI (kg/m(2)), but not smoking. Conclusions-: The observed epidemiology of lumbar spinal degeneration in the community-based population is consistent with an ordered progression beginning in the anterior structures, for the majority of individuals. However, some individuals demonstrate atypical patterns of degeneration, beginning in the posterior joints. Increased age and BMI, and female sex may be related to the occurrence of isolated posterior degeneration in these individuals. C1 [Suri, Pradeep] VA Boston Healthcare Syst, Div PM&R, Boston, MA USA. [Suri, Pradeep; Rainville, James] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, Pradeep] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, Pradeep; Hunter, David J.; Rainville, James; Li, Ling] New England Baptist Hosp, Div Res, Boston, MA USA. [Miyakoshi, Asako; Jarvik, Jeffrey G.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Miyakoshi, Asako; Jarvik, Jeffrey G.] Univ Washington, Med Ctr, Dept Neurol Surg, Seattle, WA 98195 USA. [Miyakoshi, Asako; Jarvik, Jeffrey G.] Univ Washington, Med Ctr, Dept Hlth Serv, Seattle, WA 98195 USA. [Hunter, David J.] Univ Sydney, No Clin Sch, Sydney, NSW 2006, Australia. [Guermazi, Ali] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy,Dept Med, Boston, MA USA. [Katz, Jeffrey N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA USA. RP Suri, P (reprint author), VA Boston Healthcare Syst, Div PM&R, Boston, MA USA. EM pradeepsuri1@gmail.com RI Hunter, David/A-4622-2010 OI Hunter, David/0000-0003-3197-752X FU Rehabilitation Medicine Scientist Training Program (RMSTP); National Institutes of Health [K12 HD001097]; NIH/NIAMS [K24 AR 02123, P60 AR 47782, R01 1AR 054912-01A2]; Australian Research Council; AHRQ [R01 HS19222-01] FX PS is funded by the Rehabilitation Medicine Scientist Training Program (RMSTP) and the National Institutes of Health (K12 HD001097). JNK is funded in part by NIH/NIAMS K24 AR 02123 and NIH/NIAMS P60 AR 47782. DJH is funded by an Australian Research Council Future Fellowship. JGJ is funded in part by AHRQ R01 HS19222-01 and NIH/NIAMS R01 1AR 054912-01A2 NR 32 TC 20 Z9 23 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD SEP 13 PY 2011 VL 12 AR 202 DI 10.1186/1471-2474-12-202 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 827TC UT WOS:000295450100002 PM 21914197 ER PT J AU Wedick, NM Brennan, AM Sun, Q Hu, FB Mantzoros, CS van Dam, RM AF Wedick, Nicole M. Brennan, Aoife M. Sun, Qi Hu, Frank B. Mantzoros, Christos S. van Dam, Rob M. TI Effects of caffeinated and decaffeinated coffee on biological risk factors for type 2 diabetes: a randomized controlled trial SO NUTRITION JOURNAL LA English DT Article ID INSULIN-RESISTANCE; CHLOROGENIC ACID; GLUCOSE-TOLERANCE; FETUIN-A; CONSUMPTION; METAANALYSIS; SENSITIVITY; MELLITUS; HEALTHY; PLASMA AB Background: Coffee consumption has been associated with a lower risk of type 2 diabetes in prospective cohort studies, but the underlying mechanisms remain unclear. The aim of this study was to evaluate the effects of regular and decaffeinated coffee on biological risk factors for type 2 diabetes. Methods: Randomized parallel-arm intervention conducted in 45 healthy overweight volunteers who were nonsmokers and regular coffee consumers. Participants were assigned to consumption of 5 cups (177 mL each) per day of instant caffeinated coffee, decaffeinated coffee, or no coffee (i.e., water) for 8 weeks. Results: Average age was 40 years and body mass index was 29.5 kg/m(2). Compared with consuming no coffee, consumption of caffeinated coffee increased adiponectin (difference in change from baseline 1.4 mu g/mL; 95% CI: 0.2, 2.7) and interleukin-6 (difference: 60%; 95% CI: 8, 138) concentrations and consumption of decaffeinated coffee decreased fetuin-A concentrations (difference: -20%; 95% CI: -35, -1). For measures of glucose tolerance, insulin sensitivity, and insulin secretion, no significant differences were found between treatment groups. Conclusions: Although no changes in glycemia and/or insulin sensitivity were observed after 8 weeks of coffee consumption, improvements in adipocyte and liver function as indicated by changes in adiponectin and fetuin-A concentrations may contribute to beneficial metabolic effects of long-term coffee consumption. C1 [Wedick, Nicole M.; Sun, Qi; Hu, Frank B.; van Dam, Rob M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Brennan, Aoife M.; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Hu, Frank B.; van Dam, Rob M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Sun, Qi; Hu, Frank B.; van Dam, Rob M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA 02115 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Wedick, NM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM nwedick@hsph.harvard.edu RI van Dam, Rob/F-9674-2010 OI van Dam, Rob/0000-0002-7354-8734 FU Boston Obesity Nutrition Research Center [2005-P-000377/2]; National Center for Research Resources [UL1RR025758] FX We gratefully thank the participants of the Coffee Trial for their participation and the General Clinical Research Center nurses and nutritionists at Beth Israel Deaconess Medical Center for their invaluable contribution to the conduct of the trial. We are grateful to David J. Greenblatt (Tufts University School of Medicine and Tufts Medical Center, Boston, MA) for measurement of caffeine concentrations, Peter C. Hollman and Dini Venema (RIKILT Institute of Food Safety, Wageningen, The Netherlands) for the measurement of chlorogenic acid, and Sandy Slow (Canterbury Health Laboratories, Christchurch, New Zealand) for the measurement of trigonelline. The research for this study was financially supported by a Boston Obesity Nutrition Research Center pilot and feasibility grant (grant#: 2005-P-000377/2) and by Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The clinical trial registration number is NCT00305097. The coffee was supplied by Nestle. NR 29 TC 50 Z9 50 U1 5 U2 41 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD SEP 13 PY 2011 VL 10 AR 93 DI 10.1186/1475-2891-10-93 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 826TJ UT WOS:000295377300002 PM 21914162 ER PT J AU Tucker, JD Peng, H Wang, KD Chang, H Zhang, SM Yang, LG Yang, B AF Tucker, Joseph D. Peng, Hua Wang, Kaidi Chang, Helena Zhang, Sen-Miao Yang, Li-Gang Yang, Bin TI Female Sex Worker Social Networks and STI/HIV Prevention in South China SO PLOS ONE LA English DT Article ID HIV PREVENTION; ENTERTAINMENT WORKERS; MIGRANT WORKERS; RISK-FACTORS; YUNNAN PROVINCE; KAIYUAN CITY; INFECTION; BEHAVIOR; INTERVENTION; HEALTH AB Background: Reducing harm associated with selling and purchasing sex is an important public health priority in China, yet there are few examples of sustainable, successful programs to promote sexual health among female sex workers. The limited civil society and scope of nongovernmental organizations circumscribe the local capacity of female sex workers to collectively organize, advocate for their rights, and implement STI/HIV prevention programs. The purpose of this study was to examine social networks among low-income female sex workers in South China to determine their potential for sexual health promotion. Methods/Principal Findings: Semi-structured interviews with 34 low-income female sex workers and 28 health outreach members were used to examine how social relationships affected condom use and negotiation, STI/HIV testing and health-seeking behaviors, and dealing with violent clients. These data suggested that sex worker's laoxiang (hometown social connections) were more powerful than relationships between women selling sex at the same venue in establishing the terms and risk of commercial sex. Female sex workers from the same hometown often migrated to the city with their laoxiang and these social connections fulfilled many of the functions of nongovernmental organizations, including collective mobilization, condom promotion, violence mitigation, and promotion of health-seeking behaviors. Outreach members observed that sex workers accompanied by their laoxiang were often more willing to accept STI/HIV testing and trust local sexual health services. Conclusions/Significance: Organizing STI/HIV prevention services around an explicitly defined laoxiang social network may provide a strong foundation for sex worker health programs. Further research on dyadic interpersonal relationships between female sex workers, group dynamics and norm establishment, and the social network characteristics are needed. C1 [Tucker, Joseph D.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Tucker, Joseph D.; Peng, Hua; Zhang, Sen-Miao; Yang, Li-Gang; Yang, Bin] Guangdong Prov STD Control Ctr, Guangzhou, Guangdong, Peoples R China. [Wang, Kaidi] Harvard Univ, Sch Med, Boston, MA USA. [Chang, Helena] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. EM jtucker4@partners.org FU National Institutes of Health [US NIH 1K01TW008200-01A1]; Harvard Institute for Global Health FX Support for this research came from an National Institutes of Health Fogarty K01 Award (US NIH 1K01TW008200-01A1) and the Harvard Institute for Global Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 15 Z9 16 U1 0 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 13 PY 2011 VL 6 IS 9 AR e24816 DI 10.1371/journal.pone.0024816 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 825ZV UT WOS:000295321800067 PM 21931856 ER PT J AU Taguchi, A Politi, K Pitteri, SJ Lockwood, WW Faca, VM Kelly-Spratt, K Wong, CH Zhang, Q Chin, A Park, KS Goodman, G Gazdar, AF Sage, J Dinulescu, DM Kucherlapati, R DePinho, RA Kemp, CJ Varmus, HE Hanash, SM AF Taguchi, Ayumu Politi, Katerina Pitteri, Sharon J. Lockwood, William W. Faca, Vitor M. Kelly-Spratt, Karen Wong, Chee-Hong Zhang, Qing Chin, Alice Park, Kwon-Sik Goodman, Gary Gazdar, Adi F. Sage, Julien Dinulescu, Daniela M. Kucherlapati, Raju DePinho, Ronald A. Kemp, Christopher J. Varmus, Harold E. Hanash, Samir M. TI Lung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models SO CANCER CELL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; OVARIAN-CANCER; CELL-ADHESION; CLINICOPATHOLOGICAL FEATURES; IMPROVE DETECTION; FACTOR RECEPTOR; SERUM-PROTEINS; K-RAS; MICE; ADENOCARCINOMAS AB We investigated the potential of in-depth quantitative proteomics to reveal plasma protein signatures that reflect lung tumor biology. We compared plasma protein profiles of four mouse models of lung cancer with profiles of models of pancreatic, ovarian, colon, prostate, and breast cancer and two models of inflammation. A protein signature for Titf1/Nkx2-1, a known lineage-survival oncogene in lung cancer, was found in plasmas of mouse models of lung adenocarcinoma. An EGFR signature was found in plasma of an EGFR mutant model, and a distinct plasma signature related to neuroendocrine development was uncovered in the small-cell lung cancer model. We demonstrate relevance to human lung cancer of the protein signatures identified on the basis of mouse models. C1 [Taguchi, Ayumu; Pitteri, Sharon J.; Faca, Vitor M.; Kelly-Spratt, Karen; Wong, Chee-Hong; Zhang, Qing; Chin, Alice; Goodman, Gary; Kemp, Christopher J.; Hanash, Samir M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Politi, Katerina; Lockwood, William W.; Varmus, Harold E.] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10021 USA. [Park, Kwon-Sik; Sage, Julien] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Dinulescu, Daniela M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Eugene Braunwald Res Ctr,Dept Pathol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Dana Farber Canc Inst, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med, Belfer Inst Appl Canc Sci,Dept Med Oncol, Boston, MA 02115 USA. RP Hanash, SM (reprint author), Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. EM shanash@fhcrc.org RI Xiao, Yang/B-5668-2012; Faca, Vitor/A-3989-2013; OI FACA, VITOR MARCEL/0000-0003-3205-7944; Pitteri, Sharon/0000-0002-3119-873X FU National Cancer Institute; Canary Foundation; Labrecque Foundation; Uniting Against Lung Cancer Foundation; Department of Defense (DOD) [W81XWH-10-1-0263]; Burroughs Wellcome; V Foundation; Mary Kay Ash Foundation; Rivkin Foundation FX Funding support was provided by the National Cancer Institute's Mouse Models of Human Cancer program; the Canary, Labrecque, and Uniting Against Lung Cancer Foundations; and the Department of Defense (DOD) Congressionally Mandated Lung Cancer Research program. K.S.P. is a Parker B. Francis Fellow. D.M.D. is supported by the DOD (grant no. W81XWH-10-1-0263) and by the Burroughs Wellcome, V Foundation, Mary Kay Ash, and Rivkin Foundations. The authors declare no competing financial interests. NR 55 TC 94 Z9 95 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 13 PY 2011 VL 20 IS 3 BP 289 EP 299 DI 10.1016/j.ccr.2011.08.007 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 824MJ UT WOS:000295205700006 PM 21907921 ER PT J AU De Raedt, T Walton, Z Yecies, JL Li, DA Chen, YM Malone, CF Maertens, O Jeong, SM Bronson, RT Lebleu, V Kalluri, R Normant, E Haigis, MC Manning, BD Wong, KK Macleod, KF Cichowski, K AF De Raedt, Thomas Walton, Zandra Yecies, Jessica L. Li, Danan Chen, Yimei Malone, Clare F. Maertens, Ophelia Jeong, Seung Min Bronson, Roderick T. Lebleu, Valerie Kalluri, Raghu Normant, Emmanuel Haigis, Marcia C. Manning, Brendan D. Wong, Kwok-Kin Macleod, Kay F. Cichowski, Karen TI Exploiting Cancer Cell Vulnerabilities to Develop a Combination Therapy for Ras-Driven Tumors SO CANCER CELL LA English DT Article ID ENDOPLASMIC-RETICULUM-STRESS; UNFOLDED PROTEIN RESPONSE; NEUROFIBROMATOSIS TYPE-1 GENE; OXIDATIVE STRESS; LUNG-CANCER; MUTATIONS; AUTOPHAGY; HSP90; SUPPRESSOR; REVEALS AB Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations. C1 [De Raedt, Thomas; Malone, Clare F.; Maertens, Ophelia; Wong, Kwok-Kin; Cichowski, Karen] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [De Raedt, Thomas; Walton, Zandra; Yecies, Jessica L.; Li, Danan; Malone, Clare F.; Maertens, Ophelia; Bronson, Roderick T.; Lebleu, Valerie; Kalluri, Raghu; Manning, Brendan D.; Wong, Kwok-Kin; Cichowski, Karen] Harvard Univ, Sch Med, Boston, MA 02115 USA. [De Raedt, Thomas; Wong, Kwok-Kin; Cichowski, Karen] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. [Walton, Zandra; Li, Danan] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yecies, Jessica L.; Manning, Brendan D.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Chen, Yimei; Macleod, Kay F.] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. [Jeong, Seung Min; Haigis, Marcia C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lebleu, Valerie; Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Div Matrix Biol, Boston, MA 02115 USA. [Normant, Emmanuel] Infin Pharmaceut, Cambridge, MA 02139 USA. RP Cichowski, K (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM kcichowski@rics.bwh.harvard.edu RI Kalluri, Raghu/E-2677-2015; OI Kalluri, Raghu/0000-0002-2190-547X; wong, kwok kin/0000-0001-6323-235X FU NCI [CA129814]; Ludwig Center at DF/HCC [CA122794, CA140594]; Children's Tumor Foundation; Research Foundation Flanders (FWO) FX We thank Wade Harper, Steve Elledge, Nathanael Gray, Heather Harding, and Hugues de The for helpful discussions. This work was supported by the NCI KC: (CA129814) and the Ludwig Center at DF/HCC; KWW: (CA122794, CA140594). TD is a recipient of the Young Investigator Award of the Children's Tumor Foundation. OM is a Postdoctoral Fellow of the Research Foundation Flanders (FWO). NR 52 TC 96 Z9 97 U1 2 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 13 PY 2011 VL 20 IS 3 BP 400 EP 413 DI 10.1016/j.ccr.2011.08.014 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 824MJ UT WOS:000295205700014 PM 21907929 ER PT J AU Pyati, UJ Gjini, E Carbonneau, S Lee, JS Guo, F Jette, CA Kelsell, DP Look, AT AF Pyati, Ujwal J. Gjini, Evisa Carbonneau, Seth Lee, Jeong-Soo Guo, Feng Jette, Cicely A. Kelsell, David P. Look, A. Thomas TI p63 Mediates an Apoptotic Response to Pharmacological and Disease-Related ER Stress in the Developing Epidermis SO DEVELOPMENTAL CELL LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; PROGRAMMED CELL-DEATH; TRANSCRIPTION FACTOR; TRANSMEMBRANE PROTEIN; MESSENGER-RNA; MAMMALIAN-CELLS; GENE-EXPRESSION; P53 FAMILY; ZEBRAFISH AB Endoplasmic reticulum (ER) stress triggers tissue-specific responses that culminate in either cellular adaptation or apoptosis, but the genetic networks distinguishing these responses are not well understood. Here we demonstrate that ER stress induced in the developing zebrafish causes rapid apoptosis in the brain, spinal cord, tail epidermis, lens, and epiphysis. Focusing on the tail epidermis, we uncover an apoptotic response that depends on Puma, but not on p53 or Chop. puma is transcriptionally activated during this ER stress response in a p53-independent manner, and is an essential mediator of epidermal apoptosis. We demonstrate that the p63 transcription factor is upregulated to initiate this apoptotic pathway and directly activates puma transcription in response to ER stress. We also show that a mutation of human Connexin 31, which causes erythrokeratoderma variabilis, induces ER stress and p63-dependent epidermal apoptosis in the zebrafish embryo, thus implicating this pathway in the pathogenesis of inherited disease. C1 [Pyati, Ujwal J.; Gjini, Evisa; Carbonneau, Seth; Lee, Jeong-Soo; Guo, Feng; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Pyati, Ujwal J.; Gjini, Evisa; Carbonneau, Seth; Lee, Jeong-Soo; Guo, Feng; Look, A. Thomas] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Jette, Cicely A.] Huntsman Canc Inst, Dept Oncol Sci, Salt Lake City, UT 84112 USA. [Kelsell, David P.] Queen Mary Univ London, Ctr Cutaneous Res, Inst Cell & Mol Sci, Barts & London Sch Med & Dent, London E1 2AT, England. RP Gjini, E (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM evisa_gjini@dfci.harvard.edu; thomas_look@dfci.harvard.edu FU Alex's Lemonade Stand Foundation; NIH [3R01CA119066-04S1, R01CA119066] FX We thank John Gilbert, Elspeth Payne, and Samuel Sidi for critical readings of the manuscript. Confocal microscopy images for this study were acquired in the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute with the assistance of Lisa Cameron. U.J.P. was supported by the Alex's Lemonade Stand Foundation Young Investigator Award, U.J.P. and S.C. by NIH 3R01CA119066-04S1, and A.T.L. by NIH R01CA119066. NR 51 TC 23 Z9 23 U1 0 U2 4 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 SEP 13 PY 2011 VL 21 IS 3 BP 492 EP 505 DI 10.1016/j.devcel.2011.07.012 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 822PA UT WOS:000295060900014 PM 21920315 ER PT J AU O'Brien, TX AF O'Brien, Terrence X. TI Iron Metabolism, Anemia, and Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE anemia; heart failure; iron ID MORTALITY C1 [O'Brien, Terrence X.] Med Univ S Carolina, Charleston, SC 29425 USA. [O'Brien, Terrence X.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP O'Brien, TX (reprint author), Med Univ S Carolina, 25 Courtenay Dr,ART 7063, Charleston, SC 29425 USA. EM obriente@musc.edu NR 11 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 13 PY 2011 VL 58 IS 12 BP 1252 EP 1253 DI 10.1016/j.jacc.2011.03.060 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 816NP UT WOS:000294609400011 PM 21903059 ER PT J AU DeSantis, SM Toole, JM Kratz, JM Uber, WE Wheat, MJ Stroud, MR Ikonomidis, JS Spinale, FG AF DeSantis, Stacia M. Toole, J. Matthew Kratz, John M. Uber, Walter E. Wheat, Margaret J. Stroud, Martha R. Ikonomidis, John S. Spinale, Francis G. TI Early Postoperative Outcomes and Blood Product Utilization in Adult Cardiac Surgery The Post-Aprotinin Era SO CIRCULATION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Heart-Association CY NOV 12-16, 2010 CL Chicago, IL SP Amer Heart Assoc DE aprotinin; cardiac surgery; blood products; bleeding; postoperative outcomes ID CORONARY-ARTERY-BYPASS; RANDOMIZED CLINICAL-TRIALS; GRAFT-SURGERY; RISK; METAANALYSIS; MORTALITY; SAFETY; COHORT; PUMP AB Background-Aprotinin was a commonly used pharmacological agent for homeostasis in cardiac surgery but was discontinued, resulting in the extensive use of lysine analogues. This study tested the hypothesis that early postoperative adverse events and blood product utilization would affected in this post-aprotinin era. Methods and Results-Adult patients (n = 781) undergoing coronary artery bypass, valve replacement, or both from November 1, 2005, to October 31, 2008, at a single institution were included. Multiple logistic regression modeling and propensity scoring were performed on 29 preoperative and intraoperative variables in patients receiving aprotinin (n = 325) or lysine analogues (n = 456). The propensity-adjusted relative risk (RR) for the intraoperative use of packed red blood cells (RR, 0.75; 95% confidence interval [CI], 0.57 to 0.99), fresh frozen plasma (RR, 0.37; 95% CI, 0.21 to 0.64), and cryoprecipitate (RR: 0.06; 95% CI, 0.02 to 0.22) were lower in the aprotinin versus lysine analog group (all P < 0.05). The risk for mortality (RR, 0.53; 95% CI, 0.16 to 1.79) and neurological events (RR, 0.87; 95% CI, 0.35 to 2.18) remained similar between groups, whereas a trend for reduced risk for renal dysfunction was observed in the aprotinin group. Conclusions-In the post-aprotinin era, with the exclusive use of lysine analogues, the relative risk of early postoperative outcomes such as mortality and renal dysfunction have not improved, but the risk for the intraoperative use of blood products has increased. Thus, improvements in early postoperative outcomes have not been realized with the discontinued use of aprotinin, but rather increased blood product use has occurred with the attendant costs and risks inherent with this strategy. (Circulation. 2011; 124[suppl 1]: S62-S69.) C1 [Toole, J. Matthew; Kratz, John M.; Stroud, Martha R.; Ikonomidis, John S.; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29403 USA. [DeSantis, Stacia M.] Med Univ S Carolina, Dept Biostat & Epidemiol, Charleston, SC 29403 USA. [Uber, Walter E.; Wheat, Margaret J.] Med Univ S Carolina, Dept Pharm Serv, Charleston, SC 29403 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. RP Spinale, FG (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, 114 Doughty St, Charleston, SC 29403 USA. EM wilburnm@musc.edu FU NHLBI NIH HHS [HL59165, R01 HL059165, R42 HL099258] NR 30 TC 13 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 13 PY 2011 VL 124 IS 11 SU 1 BP S62 EP S69 DI 10.1161/CIRCULATIONAHA.110.002543 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818VB UT WOS:000294782800008 PM 21911820 ER PT J AU Dixon, JA Gorman, RC Stroud, RE Mukherjee, R Meyer, EC Baker, NL Morita, M Hamamoto, H Ryan, LP Gorman, JH Spinale, FG AF Dixon, Jennifer A. Gorman, Robert C. Stroud, Robert E. Mukherjee, Rupak Meyer, Evan C. Baker, Nathaniel L. Morita, Masato Hamamoto, Hirotsugu Ryan, Liam P. Gorman, Joseph H., III Spinale, Francis G. TI Targeted Regional Injection of Biocomposite Microspheres Alters Post-Myocardial Infarction Remodeling and Matrix Proteolytic Pathways SO CIRCULATION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Heart-Association CY NOV 12-16, 2010 CL Chicago, IL SP Amer Heart Assoc DE infarct expansion; matrix metalloproteinase; tissue inhibitor of matrix metalloproteinases ID LEFT-VENTRICULAR FUNCTION; MYOCARDIAL-INFARCTION; HEART-FAILURE; CARDIAC FIBROSIS; TGF-BETA; MICRORNAS; EXPANSION; METALLOPROTEINASES; WALL; CARDIOMYOPATHY AB Background-Although localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse left ventricular (LV) remodeling after myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]) and would be associated with parameters of post-MI LV remodeling. Methods and Results-MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n = 6) or 2.6 mL of CHAM (n = 5) or saline (n = 13) and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks after MI. LV EDV decreased with 2.6 mL CHAM versus MI only (105.4 +/- 7.5 versus 80.6 +/- 4.2 respectively, P < 0.05) but not with 1.3 mL CHAM (94.5 +/- 5.0, P = 0.32). However, MI thickness increased by 2-fold in both CHAM groups compared with MI only (P < 0.05). MMP-13 increased 40-fold in the MI only group (P < 0.05) but fell by >6-fold in both CHAM groups (P < 0.05). MMP-7 increased approximately 1.5-fold in the MI only group (P < 0.05) but decreased to referent control values in both CHAM groups in the MI region (P < 0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared with MI only (P < 0.05). Conclusions-Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injection of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacological or cellular therapies. (Circulation. 2011; 124[suppl 1]:S35-S45.) C1 [Dixon, Jennifer A.; Stroud, Robert E.; Mukherjee, Rupak; Meyer, Evan C.; Baker, Nathaniel L.; Spinale, Francis G.] Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Gorman, Robert C.; Morita, Masato; Hamamoto, Hirotsugu; Ryan, Liam P.; Gorman, Joseph H., III] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Gorman, Robert C.; Morita, Masato; Hamamoto, Hirotsugu; Ryan, Liam P.; Gorman, Joseph H., III] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Spinale, FG (reprint author), Strom Thurmond Res Ctr, 114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU NHLBI NIH HHS [HL63954, R01 HL063954, HL73021, R01 HL059165-12, HL59165, HL57952, HL95608, R01 HL057952-12, P01 HL078825, R01 HL073021, R01 HL059165, R01 HL063954-12, R01 HL095608, R01 HL095608-03, R01 HL057952, HL78825, R01 HL073021-08] NR 41 TC 6 Z9 6 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 13 PY 2011 VL 124 IS 11 SU 1 BP S35 EP S45 DI 10.1161/CIRCULATIONAHA.111.035774 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818VB UT WOS:000294782800005 PM 21911817 ER PT J AU Aung, T Chapuy, B Vogel, D Wenzel, D Oppermann, M Lahmann, M Weinhage, T Menck, K Hupfeld, T Koch, R Trumper, L Wulf, GG AF Aung, Thiha Chapuy, Bjoern Vogel, Daniel Wenzel, Dirk Oppermann, Martin Lahmann, Marlen Weinhage, Toni Menck, Kerstin Hupfeld, Timo Koch, Raphael Truemper, Lorenz Wulf, Gerald G. TI Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TUMOR-DERIVED EXOSOMES; MULTIVESICULAR BODIES; MULTIDRUG-RESISTANCE; TRANSFERRIN RECEPTOR; MEMBRANE-VESICLES; DRUG-RESISTANCE; II CELLS; RITUXIMAB; ABCA3 AB Targeting the surface of malignant cells has evolved into a cornerstone in cancer therapy, paradigmatically introduced by the success of humoral immunotherapy against CD20 in malignant lymphoma. However, tumor cell susceptibility to immunochemotherapy varies, with mostly a fatal outcome in cases of resistant disease. Here, we show that lymphoma exosomes shield target cells from antibody attack and that exosome biogenesis is modulated by the lysosome-related organelle-associated ATP-binding cassette (ABC) transporter A3 (ABCA3). B-cell lymphoma cells released exosomes that carried CD20, bound therapeutic anti-CD20 antibodies, consumed complement, and protected target cells from antibody attack. ABCA3, previously shown to mediate resistance to chemotherapy, was critical for the amounts of exosomes released, and both pharmacological blockade and the silencing of ABCA3 enhanced susceptibility of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion. C1 [Aung, Thiha; Chapuy, Bjoern; Vogel, Daniel; Lahmann, Marlen; Weinhage, Toni; Menck, Kerstin; Hupfeld, Timo; Koch, Raphael; Truemper, Lorenz; Wulf, Gerald G.] Univ Gottingen, Dept Hematol & Oncol, D-37075 Gottingen, Germany. [Chapuy, Bjoern] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wenzel, Dirk] Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany. [Oppermann, Martin] Univ Gottingen, Dept Cellular & Mol Immunol, D-37073 Gottingen, Germany. RP Wulf, GG (reprint author), Univ Gottingen, Dept Hematol & Oncol, D-37075 Gottingen, Germany. EM gwulf@med.uni-goettingen.de OI Menck, Kerstin/0000-0002-8188-0163; Weinhage, Toni/0000-0003-4337-9260 FU Deutsche Forschungsgemeinschaft [DFG Wu 310/3-1]; University Medicine Goettingen FX We thank Sabrina Becker of the Flow Cytometry Core Facility at the University of Goettingen. This work was supported by the Deutsche Forschungsgemeinschaft Grant DFG Wu 310/3-1 (to G.G.W.) and by a University Medicine Goettingen Jacob-Henle program grant (to T.A.). NR 55 TC 58 Z9 61 U1 4 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 SEP 13 PY 2011 VL 108 IS 37 BP 15336 EP 15341 DI 10.1073/pnas.1102855108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DF UT WOS:000294804900069 PM 21873242 ER PT J AU Song, JW Munn, LL AF Song, Jonathan W. Munn, Lance L. TI Fluid forces control endothelial sprouting SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 3D angiogenesis on a chip; collagen gel; structural remodeling; alternative to animal model; vessel analog ID LAMINAR SHEAR-STRESS; NITRIC-OXIDE; CAPILLARY MORPHOGENESIS; CELL PROLIFERATION; INTERSTITIAL FLOW; TUMOR VASCULATURE; TIP CELLS; IN-VITRO; ANGIOGENESIS; GROWTH AB During angiogenesis, endothelial cells (ECs) from intact blood vessels quickly infiltrate avascular regions via vascular sprouting. This process is fundamental to many normal and pathological processes such as wound healing and tumor growth, but its initiation and control are poorly understood. Vascular endothelial cell growth factor (VEGF) can promote vessel dilation and angiogenic sprouting, but given the complex nature of vascular morphogenesis, additional signals are likely necessary to determine, for example, which vessel segments sprout, which dilate, and which remain quiescent. Fluid forces exerted by blood and plasma are prime candidates that might codirect these processes, but it is not known whether VEGF cooperates with mechanical fluid forces to mediate angiogenesis. Using a microfluidic tissue analog of angiogenic sprouting, we found that fluid shear stress, such as exerted by flowing blood, attenuates EC sprouting in a nitric oxide-dependent manner and that interstitial flow, such as produced by extravasating plasma, directs endothelial morphogenesis and sprout formation. Furthermore, positive VEGF gradients initiated sprouting but negative gradients inhibited sprouting, promoting instead sheet-like migration analogous to vessel dilation. These results suggest that ECs integrate signals from fluid forces and local VEGF gradients to achieve such varied goals as vessel dilation and sprouting. C1 [Munn, Lance L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Munn, LL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Charlestown, MA 02129 USA. EM munn@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016; Song, Jonathan/C-1922-2013 OI Munn, Lance/0000-0003-0698-7232; Song, Jonathan/0000-0002-6991-5298 FU National Cancer Institute FX We are grateful to P. Au, G. Cheng, and J. Tse for performing the retroviral transfections of the HUVECs provided to us by the Center for Vascular Excellence at Brigham and Women's Hospital. We thank R. Samuel for her assistance with counting filopodia, A. Jain for helpful discussions, and R. Jain for his invaluable insight and suggestions. Funding was provided by the National Cancer Institute (L.L.M). NR 50 TC 142 Z9 144 U1 5 U2 76 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 13 PY 2011 VL 108 IS 37 BP 15342 EP 15347 DI 10.1073/pnas.1105316108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DF UT WOS:000294804900070 PM 21876168 ER PT J AU Ilic, N Utermark, T Widlund, HR Roberts, TM AF Ilic, Nina Utermark, Tamara Widlund, Hans R. Roberts, Thomas M. TI PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; CHRONIC MYELOID-LEUKEMIA; CAP-BINDING PROTEIN; CELL LUNG-CANCER; C-MYC; BCR-ABL; PHOSPHATIDYLINOSITOL 3-KINASES; TRASTUZUMAB RESISTANCE; INCREASED EXPRESSION; MET AMPLIFICATION AB The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5' cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs. C1 [Ilic, Nina; Utermark, Tamara; Roberts, Thomas M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02115 USA. [Widlund, Hans R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. RP Roberts, TM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02115 USA. EM thomas_roberts@dfci.harvard.edu FU Department of Defense Breast [W81XWH-08-1-0747]; National Institutes of Health [CA089393, CA030002, CA89021]; Stand Up to Cancer FX The authors thank Dr. Edward Fox and the Dana-Farber Cancer Institute Microarray Core for excellent assistance with microarray studies and SOLiD sequencing, Dr. Julien Senechal for FACS operation, and Dr. Malcolm Whitman for helpful advice regarding lipid kinase assays. We are grateful to Drs. Daniel Silver and Linda Clayton for critical comments on the manuscript. We thank the Cytogenetics Core of Dana-Farber Harvard Cancer Center (P30 CA006516) for performing FISH analysis. This work was supported by Department of Defense Breast Cancer Research Program Pre-doctoral Fellowship W81XWH-08-1-0747 (to N.I.); National Institutes of Health Grants CA089393 (to T. M. R.), CA030002 (to T. M. R.), and CA89021 (to T. M. R.); and Stand Up to Cancer (to T.M.R.). NR 52 TC 104 Z9 105 U1 2 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 13 PY 2011 VL 108 IS 37 BP E699 EP U607 DI 10.1073/pnas.1108237108 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DF UT WOS:000294804900008 PM 21876152 ER PT J AU Sedaghat, AR Wilke, CO AF Sedaghat, Ahmad R. Wilke, Claus O. TI Kinetics of the viral cycle influence pharmacodynamics of antiretroviral therapy SO BIOLOGY DIRECT LA English DT Article DE HIV; viral dynamics; HAART; antiretroviral therapy; viral life cycle; pharmacodynamics; IC50 ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VITRO; REVERSE-TRANSCRIPTASE; PROTEASE INHIBITORS; DRUG SUSCEPTIBILITY; CLEARANCE RATE; HIV; TYPE-1; DYNAMICS; REPLICATION AB Background: More and more antiretroviral therapies are being developed for treatment of HIV infection. The in-vivo efficacy of these drugs is commonly predicted based on in-vitro measures of antiviral effect. One primary invitro measure is the IC50, the amount of drug required for 50% inhibition of viral replication. We have previously shown that HIV life-cycle kinetics impact clinically observed HIV viral dynamics. Here we present a mathematical model of how they affect the pharmacodynamics of antiretroviral drugs. Results: We find that experimentally measured antiretroviral IC50s are determined by three factors: (i) intrinsic drug properties (e. g. drug-target binding), (ii) kinetics of the HIV life cycle, and (iii) kinetics of drug-inhibited infected cells. Our model predicts that the IC50 is a declining function of the duration of the drug-susceptible stage in the host cell. We combine our model with known viral life-cycle kinetics to derive a measure of intrinsic properties, reflecting drug action, for known antiretroviral drugs from previously measured IC50s. We show that this measure of intrinsic drug property correlates very well with in vitro-measured antiviral activity, whereas experimentally measured IC50 does not. Conclusions: Our results have implications for understanding pharmacodynamics of and improving activity of antiretroviral drugs. Our findings predict that drug activity can be improved through co-administration of synergistic drugs that delay the viral life cycle but are not inhibitory by themselves. Moreover, our results may easily extend to treatment of other pathogens. C1 [Sedaghat, Ahmad R.] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Wilke, Claus O.] Univ Texas Austin, Sect Integrat Biol, Ctr Computat Biol & Bioinformat, Austin, TX 78712 USA. [Wilke, Claus O.] Univ Texas Austin, Inst Cell & Mol Biol, Austin, TX 78712 USA. RP Sedaghat, AR (reprint author), Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. EM ahmad_sedaghat@meei.harvard.edu RI Wilke, Claus/B-4643-2008 OI Wilke, Claus/0000-0002-7470-9261 FU NIH [R01 GM088344] FX The authors would like to thank Robert F. Siliciano for critical reading of and feedback regarding this manuscript. This work was supported in part by NIH grant R01 GM088344 to C.O.W. NR 33 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD SEP 12 PY 2011 VL 6 AR 42 DI 10.1186/1745-6150-6-42 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 832XX UT WOS:000295845200001 PM 21910865 ER PT J AU Grady, D Berkowitz, SA Katz, MH AF Grady, Deborah Berkowitz, Seth A. Katz, Mitchell H. TI Opioids for Chronic Pain SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID CHRONIC NONCANCER PAIN; THERAPY; PRESCRIPTIONS; MANAGEMENT; OVERDOSE C1 [Grady, Deborah; Berkowitz, Seth A.] Univ Calif San Francisco, Gen Internal Med Sect, San Francisco VA Med Ctr, San Francisco, CA 94115 USA. [Grady, Deborah; Berkowitz, Seth A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA. [Katz, Mitchell H.] Dept Hlth Serv, Los Angeles, CA USA. RP Grady, D (reprint author), Univ Calif San Francisco, Gen Internal Med Sect, San Francisco VA Med Ctr, 1635 Divisadero St,Ste 600, San Francisco, CA 94115 USA. OI Berkowitz, Seth/0000-0003-1030-4297 NR 14 TC 20 Z9 20 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2011 VL 171 IS 16 BP 1426 EP 1427 DI 10.1001/archinternmed.2011.213 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819KY UT WOS:000294825100001 PM 21670333 ER PT J AU Steinman, MA AF Steinman, Michael A. TI Using Patients to Promote Evidence-Based Prescribing SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Steinman, MA (reprint author), San Francisco VA Med Ctr, 4150 Clement St,POB 181G, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu FU NIA NIH HHS [K23 AG030999] NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2011 VL 171 IS 16 BP 1468 EP 1469 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 819KY UT WOS:000294825100009 PM 21911630 ER PT J AU Fihn, SD Bucher, JB McDonell, M Diehr, P Rumsfeld, JS Doak, M Dougherty, C Gerrity, M Heidenreich, P Larsen, G Lee, PI Lucas, L McBryde, C Nelson, K Plomondon, ME Stadius, M Bryson, C AF Fihn, Stephan D. Bucher, Joy B. McDonell, Mary Diehr, Paula Rumsfeld, John S. Doak, Melanie Dougherty, Cynthia Gerrity, Martha Heidenreich, Paul Larsen, Greg Lee, Peter I. Lucas, Linda McBryde, Connor Nelson, Karin Plomondon, Mary E. Stadius, Michael Bryson, Christopher TI Collaborative Care Intervention for Stable Ischemic Heart Disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-ARTERY-DISEASE; AMERICAN-COLLEGE; STATIN THERAPY; MANAGEMENT; HEALTH; ANGINA; POPULATION; DEPRESSION; GUIDELINES; MORTALITY AB Background: Accumulating evidence suggests that collaborative models of care enhance communication among primary care providers, improving quality of care and outcomes for patients with chronic conditions. We sought to determine whether a multifaceted intervention that used a collaborative care model and was directed through primary care providers would improve symptoms of angina, self-perceived health, and concordance with practice guidelines for managing chronic stable angina. Methods: We conducted a prospective trial, cluster randomized by provider, involving patients with symptomatic ischemic heart disease recruited from primary care clinics at 4 academically affiliated Department of Veterans Affairs health care systems. Primary end points were changes over 12 months in symptoms on the Seattle Angina Questionnaire, self-perceived health, and concordance with practice guidelines. Results: In total, 183 primary care providers and 703 patients participated in the study. Providers accepted and implemented 91.6% of 701 recommendations made by collaborative care teams. Almost half were related to medications, including adjustments to beta-blockers, long-acting nitrates, and statins. The intervention did not significantly improve symptoms of angina or selfperceived health, although end points favored collaborative care for 10 of 13 prespecified measures. While concordance with practice guidelines improved 4.5% more among patients receiving collaborative care than among those receiving usual care (P<.01), this was mainly because of increased use of diagnostic testing rather than increased use of recommended medications. Conclusion: A collaborative care intervention was well accepted by primary care providers and modestly improved receipt of guideline-concordant care but not symptoms or self-perceived health in patients with stable angina. C1 [Fihn, Stephan D.; Bucher, Joy B.; McDonell, Mary; Diehr, Paula; Dougherty, Cynthia; Nelson, Karin; Stadius, Michael; Bryson, Christopher] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98101 USA. [Fihn, Stephan D.; Nelson, Karin; Bryson, Christopher] Univ Washington, Dept Med, Seattle, WA USA. [Diehr, Paula] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Dougherty, Cynthia] Univ Washington, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Bucher, Joy B.] Virginia Mason Med Ctr, Dept Primary Care, Seattle, WA 98101 USA. [Rumsfeld, John S.; McBryde, Connor; Plomondon, Mary E.] Univ Colorado, VA Eastern Colorado Hlth Care Syst, Denver, CO 80202 USA. [Doak, Melanie; Gerrity, Martha; Larsen, Greg; Lucas, Linda] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. [Doak, Melanie; Gerrity, Martha; Larsen, Greg; Lucas, Linda] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Heidenreich, Paul; Lee, Peter I.] Stanford Univ, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Heidenreich, Paul; Lee, Peter I.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. RP Fihn, SD (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1100 Olive Way,Ste 1400, Seattle, WA 98101 USA. EM stephan.fihn@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [IHI 02-062, RCD 03-177] FX This work was supported by grant IHI 02-062 from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (Drs Fihn, Rumsfeld, Heidenreich, and Gerrity). Dr Bryson was supported by Career Development Award RCD 03-177 from the same funding source. NR 27 TC 17 Z9 17 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2011 VL 171 IS 16 BP 1471 EP 1479 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 819KY UT WOS:000294825100011 PM 21911632 ER PT J AU Cho, E Curhan, G Hankinson, SE Kantoff, P Atkins, MB Stampfer, M Choueiri, TK AF Cho, Eunyoung Curhan, Gary Hankinson, Susan E. Kantoff, Philip Atkins, Michael B. Stampfer, Meir Choueiri, Toni K. TI Prospective Evaluation of Analgesic Use and Risk of Renal Cell Cancer SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PRIMARY PREVENTION; UNITED-STATES; CARDIOVASCULAR EVENTS; ASPIRIN; WOMEN; METAANALYSIS; DISEASE; ACETAMINOPHEN; PARACETAMOL AB Background: Epidemiologic data suggest that analgesic use increases the risk of renal cell cancer (RCC), but few prospective studies have been published. We investigated the association between analgesic use and RCC in 2 large prospective studies. Methods: We examined the relationship between analgesic use and RCC risk in the Nurses' Health Study and the Health Professionals Follow-up Study. Use of aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen was ascertained in 1990 in the Nurses' Health Study and in 1986 in the Health Professionals Follow-up Study, and every 2 years thereafter. We evaluated baseline and duration of use of analgesics. Results: During follow-up of 16 years among 77 525 women and 20 years among 49 403 men, we documented 333 RCC cases. Aspirin and acetaminophen use were not associated with RCC risk. However, regular use of nonaspirin NSAIDs was associated with an increased RCC risk; the pooled multivariate relative risk was 1.51 (95% confidence interval, 1.12-2.04) at baseline. The absolute risk differences for users vs nonusers of nonaspirin NSAIDs were 9.15 per 100 000 person-years in women and 10.92 per 100 000 person-years in men. There was a dose-response relationship between duration of nonaspirin NSAID use and RCC risk; compared with non-regular use, the pooled multivariate relative risks were 0.81 (95% confidence interval, 0.59-1.11) for use less than 4 years, 1.36 (0.98-1.89) for 4 to less than 10 years, and 2.92 (1.71-5.01) for use for 10 or more years (P<.001 for trend). Conclusion: Our prospective data suggest that longer duration of use of nonaspirin NSAIDs may increase the risk of RCC. C1 [Cho, Eunyoung; Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Dept Nutr, Brigham & Womens Hosp, Boston, MA 02115 USA. [Cho, Eunyoung; Curhan, Gary; Hankinson, Susan E.; Stampfer, Meir] Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02115 USA. [Kantoff, Philip; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Curhan, Gary; Hankinson, Susan E.; Stampfer, Meir] Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Dept Epidemiol, Boston, MA 02115 USA. [Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Cho, E (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM eunyoung.cho@channing.harvard.edu FU National Institutes of Health [CA137764, CA87969, CA55075]; Kidney Cancer Association; Dana-Farber/Harvard Cancer Center [NIH P50CA101942] FX This study was supported by research grants CA137764, CA87969, and CA55075 from the National Institutes of Health; the Kidney Cancer Association; and grant NIH P50CA101942 from the Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Programs of Research Excellence. NR 40 TC 20 Z9 20 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2011 VL 171 IS 16 BP 1487 EP 1493 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 819KY UT WOS:000294825100013 PM 21911634 ER PT J AU Munshi, MN AF Munshi, Medha N. TI Hypoglycemia Associated With Impaired Renal Function Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Munshi, MN (reprint author), Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, 110 Francis St,Lowry Med Off Bldg,Ste 1B, Boston, MA 02215 USA. EM mmunshi@bidmc.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 12 PY 2011 VL 171 IS 16 BP 1512 EP 1512 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 819KY UT WOS:000294825100032 ER PT J AU Zerbini, LF Tamura, RE Correa, RG Czibere, A Cordeiro, J Bhasin, M Simabuco, FM Wang, YH Gu, XS Li, LL Sarkar, D Zhou, JR Fisher, PB Libermann, TA AF Zerbini, Luiz F. Tamura, Rodrigo E. Correa, Ricardo G. Czibere, Akos Cordeiro, Jason Bhasin, Manoj Simabuco, Fernando M. Wang, Yihong Gu, Xuesong Li, Linglin Sarkar, Devanand Zhou, Jin-Rong Fisher, Paul B. Libermann, Towia A. TI Combinatorial Effect of Non-Steroidal Anti-inflammatory Drugs and NF-kappa B Inhibitors in Ovarian Cancer Therapy SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; EXPRESSING MDA-7/IL-24-MEDIATED APOPTOSIS; SELECTIVELY INDUCES APOPTOSIS; VASCULAR-PERMEABILITY FACTOR; CARCINOMA CELL-LINES; MELANOMA DIFFERENTIATION; BREAST-CANCER; CLINICAL PHARMACOKINETICS; TUMOR-GROWTH; HUMAN-PLASMA AB Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 alpha and gamma and JNK activation. The NF-kappa B family of transcription factors has been implicated in ovarian cancer development. We previously established NF-kappa B/I kappa B signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-kB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NFkB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-kB in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer. C1 [Zerbini, Luiz F.; Tamura, Rodrigo E.] Univ Cape Town, Med Biochem Div, Fac Hlth Sci, ICGEB, ZA-7925 Cape Town, South Africa. [Correa, Ricardo G.] Sanford Burnham Inst Med Res, La Jolla, CA USA. [Czibere, Akos] Univ Dusseldorf, Dept Haematol Oncol & Clin Immunol, Dusseldorf, Germany. [Zerbini, Luiz F.; Cordeiro, Jason; Bhasin, Manoj; Simabuco, Fernando M.; Wang, Yihong; Gu, Xuesong; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, BIDMC Genom & Prote Ctr, Boston, MA 02215 USA. [Zerbini, Luiz F.; Cordeiro, Jason; Bhasin, Manoj; Simabuco, Fernando M.; Wang, Yihong; Gu, Xuesong; Li, Linglin; Zhou, Jin-Rong; Libermann, Towia A.] Harvard Univ, Sch Med, Boston, MA USA. [Li, Linglin; Zhou, Jin-Rong] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Sarkar, Devanand; Fisher, Paul B.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Sch Med, VCU Inst Mol Med,VCU Massey Canc Ctr, Richmond, VA USA. RP Zerbini, LF (reprint author), Univ Cape Town, Med Biochem Div, Fac Hlth Sci, ICGEB, ZA-7925 Cape Town, South Africa. EM luiz.zerbini@uct.ac.za RI tamura, rodrigo/C-3085-2012; Correa, Ricardo/G-7613-2012; tamura, rodrigo/O-9846-2014; Zerbini, Luiz /B-7720-2015; OI Correa, Ricardo/0000-0001-6940-7034; tamura, rodrigo/0000-0001-7767-0887; Libermann, Towia/0000-0002-4006-8179 FU ICGEB; National Institutes of Health [1R01 CA85467, P50 CA090381, P50 CA105009, 1R01 CA097318, 1R01 CA127641, P01 CA104177]; Hershey Foundation; Samuel Waxman Cancer Research Foundation; Department of Defense [PC051217, OC0060439] FX RET is a recipient of the ICGEB post-doctoral fellowship. This research was supported by National Institutes of Health grants 1R01 CA85467, P50 CA090381, P50 CA105009 and the Hershey Foundation (TAL), NIH grants 1R01 CA097318, 1R01 CA127641, P01 CA104177, the Samuel Waxman Cancer Research Foundation (PBF) and Department of Defense grants PC051217 and OC0060439 (LFZ). DS is a Harrison Scholar in Cancer Research and a Blick Scholar in the VCU Massey Cancer Center and the VCU School of Medicine. PBF holds the Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center and is a SWCRF Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 24 Z9 27 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 12 PY 2011 VL 6 IS 9 AR e24285 DI 10.1371/journal.pone.0024285 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CO UT WOS:000294803200010 PM 21931671 ER PT J AU Manola, JB Gray, RJ AF Manola, Judith B. Gray, Robert J. TI When Bad Things Happen to Good Studies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CISPLATIN PLUS FLUOROURACIL; STAGE OROPHARYNX CARCINOMA; COOPERATIVE-ONCOLOGY-GROUP; NECK-CANCER; RANDOMIZED-TRIAL; PHASE-III; RADIATION-THERAPY; COMPETING RISK; ADVANCED HEAD; CHEMOTHERAPY C1 [Manola, Judith B.; Gray, Robert J.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Manola, JB (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 22 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2011 VL 29 IS 26 BP 3497 EP 3499 DI 10.1200/JCO.2011.37.1393 PG 3 WC Oncology SC Oncology GA 818CG UT WOS:000294726400003 PM 21844501 ER PT J AU Chen, AB Schrag, D AF Chen, Aileen B. Schrag, Deborah TI Is Computed Tomography Simulation Associated With Improved Survival, or Is This Finding a Result of Confounding Variables? Reply to M. Koshy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CELL LUNG-CANCER; RADIATION-THERAPY; RADIOTHERAPY C1 [Chen, Aileen B.; Schrag, Deborah] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Chen, Aileen B.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Chen, AB (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. NR 7 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2011 VL 29 IS 26 BP 3587 EP 3588 DI 10.1200/JCO.2011.37.2334 PG 3 WC Oncology SC Oncology GA 818CG UT WOS:000294726400019 ER PT J AU Bloch, DB Nobre, RA Bernstein, GA Yang, WH AF Bloch, Donald B. Nobre, Rita A. Bernstein, Gillian A. Yang, Wei-Hong TI Identification and characterization of protein interactions in the mammalian mRNA processing body using a novel two-hybrid assay SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE mRNA degradation; mRNA processing body; Two-hybrid assay ID P-BODIES; SACCHAROMYCES-CEREVISIAE; DECAPPING COMPLEX; STRESS GRANULES; DCP1; LOCALIZATION; BINDING; EDC3; METAZOA; REGION AB Components of the mRNA processing body (P-body) regulate critical steps in mRNA storage, transport, translation and degradation. At the core of the P-body is the decapping complex, which removes the 5' cap from de-adenylated mRNAs and mediates an irreversible step in mRNA degradation. The assembly of P-bodies in Saccharomyces cerevisiae, Arabidopsis thaliana and Drosophila melanogaster has been previously described. Less is known about the assembly of mammalian P-bodies. To investigate the interactions that occur between components of mammalian P-bodies, we developed a fluorescence-based, two-hybrid assay system. The assay depends on the ability of one P-body component, fused to an exogenous nuclear localization sequence (NLS), to recruit other P-body components to the nucleus. The assay was used to investigate interactions between P-body components Ge-1, DCP2, DCP1, EDC3, RAP55, and RCK. The results of this study show that the modified two-hybrid assay can be used to identify protein interactions that occur in a macromolecular complex. The assay can also be used to efficiently detect protein interaction domains. The results provide important insights into mammalian P-body assembly and demonstrate similarities, and critical differences, between P-body assembly in mammalian cells compared with that of other species. (C) 2011 Elsevier Inc. All rights reserved. C1 [Bloch, Donald B.] Harvard Univ, Sch Med,Dept Med, Massachusetts Gen Hosp, Rheumatol Unit,Ctr Immunol & Inflammatory Dis Gen, Boston, MA 02114 USA. RP Bloch, DB (reprint author), Harvard Univ, Sch Med,Dept Med, Massachusetts Gen Hosp, Rheumatol Unit,Ctr Immunol & Inflammatory Dis Gen, Bulfinch 1,55 Fruit St, Boston, MA 02114 USA. EM bloch@helix.mgh.harvard.edu FU Massachusetts General Hospital FX Funding for this study was provided by the Massachusetts General Hospital, which did not have a role in any aspect of the conduct of the research. NR 31 TC 7 Z9 7 U1 1 U2 8 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 SEP 10 PY 2011 VL 317 IS 15 BP 2183 EP 2199 DI 10.1016/j.yexcr.2011.05.027 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 804VP UT WOS:000293682400010 PM 21672539 ER PT J AU Yin, JM Dai, AL LeCureux, J Arango, T Kutzler, MA Yan, J Lewis, MG Khan, A Sardesai, NY Montefiore, D Ruprecht, R Weiner, DB Boyer, JD AF Yin, Jiangmei Dai, Anlan LeCureux, Jonathan Arango, Tatiana Kutzler, Michele A. Yan, Jian Lewis, Mark G. Khan, Amir Sardesai, Niranjan Y. Montefiore, David Ruprecht, Ruth Weiner, David B. Boyer, Jean D. TI High antibody and cellular responses induced to HIV-1 clade C envelope following DNA vaccines delivered by electroporation SO VACCINE LA English DT Article DE SHIV; DNA vaccine; RANTES; Clade C ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-VIVO ELECTROPORATION; IMMUNE-RESPONSES; RHESUS MACAQUES; RANTES; VACCINATION; EXPRESSION; PLASMID; ENV; IMMUNOGENICITY AB Background: Clade C is the predominant HIV-1 strain infecting people in sub-Saharan Africa, India, and China and there is a critical need for a vaccine targeted to these areas. In this study we tested a DNA based vaccine that encodes the SIVgag, SIVpol and HIV-1 envelope clade C. Methods: Rhesus macaques were immunized by electroporation with the DNA plasmid encoding optimized SIVgag, SIVpol and an HIV-1 env clade C with or without the adjuvant RANTES. Animals were monitored for immune responses and challenged following the final immunization with 25 animal infectious doses (AID) of SHIV-1157ipd3N4. Results: We found that the vaccine induced high levels of antigen specific IFN-gamma producing effector cells and the capacity for CD4+ and CD8+ to proliferate upon antigen stimulation. Importantly, we found that the vaccine induced antibody titers as high as 1/4000. These antibodies were capable of neutralizing tier 1 HIV-1 viruses. Finally, when macaques were challenged with SHIV, viral loads were controlled in vaccinated groups. Conclusion: We conclude that immunization with a simian/human immunodeficiency virus DNA-based vaccine delivered by electroporation can induce cellular and humoral immune responses that are able to control viral replication. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Yin, Jiangmei; Dai, Anlan; LeCureux, Jonathan; Arango, Tatiana; Yan, Jian; Weiner, David B.; Boyer, Jean D.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kutzler, Michele A.] Drexel Univ, Coll Med, Philadelphia, PA 19102 USA. [Lewis, Mark G.] Bioqual, Res Sect, Rockville, MD 20850 USA. [Khan, Amir; Sardesai, Niranjan Y.] Inovio Pharmaceut, Blue Bell, PA 19422 USA. [Montefiore, David] Duke Univ, Durham, NC 27710 USA. [Ruprecht, Ruth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ruprecht, Ruth] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Boyer, JD (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 422 Curie Blvd,505 SCL, Philadelphia, PA 19104 USA. EM boyerj@maiLmed.upenn.edu RI Yin, Jiangmei/G-1952-2011; Weiner, David/H-8579-2014; OI LeCureux, Jonathan/0000-0003-4444-8790 FU National Institutes of Health (NIH) [N01-AI-50010, P01-A1-071739, R01-A1-071186]; NIH/NIAID/DAIDS [HHSN272200800063C] FX This research was supported in part by National Institutes of Health (NIH) Grants N01-AI-50010, P01-A1-071739, R01-A1-071186, A.K., N.Y.S. acknowledge funding in part from an NIH/NIAID/DAIDS - HVDDT award to Inovio HHSN272200800063C" - and the National Institutes of Health Intramural Research Program. J.Y. performed research, generated the data presented and wrote the paper. A.D., J.L., T.A., and M.G.L., all performed research and generated the data presented. M.A.K., J.Y., A.K., N.Y.S, and D.B.W. provided reagents and guidance. J.D.B. designed experiments and oversaw the project. NR 24 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 9 PY 2011 VL 29 IS 39 SI SI BP 6763 EP 6770 DI 10.1016/j.vaccine.2010.12.055 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 828JL UT WOS:000295497200007 PM 21195801 ER PT J AU Funkhouser, E Levine, DA Gerald, JK Houston, TK Johnson, NK Allison, JJ Kiefe, CI AF Funkhouser, Ellen Levine, Deborah A. Gerald, Joe K. Houston, Thomas K. Johnson, Nancy K. Allison, Jeroan J. Kiefe, Catarina I. TI Recruitment activities for a nationwide, population-based, group-randomized trial: the VA MI-Plus study SO IMPLEMENTATION SCIENCE LA English DT Article ID HEALTH-SERVICES RESEARCH; CARE; PARTICIPATION; INTERVENTIONS; DESIGN; IMPACT AB Background: The Veterans Health Administration (VHA) oversees the largest integrated healthcare system in the United States. The feasibility of a large-scale, nationwide, group-randomized implementation trial of VHA outpatient practices has not been reported. We describe the recruitment and enrollment of such a trial testing a clinician-directed, Internet-delivered intervention for improving the care of postmyocardial infarction patients with multiple comorbidities. Methods: With a recruitment goal of 200 eligible community-based outpatient clinics, parent VHA facilities (medical centers) were recruited because they oversee their affiliated clinics and the research conducted there. Eligible facilities had at least four VHA-owned and -operated primary care clinics, an affiliated Institutional Review Board (IRB), and no ongoing, potentially overlapping, quality-improvement study. Between December 2003 and December 2005, in two consecutive phases, we used initial and then intensified recruitment strategies. Results: Overall, 48 of 66 (73%) eligible facilities were recruited. Of the 219 clinics and 957 clinicians associated with the 48 facilities, 168 (78%) clinics and 401 (42%) clinicians participated. The median time from initial facility contact to clinic enrollment was 222 days, which decreased by over one-third from the first to the second recruitment phase (medians: 323 and 195 days, respectively; p < .001), when more structured recruitment with physician recruiters was implemented and a dedicated IRB manager was added to the coordinating center staff. Conclusions: Large group-randomized trials benefit from having dedicated physician investigators and IRB personnel involved in recruitment. A large-scale, nationally representative, group-randomized trial of community-based clinics is feasible within the VHA or a similar national healthcare system. C1 [Funkhouser, Ellen; Johnson, Nancy K.] Birmingham VA Med Ctr, VA Res Enhancement Award Program REAP, Birmingham, AL USA. [Funkhouser, Ellen; Levine, Deborah A.] Univ Alabama, Sch Med, Dept Med, Birmingham, AL USA. [Levine, Deborah A.] Univ Michigan, Ann Arbor VA Healthcare Syst, Ann Arbor, MI 48109 USA. [Levine, Deborah A.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Levine, Deborah A.] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Levine, Deborah A.] Vet Affairs Hlth Serv Res & Dev Ctr Excelle, Ann Arbor, MI USA. [Gerald, Joe K.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Houston, Thomas K.; Allison, Jeroan J.; Kiefe, Catarina I.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. RP Funkhouser, E (reprint author), Birmingham VA Med Ctr, VA Res Enhancement Award Program REAP, Birmingham, AL USA. EM emfunk@uab.edu RI Houston, Thomas/F-2469-2013; OI Allison, Jeroan/0000-0003-4472-2112 FU VA Health Services Research and Development (HSRD) [SDR 03-090-1]; National Heart, Lung, and Blood Institute [R01 HL70786] FX This project was funded in part by grant SDR 03-090-1 from the VA Health Services Research and Development (HSR&D) and by grant number R01 HL70786 from the National Heart, Lung, and Blood Institute. NR 30 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD SEP 9 PY 2011 VL 6 AR 105 DI 10.1186/1748-5908-6-105 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 828AO UT WOS:000295472800001 PM 21906278 ER PT J AU Hambardzumyan, D Cheng, YK Haeno, H Holland, EC Michor, F AF Hambardzumyan, Dolores Cheng, Yu-Kang Haeno, Hiroshi Holland, Eric C. Michor, Franziska TI The Probable Cell of Origin of NF1-and PDGF-Driven Glioblastomas SO PLOS ONE LA English DT Article ID NEURAL STEM-CELLS; SELF-RENEWAL; NEUROEPITHELIAL CELLS; GLIAL PROGENITORS; MOUSE MODELS; ADULT BRAIN; GLIOMA; PATHWAYS; CANCER; NF1 AB Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system. C1 [Hambardzumyan, Dolores] Cleveland Clin, Dept Regenerat Med, Cleveland, OH 44106 USA. [Cheng, Yu-Kang; Haeno, Hiroshi; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cheng, Yu-Kang; Haeno, Hiroshi; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Cheng, Yu-Kang] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA. [Cheng, Yu-Kang] Weill Cornell Med Coll, Triinst Training Program Computat Biol & Med, New York, NY USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, Brain Tumor Ctr, New York, NY 10021 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10021 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Hambardzumyan, D (reprint author), Cleveland Clin, Dept Regenerat Med, Cleveland, OH 44106 USA. EM michor@jimmy.harvard.edu FU National Institutes of Health [U54CA143798] FX This work was supported by National Institutes of Health U54CA143798. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 12 Z9 12 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 9 PY 2011 VL 6 IS 9 AR e24454 DI 10.1371/journal.pone.0024454 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CN UT WOS:000294803100035 PM 21931722 ER PT J AU Stefan, M Jacobson, EM Huber, AK Greenberg, DA Li, CW Skrabanek, L Conception, E Fadlalla, M Ho, K Tomer, Y AF Stefan, Mihaela Jacobson, Eric M. Huber, Amanda K. Greenberg, David A. Li, Cheuk Wun Skrabanek, Luce Conception, Erlinda Fadlalla, Mohammed Ho, Kenneth Tomer, Yaron TI Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon alpha-modulated Mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN GENOME; HASHIMOTOS-THYROIDITIS; SUSCEPTIBILITY GENE; LINKAGE ANALYSIS; DISEASE; TRANSCRIPTION; ASSOCIATION; GRAVES; IDENTIFICATION; METHYLATIONS AB Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (-1623A -> G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (-1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5' TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon alpha, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFN alpha) and genetic (TG) factors to trigger AITD. C1 [Stefan, Mihaela; Huber, Amanda K.; Conception, Erlinda; Ho, Kenneth; Tomer, Yaron] Mt Sinai Med Ctr, Dept Med, Div Endocrinol, New York, NY 10029 USA. [Jacobson, Eric M.; Li, Cheuk Wun; Fadlalla, Mohammed] Univ Cincinnati, Div Endocrinol, Cincinnati, OH 45267 USA. [Greenberg, David A.] Columbia Univ, Div Stat Genet, New York, NY 10032 USA. [Skrabanek, Luce] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Skrabanek, Luce] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA. [Stefan, Mihaela; Tomer, Yaron] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Stefan, M (reprint author), Mt Sinai Med Ctr, Dept Med, Div Endocrinol, New York, NY 10029 USA. EM mihaela.stefan@mssm.edu; yaron.tomer@mssm.edu FU National Institutes of Health [DK61659, DK067555, DK073681, MH48858, NS27941]; Veterans Affairs merit award; American Thyroid Association FX This work was supported, in whole or in part, by National Institutes of Health Grants DK61659, DK067555, and DK073681 (to Y. T.) and Grants MH48858 and NS27941 (to D. A. G.). This work was also supported by a Veterans Affairs merit award (to Y. T.).; Supported by a grant from the American Thyroid Association. NR 50 TC 22 Z9 23 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2011 VL 286 IS 36 BP 31168 EP 31179 DI 10.1074/jbc.M111.247510 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500012 PM 21757724 ER PT J AU Li, Y Si, R Feng, Y Chen, HH Zou, L Wang, E Zhang, M Warren, HS Sosnovik, DE Chao, W AF Li, Yan Si, Rui Feng, Yan Chen, Howard H. Zou, Lin Wang, E. Zhang, Ming Warren, H. Shaw Sosnovik, David E. Chao, Wei TI Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK-PROTEIN; NF-KAPPA-B; REPERFUSION INJURY; CARDIOMYOCYTE APOPTOSIS; SERUM DEPRIVATION; DEATH-DOMAIN; INFLAMMATION; TLR4; MACROPHAGES; PATHWAY AB Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia-and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4def mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R. C1 [Li, Yan; Si, Rui; Feng, Yan; Zou, Lin; Wang, E.; Zhang, Ming; Chao, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Chen, Howard H.; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. [Warren, H. Shaw] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA USA. [Li, Yan] Huazhong Univ Sci & Technol, Union Hosp, Dept Pathol, Tongji Med Coll, Wuhan 430030, Peoples R China. RP Chao, W (reprint author), Massachusetts Gen Hosp, Room 4-212,149 13th St, Charlestown, MA 02129 USA. EM wchao@partners.org RI Feng, Yan/H-5808-2012 FU National Institutes of Health [R01GM080906, R01HL093038]; American Heart Association [0755890T] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01GM080906 and R01HL093038. This work was also supported by American Heart Association Grant-in-Aid 0755890T. NR 65 TC 59 Z9 65 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 SEP 9 PY 2011 VL 286 IS 36 BP 31308 EP 31319 DI 10.1074/jbc.M111.246124 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500026 PM 21775438 ER PT J AU Yang, R Fredman, G Krishnamoorthy, S Agrawal, N Irimia, D Piomelli, D Serhan, CN AF Yang, Rong Fredman, Gabrielle Krishnamoorthy, Sriram Agrawal, Nitin Irimia, Daniel Piomelli, Daniele Serhan, Charles N. TI Decoding Functional Metabolomics with Docosahexaenoyl Ethanolamide (DHEA) Identifies Novel Bioactive Signals SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANNABINOID RECEPTOR; WHOLE-BLOOD; FATTY-ACIDS; ANANDAMIDE; ENDOCANNABINOIDS; PLATELETS; INJURY; BINDS; D1; INFLAMMATION AB Neuroinflammation and traumatic brain injury involve activation of inflammatory cells and production of local pro-inflammatory mediators that can amplify tissue damage. Using LC-UV-MS-MS-based lipidomics in tandem with functional screening at the single-cell level in microfluidic chambers, we identified a series of novel bioactive oxygenated docosahexaenoyl ethanolamide( DHEA) derived products that regulated leukocyte motility. These included 10,17-dihydroxydocosahexaenoyl ethanolamide (10,17-diHDHEA) and 15-hydroxy-16(17)-epoxy-docosapentaenoyl ethanolamide (15-HEDPEA), each of which was an agonist of recombinant CB2 receptors with EC50 3.9 X 10(-10) and 1.0 X 10(-10)M. In human whole blood, 10,17-diHDHEA and 15-HEDPEA at concentrations as low as 10 pM each prevented formation of platelet-leukocyte aggregates involving either platelet-monocyte or platelet-polymorphonuclear leukocyte. In vivo, 15-HEDPEA was organ-protective in mouse reperfusion second organ injury. Together these results indicate that DHEA oxidative metabolism produces potent novel molecules with anti-inflammatory and organ-protective properties. C1 [Yang, Rong; Fredman, Gabrielle; Krishnamoorthy, Sriram; Serhan, Charles N.] Brigham & Womens Hosp, Harvard Inst Med, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Yang, Rong; Fredman, Gabrielle; Krishnamoorthy, Sriram; Serhan, Charles N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Agrawal, Nitin; Irimia, Daniel] Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA 02129 USA. [Agrawal, Nitin; Irimia, Daniel] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Piomelli, Daniele] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92617 USA. [Piomelli, Daniele] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92617 USA. [Piomelli, Daniele] Italian Inst Technol, I-16163 Genoa, Italy. RP Serhan, CN (reprint author), Brigham & Womens Hosp, Harvard Inst Med, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 829,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cnserhan@zeus.bwh.harvard.edu OI Irimia, Daniel/0000-0001-7347-2082 FU National Institutes of Health [R01NS067686, RC2AT005909, R01DE019938] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01NS067686 (to C. N. S.), RC2AT005909 (to C. N. S.), and R01DE019938 (to C. N. S. and D. I.). NR 42 TC 29 Z9 30 U1 0 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 9 PY 2011 VL 286 IS 36 BP 31532 EP 31541 DI 10.1074/jbc.M111.237990 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 814WI UT WOS:000294487500048 PM 21757729 ER PT J AU Lane, SW Wang, YZJ Lo Celso, C Ragu, C Bullinger, L Sykes, SM Ferraro, F Shterental, S Lin, CP Gilliland, DG Scadden, DT Armstrong, SA Williams, DA AF Lane, Steven W. Wang, Yingzi J. Lo Celso, Cristina Ragu, Christine Bullinger, Lars Sykes, Stephen M. Ferraro, Francesca Shterental, Sebastian Lin, Charles P. Gilliland, D. Gary Scadden, David T. Armstrong, Scott A. Williams, David A. TI Differential niche and Wnt requirements during acute myeloid leukemia progression SO BLOOD LA English DT Article ID STEM-CELL NICHE; HEMATOPOIETIC STEM; PROGENITOR CELLS; BETA-CATENIN; IN-VIVO; AML; MICROENVIRONMENT; TRANSFORMATION; CHEMOTHERAPY; RESISTANCE AB Hematopoietic stem cells (HSCs) engage in complex bidirectional signals with the hematopoietic microenvironment (HM), and there is emerging evidence that leukemia stem cells (LSCs) may use similar interactions. Using a syngeneic retroviral model of MLL-AF9 induced acute myeloid leukemia (AML), we have identified 2 different stages of leukemia progression, propagated by "pre-LSCs" and established leukemia (LSCs) and compared the homing properties of these distinctive entities to that of normal HSCs. The homing and microlocalization of pre-LSCs was most similar to long-term HSCs and was dependent on cell-intrinsic Wnt signaling. In contrast, the homing of established LSCs was most similar to that of committed myeloid progenitors and distinct from HSCs. Although osteoblast-derived Dickkopf-1,a potent Wnt inhibitor known to impair HSC function, dramatically impaired normal HSC localization within the bone marrow, it did not affect pre-LSCs, LSC homing, or AML development. Mechanistically, cell-intrinsic Wnt activation was observed in human and murine AML samples, explaining the independence of MLL-AF9 LSCs from niche-derived Wnt signals. These data identify differential engagement of HM associated with leukemic progression and identify an LSC niche that is physically distinct and independent of the constraints of Wnt signaling that apply to normal HSCs. (Blood. 2011; 118(10): 2849-2856) C1 [Lane, Steven W.; Wang, Yingzi J.; Bullinger, Lars; Armstrong, Scott A.; Williams, David A.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA 02115 USA. [Lane, Steven W.; Wang, Yingzi J.; Bullinger, Lars; Armstrong, Scott A.; Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lane, Steven W.; Wang, Yingzi J.; Lo Celso, Cristina; Ragu, Christine; Bullinger, Lars; Sykes, Stephen M.; Ferraro, Francesca; Scadden, David T.; Armstrong, Scott A.; Williams, David A.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Lane, Steven W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Wang, Yingzi J.] Childrens Canc Inst Australia Med Res, Sydney, NSW, Australia. [Lo Celso, Cristina] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London, England. [Lo Celso, Cristina; Ragu, Christine; Sykes, Stephen M.; Ferraro, Francesca; Scadden, David T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Stem Cell & Regenerat Biol,Ctr Regenerat Med, Boston, MA 02115 USA. [Bullinger, Lars] Univ Hosp, Dept Internal Med 3, Ulm, Germany. [Sykes, Stephen M.; Shterental, Sebastian; Gilliland, D. Gary] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Gilliland, D. Gary] Merck Res Labs, N Wales, PA USA. RP Williams, DA (reprint author), Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, 300 Longwood Ave,Karp 08125-3, Boston, MA 02115 USA. EM dscadden@mgh.harvard.edu; scott.armstrong@childrens.harvard.edu; dawilliams@childrens.harvard.edu RI Lane, Steven/C-3215-2012; OI Lane, Steven/0000-0002-8050-6209; Lo Celso, Cristina/0000-0002-1163-4207; Ragu, Christine/0000-0002-1150-1105 FU National Health and Medical Research Council of Australia; Australia/United States Fulbright Commission; Hematology Society of Australia and New Zealand; National Institutes of Health [DK62757, HL44851, CA66996]; Leukemia & Lymphoma Society; American Cancer Society; Deutsche Forschungsgemeinschaft [Heisenberg-Stipendium BU 1339/3-1] FX S.W.L. was supported by the National Health and Medical Research Council of Australia, Australia/United States Fulbright Commission and Hematology Society of Australia and New Zealand. D. A. W. was supported by the National Institutes of Health (DK62757). D. T. S. was supported by the National Institutes of Health (HL44851). S. A. A. was supported by the National Institutes of Health (CA66996). Work performed in the laboratory of S. A. A. was also supported by the Leukemia & Lymphoma Society and the American Cancer Society. L. B. was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). NR 29 TC 61 Z9 62 U1 0 U2 8 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 SEP 8 PY 2011 VL 118 IS 10 BP 2849 EP 2856 DI 10.1182/blood-2011-03-345165 PG 8 WC Hematology SC Hematology GA 819BX UT WOS:000294801500032 PM 21765021 ER PT J AU Li, WH Ahn, AC AF Li, Weihui Ahn, Andrew C. TI Subcutaneous Fascial Bands-A Qualitative and Morphometric Analysis SO PLOS ONE LA English DT Article ID CONNECTIVE-TISSUE; NETWORK; BODY AB Background: Although fascial bands within the subcutaneous (SQ) layer are commonly seen in ultrasound images, little is known about their functional role, much less their structural characteristics. This study's objective is to describe the morphological features of SQ fascial bands and to systematically evaluate the bands using image analyses tools and morphometric measures. Methods: In 28 healthy volunteers, ultrasound images were obtained at three body locations: the lateral aspect of the upper arm, medial aspect of the thigh and posterior aspect of lower leg. Using image analytical techniques, the total SQ band area, fascial band number, fascial band thickness, and SQ zone (layer) thickness were determined. In addition, the SQ spatial coherence was calculated based on the eigenvalues associated with the largest and smallest eigenvectors of the images. Results: Fascial bands at these sites were contiguous with the dermis and the epimysium forming an interconnected network within the subcutaneous tissue. Subcutaneous blood vessels were also frequently encased by these fascial bands. The total SQ fascial band area was greater at the thigh and calf compared to the arm and was unrelated to SQ layer (zone) thickness. The thigh was associated with highest average number of fascial bands while calf was associated with the greatest average fascial band thickness. Across body regions, greater SQ zone thickness was associated with thinner fascial bands. SQ coherence was significantly associated with SQ zone thickness and body location (calf with statistically greater coherence compared to arm). Conclusion: Fascial bands are structural bridges that mechanically link the skin, subcutaneous layer, and deeper muscle layers. This cohesive network also encases subcutaneous vessels and may indirectly mediate blood flow. The quantity and morphological characteristics of the SQ fascial band may reflect the composite mechanical forces experienced by the body part. C1 [Li, Weihui; Ahn, Andrew C.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ahn, Andrew C.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. RP Li, WH (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM weihuil@gmail.com FU National Center for Complementary Alternative Medicine (NCCAM) [K23-AT003238, P30AT005895, K24-AT004095]; Bernard Osher Foundation; National Center for Research Resources [UL1RR025758] FX This research was supported by grant number K23-AT003238, P30AT005895, and K24-AT004095 of the National Center for Complementary Alternative Medicine (NCCAM) and supported in part by a gift from The Bernard Osher Foundation. The project described was supported by Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Complementary Alternative Medicine or the National Center for Research Resources or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 13 TC 2 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2011 VL 6 IS 9 AR e23987 DI 10.1371/journal.pone.0023987 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800017 PM 21931632 ER PT J AU Matulonis, UA Hirsch, M Palescandolo, E Kim, E Liu, J van Hummelen, P MacConaill, L Drapkin, R Hahn, WC AF Matulonis, Ursula A. Hirsch, Michelle Palescandolo, Emanuele Kim, Eejung Liu, Joyce van Hummelen, Paul MacConaill, Laura Drapkin, Ronny Hahn, William C. TI High Throughput Interrogation of Somatic Mutations in High Grade Serous Cancer of the Ovary SO PLOS ONE LA English DT Article ID PHASE-II; LUNG-CANCER; GEFITINIB; CARCINOMA; ONCOGENE; GENE AB Background: Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, and high grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. The objective of this study was to determine the frequency and types of point somatic mutations in HGSC using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology. Methodology/Principal Findings: The Center for Cancer Genome Discovery (CCGD) Program at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection protocol, termed OncoMap has been expanded to detect more than 1000 mutations in 112 oncogenes in formalin-fixed paraffin-embedded (FFPE) tissue samples. We performed OncoMap on a set of 203 FFPE advanced staged HGSC specimens. We isolated genomic DNA from these samples, and after a battery of quality assurance tests, ran each of these samples on the OncoMap v3 platform. 56% (113/203) tumor samples harbored candidate mutations. Sixty-five samples had single mutations (32%) while the remaining samples had >= 2 mutations (24%). 196 candidate mutation calls were made in 50 genes. The most common somatic oncogene mutations were found in EGFR, KRAS, PDGRF alpha, KIT, and PIK3CA. Other mutations found in additional genes were found at lower frequencies (<3%). Conclusions/Significance: Sequenom analysis using OncoMap on DNA extracted from FFPE ovarian cancer samples is feasible and leads to the detection of potentially druggable mutations. Screening HGSC for somatic mutations in oncogenes may lead to additional therapies for this patient population. C1 [Matulonis, Ursula A.; Palescandolo, Emanuele; Kim, Eejung; Liu, Joyce; van Hummelen, Paul; MacConaill, Laura; Drapkin, Ronny; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hirsch, Michelle; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Womens & Perinatal Pathol Div, Boston, MA 02115 USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM Ursula_matulonis@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU Ovarian Cancer Specialized Program of Research Excellence [P50CA105009]; Madeline Franchi Ovarian Cancer Fund; Women's Executive Council of the Dana-Farber Cancer Institute; Novartis Pharmaceuticals FX Funding was provided by the following sources: Ovarian Cancer Specialized Program of Research Excellence (P50CA105009), the Madeline Franchi Ovarian Cancer Fund, and the Women's Executive Council of the Dana-Farber Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Drs. Hahn and Drapkin both serve as consultants for and have received research grants from Novartis Pharmaceuticals. This did not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The other authors have no conflicts of interest to report. NR 21 TC 26 Z9 27 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2011 VL 6 IS 9 AR e24433 DI 10.1371/journal.pone.0024433 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800050 PM 21931712 ER PT J AU Milane, L Duan, ZF Amiji, M AF Milane, Lara Duan, Zhenfeng Amiji, Mansoor TI Therapeutic Efficacy and Safety of Paclitaxel/Lonidamine Loaded EGFR-Targeted Nanoparticles for the Treatment of Multi-Drug Resistant Cancer SO PLOS ONE LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1; PEPTIDE LIGAND; CELLS; GLYCOLYSIS; APOPTOSIS; GROWTH; DELIVERY; WARBURG; OXYGEN AB The treatment of multi-drug resistant (MDR) cancer is a clinical challenge. Many MDR cells over-express epidermal growth factor receptor (EGFR). We exploit this expression through the development of EGFR-targeted, polymer blend nanocarriers for the treatment of MDR cancer using paclitaxel (a common chemotherapeutic agent) and lonidamine (an experimental drug; mitochondrial hexokinase 2 inhibitor). An orthotopic model of MDR human breast cancer was developed in nude mice and used to evaluate the safety and efficacy of nanoparticle treatment. The efficacy parameters included tumor volume measurements from day 0 through 28 days post-treatment, terminal tumor weight measurements, tumor density and morphology assessment through hematoxylin and eosin staining of excised tumors, and immunohistochemistry of tumor sections for MDR protein markers (P-glycoprotein, Hypoxia Inducible Factor, EGFR, Hexokinase 2, and Stem Cell Factor). Toxicity was assessed by tracking changes in animal body weight from day 0 through 28 days post-treatment, by measuring plasma levels of the liver enzymes ALT (Alanine Aminotransferase) and LDH (lactate dehydrogenase), and by white blood cell and platelet counts. In these studies, this nanocarrier system demonstrated superior efficacy relative to combination (paclitaxel/lonidamine) drug solution and single agent treatments in nanoparticle and solution form. The combination nanoparticles were the only treatment group that decreased tumor volume, sustaining this decrease until the 28 day time point. In addition, treatment with the EGFR-targeted lonidamine/paclitaxel nanoparticles decreased tumor density and altered the MDR phenotype of the tumor xenografts. These EGFR-targeted combination nanoparticles were considerably less toxic than solution treatments. Due to the flexible design and simple conjugation chemistry, this nanocarrier system could be used as a platform for the development of other MDR cancer therapies; the use of this system for EGFR-targeted, combination paclitaxel/lonidamine therapy is an advance in personalized medicine. C1 [Milane, Lara; Amiji, Mansoor] Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. [Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Milane, L (reprint author), Northeastern Univ, Dept Pharmaceut Sci, Sch Pharm, Boston, MA 02115 USA. EM m.amiji@neu.edu RI Amiji, Mansoor/A-4365-2014 OI Amiji, Mansoor/0000-0001-6170-881X FU National Cancer Institute, National Institutes of Health [R01 CA-119617, R01 CA-119617S1, R21 CA-135594] FX This study was supported by the National Cancer Institute, National Institutes of Health through grants R01 CA-119617 and R01 CA-119617S1 (ARRA Supplement), and R21 CA-135594. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 37 Z9 37 U1 3 U2 40 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2011 VL 6 IS 9 AR e24075 DI 10.1371/journal.pone.0024075 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800020 PM 21931642 ER PT J AU Scheer, FAJL Michelson, AD Frelinger, AL Evoniuk, H Kelly, EE McCarthy, M Doamekpor, LA Barnard, MR Shea, SA AF Scheer, Frank A. J. L. Michelson, Alan D. Frelinger, Andrew L., III Evoniuk, Heather Kelly, Erin E. McCarthy, Mary Doamekpor, Lauren A. Barnard, Marc R. Shea, Steven A. TI The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors SO PLOS ONE LA English DT Article ID SUDDEN CARDIAC DEATH; NIGHT-SHIFT WORKERS; FLOW-CYTOMETRY; MYOCARDIAL-INFARCTION; MELATONIN; AGGREGATION; RHYTHM; THROMBOSIS; DISORDERS; FREQUENCY AB Background: Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (similar to 9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise. Methodology/Principal Findings: We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6-17% peak-trough amplitudes; p <= 0.01). These circadian peaks occurred at a circadian phase corresponding to 8-9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3-8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors. Conclusions/Significance: These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans-independent of the sleep/wake cycle, other behavioral influences and the environment. The similar to 9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies. C1 [Scheer, Frank A. J. L.; Evoniuk, Heather; Kelly, Erin E.; McCarthy, Mary; Doamekpor, Lauren A.; Shea, Steven A.] Brigham & Womens Hosp, Med Chronobiol Program, Div Sleep Med, Boston, MA 02115 USA. [Scheer, Frank A. J. L.; Shea, Steven A.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Michelson, Alan D.; Frelinger, Andrew L., III; Barnard, Marc R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol,Childr, Boston, MA 02115 USA. RP Scheer, FAJL (reprint author), Brigham & Womens Hosp, Med Chronobiol Program, Div Sleep Med, 75 Francis St, Boston, MA 02115 USA. EM fscheer@rics.bwh.harvard.edu; sshea@hms.harvard.edu RI Scheer, Frank/C-2795-2012; OI Shea, Steven/0000-0003-1949-0954 FU National Institutes of Health [NIH-R01-HL76409, NIH-K24-HL076446, NIH-P30-HL101299]; [NCRR-GCRC-M01-RR02635] FX National Institutes of Health: NIH-R01-HL76409; NIH-K24-HL076446 in support of SAS; NIH-P30-HL101299 in support of FAJLS; NCRR-GCRC-M01-RR02635. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 36 Z9 36 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 8 PY 2011 VL 6 IS 9 AR e24549 DI 10.1371/journal.pone.0024549 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CK UT WOS:000294802800064 PM 21931750 ER PT J AU Patel, MR Mahaffey, KW Garg, J Pan, GH Singer, DE Hacke, W Breithardt, G Halperin, JL Hankey, GJ Piccini, JP Becker, RC Nessel, CC Paolini, JF Berkowitz, SD Fox, KAA Califf, RM AF Patel, Manesh R. Mahaffey, Kenneth W. Garg, Jyotsna Pan, Guohua Singer, Daniel E. Hacke, Werner Breithardt, Guenter Halperin, Jonathan L. Hankey, Graeme J. Piccini, Jonathan P. Becker, Richard C. Nessel, Christopher C. Paolini, John F. Berkowitz, Scott D. Fox, Keith A. A. Califf, Robert M. CA ROCKET AF Investigators TI Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTENT-TO-TREAT; ANTITHROMBOTIC THERAPY; STROKE PREVENTION; NON-INFERIORITY; TRIALS; THROMBOPROPHYLAXIS; PHARMACODYNAMICS; PHARMACOKINETICS; ANTICOAGULATION; ARTHROPLASTY AB Background The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. Methods In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. Results In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P < 0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P < 0.001 for noninferiority; P = 0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P = 0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P = 0.02) and fatal bleeding (0.2% vs. 0.5%, P = 0.003) in the rivaroxaban group. Conclusions In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials. gov number, NCT00403767.) C1 [Patel, Manesh R.; Mahaffey, Kenneth W.; Garg, Jyotsna; Piccini, Jonathan P.; Becker, Richard C.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC 27705 USA. [Pan, Guohua; Nessel, Christopher C.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Paolini, John F.; Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Hacke, Werner] Univ Heidelberg, Heidelberg, Germany. [Breithardt, Guenter] Hosp Univ Munster, Munster, Germany. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Royal Perth Hosp, Perth, WA, Australia. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Patel, MR (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Rm 0311 Terrace Level,2400 Pratt St, Durham, NC 27705 USA. EM manesh.patel@duke.edu RI Arkhipov, Mikhail/Q-2316-2015; Urina, Miguel/H-2605-2016; Zadionchenko, Vladimir/A-7445-2016; De Caterina, Raffaele/K-3857-2016; bladin, chris/B-9136-2013; Mazurov, Vadim/J-9643-2014; Walters, Darren/A-7069-2011; Sinkiewicz, Wladyslaw/G-5169-2014; Parsons, Mark/G-3750-2014; Hankey, Graeme /H-4968-2014; Libis, Roman/O-9193-2015; OI Urina, Miguel/0000-0001-6003-4622; Zadionchenko, Vladimir/0000-0003-2377-5266; De Caterina, Raffaele/0000-0003-1637-574X; Mazurov, Vadim/0000-0002-0797-2051; Hankey, Graeme /0000-0002-6044-7328; Libis, Roman/0000-0003-0130-990X; Pardo-Oviedo, Juan Mauricio/0000-0003-0084-3449; Prabhakaran, Dorairaj/0000-0002-3172-834X; Michel, GALINIER/0000-0003-1735-3390; Kaste, Markku/0000-0001-6557-6412; Macleod, Malcolm Robert/0000-0001-9187-9839 FU Johnson Johnson; Bayer FX Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials. gov number, NCT00403767. NR 27 TC 2616 Z9 2743 U1 40 U2 232 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 SEP 8 PY 2011 VL 365 IS 10 BP 883 EP 891 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 816JX UT WOS:000294595600004 PM 21830957 ER PT J AU Winter, HS Gervais, DA Branda, JA AF Winter, Harland S. Gervais, Debra A. Branda, John A. TI Case 27-2011: A 17-Year-Old Boy with Abdominal Pain and Weight Loss SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CROHNS-DISEASE; TUBERCULOSIS; DIAGNOSIS; CHILDREN; HISTOPLASMOSIS; INFECTION; SYMPTOMS C1 [Winter, Harland S.] Massachusetts Gen Hosp, Dept Pediat Gastroenterol, Boston, MA 02114 USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Winter, Harland S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Gervais, Debra A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Winter, HS (reprint author), Massachusetts Gen Hosp, Dept Pediat Gastroenterol, Boston, MA 02114 USA. NR 14 TC 3 Z9 3 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 8 PY 2011 VL 365 IS 10 BP 940 EP 950 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 816JX UT WOS:000294595600012 PM 21899455 ER PT J AU Shen, SY Zhang, ZB Tucker, JD Chang, HL Zhang, GR Lin, AH AF Shen, Song-Ying Zhang, Zhou-Bin Tucker, Joseph D. Chang, Helena Zhang, Guan-Rong Lin, Ai-Hua TI Peer-based behavioral health program for drug users in China: a pilot study SO BMC PUBLIC HEALTH LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; HIV-INFECTION; HIV/AIDS PREVENTION; GUANGDONG PROVINCE; RISK BEHAVIORS; HARM REDUCTION; HEPATITIS-C; PREVALENCE; TRANSMISSION; EDUCATION AB Background: Many injection drug users (IDUs) in China have high risk sexual behaviors that contribute to the spread of HIV infection. Although many IDUs in China move through drug rehabilitation centers, this opportunity for sexual health education has largely been overlooked. Methods: A convenience sample of 667 drug users from two rehabilitation centers in South China was recruited in the study. Two hundred and forty seven drug users from a single Guangdong Province rehabilitation center received the peer-based education intervention, while 420 drug users from another rehabilitation center received routine HIV/STI education and was used as the control. One hundred and eighty nine (22.1%) individuals refused to participate in the study. HIV/STI behavioral and knowledge domains were assessed at 3 months in rehabilitation centers after the intervention (first follow-up) and at 2-23 months in the community after release (second follow-up). Results: Drug users who completed the intervention reported more frequent condom use with casual sex partners (60.0% vs. 12.5% condom use every time, p = 0.011) and less frequent injection (56.7% vs. 26.4% no injection per day, p = 0.008) at the second follow-up compared to those in the routine education group. Loss to follow up was substantial in both control and intervention groups, and was associated with living far from the detention center and having poor HIV knowledge at baseline. Conclusions: This study shows that rehabilitation centers may be a useful location for providing behavioral HIV/STI prevention services and referral of individuals to community-based programs upon release. More research is needed on behalf of detained drug users in China who have complex social, medical, and legal needs. C1 [Shen, Song-Ying; Zhang, Guan-Rong; Lin, Ai-Hua] Sun Yat Sen Univ, Dept Med Stat & Epidemiol, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Zhang, Zhou-Bin] Guangzhou Ctr Dis Control & Prevent, Guangzhou, Guangdong, Peoples R China. [Tucker, Joseph D.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Chang, Helena] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. RP Lin, AH (reprint author), Sun Yat Sen Univ, Dept Med Stat & Epidemiol, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. EM linaihua@mail.sysu.edu.cn FU AIDS Prevention Foundation [WA2005-6]; Ministry of Health of People's Republic of China FX We thank the managers, doctors and nurses at the Guangzhou Municipal Drug User Detention Center and the Guangzhou Baiyun District Drug User Detention Center for their support and participation in the project and all those who distributed and collected questionnaires. This study was supported by applied research program of AIDS Prevention Foundation grant number WA2005-6 funded by Ministry of Health of People's Republic of China. NR 48 TC 4 Z9 4 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD SEP 7 PY 2011 VL 11 AR 693 DI 10.1186/1471-2458-11-693 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 832HN UT WOS:000295795000001 PM 21899764 ER PT J AU Esterhazy, D Stutzer, I Wang, HY Rechsteiner, MP Beauchamp, J Dobeli, H Hilpert, H Matile, H Prummer, M Schmidt, A Lieske, N Boehm, B Marselli, L Bosco, D Kerr-Conte, J Aebersold, R Spinas, GA Moch, H Migliorini, C Stoffel, M AF Esterhazy, Daria Stuetzer, Ina Wang, Haiyan Rechsteiner, Markus P. Beauchamp, Jeremy Doebeli, Heinz Hilpert, Hans Matile, Hugues Prummer, Michael Schmidt, Alexander Lieske, Nora Boehm, Bernhard Marselli, Lorella Bosco, Domenico Kerr-Conte, Julie Aebersold, Ruedi Spinas, Giatgen Andreia Moch, Holger Migliorini, Cristiano Stoffel, Markus TI Bace2 Is a beta Cell-Enriched Protease that Regulates Pancreatic beta Cell Function and Mass SO CELL METABOLISM LA English DT Article ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE; ALZHEIMERS-DISEASE; INSULIN-SECRETION; MICE LACKING; ASP1 BACE2; COLLECTRIN; IDENTIFICATION; EXPRESSION; MOUSE AB Decreased beta cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human beta cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented beta cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of beta cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic beta cell mass. C1 [Esterhazy, Daria; Stuetzer, Ina; Schmidt, Alexander; Lieske, Nora; Aebersold, Ruedi; Stoffel, Markus] ETH, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland. [Esterhazy, Daria; Stuetzer, Ina; Rechsteiner, Markus P.; Schmidt, Alexander; Aebersold, Ruedi; Spinas, Giatgen Andreia; Moch, Holger; Stoffel, Markus] ETH, Competence Ctr Syst Physiol & Metab Dis, CH-8093 Zurich, Switzerland. [Wang, Haiyan; Beauchamp, Jeremy; Doebeli, Heinz; Hilpert, Hans; Matile, Hugues; Prummer, Michael; Migliorini, Cristiano] F Hoffmann La Roche, CH-4070 Basel, Switzerland. [Rechsteiner, Markus P.; Moch, Holger] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. [Spinas, Giatgen Andreia] Univ Zurich Hosp, Div Endocrinol Diabet & Clin Nutr, CH-8091 Zurich, Switzerland. [Boehm, Bernhard] Univ Ulm, Div Endocrinol & Diabet, D-89070 Ulm, Germany. [Marselli, Lorella] Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8091 Zurich, Switzerland. [Stoffel, Markus] Univ Zurich, Fac Med, CH-8091 Zurich, Switzerland. [Bosco, Domenico] Univ Hosp Geneva, Cell Isolat & Transplantat Ctr, CH-1121 Geneva, Switzerland. [Kerr-Conte, Julie] Univ Lille 2, INSERM, U859, Dept Surg, F-59045 Lille, France. RP Stoffel, M (reprint author), ETH, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland. EM stoffel@imsb.biol.ethz.ch RI Prummer, Michael/G-6464-2011; Boehm, Bernhard/F-8750-2015 OI Prummer, Michael/0000-0001-9896-3929; FU JDRF International; F. Hoffmann-La Roche FX This work was in part sponsored by the JDRF International and by F. Hoffmann-La Roche. We thank P. Salvioni, A. Benardeau, W. Riboulet, S. Uhles, M. Brecheisen, S. Sewing, and T. Lave for helpful discussions and technical expertise. We thank P. Halban for generously providing the 804G conditioned medium for the islet proliferation assays. NR 40 TC 54 Z9 56 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD SEP 7 PY 2011 VL 14 IS 3 BP 365 EP 377 DI 10.1016/j.cmet.2011.06.018 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 830MD UT WOS:000295660200011 PM 21907142 ER PT J AU Tucker, EJ Hershman, SG Kohrer, C Belcher-Timme, CA Patel, J Goldberger, OA Christodoulou, J Silberstein, JM McKenzie, M Ryan, MT Compton, AG Jaffe, JD Carr, SA Calvo, SE RajBhandary, UL Thorburn, DR Mootha, VK AF Tucker, Elena J. Hershman, Steven G. Koehrer, Caroline Belcher-Timme, Casey A. Patel, Jinal Goldberger, Olga A. Christodoulou, John Silberstein, Jonathon M. McKenzie, Matthew Ryan, Michael T. Compton, Alison G. Jaffe, Jacob D. Carr, Steven A. Calvo, Sarah E. RajBhandary, Uttam L. Thorburn, David R. Mootha, Vamsi K. TI Mutations in MTFMT Underlie a Human Disorder of Formylation Causing Impaired Mitochondrial Translation SO CELL METABOLISM LA English DT Article ID INITIATOR TRANSFER-RNA; COMPLEX I DEFICIENCY; PROTEIN-SYNTHESIS; SACCHAROMYCES-CEREVISIAE; GENOME; INITIATION-FACTOR-2; IDENTIFICATION; COMPENDIUM; SUBUNITS; NUCLEAR AB The metazoan mitochondrial translation machinery is unusual in having a single tRNA(Met) that fulfills the dual role of the initiator and elongator tRNA(Met). A portion of the Met-tRNA(Met) pool is formylated by mitochondrial methionyl-tRNA formyltransferase (MTFMT) to generate N-formylmethionine-tRNA(Met) (fMet-tRNA(Met)), which is used for translation initiation; however, the requirement of formylation for initiation in human mitochondria is still under debate. Using targeted sequencing of the mtDNA and nuclear exons encoding the mitochondrial proteome (MitoExome), we identified compound heterozygous mutations in MTFMT in two unrelated children presenting with Leigh syndrome and combined OXPHOS deficiency. Patient fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of MTFMT. Furthermore, patient fibroblasts have dramatically reduced fMet-tRNA(Met) levels and an abnormal formylation profile of mitochondrially translated COX1. Our findings demonstrate that MTFMT is critical for efficient human mitochondrial translation and reveal a human disorder of Met-tRNA(Met) formylation. C1 [Tucker, Elena J.; Compton, Alison G.; Thorburn, David R.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia. [Thorburn, David R.] Royal Childrens Hosp, Genet Hlth Serv Victoria, Melbourne, Vic 3052, Australia. [Tucker, Elena J.; Thorburn, David R.] Univ Melbourne, Dept Paediat, Melbourne, Vic 3052, Australia. [Hershman, Steven G.; Belcher-Timme, Casey A.; Goldberger, Olga A.; Calvo, Sarah E.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Hershman, Steven G.; Belcher-Timme, Casey A.; Goldberger, Olga A.; Calvo, Sarah E.; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Hershman, Steven G.; Belcher-Timme, Casey A.; Patel, Jinal; Goldberger, Olga A.; Jaffe, Jacob D.; Carr, Steven A.; Calvo, Sarah E.; Mootha, Vamsi K.] Broad Inst, Cambridge, MA 02142 USA. [Koehrer, Caroline; RajBhandary, Uttam L.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Christodoulou, John] Childrens Hosp Westmead, Genet Metab Disorders Res Unit, Sydney, NSW 2006, Australia. [Christodoulou, John] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Christodoulou, John] Univ Sydney, Discipline Genet Med, Sydney, NSW 2006, Australia. [Silberstein, Jonathon M.] Princess Margaret Hosp Children, Dept Neurol, Perth, WA 6008, Australia. [McKenzie, Matthew] Monash Univ, Monash Inst Med Res, Ctr Reprod & Dev, Melbourne, Vic 3168, Australia. [Ryan, Michael T.] La Trobe Univ, Dept Biochem, Melbourne, Vic 3086, Australia. [Ryan, Michael T.] La Trobe Univ, ARC Ctr Excellence Coherent Xray Sci, Melbourne, Vic 3086, Australia. RP Thorburn, DR (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Melbourne, Vic 3052, Australia. EM david.thorburn@mcri.edu.au; vamsi@hms.harvard.edu RI Ryan, Michael/C-6673-2011; Tucker, Elena/B-3487-2012; Thorburn, David/G-6266-2013; Christodoulou, John/E-5866-2015; OI Ryan, Michael/0000-0003-2586-8829; Hershman, Steven/0000-0001-9167-7380; thorburn, david/0000-0002-7725-9470; McKenzie, Matthew/0000-0001-7508-1800; Compton, Alison/0000-0002-2725-7055; Christodoulou, John/0000-0002-8431-0641 FU Australian Postgraduate Award; National Defense Science and Engineering Graduate Fellowship; Australian National Health and Medical Research Council (NHMRC); Victorian Government; Ramaciotti Foundation; James and Vera Lawson Trust; NHMRC; National Institutes of Health [GM17151, GM077465, GM097136] FX We thank J. Silke and P. Ekert for providing the pF_5x_UAS_MCS_SV40_puroGEV16-W vector, C. Guiducci, C. Sougnez, L. Ambrogia, and J. Wilkinson, for assistance with sample preparation and sequencing, T. Fennel, M. DePristo, E. Banks, and K. Garimella for assistance with bioinformatic analysis, S. Flynn for assistance with IRBs, and the subjects and referring physicians who participated in the study. This work was supported by an Australian Postgraduate Award to E.J.T., a National Defense Science and Engineering Graduate Fellowship to S.G.H., an Australian National Health and Medical Research Council (NHMRC) Career Development Award to M.M., an NHMRC Principal Research fellowship to D.R.T., the Victorian Government's Operational Infrastructure Support Program, and grants from the Ramaciotti Foundation and the James and Vera Lawson Trust to M.M., the NHMRC to MM., M.T.R. and D.R.T., and the National Institutes of Health to U.L.R. (GM17151) and to V.K.M. (GM077465 and GM097136). NR 29 TC 52 Z9 54 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD SEP 7 PY 2011 VL 14 IS 3 BP 428 EP 434 DI 10.1016/j.cmet.2011.07.010 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 830MD UT WOS:000295660200016 PM 21907147 ER PT J AU Lewis, JH Li, RJ Jia, X Watkins, WT Lou, YF Song, WY Jiang, SB AF Lewis, John H. Li, Ruijiang Jia, Xun Watkins, W. Tyler Lou, Yifei Song, William Y. Jiang, Steve B. TI Mitigation of motion artifacts in CBCT of lung tumors based on tracked tumor motion during CBCT acquisition SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CONE-BEAM CT; 4-DIMENSIONAL COMPUTED-TOMOGRAPHY; RESPIRATORY MOTION; RADIOTHERAPY; SHRINKAGE; CANCER; RECONSTRUCTION; LOCALIZATION; MODEL; PROJECTIONS AB An algorithm capable of mitigating respiratory motion blurring artifacts in cone-beam computed tomography (CBCT) lung tumor images based on the motion of the tumor during the CBCT scan is developed. The tumor motion trajectory and probability density function (PDF) are reconstructed from the acquired CBCT projection images using a recently developed algorithm Lewis et al (2010 Phys. Med. Biol. 55 2505-22). Assuming that the effects of motion blurring can be represented by convolution of the static lung (or tumor) anatomy with the motion PDF, a cost function is defined, consisting of a data fidelity term and a total variation regularization term. Deconvolution is performed through iterative minimization of this cost function. The algorithm was tested on digital respiratory phantom, physical respiratory phantom and patient data. A clear qualitative improvement is evident in the deblurred images as compared to the motion-blurred images for all cases. Line profiles show that the tumor boundaries are more accurately and clearly represented in the deblurred images. The normalized root-mean-squared error between the images used as ground truth and the motion-blurred images are 0.29, 0.12 and 0.30 in the digital phantom, physical phantom and patient data, respectively. Deblurring reduces the corresponding values to 0.13, 0.07 and 0.19. Application of a -700 HU threshold to the digital phantom results in tumor dimension measurements along the superior-inferior axis of 2.8, 1.8 and 1.9 cm in the motion-blurred, ground truth and deblurred images, respectively. Corresponding values for the physical phantom are 3.4, 2.7 and 2.7 cm. A threshold of -500 HU applied to the patient case gives measurements of 3.1, 1.6 and 1.7 cm along the SI axis in the CBCT, 4DCT and deblurred images, respectively. This technique could provide more accurate information about a lung tumor's size and shape on the day of treatment. C1 [Lewis, John H.; Li, Ruijiang; Jia, Xun; Watkins, W. Tyler; Song, William Y.; Jiang, Steve B.] Univ Calif San Diego, Ctr Adv Radiotherapy Technol, La Jolla, CA 92093 USA. [Lewis, John H.; Li, Ruijiang; Jia, Xun; Watkins, W. Tyler; Song, William Y.; Jiang, Steve B.] Univ Calif San Diego, Dept Radiat Oncol, La Jolla, CA 92093 USA. [Lewis, John H.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Lewis, John H.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Lou, Yifei] Univ Calif Los Angeles, Dept Math, Los Angeles, CA 90095 USA. RP Lewis, JH (reprint author), Univ Calif San Diego, Ctr Adv Radiotherapy Technol, La Jolla, CA 92093 USA. EM sbjiang@ucsd.edu FU Varian Medical Systems, Inc. FX This work was partially supported by Varian Medical Systems, Inc. NR 43 TC 6 Z9 6 U1 1 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 7 PY 2011 VL 56 IS 17 BP 5485 EP 5502 DI 10.1088/0031-9155/56/17/003 PG 18 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 818WK UT WOS:000294786400006 PM 21813959 ER PT J AU Liu, EB Ferreyra, L Fischer, SL Pavan, JV Nates, SV Hudson, NR Tirado, D Dyer, DW Chodosh, J Seto, D Jones, MS AF Liu, Elizabeth B. Ferreyra, Leonardo Fischer, Stephen L. Pavan, Jorge V. Nates, Silvia V. Hudson, Nolan Ryan Tirado, Damaris Dyer, David W. Chodosh, James Seto, Donald Jones, Morris S. TI Genetic Analysis of a Novel Human Adenovirus with a Serologically Unique Hexon and a Recombinant Fiber Gene SO PLOS ONE LA English DT Article ID EPIDEMIC KERATOCONJUNCTIVITIS; GASTROENTERITIS; INTERNALIZATION; PROTEINS; EVASION AB In February of 1996 a human adenovirus (formerly known as Ad-Cor-96-487) was isolated from the stool of an AIDS patient who presented with severe chronic diarrhea. To characterize this apparently novel pathogen of potential public health significance, the complete genome of this adenovirus was sequenced to elucidate its origin. Bioinformatic and phylogenetic analyses of this genome demonstrate that this virus, heretofore referred to as HAdV-D58, contains a novel hexon gene as well as a recombinant fiber gene. In addition, serological analysis demonstrated that HAdV-D58 has a different neutralization profile than all previously characterized HAdVs. Bootscan analysis of the HAdV-D58 fiber gene strongly suggests one recombination event. C1 [Liu, Elizabeth B.; Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA USA. [Liu, Elizabeth B.; Seto, Donald] George Mason Univ, Dept Syst Biol, Manassas, VA USA. [Ferreyra, Leonardo; Pavan, Jorge V.; Nates, Silvia V.] Natl Univ Cordoba, Inst Virol, Sch Med Sci, Cordoba, Argentina. [Fischer, Stephen L.] USN, Hosp Camp Pendleton, Camp Pendleton, CA USA. [Hudson, Nolan Ryan; Tirado, Damaris] David Grant USAF Med Ctr, Clin Invest Facil, Fairfield, CA USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab,Dept Ophthalmol, Boston, MA USA. [Jones, Morris S.] Calif Dept Publ Hlth, Viral & Rickettsial Dis Lab, Richmond, CA USA. RP Liu, EB (reprint author), George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA USA. EM morris.jones@cdph.ca.gov FU United States Air Force Surgeon General [FDG20040024E]; Research to Prevent Blindness, Inc.; [R01EY013124]; [P30EY014104] FX This research was supported by R01EY013124 (DS, MSJ and JC) and P30EY014104 (JC). MSJ was also funded by the United States Air Force Surgeon General-approved Clinical Investigation No. FDG20040024E. JC was also funded by an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 27 Z9 35 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 7 PY 2011 VL 6 IS 9 AR e24491 DI 10.1371/journal.pone.0024491 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819CH UT WOS:000294802500054 PM 21915339 ER PT J AU Yonesaka, K Zejnullahu, K Okamoto, I Satoh, T Cappuzzo, F Souglakos, J Ercan, D Rogers, A Roncalli, M Takeda, M Fujisaka, Y Philips, J Shimizu, T Maenishi, O Cho, YG Sun, JS Destro, A Taira, K Takeda, K Okabe, T Swanson, J Itoh, H Takada, M Lifshits, E Okuno, K Engelman, JA Shivdasani, RA Nishio, K Fukuoka, M Varella-Garcia, M Nakagawa, K Janne, PA AF Yonesaka, Kimio Zejnullahu, Kreshnik Okamoto, Isamu Satoh, Taroh Cappuzzo, Federico Souglakos, John Ercan, Dalia Rogers, Andrew Roncalli, Massimo Takeda, Masayuki Fujisaka, Yasuhito Philips, Juliet Shimizu, Toshio Maenishi, Osamu Cho, Yonggon Sun, Jason Destro, Annarita Taira, Koichi Takeda, Koji Okabe, Takafumi Swanson, Jeffrey Itoh, Hiroyuki Takada, Minoru Lifshits, Eugene Okuno, Kiyotaka Engelman, Jeffrey A. Shivdasani, Ramesh A. Nishio, Kazuto Fukuoka, Masahiro Varella-Garcia, Marileila Nakagawa, Kazuhiko Jaenne, Pasi A. TI Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR RECEPTOR; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; WILD-TYPE; MET AMPLIFICATION; IN-VIVO; GEFITINIB; MUTATIONS; CHEMOTHERAPY AB Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers. C1 [Yonesaka, Kimio; Okamoto, Isamu; Satoh, Taroh; Takeda, Masayuki; Fujisaka, Yasuhito; Shimizu, Toshio; Nakagawa, Kazuhiko] Kinki Univ, Sch Med, Dept Med Oncol, Osaka 5898511, Japan. [Yonesaka, Kimio; Zejnullahu, Kreshnik; Ercan, Dalia; Rogers, Andrew; Sun, Jason; Okabe, Takafumi; Swanson, Jeffrey; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Yonesaka, Kimio; Zejnullahu, Kreshnik; Ercan, Dalia; Rogers, Andrew; Philips, Juliet; Sun, Jason; Okabe, Takafumi; Swanson, Jeffrey; Shivdasani, Ramesh A.; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Yonesaka, Kimio; Fukuoka, Masahiro] Izumi Municipal Hosp, Dept Med Oncol, Osaka 5940071, Japan. [Cappuzzo, Federico; Roncalli, Massimo; Destro, Annarita] Ist Clin Humanitas, I-20089 Rozzano, Italy. [Souglakos, John] Univ Crete, Lab Tumor Biol, Sch Med, Iraklion 71110, Greece. [Souglakos, John] Univ Hosp Heraklion, Iraklion 71110, Greece. [Maenishi, Osamu; Itoh, Hiroyuki] Kinki Univ, Sch Med, Dept Pathol, Osaka 5898511, Japan. [Cho, Yonggon; Varella-Garcia, Marileila] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. [Taira, Koichi; Takeda, Koji] Osaka City Gen Hosp, Dept Clin Oncol, Osaka 5340021, Japan. [Takada, Minoru; Fukuoka, Masahiro] Kinki Univ, Sch Med, Sakai Hosp, Dept Med Oncol, Osaka 5900132, Japan. [Lifshits, Eugene; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Okuno, Kiyotaka] Kinki Univ, Sch Med, Dept Surg, Osaka 5898511, Japan. [Shivdasani, Ramesh A.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shivdasani, Ramesh A.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nishio, Kazuto] Kinki Univ, Sch Med, Dept Genome Biol, Osaka 5898511, Japan. RP Nakagawa, K (reprint author), Kinki Univ, Sch Med, Dept Med Oncol, Osaka 5898511, Japan. EM nakagawa@med.kindai.ac.jp; pjanne@partners.org RI Cho, Yong Gon/Q-9924-2016; OI Cho, Yong Gon/0000-0003-3011-6875; Cappuzzo, Federico/0000-0002-6295-6767; Roncalli, Massimo/0000-0002-7901-8910 FU NIH [RO1CA114465, R01CA135257, P50 CA58187]; American Cancer Society [RSG0610201CCE]; Lung Cancer [SPORE P50 CA090578]; Gastrointestinal Cancer [SPORE P50 CA127003]; William Randolph Hearst Foundation; Hazel and Samuel Bellin research fund; Cammarata Family Foundation; Roche FX Supported by NIH grants RO1CA114465 (P.A.J.), R01CA135257 (P.A.J. and J.A.E.), and P50 CA58187 (M. V.-G.); American Cancer Society RSG0610201CCE (P.A.J. and J.A.E.); the Lung Cancer SPORE P50 CA090578 (P.A.J. and J.A.E.); the Gastrointestinal Cancer SPORE P50 CA127003 (P.A.J. and J.A.E.); the William Randolph Hearst Foundation (R. A. S.); the Hazel and Samuel Bellin research fund (P.A.J.); and Cammarata Family Foundation Research Fund (P.A.J.).; P.A.J. has consulted for Genentech and Roche. J.A.E. has consulted for Roche and Bristol-Myers Squibb. T. Satoh has consulted for Merck-Serono, Bristol-Myers Squib, Chugai-Pharmaceuticals, Takeda, Sanofi-Aventis, Taiho Pharmaceutical, Pfizer, and Daiichi-Sankyo P.A.J. and J.A.E. have received royalties from Roche on intellectual property not related to this work. A patent has been filed by Dana-Farber Cancer Institute involving the use of MET and EGFR inhibitors to overcome resistance to EGFR inhibitors. NR 38 TC 186 Z9 187 U1 6 U2 21 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD SEP 7 PY 2011 VL 3 IS 99 AR 99ra86 DI 10.1126/scitranslmed.3002442 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 817HY UT WOS:000294663900005 PM 21900593 ER PT J AU Dhaliwal, G AF Dhaliwal, Gurpreet TI The Mechanics of Reasoning SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, San Francisco, CA USA. RP Dhaliwal, G (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM gurpreet.dhaliwal@ucsf.edu NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 7 PY 2011 VL 306 IS 9 BP 918 EP 919 DI 10.1001/jama.2011.1027 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 815QT UT WOS:000294542600001 PM 21900128 ER PT J AU van Ryn, M Saha, S AF van Ryn, Michelle Saha, Somnath TI Exploring Unconscious Bias in Disparities Research and Medical Education SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HEALTH-CARE; PROVIDERS; CONTRIBUTE C1 [van Ryn, Michelle] Univ Minnesota, Sch Med, Dept Family Med & Community Hlth, Minneapolis, MN 55414 USA. [Saha, Somnath] Portland VA Med Ctr, Gen Internal Med Sect, Portland, OR USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Div Gen Internal Med & Geriatr, Portland, OR 97201 USA. RP van Ryn, M (reprint author), Univ Minnesota, Sch Med, Dept Family Med & Community Hlth, 925 SE Delaware St,Ste 221, Minneapolis, MN 55414 USA. EM vanry001@umn.edu FU NHLBI NIH HHS [R01 HL085631] NR 14 TC 19 Z9 19 U1 2 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 7 PY 2011 VL 306 IS 9 BP 995 EP 996 DI 10.1001/jama.2011.1275 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 815QT UT WOS:000294542600020 PM 21900142 ER PT J AU Gao, G Xie, A Huang, SC Zhou, AY Zhang, JH Herman, AM Ghassemzadeh, S Jeong, EM Kasturirangan, S Raicu, M Sobieski, MA Bhat, G Tatooles, A Benz, EJ Kamp, TJ Dudley, SC AF Gao, Ge Xie, An Huang, Shu-Ching Zhou, Anyu Zhang, Jianhua Herman, Amanda M. Ghassemzadeh, Sassan Jeong, Euy-Myoung Kasturirangan, Srinivasan Raicu, Mihai Sobieski, Michael A., II Bhat, Geetha Tatooles, Antone Benz, Edward J., Jr. Kamp, Timothy J. Dudley, Samuel C., Jr. TI Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure SO CIRCULATION LA English DT Article DE angiotensin II; arrhythmia; cardiomyopathy; gene expression; sodium ID GENE-EXPRESSION; ATRIAL-FIBRILLATION; SELECTION; NETWORKS; PROTEIN; CANCER AB Background-Human heart failure is associated with decreased cardiac voltage-gated Na(+) channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. Methods and Results-Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na(+) channel current 91.1 +/- 9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. Conclusions-Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na(+) channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure. (Circulation. 2011; 124: 1124-1131.) C1 [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Raicu, Mihai; Dudley, Samuel C., Jr.] Univ Illinois, Cardiol Sect, Div Cardiol, Chicago, IL 60612 USA. [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Raicu, Mihai; Dudley, Samuel C., Jr.] Jesse Brown VAMC, Chicago, IL USA. [Huang, Shu-Ching; Zhou, Anyu; Benz, Edward J., Jr.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Jianhua; Herman, Amanda M.; Kamp, Timothy J.] Univ Wisconsin, Div Cardiovasc Med, Dept Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Ghassemzadeh, Sassan] Univ Illinois, Coll Med, Chicago, IL USA. [Kasturirangan, Srinivasan] Univ Illinois, Div Neonatol, Dept Pediat, Chicago, IL 60612 USA. [Sobieski, Michael A., II; Bhat, Geetha; Tatooles, Antone] Advocate Christ Med Ctr, Oak Lawn, IL USA. RP Dudley, SC (reprint author), Univ Illinois, Cardiol Sect, Div Cardiol, 840 S Wood St,MC 715, Chicago, IL 60612 USA. EM scdudley@uic.edu OI Kamp, Timothy/0000-0003-2103-7876 FU National Heart, Lung, and Blood Institute [R01 HL085558, R01 HL073753, P01 HL058000]; Veterans Affairs MERIT FX This work was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL085558, R01 HL073753, P01 HL058000) and a Veterans Affairs MERIT grant. NR 33 TC 24 Z9 28 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 6 PY 2011 VL 124 IS 10 BP 1124 EP U112 DI 10.1161/CIRCULATIONAHA.111.044495 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 815VF UT WOS:000294557400016 PM 21859973 ER PT J AU Roberts, LD AF Roberts, Lee D. TI Funding: Fondation Leducq Transatlantic Career Development Award SO CIRCULATION LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Roberts, LD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 6 PY 2011 VL 124 IS 10 BP F58 EP F58 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 815VF UT WOS:000294557400002 ER PT J AU Dabora, SL Franz, DN Ashwal, S Sagalowsky, A DiMario, FJ Miles, D Cutler, D Krueger, D Uppot, RN Rabenou, R Camposano, S Paolini, J Fennessy, F Lee, N Woodrum, C Manola, J Garber, J Thiele, EA AF Dabora, Sandra L. Franz, David Neal Ashwal, Stephen Sagalowsky, Arthur DiMario, Francis J., Jr. Miles, Daniel Cutler, Drew Krueger, Darcy Uppot, Raul N. Rabenou, Rahmin Camposano, Susana Paolini, Jan Fennessy, Fiona Lee, Nancy Woodrum, Chelsey Manola, Judith Garber, Judy Thiele, Elizabeth A. TI Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease SO PLOS ONE LA English DT Article ID RENAL-CELL CARCINOMA; GROWTH FACTOR-D; RAPAMYCIN ANALOG CCI-779; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; MUTATIONAL ANALYSIS; IMPROVED SURVIVAL; MAMMALIAN TARGET; LUNG-FUNCTION; MOUSE MODEL; COMPLEX AB Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. C1 [Dabora, Sandra L.] Biogen Idec Hemophilia, Weston, MA USA. [Uppot, Raul N.; Camposano, Susana; Paolini, Jan; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fennessy, Fiona; Manola, Judith; Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Franz, David Neal; Krueger, Darcy] Univ Cincinnati, Cincinnati, OH USA. [Ashwal, Stephen; Cutler, Drew] Loma Linda Univ, Loma Linda, CA 92350 USA. [Sagalowsky, Arthur] Univ Texas SW, Dallas, TX USA. [DiMario, Francis J., Jr.] Univ Connecticut, Hartford, CT 06112 USA. [Miles, Daniel; Rabenou, Rahmin] NYU, New York, NY USA. [Lee, Nancy; Woodrum, Chelsey] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Dabora, SL (reprint author), Biogen Idec Hemophilia, Weston, MA USA. EM sandy.dabora@gmail.com FU National Institute of Health/National Cancer Institute [R01CA107164]; Tuberous Sclerosis Alliance planning and supplement grants; Brigham and Women's Hospital Research Institute FX This trial was funded by the following grants to SD: National Institute of Health/National Cancer Institute (R01CA107164), Tuberous Sclerosis Alliance planning and supplement grants, and the Brigham and Women's Hospital Research Institute Bridge Funding Award. Wyeth/Pfizer supplied study drug at no charge per an investigator originated proposal written by SD. The funders played no role in the design of the trial, data collection and analysis, decision to publish, or preparation of the manuscript. SD designed the experiments, directed the analysis of the data, wrote the first draft of the manuscript, and directed the final editing of the manuscript. SD is currently an employee of Biogen Idec Hemophilia, however the reported trial was completed when SD was on staff at Brigham and Women's Hospital. NR 56 TC 80 Z9 84 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2011 VL 6 IS 9 AR e23379 DI 10.1371/journal.pone.0023379 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817QP UT WOS:000294689200005 PM 21915260 ER PT J AU Lindquist, S Karitkina, D Langnaese, K Posevitz-Fejfar, A Schraven, B Xavier, R Seed, B Lindquist, JA AF Lindquist, Sabine Karitkina, Diana Langnaese, Kristina Posevitz-Fejfar, Anita Schraven, Burkhart Xavier, Ramnik Seed, Brian Lindquist, Jonathan A. TI Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains Differentially Modulates Src Kinase Activity in Brain Maturation SO PLOS ONE LA English DT Article ID FAMILY TYROSINE KINASES; T-CELL-ACTIVATION; TRANSMEMBRANE ADAPTER PROTEIN; DOWN-REGULATION; MUTANT MICE; SIGNAL-TRANSDUCTION; NEGATIVE REGULATION; LIPID RAFTS; PC12 CELLS; C-SRC AB Src family kinases (SFK) control multiple processes during brain development and function. We show here that the phosphoprotein associated with glycosphigolipid-enriched microdomains (PAG)/Csk binding protein (Cbp) modulates SFK activity in the brain. The timing and localization of PAG expression overlap with Fyn and Src, both of which we find associated to PAG. We demonstrate in newborn (P1) mice that PAG negatively regulates Src family kinases (SFK). P1 Pag1(-/-)mouse brains show decreased recruitment of Csk into lipid rafts, reduced phosphorylation of the inhibitory tyrosines within SFKs, and an increase in SFK activity of >/= 50%. While in brain of P1 mice, PAG and Csk are highly and ubiquitously expressed, little Csk is found in adult brain suggesting altered modes of SFK regulation. In adult brain Pag1-deficiency has no effect upon Csk-distribution or inhibitory tyrosine phosphorylation, but kinase activity is now reduced (-20-30%), pointing to the development of a compensatory mechanism that may involve PSD93. The distribution of the Csk-homologous kinase CHK is not altered. Importantly, since the activities of Fyn and Src are decreased in adult Pag1(-/-)mice, thus presenting the reversed phenotype of P1, this provides the first in vivo evidence for a Csk-independent positive regulatory function for PAG in the brain. C1 [Lindquist, Sabine] Hannover Med Sch, Dept Neurol, D-3000 Hannover, Germany. [Lindquist, Sabine; Karitkina, Diana] Leibniz Inst Neurobiol, Magdeburg, Germany. [Langnaese, Kristina] Otto Von Guericke Univ, Inst Biochem & Cell Biol, Magdeburg, Germany. [Posevitz-Fejfar, Anita; Schraven, Burkhart; Lindquist, Jonathan A.] Otto Von Guericke Univ, Inst Mol & Clin Immunol, Magdeburg, Germany. [Schraven, Burkhart] Helmholtz Ctr Infect Res, Dept Immune Control, Braunschweig, Germany. [Xavier, Ramnik; Seed, Brian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. RP Lindquist, S (reprint author), Hannover Med Sch, Dept Neurol, D-3000 Hannover, Germany. EM lindquist.sabine@mh-hannover.de FU German Ministry for Education and Research (Bundesministerium fur Bildung und Forschung (BMBF)) [FKZ 01ZZ0407]; German Research Society (DFG) [1031/1-3] FX B.S. and J.L. are members of the Magdeburg Center for Systems Biology (MACS) and the SYBILLA consortium [European Union 7th Frame Program]. This work was supported by the German Ministry for Education and Research (Bundesministerium fur Bildung und Forschung (BMBF)) NBL3 program- FKZ 01ZZ0407, Startup grant to S. L. and in part by the German Research Society (DFG)[JL 1031/1-3] to J.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 12 Z9 12 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2011 VL 6 IS 9 AR e23978 DI 10.1371/journal.pone.0023978 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817QP UT WOS:000294689200014 PM 21915273 ER PT J AU Triantafyllou, C Wald, LL Hoge, RD AF Triantafyllou, Christina Wald, Lawrence L. Hoge, Richard D. TI Echo-Time and Field Strength Dependence of BOLD Reactivity in Veins and Parenchyma Using Flow-Normalized Hypercapnic Manipulation SO PLOS ONE LA English DT Article ID CEREBRAL-BLOOD-FLOW; HUMAN MOTOR CORTEX; FUNCTIONAL MRI; 7 T; OXYGEN-CONSUMPTION; FMRI; ACTIVATION; HUMANS; SIGNAL; EPI AB While the BOLD (Blood Oxygenation Level Dependent) contrast mechanism has demonstrated excellent sensitivity to neuronal activation, its specificity with regards to differentiating vascular and parenchymal responses has been an area of ongoing concern. By inducing a global increase in Cerebral Blood Flow (CBF), we examined the effect of magnetic field strength and echo-time (TE) on the gradient-echo BOLD response in areas of cortical gray matter and in resolvable veins. In order to define a quantitative index of BOLD reactivity, we measured the percent BOLD response per unit fractional change in global gray matter CBF induced by inhaling carbon dioxide (CO(2)). By normalizing the BOLD response to the underlying CBF change and determining the BOLD response as a function of TE, we calculated the change in R(2)* (Delta R(2)*) per unit fractional flow change; the Flow Relaxation Coefficient, (FRC) for 3T and 1.5T in parenchymal and large vein compartments. The FRC in parenchymal voxels was 1.76 +/- 0.54 fold higher at 3T than at 1.5T and was 2.96 +/- 0.66 and 3.12 +/- 0.76 fold higher for veins than parenchyma at 1.5T and 3T respectively, showing a quantitative measure of the increase in specificity to parenchymal sources at 3T compared to 1.5T. Additionally, the results allow optimization of the TE to prioritize either maximum parenchymal BOLD response or maximum parenchymal specificity. Parenchymal signals peaked at TE values of 62.0 +/- 11.5 ms and 41.5 +/- 7.5 ms for 1.5T and 3T, respectively, while the response in the major veins peaked at shorter TE values; 41.0 +/- 6.9 ms and 21.5 +/- 1.0 ms for 1.5T and 3T. These experiments showed that at 3T, the BOLD CNR in parenchymal voxels exceeded that of 1.5T by a factor of 1.9 +/- 0.4 at the optimal TE for each field. C1 [Triantafyllou, Christina] MIT, McGovern Inst Brain Res, AA Martinos Imaging Ctr, Cambridge, MA 02139 USA. [Triantafyllou, Christina; Wald, Lawrence L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA USA. [Wald, Lawrence L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hoge, Richard D.] Inst Univ Geriatrie Montreal, Ctr Rech, Unite Neuroimagerie Fonct, Montreal, PQ, Canada. [Hoge, Richard D.] Univ Montreal, Montreal, PQ, Canada. RP Triantafyllou, C (reprint author), MIT, McGovern Inst Brain Res, AA Martinos Imaging Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ctrianta@mit.edu RI Wald, Lawrence/D-4151-2009 FU National Institutes of Health; National Center for Research Resources (NCRR); P41 Regional Resource Grant [P41RR14075, RO1RR1453A01]; Mental Illness and Neuroscience Discovery (MIND) Institute; Canadian National Science and Engineering Council [355583-2010]; Canadian Institutes of Health Research [MOP 84378] FX This research was supported by grants from the National Institutes of Health, the National Center for Research Resources (NCRR), the P41 Regional Resource Grant P41RR14075, RO1RR1453A01, the Mental Illness and Neuroscience Discovery (MIND) Institute, the Canadian National Science and Engineering Council (355583-2010) and the Canadian Institutes of Health Research (MOP 84378). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 3 Z9 3 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 6 PY 2011 VL 6 IS 9 AR e24519 DI 10.1371/journal.pone.0024519 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817QP UT WOS:000294689200052 PM 21915346 ER PT J AU Zhao, B Zou, J Wang, HF Johannsen, E Peng, CW Quackenbush, J Mar, JC Morton, CC Freedman, ML Blacklow, SC Aster, JC Bernstein, BE Kieff, E AF Zhao, Bo Zou, James Wang, Hongfang Johannsen, Eric Peng, Chih-wen Quackenbush, John Mar, Jessica C. Morton, Cynthia Casson Freedman, Matthew L. Blacklow, Stephen C. Aster, Jon C. Bernstein, Bradley E. Kieff, Elliott TI Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE leukemia; lymphoma; Notch; development ID SIGNAL-BINDING-PROTEIN; LONG-RANGE INTERACTION; NUCLEAR ANTIGEN-2; C-MYC; J-KAPPA; CIS-ELEMENT; PROMOTER; GENOME; FATE; GENE AB Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NF.B (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NF.B RELA, and PU. 1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 upregulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5' of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation. C1 [Zhao, Bo; Johannsen, Eric; Peng, Chih-wen; Kieff, Elliott] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Zhao, Bo; Johannsen, Eric; Peng, Chih-wen; Kieff, Elliott] Brigham & Womens Hosp, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Wang, Hongfang; Morton, Cynthia Casson; Blacklow, Stephen C.; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Zou, James] Massachusetts Gen Hosp, Sch Engn & Appl Sci, Boston, MA 02114 USA. [Zou, James; Bernstein, Bradley E.] Massachusetts Gen Hosp, Broad Inst, Howard Hughes Med Inst, Boston, MA 02114 USA. [Zou, James; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Quackenbush, John; Mar, Jessica C.] Harvard Univ, Dana Farber Canc Inst, Dept Canc Biol, Cambridge, MA 02138 USA. [Freedman, Matthew L.] Harvard Univ, Dana Farber Canc Inst, Dept Med Oncol, Cambridge, MA 02138 USA. RP Kieff, E (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM ekieff@rics.bwh.harvard.edu FU National Institutes of Health [R01CA047006, R01CA131354, R01CA085180, 1P50 HG004233, U54 HG004570]; Roadmap Epigenomics Mapping Center [U01 ES017155] FX We thank Dr. Richard Myers and Encyclopedia of DNA Elements (ENCODE) for EBF, PU.1, P300, RELA, PolII LCL ChIP-seq data; Drs. Ben Gewurz, Federica DePalma, Mark Fogg, Ellen Cahir-McFarland, Daniel Portal, and Micheal Calderwood for discussion; and Andrew Gagne and Pedro Teixeira for data conversion. This work was supported in part by National Institutes of Health Grants R01CA047006, R01CA131354, R01CA085180, and 1P50 HG004233, ENCODE Grant U54 HG004570, and Roadmap Epigenomics Mapping Center U01 ES017155 (to B.E.B.). NR 49 TC 64 Z9 64 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2011 VL 108 IS 36 BP 14902 EP 14907 DI 10.1073/pnas.1108892108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 815QZ UT WOS:000294543400041 PM 21746931 ER PT J AU Wang, HF Zou, J Zhao, B Johannsen, E Ashworth, T Wong, HF Pear, WS Schug, J Blacklow, SC Arnett, KL Bernstein, BE Kieff, E Aster, JC AF Wang, Hongfang Zou, James Zhao, Bo Johannsen, Eric Ashworth, Todd Wong, Hoifung Pear, Warren S. Schug, Jonathan Blacklow, Stephen C. Arnett, Kelly L. Bernstein, Bradley E. Kieff, Elliott Aster, Jon C. TI Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CSL; lymphoma; transformation ID TRANSCRIPTION FACTOR-BINDING; BARR-VIRUS EBNA2; BIDIRECTIONAL PROMOTERS; HUMAN STAF/ZNF143; C-MYC; ACTIVATION; LINEAGE; GROWTH; SPECIFICATION; CHROMATIN AB Notch1 regulates gene expression by associating with the DNA-binding factor RBPJ and is oncogenic in murine and human T-cell progenitors. Using ChIP-Seq, we find that in human and murine T-lymphoblastic leukemia (TLL) genomes Notch1 binds preferentially to promoters, to RBPJ binding sites, and near imputed ZNF143, ETS, and RUNX sites. ChIP-Seq confirmed that ZNF143 binds to similar to 40% of Notch1 sites. Notch1/ZNF143 sites are characterized by high Notch1 and ZNF143 signals, frequent cobinding of RBPJ (generally through sites embedded within ZNF143 motifs), strong promoter bias, and relatively low mean levels of activating chromatin marks. RBPJ and ZNF143 binding to DNA is mutually exclusive in vitro, suggesting RBPJ/Notch1 and ZNF143 complexes exchange on these sites in cells. K-means clustering of Notch1 binding sites and associated motifs identified conserved Notch1-RUNX, Notch1-ETS, Notch1-RBPJ, Notch1-ZNF143, and Notch1-ZNF143-ETS clusters with different genomic distributions and levels of chromatin marks. Although Notch1 binds mainly to gene promoters, similar to 75% of direct target genes lack promoter binding and are presumably regulated by enhancers, which were identified near MYC, DTX1, IGF1R, IL7R, and the GIMAP cluster. Human and murine TLL genomes also have many sites that bind only RBPJ. Murine RBPJ-only sites are highly enriched for imputed REST (a DNA-binding transcriptional repressor) sites, whereas human RPBJ-only sites lack REST motifs and are more highly enriched for imputed CREB sites. Thus, there is a conserved network of cis-regulatory factors that interacts with Notch1 to regulate gene expression in TLL cells, as well as unique classes of divergent RBPJ-only sites that also likely regulate transcription. C1 [Zou, James] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Wang, Hongfang; Ashworth, Todd; Wong, Hoifung; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Zhao, Bo; Johannsen, Eric; Kieff, Elliott] Brigham & Womens Hosp, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Zhao, Bo; Johannsen, Eric; Kieff, Elliott] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Pear, Warren S.] Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. [Schug, Jonathan] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Blacklow, Stephen C.; Arnett, Kelly L.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Pathol, Boston, MA 02114 USA. RP Zou, J (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM jzou@fas.harvard.edu; ekieff@rics.bwh.harvard.edu; jaster@rics.bwh.harvard.edu RI Arnett, Kelly/C-4816-2012; OI Arnett, Kelly/0000-0001-5117-3647 FU National Institutes of Health [P01CA119070, R01CA047006, R01CA131354, R01 CA085180]; Leukemia and Lymphoma Society; The Howard Hughes Medical Institute; National Human Genome Research Institute; National Institutes of Health Epigenome Mapping Centers Consortium [U54 HG004570, U01 ES017155]; National Science Foundation FX We thank Jeremiah Huang for technical assistance and the University of Pennsylvania Diabetes and Endocrinology Center for the use of the Functional Genomics Core (P30-DK19525). This work was supported in part by National Institutes of Health Grant P01CA119070 and a Specialized Center of Research grant from the Leukemia and Lymphoma Society (to J.C.A., S.C.B., and W.S.P.); The Howard Hughes Medical Institute, the National Human Genome Research Institute, and the National Institutes of Health Epigenome Mapping Centers Consortium, Encyclopedia Of DNA Elements Grant U54 HG004570, and Roadmap Epigenomics Grant U01 ES017155 (to B.E.B.); National Institutes of Health Grants R01CA047006, R01CA131354, and R01 CA085180 (to E.K.); and a National Science Foundation Graduate Student Fellowship (to J.Z.). NR 43 TC 102 Z9 103 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 6 PY 2011 VL 108 IS 36 BP 14908 EP 14913 DI 10.1073/pnas.1109023108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 815QZ UT WOS:000294543400042 PM 21737748 ER PT J AU Jaff, MR AF Jaff, Michael R. TI The Breakthrough Balloon for Critical Limb Ischemia? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE drug-coated balloons; peripheral artery disease ID ARTERIAL-DISEASE; ANGIOPLASTY; BYPASS; METAANALYSIS; THERAPY; TRIAL; VEIN C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jaff, Michael R.] Abbott Vasc, Abbott Pk, IL USA. [Jaff, Michael R.] Boston Sci, Natick, MA USA. [Jaff, Michael R.] Covidien Corp, Dublin, Ireland. [Jaff, Michael R.] Cordis Endovasc, Bridgewater, NJ USA. [Jaff, Michael R.] Medtron Vasc, Santa Rosa, CA USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM mjaff@partners.org NR 19 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 6 PY 2011 VL 58 IS 11 BP 1110 EP 1111 DI 10.1016/j.jacc.2011.06.009 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 814KG UT WOS:000294449200004 PM 21884946 ER PT J AU McNamara, DM Starling, RC Cooper, LT Boehmer, JP Mather, PJ Janosko, KM Gorcsan, J Kip, KE Dec, GW AF McNamara, Dennis M. Starling, Randall C. Cooper, Leslie T. Boehmer, John P. Mather, Paul J. Janosko, Karen M. Gorcsan, John, III Kip, Kevin E. Dec, G. William CA IMAC Investigators TI Clinical and Demographic Predictors of Outcomes in Recent Onset Dilated Cardiomyopathy Results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiomyopathy; echocardiography; myocardial function; outcomes; recovery ID LEFT-VENTRICULAR FUNCTION; CHRONIC HEART-FAILURE; CONTROLLED TRIAL; TRANSPLANTATION; CARVEDILOL; SOCIETY AB Objectives We sought to determine clinical and demographic predictors of recovery of left ventricular function for subjects with recent onset cardiomyopathy (ROCM). Background Although ROCM is a frequent reason for consultation and transplantation referral, its prognosis and natural history on contemporary therapy are unknown. Methods In the multicenter IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study, subjects with a left ventricular ejection fraction (LVEF) of <= 0.40, fewer than 6 months of symptom duration, and an evaluation consistent with idiopathic dilated cardiomyopathy or myocarditis were enrolled. LVEF was reassessed at 6 months, and subjects were followed up for 4 years. LVEF and event-free survival were compared by race, sex, and clinical phenotype. Results The cohort of 373 persons was 38% female and 21% black, with a mean age of 45 +/- 14 years. At entry, 91% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and 82% were receiving beta-blockers, which increased to 92% and 94% at 6 months. LVEF was 0.24 +/- 0.08 at entry and 0.40 +/- 0.12 at 6 months (mean increase: 17 +/- 13 ejection fraction units). Transplant-free survival at 1, 2, and 4 years was 94%, 92%, and 88%, respectively; survival free of heart failure hospitalization was 88%, 82%, and 78%, respectively. In analyses adjusted for sex, baseline LVEF, and blood pressure, LVEF at 6 months was significantly lower in blacks than in nonblacks (p = 0.02). Left ventricular end-diastolic diameter at presentation was the strongest predictor of LVEF at 6 months (p < 0.0001). Conclusions Outcomes in ROCM are favorable but differ by race. Left ventricular end-diastolic diameter by transthoracic echo at presentation was most predictive of subsequent myocardial recovery. (Genetic Modulation of Left Ventricular Recovery in Recent Onset Cardiomyopathy; NCT00575211) (J Am Coll Cardiol 2011; 58: 1112-8) (C) 2011 by the American College of Cardiology Foundation C1 [McNamara, Dennis M.; Janosko, Karen M.; Gorcsan, John, III] Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. [Starling, Randall C.] Cleveland Clin, Cleveland, OH 44106 USA. [Cooper, Leslie T.] Mayo Clin, Rochester, MN USA. [Boehmer, John P.] Penn State Hershey Med Ctr, Hershey, PA USA. [Mather, Paul J.] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Heart Inst, Philadelphia, PA 19107 USA. [Kip, Kevin E.] Univ S Florida, Tampa, FL USA. [Dec, G. William] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Starling, Randall C.] Medtronic, Minneapolis, MN USA. [Starling, Randall C.] Novartis, Basel, Switzerland. RP McNamara, DM (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, 200 Lothrop St,566 Scaife Hall, Pittsburgh, PA 15213 USA. EM mcnamaradm@upmc.edu FU National Heart, Lung, and Blood Institute [HL075038, HL086918, HL69912]; National Institutes of Health, Bethesda, Maryland; Novartis FX From the Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; dagger Cleveland Clinic, Cleveland, Ohio; double dagger Mayo Clinic, Rochester, Minnesota; Penn State Hershey Medical Center, Hershey, Pennsylvania; vertical bar vertical bar Jefferson Heart Institute, Jefferson College of Medicine, Philadelphia, Pennsylvania; University of South Florida, Tampa, Florida; and the # Massachusetts General Hospital, Boston, Massachusetts. This study was supported by National Heart, Lung, and Blood Institute contracts HL075038, HL086918, and HL69912, National Institutes of Health, Bethesda, Maryland. Dr. Starling is on the advisory board of Medtronic and Novartis; has received research support from Novartis; and has stock options in Cardiomens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 17 TC 68 Z9 75 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 6 PY 2011 VL 58 IS 11 BP 1112 EP 1118 DI 10.1016/j.jacc.2011.05.033 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 814KG UT WOS:000294449200005 PM 21884947 ER PT J AU Ng, K Chen, CC AF Ng, Kimberly Chen, Clark C. TI Oncogene addiction and non-oncogene addiction in glioblastoma therapy SO CHINESE MEDICAL JOURNAL LA English DT Editorial Material ID ADJUVANT TEMOZOLOMIDE; CANCER-THERAPY; RADIOTHERAPY; KINASE; CELLS; MYC; TUMORIGENESIS; CONCOMITANT; GLIOMAS; GENOME C1 [Chen, Clark C.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02115 USA. [Chen, Clark C.] Beth Israel Deaconess Med Ctr, Div Neurosurg, Boston, MA 02215 USA. RP Chen, CC (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Jimmy Fund 620A,44 Binney St, Boston, MA 02115 USA. EM clarkchen@ucsd.edu NR 29 TC 1 Z9 1 U1 1 U2 2 PU CHINESE MEDICAL ASSOC PI BEIJING PA 42 DONGSI XIDAJIE, BEIJING 100710, PEOPLES R CHINA SN 0366-6999 J9 CHINESE MED J-PEKING JI Chin. Med. J. PD SEP 5 PY 2011 VL 124 IS 17 BP 2565 EP 2568 DI 10.3760/cma.j.issn.0366-6999.2011.17.001 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 825QO UT WOS:000295297400001 PM 22040404 ER PT J AU Zhu, ZL Li, GA AF Zhu, Zhonglin Li, Guoan TI Construction of 3D human distal femoral surface models using a 3D statistical deformable model SO JOURNAL OF BIOMECHANICS LA English DT Article DE Statistical shape model; Knee; 3D knee model; Fluoroscopic images ID PROXIMAL FEMUR; SHAPE MODELS; RECONSTRUCTION; VALIDATION; REGISTRATION; RADIOGRAPHS; KINEMATICS; SYSTEM AB Construction of 3D geometric surface models of human knee joint is always a challenge in biomedical engineering. This study introduced an improved statistical shape model (SSM) method that only uses 2D images of a joint to predict the 3D joint surface model. The SSM was constructed using 40 distal femur models of human knees. In this paper, a series validation and parametric analysis suggested that more than 25 distal femur models are needed to construct the SSM; each distal femur should be described using at least 3000 nodes in space; and two 2D fluoroscopic images taken in 45 directions should be used for the 3D surface shape prediction. Using this SSM method, ten independent distal femurs from 10 independent living subjects were predicted using their 2D plane fluoroscopic images. The predicted models were compared to their native 3D distal femur models constructed using their 3D MR images. The results demonstrated that using two fluoroscopic images of the knee, the overall difference between the predicted distal femur surface and the MR image-based surface was 0.16 +/- 1.16 mm. These data indicated that the SSM method could be a powerful method for construction of 3D surface geometries of the distal femur. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Zhu, Zhonglin; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Zhu, Zhonglin] Tsinghua Univ, Dept Biomed Engn, Beijing 100084, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, GRJ 1215,55 Fruit St, Boston, MA 02114 USA. EM gli1@partners.org FU National Institutes of Health [R01 AR055612]; China Scholarship Council [2010621146] FX This study was partially supported by a grant from National Institutes of Health (R01 AR055612) and a grant from the China Scholarship Council (2010621146) NR 32 TC 18 Z9 20 U1 2 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD SEP 2 PY 2011 VL 44 IS 13 BP 2362 EP 2368 DI 10.1016/j.jbiomech.2011.07.006 PG 7 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 820VM UT WOS:000294934200004 PM 21783195 ER PT J AU Son, EY Ichida, JK Wainger, BJ Toma, JS Rafuse, VF Woolf, CJ Eggan, K AF Son, Esther Y. Ichida, Justin K. Wainger, Brian J. Toma, Jeremy S. Rafuse, Victor F. Woolf, Clifford J. Eggan, Kevin TI Conversion of Mouse and Human Fibroblasts into Functional Spinal Motor Neurons SO CELL STEM CELL LA English DT Article ID EMBRYONIC STEM-CELLS; PROGENITOR CELLS; GENE-EXPRESSION; DEFINED FACTORS; MOTONEURONS; DIFFERENTIATION; NESTIN AB The mammalian nervous system comprises many distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although specific neuronal types can be isolated from rodent embryos or engineered from stem cells for translational studies, transcription factor-mediated reprogramming might provide a more direct route to their generation. Here we report that the forced expression of select transcription factors is sufficient to convert mouse and human fibroblasts into induced motor neurons (iMNs). iMNs displayed a morphology, gene expression signature, electrophysiology, synaptic functionality, in vivo engraftment capacity, and sensitivity to degenerative stimuli similar to those of embryo-derived motor neurons. We show that the converting fibroblasts do not transit through a proliferative neural progenitor state, and thus form bona fide motor neurons via a route distinct from embryonic development. Our findings demonstrate that fibroblasts can be converted directly into a specific differentiated and functional neural subtype, the spinal motor neuron. C1 [Son, Esther Y.; Ichida, Justin K.; Eggan, Kevin] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Son, Esther Y.; Ichida, Justin K.; Eggan, Kevin] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Son, Esther Y.; Eggan, Kevin] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Wainger, Brian J.; Woolf, Clifford J.] Childrens Hosp, Program Neurobiol, Boston, MA 02115 USA. [Wainger, Brian J.; Woolf, Clifford J.] Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Toma, Jeremy S.; Rafuse, Victor F.] Dalhousie Univ, Dept Anat & Neurobiol, Halifax, NS B3H 1X5, Canada. RP Eggan, K (reprint author), Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. EM keggan@scrb.harvard.edu FU Howard Hughes Medical Institute; Harvard Stem Cell Institute; P2ALS; New York Stem Cell Foundation; NIH [1RC2 NS069395-01, R01 HD045732-03, 5T32GM007592]; Novartis Institutes for BioMedical Research; Stan and Fiona Druckenmiller/New York Stem Cell Foundation; Natural Sciences and Engineering Research Council of Canada FX We are grateful to A.C. Carter for help with lineage tracing experiments and E. Kiskinis, S. de Boer, G. Boulting, and J. Rivera-Feliciano for providing reagents and helpful discussions. We would also like to thank B. Tilton for assistance with FAGS, K. Harrison for providing the mouse Hb9 cDNA, N. Atwater for assistance with glia preparation, J. Sandoe and K. Sandor for help with molecular cloning, K. Koszka for help with mouse husbandry, and M.Y. Son for help with the diagram in Figure 1. This work was made possible by support provided by the Howard Hughes Medical Institute, the Harvard Stem Cell Institute, P2ALS, the New York Stem Cell Foundation, NIH GO grant 1RC2 NS069395-01, and NIH grant R01 HD045732-03 to K.E. J.K.I. is supported by the Novartis Institutes for BioMedical Research and a Stan and Fiona Druckenmiller/New York Stem Cell Foundation postdoctoral fellowship. B.J.W. is supported by NIH Training Grant 5T32GM007592. C.J.W. used facilities provided by the Children's Hospital Boston Intellectual and Developmental Disabilities Research Center and the NIH. J.S.T. was funded by a Natural Sciences and Engineering Research Council of Canada graduate student scholarship award. V.F.R is supported by the Natural Sciences and Engineering Research Council of Canada. The authors are filing a patent based on the results reported in this paper. K.E. is a member of the iPierian scientific advisory board. NR 29 TC 270 Z9 287 U1 4 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD SEP 2 PY 2011 VL 9 IS 3 BP 205 EP 218 DI 10.1016/j.stem.2011.07.014 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 822DN UT WOS:000295024200008 PM 21852222 ER PT J AU Zacharek, SJ Fillmore, CM Lau, AN Gludish, DW Chou, A Ho, JWK Zamponi, R Gazit, R Bock, C Jager, N Smith, ZD Kim, TM Saunders, AH Wong, J Lee, JH Roach, RR Rossi, DJ Meissner, A Gimelbrant, AA Park, PJ Kim, CF AF Zacharek, Sima J. Fillmore, Christine M. Lau, Allison N. Gludish, David W. Chou, Alan Ho, Joshua W. K. Zamponi, Raffaella Gazit, Roi Bock, Christoph Jaeger, Natalie Smith, Zachary D. Kim, Tae-min Saunders, Arven H. Wong, Janice Lee, Joo-Hyeon Roach, Rebecca R. Rossi, Derrick J. Meissner, Alex Gimelbrant, Alexander A. Park, Peter J. Kim, Carla F. TI Lung Stem Cell Self-Renewal Relies on BMI1-Dependent Control of Expression at Imprinted Loci SO CELL STEM CELL LA English DT Article ID P57(KIP2) AB BMI1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally or paternally inherited allele, are known to regulate developmental processes, but what their role is in adult cells remains a fundamental question. Many imprinted genes were derepressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that BM11-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells. C1 [Zacharek, Sima J.; Fillmore, Christine M.; Lau, Allison N.; Gludish, David W.; Chou, Alan; Zamponi, Raffaella; Saunders, Arven H.; Wong, Janice; Lee, Joo-Hyeon; Roach, Rebecca R.; Kim, Carla F.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Gazit, Roi; Rossi, Derrick J.] Childrens Hosp, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Zacharek, Sima J.; Fillmore, Christine M.; Lau, Allison N.; Gludish, David W.; Chou, Alan; Zamponi, Raffaella; Saunders, Arven H.; Wong, Janice; Lee, Joo-Hyeon; Roach, Rebecca R.; Gimelbrant, Alexander A.; Kim, Carla F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ho, Joshua W. K.; Kim, Tae-min; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Zacharek, Sima J.; Fillmore, Christine M.; Lau, Allison N.; Gludish, David W.; Chou, Alan; Zamponi, Raffaella; Gazit, Roi; Bock, Christoph; Jaeger, Natalie; Smith, Zachary D.; Saunders, Arven H.; Wong, Janice; Lee, Joo-Hyeon; Roach, Rebecca R.; Rossi, Derrick J.; Meissner, Alex; Kim, Carla F.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Ho, Joshua W. K.; Park, Peter J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bock, Christoph; Jaeger, Natalie; Smith, Zachary D.; Meissner, Alex] Broad Inst, Cambridge, MA 02142 USA. [Bock, Christoph; Jaeger, Natalie; Smith, Zachary D.; Rossi, Derrick J.; Meissner, Alex] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Bock, Christoph] Max Planck Inst Informat, D-66123 Saarbrucken, Germany. [Gimelbrant, Alexander A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Kim, CF (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave, Boston, MA 02115 USA. EM carla.kim@childrens.harvard.edu RI Bock, Christoph/B-6723-2008; OI Bock, Christoph/0000-0001-6091-3088; Jaeger, Natalie/0000-0002-9589-7580; Gazit, Roi/0000-0002-0548-2147 FU Ladies Auxiliary to the Veterans of Foreign Wars; National Defense Science Engineering [RO1 HL090136, U01 HL100402]; American Cancer Society [RSG-08-082-01-MGO]; V Foundation for Cancer Research; Basil O'Conner March of Dimes Starter Award; Harvard Stem Cell Institute FX We thank Kim Lab members for discussions; S. Temple, C. Dulac, C. Gregg, D. Tenen, C. Hetherington, S. Eliedge, J. Luo, N. Solimini, M. Hemann, C. Meacham, and B. Wilson for reagents and discussions; DFCI and CHB HemOnc FACS facilities; CHB Molecular Genetics Core facility; R. Bronson for histology; L. Zon, S. Orkin, and G. Daley for critical reading; and M. Goodell for sharing unpublished data. This work was supported by the Ladies Auxiliary to the Veterans of Foreign Wars (C.M.F.), the National Defense Science & Engineering Graduate Fellowship (A.N.L.), RO1 HL090136, U01 HL100402, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O'Conner March of Dimes Starter Award, and the Harvard Stem Cell Institute (C.F.K.). NR 5 TC 62 Z9 63 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD SEP 2 PY 2011 VL 9 IS 3 BP 272 EP 280 DI 10.1016/j.stem.2011.07.007 PG 9 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 822DN UT WOS:000295024200013 PM 21885022 ER PT J AU Sykes, SM Lane, SW Bullinger, L Kalaitzidis, D Yusuf, R Saez, B Ferraro, F Mercier, F Singh, H Brumme, KM Acharya, SS Scholl, C Tothova, Z Attar, EC Frohling, S DePinho, RA Armstrong, SA Gilliland, DG Scadden, DT AF Sykes, Stephen M. Lane, Steven W. Bullinger, Lars Kalaitzidis, Demetrios Yusuf, Rushdia Saez, Borja Ferraro, Francesca Mercier, Francois Singh, Harshabad Brumme, Kristina M. Acharya, Sanket S. Schoell, Claudia Tothova, Zuzana Attar, Eyal C. Froehling, Stefan DePinho, Ronald A. Armstrong, Scott A. Gilliland, D. Gary Scadden, David T. TI AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias SO CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTOR; JUN ACTIVATION DOMAIN; OXIDATIVE STRESS; AKT PHOSPHORYLATION; TUMOR SUPPRESSORS; INITIATING CELLS; INSULIN; FOXO AB AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in similar to 40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions. C1 [Sykes, Stephen M.; Yusuf, Rushdia; Saez, Borja; Ferraro, Francesca; Mercier, Francois; Singh, Harshabad; Acharya, Sanket S.; Attar, Eyal C.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sykes, Stephen M.; Yusuf, Rushdia; Saez, Borja; Ferraro, Francesca; Mercier, Francois; Singh, Harshabad; Acharya, Sanket S.; Attar, Eyal C.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sykes, Stephen M.; Yusuf, Rushdia; Saez, Borja; Ferraro, Francesca; Mercier, Francois; Acharya, Sanket S.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lane, Steven W.; Kalaitzidis, Demetrios; Brumme, Kristina M.; Armstrong, Scott A.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA 02115 USA. [Tothova, Zuzana] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Dept Med, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bullinger, Lars; Schoell, Claudia; Froehling, Stefan] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Gilliland, D. Gary] Merck Res Labs, N Wales, PA 19454 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM dscadden@mgh.harvard.edu RI Lane, Steven/C-3215-2012 OI Lane, Steven/0000-0002-8050-6209 FU NHLBI [5T32HL007623-24, U01HL100402]; Deutsche Forschungsgemeinschaft [BU 1339/3-1]; Leukemia and Lymphoma Society; Alex Lemonade Stand Foundation; Chamber of Industry and Commerce of the Government of Spain; NCI [U01CA141508, CA140575]; NIH NHLBI [HL097794, HL097748, HL100402]; NIDDK [DK050234]; Ellison Foundation; Harvard Stem Cell Institute FX We would like to thank Dr. Christine Ragu, Dr. Andrew Lane, and Dr. David Sykes for critically reading the manuscript and providing valuable suggestions. We would also like to thank Dr. Kira Gritsman and Dr. Michael Kharas for donating the MSCV-IRES-GFP-myr-Akt construct. We would also like to thank M. Milsom for donating the LoxP-STOP-LoxP-hCD34 expression plasmid. S.M.S. was supported by NHLBI 5T32HL007623-24. L.B. was supported by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). R.Y. is supported by the Leukemia and Lymphoma Society and the Alex Lemonade Stand Foundation. B.S. is supported by the Chamber of Industry and Commerce of the Government of Spain. F.F. is supported by NHLBI U01HL100402. R.A.D. was supported by NCI U01CA141508. S.A.A. was supported by the Leukemia and Lymphoma Society and NCI CA140575. D.T.S. is supported by the NIH NHLBI HL097794, HL097748, and HL100402 and NIDDK DK050234, the Ellison Foundation, and the Harvard Stem Cell Institute. D.G.G. is a full-time employee of Merck & Company, Inc. NR 39 TC 113 Z9 120 U1 2 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 2 PY 2011 VL 146 IS 5 BP 697 EP 708 DI 10.1016/j.cell.2011.07.032 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 814SM UT WOS:000294477500011 PM 21884932 ER PT J AU Van Rechem, C Black, JC Abbas, T Allen, A Rinehart, CA Yuan, GC Dutta, A Whetstine, JR AF Van Rechem, Capucine Black, Joshua C. Abbas, Tarek Allen, Andrew Rinehart, Claire A. Yuan, Guo-Cheng Dutta, Anindya Whetstine, Johnathan R. TI The SKP1-Cul1-F-box and Leucine-rich Repeat Protein 4 (SCF-FbxL4) Ubiquitin Ligase Regulates Lysine Demethylase 4A (KDM4A)/Jumonji Domain-containing 2A (JMJD2A) Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE PROGRESSION; MAMMALIAN-CELLS; HISTONE METHYLTRANSFERASE; DYNAMIC REGULATION; GENE-EXPRESSION; S PHASE; DEGRADATION; REPLICATION; CHROMATIN; PR-SET7 AB Chromatin-modifying enzymes play a fundamental role in regulating chromatin structure so that DNA replication is spatially and temporally coordinated. For example, the lysine demethylase 4A/Jumonji domain-containing2A(KDM4A/JMJD2A) is tightly regulated during the cell cycle. Overexpression of JMJD2A leads to altered replication timing and faster S phase progression. In this study, we demonstrate that degradation of JMJD2A is regulated by the proteasome. JMJD2A turnover is coordinated through the SKP1-Cul1-F-box ubiquitin ligase complex that contains cullin 1 and the F-box and leucine-rich repeat protein 4 (FbxL4). This complex interacted with JMJD2A. Ubiquitin overexpression restored turnover and blocked the JMJD2A-dependent faster S phase progression in a cullin 1-dependent manner. Furthermore, increased ubiquitin levels decreased JMJD2A occupancy and BrdU incorporation at target sites. This study highlights a finely tuned mechanism for regulating histone demethylase levels and emphasizes the need to tightly regulate chromatin modifiers so that the cell cycle occurs properly. C1 [Van Rechem, Capucine; Black, Joshua C.; Allen, Andrew; Whetstine, Johnathan R.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. [Van Rechem, Capucine; Black, Joshua C.; Allen, Andrew; Whetstine, Johnathan R.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Abbas, Tarek; Dutta, Anindya] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Rinehart, Claire A.] Western Kentucky Univ, Dept Biol, Bowling Green, KY 42101 USA. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Whetstine, JR (reprint author), Harvard Univ, Sch Med, Dept Med, Bldg 149,13th St,Rm 7-213, Charlestown, MA 02129 USA. EM jwhetstine@hms.harvard.edu RI Black, Joshua/Q-2484-2015; Dutta, Anindya/P-3203-2016; OI Dutta, Anindya/0000-0002-4319-0073 FU Ellison Medical Foundation [CA059267]; National Institutes of Health [R01CA60499, R01HG005085]; Jane Coffin Childs Memorial Fund for Medical Research; NCI National Institutes of Health [KCA140774A] FX This work was supported, in whole or in part, by the Ellison Medical Foundation, Howard Goodman Fellowship, and Grant CA059267 (to J. R. W.). This work was also supported by National Institutes of Health Grants R01CA60499 (to A. D.) and R01HG005085 (to G. C. Y.). This work has also been aided by grants from The Jane Coffin Childs Memorial Fund for Medical Research (to J. C. B.) and from NCI National Institutes of Health Grant KCA140774A (to T. A.). NR 35 TC 30 Z9 30 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 2 PY 2011 VL 286 IS 35 BP 30462 EP 30470 DI 10.1074/jbc.M111.273508 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 812HT UT WOS:000294283600025 PM 21757720 ER PT J AU Su, XL Qiu, WH Gupta, ML Pereira-Leal, JB Reck-Peterson, SL Pellman, D AF Su, Xiaolei Qiu, Weihong Gupta, Mohan L., Jr. Pereira-Leal, Jose B. Reck-Peterson, Samara L. Pellman, David TI Mechanisms Underlying the Dual-Mode Regulation of Microtubule Dynamics by Kip3/Kinesin-8 SO MOLECULAR CELL LA English DT Article ID PLUS-END-TRACKING; MITOTIC SPINDLE; YEAST KINESIN-8; FISSION YEAST; PROTEINS; ANAPHASE; MOTOR; KIP3; CELL; DEPOLYMERIZATION AB The kinesin-8 family of microtubule motors plays a critical role in microtubule length control in cells. These motors have complex effects on microtubule dynamics: they destabilize growing microtubules yet stabilize shrinking microtubules. The budding yeast kinesin-8, Kip3, accumulates on plus ends of growing but not shrinking microtubules. Here we identify an essential role of the tail domain of Kip3 in mediating both its destabilizing and its stabilizing activities. The Kip3 tail promotes Kip3's accumulation at the plus ends and facilitates the destabilizing effect of Kip3. However, the Kip3 tail also inhibits microtubule shrinkage and is required for promoting microtubule rescue by Kip3. These effects of the tail domain are likely to be mediated by the tubulin- and microtubule-binding activities that we describe. We propose a concentration-dependent model for the coordination of the destabilizing and stabilizing activities of Kip3 and discuss its relevance to cellular microtubule organization. C1 [Su, Xiaolei; Pellman, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Su, Xiaolei; Pellman, David] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Su, Xiaolei; Pellman, David] Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Su, Xiaolei; Qiu, Weihong; Reck-Peterson, Samara L.; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Gupta, Mohan L., Jr.] Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA. [Pereira-Leal, Jose B.] Inst Gulbenkian Ciencias, P-2781901 Oeiras, Portugal. RP Pellman, D (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu RI Pereira-Leal, Jose/C-5616-2012; Qiu, Weihong/F-6790-2012; OI Pereira Leal, Jose/0000-0002-3111-7119; Qiu, Weihong/0000-0003-1413-1389 FU Howard Hughes Medical Institute; National Institutes of Health [GM61345]; HMS/Portugal FX We thank T. Mitchison, R. King, S. Gilbert, C. Moores, J. Al-Bassam, M. Betterton, M. Kwon, N. Ganem, S. Godinho, and K. Knouse for discussions and comments on the work. D.P. was supported by Howard Hughes Medical Institute and a National Institutes of Health grant (GM61345). J.B.P.-L. received support from the HMS/Portugal Program in Translational Research. NR 36 TC 53 Z9 53 U1 0 U2 3 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 SEP 2 PY 2011 VL 43 IS 5 BP 751 EP 763 DI 10.1016/j.molcel.2011.06.027 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 816JA UT WOS:000294593300010 PM 21884976 ER PT J AU Yanagihara, H Kobayashi, J Tateishi, S Kato, A Matsuura, S Tauchi, H Yamada, K Takezawa, J Sugasawa, K Masutani, C Hanaoka, F Weemaes, CM Mori, T Zou, L Komatsu, K AF Yanagihara, Hiromi Kobayashi, Junya Tateishi, Satoshi Kato, Akihiro Matsuura, Shinya Tauchi, Hiroshi Yamada, Kouichi Takezawa, Jun Sugasawa, Kaoru Masutani, Chikahide Hanaoka, Fumio Weemaes, Corry M. Mori, Toshio Zou, Lee Komatsu, Kenshi TI NBS1 Recruits RAD18 via a RAD6-like Domain and Regulates Pol eta-Dependent Translesion DNA Synthesis SO MOLECULAR CELL LA English DT Article ID NIJMEGEN-BREAKAGE-SYNDROME; DEFECTIVE POSTREPLICATION REPAIR; REPLICATION PROTEIN-A; THYMINE DIMER BYPASS; IN-VIVO MUTATIONS; POLYMERASE-ETA; HOMOLOGOUS RECOMBINATION; DAMAGE RESPONSE; CELLS; COMPLEX AB Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Pol eta focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Pol eta-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis. C1 [Yanagihara, Hiromi; Kobayashi, Junya; Kato, Akihiro; Komatsu, Kenshi] Kyoto Univ, Ctr Radiat Biol, Kyoto 6068501, Japan. [Tateishi, Satoshi] Kumamoto Univ, Inst Mol Embryol & Genet, Kumamoto 8620976, Japan. [Matsuura, Shinya] Hiroshima Univ, Res Inst Radiat Biol & Med, Hiroshima 7348553, Japan. [Tauchi, Hiroshi] Ibaraki Univ, Dept Biol Sci, Ibaraki 3108512, Japan. [Yamada, Kouichi; Takezawa, Jun] Natl Inst Hlth & Nutr, Div Genet Biochem, Shinjuku Ku, Tokyo 1628636, Japan. [Sugasawa, Kaoru] Kobe Univ, Biosignal Res Ctr, Org Adv Sci & Technol, Kobe, Hyogo 6578501, Japan. [Masutani, Chikahide] Nagoya Univ, Environm Med Res Inst, Nagoya, Aichi 4648601, Japan. [Hanaoka, Fumio] Gakushuin Univ, Fac Sci, Tokyo 1718588, Japan. [Weemaes, Corry M.] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6500 HB Nijmegen, Netherlands. [Mori, Toshio] Nara Med Univ, Radioisotope Res Ctr, Nara 6348521, Japan. [Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Cambridge, MA 02129 USA. RP Komatsu, K (reprint author), Kyoto Univ, Ctr Radiat Biol, Kyoto 6068501, Japan. EM komatsu@house.rbc.kyoto-u.ac.jp RI Weemaes, C.M.R./L-4747-2015; Masutani, Chikahide/I-6160-2014 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan FX The authors wish to thank John Petrini, Dik C. van Gent, and Kanji Ishizaki for providing Delta B/Delta B MEFs, Delta B/Delta B ESCs, and retrovirus vector pCLXSL-hTERT. We also thank Yukiko Hayuka and Douglas V.N.P. Oliveira for the excellent technical assistance and discussions. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 46 TC 22 Z9 22 U1 0 U2 10 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 SEP 2 PY 2011 VL 43 IS 5 BP 788 EP 797 DI 10.1016/j.molcel.2011.07.026 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 816JA UT WOS:000294593300013 PM 21884979 ER PT J AU Shen, DX Li, J Lepore, JJ Anderson, TJT Sinha, S Lin, AY Cheng, L Cohen, ED Roberts, JD Dedhar, S Parmacek, MS Gerszten, RE AF Shen, Dongxiao Li, Jian Lepore, John J. Anderson, Thomas J. T. Sinha, Sumita Lin, Alexander Y. Cheng, Lan Cohen, Ethan David Roberts, Jesse D., Jr. Dedhar, Shoukat Parmacek, Michael S. Gerszten, Robert E. TI Aortic Aneurysm Generation in Mice With Targeted Deletion of Integrin-Linked Kinase in Vascular Smooth Muscle Cells SO CIRCULATION RESEARCH LA English DT Article DE integrin-linked kinase; smooth muscle cells; aortic aneurysm; actin cytoskeleton; myocardin-related transcription factor-A ID PROTEIN-KINASE; EXTRACELLULAR-MATRIX; GENE-EXPRESSION; FOCAL ADHESIONS; MARFAN-SYNDROME; ANGIOTENSIN-II; ACTIN; ILK; DIFFERENTIATION; CONTRACTION AB Rationale: Integrin-linked kinase (ILK) is located at focal adhesions and links the extracellular matrix (ECM) to the actin cytoskeleton via beta 1- and beta 3-integrins. ILK plays a role in the activation of kinases including protein kinase B/Akt and glycogen synthase kinase 3 beta and regulates cell proliferation, motility, and survival. Objective: To determine the function of ILK in vascular smooth muscle cells (SMCs) in vivo. Methods and Results: SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice were generated in which the Ilk gene was selectively ablated in SMCs. SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice survive to birth but die in the perinatal period exhibiting multiple vascular pathologies including aneurysmal dilatation of the aorta and patent ductus arteriosus (PDA). Defects in morphogenetic development of the aorta were observed as early as E12.5 in SM22Cre(+)Ilk(Fl/Fl) mutant embryos. By late gestation (E16.5 to 18.5), striking expansion of the thoracic aorta was observed in ILK mutant embryos. Histological analyses revealed that the structural organization of the arterial tunica media is severely disrupted with profound derangements in SMC morphology, cell-cell, and cell-matrix relationships, including disruption of the elastic lamellae. ILK deletion in primary aortic SMCs results in alterations of RhoA/cytoskeletal signaling transduced through aberrant localization of myocardin-related transcription factor (MRTF)-A repressing the transcription and expression of SMC genes, which are required for the maintenance of the contractile SMC phenotype. Conclusions: These data identify a molecular pathway linking ILK signaling to the contractile SMC gene program. Activation of this pathway is required for morphogenetic development of the aorta and ductus arteriosus during embryonic and postnatal survival. (Circ Res. 2011;109:616-628.) C1 [Shen, Dongxiao; Sinha, Sumita; Roberts, Jesse D., Jr.; Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Shen, Dongxiao; Anderson, Thomas J. T.; Sinha, Sumita; Lin, Alexander Y.; Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Li, Jian; Cheng, Lan; Parmacek, Michael S.] Div Cardiovasc Med, Philadelphia, PA USA. [Li, Jian; Cheng, Lan; Parmacek, Michael S.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Lepore, John J.] GlaxoSmithKline, Metab Pathways Ctr Excellence Drug Discovery, King Of Prussia, PA USA. [Cohen, Ethan David] Univ Rochester, Sch Med & Dent, Div Endocrinol & Metab, Rochester, NY USA. [Dedhar, Shoukat] Univ British Columbia, Dept Biochem & Mol Biol, BC Canc Res Ctr, Vancouver, BC V5Z 1M9, Canada. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp E 8307, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org OI Parmacek, Michael/0000-0003-1449-4665; Anderson, Thomas/0000-0002-2762-6703 FU National Institutes of Health [R01HL-65584, R01HL-96779, R01HL-094520, R01HL-102968] FX We gratefully acknowledge support from the National Institutes of Health to R.E.G. (R01HL-65584), J.D.R. (R01HL-96779), and R01HL-094520 and R01HL-102968 to M.S.P. We also acknowledge the excellent technical assistance of Melinda J. Palma. NR 51 TC 16 Z9 16 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD SEP 2 PY 2011 VL 109 IS 6 BP 616 EP U78 DI 10.1161/CIRCRESAHA.110.239343 PG 27 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 814SJ UT WOS:000294477200007 PM 21778429 ER PT J AU Patti, JA AF Patti, John A. TI Planning for the Future Through Intersociety Collaboration SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Patti, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM jpatti@partners.org 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2011 VL 8 IS 9 BP 595 EP 595 DI 10.1016/j.jacr.2011.07.012 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KB UT WOS:000306201700001 PM 21889741 ER PT J AU Brown, ML Guiberteau, MJ Oates, ME Thrall, JH AF Brown, Manuel L. Guiberteau, Milton J. Oates, M. Elizabeth Thrall, James H. CA ACR ABR Writing Grp TI ACR/ABR Clinical Statement on Credentialing and Privileging of Radiologists for Diagnostic Nuclear Medicine, Including Multimodality Hybrid Imaging SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE ACR; ABR; credentialing; privileging; hybrid imaging; nuclear medicine; diagnostic radiologists AB Processes for credentialing physicians and criteria for delineating their practice-specific clinical privileges vary widely across the United States. The ACR and the ABR have jointly developed this resource document to define the requisite credentials for board-certified radiologists to be privileged to practice the full gamut of diagnostic nuclear medicine, including multimodality hybrid imaging. Through its initial certification of radiologists and maintenance of certification programs for practicing certificate holders, the ABR assesses the competence and ensures excellence of its professional diplomates for clinical practice. On the basis of their education, training, and clinical work experience, board-certified radiologists are imminently qualified to supervise, interpret, and report all diagnostic nuclear medicine studies, including radionuclide cardiovascular imaging, and uniquely so for all radionuclide-based, multimodality hybrid examinations. Optimum patient care is best served by an imaging physician with training and expertise in applying, interpreting, and correlating a broad spectrum of these diagnostic technologies. C1 [Guiberteau, Milton J.] St Joseph Med Ctr, Dept Radiol, Houston, TX 77002 USA. [Brown, Manuel L.] Henry Ford Hosp, Dept Diagnost Radiol, Detroit, MI 48202 USA. [Guiberteau, Milton J.] Univ Texas Med Sch, Houston, TX USA. [Oates, M. Elizabeth] Univ Kentucky, Dept Radiol, Lexington, KY USA. [Thrall, James H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Guiberteau, MJ (reprint author), St Joseph Med Ctr, Dept Radiol, 1919 LaBranch St, Houston, TX 77002 USA. EM guiberteau@theabr.org NR 4 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2011 VL 8 IS 9 BP 617 EP 621 DI 10.1016/j.jacr.2011.06.007 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KB UT WOS:000306201700008 ER PT J AU Abujudeh, HH Govindan, S Narin, O Johnson, JO Thrall, JH Rosenthal, DI AF Abujudeh, Hani H. Govindan, Siddharth Narin, Ozden Johnson, Jamlik Omani Thrall, James H. Rosenthal, Daniel I. TI Automatically Inserted Technical Details Improve Radiology Report Accuracy SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Radiology reports; automation; report headers; report accuracy AB Purpose: To assess the effect of automatically inserted technical details on the concordance of a radiology report header with the actual procedure performed. Methods and Materials: The study was IRB approved and informed consent was waived. We obtained radiology report audit data from the hospital's compliance office from the period of January 2005 through December 2009 spanning a total of 20 financial quarters. A "discordance percentage" was defined as the percentage of total studies in which a procedure code change was made during auditing. Using Chi-square analysis we compared discordance percentages between reports with manually inserted technical details (MITD) and automatically inserted technical details (AITD). The second quarter data of 2007 was not included in the analysis as the switch from MITD to AITD occurred during this quarter. Results: The hospital's compliance office audited 9,110 studies from 2005-2009. Excluding the 564 studies in the second quarter of 2007, we analyzed a total of 8,546 studies, 3,948 with MITD and 4,598 with AITD. The discordance percentage in the MITD group was 3.95% (156/3,948, range per quarter, 1.5-6.1%). The AITD discordance percentage was 1.37% (63/4,598, range per quarter, 0.0-2.6%). A Chi-square analysis determined a statistically significant difference between the 2 groups (P < 0.001). Conclusion: There was a statistically significant improvement in the concordance of a radiology report header with the performed procedure using automatically inserted technical details compared to manually inserted details. C1 [Abujudeh, Hani H.; Govindan, Siddharth; Narin, Ozden; Thrall, James H.; Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Johnson, Jamlik Omani] Emory Univ Hosp, Dept Radiol, Atlanta, GA 30322 USA. RP Abujudeh, HH (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Founders 213B, Boston, MA 02114 USA. EM habujudeh@partners.org NR 10 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2011 VL 8 IS 9 BP 635 EP 637 DI 10.1016/j.jacr.2011.02.009 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KB UT WOS:000306201700012 PM 21889750 ER PT J AU Singh, S Kalra, MK Thrall, JH Mahesh, M AF Singh, Sarabjeet Kalra, Mannudeep K. Thrall, James H. Mahesh, Mahadevappa TI Pointers for Optimizing Radiation Dose in Chest CT Protocols SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID IMAGE QUALITY; REDUCTION; STRATEGIES C1 [Mahesh, Mahadevappa] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Singh, Sarabjeet; Kalra, Mannudeep K.; Thrall, James H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Hosp Imaging, Boston, MA USA. RP Mahesh, M (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Caroline St, Baltimore, MD 21287 USA. EM mmahesh@jhmi.edu NR 14 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2011 VL 8 IS 9 BP 663 EP 665 DI 10.1016/j.jacr.2011.06.009 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KB UT WOS:000306201700019 PM 21889757 ER PT J AU Rider, EA AF Rider, Elizabeth A. TI Advanced Communication Strategies for Relationship-Centered Care SO PEDIATRIC ANNALS LA English DT Article ID PHYSICIAN COMMUNICATION; PATIENT SATISFACTION; MEDICAL-CARE; SKILLS; COMPETENCES; AWARENESS; OUTCOMES; CHILDREN; PARENTS; EMPATHY C1 [Rider, Elizabeth A.] Childrens Hosp Boston, Inst Professionalism & Eth Practice, Boston, MA USA. [Rider, Elizabeth A.] Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care Innovat, Programs Commun Skills, Boston, MA 02114 USA. [Rider, Elizabeth A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Rider, EA (reprint author), 1153 Ctr St,Suite 31, Boston, MA 02130 USA. EM eliza-beth_rider@hms.harvard.edu NR 41 TC 7 Z9 7 U1 0 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0090-4481 J9 PEDIATR ANN JI Pediatr. Annu. PD SEP PY 2011 VL 40 IS 9 BP 447 EP 453 DI 10.3928/00904481-20110815-08 PG 7 WC Pediatrics SC Pediatrics GA 965BV UT WOS:000305742000009 PM 21902122 ER PT J AU Bergmark, RWJ Guo, DP Lin, HW Faquin, WC Young, GS Saxon, KG AF Bergmark, Regan W. J. Guo, David P. Lin, Harrison W. Faquin, William C. Young, Geoffrey S. Saxon, Keith G. TI Vagal Schwannoma SO ENT-EAR NOSE & THROAT JOURNAL LA English DT Editorial Material ID VAGUS NERVE C1 [Bergmark, Regan W. J.; Guo, David P.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Lin, Harrison W.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Young, Geoffrey S.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Saxon, Keith G.] Brigham & Womens Hosp, Div Otolaryngol Head & Neck Surg, Boston, MA 02115 USA. RP Bergmark, RWJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU VENDOME GROUP LLC PI NEW YORK PA 149 FIFTH AVE, 10TH FLOOR, NEW YORK, NY 10010 USA SN 0145-5613 J9 ENT-EAR NOSE THROAT JI ENT-Ear Nose Throat J. PD SEP PY 2011 VL 90 IS 9 BP 410 EP 411 PG 2 WC Otorhinolaryngology SC Otorhinolaryngology GA 964UE UT WOS:000305721400005 PM 21938697 ER PT J AU Ku, TNK Naseri, A Han, Y Porco, TC Rutar, T AF Ku, Tina K. Naseri, Ayman Han, Ying Porco, Travis C. Rutar, Tina TI Effect of Timing and Duration of Tamsulosin Exposure on Complications in Resident-Performed Phacoemulsification SO OPHTHALMIC SURGERY LASERS & IMAGING LA English DT Article ID FLOPPY-IRIS-SYNDROME; BENIGN PROSTATIC HYPERTROPHY; CATARACT-SURGERY; CLINICAL FINDINGS; LEARNING-CURVE; IFIS; ASSOCIATION; EPINEPHRINE; PROPHYLAXIS; MANAGEMENT AB BACKGROUND AND OBJECTIVES: Tamsulosin can cause intraoperative floppy iris syndrome and increase the risk of phacoemulsification complications. This study evaluated whether the risk of complications was associated with the timing or duration of preoperative tamsulosin exposure. PATIENTS AND METHODS: The current study was a retrospective review of electronic medical records of resident-performed phacoemulsification surgeries from 1998 to 2008 at a Veterans Administration Hospital. There were 73 eyes with recent tamsulosin exposure (within 30 days preoperatively) and 28 eyes with remote exposure (> 30 days preoperatively but within 3 years of surgery). RESULTS: There was a trend toward more total complications in recent compared with remote tamsulosin exposure cases (31.5% vs 14.3%, P = .09). A longer duration of tamsulosin use was not statistically associated with an increased risk of total complications. CONCLUSION: The authors were unable to detect a statistically significant effect of duration of tamsulosin use on the risk of intraoperative complications in phacoemulsification surgery. C1 [Ku, Tina K.; Naseri, Ayman; Han, Ying; Porco, Travis C.; Rutar, Tina] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. [Naseri, Ayman; Porco, Travis C.] Francis I Proctor Fdn Res Ophthalmol, San Francisco, CA USA. [Naseri, Ayman] San Francisco VA Med Ctr, Dept Ophthalmol, San Francisco, CA USA. [Porco, Travis C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Prevent Med & Publ Hlth, San Francisco, CA 94143 USA. RP Rutar, T (reprint author), Univ Calif San Francisco, Dept Ophthalmol, 10 Koret Way,K301, San Francisco, CA 94143 USA. EM rutart@vision.ucsf.edu FU Research to Prevent Blindness, New York, New York; University of California, Bethesda, Maryland [NIH P30] FX Supported in part by an unrestricted grant from Research to Prevent Blindness, New York, New York, and by the University of California Institutional Core Grant For Vision Research (NIH P30), Bethesda, Maryland. NR 33 TC 1 Z9 2 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1542-8877 J9 OPHTHAL SURG LAS IM JI Ophthalmic Surg. Lasers Imaging PD SEP-OCT PY 2011 VL 42 IS 5 BP 416 EP 422 DI 10.3928/15428877-20110602-01 PG 7 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 959UX UT WOS:000305342100009 PM 21661666 ER PT J AU Impink, BG Collinger, JL Boninger, ML AF Impink, Bradley G. Collinger, Jennifer L. Boninger, Michael L. TI The Effect of Symptoms of Carpal Tunnel Syndrome on Ultrasonographic Median Nerve Measures Before and After Wheelchair Propulsion SO PM&R LA English DT Article ID CROSS-SECTIONAL AREA; BODY-MASS INDEX; HIGH-RESOLUTION SONOGRAPHY; UPPER EXTREMITY; CLINICAL IMPLICATIONS; PARAPLEGIC PATIENTS; GENERAL-POPULATION; FUNCTIONAL STATUS; CANAL PRESSURE; DIAGNOSIS AB Objective: To quantify median nerve characteristics before and after strenuous wheelchair propulsion and relate them to symptoms of carpal tunnel syndrome (CTS). We hypothesized that persons with and without symptoms of CTS would have significantly different nerve characteristics at baseline and after propulsion. Design: A repeated-measures design was used to obtain ultrasound images of the median nerve at 3 levels of the wrist (radius, pisiform, and hamate) before and after wheelchair propulsion. Investigators were blinded to subject history related to CTS. Setting: The 2007 and 2008 National Veterans Wheelchair Games and the Human Engineering Research Laboratories. Participants: Fifty-four participants between the ages of 18 and 65 years with a nonprogressive disability who used a manual wheelchair as their primary means of mobility completed this study. Methods: Participants completed questionnaires regarding demographics and the presence and severity of symptoms of CTS. Ultrasound images of the median nerve were obtained before and after a 15-minute strenuous wheelchair-propulsion task. Main Outcome Measurements: Baseline values and post-propulsion changes were determined for median nerve cross-sectional area, flattening ratio, and swelling ratio. Differences in median nerve variables between symptomatic and asymptomatic groups were assessed. Results: No significant differences between symptom groups were identified at baseline; however, persons with symptoms of CTS showed a significantly different percent change from baseline compared with the asymptomatic participants for cross-sectional area at pisiform (P = .014) and flattening ratio at hamate (P = .022), and they showed a strong trend toward a difference in swelling ratio (P = .0502). For each of these variables, the change in the symptomatic group was in the opposite direction of the change in the asymptomatic group. Conclusions: We found several median nerve responses to wheelchair propulsion associated with symptoms of CTS. These responses occurred even though no baseline ultrasound difference was found based on symptoms. Future research is necessary to determine how propulsion characteristics (ie, force, repetition, and posture) affect the median nerve response. PM R 2011;3:803-810 C1 [Impink, Bradley G.; Collinger, Jennifer L.; Boninger, Michael L.] Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Impink, Bradley G.; Collinger, Jennifer L.; Boninger, Michael L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Collinger, Jennifer L.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Boninger, ML (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Human Engn Res Labs, 7180 Highland Dr,151R1-H,Bldg 4,East Wing, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Boninger, Michael/0000-0001-6966-919X FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [B3142C]; National Institute on Disability and Rehabilitation Research [H133E070024]; National Institutes of Health [R21HD054529]; National Science Foundation [DGE0333420] FX This material is based on work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (B3142C), the National Institute on Disability and Rehabilitation Research (H133E070024), the National Institutes of Health (R21HD054529), and the National Science Foundation (DGE0333420). The findings presented are the result of work supported with resources and the use of facilities of the Human Engineering Research Laboratories, VA Pittsburgh Healthcare System. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. NR 55 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD SEP PY 2011 VL 3 IS 9 BP 803 EP 810 DI 10.1016/j.pmrj.2011.04.009 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961BE UT WOS:000305438100004 PM 21944298 ER PT J AU Plow, EB Obretenova, SN Halko, MA Kenkel, S Jackson, ML Pascual-Leone, A Merabet, LB AF Plow, Ela B. Obretenova, Souzana N. Halko, Mark A. Kenkel, Sigrid Jackson, Mary Lou Pascual-Leone, Alvaro Merabet, Lotfi B. TI Combining Visual Rehabilitative Training and Noninvasive Brain Stimulation to Enhance Visual Function in Patients With Hemianopia: A Comparative Case Study SO PM&R LA English DT Article ID VISION RESTORATION THERAPY; TRANSCRANIAL MAGNETIC STIMULATION; MOTOR CORTEX STIMULATION; CORTICAL STIMULATION; FIELD DEFECTS; STROKE PATIENTS; IMPAIRMENT QUESTIONNAIRE; HOMONYMOUS HEMIANOPIA; CEREBRAL BLINDNESS; CRITICAL-APPRAISAL AB Objective: To standardize a protocol for promoting visual rehabilitative outcomes in post-stroke hemianopia by combining occipital cortical transcranial direct current stimulation (tDCS) with Vision Restoration Therapy (VRT). Design: A comparative case study assessing feasibility and safety. Setting: A controlled laboratory setting. Patients: Two patients, both with right hemianopia after occipital stroke damage. Methods and Outcome Measurements: Both patients underwent an identical VRT protocol that lasted 3 months (30 minutes, twice a day, 3 days per week). In patient 1, anodal tDCS was delivered to the occipital cortex during VRT training, whereas in patient 2 sham tDCS with VRT was performed. The primary outcome, visual field border, was defined objectively by using high-resolution perimetry. Secondary outcomes included subjective characterization of visual deficit and functional surveys that assessed performance on activities of daily living. For patient 1, the neural correlates of visual recovery were also investigated, by using functional magnetic resonance imaging. Results: Delivery of combined tDCS with VRT was feasible and safe. High-resolution perimetry revealed a greater shift in visual field border for patient 1 versus patient 2. Patient 1 also showed greater recovery of function in activities of daily living. Contrary to the expectation, patient 2 perceived greater subjective improvement in visual field despite objective high-resolution perimetry results that indicated otherwise. In patient I., visual function recovery was associated with functional magnetic resonance imaging activity in surviving peri-lesional and bilateral higher-order visual areas. Conclusions: Results of preliminary case comparisons suggest that occipital cortical tDCS may enhance recovery of visual function associated with concurrent VRT through visual cortical reorganization. Future studies may benefit from incorporating protocol refinements such as those described here, which include global capture of function, control for potential confounds, and investigation of underlying neural substrates of recovery. PM R 2011;3:825-835 C1 [Plow, Ela B.; Obretenova, Souzana N.; Halko, Mark A.; Pascual-Leone, Alvaro; Merabet, Lotfi B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Med Sch, Boston, MA 02215 USA. [Jackson, Mary Lou; Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Vis Rehabil Ctr, Boston, MA 02114 USA. [Plow, Ela B.] Cleveland Clin Fdn, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. [Kenkel, Sigrid] NovaVis Zentrum Sehtherapie, Ctr Vis Therapy, Magdeburg, Germany. [Pascual-Leone, Alvaro] Univ Autonoma Barcelona, Inst Guttmann Neurorehabil, Badalona, Spain. RP Merabet, LB (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Med Sch, Boston, MA 02215 USA. EM lotfi_merabet@meei.harvard.edu RI Halko, Mark/G-8633-2016 OI Halko, Mark/0000-0002-7427-0789 FU investigator-initiated pilot grant from Novavision VRT Inc.; National Institutes of Health [K23-EY016131]; investigator-initiated grant from Novavision; Nexstim; Nova Vision VTR FX This work was supported by an investigator-initiated pilot grant from Novavision VRT Inc. and by the National Institutes of Health (K23-EY016131 to L.B.M.).; 9, Postdoctoral Fellow on investigator-initiated grant from Novavision; 2A, scientific and medical advisory board of Novavision VRT Inc, Star lab, Neosync, Neuronix; 7, grant from Nexstim and equipment support; 9, investigator-initiated grant from Nova Vision VTR NR 92 TC 18 Z9 18 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD SEP PY 2011 VL 3 IS 9 BP 825 EP 835 DI 10.1016/j.pmrj.2011.05.026 PG 11 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961BE UT WOS:000305438100007 PM 21944300 ER PT J AU Akiyoshi, K Dziennis, S Palmateer, J Ren, XF Vandenbark, AA Offner, H Herson, PS Hurn, PD AF Akiyoshi, Kozaburo Dziennis, Suzan Palmateer, Julie Ren, Xuefang Vandenbark, Arthur A. Offner, Halina Herson, Paco S. Hurn, Patricia D. TI Recombinant T Cell Receptor Ligands Improve Outcome After Experimental Cerebral Ischemia SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Cerebral ischemia; Cerebral infarction; Inflammation; T lymphocyte; Immunotherapy; Mouse; Middle cerebral artery occlusion; Stroke ID EXPERIMENTAL STROKE; MULTIPLE-SCLEROSIS; INFARCT VOLUME; MICE; ASSOCIATION; ARTHRITIS; SEVERITY AB A key target for novel stroke therapy is the regulation of post-ischemic inflammatory mechanisms. Recent evidence emphasizes the role of T lymphocytes of differing subtypes in the evolution is ischemic brain damage. We have recently demonstrated the benefit of myelin antigen-specific immunodulatory agents known as recombinant T cell receptor ligands (RTLs) in a standard murine model of focal stroke. The aim of the current study was to extend this initial observation to RTL treatment in a therapeutically relevant timing after middle cerebral artery occlusion (MCAO) and verify functional benefit to complement histological outcome measures. We observed that the administration of mouse-specific RTL551 reduced infarct size and improved sensorimotor outcome when administered within a 3 h post-ischemic therapeutic window. RTL551 treatment reduced cortical, caudate putamen, and total infarct volume as compared to vehicle-treated mice. Using a standard behavioral testing repertoire, we observed that RTL551 reduced sensorimotor impairment 3 days after MCAO. Humanized RTL1000 (HLA-DR2 moiety linked to hMOG-35-55 peptide) also reduced infarct size in HLA-DR2 transgenic mice. These data indicate that this neuroantigen-specific immunomodulatory agent reduces damage when administered in a therapeutically relevant reperfusion timeframe. C1 [Akiyoshi, Kozaburo; Dziennis, Suzan; Palmateer, Julie; Ren, Xuefang; Offner, Halina; Herson, Paco S.; Hurn, Patricia D.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Dziennis, Suzan; Ren, Xuefang; Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, Portland, OR 97239 USA. [Vandenbark, Arthur A.] Dept Vet Affairs Med Ctr, Res Serv, Portland, OR 97239 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Vandenbark, Arthur A.; Offner, Halina; Hurn, Patricia D.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. RP Herson, PS (reprint author), Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM hersonp@ohsu.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX The authors thank Ms. Kathy Gage, grants and publications writer for the Department of Anesthesiology and Perioperative Medicine, OHSU, for her outstanding editorial work in the preparation of this paper. This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the US government. NR 23 TC 12 Z9 12 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD SEP PY 2011 VL 2 IS 3 BP 404 EP 410 DI 10.1007/s12975-011-0085-1 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 943YH UT WOS:000304163500021 PM 21961027 ER PT J AU Thomas, JJ Keel, PK Heatherton, TF AF Thomas, J. J. Keel, P. K. Heatherton, T. F. TI Disordered eating and injuries among adolescent ballet dancers SO EATING AND WEIGHT DISORDERS-STUDIES ON ANOREXIA BULIMIA AND OBESITY LA English DT Article DE Eating disorder; vomiting; fasting; laxative; injury; ballet dancers ID ANOREXIA-NERVOSA; MUSCULOSKELETAL INJURIES; STRESS-FRACTURES; BULIMIA-NERVOSA; STUDENTS; WEIGHT; RISK; DISTURBANCES; POPULATION; BEHAVIORS AB BACKGROUND: Ballet dancers are at elevated risk for eating disorders, but the extent to which disordered eating attitudes and behaviors represent a relatively benign adaptation to an environment that values extreme thinness, or a functionally impairing form of psychopathology, has sparked considerable debate. METHOD: To determine whether disordered eating is associated with role impairment in dancers, we evaluated its association with musculoskeletal injuries among 239 adolescent female ballet students. RESULTS: Dance students reported a variety of lifetime disordered eating behaviors to control weight including fasting (29.3%), vomiting (9.6%), and laxative use (4.2%). More than half (52.3%) reported a lifetime history of injury (stress fracture, broken bone, and/or medically treated tendonitis). A greater number of lifetime disordered eating behaviors was associated with a greater number of lifetime injuries (p=0.01). Moreover, vomiting history was associated with greater likelihood of injury (p=0.004) and increased time to recover from injury (median difference=22.8 days, p=0.006). CONCLUSION: Although the direction of causality cannot be determined from this retrospective design, these results suggest that disordered eating is associated with role-relevant functional impairment, even among members of a subculture that values extreme thinness. (Eating Weight Disord. 16: e216-e222, 2011). (C)2011, Editrice Kurtis C1 [Thomas, J. J.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, J. J.] McLean Hosp, Klarman Eating Disorders Ctr, Belmont, MA 02178 USA. [Thomas, J. J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Keel, P. K.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Heatherton, T. F.] Dartmouth Coll, Dept Psychol & Brain Sci, Hanover, NH 03755 USA. RP Thomas, JJ (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, WAC 816D,15 Parkman St, Boston, MA 02114 USA. EM jjthomas@partners.org FU Dartmouth College; Klarman Family Foundation FX This study was supported by a research grant from Dartmouth College and a Klarman Family Foundation post-doctoral fellowship to Dr. Thomas. NR 40 TC 7 Z9 8 U1 4 U2 25 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1124-4909 J9 EAT WEIGHT DISORD-ST JI Eat. Weight Disord.-Stud. Anorex. PD SEP PY 2011 VL 16 IS 3 BP E216 EP E222 PG 7 WC Psychiatry SC Psychiatry GA 930VR UT WOS:000303170600012 PM 22290040 ER PT J AU Mattei, PL Johnson, RR Beachkofsky, TM Wisco, OJ Hivnor, CM Murchland, MR AF Mattei, Peter L. Johnson, Ryan R. Beachkofsky, Thomas M. Wisco, Oliver J. Hivnor, Chad M. Murchland, Michael R. TI Pruritic rash on trunk SO JOURNAL OF FAMILY PRACTICE LA English DT Editorial Material ID SYPHILIS; DISEASES C1 [Johnson, Ryan R.; Hivnor, Chad M.; Murchland, Michael R.] Wilford Hall USAF Med Ctr, Dept Dermatol, Lackland AFB, TX USA. [Beachkofsky, Thomas M.] Kunsan Air Base, Fighter Squadron 80, Kunsan, South Korea. [Wisco, Oliver J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wisco, Oliver J.] Harvard Univ, Sch Med, Boston, MA USA. RP Mattei, PL (reprint author), 641 Bainbridge Dr, Mullica Hill, NJ 08062 USA. EM peterlmattei@gmail.com NR 14 TC 0 Z9 0 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 SEP PY 2011 VL 60 IS 9 BP 539 EP 542 PG 4 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 930IM UT WOS:000303132300013 PM 21901180 ER PT J AU Adler, LA Shaw, DM Spencer, TJ Newcorn, JH Sitt, DJ Minerly, AE Davidow, JV Faraone, SV AF Adler, Lenard A. Shaw, David M. Spencer, Thomas J. Newcorn, Jeffrey H. Sitt, David J. Minerly, AnaChristina E. Davidow, Jennifer V. Faraone, Stephen V. TI Preliminary Reliability and Validity of a New Time-Sensitive ADHD Symptom Scale in Adolescents with ADHD SO POSTGRADUATE MEDICINE LA English DT Article DE ADHD; adolescents; classification; psychometrics; questionnaires ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; MIXED AMPHETAMINE SALTS; ONCE-DAILY ATOMOXETINE; DOUBLE-BLIND; CHILDREN; ADULTS; METHYLPHENIDATE; COMORBIDITY; TOLERABILITY AB Objectives: To validate the Time-Sensitive ADHD Symptom Scale (TASS) in the assessment of symptom change during the day in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 40 participants with ADHD aged 13 to 17 years completed 1 or 2 visits, 1 to 9 weeks apart. The TASS and the ADHD Rating Scale-IV (ADHD-RS-IV) were completed twice at each visit: at the time of the clinic visit (in-clinic assessment) and 2 to 6 hours afterwards (evening assessment). Results: Internal consistency of the TASS was high, with Cronbach's alpha coefficients of 0.91 (in-clinic) and 0.90 (evening) for visit 1, and 0.88 (in-clinic) and 0.86 (evening) for visit 2. Pearson's correlation coefficients between the TASS and ADHD-RS-IV were significant at both visits (P < 0.0001). Stability analyses of the TASS found no significant effect between ratings performed at different visits (P = 0.936), but there was a significant effect of the assessment time within visits (P < 0.0001). There was not a significant visit by assessment time interaction (P = 0.924). Conclusions: The TASS showed high internal consistency and high concurrent validity with the ADHD-RS-IV. Results of this preliminary study indicate that the TASS is a valid and reliable self-report scale for adolescents with ADHD. C1 [Adler, Lenard A.] NYU Sch Med, Adult ADHD Program, Dept Psychiat, New York, NY 10016 USA. [Adler, Lenard A.] NYU Sch Med, Adult ADHD Program, Dept Child & Adolescent Psychiat, New York, NY 10016 USA. [Adler, Lenard A.] NY VA Harbor Healthcare Syst, Psychiat Serv, New York, NY USA. [Spencer, Thomas J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Spencer, Thomas J.] Massachusetts Gen Hosp, Pediat Psychopharmacol Res Program, Boston, MA 02114 USA. [Newcorn, Jeffrey H.] Mt Sinai Sch Med, Div Child & Adolescent Psychiat, New York, NY USA. [Sitt, David J.] CUNY, Baruch Coll, Dept Psychol, New York, NY 10021 USA. [Minerly, AnaChristina E.] CUNY Hunter Coll, Dept Psychol, New York, NY 10021 USA. [Davidow, Jennifer V.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Adler, LA (reprint author), NYU Sch Med, Adult ADHD Program, Dept Psychiat, 650 1st Ave,7th Floor, New York, NY 10016 USA. EM lenard.adler@nyumc.org OI Newcorn, Jeffrey /0000-0001-8993-9337; Adler, Len/0000-0002-9812-8234; Faraone, Stephen/0000-0002-9217-3982 FU Shire Development, Inc., Wayne, PA; Bristol-Myers Squibb; Chelsea Therapeutics; Eli Lilly Company; National Institute of Drug Abuse; Ortho McNeil/Janssen/Johnson Johnson; Pfizer Inc; Shire Laboratories, Inc.; NYU School of Medicine; Cephalon; GlaxoSmithKline; Janssen; McNeil Pharmaceutical; NIMH; Novartis Pharmaceuticals; Ortho-McNeil-Janssen; National Institutes of Health FX This study was funded in part by an investigator-initiated research grant from Shire Development, Inc., Wayne, PA. In compliance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, established by the International Committee of Medical Journal Editors, Shire Development, Inc. did not impose any impediment, directly or indirectly, on the publication of the study's results. Employees of Shire Development, Inc. were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.; Lenard A. Adler, MD has received grant/research support from the following sources: Bristol-Myers Squibb, Chelsea Therapeutics, Eli Lilly & Company, National Institute of Drug Abuse, Ortho McNeil/Janssen/Johnson & Johnson, Pfizer Inc, and Shire Laboratories, Inc. Dr. Adler has been a speaker or on the speakers' bureaus for the following companies: Ortho McNeil/Janssen/Johnson & Johnson and Shire Laboratories, Inc. Dr. Adler has served on the advisory board for Eli Lilly & Company, i3 Research, Major League Baseball, Mindsite, Organon, Ortho McNeil/Janssen/Johnson & Johnson, and Shire Laboratories, Inc. Dr. Adler has consulted with Epi-Q, INC Research, Major League Baseball Players Association, and United Biosource Corporation. Dr. Adler has received royalty payments (as inventor) from the NYU School of Medicine for license of adult ADHD scales and training materials since 2004. Thomas J. Spencer, MD has received research support from the following sources: Cephalon, Eli Lilly & Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, NIMH, Novartis Pharmaceuticals, Pfizer Inc, and Shire Laboratories, Inc. Dr. Spencer has been a speaker or on a speaker's bureau for the following pharmaceutical companies: Eli Lilly & Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals, and Shire Laboratories, Inc. Dr Spencer has been an advisor or on an advisory board for the following pharmaceutical companies: Cephalon, Eli Lilly & Company, GlaxoSmithKline, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals, Pfizer Inc, and Shire Laboratories, Inc. Jeffrey H. Newcorn, MD has received research support from the following sources: Eli Lilly & Company, Ortho-McNeil-Janssen, and Shire Laboratories, Inc. Dr Newcorn has consulted with Eli Lilly & Company, Ortho-McNeil-Janssen, and Shire Laboratories, Inc. Dr. Newcorn has served on the advisory board for Eli Lilly & Company, Ortho-McNeil-Janssen, Schering-Plough, and Shire Laboratories, Inc. Stephen V. Faraone, PhD has consulted with, has served the advisory board, or has been a speaker for the following pharmaceutical companies: Eli Lilly & Company, Janssen, Novartis, Ortho-McNeil, McNeil, Pfizer Inc, and Shire Laboratories, Inc. Dr. Faraone has received research support from Eli Lilly & Company, the National Institutes of Health, Pfizer Inc, and Shire Laboratories, Inc. David M. Shaw, BA, David J. Sitt, PsyD, AnaChristina E. Minerly, PhD, and Jennifer V. Davidow, BS disclose no conflicts of interest. NR 41 TC 1 Z9 1 U1 2 U2 3 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD SEP PY 2011 VL 123 IS 5 BP 7 EP 13 DI 10.3810/pgm.2011.09.2455 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 934CQ UT WOS:000303419900001 PM 21904082 ER PT J AU Spencer, TJ Faraone, SV Surman, CBH Petty, C Clarke, A Batchelder, H Wozniak, J Biederman, J AF Spencer, Thomas J. Faraone, Stephen V. Surman, Craig B. H. Petty, Carter Clarke, Allison Batchelder, Holly Wozniak, Janet Biederman, Joseph TI Toward Defining Deficient Emotional Self-Regulation in Children with Attention-Deficit/Hyperactivity Disorder Using the Child Behavior Checklist: A Controlled Study SO POSTGRADUATE MEDICINE LA English DT Article DE attention-deficit/hyperactivity disorder; affective symptoms; severity of illness index; youth; emotional self-regulation ID PEDIATRIC BIPOLAR DISORDER; CHARACTERISTIC CURVE ANALYSIS; HYPERACTIVITY DISORDER; SOCIAL-ADJUSTMENT; ADHD; CBCL; PROFILE; SCALES; ADOLESCENTS; PHENOTYPE AB Objective: Deficient emotional self-regulation (DESR) is characterized by deficits in self-regulating the physiological arousal caused by strong emotions. We examined whether a unique profile of the Child Behavior Checklist (CBCL) would help identify DESR in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Subjects included 197 children with ADHD and 224 children without ADHD. We defined DESR if a child had an aggregate cut-off score of > 180 but < 210 on the Anxiety/Depression, Aggression, and Attention scales of the CBCL (CBCL-DESR). This profile was selected because of: 1) its conceptual congruence with the clinical concept of DESR; and 2) because its extreme (> 210) form has been previously associated with severe forms of mood and behavioral dysregulation in children with ADHD. All subjects were comprehensively assessed with structured diagnostic interviews and a wide range of functional measures. Results: Forty-four percent of children with ADHD had a positive CBCL-DESR profile versus 2% of controls (P < 0.001). The CBCL-DESR profile was associated with elevated rates of anxiety and disruptive behavior disorders, as well as significantly more impairments in emotional and interpersonal functioning. Conclusions: The CBCL-DESR profile helped identify a subgroup of children with ADHD who had a psychopathological and functional profile consistent with the clinical concept of DESR. C1 [Spencer, Thomas J.; Biederman, Joseph] Massachusetts Gen Hosp, Clin Program Pediat Psychopharmacol & Adult ADHD, Boston, MA 02114 USA. [Spencer, Thomas J.; Biederman, Joseph] Massachusetts Gen Hosp, Res Program Pediat Psychopharmacol & Adult ADHD, Boston, MA 02114 USA. [Spencer, Thomas J.; Surman, Craig B. H.; Wozniak, Janet; Biederman, Joseph] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Surman, Craig B. H.] Massachusetts Gen Hosp, Adult ADHD Program, Boston, MA 02114 USA. [Petty, Carter; Clarke, Allison; Batchelder, Holly] Massachusetts Gen Hosp, Pediat Psychopharmacol Res Unit, Boston, MA 02114 USA. [Wozniak, Janet] Massachusetts Gen Hosp, Pediat Bipolar Disorder Res Program, Boston, MA 02114 USA. RP Spencer, TJ (reprint author), Massachusetts Gen Hosp, Clin Program Pediat Psychopharmacol & Adult ADHD, 55 Fruit St,YAW6A, Boston, MA 02114 USA. EM tspencer@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU National Institutes of Health [R01 HD36317 R01 MH50657]; Shire Pharmaceuticals; Pediatric Psychopharmacology Research Council; Cephalon; Eli Lilly Company; GlaxoSmithKline; Janssen Pharmaceutical; McNeil Pharmaceutical; Novartis Pharmaceuticals; Pfizer Inc; Shire Laboratories, Inc.; National Institute of Mental Health; Shire; Janssen; McNeil; Novartis; Abbott; Alza; Hilda and Preston Davis Foundation; Merck and Co., Inc.; New River; Organon; Takeda; Janssen-Ortho; Johnson and Johnson; Sepracor; Elminda; NextWave Pharmaceuticals; MGH Psychiatry Academy; AstraZeneca; Fundacion Dr. Manuel Camelo A.C. in Monterrey Mexico; Fundacion Areces (Spain); Medice Pharmaceuticals (Germany); Spanish Child Psychiatry Association; Bristol-Myers Squibb; Celltech; Esai; Forest; Gliatech; NARSAD; NIDA; NICHD; Noven; Neurosearch; Otsuka; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma, Inc.; Wyeth; adult ADHD scales FX This manuscript was supported in part by grants to Joseph Biederman, MD from the National Institutes of Health (R01 HD36317 R01 MH50657) and to Thomas J. Spencer, MD from Shire Pharmaceuticals and the Pediatric Psychopharmacology Research Council Fund. The study sponsors had no role in the study design or conduct, collection, management, preparation, or analysis of the data.; Thomas J. Spencer, MD has received research support from, has been a speaker for or on a speakers' bureau for, or has been an advisor or on an advisory board of the following sources: Cephalon, Eli Lilly & Company, GlaxoSmithKline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Pfizer Inc, Shire Laboratories, Inc., the National Institute of Mental Health, and has received royalties on adult ADHD scales (research support). In the past year, Stephen V. Faraone, PhD received consulting fees and was on advisory boards for Shire Development, and received research support from Shire and the National Institutes of Health (NIH). In previous years, he received consulting fees or was on advisory boards or participated in CME education programs sponsored by: Eli Lilly & Company, Janssen, McNeil, Novartis, Pfizer Inc, and Shire. In previous years, he received research support from Eli Lilly & Company, the NIH, Pfizer Inc, and Shire. Dr. Faraone receives royalties from a book published by Guilford Press, Straight Talk About Your Child's Mental Health. Craig B. H. Surman, MD has received research support from Abbott, Alza, Cephalon, Eli Lilly & Company, the Hilda and Preston Davis Foundation, McNeil, Merck and Co., Inc., New River, the NIH, Organon, Pfizer Inc, Shire, and Takeda; has received support from Janssen-Ortho, McNeil, Novartis, and Shire for speaking and other educational activities; and has been a consultant/advisor for McNeil, Shire, and Takeda. Dr. Surman has also received honoraria from Reed Medical Education (a logistics collaborator for the MGH Psychiatry Academy). Commercial entities supporting the MGH Psychiatry Academy are listed on the Academy's Web site (www.mghcme.org). Janet Wozniak, MD is the author of a book published by Bantam Books, Is Your Child Bipolar. She is a speaker for Primedia/MGH Psychiatry Academy. She has received research support from Janssen, Johnson and Johnson, McNeil, and Shire. Her spouse, John Winkelman MD, PhD, is on the speakers' bureaus for sanofi-aventis and Sepracor. He is a consultant or on advisory boards for Covance, GlaxoSmithKline, Impax Laboratories, Luitpold Pharmaceuticals, Neurogen, Pfizer Inc, UCB, and Zeo, Inc. He has received research support from GlaxoSmithKline and Sepracor. Joseph Biederman, MD is currently receiving research support from the following sources: Elminda, Janssen, McNeil, NextWave Pharmaceuticals, and Shire. In 2011, Dr. Biederman gave a single unpaid talk for Juste Pharmaceutical Spain, and received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. He also received an honorarium from Cambridge University Press for a chapter publication. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly and Company, Shire, and AstraZeneca; these royalties are paid to the Department of Psychiatry at MGH. In 2010, Dr. Joseph Biederman received a speaker's fee from a single talk given at Fundacion Dr. Manuel Camelo A.C. in Monterrey Mexico. Dr. Biederman provided single consultations for Shionogi Pharma, Inc. and Cipher Pharmaceuticals, Inc.; the honoraria for these consultations were paid to the Department of Psychiatry at the MGH. Dr. Biederman received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. In 2009, Dr. Joseph Biederman received a speaker's fee from the following sources: Fundacion Areces (Spain), Medice Pharmaceuticals (Germany), and the Spanish Child Psychiatry Association. In previous years, Dr.; Biederman received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly and Company, Esai, Forest, GlaxoSmithKline, Gliatech, Janssen, McNeil, Merck and Co., Inc., NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer Inc, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc., and Wyeth. Carter Petty, MA, Allison Clarke, BA, and Holly Batchelder, BS disclose no conflicts of interest. NR 35 TC 32 Z9 33 U1 2 U2 22 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD SEP PY 2011 VL 123 IS 5 BP 50 EP 59 DI 10.3810/pgm.2011.09.2459 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 934CQ UT WOS:000303419900005 PM 21904086 ER PT J AU Dubovsky, SL Leonard, K Griswold, K Daurignac, E Hewitt, B Fox, C Seymour, D Dubovsky, AN DeGruy, F AF Dubovsky, Steven L. Leonard, Kenneth Griswold, Kim Daurignac, Elsa Hewitt, Burlleen Fox, Chester Seymour, Deborah Dubovsky, Amelia N. DeGruy, Frank TI Bipolar Disorder is Common in Depressed Primary Care Patients SO POSTGRADUATE MEDICINE LA English DT Article DE depression; bipolar disorder; primary care; antidepressant; mood stabilizer; diagnosis ID COMORBIDITY SURVEY REPLICATION; SPECTRUM DISORDER; ANTIDEPRESSANT TREATMENT; PSYCHIATRIC-DISORDERS; VALIDITY; QUESTIONNAIRE; PREVALENCE; VALIDATION; DIAGNOSIS; INTERVIEW AB Objective: To examine the prevalence and treatment of typical and subsyndromal bipolar disorder (BD) in depressed primary care patients. Methods: Patients with a diagnosis of a mood disorder being treated with antidepressants in 2 academic family practice clinics underwent a structured diagnostic interview (Mini International Neuropsychiatric Inventory) for manic and hypomanic symptoms. Results: Of 58 patients evaluated, 19% met full criteria for bipolar 1 disorder and 8.6% for bipolar 11 disorder; 31% had subsyndromal BD (ie, persistent elation or irritability accompanied by additional symptoms of hypomania but not enough symptoms to meet full criteria for bipolar I or 11 disorder). Only 5 patients with BD were receiving mood stabilizers, which had not been instituted in any patient by the primary care physician. Conclusions: The high prevalence of patients meeting full criteria for BD and the low rate of identification of BD in primary care patients are consistent with estimates using self-administered questionnaires, but the interview revealed a substantial additional population that could be considered to have subsyndromal BD. Because subsyndromal forms of BD are associated with significant impairment and comorbidity as well as progression to frank BD, recognition of both full and subthreshold BD in primary care practice should be improved. C1 [Dubovsky, Steven L.; Leonard, Kenneth] SUNY Buffalo, Dept Psychiat, Buffalo, NY 14260 USA. [DeGruy, Frank] Univ Colorado, Dept Family Med, Denver, CO 80202 USA. [Hewitt, Burlleen] Radiant Res, Denver, CO USA. [Dubovsky, Amelia N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dubovsky, SL (reprint author), 462 Grider St,Room 1182, Buffalo, NY 14215 USA. EM dubovsky@buffalo.edu FU Pfizer Inc.; Eli Lilly; Otsuka; Sumitomo; National Institutes of Health FX Steven L. Dubovsky, MD receives research support from Pfizer Inc., Eli Lilly, Otsuka, and Sumitomo. Kenneth Leonard, PhD receives research support from the National Institutes of Health. Burlleen Hewitt, BA is an employee of Radiant Research, which receives grant support from multiple manufacturers. Kim Griswold, MD, Elsa Daurignac, PhD, Chester Fox, MD, Deborah Seymour, PhD, Amelia N. Dubovsky, MD, and Frank DeGruy, MD disclose no conflicts of interest. NR 30 TC 7 Z9 7 U1 2 U2 4 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD SEP PY 2011 VL 123 IS 5 BP 129 EP 133 DI 10.3810/pgm.2011.09.2468 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 934CQ UT WOS:000303419900014 PM 21904095 ER PT J AU Mendez, MF AF Mendez, Mario F. TI Malapropisms, or "The Archie Bunker Syndrome," and Frontotemporal Dementia SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Letter C1 [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, Los Angeles, CA 90095 USA. [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Mendez, MF (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Ctr, Dept Neurol, Los Angeles, CA 90095 USA. EM mmendez@UCLA.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD FAL PY 2011 VL 23 IS 4 BP E3 EP E3 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 924XS UT WOS:000302725200003 ER PT J AU Marques, L Weingarden, HM LeBlanc, NJ Siev, J Wilhelm, S AF Marques, Luana Weingarden, Hilary M. LeBlanc, Nicole J. Siev, Jedidiah Wilhelm, Sabine TI The relationship between perceived social support and severity of body dysmorphic disorder symptoms: the role of gender SO REVISTA BRASILEIRA DE PSIQUIATRIA LA English DT Article DE Body dysmorphic disorders; Signs and symptoms; Gender; Social support ID OBSESSIVE-COMPULSIVE DISORDER; STRESS SCALES DASS; QUALITY-OF-LIFE; FOLLOW-UP; PSYCHOMETRIC PROPERTIES; FUNCTIONAL IMPAIRMENT; CLINICAL-FEATURES; ADOLESCENT GIRLS; 200 INDIVIDUALS; DEPRESSION AB Objective: Whether social support is associated with severity of body dysmorphic symptoms is unknown. To address this gap in the literature, the present study aims to examine the association between three domains of perceived social support (i.e., family, friends, and significant others) and severity of body dysmorphic disorder symptoms. Method: Participants (N = 400) with symptoms consistent with diagnosis of body dysmorphic disorder completed measures of symptomatology and social support via the internet. Results: More perceived social support from friends and significant others was associated with less severe body dysmorphic disorder symptoms for males, and more perceived social support from family and friends was associated with less severe body dysmorphic disorder symptoms among females. Additionally, gender moderated the association between perceived social support from significant others and symptom severity, such that perceived social support from a significant other was significantly negatively associated with body dysmorphic symptom severity in males, but not females. Conclusion: The present study implicates social support as an important area of future body dysmorphic disorder research. C1 [Marques, Luana; Siev, Jedidiah; Wilhelm, Sabine] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Marques, Luana; Siev, Jedidiah] Harvard Univ, Sch Med, Boston, MA USA. [Weingarden, Hilary M.; LeBlanc, Nicole J.; Wilhelm, Sabine] Massachusetts Gen Hosp, Obsess Compuls & Related Disorders Clin, Boston, MA 02114 USA. [Weingarden, Hilary M.; LeBlanc, Nicole J.] Tufts Univ, Boston, MA 02111 USA. RP Marques, L (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. EM lmarques@partners.org NR 43 TC 3 Z9 3 U1 1 U2 12 PU ASSOC BRASILEIRA PSIQUIATRIA PI SAO PAULO PA SUBSCRIPTION DEPARTMENT, RUA PEDRO DE TOLEDO, 967 - CASA 01, SAO PAULO, SP 04039-032 A, BRAZIL SN 1516-4446 J9 REV BRAS PSIQUIATR JI Rev. Bras. Psiquiatr. PD SEP PY 2011 VL 33 IS 3 BP 238 EP 244 PG 7 WC Psychiatry SC Psychiatry GA 908YF UT WOS:000301528300006 PM 21971776 ER PT J AU Dewanwala, A Chittenden, A Rosenblatt, M Mercado, R Garber, JE Syngal, S Stoffel, EM AF Dewanwala, Akriti Chittenden, Anu Rosenblatt, Margery Mercado, Rowena Garber, Judy E. Syngal, Sapna Stoffel, Elena M. TI Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch Syndrome SO FAMILIAL CANCER LA English DT Article DE Lynch syndrome; Prenatal testing; Preimplantation genetic diagnosis; Family; Genetic testing; Genetic counseling ID NONPOLYPOSIS COLORECTAL-CANCER; FAMILIAL ADENOMATOUS POLYPOSIS; COMPLEMENTARY MEDICINE USE; LI-FRAUMENI-SYNDROME; OVARIAN-CANCER; HEREDITARY RETINOBLASTOMA; PREDISPOSITION SYNDROMES; MUTATION CARRIERS; CYSTIC-FIBROSIS; DIAGNOSIS AB To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch Syndrome (LS), the most common type of hereditary colorectal cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20-75), 71% were female, 53% had a personal diagnosis of cancer, and 68% had children. Eighty percent worried about their children's risk for developing cancer; however only 9% reported their decision to have children was affected by their family history of cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations was ethical, 66% (86/ 130) of respondents agreed/ strongly agreed, 25% (32) were neutral and 9% (12) disagreed/ strongly disagreed. Of 48 individuals planning to have children in the future, 57% (27) intended to have children regardless of their genetic test result. If found to carry a MMR gene mutation that confirmed LS, 42% (20) would consider prenatal testing for a future pregnancy and 20% (7/ 35) of women would consider having children earlier in order to have prophylactic surgery to reduce their risk for gynecologic cancers. Individuals undergoing genetic testing for LS may utilize test results to make reproductive decisions. Clinicians should be prepared to discuss options of reproductive genetic technologies during counseling of LS patients of childbearing age. C1 [Syngal, Sapna; Stoffel, Elena M.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Dewanwala, Akriti; Chittenden, Anu; Rosenblatt, Margery; Mercado, Rowena; Garber, Judy E.; Syngal, Sapna; Stoffel, Elena M.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Garber, Judy E.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Garber, Judy E.; Syngal, Sapna; Stoffel, Elena M.] Harvard Univ, Sch Med, Boston, MA USA. RP Stoffel, EM (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. EM estoffel@partners.org FU National Cancer Institute [K07 CA 120448-04, K24 CA 113433]; American Recovery and Reinvestment Act [3K07CA120448-03S1]; American College of Gastroenterology Junior Faculty FX The authors would like to thank Bridget Neville, MS, for her assistance with statistical programming. The authors acknowledge the following sources of grant support: National Cancer Institute K07 CA 120448-04 (Dr. Stoffel), American Recovery and Reinvestment Act 3K07CA120448-03S1 (Dr. Stoffel), American College of Gastroenterology Junior Faculty Award (2004-Dr. Stoffel), National Cancer Institute K24 CA 113433 (Dr. Syngal). NR 53 TC 7 Z9 7 U1 1 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9600 J9 FAM CANCER JI Fam. Cancer PD SEP PY 2011 VL 10 IS 3 SI SI BP 549 EP 556 DI 10.1007/s10689-011-9448-8 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 908RI UT WOS:000301507400019 PM 21567236 ER PT J AU Kunik, M AF Kunik, Mark TI CBT for older adults with chronic medical illnesses and psychological comorbidity SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Meeting Abstract C1 [Kunik, Mark] Houston Vet Affairs Med Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD SEP PY 2011 VL 23 SU 1 BP S68 EP S69 PG 2 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA 889UX UT WOS:000300101100114 ER PT J AU Mintzer, J Brawman-Mintzer, O Nietert, P Vankirk, K Longmire, CF Jones, E Stuckey, M AF Mintzer, Jacobo Brawman-Mintzer, O. Nietert, P. Vankirk, K. Longmire, C. Flynn Jones, E. Stuckey, M. TI Escitalopram in the treatment of non-depressed elderly patients with generalized anxiety disorder SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Meeting Abstract ID CONTROLLED-TRIAL C1 [Mintzer, Jacobo; Brawman-Mintzer, O.; Nietert, P.; Jones, E.; Stuckey, M.] Ralph Johnson VA Med Ctr, N Charleston, SC USA. [Mintzer, Jacobo; Brawman-Mintzer, O.; Nietert, P.; Vankirk, K.; Longmire, C. Flynn] Med Univ S Carolina, N Charleston, SC USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD SEP PY 2011 VL 23 SU 1 BP S305 EP S306 PG 2 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA 889UX UT WOS:000300101100410 ER PT J AU Belanger, E Henry, FP Vallee, R Randolph, MA Kochevar, IE Winograd, JM Lin, CP Cote, D AF Belanger, E. Henry, F. P. Vallee, R. Randolph, M. A. Kochevar, I. E. Winograd, J. M. Lin, C. P. Cote, D. TI In vivo evaluation of demyelination and remyelination in a nerve crush injury model SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID STOKES-RAMAN SCATTERING; MICROSCOPY; MYELIN; DEGENERATION; TISSUE; MECHANISMS; CONTRAST; BIOLOGY AB Nerves of the peripheral nervous system have, to some extent, the ability to regenerate after injury, particularly in instances of crush or contusion injuries. After a controlled crush injury of the rat sciatic nerve, demyelination and remyelination are followed with functional assessments and imaged both ex vivo and in vivo over the course of 4 weeks with video-rate coherent anti-Stokes Raman scattering (CARS) microscopy. A new procedure compatible with live animal imaging is developed for performing histomorphometry of myelinated axons. This allows quantification of demyelination proximal and remyelination distal to the crush site ex vivo and in vivo respectively. (C) 2011 Optical Society of America C1 [Belanger, E.; Vallee, R.; Cote, D.] Univ Laval, CRULRG, Quebec City, PQ G1J 2G3, Canada. [Belanger, E.; Vallee, R.; Cote, D.] Univ Laval, COPL, Quebec City, PQ G1V 0A6, Canada. [Henry, F. P.; Randolph, M. A.; Kochevar, I. E.; Winograd, J. M.; Lin, C. P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Belanger, E (reprint author), Univ Laval, CRULRG, Quebec City, PQ G1J 2G3, Canada. EM daniel.cote@crulrg.ulaval.ca OI Henry, Francis P./0000-0003-4170-7806 FU Plastic Surgery Educational Foundation (PSEF),; Bullock-Wellman Fellowship; Canada Research Chair (CRC) program; National Science and Engineering Research Council of Canada (NSERC); Multiple Sclerosis Society of Canada (MSSOC) FX The authors gratefully acknowledge funding from the Plastic Surgery Educational Foundation (PSEF), Basic Science Grant 2007 and the Bullock-Wellman Fellowship, the Canada Research Chair (CRC) program and National Science and Engineering Research Council of Canada (NSERC). This investigation was supported by a Dr. William J. McIlroy Studentship from the Multiple Sclerosis Society of Canada (MSSOC) awarded to E. Belanger. NR 24 TC 32 Z9 32 U1 0 U2 9 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD SEP 1 PY 2011 VL 2 IS 9 BP 2698 EP 2708 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886VY UT WOS:000299883200024 PM 22091449 ER PT J AU Kraker, J Zivkovic, SA AF Kraker, Jessica Zivkovic, Sasa A. TI Autoimmune Neuromuscular Disorders SO CURRENT NEUROPHARMACOLOGY LA English DT Article DE Autoimmune; neuromuscular; neuropathy; myositis; myasthenia gravis; treatment ID INFLAMMATORY-DEMYELINATING POLYNEUROPATHY; EATON-MYASTHENIC-SYNDROME; GUILLAIN-BARRE-SYNDROME; QUALITY STANDARDS SUBCOMMITTEE; MULTIFOCAL MOTOR NEUROPATHY; LONG-TERM PROGNOSIS; FOLLOW-UP; MONOCLONAL GAMMOPATHY; PLASMA-EXCHANGE; UNDETERMINED SIGNIFICANCE AB Autoimmune neuromuscular disorders affecting peripheral nerves, neuromuscular junction or muscle have a wide clinical spectrum with diverse pathogenetic mechanisms. Peripheral nervous system may be targeted in the context of complex immune reactions involving different cytokines, antigen-presenting cells, B cells and different types of T cells. Various immunomodulating and cytotoxic treatments block proliferation or activation of immune cells by different mechanisms attempting to control the response of the immune system and limit target organ injury. Most treatment protocols for autoimmune neuromuscular disorders are based on the use of corticosteroids, intravenous immunoglobulins and plasmapheresis, with cytotoxic agents mostly used as steroid-sparing medications. More recently, development of specific monoclonal antibodies targeting individual cell types allowed a different approach targeting specific immune pathways, but these new treatments are also associated with various adverse effects and their long-term efficacy is still unknown. C1 [Kraker, Jessica; Zivkovic, Sasa A.] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA 15213 USA. [Zivkovic, Sasa A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Zivkovic, SA (reprint author), Univ Pittsburgh, Med Ctr, Dept Neurol, 200 Lothrop St,PUH F878, Pittsburgh, PA 15213 USA. EM zivkovics@upmc.edu NR 71 TC 1 Z9 1 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PD SEP PY 2011 VL 9 IS 3 BP 400 EP 408 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 883HF UT WOS:000299624100002 PM 22379454 ER PT J AU Hirsch, AE Jha, RM Yoo, AJ Saxena, A Ozonoff, A Growney, MJ Hirsch, JA AF Hirsch, Ariel E. Jha, Ruchira M. Yoo, Albert J. Saxena, Akriti Ozonoff, Al Growney, Marion J. Hirsch, Joshua A. TI The Use of Vertebral Augmentation and External Beam Radiation Therapy in the Multimodal Management of Malignant Vertebral Compression Fractures SO PAIN PHYSICIAN LA English DT Article DE malignant compression fractures; palliation; vertebroplasty; radiation therapy ID INTERVENTIONAL PAIN MANAGEMENT; EVIDENCE-BASED MEDICINE; CLINICAL-PRACTICE GUIDELINES; CT-GUIDED VERTEBROPLASTY; CHRONIC SPINAL PAIN; PERCUTANEOUS VERTEBROPLASTY; SYSTEMATIC REVIEWS; RANDOMIZED-TRIAL; CEMENT AUGMENTATION; METASTATIC-DISEASE AB Background: Vertebral augmentation (VA) techniques such as vertebroplasty and kyphoplasty are increasingly performed minimally invasive procedures for osteoporotic or malignant compression fractures (MCFs) and involve injection of polymethylmethacrylate (PMMA) cement directly into a compressed vertebral body. Objective: This article will evaluate the efficacy of VA in relieving fracture-related pain. We also intend to identify procedural and clinical variables that could potentially influence outcomes in this population. In the subset of patients with cancer who received both external beam radiation therapy (EBRT) and VA, we will assess the impact of the treatment sequence on pain outcomes. Study Design: We performed a retrospective analysis of 201 cases of patients with cancer and MCFs who underwent one or more vertebral augmentation procedures at our institution between 2003 and 2009. The majority of cancers represented were multiple myeloma, metastatic lung cancer, and metastatic breast cancer. The primary outcome measure was pain relief, as measured by the Visual Analog Scale and a 4-point pain scale. Setting: We present an institutional experience at an academic medical center of 201 cases of MCFs. Methods: We compiled an institutional database of vertebroplasty and kyphoplasty cases using paper and electronic medical records. Our data collection methodology has been previously reported and includes variables such as procedure dates, gender, age, type of malignancy, fracture etiology, history of cancer treatment, type of procedure performed, vertebral level treated, the number of levels treated per procedure, complications, and follow-up information on pain response. The updated dataset incorporates new variables including information on pain medications and standardized questionnaires such as the Visual Analog Scale (VAS) for pain and the Roland Morris Disability Questionnaire (RMDQ). Results: In the 201 cases of MCFs, a total of 316 vertebral levels were treated with either vertebroplasty or kyphoplasty. Follow-up data on pain relief was available for 190 out of 201 cases (95%). Among this subgroup, 168 cases (88%) with MCFs responded. Thirty-nine percent (39%) of the time patients experienced complete pain resolution. In only 4% of cases did patients report worsening of their fracture-related pain post-procedure. There was no difference in pain outcomes with regard to sequencing of EBRT and VA. Limitations: One of the limitations of our analysis is that it did not evaluate the effect of pain improvement or resolution before and after EBRT alone and on activities of daily living in the majority of patients. However, one of the main goals of this analysis is to address previous limitations. We attempt to standardize outcome measures by using the Visual Analog Scale (VAS) for pain and the Roland Morris Disability Questionnaire (RMDQ). Conclusion: A multimodality approach for the management of MCFs includes VA procedures. The majority of patients with MCFs have excellent palliation with this approach. In patients who receive both EBRT and VA, the sequence in which they are given does not affect pain improvement outcomes. C1 [Hirsch, Ariel E.] Boston Univ, Med Ctr, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02118 USA. [Jha, Ruchira M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Yoo, Albert J.; Growney, Marion J.; Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Neuroradiol, Boston, MA 02114 USA. [Saxena, Akriti] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Ozonoff, Al] Childrens Hosp, Clin Res Program, Boston, MA 02115 USA. RP Hirsch, AE (reprint author), Boston Univ, Med Ctr, Massachusetts Gen Hosp, Dept Radiat Oncol, 830 Harrison Ave,Moakley Bldg LL, Boston, MA 02118 USA. EM Ariel.hirsch@bmc.org NR 71 TC 12 Z9 14 U1 1 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD SEP-OCT PY 2011 VL 14 IS 5 BP 447 EP 458 PG 12 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 885MW UT WOS:000299784100013 PM 21927049 ER PT J AU Manchikanti, L Falco, FJE Hirsch, JA AF Manchikanti, Laxmaiah Falco, Frank J. E. Hirsch, Joshua A. TI Necessity and Implications of ICD-10: Facts and Fallacies SO PAIN PHYSICIAN LA English DT Review DE Diagnostic coding systems; International Statistical Classification of Diseases and Related Health Problems (ICD); ICD-9-CM; ICD-10-CM; regulations; growth; evidence-based literature; reimbursement; claims; Health Insurance Portability and Accountability Act (HIPAA) ID INTERVENTIONAL PAIN MANAGEMENT; EVIDENCE-BASED MEDICINE; CHRONIC SPINAL PAIN; REFLEX SYMPATHETIC DYSTROPHY; CLINICAL-PRACTICE GUIDELINES; AFFORDABLE CARE ACT; LOW-BACK-PAIN; ADMINISTRATIVE DATA; HEALTH-CARE; SYSTEMATIC REVIEWS AB The International Classification of Diseases-10 (ICD-10 is a new system that is expected to be implemented effective on October 1, 2013. This new system is a federally mandated change affecting all payers and providers, and is expected to exceed both the Health Insurance Portability and Accountability Act (HIPAA) and Y2K in terms of costs and risks. However, the Administration is poised to implement these changes at a rapid pace which could be problematic for health care in the United States. In 2003, HIPAA named ICD-9 as the code set for supporting diagnoses and procedures in electronic administrative transactions. However, on January 16, 2009, the Department of Health and Human Services (HHS) published a regulation requiring the replacement of ICD-9 with ICD-10 as of October 1, 2013. While ICD-9 and 10 have a similar type of hierarchy in their structures, the ICD-10 is more complex and incorporates numerous changes. Overall, ICD-10 contains over 141,000 codes, a whopping 712% increase over the less than 20,000 codes in ICD-9, creating enormous complexities, confusion, and expense. Multiple published statistics illustrate that there are approximately 119 instances where a single ICD-9 code can map to more than 100 distinct ICD-10 codes, whereas there are 255 instances where a single ICD-9 code can map to more than 50 ICD-10 codes. To add to the confusion, there are 3,684 instances in the mapping for diseases where a single ICD-10 code can map to more than one ICD-9 code. Proponents of the new ICD-10 system argue that the granularity should lead to improvements in the quality of health care, since more precise coding that more accurately reflects actual patient conditions will permit smarter and more effective disease management in pay-for-performance programs. This, in essence, encapsulates the benefits that supporters of this new system believe will be realized, even though many of these experts may not be involved in actual day-to-day medical practices. Detractors of the system see the same granularity as burdensome. The estimated cost per physician is projected to range from $25,000 to $50,000. Further, they argue that the ICD-10 classification is extremely complicated, and expensive. Concerns exist that it is being implemented without establishing either the necessity or thinking through the unintended consequences. Opponents also argue that beyond financial expense, it is also costly in terms of human toll, hardware and software expenses and has the potential to delay reimbursement. There is also concern that an unintended consequence of granularity would be the potential for enhanced and unnecessary fraud and abuse investigations. The authors of this article favor postponing the implementation of the ICD-10 until such time as its necessity is proven and implications are understood. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys Newark, Newark, DE USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 107 TC 25 Z9 25 U1 0 U2 22 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD SEP-OCT PY 2011 VL 14 IS 5 BP E405 EP E425 PG 21 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 885MW UT WOS:000299784100001 PM 21927055 ER PT J AU Felts, AS Bates, BS Rodriguez, AL Menon, UN Jadhav, S Blobaum, AL Byers, FW Daniels, JS Lawson, KP Jones, CK Conn, PJ Lindsley, CW Emmitte, KA AF Felts, A. S. Bates, B. S. Rodriguez, A. L. Menon, U. N. Jadhav, S. Blobaum, A. L. Byers, F. W. Daniels, J. S. Lawson, K. P. Jones, C. K. Conn, P. J. Lindsley, C. W. Emmitte, K. A. TI SAR and in vitro/vivo Evaluation of a Novel Series of Substituted Aryl Ether Benzamides as Negative Allosteric Modulators of mGlu(5) SO CURRENT NEUROPHARMACOLOGY LA English DT Meeting Abstract C1 [Felts, A. S.; Bates, B. S.; Rodriguez, A. L.; Menon, U. N.; Jadhav, S.; Blobaum, A. L.; Byers, F. W.; Daniels, J. S.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Felts, A. S.; Bates, B. S.; Rodriguez, A. L.; Menon, U. N.; Jadhav, S.; Blobaum, A. L.; Byers, F. W.; Daniels, J. S.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Emmitte, K. A.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Jones, C. K.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN USA. Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. RI Conn, Peter/D-7848-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PD SEP PY 2011 VL 9 SU 1 MA 55 BP 20 EP 20 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 883IJ UT WOS:000299627200056 ER PT J AU Niswender, CM Jones, CK Hopkins, CR Thompson, AD Bubser, M Engers, D Gogliotti, RD Blobaum, AL Salovich, JM Cheung, YY Morrison, RD Dawson, ES Zamorano, R Brewer, KA Daniels, JS Lindsley, CW Conn, PJ AF Niswender, C. M. Jones, C. K. Hopkins, C. R. Thompson, A. D. Bubser, M. Engers, D. Gogliotti, R. D. Blobaum, A. L. Salovich, J. M. Cheung, Y. Y. Morrison, R. D. Dawson, E. S. Zamorano, R. Brewer, K. A. Daniels, J. S. Lindsley, C. W. Conn, P. J. TI mGlu4 Receptor Positive Allosteric Modulator Development for the Treatment of CNS Disorders SO CURRENT NEUROPHARMACOLOGY LA English DT Meeting Abstract C1 [Niswender, C. M.; Jones, C. K.; Hopkins, C. R.; Thompson, A. D.; Bubser, M.; Engers, D.; Gogliotti, R. D.; Blobaum, A. L.; Salovich, J. M.; Cheung, Y. Y.; Morrison, R. D.; Dawson, E. S.; Zamorano, R.; Brewer, K. A.; Daniels, J. S.; Lindsley, C. W.; Conn, P. J.] Vanderbilt Univ, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37212 USA. [Niswender, C. M.; Jones, C. K.; Hopkins, C. R.; Thompson, A. D.; Bubser, M.; Engers, D.; Gogliotti, R. D.; Blobaum, A. L.; Salovich, J. M.; Cheung, Y. Y.; Morrison, R. D.; Dawson, E. S.; Zamorano, R.; Brewer, K. A.; Daniels, J. S.; Lindsley, C. W.; Conn, P. J.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37212 USA. [Hopkins, C. R.; Lindsley, C. W.] Vanderbilt Univ, Dept Chem, Nashville, TN 37212 USA. [Jones, C. K.] Vanderbilt Univ, US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Lindsley, C. W.] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37212 USA. RI Conn, Peter/D-7848-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PD SEP PY 2011 VL 9 SU 1 MA 131 BP 48 EP 48 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 883IJ UT WOS:000299627200131 ER PT J AU Welsh, CA Flanagan, ME Kiess, C Doebbeling, BN AF Welsh, Catherine Amber Flanagan, Mindy E. Kiess, Chris Doebbeling, Bradley N. TI Implementing the MRSA Bundle in ICUs: One Citywide Collaborative's Key Lessons Learned SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID HEALTH-CARE; INNOVATIONS AB Because bundle implementation in intensive care units to reduce methicillin-resistant Staphylococcus aureus is challenging, we conducted in-depth interviews with implementation teams at 5 participating hospitals. Key lessons learned across hospitals included the following: maintain management support, engage frontline staff, build the right multidisciplinary team, conduct process mapping, and commit to data collection and feedback. Infect Control Hosp Epidemiol 2011;32(9):918-921 C1 [Welsh, Catherine Amber; Flanagan, Mindy E.; Doebbeling, Bradley N.] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Indianapolis, IN 46204 USA. [Welsh, Catherine Amber] IU Purdue Univ Indianapolis, Sch Engn & Technol, Indianapolis, IN USA. [Kiess, Chris; Doebbeling, Bradley N.] Regenstrief Inst Hlth Care, Indianapolis, IN USA. [Doebbeling, Bradley N.] US Dept Vet Affairs, Hlth Serv Res & Dev Serv, Ctr Excellence, Indianapolis, IN USA. [Doebbeling, Bradley N.] IU Sch Med, Dept Med, Indianapolis, IN USA. RP Welsh, CA (reprint author), 799 W Michigan St, Indianapolis, IN 46202 USA. EM amwelsh@hotmail.com FU US Agency for Healthcare Research and Quality under Office of Management and Budget [HHSA2902006000131] FX US Agency for Healthcare Research and Quality (contract HHSA2902006000131, under Office of Management and Budget control no. 0935-0168, expiration date September 30, 2012). NR 7 TC 4 Z9 4 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP PY 2011 VL 32 IS 9 BP 918 EP 921 DI 10.1086/661101 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 876BW UT WOS:000299083000014 PM 21828975 ER PT J AU Chae, CU Derby, CA AF Chae, Claudia U. Derby, Carol A. TI The Menopausal Transition and Cardiovascular Risk SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Lipids; Blood pressure; Diabetes; Metabolic syndrome; Menopause; Perimenopause ID CORONARY-HEART-DISEASE; RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL HORMONE-THERAPY; MIDDLE-AGED WOMEN; BODY-MASS INDEX; BLOOD-PRESSURE; METABOLIC SYNDROME; HEALTHY WOMEN; MIDLIFE WOMEN; ENDOTHELIAL DYSFUNCTION AB The incidence of cardiovascular disease, which is the leading single cause of death among women, increases substantially after menopause. This may be related to adverse changes in cardiovascular risk factors that occur during the menopausal transition. Proatherogenic changes in lipid and apolipoprotein profiles seem to be specifically related to ovarian aging; unfavorable changes in other cardiovascular risk factors may be influenced more by chronologic aging. Whether these changes are due to aging or to menopause itself, increased attention to risk factor modification in the pre- and perimenopausal years will help reduce future cardiovascular disease risk among women. C1 [Chae, Claudia U.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA 02114 USA. [Derby, Carol A.] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10461 USA. [Derby, Carol A.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Derby, Carol A.] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10461 USA. [Derby, Carol A.] Albert Einstein Coll Med, Dept Populat Hlth, Bronx, NY 10461 USA. RP Chae, CU (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, 55 Fruit St, Boston, MA 02114 USA. EM cchae@partners.org FU Bristol Meyers Squibb; National Institutes of Health [2U01AG012535-16, 5 UO1 AG12531-17] FX Dr Derby receives research support from Bristol Meyers Squibb.; Supported by Grant No. 2U01AG012535-16 (C.A.D.) and 5 UO1 AG12531-17 (C.U.C.) from the National Institutes of Health. NR 71 TC 19 Z9 19 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 0889-8545 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD SEP PY 2011 VL 38 IS 3 BP 477 EP + DI 10.1016/j.ogc.2011.05.005 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 878DU UT WOS:000299234700008 PM 21961715 ER PT J AU Thurston, RC Joffe, N AF Thurston, Rebecca C. Joffe, Nadine TI Vasomotor Symptoms and Menopause: Findings from the Study of Women's Health across the Nation SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Hot flashes; Hot flushes; Vasomotor symptoms; Menopause; Climacteric symptoms; Menopausal symptoms ID MIDDLE-AGED WOMEN; CORONARY-HEART-DISEASE; QUALITY-OF-LIFE; HOT FLASHES; MIDLIFE WOMEN; POSTMENOPAUSAL WOMEN; HORMONE-LEVELS; MULTIETHNIC COMMUNITY; DEPRESSIVE SYMPTOMS; CARDIOVASCULAR-DISEASE AB Vasomotor symptoms (VMS), or hot flashes and night sweats, are often considered the cardinal symptoms of menopause. SWAN, one of the largest and most ethnically diverse longitudinal studies of the menopausal transition, has allowed unique insights into VMS. Specifically, SWAN has helped yield important information about the prevalence of, racial/ethnic differences in, risk factors for, and implications of VMS for midlife women's mental and physical health. We have reviewed the literature on VMS, emphasizing findings that have emerged from SWAN and new areas of inquiry in the area of VMS. C1 [Thurston, Rebecca C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Thurston, Rebecca C.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Joffe, Nadine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Ctr Womens Mental Hlth, Boston, MA 02114 USA. RP Thurston, RC (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM thurstonrc@upmc.edu FU NIH [AG029216, NH082922]; Bayer Health Care Pharmaceuticals; Forest Laboratories; GlaxoSmithKline FX In addition to the SWAN funding described in the overview, this work was also supported by NIH grants AG029216 (Thurston) and NH082922 (Joffe).; Hadine Joffe has received research support from Bayer Health Care Pharmaceuticals (co-Pl), Forest Laboratories (co-l), GlaxoSmithKline (co-l), and served as an advisor/consultant to Sunovion. NR 80 TC 49 Z9 52 U1 2 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 EI 1558-0474 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD SEP PY 2011 VL 38 IS 3 BP 489 EP + DI 10.1016/j.ogc.2011.05.006 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 878DU UT WOS:000299234700009 PM 21961716 ER PT J AU Lo, JC Burnett-Bowie, SAM Finkelstein, JS AF Lo, Joan C. Burnett-Bowie, Sherri-Ann M. Finkelstein, Joel S. TI Bone and the Perimenopause SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Osteoporosis; Perimenopause; Menopause; Bone; Fractures ID EARLY POSTMENOPAUSAL WOMEN; VITAMIN-D SUPPLEMENTATION; ESTROGEN REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIALS; MINERAL DENSITY CHANGES; CLINICAL RISK-FACTORS; HEALTHY OLDER WOMEN; LIFE-STYLE FACTORS; MENOPAUSAL TRANSITION; BIOCHEMICAL MARKERS AB Loss of ovarian function has a profound impact on female skeletal health. Bone mineral density findings from the Study of Women's Health Across the Nation demonstrate an accelerated rate of bone loss during the menopausal transition. The greatest reduction occurs in the year before the final menstrual period and the first 2 years thereafter. Clinical management includes maintenance of adequate dietary calcium and vitamin D intake, attention to modifiable risk factors, and osteoporosis screening. Indications, benefits, and risks of pharmacologic osteoporosis therapy should be assessed individually; there are currently no established guidelines addressing the treatment and prevention of osteoporosis in perimenopausal women. C1 [Lo, Joan C.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Lo, Joan C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Burnett-Bowie, Sherri-Ann M.; Finkelstein, Joel S.] Harvard Univ, Sch Med, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Burnett-Bowie, Sherri-Ann M.; Finkelstein, Joel S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lo, JC (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Joan.C.Lo@kp.org OI Burnett-Bowie, Sherri-Ann/0000-0002-0064-096X FU Amgen, Inc. FX Drs Lo and Burnett-Bowie have received research funding from Amgen, Inc. NR 92 TC 16 Z9 17 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 EI 1558-0474 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD SEP PY 2011 VL 38 IS 3 BP 503 EP + DI 10.1016/j.ogc.2011.07.001 PG 16 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 878DU UT WOS:000299234700010 PM 21961717 ER PT J AU Kravitz, HM Joffe, H AF Kravitz, Howard M. Joffe, Hadine TI Sleep During the Perimenopause: A SWAN Story SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Aging; Menopausal transition; Perimenopause; Psychosocial; Reproductive hormones; Sleep ID MIDDLE-AGED ADULTS; MENOPAUSAL TRANSITION; WOMENS HEALTH; MIDLIFE WOMEN; QUALITY INDEX; INSOMNIA; SYMPTOMS; HORMONE; DISTURBANCE; PREVALENCE AB Is there evidence for a perimenopausal sleep disorder? We address this question in our presentation of the Study of Women's Health Across the Nation (SWAN) "sleep story," in which we summarize and discuss data addressing sleep quality, objective measures of sleep patterns, and sleep disorders that have been published to date by the SWAN and the ancillary SWAN Sleep Study. We describe what has been learned about sleep during the perimenopause. Analyses exploring racial/ethnic diversity and the role of hot flashes and mood disturbance in sleep-perimenopause associations are described. Implications for clinical practice are considered. C1 [Kravitz, Howard M.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Kravitz, Howard M.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. [Joffe, Hadine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Ctr Womens Mental Hlth, Boston, MA 02114 USA. RP Kravitz, HM (reprint author), Rush Univ, Med Ctr, Dept Psychiat, 2150 W Harrison St,Room 275, Chicago, IL 60612 USA. EM hkravitz@rush.edu FU National Institute on Aging [AG019360, AG019361, AG019362, AG019363]; National Institute of Mental Health [5R01MH082922]; Bayer Health Care Pharmaceuticals; Forest Laboratories; GlaxoSmithKline FX Funding for the SWAN Sleep Study is from the National Institute on Aging (Grants AG019360, AG019361, AG019362, AG019363). Support for this manuscript was also provided in part by National Institute of Mental Health (5R01MH082922; H. Joffe, PI). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. The authors also acknowledge the graphics assistance of Dr Imke Janssen in preparing Fig. 7.; Dr Joffe discloses that over the past 12 months she has served as a co-investigator on clinical trials supported by Bayer Health Care Pharmaceuticals, Forest Laboratories, and GlaxoSmithKline, and served as a consultant to Sunovion. NR 48 TC 27 Z9 28 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD SEP PY 2011 VL 38 IS 3 BP 567 EP + DI 10.1016/j.ogc.2011.06.002 PG 21 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 878DU UT WOS:000299234700013 PM 21961720 ER PT J AU Gordon, CR Yaremchuk, MJ AF Gordon, Chad R. Yaremchuk, Michael J. TI Temporal Augmentation With Methyl Methacrylate SO AESTHETIC SURGERY JOURNAL LA English DT Article DE temporal hollowing; temporal atrophy; temporal augmentation; methyl methacrylate; facial contouring ID FREE-FLAP; RECONSTRUCTION AB Concavity in the temporal area reflects a deficiency in the bulk of the temporalis muscle or overlying temporal fat pad. It may be a reflection of senescence, low body fat, exaggerated adjacent skeletal or soft-tissue contours, idiopathic progressive atrophy, or postsurgical deformities. The authors describe the application of methyl methacrylate (MMA) to fill depressions in the temporal area. In instances in which no previous surgery has been performed or when the temporal area has served as a dissection plane for surgery in adjacent areas (eg, a subperiosteal facelift), the implant material is placed beneath the temporal muscle through a limited incision in the hair-bearing scalp. When previous reconstructive surgery has been performed in the temporal area, the area of depression is accessed through existing surgical incision scars to place MMA over the temporal muscle. These operative techniques have been reliable, durable, and relatively free of complications. C1 [Gordon, Chad R.; Yaremchuk, Michael J.] Harvard Univ, Sch Med, Div Plast & Reconstruct Surg, Dept Surg,Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yaremchuk, MJ (reprint author), Harvard Univ, Sch Med, Div Plast & Reconstruct Surg, Dept Surg,Massachusetts Gen Hosp, 15 Parkman St,WACC 435, Boston, MA 02114 USA. EM myaremchuk@partners.org NR 15 TC 5 Z9 5 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-820X J9 AESTHET SURG J JI Aesthet. Surg. J. PD SEP PY 2011 VL 31 IS 7 BP 827 EP 833 DI 10.1177/1090820X11417425 PG 7 WC Surgery SC Surgery GA 864MK UT WOS:000298244000012 PM 21908815 ER PT J AU Rokkam, D LaFemina, MJ Lee, JW Matthay, MA Frank, JA AF Rokkam, Deepti LaFemina, Michael J. Lee, Jae Woo Matthay, Michael A. Frank, James A. TI Claudin-4 Levels Are Associated with Intact Alveolar Fluid Clearance in Human Lungs SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; JUNCTION FIBRIL ARCHITECTURE; EPITHELIAL BARRIER FUNCTION; PERFUSED HUMAN LUNGS; CHARGE SELECTIVITY; EXPRESSION; INJURY; CELLS; PERMEABILITY; RESISTANCE AB The removal of edema from the air spaces is a critical function of the alveolar barrier requiring intact tight junctions. Alveolar fluid clearance contributes to graft function after transplantation and is associated with survival in patients with acute lung injury. Claudin-4 concentrations are known to increase during lung injury and the loss of claudin-4 decreases alveolar fluid clearance in mice. This study was therefore undertaken to evaluate whether differences in lung expression of the tight junction protein claudin-4 are associated with alveolar fluid clearance or clinical measures of lung function. Alveolar fluid clearance rates were measured in ex vivo perfused human lungs not used for transplantation and were compared with histological lung injury and clinical measures of lung injury in the donors. Claudin-4 staining demonstrated a positive correlation with alveolar fluid clearance (Spearman rank correlation [r(s)] = 0.71; P < 0.003); however, claudin-4 staining was not strongly associated with histological measures of lung injury. The expression of other tight junction proteins (including ZO-1) was not associated with alveolar fluid clearance or claudin-4 levels. Claudin-4 staining was lower in lungs from donors with greater impairment in respiratory physiology. These data suggest that claudin-4 may promote alveolar fluid clearance and demonstrate that the amount of claudin-4 expressed may provide specific information regarding alveolar epithelial barrier function that strengthens the link between histological changes and physiological impairment. (Am J Pathol 2011, 179:1081-1087; DOI: 10.1016/j.ajpath.2011.05.017) C1 [Frank, James A.] Univ Calif San Francisco, Cardiovasc Res Inst, No Calif Inst Res & Educ, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Frank, JA (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, No Calif Inst Res & Educ, San Francisco VA Med Ctr, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. EM james.frank@ucsf.edu FU National Institutes of Health [HL88440]; National Heart, Lung and Blood Institute [HL551856] FX Supported by grants from the National Institutes of Health (HL88440 to J.A.F.) and the National Heart, Lung and Blood Institute (HL551856 to J.A.F. and M.A.M.). NR 28 TC 31 Z9 31 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1081 EP 1087 DI 10.1016/j.ajpath.2011.05.017 PG 7 WC Pathology SC Pathology GA 865JN UT WOS:000298307300002 PM 21741940 ER PT J AU Serrano-Pozo, A Mielke, ML Gomez-Isla, T Betensky, RA Growdon, JH Frosch, MP Hyman, BT AF Serrano-Pozo, Alberto Mielke, Matthew L. Gomez-Isla, Teresa Betensky, Rebecca A. Growdon, John H. Frosch, Matthew P. Hyman, Bradley T. TI Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer's Disease SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MILD COGNITIVE IMPAIRMENT; AMYLOID-BETA; NEUROFIBRILLARY TANGLES; MICROGLIAL ACTIVATION; SYNAPSE LOSS; MOUSE MODEL; TRANSGENIC MICE; SENILE PLAQUES; NEURONAL LOSS AB Senile plaques are a prominent pathological feature of Alzheimer's disease (AD)), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (<= 50 mu m) of dense-core plaques anti tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration. (Am J Pathol 2011, 179:1373-1384; DOI: 10.1016/j.ajpath.2011.05.047) C1 [Serrano-Pozo, Alberto; Mielke, Matthew L.; Gomez-Isla, Teresa; Growdon, John H.; Frosch, Matthew P.; Hyman, Bradley T.] Massachusetts Gen Hosp, Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Serrano-Pozo, Alberto; Gomez-Isla, Teresa; Betensky, Rebecca A.; Growdon, John H.; Frosch, Matthew P.; Hyman, Bradley T.] Massachusetts Alzheimer Dis Res Ctr, Charlestown, MA USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Inst Neurodegenerat Dis, 16th St,Bldg 114, Charlestown, MA 02129 USA. EM bhyman@partners.org RI SERRANO-POZO, ALBERTO/F-5119-2013; OI SERRANO-POZO, ALBERTO/0000-0003-0899-7530 FU NIH [P50AG05134, AG08487]; Foundation Alfonso Martin Escudero, Madrid, Spain FX Supported by grants from the NIH (P50AG05134 and AG08487) and a research fellowship from the Foundation Alfonso Martin Escudero, Madrid, Spain (AS.-P.). NR 53 TC 77 Z9 78 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1373 EP 1384 DI 10.1016/j.ajpath.2011.05.047 PG 12 WC Pathology SC Pathology GA 865JN UT WOS:000298307300031 PM 21777559 ER PT J AU Chen, CC Pekow, J Llado, V Kanneganti, M Lau, CW Mizoguchi, A Mino-Kenudson, M Bissonnette, M Mizoguchi, E AF Chen, Chun-Chuan Pekow, Joel Llado, Victoria Kanneganti, Manasa Lau, Cindy W. Mizoguchi, Atsushi Mino-Kenudson, Mari Bissonnette, Marc Mizoguchi, Emiko TI Chitinase 3-Like-1 Expression in Colonic Epithelial Cells as a Potentially Novel Marker for Colitis-Associated Neoplasia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; HUMAN CARTILAGE GLYCOPROTEIN-39; COLORECTAL-CANCER; SERUM YKL-40; ARTICULAR CHONDROCYTES; ULCERATIVE-COLITIS; PROTEIN FAMILY; MUTANT MICE; MACROPHAGES; CARCINOMA AB Chitinase 3-like-1 (CHI3L1/YKL-40) is a protein secreted from restricted cell types including colonic epithelial cells (CECs) and macrophages. CHI3L1 is an inflammation-associated molecule, and its expression is enhanced in persons with colitis and colon cancer. The biological function of CHI3L1 on CECs is unclear. In this study, we investigated the role of CHI3L1 on CECs during the development of colitis-associated neoplasia. We analyzed colonic samples obtained from healthy persons and from persons with ulcerative colitis with or without premalignant or malignant changes. DNA microarray and RT-PCR analyses significantly increased CHI3L1 expression in non-dysplastic mucosa from patients with inflammatory bowel disease (IBD) who had dysplasia/adenocarcinoma compared with that in healthy persons and in patients with IBD who did not have dysplasia. As determined by MC, CHI3L1 was expressed in specific cell types in the crypts of colonic biopsies obtained from patients with ulcerative colitis who have remote dysplasia. Purified CHI3L1 efficiently activated the NF-kappa B signaling pathway and enhanced the secretion of IL-8 and TNF-alpha in SW480 human colon cancer cells. In addition, colon cancer cell proliferation and migration were significantly promoted in response to CHI3L1 in these cells. In summary, CHI3L1 may contribute to the proliferation, migration, and neoplastic progression of CECs under inflammatory conditions and could be a useful biomarker for neoplastic changes in patients with IBD. (Am J Pathol 2011, 179:1494-1503; DOI: 10.1016/j.ajpath.2011.05.038) C1 [Chen, Chun-Chuan; Llado, Victoria; Kanneganti, Manasa; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02114 USA. [Lau, Cindy W.; Mizoguchi, Atsushi; Mino-Kenudson, Mari] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Mizoguchi, Atsushi; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Pekow, Joel; Bissonnette, Marc] Univ Chicago, Div Gastroenterol, Dept Med, Chicago, IL 60637 USA. Univ Chicago, Digest Dis Res Core Ctr, Chicago, IL 60637 USA. RP Mizoguchi, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, GRJ 702,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU National Institutes of Health [DK80070, DK74454, DK64289, DK43351, AI81807]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation; Crohn's and Colitis Foundation of America Inc. FX Supported by grants from the National Institutes of Health (DK80070, DK74454, DK64289, and DK43351 to E.M. and AI81807 to A.M.) and the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation (E.M.). M.K. is the recipient of a 2010 Student Research Fellowship Award from the Crohn's and Colitis Foundation of America Inc. NR 44 TC 28 Z9 28 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD SEP PY 2011 VL 179 IS 3 BP 1494 EP 1503 DI 10.1016/j.ajpath.2011.05.038 PG 10 WC Pathology SC Pathology GA 865JN UT WOS:000298307300042 PM 21763261 ER PT J AU Lai, GGY Penson, RT AF Lai, G. G. Y. Penson, R. T. TI BEVACIZUMAB AND OVARIAN CANCER SO DRUGS OF TODAY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; PHASE-III TRIAL; METRONOMIC ORAL CYCLOPHOSPHAMIDE; COOPERATIVE-ONCOLOGY-GROUP; ADVANCED BREAST-CANCER; FALLOPIAN-TUBE CANCER; EPITHELIAL OVARIAN; RECURRENT OVARIAN AB Epithelial ovarian cancer is the most lethal of gynecologic malignancies in the United States, with a significant proportion of patients with advanced disease achieving clinical remission with conventional treatment approaches, but dying of recurrence. Bevacizumab is a first-in-class antiangiogenic. This recombinant humanized monoclonal antibody neutralizes vascular endothelial growth factor (VEGF) and inhibits endothelial and tumor cell activation and proliferation. It has a low clearance and long elimination half-life, supporting a convenient 2- or 3-weekly dosing schedule. It is generally well tolerated, although trials have highlighted some toxicity-related concerns, notably gastrointestinal perforation. Phase III trials that evaluate overall survival are not yet mature, and cost-effectiveness of bevacizumab is hotly debated. As more evidence for the role of anti-VEGF agents in augmenting therapy and inducing durable tumor dormancy continues to emerge, it is anticipated that antiangiogenic therapy will play an important role in the management ovarian malignancy. C1 [Lai, G. G. Y.; Penson, R. T.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Penson, RT (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Yawkey 9066,55 Fruit St, Boston, MA 02114 USA. EM rpenson@partners.org FU Genentech; DARA BioSciences; MGI Pharma; Berlex Labs (Bayer HealthCare Pharmaceuticals); CuraGen; PDL BioPharma; ImClone Systems; Endocyte; Eisai; Amgen FX R.T. Penson has received research funding from Genentech, DARA BioSciences, MGI Pharma, Berlex Labs (Bayer HealthCare Pharmaceuticals), CuraGen, PDL BioPharma, ImClone Systems, Endocyte, Eisai and Amgen. He has also acted as a consultant for DARA BioSciences and Lilly, and has served on the scientific advisory boards of Genentech, GlaxoSmithKline, Abbott and AstraZeneca. G.G.Y. Lai states no conflicts of interest. NR 126 TC 4 Z9 4 U1 0 U2 1 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 1699-3993 J9 DRUG TODAY JI Drugs Today PD SEP PY 2011 VL 47 IS 9 BP 669 EP 681 DI 10.1358/dot.2011.47.9.1673557 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852SQ UT WOS:000297378200003 PM 21971541 ER PT J AU Kanji, Z Powe, CE Wenger, JB Huang, C Ankers, E Sullivan, DA Collerone, G Powe, NR Tonelli, M Bhan, I Bernhardy, AJ DiBartolo, S Friedman, D Genovese, G Pollak, MR Thadhani, R AF Kanji, Z. Powe, C. E. Wenger, J. B. Huang, C. Ankers, E. Sullivan, D. A. Collerone, G. Powe, N. R. Tonelli, M. Bhan, I. Bernhardy, A. J. DiBartolo, S. Friedman, D. Genovese, G. Pollak, M. R. Thadhani, R. TI GENETIC VARIATION IN APOL1 AND AGE AT HEMODIALYSIS INITIATION IN AFRICAN AMERICANS SO ETHNICITY & DISEASE LA English DT Meeting Abstract C1 [Kanji, Z.; Powe, C. E.; Wenger, J. B.; Huang, C.; Ankers, E.; Sullivan, D. A.; Collerone, G.; Bhan, I.; Thadhani, R.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Powe, N. R.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA. [Tonelli, M.] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Bernhardy, A. J.; DiBartolo, S.; Friedman, D.; Genovese, G.; Pollak, M. R.] Harvard Univ, Sch Med, Boston, MA USA. [Bernhardy, A. J.; DiBartolo, S.; Friedman, D.; Genovese, G.; Pollak, M. R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Pollak, M. R.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2011 VL 21 IS 4 MA 019 BP S11 EP S11 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 867FH UT WOS:000298439800039 ER PT J AU Kapuku, G Davis, H Choksy, P Januzzi, J Harshfield, G AF Kapuku, G. Davis, H. Choksy, P. Januzzi, J. Harshfield, G. TI STRESS-INDUCED CHANGES IN DIASTOLIC FUNCTION IS PREDICTED BY BRAIN NATRIURETIC HORMONE SO ETHNICITY & DISEASE LA English DT Meeting Abstract C1 [Kapuku, G.; Davis, H.; Choksy, P.; Harshfield, G.] Georgia Hlth Sci Univ, Georgia Prevent Inst, Dept Pediat & Med, Augusta, GA USA. [Januzzi, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2011 VL 21 IS 4 MA 011 BP S6 EP S6 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 867FH UT WOS:000298439800031 ER PT J AU Scott, JB Chandler, P Emmons, K Fuchs, C AF Scott, J. B. Chandler, P. Emmons, K. Fuchs, C. TI VITAMIN D SUPPLEMENTATION AND RISK OF HYPERCALCEMIA IN HYPERTENSIVE BLACKS TAKING HYDROCHLOROTHIAZIDE SO ETHNICITY & DISEASE LA English DT Meeting Abstract C1 [Scott, J. B.; Emmons, K.; Fuchs, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Scott, J. B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chandler, P.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD FAL PY 2011 VL 21 IS 4 MA 017 BP S9 EP S9 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 867FH UT WOS:000298439800037 ER PT J AU Beadling, C Heinrich, MC Warrick, A Forbes, EM Nelson, D Justusson, E Levine, J Neff, TL Patterson, J Presnell, A McKinley, A Winter, LJ Dewey, C Harlow, A Barney, O Druker, BJ Schuff, KG Corless, CL AF Beadling, Carol Heinrich, Michael C. Warrick, Andrea Forbes, Erin M. Nelson, Dylan Justusson, Emily Levine, Judith Neff, Tanaya L. Patterson, Janice Presnell, Ajia McKinley, Arin Winter, Laura J. Dewey, Christie Harlow, Amy Barney, Oscar Druker, Brian J. Schuff, Kathryn G. Corless, Christopher L. TI Multiplex Mutation Screening by Mass Spectrometry Evaluation of 820 Cases from a Personalized Cancer Medicine Registry SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; CHRONIC MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTOR; ABL TYROSINE KINASE; BRAF MUTATIONS; IMATINIB MESYLATE; BETA-CATENIN; PHILADELPHIA-CHROMOSOME; ENDOMETRIAL CARCINOMAS AB There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3C4, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3C4-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broad-spectrum, prospective genotyping approach to personalized cancer medicine. (J Mol Diagn 2011, 13: 504-513; DOI: 10.1016/j.jmoldx.2011.04.003) C1 [Corless, Christopher L.] OHSU, Dept Pathol, Knight Canc Inst, Portland, OR 97239 USA. [Beadling, Carol; Heinrich, Michael C.] OHSU, Div Hematol Oncol, Portland, OR 97239 USA. [Schuff, Kathryn G.] OHSU, Div Endocrinol, Portland, OR 97239 USA. [Corless, Christopher L.] Portland VA Med Ctr, Portland, OR USA. RP Corless, CL (reprint author), OHSU, Dept Pathol, Knight Canc Inst, Mailcode L471,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM corlessc@ohsu.edu OI Patterson, Janice/0000-0002-8969-2933 FU Novartis Pharmaceuticals FX This study was supported in part with funding from Novartis Pharmaceuticals. NR 65 TC 54 Z9 54 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD SEP PY 2011 VL 13 IS 5 BP 504 EP 513 DI 10.1016/j.jmoldx.2011.04.003 PG 10 WC Pathology SC Pathology GA 865JG UT WOS:000298306600006 PM 21726664 ER PT J AU Hurley, RA Filley, CM Taber, KH AF Hurley, Robin A. Filley, Christopher M. Taber, Katherine H. TI Central Pontine Myelinolysis: A Metabolic Disorder of Myelin SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Editorial Material ID OSMOTIC DEMYELINATION SYNDROME; MAGNETIC-RESONANCE-SPECTROSCOPY; EXTRAPONTINE MYELINOLYSIS; DIFFUSION; PATIENT; HYPONATREMIA; MANIFESTATIONS; PLASMAPHERESIS; COMPLICATION; ALCOHOLISM C1 [Hurley, Robin A.; Taber, Katherine H.] WG Hefner Vet Affairs Med Ctr, Vet Affairs Midatlantic Mental Illness Res Educ &, Salisbury, NC 28144 USA. [Hurley, Robin A.; Taber, Katherine H.] WG Hefner Vet Affairs Med Ctr, Res & Educ Serv Line, Salisbury, NC USA. [Hurley, Robin A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Psychiat, Winston Salem, NC USA. [Hurley, Robin A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Hurley, Robin A.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Filley, Christopher M.] Univ Colorado, Sch Med, Behav Sect, Denver, CO USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Neurol Serv, Denver, CO USA. [Taber, Katherine H.] Edward Via Coll Osteopath Med, Div Biomed Sci, Blacksburg, VA USA. [Taber, Katherine H.] Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. RP Hurley, RA (reprint author), Hefner VA Med Ctr, Salisbury, NC 28144 USA. EM Robin.Hurley@va.gov NR 56 TC 0 Z9 0 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD FAL PY 2011 VL 23 IS 4 BP IV EP 374 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 875GT UT WOS:000299019100001 ER PT J AU Wagner, PJ Wortzel, HS Frey, KL Anderson, CA Arciniegas, DB AF Wagner, Peter J. Wortzel, Hal S. Frey, Kimberly L. Anderson, C. Alan Arciniegas, David B. TI Clock-Drawing Performance Predicts Inpatient Rehabilitation Outcomes After Traumatic Brain Injury SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID POSTTRAUMATIC AMNESIA; PRACTICAL SCALE; SEVERITY; MODERATE; BATTERY AB The authors used clock-drawing performance to assess cognition and predict inpatient rehabilitation outcomes among persons with traumatic brain injury. Clock-drawing performance, as assessed with the Clock Drawing Interpretation Scale, predicts rehabilitation length of stay as well as Functional Independence Measure scores at the time of neurobehavioral assessment and rehabilitation discharge. (The Journal of Neuropsychiatry and Clinical Neurosciences 2011; 23:449-453) C1 [Wagner, Peter J.; Wortzel, Hal S.; Frey, Kimberly L.; Anderson, C. Alan; Arciniegas, David B.] Univ Colorado, Sch Med, Dept Psychiat, Neurobehav Disorders Program, Aurora, CO 80045 USA. [Wortzel, Hal S.] Denver Vet Affairs Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 19, Denver, CO USA. [Anderson, C. Alan; Arciniegas, David B.] Univ Colorado, Sch Med, Dept Neurol, Behav Neurol Sect, Aurora, CO USA. [Anderson, C. Alan] Denver Vet Affairs Med Ctr, Neurol Serv, Denver, CO USA. RP Arciniegas, DB (reprint author), Univ Colorado, Sch Med, Dept Psychiat, Neurobehav Disorders Program, Aurora, CO 80045 USA. EM David.Arciniegas@UCDenver.edu FU HCA/HealthONE Spalding Rehabilitation Hospital; VA VISN-19 Mental Illness Research, Education, and Clinical Center FX This work was supported in part by HCA/HealthONE Spalding Rehabilitation Hospital and the VA VISN-19 Mental Illness Research, Education, and Clinical Center. NR 17 TC 5 Z9 5 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD FAL PY 2011 VL 23 IS 4 BP 449 EP 453 PG 5 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 875GT UT WOS:000299019100012 PM 22231317 ER PT J AU Zelenetz, AD Ahmed, I Braud, EL Cross, JD Davenport-Ennis, N Dickinson, BD Goldberg, SE Gottlieb, S Johnson, PE Lyman, GH Markus, R Matulonis, UA Reinke, D Li, EC DeMartino, J Larsen, JK Hoffman, JM AF Zelenetz, Andrew D. Ahmed, Islah Braud, Edward Louis Cross, James D. Davenport-Ennis, Nancy Dickinson, Barry D. Goldberg, Steven E. Gottlieb, Scott Johnson, Philip E. Lyman, Gary H. Markus, Richard Matulonis, Ursula A. Reinke, Denise Li, Edward C. DeMartino, Jessica Larsen, Jonathan K. Hoffman, James M. TI NCCN Biosimilars White Paper: Regulatory, Scientific, and Patient Safety Perspectives SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article DE Biosimilars; follow-on biologics; health policy ID DRUG-THERAPY; NAMES AB Biologics are essential to oncology care. As patents for older biologics begin to expire, the United States is developing an abbreviated regulatory process for the approval of similar biologics (biosimilars), which raises important considerations for the safe and appropriate incorporation of biosimilars into clinical practice for patients with cancer. The potential for biosimilars to reduce the cost of biologics, which are often high-cost components of oncology care, was the impetus behind the Biologics Price Competition and Innovation Act of 2009, a part of the 2010 Affordable Care Act. In March 2011, NCCN assembled a work group consisting of thought leaders from NCCN Member Institutions and other organizations, to provide guidance regarding the challenges health care providers and other key stakeholders face in incorporating biosimilars in health care practice. The work group identified challenges surrounding biosimilars, including health care provider knowledge, substitution practices, pharmacovigilance, naming and product tracking, coverage and reimbursement, use in off-label settings, and data requirements for approval. (JNCCN 2011; 9[Suppl 4]: S1-S22) C1 [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ahmed, Islah] Hospira Inc, Lake Forest, IL USA. [Braud, Edward Louis] Springfield Reg Canc Ctr, Springfield, MO USA. [Dickinson, Barry D.] Amer Med Assoc, Chicago, IL 60610 USA. [Hoffman, James M.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Lyman, Gary H.] Duke Canc Inst, Durham, NC USA. [Matulonis, Ursula A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Reinke, Denise] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Zelenetz, AD (reprint author), Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 30 TC 50 Z9 51 U1 0 U2 5 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2011 VL 9 SU 4 BP S1 EP S22 PG 22 WC Oncology SC Oncology GA 865XP UT WOS:000298344500001 PM 21976013 ER PT J AU Spigner, C Lyles, CR Galvin, G Sabin, J Davis, C Dick, A Young, BA AF Spigner, Clarence Lyles, Courtney Rees Galvin, Georgia Sabin, Janice Davis, Connie Dick, Andre Young, Bessie A. TI A Qualitative Assessment of Personal and Social Responsibility for Kidney Disease: The Increasing Kidney Disease Awareness Network Transplant Project SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE kidney; transplant; race/ethnicity; physicians; patient self-management; qualitative research ID STAGE RENAL-DISEASE; SICK ROLE; ETHNIC-DIFFERENCES; PUBLIC-HEALTH; UNITED-STATES; POPULATION; CARE; END; RACE; DISPARITIES AB Introduction: Limited qualitative research has explored opinions of kidney disease health care providers regarding racial and ethnic disparities in access to and receipt of kidney transplantation. Methods: Key informant interviews were conducted among transplant nephrologists, nephrologists, transplant social workers, and transplant coordinators to determine barriers to transplantation among African Americans compared to whites with end-stage renal disease (ESRD). Analysis: Thirty-eight interviews were audio recorded and transcribed to hardcopy for content analysis. Grounded theory was used to determine dominant themes within the interviews. Reliability and validity were ensured by several coinvestigators independently sorting verbatim responses used for generating themes and subsequent explanations. Results: Several major categories arose from analysis of the transcripts. Under the category of personal and social responsibility for kidney transplantation, interviews revealed 4 major themes: negative personal behaviors, acquisition of and lack of self-treatment of comorbid conditions, lack of individual responsibility, and the need for more social responsibility. Many providers perceived patients as being largely responsible for the development of ESRD, while some providers expressed the idea that more social responsibility was needed to improve poor health status and disparities in kidney transplantation rates. Conclusion: Kidney disease health providers seemed torn between notions of patients' accountability and social responsibility for racial disparities in chronic kidney disease and ESRD. Further research is needed to clarify which aspects contribute most to disparities in access to transplantation. C1 [Spigner, Clarence; Lyles, Courtney Rees; Young, Bessie A.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Sabin, Janice] Univ Washington, Dept Med Educ & Biomed Informat, Seattle, WA 98195 USA. [Young, Bessie A.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Davis, Connie] Univ Washington, Div Nephrol & Transplantat, Seattle, WA 98195 USA. [Galvin, Georgia; Young, Bessie A.] Puget Sound Hlth Care Syst, Vet Adm, Seattle, WA USA. RP Young, BA (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,152-E, Seattle, WA 98108 USA. EM youngb@u.wash-ington.edu FU NIH [R01DK079745]; National Institute of Diabetes and Digestive and Kidney Diseases; Veterans Affairs Puget Sound Health Care System, Seattle, Washington FX The project described was supported by Dr Young's NIH grant award (R01DK079745) from the National Institute of Diabetes and Digestive and Kidney Diseases. This material is also the result of work supported by resources (Dr Young) from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. NR 37 TC 2 Z9 2 U1 2 U2 8 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD SEP-OCT PY 2011 VL 103 IS 9-10 BP 879 EP 884 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 869BU UT WOS:000298571500012 PM 22364056 ER PT J AU Andreotti, RF Lee, SI Allison, SOD Bennett, GL Brown, DL Dubinsky, T Glanc, P Javitt, MC Mitchell, DG Podrasky, AE Shipp, TD Siegel, CL Wong-You-Cheong, JJ Zelop, CM AF Andreotti, Rochelle F. Lee, Susanna I. Allison, Sandra O. DeJesus Bennett, Genevieve L. Brown, Douglas L. Dubinsky, Theodore Glanc, Phyllis Javitt, Marcia C. Mitchell, Donald G. Podrasky, Ann E. Shipp, Thomas D. Siegel, Cary Lynn Wong-You-Cheong, Jade J. Zelop, Carolyn M. TI ACR Appropriateness Criteria (R) Acute Pelvic Pain in the Reproductive Age Group SO ULTRASOUND QUARTERLY LA English DT Article DE appropriateness criteria; pelvic pain; acute; imaging; diagnosis ID DEEP VENOUS THROMBOSIS; HELICAL COMPUTED-TOMOGRAPHY; ACUTE APPENDICITIS; ADNEXAL TORSION; INFLAMMATORY-DISEASE; PREGNANT PATIENTS; SUSPECTED APPENDICITIS; SONOGRAPHIC FINDINGS; RADIATION-EXPOSURE; ECTOPIC PREGNANCY AB Premenopausal women who present with acute pelvic pain frequently pose a diagnostic dilemma, exhibiting nonspecific signs and symptoms, the most common being nausea, vomiting, and leukocytosis. Diagnostic considerations encompass multiple organ systems, including obstetric, gynecologic, urologic, gastrointestinal, and vascular etiologies. The selection of imaging modality is determined by the clinically suspected differential diagnosis. Thus, a careful evaluation of such a patient should be performed and diagnostic considerations narrowed before a modality is chosen. Transvaginal and transabdominal pelvic sonography is the modality of choice when an obstetric or gynecologic abnormality is suspected, and computed tomography is more useful when gastrointestinal or genitourinary pathology is more likely. Magnetic resonance imaging, when available in the acute setting, is favored over computed tomography for assessing pregnant patients for nongynecologic etiologies because of the lack of ionizing radiation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Andreotti, Rochelle F.] Vanderbilt Univ, Med Ctr, Dept Radiol, Nashville, TN 37232 USA. [Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Allison, Sandra O. DeJesus] Georgetown Univ Hosp, Dept Radiol, Washington, DC 20007 USA. [Bennett, Genevieve L.] NYU Med Ctr, Dept Radiol, New York, NY 10016 USA. [Brown, Douglas L.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Dubinsky, Theodore] Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. [Glanc, Phyllis] Sunnybrook Hlth Sci Ctr, Dept Med Imaging, Toronto, ON M4N 3M5, Canada. [Javitt, Marcia C.] Walter Reed Army Med Ctr, Dept Radiol, Washington, DC 20307 USA. [Mitchell, Donald G.] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Podrasky, Ann E.] Baptist Hosp Miami, S Miami Ctr Women & Infants, Dept Radiol, Miami, FL USA. [Shipp, Thomas D.] Amer Coll Obstetricians & Gynecologists, Washington, DC USA. [Shipp, Thomas D.] Diagnost Ultrasound Associates, Boston, MA USA. [Siegel, Cary Lynn] Mallinckrodt Inst Radiol, Dept Radiol, St Louis, MO USA. [Wong-You-Cheong, Jade J.] Univ Maryland, Sch Med, Dept Diagnost Radiol, Baltimore, MD 21201 USA. [Zelop, Carolyn M.] Univ Connecticut, Sch Med, Dept Radiol, Farmington, CT USA. RP Andreotti, RF (reprint author), Amer Coll Radiol, Dept Qual & Safety, 1891 Preston White Dr, Reston, VA 20191 USA. EM acr_ac@acr.org NR 53 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 J9 ULTRASOUND Q JI Ultrasound Q. PD SEP PY 2011 VL 27 IS 3 BP 205 EP 210 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 854XF UT WOS:000297527400008 PM 21873877 ER PT J AU Lam, A Wolpin, S Nguyen, J Berry, DL Kurth, A Morisky, DE AF Lam, Annie Wolpin, Seth Nguyen, Juliet Berry, Donna L. Kurth, Ann Morisky, Donald E. TI Is 60 seconds enough? Can talking pill bottles be used in the community pharmacy setting? SO JOURNAL OF THE AMERICAN PHARMACISTS ASSOCIATION LA English DT Letter C1 [Lam, Annie] Univ Washington, Sch Pharm, Seattle, WA 98195 USA. [Berry, Donna L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. [Kurth, Ann] NYU, Global Hlth Initiat, Coll Nursing, New York, NY USA. [Morisky, Donald E.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Community Hlth Sci, Los Angeles, CA 90024 USA. RP Lam, A (reprint author), Univ Washington, Sch Pharm, Seattle, WA 98195 USA. EM aylam@u.washington.edu RI Kurth, Ann/A-1615-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER PHARMACEUTICAL ASSOC PI WASHINGTON PA 2215 CONSTITUTION AVE NW, WASHINGTON, DC 20037 USA SN 1544-3191 J9 J AM PHARM ASSOC JI J. Am. Pharm. Assoc. PD SEP-OCT PY 2011 VL 51 IS 5 BP 569 EP 570 DI 10.1331/JAPhA.2011.10096 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 857XD UT WOS:000297757100004 PM 21896452 ER PT J AU Borg-Stein, JP Fogelman, DJ Ackerman, KE AF Borg-Stein, Joanne P. Fogelman, David J. Ackerman, Kathryn E. TI Exercise, Sports Participation, and Musculoskeletal Disorders of Pregnancy and Postpartum SO SEMINARS IN NEUROLOGY LA English DT Article DE Pregnancy; orthopedic; musculoskeletal; exercise; sports ID GESTATIONAL DIABETES-MELLITUS; RECREATIONAL PHYSICAL-ACTIVITY; CARPAL-TUNNEL SYNDROME; NECROSIS-FACTOR-ALPHA; TRANSIENT OSTEOPOROSIS; SYMPHYSIS PUBIS; BACK-PAIN; FETOPLACENTAL GROWTH; REGULAR EXERCISE; BIRTH-WEIGHT AB The benefits of rigorous physical activity have long been proclaimed by the medical community. However, consensus regarding exercise duration and intensity in pregnancy has been more difficult to achieve. Conservative exercise guidelines for pregnant women were issued broadly in the 1980s due to limited evidence regarding safety. More recent evidence has failed to demonstrate ill effects of physical activity during pregnancy, as any effects on the mother and the fetus have thus far shown to be positive. The physical discomfort experienced by virtually all women during pregnancy, nearly 25% of whom experience at least temporarily disabling symptoms, is often a barrier to participation in an exercise program. An approach to developing an exercise program during pregnancy will be discussed in this article, as well as the potential benefits of such a program for the maternal-fetal unit, and common pregnancy-related musculoskeletal conditions, including a discussion of the anatomy, physiology, diagnosis, and treatment of such disorders. C1 [Borg-Stein, Joanne P.; Fogelman, David J.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Borg-Stein, Joanne P.] Newton Wellesley Hosp, Spine Ctr, Newton, MA USA. [Borg-Stein, Joanne P.] Spaulding Rehabil Hosp Wellesley, Boston, MA 02114 USA. [Fogelman, David J.] Spaulding Rehabil Hosp, Boston, MA USA. [Ackerman, Kathryn E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ackerman, Kathryn E.] Childrens Hosp Boston, Div Sports Med, Boston, MA USA. [Ackerman, Kathryn E.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Borg-Stein, JP (reprint author), Spaulding Rehabil Hosp Wellesley, 125 Nashua St, Boston, MA 02114 USA. EM jborgstein@partners.org NR 75 TC 0 Z9 0 U1 4 U2 21 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD SEP PY 2011 VL 31 IS 4 BP 413 EP 422 DI 10.1055/s-0031-1293541 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 856MF UT WOS:000297645100009 PM 22113514 ER PT J AU Vaillant, G AF Vaillant, George TI A FIRST-RATE MADNESS: Uncovering the Links Between Leadership and Mental Illness SO AMERICAN SCHOLAR LA English DT Book Review C1 [Vaillant, George] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Vaillant, George] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vaillant, George] Harvard Univ, Study Adult Dev, Hlth Serv, Cambridge, MA 02138 USA. RP Vaillant, G (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU PHI BETA KAPPA SOC PI WASHINGTON PA 1785 MASSACHUSETTS AVENUE, N W FOURTH FL,, WASHINGTON, DC 20036 USA SN 0003-0937 J9 AM SCHOLAR JI Am. Sch. PD FAL PY 2011 VL 80 IS 4 BP 125 EP 127 PG 3 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 856RM UT WOS:000297661100036 ER PT J AU Bauer, M Demyttenaere, K El-Khalili, N Thase, M Papakostas, GI Szamosi, J Earley, W Eriksson, H AF Bauer, M. Demyttenaere, K. El-Khalili, N. Thase, M. Papakostas, G. I. Szamosi, J. Earley, W. Eriksson, H. TI Efficacy of adjunct quetiapine extended-release in major depressive disorder: a pooled analysis of SSRI and SNRI patient subgroups SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress Meeting of European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol ID DOUBLE-BLIND; ANTIDEPRESSANT; THERAPY C1 [Bauer, M.] Univ Hosp Carl Gustav Carus, Dept Psychiat & Psychotherapy, Dresden, Germany. [Demyttenaere, K.] Univ Hosp Gasthuisberg, Dept Psychiat, B-3000 Louvain, Belgium. [Thase, M.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Papakostas, G. I.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Szamosi, J.; Eriksson, H.] AstraZeneca, R&D, Sodertalje, Sweden. NR 3 TC 1 Z9 1 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S441 EP S442 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600483 ER PT J AU Papakostas, GI AF Papakostas, G. I. TI No time to lose: rethinking treatment options in MDD SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress Meeting of European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol ID MAJOR DEPRESSIVE DISORDER; METAANALYSIS; PLACEBO C1 [Papakostas, G. I.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S629 EP S630 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600804 ER PT J AU Tran, P Bradshaw, M McKinney, A Bymaster, F Skolnick, P Czobor, P Huang, N Manthis, J Fava, M AF Tran, P. Bradshaw, M. McKinney, A. Bymaster, F. Skolnick, P. Czobor, P. Huang, N. Manthis, J. Fava, M. TI A placebo-controlled study of EB-1010, a novel triple re-uptake inhibitor, in patients with major depressive disorder SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT 24th Congress Meeting of European-College-of-Neuropsychopharmacology CY SEP 03-07, 2011 CL Paris, FRANCE SP European Coll Neuropsychopharmacol C1 [Tran, P.; Bymaster, F.; Manthis, J.] Euthym Biosci Inc, Res & Dev, Cambridge, MA USA. [Bradshaw, M.] Global Consulting Partners LLC, Res & Dev, Princeton, NJ USA. [McKinney, A.] Euthym Biosci Inc, Management, Cambridge, MA USA. [Skolnick, P.; Czobor, P.] DOV Pharmaceut, Res & Dev, Somerset, NJ USA. [Huang, N.] QRx Pharma, Res & Dev, Bedminster, NJ USA. [Fava, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD SEP PY 2011 VL 21 SU 3 BP S384 EP S385 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 852US UT WOS:000297383600386 ER PT J AU Bamboat, ZM DePeralta, D Dursun, A Berger, DL Bordeianou, L AF Bamboat, Zubin M. DePeralta, Danielle Dursun, Abdulmetin Berger, David L. Bordeianou, Liliana TI Factors affecting lymph node yield from patients undergoing colectomy for cancer SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Lymph node yield; Colon cancer; Colectomy; Pathologist training ID COMPLETE MESOCOLIC EXCISION; AMERICAN JOINT COMMITTEE; COLON-CANCER; COLORECTAL-CANCER; PROGNOSTIC-FACTORS; MINIMUM NUMBER; SURVIVAL; SURGERY; PATHOLOGISTS; RESECTION AB Purpose Lymph node (LN) yield is a critical component of colon cancer staging and is often a surrogate for quality assessment in surgery. We investigated the impact of pathologists' training on LN harvest. Methods This is a retrospective review on 137 patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. We studied surgeon-, patient- and pathologist-derived factors, and identified independent variables affecting LN yield using logistic regression. Results LN yield was similar between open and laparoscopic resections (21 versus 23, p=0.54). Similarly, nodal counts were independent of tumor location (p=0.08) and no difference was noted between colorectal and general surgeons (24 versus 21, p=0.31). Strikingly, the number of LNs reported by PGY-1 pathology residents was significantly higher than those with two or more years of training (24 versus 19, p=0.02). On logistic regression, only the reporting pathologists' year in training remained a significant predictor of the number of nodes reported (OR=5.28, p=0.0001). Conclusions LN retrieval in patients with colon cancer is inversely related to the interpreting pathologists' level of training. C1 [Bamboat, Zubin M.; DePeralta, Danielle; Dursun, Abdulmetin; Berger, David L.; Bordeianou, Liliana] Massachusetts Gen Hosp, Div Gastrointestinal Surg, Boston, MA 02114 USA. [Bamboat, Zubin M.; DePeralta, Danielle; Dursun, Abdulmetin; Berger, David L.; Bordeianou, Liliana] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Div Gastrointestinal Surg, Boston, MA 02114 USA. EM lbordeianou@partners.org NR 30 TC 14 Z9 14 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD SEP PY 2011 VL 26 IS 9 BP 1163 EP 1168 DI 10.1007/s00384-011-1240-6 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 851CS UT WOS:000297246500011 PM 21573900 ER PT J AU Beauchamp, JP Cesarini, D Johannesson, M van der Loos, MJHM Koellinger, PD Groenen, PJF Fowler, JH Rosenquist, JN Thurik, AR Christakis, NA AF Beauchamp, Jonathan P. Cesarini, David Johannesson, Magnus van der Loos, Matthijs J. H. M. Koellinger, Philipp D. Groenen, Patrick J. F. Fowler, James H. Rosenquist, J. Niels Thurik, A. Roy Christakis, Nicholas A. TI Molecular Genetics and Economics SO JOURNAL OF ECONOMIC PERSPECTIVES LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN HEIGHT; INDIVIDUAL-DIFFERENCES; MISSING HERITABILITY; MONOAMINE-OXIDASE; DICTATOR GAME; RISK-TAKING; BEHAVIOR; DETERMINANTS; STRATIFICATION C1 [Beauchamp, Jonathan P.; Rosenquist, J. Niels; Christakis, Nicholas A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Cesarini, David] NYU, Ctr Expt Social Sci, New York, NY USA. [Cesarini, David] Inst Ind Econ IFN, Stockholm, Sweden. [Johannesson, Magnus] Stockholm Sch Econ, S-11383 Stockholm, Sweden. [van der Loos, Matthijs J. H. M.; Koellinger, Philipp D.; Groenen, Patrick J. F.; Thurik, A. Roy] Erasmus Sch Econ, Rotterdam, Netherlands. [Fowler, James H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Rosenquist, J. Niels] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Cambridge, MA USA. [Rosenquist, J. Niels] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. RP Beauchamp, JP (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM beauchamp.jonathan.pierre@gmail.com RI Fowler, James/C-2750-2008; Thurik, Roy/A-9386-2012; Johannesson, Magnus/E-9680-2011; Groenen, Patrick/D-3667-2009; OI Fowler, James/0000-0001-7795-1638; Thurik, Roy/0000-0002-0242-6908; Johannesson, Magnus/0000-0001-8759-6393; Groenen, Patrick/0000-0001-6683-8971; Koellinger, Philipp/0000-0001-7413-0412; Cesarini, David/0000-0002-0043-009X FU NIA NIH HHS [P01 AG031093, P01 AG031093-04]; NIGMS NIH HHS [P41 GM103504] NR 102 TC 33 Z9 34 U1 1 U2 27 PU AMER ECONOMIC ASSOC PI NASHVILLE PA 2014 BROADWAY, STE 305, NASHVILLE, TN 37203 USA SN 0895-3309 J9 J ECON PERSPECT JI J. Econ. Perspect. PD FAL PY 2011 VL 25 IS 4 BP 57 EP 82 DI 10.1257/jep.25.4.57 PG 26 WC Economics SC Business & Economics GA 851IX UT WOS:000297262800003 PM 22427719 ER PT J AU Arriaga, AF Elbardissi, AW Regenbogen, SE Greenberg, CC Berry, WR Lipsitz, S Moorman, D Kasser, J Warshaw, AL Zinner, MJ Gawande, AA AF Arriaga, Alexander F. Elbardissi, Andrew W. Regenbogen, Scott E. Greenberg, Caprice C. Berry, William R. Lipsitz, Stuart Moorman, Donald Kasser, James Warshaw, Andrew L. Zinner, Michael J. Gawande, Atul A. TI A Policy-Based Intervention for the Reduction of Communication Breakdowns in Inpatient Surgical Care: Results From a Harvard Surgical Safety Collaborative EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB After technical errors, the most common cause of avoidable adverse events during inpatient surgical care is communication-related breakdowns. Lapses in communication have been associated with delays in care and increased patient morbidity. A previous study conducted at 4 academic medical centers examined surgical resident and attending surgeon communication practices and identified errors in communication for more than 30% of identified critical events. The data in that study also showed that residents and attending surgeons had not discussed the plan of care for 15% of randomly selected patients and that more than 20% of weekend patients had not been seen for more than 48 hours by an attending surgeon. This nonrandomized study was designed to investigate whether development and implementation of an interventional policy in surgical departments would lead to improved resident-attending communication practices, increased frequency of attending-patient interactions, and reduced failures in communication associated with critical patient events. Communication practices were compared before and after implementation of the policy according to the following 3 measures: (1) transfer into the intensive unit; (2) unplanned intubation or ventilatory support; and (3) cardiac arrest, new arrhythmia, or hemodynamic instability. The results of intervention were examined for a 19-month period. Specific measures to reinforce use of the policies included a resident-pocket information card and periodic reminders. Medical charts and audit information of randomly selected surgical services and care units for surgical patients were reviewed; repeat audits were conducted. Information on resident and attending surgeon communication practices for 211 critical events and 1360 patients were reviewed. After the policy was implemented, the proportion of critical events not conveyed by a resident to an attending surgeon decreased from 33% (26/80) to 2% (1/47), gaps in the frequency of reporting of patient status on weekends by the attending surgeon were virtually eliminated (P < 0.0001), and the percentage of patients not visited by an attending surgeon for more than 24 hours on a weekend decreased from 61% to 33% (P = 0.0002). Improvements in resident-attending communication led to changes in patient management in one third of cases. These findings show that implementation of this policy significantly improved resident-attending communication practices, reduced the incidence of potentially harmful communication breakdowns, and led to changes in patient management in inpatient surgical care. C1 [Arriaga, Alexander F.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. Childrens Hosp, Dept Surg, Boston, MA 02115 USA. RP Arriaga, AF (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD SEP PY 2011 VL 66 IS 9 BP 535 EP 537 DI 10.1097/OGX.0b013e31823b6056 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 851EQ UT WOS:000297251600003 ER PT J AU Buscher, A Hartman, C Kallen, MA Giordano, TP AF Buscher, April Hartman, Christine Kallen, Michael A. Giordano, Thomas P. TI Validity of Self-Report Measures in Assessing Antiretroviral Adherence of Newly Diagnosed, HAART-Naive, HIV Patients SO HIV CLINICAL TRIALS LA English DT Article DE adherence; cohort study; HIV; self-report; Spanish ID THERAPY ADHERENCE; VIRAL SUPPRESSION; CLINICAL-PRACTICE; QUESTIONNAIRE; TRIALS AB Purpose: To compare the performance of self-report instruments assessing adherence to antiretroviral therapy (ART) in patients starting ART for the first time and in a predominately Hispanic population. Methods: Of 184 patients in a prospective observational cohort study of newly diagnosed, minority patients of low socioeconomic status, 54 were given Medication Event Monitoring System (MEMS) caps for their boosted protease inhibitor (RI) or non-nucleoside reverse transcriptase inhibitor (NNRTI). They completed a 4-week recall visual analogue scale (VAS), the Adult AIDS Clinical Trial Group (AACTG) 4-day recall instrument, and a 1-month recall qualitative single-item measure every 3 months for up to 18 months in English or Spanish. Electronic pharmacy records recorded refill dates. Spearman correlation coefficients were calculated to compare self-report measures with MEMS data and pharmacy data. Results: Of 46 patients with MEMS data, mean adherence was 84.7% (SD 35.6) by MEMS, 84.5% (SD 15.1) by pharmacy, 95.4% (SD 11.9) by VAS, 95.8% (SD 17.2) by AACTG, and 87.6% (SD 28.2) by qualitative single item. The correlation coefficient (CC) of VAS with MEMS was 0.37 (P < .01), and with pharmacy it was 0.34 (P < .01). The CC of the AACTG with MEMS was 0.32 (P < .01), and with pharmacy it was 0.28 (P < .01). The qualitative single item had a CC with MEMS of 0.24 (P < .01) and with pharmacy of 0.32 (P < .01). Spanish-speaking patients' VAS adherence had a CC of 0.40 (P < .01) with MEMS. Conclusions: The VAS, AACTG, and qualitative single-item measures correlated significantly with MEMS and pharmacy data. Our data support self-administration of the VAS, even in Spanish speakers. C1 [Buscher, April; Hartman, Christine; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Buscher, April; Hartman, Christine; Giordano, Thomas P.] Michael E DeBakey VA Med Ctr, Houston Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. [Kallen, Michael A.] Univ Texas MD Anderson Canc Ctr, Dept Gen Internal Med, Houston, TX 77030 USA. RP Giordano, TP (reprint author), Michael E DeBakey VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM tpg@bcm.tmc.edu FU National Institute of Mental Health (NIMH) [R34MH074360]; Agency for Healthcare Research and Quality (AHRQ) [U18HS016093]; Baylor/UT Houston Center for AIDS [P30AI036211]; NIH HIV [T32AI07456] FX Supported by National Institute of Mental Health (NIMH) grant R34MH074360, Agency for Healthcare Research and Quality (AHRQ) grant U18HS016093, the Baylor/UT Houston Center for AIDS Research grant P30AI036211, NIH HIV T32AI07456, and the facilities and resources of the Harris County Hospital District and the Michael E. DeBakey VA Medical Center. Dr. Giordano is a researcher at the Michael E. DeBakey VA Medical Center Health Services Research and Development Center of Excellence, Houston, Texas. The views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. NR 25 TC 22 Z9 22 U1 0 U2 5 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD SEP-OCT PY 2011 VL 12 IS 5 BP 244 EP 254 DI 10.1310/hct1205-244 PG 11 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 847UT UT WOS:000296998700002 PM 22180522 ER PT J AU Haas, DW Kuritzkes, DR Ritchie, MD Amur, S Gage, BF Maartens, G Masys, D Fellay, J Phillips, E Ribaudo, HJ Freedberg, KA Petropoulos, C Manolio, TA Gulick, RM Haubrich, R Kim, P Dehlinger, M Abebe, R Telenti, A AF Haas, David W. Kuritzkes, Daniel R. Ritchie, Marylyn D. Amur, Shashi Gage, Brian F. Maartens, Gary Masys, Dan Fellay, Jacques Phillips, Elizabeth Ribaudo, Heather J. Freedberg, Kenneth A. Petropoulos, Christos Manolio, Teri A. Gulick, Roy M. Haubrich, Richard Kim, Peter Dehlinger, Marjorie Abebe, Rahel Telenti, Amalio CA Participants Workshop Pharmacogeno TI Pharmacogenomics of HIV Therapy: Summary of a Workshop Sponsored by the National Institute of Allergy and Infectious Diseases SO HIV CLINICAL TRIALS LA English DT Article DE HIV therapy; pharmacogenetics; pharmacogenomics; workshop ID SINGLE-NUCLEOTIDE POLYMORPHISMS; ANTIRETROVIRAL THERAPY; PLASMA-CONCENTRATIONS; HIV-1-INFECTED INDIVIDUALS; SLCO1B1 POLYMORPHISMS; EFAVIRENZ; HYPERSENSITIVITY; NEVIRAPINE; CYP2B6; ABACAVIR AB Approximately 1 million people in the United States and over 30 million worldwide are living with human immunodeficiency virus type 1 (HIV-1). While mortality from untreated infection approaches 100%, survival improves markedly with use of contemporary antiretroviral therapies (ART). In the United States, 25 drugs are approved for treating HIV-1, and increasing numbers are available in resource-limited countries. Safe and effective ART is a cornerstone in the global struggle against the acquired immunodeficiency syndrome. Variable responses to ART are due at least in part to human genetic variants that affect drug metabolism, drug disposition, and off-site drug targets. Defining effects of human genetic variants on HIV treatment toxicity, efficacy, and pharmacokinetics has far-reaching implications. In 2010, the National Institute of Allergy and Infectious Diseases sponsored a workshop entitled, Pharmacogenomics A Path Towards Personalized HIV Care. This article summarizes workshop objectives, presentations, discussions, and recommendations derived from this meeting. C1 [Haas, David W.; Ritchie, Marylyn D.; Masys, Dan] Vanderbilt Univ, Sch Med, Nashville, TN 37204 USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kuritzkes, Daniel R.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Boston, MA USA. [Amur, Shashi] US FDA, Silver Spring, MD USA. [Gage, Brian F.] Washington Univ, St Louis, MO USA. [Maartens, Gary] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Fellay, Jacques; Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Phillips, Elizabeth] Murdoch Univ, Royal Perth Hosp, Sir Charles Gairdner Hosp, Perth, WA, Australia. [Phillips, Elizabeth] Univ Western Australia, Perth, WA 6009, Australia. [Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Stat Data Anal Ctr, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Massachussetts Gen Hosp, Boston, MA USA. [Petropoulos, Christos] Monogram Biosci, San Francisco, CA USA. [Manolio, Teri A.] Natl Genome Res Inst, NIH, Bethesda, MD USA. [Gulick, Roy M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Haubrich, Richard] Univ Calif San Diego, San Diego, CA 92103 USA. [Kim, Peter; Dehlinger, Marjorie] NIAID, NIH, Bethesda, MD 20892 USA. [Abebe, Rahel] Henry M Jackson Fdn DAIDS, Bethesda, MD USA. RP Haas, DW (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Hlth 1 Hundred Oaks,719 Thompson Lane,, Nashville, TN 37204 USA. EM david.w.haas@vanderbilt.edu RI Ritchie, Marylyn/C-1114-2012; Maartens, Gary/F-3836-2014; Fellay, Jacques/A-6681-2009 OI Maartens, Gary/0000-0003-3080-6606; Fellay, Jacques/0000-0002-8240-939X FU National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; Bristol Myers Squibb; Boehringer Ingelheim; Merck; Gilead Sciences; Abbott; Avexa; Boehringer-Ingelheim; Gilead; GlaxoSmithKline (GSK); Oncolys; Roche; Siemens; Tobira; Vertex; ViiV; Viro-Statics; VIRxSYS; ViiV Australia; Merck Pty Ltd; Tibotec; Pfizer; Bristol-Myers Squibb; GSK; Monogram; GlaxoSmithKline; National Institute of Allergy and Infectious Diseases; NIH Office of AIDS Research; AIDS Clinical Trials Group [AI68636, AI38858, AI68634, AI38855]; Swiss National Foundation [324730-124943, HL097036, AI64086, AI36214, AI69432]; CHRP [MC08-SD-700, AI069472, HL065962, AI077505, AI42006, AI085736]; [AI069439]; [RR024975]; [AI54999]; [AI51966]; [RR024996]; [RR69419] FX The views expressed in written conference materials or publications and by speakers and moderators at HHS-sponsored conferences do not necessarily reflect the official policies of the US Department of Health and Human Services nor does mention of trade names, commercial practices, or organizations imply endorsement by the US Government. This project has been funded in whole or in part with federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200800014C.; David W. Haas: Principal Investigator for research grants to Vanderbilt from Bristol Myers Squibb, Boehringer Ingelheim, Merck, Gilead Sciences. Daniel Kuritzkes: Consultant to and/or received research support from Abbott, Avexa, Boehringer-Ingelheim, Gilead, GlaxoSmithKline (GSK), Merck, Oncolys, Roche, Siemens, Tobira, Vertex, ViiV, Viro-Statics and VIRxSYS. Marylyn D. Ritchie: Consultant for Boehringer Ingelheim. Elizabeth Phillips: Honoraria and consulting fees from ViiV Australia, Merck Pty Ltd, and Tibotec. Christos Petropoulos: Employee of Monogram Biosciences, South San Francisco, CA. Roy M. Gulick: Ad hoc consultant for Bristol-Myers, Gilead, GSK, MedImmune, ViiV, and Virostatics, and as Principal Investigator for research grants to Weill Cornell from Merck and Pfizer. Richard Haubrich: Received honoraria or consultant fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, GSK, Merck, Monogram, Pfizer, Roche, Tibotec, and ViiV and research support (to UCSD) from Abbott, GlaxoSmithKline, Merck, Pfizer, and ViiV. No potential conflicts of interest: Shashi Amur, Brian Gage, Gary Maartens, Dan Masys, Jacques Fellay, Heather J. Ribaudo, Kenneth A. Freedberg, Ten A. Manolio, Peter Kim, Marjorie Dehlinger, Rahel Abebe, and Amalio Telenti.; The workshop entitled, Pharmacogenomics - A Path Towards Personalized HIV Care, was supported by the National Institute of Allergy and Infectious Diseases and the NIH Office of AIDS Research. This work was supported in part by the AIDS Clinical Trials Group (grants AI68636, AI38858, AI68634, and AI38855). Participants were also supported by the following: grants AI069439, RR024975, and AI54999 (DWH); AI51966 (RMG); RR024996 (Cornell CTSC); RR69419 (CTU); Swiss National Foundation 324730-124943 (AT); HL097036 (BFG); AI64086, AI36214, AI69432, and CHRP MC08-SD-700 (RH); AI069472 (DK); HL065962 and AI077505 (MDR); AI42006 and AI085736 (KAF). NR 34 TC 8 Z9 9 U1 0 U2 4 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD SEP-OCT PY 2011 VL 12 IS 5 BP 277 EP 285 DI 10.1310/hct1205-277 PG 9 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 847UT UT WOS:000296998700006 PM 22180526 ER PT J AU Mankey, VL AF Mankey, Vaughn L. TI Using Multimodal and Multimedia Tools in the Psychiatric Education of Diverse Learners: Examples From the Mental Status Exam SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID LEARNING STYLES; WORKING-MEMORY; COGNITIVE LOAD; CAPACITY; INFORMATION; STUDENTS; ATTENTION; LIMITS C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Mankey, VL (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM vmankey@gmail.com NR 29 TC 1 Z9 1 U1 1 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 J9 ACAD PSYCHIATR JI Acad. Psych. PD SEP-OCT PY 2011 VL 35 IS 5 BP 335 EP 339 PG 5 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 846JF UT WOS:000296892500015 PM 22007095 ER PT J AU Shin, JH Chao, ST Angelov, L AF Shin, J. H. Chao, S. T. Angelov, L. TI Stereotactic radiosurgery for spinal metastases: update on treatment strategies SO JOURNAL OF NEUROSURGICAL SCIENCES LA English DT Article DE Spine; Radiosurgery; Neoplasm metastases; Radiation oncology ID INTENSITY-MODULATED RADIOTHERAPY; CORD COMPRESSION; CONVENTIONAL RADIOTHERAPY; PREOPERATIVE EVALUATION; PROGNOSTIC-FACTORS; PARASPINAL TUMORS; BODY RADIOTHERAPY; SCORING SYSTEM; RADIATION; DISEASE AB Metastatic tumors are the most common tumors that affect the spinal column and are the source of significant pain and disability in cancer patients. The management of symptomatic spinal metastases presents unique challenges to surgeons as a number of considerations specific to the underlying tumor histology, extent of disease, the functional status of the patient and response to systemic therapy often affect the role, timing and effectiveness of any surgical intervention. As surgical techniques have evolved, the focus of therapy has shifted towards minimizing the morbidity associated with treatments for patients in whom limited nutrition and functional reserve impact their overall survival. As such, stereotactic spinal radiosurgery (SRS) has emerged as a powerful adjunct to surgery as well as a stand-alone treatment option for patients with metastatic disease. Recent technological innovations such as intensity-modulated radiation therapy, image-guidance, and non-invasive spine immobilization have made significant improvements to the delivery of highly conformal radiation to spinal tumors. In this article, current treatment strategies utilizing SRS in the multidisciplinary management of spinal metastases are discussed. C1 [Shin, J. H.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, Boston, MA 02114 USA. [Chao, S. T.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Angelov, L.] Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. RP Shin, JH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, 55 Fruit St,WAC 745, Boston, MA 02114 USA. EM johnhongshin@gmail.com NR 59 TC 5 Z9 5 U1 0 U2 1 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0390-5616 J9 J NEUROSURG SCI JI J. Neurosurg. Sci. PD SEP PY 2011 VL 55 IS 3 BP 197 EP 209 PG 13 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 837TH UT WOS:000296225600005 PM 21968584 ER PT J AU Vachharajani, TJ Moossavi, S Salman, L Wu, S Dwyer, AC Ross, J Dukkipati, R Maya, ID Yevzlin, AS Agarwal, A Abreo, KD Work, J Asif, A AF Vachharajani, Tushar J. Moossavi, Shahriar Salman, Loay Wu, Steven Dwyer, Amy C. Ross, Jamie Dukkipati, Ramanath Maya, Ivan D. Yevzlin, Alexander S. Agarwal, Anil Abreo, Kenneth D. Work, Jack Asif, Arif TI Dialysis Vascular Access Management by Interventional Nephrology Programs at University Medical Centers in the United States SO SEMINARS IN DIALYSIS LA English DT Article ID MULTIDISCIPLINARY APPROACH; HEALTH-CARE AB The development of interventional nephrology has undoubtedly led to an improvement in patient care at many facilities across the United States. However, these services have traditionally been offered by interventional nephrologists in the private practice arena. While interventional nephrology was born in the private practice setting, several academic medical centers across the United States have now developed interventional nephrology programs. University Medical Centers (UMCs) that offer interventional nephrology face challenges, such as smaller dialysis populations, limited financial resources, and real or perceived political "turf'' issues.'' Despite these hurdles, several UMCs have successfully established interventional nephrology as an intricate part of a larger nephrology program. This has largely been accomplished by consolidating available resources and collaborating with other specialties irrespective of the size of the dialysis population. The collaboration with other specialties also offers an opportunity to perform advanced procedures, such as application of excimer laser and endovascular ultrasound. As more UMCs establish interventional nephrology programs, opportunities for developing standardized training centers will improve, resulting in better quality and availability of nephrology-related procedures, and providing an impetus for research activities. C1 [Vachharajani, Tushar J.; Moossavi, Shahriar] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Nephrol, Dialysis Access Grp, Winston Salem, NC 27157 USA. [Salman, Loay; Asif, Arif] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Wu, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Dwyer, Amy C.] Univ Louisville, Louisville, KY 40292 USA. [Ross, Jamie] Univ Calif, Davis Sch Med, Vasc Access Unit, Sacramento, CA USA. [Dukkipati, Ramanath] Harbor UCLA Med Ctr, Div Nephrol, Torrance, CA 90509 USA. [Maya, Ivan D.] Univ Alabama, Birmingham, AL USA. [Yevzlin, Alexander S.] Univ Wisconsin, Madison, WI USA. [Agarwal, Anil] Ohio State Univ, Columbus, OH 43210 USA. [Abreo, Kenneth D.] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Work, Jack] Emory Univ, Atlanta, GA 30322 USA. RP Vachharajani, TJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Nephrol, Dialysis Access Grp, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM tvachhar@wfubmc.edu NR 23 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD SEP-OCT PY 2011 VL 24 IS 5 BP 564 EP 569 DI 10.1111/j.1525-139X.2011.00985.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 835GW UT WOS:000296025300017 PM 21999740 ER PT J AU Swearingen, B Wu, N Chen, SY Pulgar, S Biller, BMK AF Swearingen, Brooke Wu, Ning Chen, Shih-Yin Pulgar, Sonia Biller, Beverly M. K. TI HEALTH CARE RESOURCE USE AND COSTS AMONG PATIENTS WITH GUSHING DISEASE SO ENDOCRINE PRACTICE LA English DT Article ID CUSHINGS-DISEASE; TRANSSPHENOIDAL SURGERY; CARDIOVASCULAR RISK; CONSENSUS STATEMENT; MORTALITY; COMPLICATIONS; PERSISTENT; REMISSION; MASS; CURE AB Objective: To assess health care costs associated with Cushing disease and to determine changes in overall and comorbidity-related costs after surgical treatment. Methods: In this retrospective cohort study, patients with Cushing disease were identified from insurance claims databases by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for Cushing syndrome (255.0) and either benign pituitary adenomas (227.3) or hypophysectomy (07.6x) between 2004 and 2008. Each patient with Cushing disease was age- and sex-matched with 4 patients with nonfunctioning pituitary adenomas and 10 population control subjects. Comorbid conditions and annual direct health care costs were assessed within each calendar year. Postoperative changes in health care costs and comorbidity-related costs were compared between patients presumed to be in remission and those with presumed persistent disease. Results: Of 877 identified patients with Cushing disease, 79% were female and the average age was 43.4 years. Hypertension, diabetes mellitus, and hyperlipidemia were more common among patients with Cushing disease than in patients with nonfunctioning pituitary adenomas or in control patients (P<.01). For every calendar year studied, patients with Cushing disease had significantly higher total health care costs (2008: $26440 [Cushing disease] vs $13708 [nonfunctioning pituitary adenomas] vs $5954 [population control], P<.01). Annual outpatient costs decreased significantly for patients in remission after surgery, and there was a trend towards improvement in overall disease-related costs with remission. A significant increase in postoperative health care costs was observed in those patients not in remission. Conclusions: Patients with Cushing disease had more comorbidities than patients with nonfunctioning pituitary adenomas or control patients and incurred significantly higher annual health care costs; these costs decreased after successful surgery and increased after unsuccessful surgery. (Endocr Pract. 2011;17:681-690) C1 [Swearingen, Brooke] Massachusetts Gen Hosp, Neurosurg Serv, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. [Wu, Ning; Chen, Shih-Yin] United BioSource Corp, Lexington, MA USA. [Pulgar, Sonia] Novartis Pharmaceut, Florham Pk, NJ USA. RP Swearingen, B (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, Neuroendocrine Clin Ctr, 15 Parkman St, Boston, MA 02114 USA. EM BSwearingen@partners.org FU Novartis Pharmaceuticals Corporation FX Funding for this project was provided by Novartis Pharmaceuticals Corporation. Dr. Swearingen has served as a consultant for Novartis. Ms. Pulgar is an employee of Novartis. Dr. Biller has served as a consultant and principal investigator for Novartis and as a principal investigator for Corcept. Dr. Wu and Dr. Chen have no multiplicity of interest to declare. NR 26 TC 15 Z9 15 U1 0 U2 0 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD SEP-OCT PY 2011 VL 17 IS 5 BP 681 EP 690 DI 10.4158/EP10368.OR PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 838TJ UT WOS:000296314800001 PM 21454233 ER PT J AU Daniels, GH AF Daniels, Gilbert H. TI WHAT IF MANY FOLLICULAR VARIANT PAPILLARY THYROID CARCINOMAS ARE NOT MALIGNANT? A REVIEW OF FOLLICULAR VARIANT PAPILLARY THYROID CARCINOMA AND A PROPOSAL FOR A NEW CLASSIFICATION SO ENDOCRINE PRACTICE LA English DT Review ID FINE-NEEDLE-ASPIRATION; FOLLOW-UP; MACROFOLLICULAR VARIANT; DIFFERENTIAL-DIAGNOSIS; OBSERVER VARIATION; CLINICAL-FEATURES; PATTERNED LESIONS; RAS MUTATIONS; PAX8-PPAR-GAMMA REARRANGEMENT; GENETIC ALTERATIONS AB Objectives: To review the relevant literature concerning follicular variant of papillary thyroid carcinoma (FVPTC) with an emphasis on the heterogeneity of this disorder and to propose a new classification for FVPTC on the basis of molecular diagnostics and apply the classification to a typical case. Methods: English-language articles pertaining to FVPTC published between January 1990 and December 2010 were reviewed. Results: FVPTC is particularly vexing. The criteria for diagnosing FVPTC appear to have changed over the years. Pathologists often disagree about the diagnosis of FVPTC. The clinical behavior of these tumors is variable. Molecular diagnostic studies suggest that FVPTC represents a heterogeneous group of disorders rather than a single entity. Conclusions: On the basis of the available data, it is proposed that individual cases of FVPTC be reclassified as papillary thyroid carcinoma, follicular thyroid carcinoma, or follicular adenomas, after appropriate molecular biologic studies have been completed. Long-term follow-up studies to validate this classification are necessary. (Endocr Pract. 2011;17:768-787) C1 [Daniels, Gilbert H.] Harvard Univ, Thyroid Unit, Massachusetts Gen Hosp, Canc Ctr,Med Sch, Boston, MA 02114 USA. [Daniels, Gilbert H.] Harvard Univ, Dept Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Daniels, GH (reprint author), Harvard Univ, Thyroid Unit, Massachusetts Gen Hosp, Canc Ctr,Med Sch, ACC 730, Boston, MA 02114 USA. EM gdaniels@partners.org NR 135 TC 14 Z9 14 U1 0 U2 4 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD SEP-OCT PY 2011 VL 17 IS 5 BP 768 EP 787 DI 10.4158/EP10407.RA PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 838TJ UT WOS:000296314800011 PM 21940284 ER PT J AU Schoenfeld, JD Dranoff, G AF Schoenfeld, Jonathan D. Dranoff, Glenn TI Anti-angiogenic immunotherapy SO HUMAN VACCINES LA English DT Editorial Material DE angiogenesis; vaccine; immunotherapy; GM-CSF; angiopoietin ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-INFILTRATING LYMPHOCYTES; IMMATURE MYELOID CELLS; REGULATORY T-CELLS; ANTITUMOR IMMUNITY; OVARIAN-CANCER; METASTATIC MELANOMA; COLORECTAL-CANCER; FACTOR RECEPTOR-2; THERAPEUTIC IMPLICATIONS C1 [Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Schoenfeld, Jonathan D.; Dranoff, Glenn] Harvard Univ, Sch Med, Boston, MA USA. [Schoenfeld, Jonathan D.] Harvard Radiat Oncol Program, Boston, MA USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM glenn_dranoff@dfci.harvard.edu FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA111506, R01 CA143083, CA78378, CA111506, P01 CA078378]; NIAID NIH HHS [AI29530, U19 AI029530, P01 AI029530] NR 96 TC 9 Z9 9 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8600 EI 1554-8619 J9 HUM VACCINES JI Hum. Vaccines PD SEP PY 2011 VL 7 IS 9 BP 976 EP 981 DI 10.4161/hv.7.9.16407 PG 6 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 832VN UT WOS:000295837200023 PM 21860259 ER PT J AU Urdaneta, RA Daher, S Leary, J Emanuel, K Chuang, SK AF Urdaneta, Rainier A. Daher, Shadi Leary, Joseph Emanuel, Kimberly Chuang, Sung-Kiang TI Factors Associated with Crestal Bone Gain on Single-Tooth Locking-Taper Implants: The Effect of Nonsteroidal Anti-Inflammatory Drugs SO INTERNATIONAL JOURNAL OF ORAL & MAXILLOFACIAL IMPLANTS LA English DT Article DE dental implants; nonsteroidal anti-inflammatory drugs; peri-implant bone gain; prospective cohort study; risk factors ID DENTAL IMPLANTS; RADIOGRAPHIC EVALUATION; BRANEMARK IMPLANTS; TITANIUM IMPLANTS; WIDE-DIAMETER; REPLACEMENT; RATS; INHIBITION; DICLOFENAC; MECHANISM AB Purpose: To identify factors associated with crestal bone gain around single-tooth implants. Materials and Methods: A retrospective cohort study was conducted. More than 90 different local and systemic factors were documented. Descriptive statistics and univariate and multivariate mixed-effects regression models, adjusted for multiple implants in the same patient, were used to identify predictors of crestal bone gain after insertion of definitive restorations. Results: Eighty-one subjects who received 326 Bicon implants were followed for an average of 70.7 months. Eighty-one implants in 46 patients showed varying degrees of apparent bone gain over time. Variables associated with peri-implant bone gain in the first multivariate model were: type of opposing structure, tooth (P = .02); type of restoration, crown cemented on a prefabricated titanium abutment with a spherical base (P = .006); hydroxyapatite coating (P = .0005); implant size 5 x 8 mm (P = .02); and daily intake of nonsteroidal anti-inflammatory drugs (NSAIDs) (P =. 04). NSAIDs remained significantly correlated to crestal bone gain in the second multivariate analysis; an implant was significantly more likely to gain bone if the patient was taking NSAIDs daily (P = .02), but this effect was specific to hydroxyapatite-coated implants (P = .01). Conclusion: Daily doses of NSAIDs were correlated with a significant increase in crestal bone levels around single-tooth hydroxyapatite-coated implants following crown insertion. INT J ORAL MAXILLOFAC IMPLANTS 2011;26:1063-1078 C1 [Urdaneta, Rainier A.; Daher, Shadi; Emanuel, Kimberly] Implant Dent Ctr, Boston, MA USA. [Daher, Shadi] Boston Univ, Dept Oral & Maxillofacial Surg, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. [Chuang, Sung-Kiang] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Leary, Joseph] Private Practice Ltd Periodont, Norwood, MA USA. RP Urdaneta, RA (reprint author), 25 Prairie Ave, Auburndale, MA 02466 USA. EM rainieru@yahoo.com NR 46 TC 12 Z9 12 U1 0 U2 2 PU QUINTESSENCE PUBLISHING CO INC PI HANOVER PARK PA 4350 CHANDLER DRIVE, HANOVER PARK, IL 60133 USA SN 0882-2786 J9 INT J ORAL MAX IMPL JI Int. J. Oral Maxillofac. Implants PD SEP-OCT PY 2011 VL 26 IS 5 BP 1063 EP 1078 PG 16 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 837WB UT WOS:000296237700021 PM 22010091 ER PT J AU Tobin, MJ AF Tobin, Martin J. TI The new irrationalism in weaning A nova irracionalidade no desmame SO JORNAL BRASILEIRO DE PNEUMOLOGIA LA English DT Editorial Material ID MECHANICAL VENTILATION; SUPPORT C1 [Tobin, Martin J.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Hines, IL 60141 USA. [Tobin, Martin J.] Loyola Univ Chicago, Stritch Sch Med, Hines, IL USA. RP Tobin, MJ (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. NR 16 TC 3 Z9 3 U1 0 U2 0 PU SOC BRASILEIRA PNEUMOLOGIA TISIOLOGIA PI BRASILIA DF PA SEPS 714-719, BLOCO E ASA SUL, SALAS 220-223, BRASILIA DF, CEP70390-145, BRAZIL SN 1806-3713 J9 J BRAS PNEUMOL JI J. Bras. Pneumol. PD SEP-OCT PY 2011 VL 37 IS 5 BP 571 EP 573 PG 3 WC Respiratory System SC Respiratory System GA 837PA UT WOS:000296214500001 PM 22042386 ER PT J AU Kradin, R AF Kradin, Richard TI THE PLACEBO RESPONSE an attachment strategy that counteracts the effects of stress-related dysfunction SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND; MECHANISM; BRAIN; EXPECTATION; MEDICINE; DISEASE; FMRI; LIFE AB The placebo response represents an enigmatic element of therapeutics. The potency of placebo effects is highlighted by the fact that the current gold standard for determining therapeutic efficacy, the randomized controlled clinical trial, is based on identifying treatment responses that are statistically superior to those elicited by a placebo. Although much has been written concerning the phenomenology of placebos, little is known concerning how they are elicited, although recent research has demonstrated that placebo effects are mediated via objective physiological pathways. I have previously argued that the placebo response is a developmental achievement, rooted in implicit procedural memories that are linked to background affects of wellbeing evoked by a relational dynamic with a caregiver. This article develops this idea further, suggesting that placebo response represents a nervous-system response aimed at countering the dysphoric effects attributable to chronic stress, and that it is dependent on developmental attachment dynamics. A range of behaviors by caregivers that mimic those achieved during secure attachment are suggested to promote placebo responses. C1 [Kradin, Richard] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kradin, Richard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kradin, Richard] Massachusetts Gen Hosp, Ctr Psychoanalyt Studies, Boston, MA 02114 USA. RP Kradin, R (reprint author), Massachusetts Gen Hosp, Dept Med, Warren 253, Boston, MA 02114 USA. EM rkradin@partners.org NR 74 TC 1 Z9 1 U1 3 U2 5 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2011 VL 54 IS 4 BP 438 EP 454 PG 17 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 835YV UT WOS:000296074100002 PM 22019533 ER PT J AU Flores-Moreno, JM Furlong, C Rosowski, JJ Harrington, E Cheng, JT Scarpino, C Santoyo, FM AF Flores-Moreno, J. M. Furlong, Cosme Rosowski, John J. Harrington, Ellery Cheng, Jeffrey T. Scarpino, C. Mendoza Santoyo, F. TI Holographic Otoscope for Nanodisplacement Measurements of Surfaces Under Dynamic Excitation SO SCANNING LA English DT Article DE optoelectronic holography; digital holography; otology; middle-ear ID TYMPANIC-MEMBRANE; STROBOSCOPIC HOLOGRAPHY; MOTION; INTERFEROMETRY; COMPONENTS; VIBRATION AB We describe a novel holographic otoscope system for measuring nanodisplacements of objects subjected to dynamic excitation. Such measurements are necessary to quantify the mechanical deformation of surfaces in mechanics, acoustics, electronics, biology, and many other fields. In particular, we are interested in measuring the sound-induced motion of biological samples, such as an eardrum. Our holographic otoscope system consists of laser illumination delivery (IS), optical head (OH), and image processing computer (IP) systems. The IS delivers the object beam (OB) and the reference beam (RB) to the OH. The back-scattered light coming from the object illuminated by the OB interferes with the RB at the camera sensor plane to be digitally recorded as a hologram. The hologram is processed by the IP using the Fresnel numerical reconstruction algorithm, where the focal plane can be selected freely. Our holographic otoscope system is currently deployed in a clinic, and is packaged in a custom design. It is mounted in a mechatronic positioning system to increase its maneuverability degrees to be conveniently positioned in front of the object to be measured. We present representative results highlighting the versatility of our system to measure deformations of complex elastic surfaces in the wavelength scale including a copper foil membrane and postmortem tympanic membrane. SCANNING 33: 342-352, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Flores-Moreno, J. M.; Furlong, Cosme; Harrington, Ellery] Worcester Polytech Inst, Dept Mech Engn, Worcester, MA 01609 USA. [Flores-Moreno, J. M.; Furlong, Cosme; Harrington, Ellery] Worcester Polytech Inst, Ctr Holog Studies & Laser MicromechaTron, Worcester, MA 01609 USA. [Flores-Moreno, J. M.; Mendoza Santoyo, F.] Ctr Invest Opt AC, Leon, Gto, Mexico. [Furlong, Cosme; Rosowski, John J.; Cheng, Jeffrey T.; Scarpino, C.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Furlong, Cosme; Rosowski, John J.; Cheng, Jeffrey T.; Scarpino, C.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Rosowski, John J.] MIT, Harvard Mit Div Hlth Sci & Technol, Speech & Hearing Biosci & Technol Program, Cambridge, MA 02139 USA. RP Flores-Moreno, JM (reprint author), Worcester Polytech Inst, Dept Mech Engn, Worcester, MA 01609 USA. EM mflores@wpi.edu OI Mendoza-Santoyo, Fernando/0000-0002-4596-3316 FU U.S. National Institute for Deafness and other Communicative Disorders; Worcester Polytechnic Institute (WPI); Centro de Investigaciones en Optica, A.C. (CIO); Massachusetts Eye and Ear Infirmary (MEEI); Lakshmi Mittal Fund FX Contract grant sponsors: U.S. National Institute for Deafness and other Communicative Disorders; Worcester Polytechnic Institute (WPI); Centro de Investigaciones en Optica, A.C. (CIO); Massachusetts Eye and Ear Infirmary (MEEI); Lakshmi Mittal Fund. NR 27 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0161-0457 J9 SCANNING JI Scanning PD SEP-OCT PY 2011 VL 33 IS 5 SI SI BP 342 EP 352 DI 10.1002/sca.20283 PG 11 WC Instruments & Instrumentation; Microscopy SC Instruments & Instrumentation; Microscopy GA 839QZ UT WOS:000296385000009 PM 21898459 ER PT J AU Devaraj, NK Weissleder, R AF Devaraj, Neal K. Weissleder, Ralph TI Biomedical Applications of Tetrazine Cycloadditions SO ACCOUNTS OF CHEMICAL RESEARCH LA English DT Review ID GROWTH-FACTOR RECEPTOR; LIVING CELLS; CLICK CHEMISTRY; BUILDING-BLOCKS; CANCER-CELLS; REACTIVITY; SYSTEMS; MOLECULES; LIGATION; PROBES AB Disease mechanisms are increasingly being resolved at the molecular level. Biomedical success at this scale creates synthetic opportunities for combining specifically designed orthogonal reactions In applications such as imaging, diagnostics, and therapy. For practical reasons, it would be helpful If bioorthogonal coupling reactions proceeded with extremely rapid kinetics (k>10(3) M(-1) s(-1)) and high specificity. Improving kinetics would minimize both the time and amount of labeling agent required to maintain high coupling yields. In this Account, we discuss our recent efforts to design extremely rapid bioorthogonal coupling reactions between tetrazines and strained alkenes. These selective reactions were first used to covalently couple conjugated tetrazine near-Infrared-emitting fluorophores to dienophile-modifed extracellular proteins on living cancer cells. Confocal fluorescence microscopy demonstrated efficient and selective labeling, and control experiments showed minimal background fluorescence. Multistep techniques were optimized to work with nanomolar concentrations of labeling agent over a time scale of minutes: the result was successful real-time imaging of covalent modification. We subsequently discovered fluorogenic probes that Increase in fluorescence Intensity after the chemical reaction, leading to an improved signal-to-background ratio. Fluorogenic probes were used for Intracellular imaging of dienophiles. We further developed strategies to react and image chemotherapeutics, such as trans-cyclooctene taxol analogues, inside living cells. Because the coupling partners are small molecules (<300 Da), they offer unique steric advantages in multistep amplification. We also describe recent success in using tetrazine reactions to label biomarkers on cells with magneto-fluorescent nanoparticles. Two-step protocols that use bioorthogonal chemistry can significantly amplify signals over both one-step labeling procedures as well as two-step procedures that use more sterically hindered biotin avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clinical samples for biomarker profiling to predict malignancy and patient outcome. Finally, we discuss recent results with tetrazine reactions used for in vivo molecular imaging applications. Rapid tetrazine cycloadditions allow modular labeling of small molecules with the most commonly used positron emission tomography isotope, (18)F. Additionally, recent work has applied this reaction directly in vivo for the pretargeted imaging of solid tumors. Future work with tetrazine cycloadditions will undoubtedly lead to optimized protocols, improved probes, and additional biomedical applications. C1 [Devaraj, Neal K.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Devaraj, NK (reprint author), Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. EM ndevaraj@ucsd.edu; rweissleder@mgh.harvard.edu RI Devaraj, Neal/B-4712-2014 FU NIH [P50CA86355, R01EB010011, K01EB010078, T32CA079443] FX The authors gratefully acknowledge S. A. Hilderbrand, J. B. Haun, G. M. Thurber, C. Castro, T. Reiner, N. Keliher, and R. Mazitschek for their contributions to the above-discussed research as well as for their many helpful discussions and suggestions. This work was funded in part by NIH Grants P50CA86355, R01EB010011, K01EB010078, and T32CA079443. NR 48 TC 179 Z9 180 U1 17 U2 201 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0001-4842 J9 ACCOUNTS CHEM RES JI Accounts Chem. Res. PD SEP PY 2011 VL 44 IS 9 SI SI BP 816 EP 827 DI 10.1021/ar200037t PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 835ZH UT WOS:000296075300017 PM 21627112 ER PT J AU Anderson, ICW Sedaghat, AR McGinley, BM Redett, RJ Boss, EF Ishman, SL AF Anderson, Iee Ching W. Sedaghat, Ahmad R. McGinley, Brian M. Redett, Richard J. Boss, Emily F. Ishman, Stacey L. TI Prevalence and Severity of Obstructive Sleep Apnea and Snoring in Infants With Pierre Robin Sequence SO CLEFT PALATE-CRANIOFACIAL JOURNAL LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the American-Cleft-Palate-Craniofacial-Association CY APR 20-25, 2009 CL Scottsdale, AZ SP Amer Cleft Palate Craniofacial Assoc DE infants; OSA; Pierre Robin sequence; snoring ID CHILDREN; MANAGEMENT AB Objective: To evaluate the prevalence and severity of obstructive sleep apnea in infants with Pierre Robin sequence prior to airway intervention and determine whether snoring correlates with the presence of obstructive sleep apnea in this population. Design: Retrospective case series. Setting: Urban tertiary care teaching hospital. Participants/Methods: Review of infants with Pierre Robin sequence who underwent polysomnography in the first year of life from 2002 to 2007. Only results from the initial polysomnography were analyzed. A subgroup of consecutive prospectively tested patients was also evaluated. Results: A total of 33 infants with Pierre Robin sequence were identified. Of these, 13 (39%), 11 girls and two boys, underwent polysomnography in the first year of life. The mean age at evaluation was 48 days (range, 7 to 214 days). Seven nonconsecutive and six consecutive patients were included, and no significant differences were seen between groups. Obstructive sleep apnea was identified in 11 of 13 (85%) infants. The mean obstructive apnea-hypopnea index was 33.5 (range, 0 to 85.7). Obstructive sleep apnea severity was mild in 2 of 11 (18%), moderate in 3 of 11 (27%), and severe in 6 of 11 (55%). Mean endtidal Pco(2) measurements were elevated at 59 mm Hg (range, 47 to 76 mm Hg). Mean oxygen saturation nadir was decreased at 80% (range, 68% to 93%). Snoring occurred in only 7 of 13 (54%). Of the subjects with obstructive sleep apnea, snoring occurred in 6 of 11 (55%). Conclusion: The high incidence of obstructive sleep apnea in this group suggests that polysomnography should be promptly performed in children with Pierre Robin sequence. Although snoring was seen in the majority, the absence of snoring did not exclude the presence of obstructive sleep apnea. C1 [Boss, Emily F.; Ishman, Stacey L.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Anderson, Iee Ching W.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Sedaghat, Ahmad R.] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA USA. [McGinley, Brian M.] Johns Hopkins Sch Med, Dept Pediat, Eudowood Div Pediat Pulmonol, Baltimore, MD 21287 USA. [Redett, Richard J.] Johns Hopkins Sch Med, Dept Surg, Div Plast Surg, Baltimore, MD 21287 USA. RP Ishman, SL (reprint author), Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St,Room 6231, Baltimore, MD 21287 USA. EM sishman1@jhmi.edu OI Ishman, Stacey/0000-0003-0997-9692 NR 19 TC 28 Z9 30 U1 1 U2 2 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1545-1569 J9 CLEFT PALATE-CRAN J JI Cleft Palate-Craniofac. J. PD SEP PY 2011 VL 48 IS 5 BP 614 EP 618 DI 10.1597/10-100 PG 5 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 835FK UT WOS:000296020700017 PM 20815709 ER PT J AU Spicka, I Mateos, MV Redman, K Dimopoulos, MA Richardson, PG AF Spicka, Ivan Mateos, M. V. Redman, K. Dimopoulos, M. A. Richardson, P. G. TI An overview of the VISTA trial: newly diagnosed, untreated patients with multiple myeloma ineligible for stem cell transplantation SO IMMUNOTHERAPY LA English DT Editorial Material DE bortezomib; multiple myeloma; peripheral neuropathy; proteasome inhibition; treatment-naive older patients ID BORTEZOMIB PLUS MELPHALAN; RANDOMIZED CONTROLLED-TRIAL; PERIPHERAL NEUROPATHY; INITIAL TREATMENT; ELDERLY-PATIENTS; PHASE-3 VISTA; WORKING GROUP; PREDNISONE; THERAPY; THALIDOMIDE AB Multiple myeloma, a plasma cell neoplasm, is the second most common hematologic malignancy after non-Hodgkins lymphoma and is responsible for 2% of cancer deaths. Melphalan and prednisone (MP) has been the standard treatment in elderly patients for many decades. The VISTA study evaluated the effect of this combination with or without the first-in-class proteasome inhibitor bortezomib in newly diagnosed myeloma patients who were not candidates for autologous stem cell transplantation. Altogether 682 patients were enrolled and prospectively randomized in this trial. All patients received nine 6-week cycles of oral melphalan (9 mg/m(2)) and prednisone (60 mg/m(2)) on days 1-4, either alone or with bortezomib administered intravenously (1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29 and 32 during the first four cycles and on days 1, 8, 22, 29 during remaining course of therapy). Median time to progression (the primary end point of the trial) was 24 months in the bortezomib-containing group compared with 16.6 months in the control group (p < 0.001). Response was evaluated in 337 patients receiving bortezomib compared with 331 patients in the control group who received MP alone; the percentages of partial response or better was 71 vs 35% (p < 0.001), with complete response seen in 30 vs 4%, respectively (p < 0.001). Median response duration in both groups was 19.9 versus 13.1 months, respectively. Median overall survival has not been reached in VMP group compared with 43 months in the MP group (p < 0.001), and this benefit is maintained after long term follow-up and subsequent antimyeloma therapies. Hematological adverse events (AEs) were similar in both groups, although patients in the bortezomib group experienced more frequent peripheral sensory neuropathy (including 13% grade 3, with less than 1% grade 4). Overall, the occurrence of grade 3 AEs was higher in patients receiving bortezomib (53 vs 44%, p = 0.02), but the risk of grade 4 AEs was identical (28 vs 27%). These results confirm the superiority of MP plus bortezomib combination over MP therapy in treatment-naive patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation. C1 [Mateos, M. V.] Hosp Univ Salamanca, Salamanca, Spain. [Redman, K.; Richardson, P. G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dimopoulos, M. A.] Univ Athens, Sch Med, GR-11527 Athens, Greece. RP Spicka, I (reprint author), Charles Univ Prague, Fac Med 1, Dept Med 1, Dept Clin Haematol, U Nemocnice 2, Prague 12808 2, Czech Republic. EM spicka@cesnet.cz RI 2011, Secribsal/D-9425-2012 NR 33 TC 3 Z9 4 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 1750-743X EI 1750-7448 J9 IMMUNOTHERAPY-UK JI Immunotherapy PD SEP PY 2011 VL 3 IS 9 BP 1033 EP 1040 DI 10.2217/IMT.11.104 PG 8 WC Immunology SC Immunology GA 838LS UT WOS:000296293800006 PM 21913826 ER PT J AU Reiman, EM McKhann, GM Albert, MS Sperling, RA Petersen, RC Blacker, D AF Reiman, Eric M. McKhann, Guy M. Albert, Marilyn S. Sperling, Reisa A. Petersen, Ronald C. Blacker, Deborah TI Alzheimer's Disease: Implications of the Updated Diagnostic and Research Criteria SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material ID MILD COGNITIVE IMPAIRMENT; ASSOCIATION WORKGROUPS; NATIONAL INSTITUTE; RECOMMENDATIONS; GUIDELINES; DEMENTIA C1 [Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ USA. [McKhann, Guy M.; Albert, Marilyn S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Sperling, Reisa A.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Sperling, Reisa A.; Blacker, Deborah] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Petersen, Ronald C.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Reiman, EM (reprint author), Banner Alzheimers Inst, Phoenix, AZ USA. FU NIA NIH HHS [P50 AG005146, P30 AG019610] NR 16 TC 11 Z9 12 U1 0 U2 10 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2011 VL 72 IS 9 BP 1190 EP 1196 DI 10.4088/JCP.10087colc PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 828LO UT WOS:000295502700005 PM 21951985 ER PT J AU Gurrera, RJ Caroff, SN Cohen, A Carroll, BT DeRoos, F Francis, A Frucht, S Gupta, S Levenson, JL Mahmood, A Mann, SC Policastro, MA Rosebush, PI Rosenberg, H Sachdev, PS Trollor, JN Velamoor, VR Watson, CB Wilkinson, JR AF Gurrera, Ronald J. Caroff, Stanley N. Cohen, Abigail Carroll, Brendan T. DeRoos, Francis Francis, Andrew Frucht, Steven Gupta, Sanjay Levenson, James L. Mahmood, Ahsan Mann, Stephan C. Policastro, Michael A. Rosebush, Patricia I. Rosenberg, Henry Sachdev, Perminder S. Trollor, Julian N. Velamoor, Varadaraj R. Watson, Charles B. Wilkinson, Jayne R. TI An International Consensus Study of Neuroleptic Malignant Syndrome Diagnostic Criteria Using the Delphi Method SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID SYMPTOMS; SCALE AB Objective: The lack of generally accepted diagnostic criteria for neuroleptic malignant syndrome (NMS) impedes research and clinical management of patients receiving antipsychotic medications The purpose of this study was to develop NMS diagnostic criteria reflecting a broad consensus among clinical knowledge experts, represented by an international multispecialty physician panel. Participants: Eleven psychiatrists, 2 neurologists, 2 anesthesiologists, and 2 emergency medicine specialists participated in a formal Delphi consensus procedure. Evidence: A core bibliography consisting of 12 prominent, current reviews of the NMS literature was identified by an objective, comprehensive electronic search strategy. Each panel member was given a copy of these references and asked to examine them before commencing the survey process. Consensus Process: After reviewing the core bibliography, panel members were asked to list any clinical signs or symptoms or diagnostic studies that they believed, on the basis of their knowledge and clinical experience, were useful in making a diagnosis of NMS. In subsequent survey rounds, panel members assigned priority points to these items, and items that failed to receive a minimum priority score were eliminated from the next round. Information about individual panel member responses was fed back to the group anonymously in the form of the group median or mean and the number of members who had ranked or scored each survey item. The a priori consensus endpoint was defined operationally as a change of 10% or less in the mean priority score for any individual item, and an average absolute value change of 5% or less across all items, between consecutive rounds. The survey was conducted from January 2009 through September 2009. Results: Consensus was reached on the fifth round regarding the following criteria: recent dopamine antagonist exposure, or dopamine agonist withdrawal; hyperthermia; rigidity; mental status alteration; creatine kinase elevation; sympathetic nervous system lability; tachycardia plus tachypnea; and a negative work-up for other causes. The panel also reached a consensus on the relative importance of these criteria and on the following critical values for quantitative criteria: hyperthermia, > 100.4 degrees F or > 38.0 degrees C on at least 2 occasions; creatine kinase elevation, at least 4 times the upper limit of normal; blood pressure elevation, >= 25% above baseline; blood pressure fluctuation, >= 20 mm Hg (diastolic) or >= 25 mm Hg (systolic) change within 24 hours; tachycardia, >= 25% above baseline; and tachypnea, >= 50% above baseline. Conclusions: These diagnostic criteria significantly advance the field because they represent the consensus of an international multispecialty expert panel, include critical values, provide guidance regarding the relative importance of individual elements, and are less influenced by particular theoretical biases than most previously published criteria. They require validation before being applied in clinical settings. J Clin Psychiatry 2011;72(9):1222-1228 (C) Copyright 2011 Physicians Postgraduate Press, Inc. C1 [Gurrera, Ronald J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Gurrera, Ronald J.] Vet Affairs VA Boston Healthcare Syst, Boston, MA USA. [Caroff, Stanley N.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Cohen, Abigail] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [DeRoos, Francis] Univ Penn, Sch Med, Dept Emergency Med, Philadelphia, PA 19104 USA. [Wilkinson, Jayne R.] Univ Penn, Sch Med, Dept Clin Neurol, Philadelphia, PA 19104 USA. [Caroff, Stanley N.; DeRoos, Francis; Wilkinson, Jayne R.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Carroll, Brendan T.] Ohio Univ, Coll Osteopath Med, Athens, OH 45701 USA. [Carroll, Brendan T.] Chillicothe VA Med Ctr, Chillicothe, OH USA. [Francis, Andrew] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. [Frucht, Steven] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Gupta, Sanjay] SUNY Syracuse, Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Gupta, Sanjay; Mahmood, Ahsan] SUNY Buffalo, Dept Psychiat, Buffalo, NY 14260 USA. [Levenson, James L.] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA 23284 USA. [Mahmood, Ahsan] Buffalo Psychiat Ctr, Buffalo, NY USA. [Mann, Stephan C.] Univ Louisville, Sch Med, Dept Psychiat & Behav Sci, Louisville, KY 40292 USA. [Mann, Stephan C.] Cent Montgomery Mental Hlth & Mental Retardat Ctr, Norristown, PA USA. [Policastro, Michael A.] Wright State Univ, Boonshoft Sch Med, Dept Emergency Med, Dayton, OH 45435 USA. [Policastro, Michael A.] Good Samaritan Hosp, Cincinnati, OH USA. [Rosebush, Patricia I.] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON, Canada. [Rosenberg, Henry] St Barnabas Hosp, Dept Med Educ, Livingston, NJ USA. [Rosenberg, Henry] St Barnabas Hosp, Dept Clin Res, Livingston, NJ USA. [Rosenberg, Henry] Malignant Hyperthermia Assoc US, Sherburne, NY USA. [Sachdev, Perminder S.; Trollor, Julian N.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Trollor, Julian N.] Univ New S Wales, Dept Dev Disabil Neuropsychiat, Sydney, NSW, Australia. [Sachdev, Perminder S.] Prince Wales Hosp, Inst Neuropsychiat, Randwick, NSW 2031, Australia. [Velamoor, Varadaraj R.] Univ Western Ontario, Dept Psychiat, Schulich Sch Med & Dent, London, ON N6A 3K7, Canada. [Watson, Charles B.] Yale New Haven Hlth Syst, Bridgeport Hosp, Dept Anesthesia, Bridgeport, CT USA. RP Gurrera, RJ (reprint author), Vet Affairs Boston Healthcare Syst, 940 Belmont St,116A, Brockton, MA 02301 USA. EM ronald.gurrera@va.gov RI Cohen, Abigail/K-9180-2013; OI Cohen, Abigail/0000-0002-7425-7218; Sachdev, Perminder/0000-0002-9595-3220; Trollor, Julian/0000-0002-7685-2977 FU Eli Lilly; GlaxoSmithKline; AstraZeneca; Pfizer; Takeda; Forest; Myriad; Ono; NMSIS; AstraZeneca Pharmaceuticals LP [48804]; National Center for Research Resources [UL1-RR024134]; VA Boston Healthcare System; American Academy of Child & Adolescent Psychiatry; Malignant Hyperthermia Association of the United States FX Dr Gurrera has served as a volunteer consultant for the Neuroleptic Malignant Syndrome Information Service (NMSIS) and is a member of the NMSIS Professional Advisory Council. Dr Caroff has served as a consultant for Eli Lilly and is a member of the NMSIS Professional Advisory Council. Dr Carroll has received speakers bureau honoraria from Eli Lilly and Pfizer and is an NMSIS hotline volunteer consultant. Dr Francis is a member of the NMSIS Professional Advisory Council. Dr Frucht has served as a consultant for UCB Pharma, Lundbeck, GE Healthcare, Gerson Lehrman Group, and Guidepoint Global and is a member of the NMSIS Professional Advisory Council. Dr Gupta has been a consultant for Eli Lilly; has received research support from Eli Lilly, GlaxoSmithKline, AstraZeneca, Pfizer, Takeda, Forest, Myriad, and Ono; has served on advisory panels for Eli Lilly and Pamlab; has received speakers bureau honoraria from Eli Lilly, GlaxoSmithKline, Novartis, Forest, Merck, and AstraZeneca; and is a member of the NMSIS Professional Advisory Council. Dr Levenson is a member of the NMSIS Professional Advisory Council. Dr Mann is an NMSIS hotline volunteer consultant. Dr Policastro has been an employee of Qualified Emergency Specialists, Cincinnati, Ohio; has been a consultant to the US Drug Enforcement Administration and Dyax Corporation; has received honoraria from the Malignant Hyperthermia Association of the United States and NMSIS; and has served as an advisory panel member for Dyax Corporation and the Malignant Hyperthermia Association of the United States. Drs Rosebush and Rosenberg are members of the NMSIS Professional Advisory Council. Drs Sachdev and Trollor are NMSIS International Partners. Dr Velamoor is a member of the NMSIS Professional Advisory Council. Dr Watson is an NMSIS hotline volunteer consultant. Drs Cohen, DeRoos, Mahmood, and Wilkinson report no financial relationships with any commercial interest. All expert panel members received a small honorarium from NMSIS for their participation.; This study received administrative support from NMSIS (www.nmsis.org) and received financial support from the Shah Educational Awareness Fund of NMSIS and from an independent educational grant (#48804) from AstraZeneca Pharmaceuticals LP to NMSIS. Dr. Cohen was supported by the Outcomes Measurement Methods Core of the Center for Translational Science Award, National Center for Research Resources grant number UL1-RR024134. This work was also supported by the resources of and the use of the facilities at the VA Boston Healthcare System.; The authors thank Jeffrey R. Strawn, MD, of the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio, for his assistance in assembling the core bibliography for the expert panel and Marilyn Green Larach, MD, FAAP, who is affiliated with the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States, Pittsburgh, Pennsylvania, for her helpful comments about the Delphi consensus process. Dr Strawn has received research support from the American Academy of Child & Adolescent Psychiatry and Eli Lilly and has received honoraria from Qualcom Medical Media. Dr Larach has received a consulting fee from the Malignant Hyperthermia Association of the United States to develop an ambulatory surgery center transfer-of-care document for malignant hyperthermia patients and has been reimbursed by the Association for travel expenses to attend scientific conferences. NR 29 TC 38 Z9 40 U1 0 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2011 VL 72 IS 9 BP 1222 EP 1228 DI 10.4088/JCP.10m06438 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 828LO UT WOS:000295502700009 PM 21733489 ER PT J AU Kontos, N AF Kontos, Nicholas TI The Rise and Fall of the Biopsychosocial Model: Reconciling Art and Science in Psychiatry SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Book Review C1 [Kontos, Nicholas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Kontos, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. EM nkontos@partners.org NR 1 TC 0 Z9 0 U1 1 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD SEP PY 2011 VL 72 IS 9 BP 1287 EP 1288 DI 10.4088/JCP.11bk07158 PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 828LO UT WOS:000295502700024 ER PT J AU Denisenko, O Lin, BY Bagby, S AF Denisenko, Oleg Lin, Baoyu Bagby, Susan TI Maternal Malnutrition Upregulates Expression and Alters Splicing of Angiotensin II Receptor Gene, AT1R, in Prenatal and Neonatal Kidneys SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [Denisenko, Oleg] Univ Washington, Seattle, WA 98195 USA. [Bagby, Susan] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S25 EP S25 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500078 ER PT J AU DuPriest, EA Kupfer, P Lin, B Sekiguchi, K Morgan, TK Saunders, KE Chatkupt, TT Purnell, JQ Bagby, SP AF DuPriest, E. A. Kupfer, P. Lin, B. Sekiguchi, K. Morgan, T. K. Saunders, K. E. Chatkupt, T. T. Purnell, J. Q. Bagby, S. P. TI Prevention of Accelerated Growth in Nutritionally Programmed Offspring Does Not Ameliorate Adipose Tissue Dysfunction SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [DuPriest, E. A.; Kupfer, P.; Lin, B.; Sekiguchi, K.; Morgan, T. K.; Saunders, K. E.; Chatkupt, T. T.; Purnell, J. Q.; Bagby, S. P.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [DuPriest, E. A.; Kupfer, P.; Lin, B.; Sekiguchi, K.; Bagby, S. P.] Portland VA Med Ctr, Portland, OR USA. [DuPriest, E. A.] Warner Pacific Coll, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S60 EP S60 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500198 ER PT J AU DuPriest, EA Kupfer, P Lin, BY Sekiguchi, K Morgan, TK Saunders, KE Chatkupt, TT Purnell, JQ Bagby, SP AF DuPriest, Elizabeth A. Kupfer, Philipp Lin, Baoyu Sekiguchi, Kaiu Morgan, Terry K. Saunders, Kim E. Chatkupt, Tom T. Purnell, Jonathan Q. Bagby, Susan P. TI Altered Adipocyte Structure and Function in Nutritionally Programmed Microswine Offspring SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [DuPriest, Elizabeth A.; Kupfer, Philipp; Lin, Baoyu; Sekiguchi, Kaiu; Morgan, Terry K.; Saunders, Kim E.; Chatkupt, Tom T.; Purnell, Jonathan Q.; Bagby, Susan P.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [DuPriest, Elizabeth A.; Kupfer, Philipp; Lin, Baoyu; Sekiguchi, Kaiu; Bagby, Susan P.] Portland VA Med Ctr, Portland, OR USA. [DuPriest, Elizabeth A.] Warner Pacific Coll, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S54 EP S54 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500179 ER PT J AU Isganaitis, E Radford, E Lytras, A Chen, M Schroeder, J Sharma, A Ferguson-Smith, A Patti, ME AF Isganaitis, Elvira Radford, Elizabeth Lytras, Aristides Chen, Michael Schroeder, Joshua Sharma, Aparna Ferguson-Smith, Anne Patti, Mary-Elizabeth TI Paternal History of Exposure to Prenatal Undernutrition Alters Placental Expression of Nutrient Transporters and mTor Targets in F2 Offspring: Potential Contribution to Intergenerational Transmission of Diabetes and Obesity Risk SO JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE LA English DT Meeting Abstract C1 [Isganaitis, Elvira; Lytras, Aristides; Chen, Michael; Schroeder, Joshua; Sharma, Aparna] Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. [Radford, Elizabeth; Ferguson-Smith, Anne; Patti, Mary-Elizabeth] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 1TN, England. RI Ferguson-Smith, Anne/G-7534-2011 NR 0 TC 1 Z9 1 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2040-1744 J9 J DEV ORIG HLTH DIS JI J. Dev. Orig. Health Dis. PD SEP PY 2011 VL 2 SU 1 BP S4 EP S4 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837CK UT WOS:000296168500009 ER PT J AU Kirchner, JE Farmer, MS Shue, VM Blevins, D Sullivan, G AF Kirchner, Joann E. Farmer, Mary Sue Shue, Valorie M. Blevins, Dean Sullivan, Greer TI Partnering With Communities to Address the Mental Health Needs of Rural Veterans SO JOURNAL OF RURAL HEALTH LA English DT Article DE clergy; criminal justice; education; mental health; rural veterans ID POSTTRAUMATIC-STRESS-DISORDER; COMORBIDITY SURVEY REPLICATION; UNITED-STATES; URBAN DIFFERENCES; SERVICES UTILIZATION; DEPRESSION; CARE; PREVALENCE; AFGHANISTAN; OUTCOMES AB Purpose: Many veterans who face mental illness and live in rural areas never obtain the mental health care they need. To address these needs, it is important to reach out to community stakeholders who are likely to have frequent interactions with veterans, particularly those returning from Operations Enduring and Iraqi Freedom (OEF/OIF). Methods: Three community stakeholder groups-clergy, postsecondary educators, and criminal justice personnel-are of particular importance for OEF/OIF veterans living in rural areas and may be more likely to come into contact with rural veterans struggling with mental illness or substance abuse than the formal health care system. This article briefly describes the conceptualization, development, initial implementation, and early evaluation of a Veterans Affairs (VA) medical center-based program designed to improve engagement in, and access to, mental health care for veterans returning to rural areas. Findings: One year since initial funding, 90 stakeholders have attended formal training workshops (criminal justice personnel = 36; educators = 31; clergy = 23). Two training formats (a 2-hour workshop and an intensive 2.5-day workshop) have been developed and provided to clergy in 1 rural county with another county scheduled for training. A veteran outreach initiative, which has received 32 referrals for various student services, has been established on 4 rural college campuses. A Veterans Treatment Court also has been established with 16 referrals for eligibility assessments. Conclusions: While this pilot program is in the early stages of evaluation, its success to date has encouraged program and VA clinical leadership to expand beyond the original sites. C1 [Kirchner, Joann E.] US Dept Vet Affairs, Mental Hlth Qual Enhancement Res Initiat, N Little Rock, AR USA. [Farmer, Mary Sue; Blevins, Dean; Sullivan, Greer] US Dept Vet Affairs, Mental Illness Res Educ Clin Ctr, N Little Rock, AR USA. [Kirchner, Joann E.; Shue, Valorie M.; Blevins, Dean; Sullivan, Greer] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Kirchner, Joann E.; Blevins, Dean; Sullivan, Greer] US Dept Vet Affairs, Hlth Serv Res & Dev Ctr Mental Healthcare & Outco, N Little Rock, AR USA. RP Kirchner, JE (reprint author), VA HSR & Ctr Mental Healthcare & Outcomes Res, 2200 Ft Roots Dr,Bldg 58, N Little Rock, AR 72114 USA. EM kirchnerjoanne@uams.edu FU United States Department of Veterans Affairs Office of Rural Health; South Central Mental Illness Research Education Clinical Center FX We would like to thank the clinicians, OEF-OIF Veterans, and clinical teams who made this work possible. Specifically, we would like to acknowledge Michael T. Lambert, LCSW; Bridgett Larkin, MBA (OEF-IOF Veteran); William M. Moore, PhD; Jamie Mucciarelli, MA (OEF/OIF Veteran); Vince Roca, PhD; Steve Sullivan, M.Div, Th.M; Elizabeth White, LMSW; and Linda Worley, MD. This project was supported by the United States Department of Veterans Affairs Office of Rural Health and South Central Mental Illness Research Education Clinical Center. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. For further information contact: JoAnn E. Kirchner, MD, VA HSR & D Center for Mental Healthcare and Outcomes Research, 2200 Fort Roots Drive, Bldg 58, North Little Rock, AR 72114; e-mail kirchnerjoanne@uams.edu. NR 70 TC 7 Z9 7 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD FAL PY 2011 VL 27 IS 4 BP 416 EP 424 DI 10.1111/j.1748-0361.2011.00362.x PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 833HU UT WOS:000295875200011 PM 21967386 ER PT J AU Bauman, WA Emmons, RR Cirnigliaro, CM Kirshblum, SC Spungen, AM AF A. Bauman, William Emmons, Racine R. Cirnigliaro, Christopher M. Kirshblum, Steven C. Spungen, Ann M. TI An effective oral vitamin D replacement therapy in persons with spinal cord injury SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Vitamin D deficiency; Nutritional supplementation; Calcium; Vitamin D; Osteoporosis; Spinal cord injuries; Bone loss; Cholecalciferol; Paraplegia; Tetraplegia; Veterans ID BONE-MINERAL DENSITY; D DEFICIENCY; COLORECTAL-CANCER; RISK; DISEASE; MORTALITY; CALCIUM; HEALTH; ADULTS; INDIVIDUALS AB Background/objective: Vitamin D deficiency is prevalent in chronic spinal cord injury (SCI). A 3-month course of oral vitamin D-3 to 'normalize' serum vitamin D levels was investigated. Design: Prospective drug-intervention study. Setting: VA Medical Center; private rehabilitation facility. Methods: Seven individuals with chronic SCI and vitamin D deficiency completed 3 months of oral vitamin D-3 (i.e. cholecalciferol) supplementation. At screening, baseline, and months 1 and 3, blood was collected for serum calcium, 25 hydroxyvitamin D [25(OH) D], intact parathyroid hormone (iPTH), and N-telopeptide (NTx); 24-hour urine for calcium, creatinine, and NTx was performed. Oral vitamin D-3 (2000 IU daily) and elemental calcium (1.3 g daily) were prescribed for 90 days. The results are expressed as mean +/- standard deviation (SD). Analysis of variance with a Fisher's post-hoc analysis was performed to test for differences between study visits. Subjects were classified as deficient (<20 ng/ml), relatively deficient (20-30 ng/ml), or not deficient (>30 ng/ml) in 25(OH) D. Results: Serum 25(OH) D levels were greater at months 1 and 3 than at baseline (26 +/- 6 and 48 +/- 17 vs. 14 +/- 2 ng/ml; P = 0.005). Six of seven subjects were no longer deficient [25(OH) D >30 ng/ml] by month 3. Serum iPTH levels were significantly decreased at month 1 and month 3; serum NTx levels were significantly lower at month 3 than at baseline. Serum and urinary calcium levels remained within the normal range. Conclusion: A daily prescription of 2000 IU of oral vitamin D-3 for 3 months safely raised serum 25(OH) D levels into the normal range in persons with chronic SCI on calcium supplementation. C1 [A. Bauman, William; Emmons, Racine R.; Cirnigliaro, Christopher M.; Spungen, Ann M.] James J Peters VA Med Ctr, Dept Vet Affairs, Rehabil Res & Dev Ctr Excellence Med Consequences, Bronx, NY 10468 USA. [A. Bauman, William; Spungen, Ann M.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [A. Bauman, William; Spungen, Ann M.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Emmons, Racine R.] Columbia Univ Teachers Coll, New York, NY 10027 USA. [Kirshblum, Steven C.] Kessler Inst Rehabil, W Orange, NJ USA. [Kirshblum, Steven C.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Phys Med & Rehabil, Newark, NJ 07103 USA. RP Bauman, WA (reprint author), James J Peters VA Med Ctr, Dept Vet Affairs, Rehabil Res & Dev Ctr Excellence Med Consequences, Room 7A-13,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM william.bauman@va.gov NR 43 TC 5 Z9 6 U1 1 U2 12 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 EI 2045-7723 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2011 VL 34 IS 5 BP 455 EP 460 DI 10.1179/2045772311Y.0000000032 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 835OS UT WOS:000296046300003 PM 22118252 ER PT J AU Stroud, MW Bombardier, CH Dyer, JR Rimmele, CT Esselman, PC AF Stroud, Michael W. Bombardier, Charles H. Dyer, Joshua R. Rimmele, Carl T. Esselman, Peter C. TI Preinjury alcohol and drug use among persons with spinal cord injury: Implications for rehabilitation SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Alcohol; Drug; Substance-related disorders; Spinal cord injuries; Rehabilitation; Paraplegia; Tetraplegia; Toxicology screening ID TRAUMATIC BRAIN-INJURY; SUBSTANCE-ABUSE; CHANGE QUESTIONNAIRE; USE DISORDERS; READINESS; RISK; INTERVENTIONS; COMPLICATIONS; MAGNITUDE; DRINKERS AB Context/objective: To describe preinjury alcohol and drug use and opportunities for secondary prevention among persons with recent spinal cord injury (SCI). Design: Survey. Setting: Acute inpatient rehabilitation program. Participants: Participants were 118 (84.8%) of 139 consecutive admissions who met inclusion criteria and were screened for preinjury alcohol and drug use. Interventions: None. Outcome measures: Alcohol and drug use, toxicology results, alcohol problems, readiness to change, and treatment preferences. Results: Participants were on average 37 years old, 84% were men, and 85% were white. Fifty-one percent of the sample was considered 'at-risk' drinkers. Significant lifetime alcohol-related problems were reported by 38% of the total sample. Thirty-three percent reported recent illicit drug use and 44% of the 82 cases with toxicology results were positive for illicit drugs. Seventy-one percent of at-risk drinkers reported either considering changes in alcohol use or already taking action. Forty-one percent reported interest in trying substance abuse treatment or Alcoholics Anonymous (AA). Motivation to change alcohol use was significantly and positively associated with self-reported indicators of alcohol problem severity. Conclusion: Preinjury alcohol and drug abuse are common among persons with recent SCI. Substance abuse screening is feasible and detects not only salient clinical problems but also significant motivation to change and interest in AA or treatment, all of which represent an important window of opportunity for appropriate brief interventions and referrals. In contrast with the idea that alcoholism is a 'disease of denial', the majority of at-risk drinkers with new onset SCI indicate they are considering making changes. C1 [Bombardier, Charles H.] Univ Washington, Harborview Med Ctr, Dept Rehabil Med, Sch Med, Seattle, WA 98104 USA. [Stroud, Michael W.] Vet Adm Med Ctr, Denver, CO USA. [Rimmele, Carl T.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Rimmele, Carl T.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Bombardier, CH (reprint author), Univ Washington, Harborview Med Ctr, Dept Rehabil Med, Sch Med, Box 359612,325 9th Ave, Seattle, WA 98104 USA. EM chb@uw.edu FU Northwest Regional Spinal Cord Injury System; National Institute on Disability and Rehabilitation Research [H133N50025, H133N060033] FX This research was supported by the Northwest Regional Spinal Cord Injury System grant and funded by the National Institute on Disability and Rehabilitation Research (H133N50025; H133N060033). The contents of this paper are solely the responsibility of the authors and do not represent the official views of the granting agency. No commercial party having a direct financial interest in the results of the research has or will confer a benefit upon the authors or upon any organization with which the authors are associated. NR 45 TC 3 Z9 4 U1 2 U2 5 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2011 VL 34 IS 5 BP 461 EP 472 DI 10.1179/2045772311Y.0000000033 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 835OS UT WOS:000296046300004 PM 22118253 ER PT J AU Turner, PV Brabb, T Pekow, C Vasbinder, MA AF Turner, Patricia V. Brabb, Thea Pekow, Cynthia Vasbinder, Mary Ann TI Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Editorial Material ID HYDRODYNAMIC GENE DELIVERY; INBRED MOUSE STRAINS; DRUG-DELIVERY; INTRAPERITONEAL INJECTIONS; INTRAMUSCULAR INJECTION; SELF-MUTILATION; GASTROINTESTINAL ABSORPTION; INTRAARTERIAL INJECTION; PARENTERAL-NUTRITION; EPIDURAL ANALGESIA AB Administration of substances to laboratory animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. For all species, many different routes are available for administration of substances. The research team and IACUC members should be aware of reasons for selecting specific routes and of training and competency necessary for personnel to use these routes effectively. Once a route is selected, issues such as volume of administration, site of delivery, pH of the substance, and other factors must be considered to refine the technique. Inadequate training or inattention to detail during this aspect of a study may result in unintentional adverse effects on experimental animals and confounded results. C1 [Turner, Patricia V.] Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. [Brabb, Thea] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98195 USA. [Pekow, Cynthia] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Vasbinder, Mary Ann] GlaxoSmithKline, Platform Technol & Sci Qual & Risk Management, Res Triangle Pk, NC USA. RP Turner, PV (reprint author), Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. EM pvturner@uoguelph.ca NR 145 TC 86 Z9 89 U1 10 U2 41 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 600 EP 613 PG 14 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000001 PM 22330705 ER PT J AU Turner, PV Pekow, C Vasbinder, MA Brabb, T AF Turner, Patricia V. Pekow, Cynthia Vasbinder, Mary Ann Brabb, Thea TI Administration of Substances to Laboratory Animals: Equipment Considerations, Vehicle Selection, and Solute Preparation SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Editorial Material ID VASCULAR ACCESS PORTS; BIOMEDICAL-RESEARCH; RHESUS-MONKEYS; RESTRAINT; CATHETER; PATENCY; RAT; DIMETHYLSULFOXIDE; CYCLODEXTRIN; FORMULATIONS AB Administration of substances to laboratory animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. The equipment selected to deliver substances to animals depends on the length of the study and the nature of the material being administered. This selection provides a significant opportunity for refining animal treatment. Similarly, when substances are administered as solutions or suspensions, attention should be given to selection of vehicles and methods used for preparing the solutions and suspensions. The research team, veterinarian, technical personnel, and IACUC members should be aware of reasons underlying selection of equipment for substance delivery and should consider carefully how substances will be prepared and stored prior to administration to animals. Failure to consider these factors during experimental planning may result in unintentional adverse effects on experimental animals and confounded results. C1 [Turner, Patricia V.] Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. [Pekow, Cynthia] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Brabb, Thea] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98195 USA. [Vasbinder, Mary Ann] GlaxoSmithKline, Platform Technol & Sci Qual & Risk Management, Res Triangle Pk, NC USA. RP Turner, PV (reprint author), Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. EM pvturner@uoguelph.ca NR 89 TC 32 Z9 33 U1 3 U2 15 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 614 EP 627 PG 14 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000002 PM 22330706 ER PT J AU Huang, P Samuel, R Chen, Y Fukumura, D Jain, RK Duda, DG AF Huang, P. Samuel, R. Chen, Y. Fukumura, D. Jain, R. K. Duda, D. G. TI The Development of Diethylnitrosamine-Induced Carcinogenesis in Mouse Models is Gender and Genetic Strain Dependent SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Huang, P.; Samuel, R.; Chen, Y.; Fukumura, D.; Jain, R. K.; Duda, D. G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 743 EP 744 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000112 ER PT J AU Mikkola, A Debrace, MO Brown, D AF Mikkola, A. Ocampo Debrace, M. Brown, D. TI Affordable Laboratory Animal Clinical Pathology for Emerging Economies SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Mikkola, A.; Brown, D.] Massachusetts Gen Hosp, Ctr Comparat Med, Charlestown, MA USA. [Ocampo Debrace, M.] Univ Republ Oriental Uruguay, Montevideo, Uruguay. [Brown, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 759 EP 759 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000180 ER PT J AU Hall, C Gibbons, C Jarrell, DM AF Hall, C. Gibbons, C. Jarrell, D. M. TI Improving Onboarding of New Husbandry Staff via Lean Management Principles SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Hall, C.; Gibbons, C.; Jarrell, D. M.] Massachusetts Gen Hosp, Ctr Comparat Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 762 EP 762 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000195 ER PT J AU Hankenson, FC Cooper, DR Weigler, BJ AF Hankenson, F. C. Cooper, D. R. Weigler, B. J. TI A National Assessment of Occupational Health Programs for Animal Care and Research Personnel in the United States SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Hankenson, F. C.] Univ Penn, Philadelphia, PA 19104 USA. [Cooper, D. R.] Massachusetts Gen Hosp, Ctr Comparat Med, Charlestown, MA USA. [Weigler, B. J.] Washington Natl Primate Res Ctr, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 767 EP 767 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000217 ER PT J AU Swanson, LK Beckman, WJ Dehlinger, K AF Swanson, L. K. Beckman, W. J. Dehlinger, K. TI Characterization of Prairie Vole (Microtus ochrogaster) Pup Development SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Swanson, L. K.; Beckman, W. J.; Dehlinger, K.] Portland VA Med Ctr, Vet Med Unit, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 776 EP 776 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000259 ER PT J AU Campbell, S AF Campbell, S. TI Standardizing Nonhuman Primate Dietary Instructions with Visual Cues SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Campbell, S.] Massachusetts Gen Hosp, Ctr Comparat Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2011 VL 50 IS 5 BP 782 EP 783 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 835XJ UT WOS:000296070000290 ER PT J AU Bonn-Miller, MO Vujanovic, AA Drescher, KD AF Bonn-Miller, Marcel O. Vujanovic, Anka A. Drescher, Kent D. TI Cannabis Use Among Military Veterans After Residential Treatment for Posttraumatic Stress Disorder SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE posttraumatic stress disorder; trauma; cannabis; marijuana; relapse; treatment ID SELF-MEDICATION HYPOTHESIS; ADMINISTERED PTSD SCALE; USE COPING MOTIVES; SUBSTANCE USE; PSYCHOMETRIC PROPERTIES; DRUG-USE; ABUSE; DEPENDENCE; MARIJUANA; SEVERITY AB The present investigation prospectively evaluated whether treatment changes in PTSD symptom severity, among military Veterans in residential PTSD treatment, were related to cannabis use 4 months after discharge from residential rehabilitation. The sample was comprised of 432 male military Veteran patients (M(age) = 51.06 years, SD = 4.17), who had a primary diagnosis of PTSD and were admitted to a VA residential rehabilitation program for PTSD. Results demonstrated that lower levels of change in PCL-M scores between treatment intake and discharge were significantly predictive of greater frequency of cannabis use at 4-month follow-up (p < .05), even after accounting for the effects of length of treatment stay and frequency of cannabis use during the 2 months before treatment intake. Furthermore, post hoc analyses revealed that less change in PTSD avoidance/numbing and hyperarousal symptom severity during treatment was significantly predictive of a greater frequency of cannabis use at 4-month follow-up, after controlling for relevant covariates. Notably, these effects were specific to cannabis and were not found for the other substances examined among this sample, including alcohol and opiates. Implications of the findings are discussed with regard to the extant literature and future directions. C1 [Bonn-Miller, Marcel O.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk Div 152, Menlo Pk, CA 94025 USA. [Drescher, Kent D.] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA 94025 USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Vujanovic, Anka A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. RP Bonn-Miller, MO (reprint author), VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk Div 152, 795 Willow Rd, Menlo Pk, CA 94025 USA. EM Marcel.Bonn-Miller@va.gov RI Schueter, nicos/A-3625-2014 NR 40 TC 32 Z9 32 U1 4 U2 15 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD SEP PY 2011 VL 25 IS 3 BP 485 EP 491 DI 10.1037/a0021945 PG 7 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 827CP UT WOS:000295404100011 PM 21261407 ER PT J AU Cougle, JR Bonn-Miller, MO Vujanovic, AA Zvolensky, MJ Hawkins, KA AF Cougle, Jesse R. Bonn-Miller, Marcel O. Vujanovic, Anka A. Zvolensky, Michael J. Hawkins, Kirsten A. TI Posttraumatic Stress Disorder and Cannabis Use in a Nationally Representative Sample SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE cannabis; marijuana; posttraumatic stress disorder; trauma; anxiety ID USE COPING MOTIVES; SUBSTANCE-ABUSE; COMORBIDITY SURVEY; CAUSAL PATHWAYS; DEPENDENCE; PTSD; VETERANS; RATES AB The present study examined the relations between posttraumatic stress disorder (PTSD) and cannabis use in a large representative survey of adults (N = 5,672) from the United States (Kessler et al., 2004). After adjusting for sociodemographic variables (i.e., age, marital status, ethnicity, education, income, and sex), alcohol use disorders, and nicotine dependence, lifetime and current (past year) PTSD diagnoses were associated with increased odds of lifetime history of cannabis use as well as past year daily cannabis use. Lifetime, but not current, PTSD diagnosis also was uniquely associated with increased risk for any past year cannabis use. Additional analyses revealed that the relations between PTSD (lifetime and current) and lifetime cannabis use remained statistically significant when adjusting for co-occurring anxiety and mood disorders and trauma type frequency. Overall, these findings add to the emerging literature demonstrating a possibly important relationship between PTSD and cannabis use. C1 [Cougle, Jesse R.; Hawkins, Kirsten A.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Bonn-Miller, Marcel O.] Natl Ctr PTSD, Palo Alto, CA USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Palo Alto, CA USA. [Vujanovic, Anka A.] VA Boston Healthcare, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Zvolensky, Michael J.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. RP Cougle, JR (reprint author), Florida State Univ, Dept Psychol, POB 3064301, Tallahassee, FL 32306 USA. EM cougle@psy.fsu.edu FU NIMH NIH HHS [1 R01 MH076629-01] NR 20 TC 46 Z9 47 U1 2 U2 8 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD SEP PY 2011 VL 25 IS 3 BP 554 EP 558 DI 10.1037/a0023076 PG 5 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 827CP UT WOS:000295404100019 PM 21480682 ER PT J AU Sales, AE Lapham, GG Squires, J Hutchinson, A Almenoff, P Sharp, ND Lowy, E Li, YF AF Sales, Anne E. Lapham, Gwendolyn G. Squires, Janet Hutchinson, Alison Almenoff, Peter Sharp, Nancy D. Lowy, Elliott Li, Yu-Fang TI Organizational Factors Associated With Decreased Mortality Among Veterans Affairs Patients With an ICU Stay SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Article DE Electronic record; Hospital organization; In-hospital mortality; Intensive care ID INTENSIVE-CARE UNITS; ILL HOSPITALIZED ADULTS; OUTCOMES; QUALITY; IMPACT AB In-hospital mortality rates associated with an ICU stay are high and vary widely among units. This variation may be related to organizational factors such as staffing patterns, ICU structure, and care processes. We aimed to identify organizational factors associated with variation in in-hospital mortality for patients with an ICU stay. This was a retrospective observational cross-sectional study using administrative data from 34 093 patients from 171 ICUs in 119 Veterans Health Administration hospitals. Staffing and patient data came from Veterans Health Administration national databases. ICU characteristics came from a survey in 2004 of ICUs within the Veterans Health Administration. We conducted multilevel multivariable estimation with patient-, unit-, and hospital-level data. The primary outcome was in-hospital mortality. Of 34 093 patients, 2141 (6.3%) died in the hospital. At the patient level, risk of complications and having a medical diagnosis were significantly associated with a higher risk of mortality. At the unit level, having an interface with the electronic medical record was significantly associated with a lower risk of mortality. The finding that electronic medical records integrated with ICU information systems are associated with lower in-hospital mortality adds support to existing evidence on organizational characteristics associated with in-hospital mortality among ICU patients. C1 [Sales, Anne E.; Squires, Janet; Hutchinson, Alison] Univ Alberta, Fac Nursing, Edmonton, AB T6G 2T4, Canada. [Lapham, Gwendolyn G.; Sharp, Nancy D.; Lowy, Elliott; Li, Yu-Fang] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Almenoff, Peter] VA Cent Off, Washington, DC USA. RP Sales, AE (reprint author), Univ Alberta, Fac Nursing, Edmonton, AB T6G 2T4, Canada. EM anne.sales@ualberta.ca RI Sales, Anne/D-9678-2012; OI Sales, Anne/0000-0001-9360-3334 FU Office of Research and Development, Health Services R&D Service, Department of Veterans Affairs [IIR 01-160] FX This study was supported by the Office of Research and Development, Health Services R&D Service, Department of Veterans Affairs (project number IIR 01-160). NR 18 TC 5 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1538-2931 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD SEP PY 2011 VL 29 IS 9 BP 496 EP 501 DI 10.1097/NCN.0b013e3182148c47 PG 6 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA 833IR UT WOS:000295878200004 PM 21983432 ER PT J AU Numis, AL Yellen, MB Chu-Shore, CJ Pfeifer, HH Thiele, EA AF Numis, Adam L. Yellen, Margaret B. Chu-Shore, Catherine J. Pfeifer, Heidi H. Thiele, Elizabeth A. TI The relationship of ketosis and growth to the efficacy of the ketogenic diet in infantile spasms SO EPILEPSY RESEARCH LA English DT Article DE Ketogenic diet; West syndrome; Refractory epilepsy; Ketone bodies; Anthropometry ID CHILDREN; EXPERIENCE; EPILEPSY AB The ketogenic diet (KO) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, 46% of twenty-six patients had a greater than 90% reduction in IS. No significant relationships between reduction in IS and serum p-hydroxybutyrate, or glucose levels were identified. Also, the KD had not significantly altered patient's growth parameters. Thus, in corroborating with prior studies, we demonstrate the KD is a well-tolerated and efficacious treatment of IS. (C) 2011 Elsevier B.V. All rights reserved. C1 [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Pediat Epilepsy Program, Dept Neurol, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Pediat Epilepsy Program, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Carol and James Herscot Center for Tuberous Sclerosis Complex FX This study was supported by the Carol and James Herscot Center for Tuberous Sclerosis Complex. NR 12 TC 18 Z9 22 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD SEP PY 2011 VL 96 IS 1-2 BP 172 EP 175 DI 10.1016/j.eplepsyres.2011.05.012 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 831CQ UT WOS:000295706700023 PM 21700429 ER PT J AU Blanke, C Rankin, C Benjamin, RS Raymond, AK Heinrich, MC Fletcher, CDM Crowley, J Borden, EC Demetri, GD Baker, LH AF Blanke, C. Rankin, C. Benjamin, R. S. Raymond, A. K. Heinrich, M. C. Fletcher, C. D. M. Crowley, J. Borden, E. C. Demetri, G. D. Baker, L. H. TI Long-term Survival on S0033-a Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate at Two Dose Levels in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumours (GISTs) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Blanke, C.] BC Canc Agcy, Med Oncol, Vancouver, BC, Canada. [Rankin, C.; Crowley, J.] SW Oncol Grp, Seattle, WA USA. [Benjamin, R. S.; Raymond, A. K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Heinrich, M. C.] OHSU, Portland, OR USA. [Fletcher, C. D. M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Borden, E. C.] Cleveland Clin, Cleveland, OH 44106 USA. [Demetri, G. D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baker, L. H.] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S664 EP S664 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802343 ER PT J AU Bruno, R Jonsson, F Zaki, M Jacques, C Richardson, P Rajkumar, VS Claret, L AF Bruno, R. Jonsson, F. Zaki, M. Jacques, C. Richardson, P. Rajkumar, V. S. Claret, L. TI Simulation of Clinical Endpoints (Survival, PFS) in Patients With Refractory Multiple Myeloma Treated With Pomalidomide Based on Interim Week 8 M-protein Response SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Bruno, R.; Claret, L.] Consulting Serv, Marseille, France. [Jonsson, F.] Consulting Serv, Stockholm, Sweden. [Zaki, M.; Jacques, C.] Celgene, Clin Res & Dev, Summit, NJ USA. [Richardson, P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Rajkumar, V. S.] Mayo Clin, Dept Internal Med, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S647 EP S647 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802287 ER PT J AU Cella, D Bushmakin, AG Cappelleri, JC Charbonneau, C Sandin, R Negriers, S Figlin, RA Michaelson, MD Davis, MP Motzer, RJ AF Cella, D. Bushmakin, A. G. Cappelleri, J. C. Charbonneau, C. Sandin, R. Negriers, S. Figlin, R. A. Michaelson, M. D. Davis, M. P. Motzer, R. J. TI Comparison of Health-related Quality of Life (HRQoL) in Patients Reporting the Same Adverse Event (AE) Fatigue on Different Treatments SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Cella, D.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Bushmakin, A. G.; Cappelleri, J. C.] Pfizer Oncol, Global Res & Dev, New London, CT USA. [Charbonneau, C.] Pfizer Oncol, Global Outcomes Res, New York, NY USA. [Sandin, R.] Pfizer Oncol, Global Hlth Econ & Outcomes Res, Sollentuna, Sweden. [Negriers, S.] Ctr Leon Berard, F-69373 Lyon, France. [Figlin, R. A.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Michaelson, M. D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Davis, M. P.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S233 EP S233 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800803 ER PT J AU Davis, MP Goldstein, D George, S Casali, PG Li, S Perkins, J Demetri, GD AF Davis, M. P. Goldstein, D. George, S. Casali, P. G. Li, S. Perkins, J. Demetri, G. D. TI Asthenia and Fatigue as Predictors of Sunitinib Efficacy In Gastrointestinal Stromal Tumour (GIST) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Davis, M. P.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [Goldstein, D.] Prince Wales Hosp, Dept Med Oncol, Randwick, NSW 2031, Australia. [George, S.; Demetri, G. D.] Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Boston, MA USA. [Casali, P. G.] Ist Nazl Tumori, Dept Canc Med, I-20133 Milan, Italy. [Li, S.] Pfizer Oncol, Clin Stat, Shanghai, Peoples R China. [Perkins, J.] Pfizer Oncol, Oncol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S135 EP S136 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800477 ER PT J AU Donskov, F von Mehren, M Carus, A George, S Casali, PG Li, S Perkins, J Demetri, GD AF Donskov, F. von Mehren, M. Carus, A. George, S. Casali, P. G. Li, S. Perkins, J. Demetri, G. D. TI Neutropenia as a Biomarker of Sunitinib Efficacy in Patients (Pts) With Gastrointestinal Stromal Tumour (GIST) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Donskov, F.; Carus, A.] Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. [von Mehren, M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [George, S.; Demetri, G. D.] Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Boston, MA USA. [Casali, P. G.] Ist Nazl Tumori, Dept Canc Med, I-20133 Milan, Italy. [Li, S.] Pfizer Oncol, Clin Stat, Shanghai, Peoples R China. [Perkins, J.] Pfizer Oncol, Oncol, New York, NY USA. NR 0 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S135 EP S135 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800475 ER PT J AU Flaherty, K AF Flaherty, K. TI Melanoma Therapy - Realising the Potential In Targeted Therapy SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Flaherty, K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S31 EP S32 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800109 ER PT J AU Gamez, C Flamen, P Holmes, E Robles, J Gebhart, G Di Cosimo, S Eidtmann, H Piccart-Gebhart, M Baselga, J De Azambuja, E AF Gamez, C. Flamen, P. Holmes, E. Robles, J. Gebhart, G. Di Cosimo, S. Eidtmann, H. Piccart-Gebhart, M. Baselga, J. De Azambuja, E. TI FDG-PET/CT for Early Prediction of Response to Neoadjuvant Lapatinib, Trastuzumab, and Their Combination in HER2-positive Breast Cancer Patients: the Neo-ALTTO Study Results SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Gamez, C.; Robles, J.] Univ Hosp Bellvitge, PET Unit IDI IDIBELL, Barcelona, Spain. [Flamen, P.] Univ Libre Bruxelles, Inst Jules Bordet, Dept Nucl Med, Brussels, Belgium. [Holmes, E.] Frontier Sci, Inverness, Scotland. [Di Cosimo, S.] Vail dHebron Univ Hosp, Breast Canc Ctr, Barcelona, Spain. [Di Cosimo, S.] SOLTI, Med Oncol Serv, Barcelona, Spain. [Eidtmann, H.] Univ Hosp Kiel, Univ Klinikum Schleswig Holstein, Dept Gynecol & Obstet, Kiel, Germany. [Piccart-Gebhart, M.; De Azambuja, E.] Univ Libre Bruxelles, Dept Med, Inst Jules Bordet, Brussels, Belgium. [Baselga, J.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S333 EP S334 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752801181 ER PT J AU Johnson, BE Kris, MG Kwiatkowski, DJ Wistuba, II Engelman, JA Pao, W Rudin, CM Berry, L Minna, JD Bunn, PA AF Johnson, B. E. Kris, M. G. Kwiatkowski, D. J. Wistuba, I. I. Engelman, J. A. Pao, W. Rudin, C. M. Berry, L. Minna, J. D. Bunn, P. A. TI Identification of Driver Mutations in Tumour Specimens From 1000 Patients With Lung Adenocarcinoma for the Lung Cancer Mutation Consortium (LCMC) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Johnson, B. E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kris, M. G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kwiatkowski, D. J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wistuba, I. I.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Engelman, J. A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Pao, W.; Berry, L.] Vanderbilt Ingram Comprehens Canc Ctr, Nashville, TN USA. [Rudin, C. M.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Minna, J. D.] Harold C Simmons Comprehens Canc Ctr, Dallas, TX USA. [Bunn, P. A.] Univ Colorado, Ctr Comprehens Canc, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S597 EP S597 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802125 ER PT J AU Kwak, EL Shapiro, GI Cohen, SM Becerra, CR Lenz, HJ Gooden, S Robohn, M Le-Maulf, F Chand, VK Iafrate, AJ AF Kwak, E. L. Shapiro, G. I. Cohen, S. M. Becerra, C. R. Lenz, H. J. Gooden, S. Robohn, M. Le-Maulf, F. Chand, V. K. Iafrate, A. J. TI A Phase II Trial of Afatinib (BIBW 2992) in Patients With Tumours Prospectively Screened for EGFR And/or HER2 Gene Amplification or EGFR Activating Mutations SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Kwak, E. L.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Shapiro, G. I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cohen, S. M.] St Lukes Roosevelt Hosp, New York, NY USA. [Becerra, C. R.] USON Texas Oncol, Sammons Canc Ctr, Dallas, TX USA. [Lenz, H. J.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA USA. [Gooden, S.; Robohn, M.; Chand, V. K.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Le-Maulf, F.] Boehringer Ingelheim Pharmaceut Inc, Reims, France. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S174 EP S174 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800604 ER PT J AU Levanon, K Hirsch, M Miron, A Ligon, A Birrer, M Drapkin, R AF Levanon, K. Hirsch, M. Miron, A. Ligon, A. Birrer, M. Drapkin, R. TI Foxo3a Loss is a Key Event in High-grade Pelvic Serous Carcinogenesis SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Levanon, K.] Chaim Sheba Med Ctr, Ramat Gan, Israel. [Hirsch, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ligon, A.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Birrer, M.] NCI, NIH, Bethesda, MD 20892 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S113 EP S114 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800398 ER PT J AU Lu, J Kuchimanchi, M Tang, R Deng, H Kindler, H Fuchs, C Suzuki, S Gansert, J Loh, E Zhu, M AF Lu, J. Kuchimanchi, M. Tang, R. Deng, H. Kindler, H. Fuchs, C. Suzuki, S. Gansert, J. Loh, E. Zhu, M. TI Phase 3 Dose Selection for Ganitumab (AMG 479) in Pancreatic Cancer Based on Clinical Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Assessments SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Lu, J.; Kuchimanchi, M.; Zhu, M.] Amgen Inc, Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA. [Tang, R.; Deng, H.] Amgen Inc, Biostat, Thousand Oaks, CA 91320 USA. [Kindler, H.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Fuchs, C.] Dana Farber Canc Inst, Ctr Gastrointestinal Canc, Boston, MA 02115 USA. [Suzuki, S.] Amgen Inc, Biostat, San Francisco, CA USA. [Gansert, J.] Amgen Inc, Oncol, Thousand Oaks, CA 91320 USA. [Loh, E.] Amgen Inc, Oncol, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S468 EP S468 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801625 ER PT J AU Lyons, J Smyth, T Curry, J Fletcher, JA Wallis, N Thompson, N AF Lyons, J. Smyth, T. Curry, J. Fletcher, J. A. Wallis, N. Thompson, N. TI AT13387, a Heat Shock Protein 90 Inhibitor in a Phase I Study Exhibits Potent Activity in GIST Models SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Lyons, J.; Smyth, T.; Curry, J.; Wallis, N.; Thompson, N.] Astex Therapeut Ltd, Biol, Cambridge, England. [Fletcher, J. A.] Dana Farber Canc Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S665 EP S665 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802346 ER PT J AU Margolin, K Hodi, FS McDermott, DF Lawrence, DP Hamid, O Puzanov, I Thompson, JA Ernstoff, MS Michener, TL Heller, KN AF Margolin, K. Hodi, F. S. McDermott, D. F. Lawrence, D. P. Hamid, O. Puzanov, I. Thompson, J. A. Ernstoff, M. S. Michener, T. L. Heller, K. N. TI Safety and Efficacy of Ipilimumab-treated Patients With Melanoma and Brain Metastases SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Margolin, K.] Univ Washington, Div Med Oncol, Seattle, WA 98195 USA. [Hodi, F. S.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Dept Cell Biol, Boston, MA 02215 USA. [Lawrence, D. P.] Massachusetts Gen Hosp, Ctr Canc, Dept Hematol Oncol, Boston, MA USA. [Hamid, O.] Angeles Clin & Res Inst, Neurooncol Clin, Santa Monica, CA USA. [Puzanov, I.] Vanderbilt Univ, Med Ctr, Dept Oncol, Nashville, TN USA. [Thompson, J. A.] Univ Washington, SCCA Melanoma Clin, Seattle, WA USA. [Ernstoff, M. S.] Dartmouth Hitchcock Med Ctr, Dept Hematol Oncol, Lebanon, NH 03766 USA. [Michener, T. L.] Bristol Myers Squibb Co, Collaborat Sci Ctr Excellence, Plainsboro, NJ USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S654 EP S654 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802310 ER PT J AU Negrier, S Bushmakin, AG Cappelleri, JC Charbonneau, C Sandin, R Michaelson, MD Figlin, RA Motzer, RJ AF Negrier, S. Bushmakin, A. G. Cappelleri, J. C. Charbonneau, C. Sandin, R. Michaelson, M. D. Figlin, R. A. Motzer, R. J. TI Assessment of Progression-free Survival as a Surrogate Endpoint for Overall Survival in Patients With Metastatic Renal Cell Carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Negrier, S.] Ctr Leon Berard, F-69373 Lyon, France. [Bushmakin, A. G.; Cappelleri, J. C.] Pfizer Oncol, Global Res & Dev, New London, CT USA. [Charbonneau, C.] Pfizer Oncol, Global Outcomes Res, New York, NY USA. [Sandin, R.] Pfizer Oncol, Global Hlth Econ & Outcomes Res, Sollentuna, Sweden. [Michaelson, M. D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Figlin, R. A.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S163 EP S163 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800569 ER PT J AU Ngwa, W AF Ngwa, W. TI Feasibility of Boosting Local Dose to Tumour Endothelial Cells Using Vascular-targeted Bismuth Nanoparticles During Radiotherapy SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Ngwa, W.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S212 EP S213 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800736 ER PT J AU O'Shaughnessy, J Telli, M Swain, S Gralow, J Rugo, H Litton, J Charpentier, E Smith, J Blackwood-Chirchir, A Winer, E AF O'Shaughnessy, J. Telli, M. Swain, S. Gralow, J. Rugo, H. Litton, J. Charpentier, E. Smith, J. Blackwood-Chirchir, A. Winer, E. TI Phase 3 Study of Iniparib (I) Plus Gemcitabine (G) and Carboplatin (C) in Metastatic Triple-negative Breast Cancer (mTNBC) - Results of an Exploratory Analysis by Prior Therapy SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [O'Shaughnessy, J.] Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Telli, M.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Swain, S.] Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. [Gralow, J.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Rugo, H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Litton, J.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Charpentier, E.] Sanofi Aventis Oncol, Dept Stat, Cambridge, MA 02138 USA. [Smith, J.] BiPar Sci, Dept Stat, San Francisco, CA USA. [Winer, E.] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S338 EP S338 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801193 ER PT J AU Oudard, S Smith, M Karsh, L Egerdie, B Van Veldhuizen, P Gomez-Veiga, F Dearnaley, D Ye, Z Dansey, R Goessl, C AF Oudard, S. Smith, M. Karsh, L. Egerdie, B. Van Veldhuizen, P. Gomez-Veiga, F. Dearnaley, D. Ye, Z. Dansey, R. Goessl, C. TI Denosumab and Bone Metastasis-free Survival in Men With Castrate-resistant Prostate Cancer - Subgroup Analyses From an International, Double-blind, Randomized, Phase 3 Trial SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Oudard, S.] Georges Pompidou Hosp, Paris, France. [Smith, M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Karsh, L.] Urol Ctr Colorado, Dept Clin Res, Denver, CO USA. [Egerdie, B.] Urol Associates, Urol Med Res, Med Res, Kitchener, ON, Canada. [Van Veldhuizen, P.] Kansas City VA Med Ctr, Kansas City, MO USA. [Gomez-Veiga, F.] Hosp Univ Juan Canalejo, La Coruna, Spain. [Dearnaley, D.] Royal Marsden Hosp, Inst Canc Res, Sutton, Surrey, England. [Ye, Z.] Amgen Inc, Gobal Biostat Sci, Thousand Oaks, CA 91320 USA. [Dansey, R.; Goessl, C.] Amgen Inc, Hematol Oncol, Thousand Oaks, CA 91320 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S484 EP S485 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752801680 ER PT J AU Puzanov, I Michaelson, D Cohen, D Li, S Burnett, P Desai, J AF Puzanov, I. Michaelson, D. Cohen, D. Li, S. Burnett, P. Desai, J. TI Evaluation of Hand-foot Syndrome (HFS) as a Potential Biomarker of Sunitinib (SU) Efficacy in Patients (pts) With Metastatic Renal Cell Carcinoma (mRCC) and Gastrointestinal Stromal Tumour (GIST) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Puzanov, I.] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [Michaelson, D.] Massachusetts Gen Hosp Canc, Genitourinary Canc Ctr, Boston, MA USA. [Cohen, D.] Pfizer Oncol, La Jolla, CA USA. [Li, S.] Pfizer Oncol, Shanghai, Peoples R China. [Burnett, P.] Vanderbilt Univ, Med Ctr, Genitourinary Canc Ctr, Boston, MA USA. [Desai, J.] Royal Melbourne Hosp, Dept Med Oncol, Parkville, Vic 3050, Australia. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S182 EP S182 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800631 ER PT J AU Reichardt, P Kang, YK Rutkowski, P Schuette, J Rosen, LS Seddon, B Yalcin, S Chen, L Fly, K Demetri, GD AF Reichardt, P. Kang, Y. K. Rutkowski, P. Schuette, J. Rosen, L. S. Seddon, B. Yalcin, S. Chen, L. Fly, K. Demetri, G. D. TI Optimizing Management of Sunitinib Treatment in a Worldwide Treatment-use Trial of Patients (Pts) With Advanced Gastrointestinal Stromal Tumour (GIST) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Reichardt, P.] Helios Klinikum Bad Saarow, Innere Med Klin 3, Bad Saarow Pieskow, Germany. [Kang, Y. K.] Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr, Dept Soft Tissue Bone Sarcoma & Melanoma, Warsaw, Poland. [Schuette, J.] Marien Hosp Duesseldorf, Dept Hematol & Oncol, Dusseldorf, Germany. [Seddon, B.] Univ Coll Hosp, Dept Oncol, London, England. [Chen, L.] Pfizer Oncol, Biostat, New York, NY USA. [Fly, K.] Pfizer Oncol, Oncol, New London, CT USA. [Demetri, G. D.] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S669 EP S669 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752802360 ER PT J AU Seki, H Hayashida, T Jinno, H Hirose, S Takahashi, M Maheswaran, S Mukai, M Kitagawa, Y AF Seki, H. Hayashida, T. Jinno, H. Hirose, S. Takahashi, M. Maheswaran, S. Mukai, M. Kitagawa, Y. TI HOXB9, a Gene Promoting Tumour Angiogenesis and Proliferation, is a Novel Prognostic Biomarker in Human Breast Cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Seki, H.; Hayashida, T.; Jinno, H.; Hirose, S.; Takahashi, M.; Mukai, M.; Kitagawa, Y.] Keio Univ, Sch Med, Tokyo, Japan. [Maheswaran, S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Maheswaran, S.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S182 EP S183 PG 2 WC Oncology SC Oncology GA 831TA UT WOS:000295752800632 ER PT J AU Shulman, L AF Shulman, L. TI Electronic Health Records and Other Health Information Technology and Their Ability to Measure and Improve Cancer Care SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Shulman, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S43 EP S43 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752800154 ER PT J AU Small, EJ Higano, CS Kantoff, PW Whitmore, JB Frohlich, MW Petrylak, DP AF Small, E. J. Higano, C. S. Kantoff, P. W. Whitmore, J. B. Frohlich, M. W. Petrylak, D. P. TI Time to Disease-related Pain After Sipuleucel-T in Asymptomatic Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC): Results From 3 Randomized Phase III Trials SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Small, E. J.] UCSF Comprehens Canc Ctr, San Francisco, CA USA. [Higano, C. S.] Univ Washington, Seattle, WA 98195 USA. [Kantoff, P. W.] Dana Farber Canc Inst, Div Solid Tumour Oncol, Boston, MA 02115 USA. [Whitmore, J. B.; Frohlich, M. W.] Dendreon Corp, Seattle, WA USA. [Petrylak, D. P.] Columbia Univ, Med Ctr, Div Hematol Oncol, New York, NY USA. NR 0 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S484 EP S484 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801679 ER PT J AU Wolpin, BM O'Reilly, EM Ko, YJ Lima, MSR Spratlin, JL Macarulla, T Pezet, D Hartford, A Jackson, LS Hidalgo, M AF Wolpin, B. M. O'Reilly, E. M. Ko, Y. J. Lima, M. S. Rocha Spratlin, J. L. Macarulla, T. Pezet, D. Hartford, A. Jackson, L. S. Hidalgo, M. TI Improved 6-month Survival Rate in Subjects With Prostate Stem Cell Antigen (PSCA) Positive Tumours in a Global, Randomized Phase 2 Trial Comparing Gemcitabine Vs. Gemcitabine + Ags-1c4d4 (asp6182) in Metastatic Pancreatic Cancer (mPC) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care CY SEP 23-27, 2011 CL Stockholm, SWEDEN C1 [Wolpin, B. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [O'Reilly, E. M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Ko, Y. J.] Univ Toronto, Dept Med, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Lima, M. S. Rocha] Univ Miami, Sylvester Comprehens Canc Ctr, Dept Oncol, Miami, FL USA. [Spratlin, J. L.] Cross Canc Inst, Dept Med, Edmonton, AB T6G 1Z2, Canada. [Macarulla, T.] Hosp Vail dHebron, Dept Med, Barcelona, Spain. [Pezet, D.] Chu Estaing, Dept Digest Surg & Oncol, Clermont Ferrand, France. [Hartford, A.; Jackson, L. S.] Agensys Inc, Dept Clin Res & Dev, Santa Monica, CA USA. [Hidalgo, M.] Ctr Integral Oncol Clara Campal, Dept Med, Madrid, Spain. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2011 VL 47 SU 1 BP S469 EP S469 PG 1 WC Oncology SC Oncology GA 831TA UT WOS:000295752801628 ER PT J AU Zhang, Y Nateras, OS Peng, Q Kuranov, RV Harrison, JM Milner, TE Duong, TQ AF Zhang, Yi Nateras, Oscar San Emeterio Peng, Qi Kuranov, Roman V. Harrison, Joseph M. Milner, Thomas E. Duong, Timothy Q. TI Lamina-Specific Anatomic Magnetic Resonance Imaging of the Human Retina SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; MANGANESE-ENHANCED MRI; BLOOD-FLOW; IN-VIVO; FUNCTIONAL MRI; RAT RETINA; 7 TESLA; QUANTIFICATION; RESOLUTION; THICKNESS AB PURPOSE. Magnetic resonance imaging (MRI) of the human retina faces two major challenges: eye movement and hardware limitation that could preclude human retinal MRI with adequate spatiotemporal resolution. This study investigated eye-fixation stability and high-resolution anatomic MRI of the human retina on a 3-Tesla (T) MRI scanner. Comparison was made with optical coherence tomography (OCT) on the same subjects. METHODS. Eye-fixation stability of protocols used in MRI was evaluated on four normal volunteers using an eye tracker. High-resolution MRI (100 x 200 x 2000 mu m) protocol was developed on a 3-T scanner. Subjects were instructed to maintain stable eye fixation on a target with cued blinks every 8 seconds during MRI. OCT imaging of the retina was performed. Retinal layer thicknesses measured with MRI and OCT were analyzed for matching regions of the same eyes close to the optic nerve head. RESULTS. The temporal SDs of the horizontal and vertical displacements were 78 +/- 51 and 130 +/- 51 mu m (+/- SD, n = 4), respectively. MRI detected three layers within the human retina, consistent with MRI findings in rodent, feline, and baboon retinas. The hyperintense layer 1 closest to the vitreous likely consisted of nerve fiber, ganglion cell, and inner nuclear layer; the hypointense layer 2, the outer nuclear layer and the inner and outer segments; and the hyperintense layer 3, the choroid. The MRI retina/choroid thickness was 711 +/- 37 mu m, 19% (P < 0.05) thicker than OCT thickness (579 +/- 34 mu m). CONCLUSIONS. This study reports high-resolution MRI of laminaspecific structures in the human retina. These initial results are encouraging. Further improvement in spatiotemporal resolution is warranted. (Invest Ophthalmol Vis Sci. 2011;52:7232-7237) DOI:10.1167/iovs.11-7623 C1 [Zhang, Yi; Nateras, Oscar San Emeterio; Peng, Qi; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Zhang, Yi; Nateras, Oscar San Emeterio; Peng, Qi; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Kuranov, Roman V.; Harrison, Joseph M.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Milner, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008 FU Clinical Translational Science Award; Translational Technology Resource Grant [UL1RR025767]; National Institutes of Health/National Eye Institute [R01 EY014211, EY018855]; Department of Veterans Affairs FX Supported in part by a Clinical Translational Science Award Pilot grant (TQD) and a Translational Technology Resource Grant UL1RR025767 (QP), National Institutes of Health/National Eye Institute Grants R01 EY014211 and EY018855, and Department of Veterans Affairs Merit awards (TQD). NR 46 TC 20 Z9 20 U1 0 U2 2 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 SEP PY 2011 VL 52 IS 10 BP 7232 EP 7237 DI 10.1167/iovs.11-7623 PG 6 WC Ophthalmology SC Ophthalmology GA 827YU UT WOS:000295467200027 PM 21828153 ER PT J AU Wang, LQ Jeong, KJ Chiang, HH Zurakowski, D Behlau, I Chodosh, J Dohlman, CH Langer, R Kohane, DS AF Wang, Liqiang Jeong, Kyung Jae Chiang, Homer H. Zurakowski, David Behlau, Irmgard Chodosh, James Dohlman, Claes H. Langer, Robert Kohane, Daniel S. TI Hydroxyapatite for Keratoprosthesis Biointegration SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID COATINGS; TRANSPLANTATION; HYDROXYLAPATITE; ENDOPHTHALMITIS; CHROMATOGRAPHY; SUBSTRATE; PROTEINS; SURVIVAL; TITANIUM; ADHESION AB PURPOSE. Integration of keratoprosthesis with the surrounding cornea is very important in preventing bacterial invasion, which may cause ocular injury. Here the authors investigated whether hydroxyapatite (HAp) coating can improve keratoprosthesis (KPro) biointegration, using polymethyl methacrylate (PMMA)-the principal component of the Boston KPro-as a model polymer. METHODS. HAp coatings were induced on PMMA discs after treatment with concentrated NaOH and coating with polydopamine (PDA) or polydopamine and then with 11-mercaptoundecanoic acid (11-MUA). Coatings were characterized chemically (Fourier transform infrared spectroscopy [FTIR], energy dispersive X-ray spectroscopy [EDX]) and morphologically (SEM) and were used as substrates for keratocyte growth in vitro. Cylinders of coated PMMA were implanted in porcine corneas ex vivo for 2 weeks, and the force required to pull them out was measured. The inflammatory reaction to coated discs was assessed in the rabbit cornea in vivo. RESULTS. FTIR of the coatings showed absorption bands characteristic of phosphate groups, and EDX showed that the Ca/P ratios were close to those of HAp. By SEM, each method resulted in morphologically distinct HAp films; the 11-MUA group had the most uniform coating. The hydroxyapatite coatings caused comparable enhancement of keratocyte proliferation compared with unmodified PMMA surfaces. HAp coating significantly increased the force and work required to pull PMMA cylinders out of porcine corneas ex vivo. HAp coating of implants reduced the inflammatory response around the PMMA implants in vivo. CONCLUSIONS. These results are encouraging for the potential of HAp-coated surfaces for use in keratoprostheses. (Invest Ophthalmol Vis Sci. 2011;52:7392-7399) DOI:10.1167/iovs.11-7601 C1 [Jeong, Kyung Jae; Chiang, Homer H.; Kohane, Daniel S.] Harvard Univ, Childrens Hosp, Lab Biomat & Drug Delivery, Dept Anesthesiol,Div Crit Care Med,Sch Med, Boston, MA 02115 USA. [Wang, Liqiang; Behlau, Irmgard; Chodosh, James; Dohlman, Claes H.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Wang, Liqiang] Chinese Peoples Liberat Army Gen Hosp, Dept Ophthalmol, Beijing, Peoples R China. [Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Kohane, DS (reprint author), Harvard Univ, Childrens Hosp, Lab Biomat & Drug Delivery, Dept Anesthesiol,Div Crit Care Med,Sch Med, Boston, MA 02115 USA. EM daniel.kohane@childrens.harvard.edu FU National Institute of General Medical Sciences [GM073626]; Massachusetts Eye and Ear Infirmary FX Supported by National Institute of General Medical Sciences Grant GM073626 (DSK) and the Boston KPro Fund, Massachusetts Eye and Ear Infirmary (DSK). NR 35 TC 12 Z9 14 U1 1 U2 18 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 SEP PY 2011 VL 52 IS 10 BP 7392 EP 7399 DI 10.1167/iovs.11-7601 PG 8 WC Ophthalmology SC Ophthalmology GA 827YU UT WOS:000295467200047 PM 21849419 ER PT J AU Sobrin, L Green, T Sim, X Jensen, RA Tai, ES Tay, WT Wang, JJ Mitchell, P Sandholm, N Liu, YY Hietala, K Iyengar, SK Brooks, M Buraczynska, M Van Zuydam, N Smith, AV Gudnason, V Doney, ASF Morris, AD Leese, GP Palmer, CNA Swaroop, A Taylor, HA Wilson, JG Penman, A Chen, CJ Groop, PH Saw, SM Aung, T Klein, BE Rotter, JI Siscovick, DS Cotch, MF Klein, R Daly, MJ Wong, TY AF Sobrin, Lucia Green, Todd Sim, Xueling Jensen, Richard A. Tai, E. Shyong Tay, Wan Ting Wang, Jie Jin Mitchell, Paul Sandholm, Niina Liu, Yiyuan Hietala, Kustaa Iyengar, Sudha K. Brooks, Matthew Buraczynska, Monika Van Zuydam, Natalie Smith, Albert V. Gudnason, Vilmundur Doney, Alex S. F. Morris, Andrew D. Leese, Graham P. Palmer, Colin N. A. Swaroop, Anand Taylor, Herman A., Jr. Wilson, James G. Penman, Alan Chen, Ching J. Groop, Per-Henrik Saw, Seang-Mei Aung, Tin Klein, Barbara E. Rotter, Jerome I. Siscovick, David S. Cotch, Mary Frances Klein, Ronald Daly, Mark J. Wong, Tien Y. CA Family Invest Nephropathy Diabet-E Wellcome Trust Case Control Consor TI Candidate Gene Association Study for Diabetic Retinopathy in Persons with Type 2 Diabetes: The Candidate Gene Association Resource (CARe) SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; COMMON VARIANTS; RISK-FACTORS; ERYTHROPOIETIN GENE; LINKAGE ANALYSES; BLOOD-PRESSURE; UNITED-STATES; FTO GENE; COMPLICATIONS AB PURPOSE. To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe). METHODS. Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The chi(2) analyses for each CARe cohort were combined by Cochran-Mantel- Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods. RESULTS. Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging alpha-Liduronidase (IDUA) (P = 2.1 X 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively. CONCLUSIONS. Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts. (Invest Ophthalmol Vis Sci. 2011;52:7593-7602) DOI:10.1167/iovs.11-7510 C1 [Sobrin, Lucia] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Green, Todd; Daly, Mark J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Green, Todd; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore. [Tai, E. Shyong; Saw, Seang-Mei] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore. [Aung, Tin; Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Jensen, Richard A.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. [Tay, Wan Ting; Aung, Tin] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Sandholm, Niina; Groop, Per-Henrik] Univ Helsinki, Dept Med, Div Nephrol, Helsinki, Finland. [Sandholm, Niina; Hietala, Kustaa; Groop, Per-Henrik] Biomedicum Helsinki, Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Liu, Yiyuan; Van Zuydam, Natalie; Palmer, Colin N. A.] Univ Dundee, Inst Biomed Res, Dundee, Scotland. [Hietala, Kustaa] Univ Helsinki, Cent Hosp, Dept Ophthalmol, Helsinki, Finland. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Brooks, Matthew; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Buraczynska, Monika] Med Univ Lublin, Lab DNA Anal & Mol Diagnost, Dept Nephrol, Lublin, Poland. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Doney, Alex S. F.; Morris, Andrew D.; Leese, Graham P.] Univ Dundee, Ninewells Hosp & Med Sch, Dept Med & Therapeut, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland. [Taylor, Herman A., Jr.; Penman, Alan] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Penman, Alan] Univ Mississippi, Med Ctr, Dept Biostat, Jackson, MS 39216 USA. [Chen, Ching J.] Univ Mississippi, Med Ctr, Dept Ophthalmol, Jackson, MS 39216 USA. [Klein, Barbara E.; Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. RP Sobrin, L (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM lucia_sobrin@meei.harvard.edu RI Nelson, Robert/B-1470-2012; Palmer, Colin/C-7053-2008; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Blackwell, Jenefer/H-3015-2015; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Study, GoDARTS/K-9448-2016; OI Swaroop, Anand/0000-0002-1975-1141; Gillman, Matthew/0000-0002-2340-6930; Plomin, Robert/0000-0002-0756-3629; Klein, Ronald/0000-0002-4428-6237; Tai, E Shyong/0000-0003-2929-8966; Palmer, Colin/0000-0002-6415-6560; Wang, Jie Jin/0000-0001-9491-4898; Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350; Smith, Albert/0000-0003-1942-5845; Sandholm, Niina/0000-0003-4322-6942; Potter, Simon/0000-0003-4208-4102 FU National Eye Institute [K12-EY16335]; Research to Prevent Blindness Career Development Award; Massachusetts Lions Eye Research Fund; Sara Elizabeth O'Brien Trust; Harvard Catalyst/The Harvard Clinical and Translational Science Center; National Institutes of Health [UL1 RR 025758]; Harvard University; affiliated academic health care centers; National Heart, Lung Blood Institute (NHLBI) [N01-HC-65226]; Atherosclerosis Risk in Communities (ARIC) Study,; Cardiovascular Health Study (CHS); Jackson Heart Study (JHS); Multi-ethnic Study of Atherosclerosis (MESA) FX Supported by National Eye Institute Grant K12-EY16335; a Research to Prevent Blindness Career Development Award; the Massachusetts Lions Eye Research Fund; the Sara Elizabeth O'Brien Trust; and Harvard Catalyst/The Harvard Clinical and Translational Science Center, National Institutes of Health Award Grant UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers. The National Heart, Lung Blood Institute (NHLBI) Grant N01-HC-65226 has supported genotyping and has created a genotype-phenotype database with data and samples from nine cohorts as part of Candidate Gene Association Resource (CARe). Please see the Supplementary Material (http://www.iovs.org/lookup/suppl/doi:10.1167/iovs.11-7510/-/DC Supplemental), as well as http://public.nhlbi.nih.gov/Genetics Genomics/home/care.aspx for detailed information about the grants supporting the four cohorts in this study: Atherosclerosis Risk in Communities (ARIC) Study, Cardiovascular Health Study (CHS), Jackson Heart Study (JHS), and Multi-ethnic Study of Atherosclerosis (MESA). Please see the Supplementary Material (http://www.iovs.org/lookup/suppl/doi: 10.1167/iovs.11-7510/-/DC Supplemental) for detailed information about the grants supporting the replication cohorts. NR 69 TC 34 Z9 34 U1 0 U2 9 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD SEP PY 2011 VL 52 IS 10 BP 7593 EP 7602 DI 10.1167/iovs.11-7510 PG 10 WC Ophthalmology SC Ophthalmology GA 827YU UT WOS:000295467200072 PM 21873659 ER PT J AU Yu, YG Zhu, HT Miller, DT Gusella, JF Platt, OS Wu, BL Shen, YP AF Yu, Yongguo Zhu, Haitao Miller, David T. Gusella, James F. Platt, Orah S. Wu, Bai-Lin Shen, Yiping CA Children's Hosp Boston Genotype TI Age- and gender-dependent obesity in individuals with 16p11.2 deletion SO JOURNAL OF GENETICS AND GENOMICS LA English DT Article DE Obesity; Chromosome deletion; 16p11.2; Developmental delay; Autism spectrum disorders; Chromosomal microarray analysis; Genetic testing ID AUTISM SPECTRUM DISORDER; BODY-MASS INDEX; PERVASIVE DEVELOPMENTAL DISORDERS; MENTAL-RETARDATION; CHROMOSOME 16P11.2; FEMALE-CHILDREN; MICRODELETION; ASSOCIATION; PHENOTYPE; GENES AB Recurrent genomic imbalances at 16p11.2 are genetic risk factors of variable penetrance for developmental delay and autism. Recently, 16p11.2 (chr16:29.5 Mb-30.1 Mb) deletion has also been detected in individuals with early-onset severe obesity. The penetrance of 16p11.2 deletion as a genetic risk factor for obesity is unknown. We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2 (chr16: 29.5 Mbe30.1 Mb) deletion originally ascertained for their developmental disorders by reviewing their medical records. We found that nine individuals could be classified as obese and six as overweight. These individuals generally had early feeding and growth difficulties, and started to gain excessive weight around 5-6 years of age. Thirteen out of the 18 deletion carriers aged 5 years and older (72%) were overweight or obese, whereas only two of 10 deletion carriers (20%) younger than five were overweight or obese. Males exhibited more severe obesity than females. Thus, the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset, exhibited an age-and gender-dependent penetrance. 16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome (PWS). Early detection of this deletion will provide opportunity to prevent obesity. C1 [Yu, Yongguo; Zhu, Haitao; Miller, David T.; Platt, Orah S.; Wu, Bai-Lin; Shen, Yiping] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Gusella, James F.; Shen, Yiping] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Miller, David T.; Gusella, James F.; Platt, Orah S.; Wu, Bai-Lin; Shen, Yiping] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yu, Yongguo; Shen, Yiping] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China. [Zhu, Haitao; Wu, Bai-Lin] Fudan Univ, Childrens Hosp, Shanghai 201102, Peoples R China. [Zhu, Haitao; Wu, Bai-Lin] Fudan Univ, Inst Biomed Sci, Shanghai 201102, Peoples R China. RP Wu, BL (reprint author), Childrens Hosp, Dept Lab Med, 300 Longwood Ave, Boston, MA 02115 USA. EM Bai-lin.Wu@childrens.harvard.edu; yiping.shen@childrens.harvard.edu OI yu, yongguo/0000-0002-4472-0910 FU Chinese National Natural Science Foundation [81000346]; Center for Clinical Nutrition Study [SCMC-YP-HOPE-KY-0905]; social development branch of Pudong New District [PW2009D-9]; Simons Foundation; Developmental Genome Anatomy Project [P01 GM061354]; Chinese National "973" Project on Population and Health [2010CB529601]; Science and Technology Council of Shanghai [09JC1402400]; Children's Tumor Foundation; Harvard Medical School FX This work was supported by the Chinese National Natural Science Foundation (No. 81000346, Y.G.Y.); foundation grant from the Center for Clinical Nutrition Study (SCMC-YP-HOPE-KY-0905 for Y.G.Y); Health Science grant from the social development branch of Pudong New District (PW2009D-9 for Y.G.Y); the Simons Foundation (J.F.G.), Autism Speaks (J.F.G.) and Developmental Genome Anatomy Project (P01 GM061354); Chinese National "973" Project on Population and Health (No. 2010CB529601, B.-L. W.); Science and Technology Council of Shanghai (No. 09JC1402400 (B.-L. W.); Y. Shen holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School. We would like to thank Joel Hirschhorn MD, PhD for helpful discussion and review of the manuscript. We gratefully acknowledge the assistance by our colleagues from the DNA Diagnostics Lab: Va Lip, Xiaoming Sheng, Ann Reinhard, Hong Fang, Siv Tang, Hong Shao, Sam Tang, and Andrew Cheng for technical support of array CGH. NR 28 TC 7 Z9 9 U1 1 U2 14 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1673-8527 J9 J GENET GENOMICS JI J. Genet. Genomics PD SEP PY 2011 VL 38 IS 9 BP 403 EP 409 DI 10.1016/j.jgg.2011.08.003 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 831LT UT WOS:000295732900003 PM 21930099 ER PT J AU Amariglio, RE Townsend, MK Grodstein, F Sperling, RA Rentz, DM AF Amariglio, Rebecca England Townsend, Mary K. Grodstein, Francine Sperling, Reisa A. Rentz, Dorene M. TI Specific Subjective Memory Complaints in Older Persons May Indicate Poor Cognitive Function SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE memory complaints; cognitive function; aging ID ALZHEIMERS-DISEASE; IMPAIRMENT; COMMUNITY; PERFORMANCE; DEMENTIA AB OBJECTIVES: To examine the association between the type and number of subjective memory complaints (SMCs) and performance on objective cognitive tests. DESIGN: Cross-sectional. SETTING: Nurses' Health Study. PARTICIPANTS: Sixteen thousand nine hundred sixty-four women (mean age 74) who provided information on SMCs. MEASUREMENTS: Telephone cognitive assessments and seven questions regarding SMCs were administered. Cognitive impairment was defined as a score of less than 31 on the Telephone Interview for Cognitive Status (TICS) and below the 10th percentile on other cognitive measures. To assess associations with SMCs, multivariable logistic regression was used to calculate odds ratios for cognitive impairment and multivariable linear regression to calculate mean differences in cognitive test scores, adjusting for age and depressive symptoms. RESULTS: Some SMCs, such as trouble following a group conversation or finding one's way around familiar streets, were more highly associated than others with odds of cognitive impairment. The complaint of forgetting things from one second to the next, generally considered part of normal aging, was not associated with cognitive impairment. In addition, there were strong, linear trends of increasingly worse scores on cognitive tests with increasing numbers of memory complaints. For each additional SMC endorsed, the odds of cognitive impairment increased approximately 20% when each SMC was weighted equally. CONCLUSION: SMCs are associated with objective cognitive status and may be considered by primary care physicians in determining whether follow-up is warranted. J Am Geriatr Soc 59: 1612-1617, 2011. C1 [Amariglio, Rebecca England] Brigham & Womens Hosp, Div Cognit & Behav Neurol, Dept Neurol, Boston, MA 02115 USA. [Townsend, Mary K.; Grodstein, Francine] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Townsend, Mary K.; Grodstein, Francine] Harvard Univ, Sch Med, Boston, MA USA. [Sperling, Reisa A.; Rentz, Dorene M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Grodstein, Francine] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Amariglio, RE (reprint author), Brigham & Womens Hosp, Div Cognit & Behav Neurol, Dept Neurol, 221 Longwood Ave, Boston, MA 02115 USA. EM rengland@partners.org FU National Institutes of Health [CA87969, AG15424]; Yerby Postdoctoral Fellowship Program FX This research was supported by Grants CA87969 and AG15424 from the National Institutes of Health. Dr. Townsend was supported by the Yerby Postdoctoral Fellowship Program. NR 21 TC 59 Z9 60 U1 1 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1612 EP 1617 DI 10.1111/j.1532-5415.2011.03543.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000006 PM 21919893 ER PT J AU Pham, AN Datta, SK Weber, TJ Walter, LC Colon-Emeric, CS AF Pham, Annalise N. Datta, Santanu K. Weber, Thomas J. Walter, Louise C. Colon-Emeric, Cathleen S. TI Cost-Effectiveness of Oral Bisphosphonates for Osteoporosis at Different Ages and Levels of Life Expectancy SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE osteoporosis; bisphosphonates; cost-effectiveness ID FRACTURE INTERVENTION TRIAL; VERTEBRAL FRACTURES; HIP FRACTURE; UNITED-STATES; BONE-DENSITY; OLDER WOMEN; ALENDRONATE; RISK; RISEDRONATE; MORTALITY AB OBJECTIVES: To evaluate the cost-effectiveness of oral bisphosphonate therapy for osteoporosis in women at different ages and life expectancies. DESIGN: A Markov model was used to analyze oral bisphosphonate treatment for 5 years compared to no intervention. Women at each age were divided into life expectancy quartiles: the lowest 1% to 25% (sickest group), the two middle 26% to 75% (average health group), and the highest 76% to 100% of life expectancy (healthiest group). Simulations were performed for hypothetical cohorts at 5-year intervals with starting ages between 50 and 90 and for each life expectancy group and followed for up to 100 years or until death. Data sources included published fracture rates, costs, utility values, and mortality risks. SETTING: Computer simulation using a societal perspective. PARTICIPANTS: Hypothetical cohort of women with various life expectancies beginning osteoporosis treatment between the age of 50 and 90 years. MEASUREMENTS: Cost per quality-adjusted life years (QALY) gained for 5 years of bisphosphonate therapy compared to no treatment. Cost-effectiveness was defined at a willingness-to-pay of $50,000. RESULTS: In the healthiest group, all costs were less than $18,000 per QALY. In the median quartiles of life expectancy, lifetime costs per QALY were less than $27,000 for patients at all ages; treatment became cost-saving at a starting age of 75 and remained so through a starting age of 85. Even in the sickest group, although osteoporosis treatment was not cost-saving, it remained cost-effective through a starting age of 90 with lifetime costs of less than $43,000 per QALY. CONCLUSION: Treatment with an oral bisphosphonate for 5 years was cost-effective for all women, regardless of quartile of life expectancy. Advanced age should not prevent consideration of osteoporosis treatment based on cost effectiveness, and strategies to improve care, such as nurseled screening programs or electronic medical record tools, are needed. J Am Geriatr Soc 59: 1642-1649, 2011. C1 [Colon-Emeric, Cathleen S.] Duke Univ, Div Geriatr, Med Ctr, Durham, NC 27705 USA. [Weber, Thomas J.] Duke Univ, Div Endocrinol, Med Ctr, Durham, NC 27705 USA. [Datta, Santanu K.] Duke Univ, Div Gen Internal Med, Med Ctr, Durham, NC 27705 USA. [Pham, Annalise N.] Canberra Hosp, Dept Endocrinol, Canberra, ACT, Australia. [Colon-Emeric, Cathleen S.] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Datta, Santanu K.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res, Durham, NC USA. [Walter, Louise C.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Div Geriatr, San Francisco, CA 94143 USA. RP Colon-Emeric, CS (reprint author), Duke Univ, Div Geriatr, Med Ctr, 508 Fulton St,GRECC 182, Durham, NC 27705 USA. EM colon001@mc.duke.edu FU Presidential Poster Award in Geriatric Syndromes; Novartis; Amgen; Eli Lilly; Wyeth; Pfizer FX Presented as a poster at the Annual Scientific Meeting of the American Geriatrics Society, May 2010, and recipient of the Presidential Poster Award in Geriatric Syndromes.; Dr. Pham received an educational grant from Novartis in 2009 for medical research at Duke University. Dr. Weber receives funding from Amgen, Eli Lilly, and Novartis and is a consultant for Proctor and Gamble and GlaxoSmithKline. Dr. Colon-Emeric receives research funding from Novartis, Wyeth, and Pfizer for osteoporosis-related studies and is a consultant for Novartis and Amgen. NR 43 TC 9 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2011 VL 59 IS 9 BP 1642 EP 1649 DI 10.1111/j.1532-5415.2011.03571.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 829WD UT WOS:000295615000010 PM 21883116 ER PT J AU Latourelle, JC Hendricks, AE Pankratz, N Wilk, JB Halter, C Nichols, WC Gusella, JF Destefano, AL Myers, RH Foroud, T AF Latourelle, Jeanne C. Hendricks, Audrey E. Pankratz, Nathan Wilk, Jemma B. Halter, Cheryl Nichols, William C. Gusella, James F. Destefano, Anita L. Myers, Richard H. Foroud, Tatiana CA PSG Progeni GenePD Investigators TI Genomewide Linkage Study of Modifiers of LRRK2-Related Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; leucine-rich repeat kinase 2; linkage ID LRRK2 MUTATION; ONSET AGE; ASSOCIATION; GENE; G2019S; FAMILIES; HETEROZYGOSITY; RELEVANCE; MAPS AB Mutations in the leucine-rich repeat kinase 2 gene, located at 12q12, are the most common known genetic causes of Parkinson's disease. Studies of leucine-rich repeat kinase 2 mutation carriers have shown incomplete and age-dependent penetrance, and previous studies have suggested that inherited susceptibility factors may modify the penetrance of leucine-rich repeat kinase 2 mutations. Genomewide linkage to age of onset of leucine-rich repeat kinase 2-related Parkinson's disease was evaluated in a sample of 113 leucine-rich repeat kinase 2 mutation carriers from 64 families using single-nucleotide polymorphism data from the Illumina HumanCNV370 genotyping array. Association between onset age and single-nucleotide polymorphisms under suggestive linkage peaks was also evaluated. The top logarithmic odds score for onset age (logarithmic odds score = 2.43) was in the chromosome 1q32.1 region. Moderate linkage to onset was also identified at 16q12.1 (logarithmic odds score = 1.58). Examination of single-nucleotide polymorphism association to Parkinson's disease onset under the linkage peaks revealed no statistically significant single-nucleotide polymorphism associations. The 2 novel genomic regions identified may harbor modifiers of leucine-rich repeat kinase 2-related Parkinson's disease onset age or penetrance, and further study of these regions may provide important insight into leucine-rich repeat kinase 2-related Parkinson's disease. (C) 2011 Movement Disorder Society C1 [Latourelle, Jeanne C.; Wilk, Jemma B.; Destefano, Anita L.; Myers, Richard H.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hendricks, Audrey E.; Destefano, Anita L.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Pankratz, Nathan; Halter, Cheryl; Foroud, Tatiana] Indiana Univ Sch Med, Indianapolis, IN USA. [Nichols, William C.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Nichols, William C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Gusella, James F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gusella, James F.] Harvard Univ, Sch Med, Boston, MA USA. RP Latourelle, JC (reprint author), 72 E Concord St,B-617, Boston, MA 02119 USA. EM jlatoure@bu.edu RI Hendricks, Audrey/I-4127-2016; OI Hendricks, Audrey/0000-0002-7152-0287; Latourelle, Jeanne/0000-0002-4218-9572; Myers, Richard/0000-0002-8365-2674 FU Robert P. & Judith N. Goldberg Foundation; Bumpus Foundation; Harvard NeuroDiscovery Center; Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institutes of Health [HHSN268200782096C]; Italian Telethon [GTB07001]; Fondazione Grigioni per il Morbo di Parkinson; [R01 NS37167]; [R01 NS036711] FX This project was supported by R01 NS37167, R01 NS036711, the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation, and the Harvard NeuroDiscovery Center. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine, and Boston Medical Center. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), fully funded through a federal contract from the National Institutes of Health to Johns Hopkins University (contract HHSN268200782096C).; This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), as well as clinical data. DNA samples contributed by the Parkinson Institute-Istituti Clinici di Perfezionamento, Milan, Italy, were from the Human Genetic Bank of Patients Affected by PD and Parkinsonisms, supported by Italian Telethon grant number GTB07001, and by the Fondazione Grigioni per il Morbo di Parkinson. We particularly thank Drs. Kimberly Doheny and Elizabeth Pugh from CIDR and Mr. Justin Paschall from NCBI for their assistance. The data used in this study are available at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession number phs000126.v1.p1. We thank the subjects for their participation in this research study. NR 35 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2039 EP 2044 DI 10.1002/mds.23781 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300014 PM 21661047 ER PT J AU Morley, JF Weintraub, D Mamikonyan, E Moberg, PJ Siderowf, AD Duda, JE AF Morley, James F. Weintraub, Daniel Mamikonyan, Eugenia Moberg, Paul J. Siderowf, Andrew D. Duda, John E. TI Olfactory Dysfunction Is Associated with Neuropsychiatric Manifestations in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; olfaction; nonmotor symptoms; psychiatric symptoms; cognitive symptoms ID MINI-MENTAL-STATE; MILD COGNITIVE IMPAIRMENT; NONMOTOR SYMPTOMS; ODOR IDENTIFICATION; DE-NOVO; DEFICITS; RISK; COMMON; APATHY; TESTS AB Hyposmia, psychiatric disorders, and cognitive problems are common nonmotor manifestations in Parkinson's disease, but how they are related remains unclear. We investigated the relationship between olfactory dysfunction and neuropsychiatric manifestations and performed a cross-sectional study of 248 patients at two movement disorders clinics at academic medical centers. Psychiatric measures were the Geriatric Depression Scale-15, Inventory of Depressive Symptomatology, State Anxiety Inventory, Apathy Scale, and Parkinson's Psychosis Rating Scale. Cognitive measures were the Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Digit Span, Tower of London-Drexel, and the Stroop Color Word Test. Olfaction was tested with the University of Pennsylvania Smell Identification Test. There was no significant association between olfaction and mood measures, but psychotic symptoms were more common in patients with olfaction scores below the median (30% vs. 12%; P < 0.001). Worse olfaction was associated with poorer memory (Hopkins Verbal Learning Test-Revised delayed recall items: mean [standard deviation], 6.2 [3.2] vs. 8.4 [2.8]; P < 0.001) and executive performance (Tower of London total moves, 52 [38] vs. 34 [21]; P < 0.001). Odor-identification score was a significant predictor of abnormal performance on these cognitive tests after adjustment for age, sex, and disease characteristics in logistic regression models. The relationship between hyposmia, psychosis, and specific cognitive impairments may reflect the anatomic distribution of Lewy pathology and suggests that olfactory dysfunction could be a biomarker of additional extranigral disease. Future prospective studies are warranted to assess whether hyposmia, a very early feature of Parkinson's disease, might be used to predict the appearance of other common nonmotor symptoms. (C) 2011 Movement Disorder Society C1 [Morley, James F.; Weintraub, Daniel; Moberg, Paul J.; Siderowf, Andrew D.; Duda, John E.] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Morley, James F.; Weintraub, Daniel; Moberg, Paul J.; Siderowf, Andrew D.; Duda, John E.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel; Mamikonyan, Eugenia; Moberg, Paul J.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. RP Duda, JE (reprint author), Philadelphia Vet Adm Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM John.Duda@va.gov FU NIH [K23 MH067894, NINDS U10 NS044451-023, NINDS P50 NS053488-01, NINDS R43NS0636071, NINDS R01NS065087]; Teva Pharmaceutical Industries Ltd.; Avid Radiopharmaceuticals, Inc.; Boehringer Ingelheim; National Institutes of Health [NIMH K23 MH067894]; NINDS [P50 NS053488-01, R01NS065087]; NIA [RO1AG031348]; Michael J. Fox Foundation for Parkinson's Research; Institute for Neurodegenerative Disorders; U.S. Department of Veterans Affairs; Michael J. Fox Foundation; Samueli Institute; C.R. Bard, Inc.; Celgene; Clarient, Inc.; Johnson Johnson FX This work was supported by NIH grant K23 MH067894 (to D.W.).; Dr. Morley has received travel funding from Teva Pharmaceutical Industries Ltd. Dr. Weintraub has served on a scientific advisory board for Boehringer Ingelheim; serves on the editorial board of Movement Disorders; has received speaker honoraria from Boehringer Ingelheim, ACADIA Pharmaceuticals, Novartis, Osmotica Pharmaceutical Corp., BrainCells Inc., Merck Serono, Sanofi-aventis, and Pfizer Inc; and has received/receives research support from Avid Radiopharmaceuticals, Inc., Boehringer Ingelheim, National Institutes of Health (NIMH K23 MH067894 [PI], NINDS P50 NS053488-01 [coinvestigator], NIA RO1AG031348 [site PI], and NINDS R01NS065087 [coinvestigator]), and from the Michael J. Fox Foundation for Parkinson's Research. Ms. Mamikonyan reports no disclosures. Dr. Siderowf serves on a scientific advisory board for, and has received speaker honoraria from, Teva Pharmaceutical Industries Ltd.; serves as a consultant for Supernus Pharmaceuticals, Inc.; and receives research support from Avid Radiopharmaceuticals, Inc., the NIH (NINDS U10 NS044451-023 [Site PI], NINDS P50 NS053488-01 [cocore leader and project leader], NINDS R43NS0636071 [site PI], and NINDS R01NS065087 coinvestigator]), and from the Institute for Neurodegenerative Disorders. Dr. Duda serves on a grant review panel for the Michael J. Fox Foundation for Parkinson's Research; receives research support from the U.S. Department of Veterans Affairs (Merit Award [PI]), the Michael J. Fox Foundation, and the Samueli Institute; and holds stock in C.R. Bard, Inc., Celgene, Clarient, Inc., and Johnson & Johnson. NR 53 TC 30 Z9 33 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2051 EP 2057 DI 10.1002/mds.23792 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300016 PM 21611985 ER PT J AU Sharma, N Armata, IA Multhaupt-Buell, TJ Ozelius, LJ Xin, WN Sims, KB AF Sharma, Nutan Armata, Ioanna A. Multhaupt-Buell, Trisha J. Ozelius, Laurie J. Xin, Winnie Sims, Katherine B. TI Mutation in 5 ' Upstream Region of GCHI Gene Causes Familial Dopa-Responsive Dystonia SO MOVEMENT DISORDERS LA English DT Letter C1 [Sharma, Nutan; Armata, Ioanna A.; Multhaupt-Buell, Trisha J.; Xin, Winnie; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ozelius, Laurie J.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Ozelius, Laurie J.] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Xin, Winnie; Sims, Katherine B.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Sharma, N (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM nsharma@partners.org FU NCRR NIH HHS [R21 RR026123]; NINDS NIH HHS [P50 NS037409, R01 NS046340, 5P50NS037409, R01 NS058949, P50 NS037409-11] NR 5 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP PY 2011 VL 26 IS 11 BP 2140 EP 2140 DI 10.1002/mds.23786 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 827VF UT WOS:000295456300035 PM 21674621 ER PT J AU Brun, R Surjanhata, B Kuo, B AF Brun, R. Surjanhata, B. Kuo, B. TI pH profiles of gi tract by wireless motility capsule (WMC) in healthy (H), gastroparetics (GP) and constipated (C) SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Brun, R.; Surjanhata, B.; Kuo, B.] Massachusetts Gen Hosp, GI Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 48 BP 15 EP 15 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100049 ER PT J AU Brun, R Michalek, W Kuo, B AF Brun, R. Michalek, W. Kuo, B. TI Cephalic phase of small bowel fed response as measured by wireless motility capsule (WMC) SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Brun, R.; Michalek, W.; Kuo, B.] Massachusetts Gen Hosp, GI Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 47 BP 15 EP 15 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100048 ER PT J AU Leung, FW AF Leung, F. W. TI Treatment of fecal incontinence (FI) by injection of bulking agent into peri-anal tissue - review of observational studies (OS) and randomized controlled trials (RCT) SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Leung, F. W.] VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Med Serv, North Hills, CA USA. [Leung, F. W.] VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Res Serv, North Hills, CA USA. [Leung, F. W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 68 BP 21 EP 21 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100069 ER PT J AU Brun, R Surjanhata, B Michalek, W Baker, JR Wilding, G Hasler, W Kuo, B AF Brun, R. Surjanhata, B. Michalek, W. Baker, J. R. Wilding, G. Hasler, W. Kuo, B. TI Mild and severe gastroparesis (gp) as defined by wireless motility capsule (wmc) - comparison of clinical characteristics and pressure profiles SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 [Brun, R.; Surjanhata, B.; Michalek, W.; Kuo, B.] Massachusetts Gen Hosp, GI Unit, Boston, MA 02114 USA. [Baker, J. R.; Hasler, W.] Univ Michigan, GI Unit, Ann Arbor, MI 48109 USA. [Wilding, G.] SUNY Buffalo, Buffalo, NY 14260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 127 BP 37 EP 37 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100127 ER PT J AU Chaudhury, A He, XD Goyal, RK AF Chaudhury, A. He, X. D. Goyal, R. K. TI Myosin Va plays a key role in enteric purinergic neurotransmission by transporting purinergic secretory vesicles to the varicosity membrane for exocytosis SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Meeting Abstract C1 VA Boston HealthCare Syst, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD SEP PY 2011 VL 23 SU 1 SI SI MA 163 BP 47 EP 47 PG 1 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 822NL UT WOS:000295055100163 ER PT J AU Mata, IF Wilhoite, GJ Yearout, D Bacon, JA Cornejo-Olivas, M Mazzetti, P Marca, V Ortega, O Acosta, O Cosentino, C Torres, L Medina, AC Perez-Pastene, C Diaz-Grez, F Vilarino-Guell, C Venegas, P Miranda, M Trujillo-Godoy, O Layson, L Avello, R Dieguez, E Raggio, V Micheli, F Perandones, C Alvarez, V Segura-Aguilar, J Farrer, MJ Zabetian, CP Ross, OA AF Mata, Ignacio F. Wilhoite, Greggory J. Yearout, Dora Bacon, Justin A. Cornejo-Olivas, Mario Mazzetti, Pilar Marca, Victoria Ortega, Olimpio Acosta, Oscar Cosentino, Carlos Torres, Luis Medina, Angel C. Perez-Pastene, Carolina Diaz-Grez, Fernando Vilarino-Gueell, Carles Venegas, Pablo Miranda, Marcelo Trujillo-Godoy, Osvaldo Layson, Luis Avello, Rodrigo Dieguez, Elena Raggio, Victor Micheli, Federico Perandones, Claudia Alvarez, Victoria Segura-Aguilar, Juan Farrer, Matthew J. Zabetian, Cyrus P. Ross, Owen A. TI Lrrk2 p.Q1111H substitution and Parkinson's disease in Latin America SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson disease; Lrrk2; Latin America ID COMPREHENSIVE ANALYSIS; MUTATIONS; FAMILIES; RISK; GENE AB Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson's disease. Screening in Parkinson's disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Mata, Ignacio F.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr S182, Seattle, WA 98108 USA. [Mata, Ignacio F.; Yearout, Dora; Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Wilhoite, Greggory J.; Bacon, Justin A.; Vilarino-Gueell, Carles; Farrer, Matthew J.; Ross, Owen A.] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. [Cornejo-Olivas, Mario; Mazzetti, Pilar; Marca, Victoria; Ortega, Olimpio; Segura-Aguilar, Juan] Inst Nacl Ciencias Neurol, Neurogenet Unit, Lima, Peru. [Acosta, Oscar] Univ Nacl Mayor San Marcos, Sch Med, Lima 14, Peru. [Medina, Angel C.] Univ Nacl Altiplano, Puno, Peru. [Perez-Pastene, Carolina; Diaz-Grez, Fernando] Univ Chile, Fac Med, ICBM, Santiago 7, Chile. [Vilarino-Gueell, Carles; Farrer, Matthew J.] Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 1M9, Canada. [Miranda, Marcelo] Clin Las Condes, Santiago, Chile. [Layson, Luis] Hosp Barros Luco, Santiago, Chile. [Dieguez, Elena] Univ Republica, Fac Med, Dept Neurol, Montevideo, Uruguay. [Raggio, Victor] Univ Republica, Fac Med, Dept Genet, Montevideo, Uruguay. [Micheli, Federico; Perandones, Claudia] Hosp Clin Buenos Aires, Dept Neurol, Buenos Aires, DF, Argentina. [Alvarez, Victoria] Hosp Univ Cent Asturias, Inst Invest Nefrol IRSINFRIAT, Lab Genet Mol, Oviedo, Spain. RP Mata, IF (reprint author), VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr S182, 1660 S Columbian Way, Seattle, WA 98108 USA. EM nachofm@u.washington.edu RI Micheli, Federico/A-8358-2012; Ross, Owen/D-7573-2013; Vilarino-Guell, Carles/D-8628-2011; Segura-Aguilar, Juan/H-8839-2013; OI Vilarino-Guell, Carles/0000-0002-5612-5940; Segura-Aguilar, Juan/0000-0002-1018-673X; Fernandez Mata, Ignacio/0000-0003-1198-0633; Zabetian, Cyrus/0000-0002-7739-4306; Cornejo-Olivas, Mario /0000-0001-6313-5680 FU National Institutes of Health [R01 NS065070, P50 NS062684, P50 NS072187]; Department of Veterans Affairs [1101BX000531]; FONDECYT [1061083]; Parkinson's Disease Foundation; Michael J. Fox Foundation; family of Carl and Susan Bolch; NIH [R24 TW007988] FX This work was supported by the National Institutes of Health (R01 NS065070, P50 NS062684, P50 NS072187), Department of Veterans Affairs (1101BX000531), FONDECYT (#1061083), Parkinson's Disease Foundation, Michael J. Fox Foundation, and the family of Carl and Susan Bolch. Dr Cornejo-Olivas is the recipient of an NIH Fogarty International Clinical Research Fellowship at Vanderbilt University (R24 TW007988). NR 12 TC 3 Z9 4 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2011 VL 17 IS 8 BP 629 EP 631 DI 10.1016/j.parkreldis.2011.05.003 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 831WE UT WOS:000295761000010 PM 21632271 ER PT J AU Stengel, A Goebel-Stengel, M Jawien, J Kobelt, P Tache, Y Lambrecht, NWG AF Stengel, Andreas Goebel-Stengel, Miriam Jawien, Janusz Kobelt, Peter Tache, Yvette Lambrecht, Nils W. G. TI Lipopolysaccharide increases gastric and circulating NUCB2/nesfatin-1 concentrations in rats SO PEPTIDES LA English DT Article DE Endotoxin; Ghrelin; Nucleobindin2; Stomach; X/A-like cell ID REGULATED TRANSCRIPT PEPTIDE; EDINGER-WESTPHAL NUCLEUS; FASTED PLASMA GHRELIN; FOOD-INTAKE; NESFATIN-1 NEURONS; BODY-WEIGHT; IMMUNOREACTIVITY; BRAIN; EXPRESSION; RECEPTOR AB Bacterial lipopolysaccharide (LPS) is an established animal model to study the innate immune response to Gram-negative bacteria mimicking symptoms of infection including reduction of food intake. LPS decreases acyl ghrelin associated with decreased concentrations of circulating ghrelin-O-acyltransferase (GOAT) likely contributing to the anorexigenic effect. We also recently described the prominent expression of the novel anorexigenic hormone, nucleobindin2 (NUCB2)/nesfatin-1 in gastric X/A-like cells co-localized with ghrelin in different pools of vesicles. To investigate whether LPS would affect gastric and circulating NUCB2/nesfatin-1 concentration, ad libitum fed rats were equipped with an intravenous (iv) catheter. LPS was injected intraperitoneally (ip, 100 mu g/kg) and blood was withdrawn before and at 2, 5, 7 and 24 h post injection and processed for NUCB2/nesfatin-1 radioimmunoassay. Gastric corpus was collected to measure NUCB2 mRNA expression by RT-qPCR and NUCB2/nesfatin-1 protein concentration by Western blot. Injection of LPS increased plasma NUCB2/nesfatin-1 concentrations by 43%, 78% and 62% compared to vehicle at 2 h, 5 h and 7 h post injection respectively (p < 0.05) and returned to baseline at 24 h. The plasma NUCB2/nesfatin-1 increase at 2 h was associated with increased corpus NUCB2 mRNA expression (p < 0.01), whereas NUCB2 mRNA was not detectable in white blood cells. Likewise, gastric NUCB2 protein concentration was increased by 62% after LPS compared to vehicle (p < 0.01). These data show that gastric NUCB2 production and release are increased in response to LPS. These changes are opposite to those of ghrelin in response to LPS supporting a differential gastric regulation of NUCB2/nesfatin-1 and ghrelin expression derived from the same cell by immune challenge. (C) 2011 Published by Elsevier Inc. C1 [Stengel, Andreas; Goebel-Stengel, Miriam; Tache, Yvette] Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Ctr Neurobiol Stress, Dept Med,Digest Dis Div, Los Angeles, CA 90073 USA. [Stengel, Andreas; Goebel-Stengel, Miriam; Tache, Yvette] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. [Stengel, Andreas; Kobelt, Peter] Univ Med Berlin, Dept Med, Div Psychosomat Med & Psychotherapy, Charite, Berlin, Germany. [Goebel-Stengel, Miriam] Martin Luther Krankenhaus, Dept Med, Berlin, Germany. [Goebel-Stengel, Miriam] Martin Luther Krankenhaus, Inst Neurogastroenterol, Berlin, Germany. [Lambrecht, Nils W. G.] Vet Affairs Long Beach Healthcare Syst, Gastrointestinal Endocrinol, Long Beach, CA 90822 USA. RP Lambrecht, NWG (reprint author), VA Long Beach HCS, 5901 E 7th St,Bldg 1,Rm 200M, Long Beach, CA 90822 USA. EM Nils.Lambrecht2@va.gov OI Lambrecht, Nils/0000-0002-1275-1384 FU Department of Veterans Affairs; VA Research Career Scientist Award; NIH [DK-33061]; Center [DK-41301] FX This work was supported by Department of Veterans Affairs Merit Awards (N.W.G.L. and Y.T.), VA Research Career Scientist Award (Y.T.), NIH DK-33061 (Y.T.) and Center grant DK-41301 (Animal Core, Y.T.). NR 45 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 EI 1873-5169 J9 PEPTIDES JI Peptides PD SEP PY 2011 VL 32 IS 9 BP 1942 EP 1947 DI 10.1016/j.peptides.2011.07.006 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 831YQ UT WOS:000295767400022 PM 21782869 ER PT J AU Anguera, MC Ma, WY Clift, D Namekawa, S Kelleher, RJ Lee, JT AF Anguera, Montserrat C. Ma, Weiyuan Clift, Danielle Namekawa, Satoshi Kelleher, Raymond J., III Lee, Jeannie T. TI Tsx Produces a Long Noncoding RNA and Has General Functions in the Germline, Stem Cells, and Brain SO PLOS GENETICS LA English DT Article ID X-CHROMOSOME INACTIVATION; TESTIS-SPECIFIC GENE; DOSAGE COMPENSATION; SYNAPTIC PLASTICITY; MOUSE EMBRYOS; TSIX; MEMORY; MICE; SPERMATOGENESIS; HIPPOCAMPUS AB The Tsx gene resides at the X-inactivation center and is thought to encode a protein expressed in testis, but its function has remained mysterious. Given its proximity to noncoding genes that regulate X-inactivation, here we characterize Tsx and determine its function in mice. We find that Tsx is actually noncoding and the long transcript is expressed robustly in meiotic germ cells, embryonic stem cells, and brain. Targeted deletion of Tsx generates viable offspring and X-inactivation is only mildly affected in embryonic stem cells. However, mutant embryonic stem cells are severely growth-retarded, differentiate poorly, and show elevated cell death. Furthermore, male mice have smaller testes resulting from pachytene-specific apoptosis and a maternal-specific effect results in slightly smaller litters. Intriguingly, male mice lacking Tsx are less fearful and have measurably enhanced hippocampal short-term memory. Combined, our study indicates that Tsx performs general functions in multiple cell types and links the noncoding locus to stem and germ cell development, learning, and behavior in mammals. C1 [Anguera, Montserrat C.; Clift, Danielle; Lee, Jeannie T.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Anguera, Montserrat C.; Clift, Danielle; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Anguera, Montserrat C.; Clift, Danielle; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Ma, Weiyuan; Kelleher, Raymond J., III] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ma, Weiyuan; Kelleher, Raymond J., III] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Namekawa, Satoshi] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH USA. RP Anguera, MC (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA. EM lee@molbio.mgh.harvard.edu FU NIH; HHMI FX This work was supported by the NIH and HHMI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 45 Z9 49 U1 1 U2 7 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 SEP PY 2011 VL 7 IS 9 AR e1002248 DI 10.1371/journal.pgen.1002248 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100007 PM 21912526 ER PT J AU Boger, CA Gorski, M Li, M Hoffmann, MM Huang, CM Yang, Q Teumer, A Krane, V O'Seaghdha, CM Kutalik, Z Wichmann, HE Haak, T Boes, E Coassin, S Coresh, J Kollerits, B Haun, M Paulweber, B Kottgen, A Li, G Shlipak, MG Powe, N Hwang, SJ Dehghan, A Rivadeneira, F Uitterlinden, A Hofman, A Beckmann, JS Kramer, BK Witteman, J Bochud, M Siscovick, D Rettig, R Kronenberg, F Wanner, C Thadhani, RI Heid, IM Fox, CS Kao, WH AF Boeger, Carsten A. Gorski, Mathias Li, Man Hoffmann, Michael M. Huang, Chunmei Yang, Qiong Teumer, Alexander Krane, Vera O'Seaghdha, Conall M. Kutalik, Zoltan Wichmann, H. -Erich Haak, Thomas Boes, Eva Coassin, Stefan Coresh, Josef Kollerits, Barbara Haun, Margot Paulweber, Bernhard Koettgen, Anna Li, Guo Shlipak, Michael G. Powe, Neil Hwang, Shih-Jen Dehghan, Abbas Rivadeneira, Fernando Uitterlinden, Andre Hofman, Albert Beckmann, Jacques S. Kraemer, Bernhard K. Witteman, Jacqueline Bochud, Murielle Siscovick, David Rettig, Rainer Kronenberg, Florian Wanner, Christoph Thadhani, Ravi I. Heid, Iris M. Fox, Caroline S. Kao, W. H. CA CKDGen Consortium TI Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD SO PLOS GENETICS LA English DT Article ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; DIABETIC-NEPHROPATHY; GENERAL-POPULATION; AFRICAN-AMERICANS; RISK; PROGRESSION; MORTALITY; VARIANTS AB Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression. C1 [Boeger, Carsten A.] Univ Hosp Regensburg, Dept Internal Med 2, Regensburg, Germany. [Gorski, Mathias; Heid, Iris M.] Univ Hosp Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Gorski, Mathias; Wichmann, H. -Erich; Heid, Iris M.] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Li, Man; Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hoffmann, Michael M.] Univ Freiburg, Univ Med Ctr Freiburg, Freiburg, Germany. [Huang, Chunmei; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Krane, Vera; Wanner, Christoph] Univ Wurzburg, Div Nephrol, Dept Med 1, Univ Hosp Wurzburg, Wurzburg, Germany. [O'Seaghdha, Conall M.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Kutalik, Zoltan] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kutalik, Zoltan] Swiss Inst Bioinformat, Lausanne, Switzerland. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Haak, Thomas] Diabet Klin Bad Mergentheim, Bad Mergentheim, Germany. [Boes, Eva; Coassin, Stefan; Kollerits, Barbara; Haun, Margot; Kronenberg, Florian] Innsbruck Med Univ, Div Genet Epidemiol, Innsbruck, Austria. [Coresh, Josef; Kao, W. H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef; Kao, W. H.] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, Salzburg, Austria. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Li, Guo] Univ Washington, Dept Med, Seattle, WA USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med Epidemiol & Biostat, San Francisco, CA 94143 USA. [Powe, Neil] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Dehghan, Abbas; Hofman, Albert; Witteman, Jacqueline] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kraemer, Bernhard K.] Univ Med Ctr Mannheim, Dept Med 5, Mannheim, Germany. [Bochud, Murielle] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland. [Siscovick, David] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Boger, CA (reprint author), Univ Hosp Regensburg, Dept Internal Med 2, Regensburg, Germany. EM foxca@nhlbi.nih.gov; wkao@jhsph.edu RI Beckmann, Jacques S /A-9772-2008; Kronenberg, Florian/B-1736-2008; Kottgen, Anna/D-2920-2012; Li, Guo/E-5613-2012; Yang, Qiong/G-5438-2014; Hoffmann, Michael/D-4074-2015; Colaus, PsyColaus/K-6607-2013; Rivadeneira, Fernando/O-5385-2015; Bochud, Murielle/A-3981-2010 OI Beckmann, Jacques S /0000-0002-9741-1900; Kronenberg, Florian/0000-0003-2229-1120; Dehghan, Abbas/0000-0001-6403-016X; Hoffmann, Michael/0000-0001-8459-6080; Rivadeneira, Fernando/0000-0001-9435-9441; Bochud, Murielle/0000-0002-5727-0218 FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; German Research Foundation; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552]; Swiss School of Public Health Plus; Giorgi-Cavaglieri Foundation; European Framework Project 6 (EuroDia, AnEuploidy and Hypergenes projects); National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; NIH, Children's Hospital, Boston, US [1 R01 DK075787-01A1]; German National Genome Research Net [01GS0823, A3, 01GS0834]; Munich Center of Health Sciences (MC Health); Else Kroner-Fresenius-Stiftung [P48/08//A11/08]; Regensburg University Medical Center, Germany; University of Ulm, Germany; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; State of Bavaria; University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus University Medical Center; Netherlands Organisation for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; German Bundesministerium fur Forschung und Technologie [01 AK 803 A-H, 01 IG 07015]; NWO [918-76-619]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Germany; Federal State of Mecklenburg-West Pomerania; Kamillo Eisner Stiftung; Genomics Of Lipid-associated Disorders (GOLD) of the Austrian Genome Research Programme GEN-AU; Interdisziplinares Zentrum fur Klinische Forschung (IZKF); Bundesministerium fuer Bildung und Forschung (BMBF); Comprehensive Heart Failure Center; Pfizer; NIH [DK071674, DK084974, 5T32DK007540-25]; National Institute of Diabetes, Digestive and Kidney Diseases [R01DK080123, R01DK059616]; Agency for Health Care Research and Quality [R01HS008365]; Dr Robert Pfleger-Stiftung; University of Regensburg; KfH-Stiftung Praventivmedizin e.V. FX The Atherosclerosis Risk in Communities Study (ARIC) was supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005 from NIH Roadmap for Medical Research. AK was supported by the Emmy Noether Programme of the German Research Foundation. The Cardiovascular Health Study (CHS) research was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652, and R01 AG027002 from the National Heart, Lung, and Blood Institute, with additional contributions from the National Institute of Neurological Disorders and Stroke. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping Core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552), the Swiss School of Public Health Plus, the Giorgi-Cavaglieri Foundation, and the European Framework Project 6 (EuroDia, AnEuploidy and Hypergenes projects). The Framingham Heart Study (FHS): This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix for genotyping services (N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. KORA cohorts: The genetic epidemiological work was funded by the NIH subcontract from the Children's Hospital, Boston, US (HEW, IMH; prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (HEW, 01GS0823; WK, project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kroner-Fresenius-Stiftung (CAB, BKK; P48/08//A11/08). The kidney parameter measurements in F3 were funded by the Else Kroner-Fresenius-Stiftung (CAB, BKK) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (WK). The Else Kroner-Fresenius-Stiftung funded de novo and (in part) genome-wide genotyping in F3 and F4 (CAB, BKK). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria.; Genotyping was performed in the Genome Analysis Center (GAC) of the Helmoltz Zentrum Munchen. The LINUX platform for computation was funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. The Rotterdam Study: The GWAS was funded by the Netherlands Organisation of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project 050-060-810. The Rotterdam Study is funded by the Erasmus University Medical Center, the Netherlands Organisation for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The national German MediGRID and Services@MediGRID, part of the German D-Grid provided access to their grid resources, both funded by the German Bundesministerium fur Forschung und Technologie under grants #01 AK 803 A-H and # 01 IG 07015 G. AD is supported by NWO grant (vici, 918-76-619). The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG. The SAPHIR study was partially supported by a grant from the Kamillo Eisner Stiftung to BP and by grants from the Genomics Of Lipid-associated Disorders (GOLD) of the Austrian Genome Research Programme GEN-AU to FK. Genotyping was funded by the Else Kroner-Fresenius-Stiftung (CAB, BKK; P48/08//A11/08). 4D Study: The Interdisziplinares Zentrum fur Klinische Forschung (IZKF) provided an intramural grant and the Bundesministerium fuer Bildung und Forschung (BMBF) sponsored Comprehensive Heart Failure Center supported subanalyses in the 4D study. Genotyping was funded by the Else Kroner-Fresenius-Stiftung (CAB, BKK; P48/08//A11/08). The original study was supported by Pfizer. ArMORR received funding from the NIH (DK071674). RT is supported by NIH grant DK084974 and CH by 5T32DK007540-25. CHOICE was supported by grants R01DK080123 and R01DK059616 from the National Institute of Diabetes, Digestive and Kidney Diseases, grant R01HL62985 from the National Heart Lung and Blood Institute, and grant R01HS008365 from the Agency for Health Care Research and Quality. The Family Heart and Kidney Study (FHKS) was partially supported by a grant from GOLD to FK. Genotyping was funded by the Else Kroner-Fresenius-Stiftung (CAB, BKK; P48/08//A11/08). GENDIAN has received funding from the Dr Robert Pfleger-Stiftung, the Else Kroner-Fresenius-Stiftung, the University of Regensburg's intramural grants ReForM A, B, and C, and from the KfH-Stiftung Praventivmedizin e.V. The Mild to Moderate Kidney Disease (MMKD) Study was partially supported by a grant from GOLD to FK. Genotyping was funded by the Else Kroner-Fresenius-Stiftung (CAB, BKK; P48/08//A11/08).; The funders had no rol in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 60 Z9 62 U1 2 U2 8 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 SEP PY 2011 VL 7 IS 9 AR e1002292 DI 10.1371/journal.pgen.1002292 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100041 PM 21980298 ER PT J AU Butterworth, AS Braund, PS Farrall, M Hardwick, RJ Saleheen, D Peden, JF Soranzo, N Chambers, JC Sivapalaratnam, S Kleber, ME Keating, B Qasim, A Klopp, N Erdmann, J Assimes, TL Ball, SG Balmforth, AJ Barnes, TA Basart, H Baumert, J Bezzina, CR Boerwinkle, E Boehm, BO Brocheton, J Bugert, P Cambien, F Clarke, R Codd, V Collins, R Couper, D Cupples, LA de Jong, JS Diemert, P Ejebe, K Elbers, CC Elliott, P Fornage, M Franzosi, MG Frossard, P Garner, S Goel, A Goodall, AH Hengstenberg, C Hunt, SE Kastelein, JJP Klungel, OH Kluter, H Koch, K Konig, IR Kooner, AS Laaksonen, R Lathrop, M Li, MY Liu, K McPherson, R Musameh, MD Musani, S Nelson, CP O'Donnell, CJ Ongen, H Papanicolaou, G Peters, A Peters, BJM Potter, S Psaty, BM Qu, LM Rader, DJ Rasheed, A Rice, C Scott, J Seedorf, U Sehmi, JS Sotoodehnia, N Stark, K Stephens, J van der Schoot, CE van der Schouw, YT Thorsteinsdottir, U Tomaszewski, M van der Harst, P Vasan, RS Wilde, AAM Willenborg, C Winkelmann, BR Zaidi, M Zhang, WH Ziegler, A de Bakker, PIW Koenig, W Marz, W Trip, MD Reilly, MP Kathiresan, S Schunkert, H Hamsten, A Hall, AS Kooner, JS Thompson, SG Thompson, JR Deloukas, P Ouwehand, WH Watkins, H Danesh, J Samani, NJ AF Butterworth, Adam S. Braund, Peter S. Farrall, Martin Hardwick, Robert J. Saleheen, Danish Peden, John F. Soranzo, Nicole Chambers, John C. Sivapalaratnam, Suthesh Kleber, Marcus E. Keating, Brendan Qasim, Atif Klopp, Norman Erdmann, Jeanette Assimes, Themistocles L. Ball, Stephen G. Balmforth, Anthony J. Barnes, Timothy A. Basart, Hanneke Baumert, Jens Bezzina, Connie R. Boerwinkle, Eric Boehm, Bernhard O. Brocheton, Jessy Bugert, Peter Cambien, Francois Clarke, Robert Codd, Veryan Collins, Rory Couper, David Cupples, L. Adrienne de Jong, Jonas S. Diemert, Patrick Ejebe, Kenechi Elbers, Clara C. Elliott, Paul Fornage, Myriam Franzosi, Maria-Grazia Frossard, Philippe Garner, Stephen Goel, Anuj Goodall, Alison H. Hengstenberg, Christian Hunt, Sarah E. Kastelein, John J. P. Klungel, Olaf H. Klueter, Harald Koch, Kerstin Koenig, Inke R. Kooner, Angad S. Laaksonen, Reijo Lathrop, Mark Li, Mingyao Liu, Kiang McPherson, Ruth Musameh, Muntaser D. Musani, Solomon Nelson, Christopher P. O'Donnell, Christopher J. Ongen, Halit Papanicolaou, George Peters, Annette Peters, Bas J. M. Potter, Simon Psaty, Bruce M. Qu, Liming Rader, Daniel J. Rasheed, Asif Rice, Catherine Scott, James Seedorf, Udo Sehmi, Joban S. Sotoodehnia, Nona Stark, Klaus Stephens, Jonathan van der Schoot, C. Ellen van der Schouw, Yvonne T. Thorsteinsdottir, Unnur Tomaszewski, Maciej van der Harst, Pim Vasan, Ramachandran S. Wilde, Arthur A. M. Willenborg, Christina Winkelmann, Bernhard R. Zaidi, Moazzam Zhang, Weihua Ziegler, Andreas de Bakker, Paul I. W. Koenig, Wolfgang Maerz, Winfried Trip, Mieke D. Reilly, Muredach P. Kathiresan, Sekar Schunkert, Heribert Hamsten, Anders Hall, Alistair S. Kooner, Jaspal S. Thompson, Simon G. Thompson, John R. Deloukas, Panos Ouwehand, Willem H. Watkins, Hugh Danesh, John Samani, Nilesh J. CA IBC 50K CAD Consortium TI Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCI; RISK; ATHEROSCLEROSIS; METAANALYSIS; LIPOPROTEIN AB Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in similar to 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other similar to 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. C1 [Butterworth, Adam S.; Saleheen, Danish; Thompson, Simon G.; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Braund, Peter S.; Hardwick, Robert J.; Barnes, Timothy A.; Codd, Veryan; Goodall, Alison H.; Musameh, Muntaser D.; Nelson, Christopher P.; Tomaszewski, Maciej; van der Harst, Pim; Samani, Nilesh J.] Univ Leicester, Dept Cardiovas Sci, Glenfield Gen Hosp, Leicester, Leics, England. [Braund, Peter S.; Hardwick, Robert J.; Barnes, Timothy A.; Codd, Veryan; Goodall, Alison H.; Musameh, Muntaser D.; Nelson, Christopher P.; Tomaszewski, Maciej; van der Harst, Pim; Samani, Nilesh J.] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE3 9QP, Leics, England. [Farrall, Martin; Peden, John F.; Goel, Anuj; Ongen, Halit; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Farrall, Martin; Peden, John F.; Goel, Anuj; Ongen, Halit; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hardwick, Robert J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Saleheen, Danish; Frossard, Philippe; Rasheed, Asif; Zaidi, Moazzam] Ctr Noncommunicable Dis, Karachi, Pakistan. [Soranzo, Nicole; Hunt, Sarah E.; Potter, Simon; Rice, Catherine; Deloukas, Panos; Ouwehand, Willem H.] Wellcome Trust Sanger Inst, Hinxton, England. [Chambers, John C.; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Sivapalaratnam, Suthesh; Basart, Hanneke; Kastelein, John J. P.; Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Kleber, Marcus E.] LURIC Non Profit LLC, Freiburg, Germany. [Keating, Brendan] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Qasim, Atif; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Klopp, Norman; Baumert, Jens; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Erdmann, Jeanette; Diemert, Patrick; Willenborg, Christina; Schunkert, Heribert] Univ Lubeck, Med Klin 2, Lubeck, Germany. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Ball, Stephen G.] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds, W Yorkshire, England. [Balmforth, Anthony J.] Univ Leeds, Div Cardiovasc & Diabet Res, Multidisciplinary Cardiovasc Res Ctr, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Bezzina, Connie R.; de Jong, Jonas S.; Wilde, Arthur A. M.; Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Boehm, Bernhard O.] Univ Ulm, Div Endocrinol & Diabet, Ctr Excellence Metab Dis, Dept Internal Med, Ulm, Germany. [Brocheton, Jessy; Cambien, Francois] Univ Paris 06, INSERM, UMRS 937, Paris, France. [Brocheton, Jessy; Cambien, Francois] Sch Med, Paris, France. [Bugert, Peter; Klueter, Harald] Univ Heidelberg, Inst Transfus Med & Immunol, Germany Red Cross Blood Serv, Baden Wurttemberg Hessen gGmbH,Med Fac Mannheim, D-6800 Mannheim, Germany. [Clarke, Robert; Collins, Rory] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Clarke, Robert; Collins, Rory] Univ Oxford, Epidemiol Studies Unit, Oxford, England. [Couper, David] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ejebe, Kenechi; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ejebe, Kenechi; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ejebe, Kenechi; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Elbers, Clara C.; van der Schouw, Yvonne T.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Elbers, Clara C.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Div Biomed Genet, Dept Med Genet, Utrecht, Netherlands. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London, England. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Franzosi, Maria-Grazia] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Garner, Stephen; Koch, Kerstin; Stephens, Jonathan; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Garner, Stephen; Koch, Kerstin; Stephens, Jonathan; Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge, England. [Hengstenberg, Christian; Stark, Klaus] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Klungel, Olaf H.; Peters, Bas J. M.] Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Koenig, Inke R.; Ziegler, Andreas] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Kooner, Angad S.; Scott, James; Sehmi, Joban S.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Lathrop, Mark] CEA, Inst Genom, Ctr Natl Genotypage, F-91057 Evry, France. [Lathrop, Mark] Fdn Jean Dausset CEPH, F-75010 Paris, France. [Li, Mingyao; Qu, Liming] Univ Penn, Med Ctr, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [McPherson, Ruth] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Musani, Solomon] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Papanicolaou, George; Reilly, Muredach P.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [van der Schoot, C. Ellen] Sanquin Res, Dept Expt Immunohematol, Amsterdam, Netherlands. [Thorsteinsdottir, Unnur] deCODE Genet, IS-101 Reykjavik, Iceland. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Echocardiog Vasc Lab, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Dept Med, Prevent Med & Epidemiol Sect, Framingham, MA USA. [Winkelmann, Bernhard R.] Cardiol Grp Frankfurt Sachsenhausen, Frankfurt, Germany. [Winkelmann, Bernhard R.] Clin Phen GmbH, Frankfurt, Germany. [de Bakker, Paul I. W.; Kathiresan, Sekar] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany. [Maerz, Winfried] Synlab Serv GmbH, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, Winfried] Univ Heidelberg, Inst Publ Heath Social Med & Epidemiol, Med Fac Mannheim, D-6800 Mannheim, Germany. [Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden. [Hall, Alistair S.] Univ Leeds, Inst Genet Hlth & Therapeut, Multidisciplinary Cardiovasc Res Ctr, Div Cardiovasc & Neuronal Remodelling, Leeds, W Yorkshire, England. [Thompson, Simon G.] Med Res Council Biostat Unit, Cambridge, England. [Thompson, Simon G.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. RP Butterworth, AS (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. EM hugh.watkins@cardiov.ox.ac.uk; jd292@medschl.cam.ac.uk; njs@leicester.ac.uk RI Leander, Karin/C-7261-2017; Smith, Albert Vernon/K-5150-2015; Morgan, Tom/C-3478-2012; de Bakker, Paul/B-8730-2009; Laaksonen, Reijo/D-6323-2014; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Peters, Annette/A-6117-2011; Ejebe, Kenechi/I-9238-2016; Martinelli, Nicola/J-5622-2016; Klungel, Olaf/I-9563-2016; Konig, Inke/A-4544-2009; Stark, Klaus/D-3813-2009; Willenborg, Christina/D-2668-2012; Deloukas, Panos/B-2922-2013; Erdmann, Jeanette/A-4417-2009; Erdmann, Jeanette/P-7513-2014; OI Ouwehand, Willem/0000-0002-7744-1790; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Sabater Lleal, Maria/0000-0002-0128-379X; Leander, Karin/0000-0002-1404-9222; Meisinger, Christa/0000-0002-9026-6544; ELOSUA, ROBERTO/0000-0001-8235-0095; Hunt, Sarah/0000-0002-8350-1235; Smith, Albert Vernon/0000-0003-1942-5845; Stewart, Alexandre/0000-0003-2673-9164; Seedorf, Udo/0000-0003-4652-5358; Ramachandran, Vasan/0000-0001-7357-5970; de Bakker, Paul/0000-0001-7735-7858; Strawbridge, Rona/0000-0001-8506-3585; Ejebe, Kenechi/0000-0002-6090-8657; Martinelli, Nicola/0000-0001-6465-5119; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Deloukas, Panos/0000-0001-9251-070X; Erdmann, Jeanette/0000-0002-4486-6231; Peyvandi, Flora/0000-0001-7423-9864; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Ziegler, Andreas/0000-0002-8386-5397; Ferguson, Jane/0000-0001-6896-1025; Nothen, Markus/0000-0002-8770-2464; Watkins, Hugh/0000-0002-5287-9016; Jones, Gregory T/0000-0002-6950-4210 FU British Heart Foundation (BHF); UK Medical Research Council; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease; AMC (The Netherlands); LURIC (Germany); University of Cambridge (UK); Wellcome Trust Sanger Institute (UK); Bloodomics [LSHM-CT-2004-503485]; British Heart Foundation [RG/09/12/28096]; National Institute for Health Research [RP-PG-0310-1002]; Netherlands Heart Foundation [2001D019, 2003T302, 2007B202]; Leducq Foundation [05-CVD]; Center for Translational Molecular Medicine (CTMM COHFAR); Interuniversity Cardiology Institute of The Netherlands; LURIC [LSHM-CT-2004-503485]; European Union [201668, LSHM-CT-2006-037593]; National Heart, Lung, and Blood Institute; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network [01GS0834]; University of Ulm; Munich Center of Health Sciences (MC Health); Penn Cardiovascular Institute; GlaxoSmithKline; British Heart Foundation; European Community [LSHM-CT-2007-037273]; AstraZeneca; Wellcome Trust; United Kingdom Medical Research Council; Swedish Heart-Lung Foundation; Swedish Medical Research Council; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Karolinska Institutet and Stockholm County Council; Foundation for Strategic Research; Stockholm County Council [560283]; University of Cambridge and in Pakistan; EU Framework 6-funded Bloodomics Integrated Project [LSHM-CT-2004-503485]; Yousef Jameel Foundation; European Commission (SANCO); Dutch Ministry of Health; Dutch Cancer Society; ZonMW; Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF); NL Agency [IGE 05012]; Organization for Scientific Research (NWO); Netherlands Heart Foundation (NHS) [2001.064]; TI Pharma [T6-101]; Novo Nordisk; Top Institute Pharma; Dutch Medicines Evaluation Board FX BHF-FHS: Recruitment of CAD cases for the BHF-FHS study was supported by the British Heart Foundation (BHF) and the UK Medical Research Council. Controls were provided by the Wellcome Trust Case Control Consortium. Genotyping of the IBC 50K array for the BHF-FHS study was funded by the BHF. NJS and SGB hold personal chairs supported by the BHF. The work described in this paper forms part of the portfolio of translational research supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. BLOODOMICS: The Bloodomics partners from AMC (The Netherlands), LURIC (Germany), the University of Cambridge (UK), and the Wellcome Trust Sanger Institute (UK) received funding through the 6th Framework funded Integrated Project Bloodomics (grant LSHM-CT-2004-503485). The University of Cambridge group in the Department of Haematology also received programme grant funding from the British Heart Foundation (RG/09/12/28096) and the National Institute for Health Research (RP-PG-0310-1002). BLOODOMICS-Dutch: This study was supported by research grants from The Netherlands Heart Foundation (grants 2001D019, 2003T302 and 2007B202), the Leducq Foundation (grant 05-CVD), the Center for Translational Molecular Medicine (CTMM COHFAR), and the Interuniversity Cardiology Institute of The Netherlands (project 27). BLOODOMICS-German: LURIC has received funding through the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. CARe Consortium: CARe was performed with the support of the National Heart, Lung, and Blood Institute and acknowledges the contributions of the research institutions, study investigators, and field staff in creating this resource for biomedical research. Full details of the studies in the CARe Consortium can be found in Text S1. LOLIPOP: Genotyping of the IBC 50K array for the LOLIPOP Study was funded by the British Heart Foundation. Paul Elliott is a National Institute for Health Research Senior Investigator. MONICA-KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative. PennCATH: Muredach P Reilly and Daniel J Rader have been supported by the Penn Cardiovascular Institute and GlaxoSmithKline. PROCARDIS: The PROCARDIS study has been supported by the British Heart Foundation, the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the Wellcome Trust, the United Kingdom Medical Research Council, the Swedish Heart-Lung Foundation, the Swedish Medical Research Council, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). PROMIS: Epidemiological field work in PROMIS was supported by unrestricted grants to investigators at the University of Cambridge and in Pakistan.; Genotyping for this study was funded by the Wellcome Trust and the EU Framework 6-funded Bloodomics Integrated Project(LSHM-CT-2004-503485). The British Heart Foundation has supported some biochemical assays. The Yousef Jameel Foundation supported D Saleheen. The cardiovascular disease epidemiology group of J Danesh is underpinned by programme grants from the British Heart Foundation and the UK Medical Research Council. EPIC-NL: The EPIC-NL study was funded by "Europe against Cancer'' Programme of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF). We thank the institute PHARMO for follow-up data on diabetes. Genotyping was funded by IOP Genomics grant IGE 05012 from NL Agency. UCP: The project was funded by Veni grant Organization for Scientific Research (NWO), Grant no. 2001.064 Netherlands Heart Foundation (NHS), and TI Pharma Grant T6-101 Mondriaan. Cardiogenics: Cardiogenics was funded through the 6th Framework Programme (integrated project Cardiogenics, grant LSHM-CT-2006-037593) of the European Union. None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.; Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (www.tipharma.nl ,includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported. NR 32 TC 15 Z9 15 U1 0 U2 38 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 SEP PY 2011 VL 7 IS 9 AR e1002260 DI 10.1371/journal.pgen.1002260 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100015 ER PT J AU Dewey, FE Chen, R Cordero, SP Ormond, KE Caleshu, C Karczewski, KJ Whirl-Carrillo, M Wheeler, MT Dudley, JT Byrnes, JK Cornejo, OE Knowles, JW Woon, M Sangkuhl, K Gong, L Thorn, CF Hebert, JM Capriotti, E David, SP Pavlovic, A West, A Thakuria, JV Ball, MP Zaranek, AW Rehm, HL Church, GM West, JS Bustamante, CD Snyder, M Altman, RB Klein, TE Butte, AJ Ashley, EA AF Dewey, Frederick E. Chen, Rong Cordero, Sergio P. Ormond, Kelly E. Caleshu, Colleen Karczewski, Konrad J. Whirl-Carrillo, Michelle Wheeler, Matthew T. Dudley, Joel T. Byrnes, Jake K. Cornejo, Omar E. Knowles, Joshua W. Woon, Mark Sangkuhl, Katrin Gong, Li Thorn, Caroline F. Hebert, Joan M. Capriotti, Emidio David, Sean P. Pavlovic, Aleksandra West, Anne Thakuria, Joseph V. Ball, Madeleine P. Zaranek, Alexander W. Rehm, Heidi L. Church, George M. West, John S. Bustamante, Carlos D. Snyder, Michael Altman, Russ B. Klein, Teri E. Butte, Atul J. Ashley, Euan A. TI Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence SO PLOS GENETICS LA English DT Article ID VII-ACTIVATING PROTEASE; MARBURG-I POLYMORPHISM; VENOUS THROMBOSIS; RECOMBINATION HOTSPOTS; MEIOTIC RECOMBINATION; PERSONAL GENOME; FACTOR-V; DISEASE; MUTATIONS; GENOTYPE AB Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing. C1 [Dewey, Frederick E.; Caleshu, Colleen; Wheeler, Matthew T.; Knowles, Joshua W.; Pavlovic, Aleksandra; Ashley, Euan A.] Stanford Univ, Div Cardiovasc Med, Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA. [Chen, Rong; Dudley, Joel T.; Butte, Atul J.] Stanford Univ, Dept Pediat, Sch Med, Div Syst Med, Stanford, CA 94305 USA. [Cordero, Sergio P.; Karczewski, Konrad J.; Dudley, Joel T.] Stanford Univ, Sch Med, Biomed Informat Grad Training Program, Stanford, CA 94305 USA. [Ormond, Kelly E.; Karczewski, Konrad J.; Whirl-Carrillo, Michelle; Byrnes, Jake K.; Cornejo, Omar E.; Woon, Mark; Sangkuhl, Katrin; Gong, Li; Thorn, Caroline F.; Hebert, Joan M.; Capriotti, Emidio; David, Sean P.; Bustamante, Carlos D.; Snyder, Michael; Altman, Russ B.; Klein, Teri E.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Ormond, Kelly E.] Stanford Univ, Ctr Biomed Eth, Stanford, CA 94305 USA. [West, Anne] Wellesley Coll, Wellesley, MA 02181 USA. [Thakuria, Joseph V.] Massachusetts Gen Hosp, Div Genet, Boston, MA 02114 USA. [Ball, Madeleine P.; Zaranek, Alexander W.; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Rehm, Heidi L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [West, John S.] Personalis, Palo Alto, CA USA. [Altman, Russ B.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. RP Dewey, FE (reprint author), Stanford Univ, Div Cardiovasc Med, Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA. EM euan@stanford.edu RI Sincan, Murat /A-3794-2010; Knowles, Josh/C-9241-2013; Capriotti, Emidio/D-9318-2011; OI Capriotti, Emidio/0000-0002-2323-0963; David, Sean/0000-0002-4922-2603; Karczewski, Konrad/0000-0003-2878-4671 FU NIH/NHLBI [T32 HL094274-01A2, KO8 HL083914]; Stanford University School of Medicine; NIH National Research Service [F32 HL097462]; NHGRI [U01HG005715]; NIH/NIGMS [U01 GM61374, R01 GM079719]; NIH/NHGRI [5 P50 HG003389-05]; Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; NIH/NLM [T15 LM007033]; NIH [OD004613]; Breetwor Family Foundation; Novartis; 23andMe; Lilly; NuMedii; Johnson and Johnson; Genstruct; Tercica; Prevendia FX FED was supported by NIH/NHLBI training grant T32 HL094274-01A2 and the Stanford University School of Medicine Dean's Postdoctoral Fellowship. MTW was supported by NIH National Research Service Award fellowship F32 HL097462. JKB, OEC, and CDB were supported by NHGRI grant U01HG005715. CFT, JMH, KS, LG, MW-C, MW, and RBA were supported by grants from the NIH/NIGMS U01 GM61374. KEO was supported by NIH/NHGRI 5 P50 HG003389-05. AJB was supported by the Lucile Packard Foundation for Children's Health, Hewlett Packard Foundation, and NIH/NIGMS R01 GM079719. JTD and KJK were supported by NIH/NLM T15 LM007033. EAA was supported by NIH/NHLBI KO8 HL083914, NIH New Investigator DP2 Award OD004613, and a grant from the Breetwor Family Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; JVT and AWZ are founders, consultants, and equity holders in Clinical Future; GMC has advisory roles in and research sponsorships from several companies involved in genome sequencing technology and personal genomics (see http://arep.med.harvard.edu/gmc/tech.html); MS is on the scientific advisory board of DNA Nexus and holds stock in Personalis; RBA has received consultancy fees from Novartis and 23andMe and holds stock in Personalis; AJB is a scientific advisory board member and founder for NuMedii and Genstruct, a scientific advisory board member for Johnson and Johnson, has received consultancy fees from Lilly, NuMedii, Johnson and Johnson, Genstruct, Tercica, and Prevendia and honoraria from Lilly and Siemens, and holds stock in NuMedii, Genstruct, and Personalis. EAA holds stock in Personalis. NR 53 TC 64 Z9 65 U1 1 U2 4 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 SEP PY 2011 VL 7 IS 9 AR e1002280 DI 10.1371/journal.pgen.1002280 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100031 PM 21935354 ER PT J AU Gouzi, JY Moressis, A Walker, JA Apostolopoulou, AA Palmer, RH Bernards, A Skoulakis, EMC AF Gouzi, Jean Y. Moressis, Anastasios Walker, James A. Apostolopoulou, Anthi A. Palmer, Ruth H. Bernards, Andre Skoulakis, Efthimios M. C. TI The Receptor Tyrosine Kinase Alk Controls Neurofibromin Functions in Drosophila Growth and Learning SO PLOS GENETICS LA English DT Article ID ANAPLASTIC LYMPHOMA KINASE; ADENYLYL-CYCLASE; MUSHROOM BODY; MOUSE MODEL; PC12 CELLS; IN-VIVO; PROTEIN; GENE; MEMORY; NF1 AB Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1. C1 [Gouzi, Jean Y.; Moressis, Anastasios; Apostolopoulou, Anthi A.; Skoulakis, Efthimios M. C.] Biomed Sci Res Ctr Alexander Fleming, Inst Cellular & Dev Biol, Vari, Greece. [Moressis, Anastasios] Univ Athens, Dept Basic Sci, Sch Hlth Sci, Athens 11528, Greece. [Walker, James A.; Bernards, Andre] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Walker, James A.; Bernards, Andre] Harvard Univ, Sch Med, Charlestown, MA USA. [Palmer, Ruth H.] Umea Univ, Dept Mol Biol, Umea, Sweden. RP Gouzi, JY (reprint author), Biomed Sci Res Ctr Alexander Fleming, Inst Cellular & Dev Biol, Vari, Greece. EM skoulakis@fleming.gr OI Apostolopoulou, Anthi/0000-0002-8174-4372 FU Ministere Francais des Affaires Etrangeres et Europeennes; Children's Tumor Foundation; Greek National Scholarships Foundation; Biomedical Sciences Research Center; NIH/NGMS [1-R01 GM084220] FX JYG was supported by a post-doctoral fellowship from the "Programme Lavoisier - Ministere Francais des Affaires Etrangeres et Europeennes" and by a Young Investigator Award from the Children's Tumor Foundation. AM was supported by scholarships from the Greek National Scholarships Foundation (IKY) and from the Biomedical Sciences Research Center "Alexander Fleming." AB and JAW were supported by NIH/NGMS grant 1-R01 GM084220 and by an anonymous donor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 25 Z9 27 U1 0 U2 5 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 SEP PY 2011 VL 7 IS 9 AR e1002281 DI 10.1371/journal.pgen.1002281 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100032 PM 21949657 ER PT J AU Hendel, A Krijger, PHL Diamant, N Goren, Z Langerak, P Kim, J Reissner, T Lee, KY Geacintov, NE Carell, T Myung, K Tateishi, S D'Andrea, A Jacobs, H Livneh, Z AF Hendel, Ayal Krijger, Peter H. L. Diamant, Noam Goren, Zohar Langerak, Petra Kim, Jungmin Reissner, Thomas Lee, Kyoo-young Geacintov, Nicholas E. Carell, Thomas Myung, Kyungjae Tateishi, Satoshi D'Andrea, Alan Jacobs, Heinz Livneh, Zvi TI PCNA Ubiquitination Is Important, But Not Essential for Translesion DNA Synthesis in Mammalian Cells SO PLOS GENETICS LA English DT Article ID POLYMERASE-ETA; 2-POLYMERASE MECHANISMS; MONOUBIQUITINATED PCNA; XERODERMA-PIGMENTOSUM; GENOMIC INSTABILITY; REPLICATION FORK; BINDING DOMAINS; NUCLEAR ANTIGEN; MUTATION LOAD; POL-ETA AB Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism in which specialized low-fidelity DNA polymerases bypass replication-blocking lesions, and it is usually associated with mutagenesis. In Saccharomyces cerevisiae a key event in TLS is the monoubiquitination of PCNA, which enables recruitment of the specialized polymerases to the damaged site through their ubiquitin-binding domain. In mammals, however, there is a debate on the requirement for ubiquitinated PCNA (PCNA-Ub) in TLS. We show that UV-induced Rpa foci, indicative of single-stranded DNA (ssDNA) regions caused by UV, accumulate faster and disappear more slowly in Pcna(K164R/K164R) cells, which are resistant to PCNA ubiquitination, compared to Pcna(+/+) cells, consistent with a TLS defect. Direct analysis of TLS in these cells, using gapped plasmids with site-specific lesions, showed that TLS is strongly reduced across UV lesions and the cisplatin-induced intrastrand GG crosslink. A similar effect was obtained in cells lacking Rad18, the E3 ubiquitin ligase which monoubiquitinates PCNA. Consistently, cells lacking Usp1, the enzyme that de-ubiquitinates PCNA exhibited increased TLS across a UV lesion and the cisplatin adduct. In contrast, cells lacking the Rad5-homologs Shprh and Hltf, which polyubiquitinate PCNA, exhibited normal TLS. Knocking down the expression of the TLS genes Rev3L, PolH, or Rev1 in Pcna(K164R/K164R) mouse embryo fibroblasts caused each an increased sensitivity to UV radiation, indicating the existence of TLS pathways that are independent of PCNA-Ub. Taken together these results indicate that PCNA-Ub is required for maximal TLS. However, TLS polymerases can be recruited to damaged DNA also in the absence of PCNA-Ub, and perform TLS, albeit at a significantly lower efficiency and altered mutagenic specificity. C1 [Hendel, Ayal; Diamant, Noam; Goren, Zohar; Livneh, Zvi] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Krijger, Peter H. L.; Langerak, Petra; Jacobs, Heinz] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Kim, Jungmin; D'Andrea, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol & Pediat Oncol, Boston, MA 02115 USA. [Reissner, Thomas; Carell, Thomas] Univ Munich, Dept Chem & Biochem, Munich, Germany. [Lee, Kyoo-young; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Geacintov, Nicholas E.] NYU, Dept Chem, New York, NY 10003 USA. [Tateishi, Satoshi] Kumamoto Univ, Inst Mol Embryol & Genet, Kumamoto, Japan. RP Hendel, A (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. EM h.jacobs@nki.nl; zvi.livneh@weizmann.ac.il RI Carell, Thomas/G-4799-2012; OI Krijger, Peter/0000-0003-1702-348X; Jacobs, Heinz/0000-0001-6227-9850; Carell, Thomas/0000-0001-7898-2831 FU Flight Attendant Medical Research Institute; Leona M. and Harry B. Helmsley Charitable Trust; Israel Science Foundation [1136/08]; Netherlands Organization for Scientific Research; Dutch Cancer Foundation [917.56.328, 2008-4112]; NIH USA [CA099194] FX ZL is the incumbent of the Maxwell Ellis Professorial Chair in Biomedical Research. This work was supported by grants to ZL from the Flight Attendant Medical Research Institute, the Leona M. and Harry B. Helmsley Charitable Trust, and the Israel Science Foundation (no. 1136/08); to HJ from The Netherlands Organization for Scientific Research and the Dutch Cancer Foundation (VIDI program 917.56.328 and KWF 2008-4112); and to NEG from NIH USA (no. CA099194). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 49 Z9 50 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002262 DI 10.1371/journal.pgen.1002262 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100017 PM 21931560 ER PT J AU Le, MTN Shyh-Chang, N Khaw, SL Chin, LZ Teh, C Tay, J O'Day, E Korzh, V Yang, H Lal, A Lieberman, J Lodish, HF Lim, B AF Le, Minh T. N. Shyh-Chang, Ng Khaw, Swea Ling Chin, Lingzi Teh, Cathleen Tay, Junliang O'Day, Elizabeth Korzh, Vladimir Yang, Henry Lal, Ashish Lieberman, Judy Lodish, Harvey F. Lim, Bing TI Conserved Regulation of p53 Network Dosage by MicroRNA-125b Occurs through Evolving miRNA-Target Gene Pairs SO PLOS GENETICS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; NEGATIVE REGULATOR; ESCHERICHIA-COLI; BAK1 EXPRESSION; CANCER CELLS; C-ELEGANS; MIR-125B; PROLIFERATION; CANALIZATION AB MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain-and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA-target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis. C1 [Le, Minh T. N.; Shyh-Chang, Ng; Khaw, Swea Ling; Chin, Lingzi; Tay, Junliang; Lim, Bing] Genome Inst Singapore, Singapore, Singapore. [Le, Minh T. N.; O'Day, Elizabeth; Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst, Boston, MA USA. [Le, Minh T. N.; O'Day, Elizabeth; Lal, Ashish; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Le, Minh T. N.; Lodish, Harvey F.; Lim, Bing] Singapore MIT Alliance, Computat & Syst Biol, Singapore, Singapore. [Shyh-Chang, Ng] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Khaw, Swea Ling; Korzh, Vladimir] NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore. [Teh, Cathleen] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. [Yang, Henry] Singapore Immunol Network, Bioinformat Grp, Singapore, Singapore. [Lal, Ashish] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA USA. [Lim, Bing] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Le, MTN (reprint author), Genome Inst Singapore, Singapore, Singapore. EM lodish@wi.mit.edu; limb1@gis.a-star.edu.sg RI ASTAR, IMCB/E-2320-2012; Xie, Huangming/B-2260-2012; Le, Minh/D-7651-2013; Lieberman, Judy/A-2717-2015; Korzh, Vladimir/H-1596-2011; OI Shyh-Chang, Ng/0000-0003-3138-9525; Korzh, Vladimir/0000-0002-6580-7986; LE, Thi Nguyet Minh/0000-0002-6077-1566 FU ASTAR, Singapore; SMA [C-382-641-001-091]; NIH [R01 DK068348] FX MTNL, NS-C, SLK, LC, JT, CT, VK, and BL were supported by ASTAR, Singapore. MTNL was a L'Oreal Singapore for Women in Science National Fellow. BL and HFL were partially supported by SMA grant C-382-641-001-091. HFL was supported by NIH grant R01 DK068348. JL, EO, MTNL, and AL were supported by NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 65 Z9 71 U1 0 U2 20 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 SEP PY 2011 VL 7 IS 9 AR e1002242 DI 10.1371/journal.pgen.1002242 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100005 PM 21935352 ER PT J AU Liu, CT Garnaas, MK Tin, A Kottgen, A Franceschini, N Peralta, CA de Boer, IH Lu, XN Atkinson, E Ding, JZ Nalls, M Shriner, D Coresh, J Kutlar, A Bibbins-Domingo, K Siscovick, D Akylbekova, E Wyatt, S Astor, B Mychaleckjy, J Li, M Reilly, MP Townsend, RR Adeyemo, A Zonderman, AB de Andrade, M Turner, ST Mosley, TH Harris, TB Rotimi, CN Liu, YM Kardia, SLR Evans, MK Shlipak, MG Kramer, H Flessner, MF Dreisbach, AW Goessling, W Cupples, LA Kao, WL Fox, CS AF Liu, Ching-Ti Garnaas, Maija K. Tin, Adrienne Kottgen, Anna Franceschini, Nora Peralta, Carmen A. de Boer, Ian H. Lu, Xiaoning Atkinson, Elizabeth Ding, Jingzhong Nalls, Michael Shriner, Daniel Coresh, Josef Kutlar, Abdullah Bibbins-Domingo, Kirsten Siscovick, David Akylbekova, Ermeg Wyatt, Sharon Astor, Brad Mychaleckjy, Josef Li, Man Reilly, Muredach P. Townsend, Raymond R. Adeyemo, Adebowale Zonderman, Alan B. de Andrade, Mariza Turner, Stephen T. Mosley, Thomas H. Harris, Tamara B. Rotimi, Charles N. Liu, Yongmei Kardia, Sharon L. R. Evans, Michele K. Shlipak, Michael G. Kramer, Holly Flessner, Michael F. Dreisbach, Albert W. Goessling, Wolfram Cupples, L. Adrienne Kao, W. Linda Fox, Caroline S. CA CKDGen Consortium TI Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function SO PLOS GENETICS LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; DIABETIC-NEPHROPATHY; UNITED-STATES; ZEBRAFISH; POPULATIONS; PROGRESSION; SUSCEPTIBILITY; PREDICTORS; MUTATIONS AB Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR,60 mL/min/1.73 m(2)), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR>30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3x10(-7)) and FNDC1 (p-value = 3.0x10(-7)) for UACR, and KCNQ1 with eGFR (p = 3.6x10(-6)). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish. C1 [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Garnaas, Maija K.; Goessling, Wolfram] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Garnaas, Maija K.; Goessling, Wolfram; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Garnaas, Maija K.; Goessling, Wolfram; Kao, W. Linda] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tin, Adrienne; Kottgen, Anna; Li, Man] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kottgen, Anna] Univ Hosp Freiburg, Div Renal, Freiburg, Germany. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Peralta, Carmen A.] Univ Calif San Francisco, Sch Med, Div Nephrol, San Francisco, CA USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [de Boer, Ian H.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [de Boer, Ian H.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Atkinson, Elizabeth; de Andrade, Mariza] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Ding, Jingzhong] Wake Forest Univ Hlth Sci, J Paul Sticht Ctr Aging, Winston Salem, NC USA. [Nalls, Michael] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Coresh, Josef] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kutlar, Abdullah] Med Coll Georgia, Augusta, GA 30912 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Akylbekova, Ermeg] Jackson State Univ, Jackson, MS USA. [Wyatt, Sharon] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Astor, Brad] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Mychaleckjy, Josef] Ctr Publ Hlth Genom, Charlottesville, VA USA. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Townsend, Raymond R.] Univ Penn, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Dept Internal Med, Rochester, MN USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Kramer, Holly] Loyola Univ, Maywood, IL 60153 USA. [Flessner, Michael F.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Dreisbach, Albert W.] Univ Mississippi, Div Nephrol, Jackson, MS 39216 USA. [Goessling, Wolfram] Brigham & Womens Hosp, Dept Med, Div Gastroenterol, Boston, MA 02115 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Liu, CT (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM wgoessling@partners.org; wkao@jhsph.edu; foxca@nhlbi.nih.gov RI Kottgen, Anna/D-2920-2012; OI Zonderman, Alan B/0000-0002-6523-4778; Cupples, L. Adrienne/0000-0003-0273-7965; Kramer, Holly/0000-0002-6374-837X; Adeyemo, Adebowale/0000-0002-3105-3231; Goessling, Wolfram/0000-0001-9972-1569 FU NHLBI [R01-HL087660]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; NIH, National Institute on Aging. Howard University Family Study; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; National Heart, Lung, and Blood Institute FX The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute (N01-HC-65226) to create this genotype/phenotype data base for wide dissemination to the biomedical research community: Atherosclerotic Risk in Communities (ARIC): University of North Carolina at Chapel Hill (N01-HC-55015), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center (N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas Houston (N01-HC-55022), University of North Carolina Forsyth County (N01-HC-55018); Cardiovascular Health Study (CHS): University of Washington (N01-HC-85079), Wake Forest University (N01-HC-85080), Johns Hopkins University (N01-HC-85081), University of Pittsburgh (N01-HC-85082), University of California Davis (N01-HC-85083), University of California Irvine (N01-HC-85084), New England Medical Center (N01-HC-85085), University of Vermont (N01-HC-85086), Georgetown University (N01-HC-35129), Johns Hopkins University (N01 HC-15103), University of Wisconsin (N01-HC-75150), Geisinger Clinic (N01-HC-45133), University of Washington (N01 HC-55222, U01 HL080295); Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080); Cooperative Study of Sickle Cell Disease (CSSCD): University of Illinois (N01-HB-72982, N01-HB-97062), Howard University (N01-HB-72991, N01-HB-97061), University of Miami (N01-HB-72992, N01-HB-97064), Duke University (N01-HB-72993), George Washington University (N01-HB-72994), University of Tennessee (N01-HB-72995, N01-HB-97070), Yale University (N01-HB-72996, N01-HB-97072), Children's Hospital-Philadelphia (N01-HB-72997, N01-HB-97056), University of Chicago (N01-HB-72998, N01-HB-97053), Medical College of Georgia (N01-HB-73000, N01-HB-97060), Washington University (N01-HB-73001, N01-HB-97071), Jewish Hospital and Medical Center of Brooklyn (N01-HB-73002), Trustees of Health and Hospitals of the City of Boston (N01-HB-73003), Children's Hospital-Oakland (N01-HB-73004, N01-HB-97054), University of Mississippi (N01-HB-73005), St. Luke's Hospital-New York (N01-HB-73006), Alta Bates-Herrick Hospital (N01-HB-97051), Columbia University (N01-HB97058), St.; Jude's Children's Research Hospital (N01-HB-97066), Research Foundation of the State University of New York-Albany (N01-HB-97068, N01-HB-97069), New England Research Institute (N01-HB-97073), Interfaith Medical Center-Brooklyn (N01-HB-97085); Coronary Artery Risk in Young Adults (CARDIA): University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100); Framingham Heart Study (FHS): Boston University (N01-HC-25195, R01HL092577-01A1, RO1 HL076784, R01 AG028321); Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern Universiy (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205); Sleep Heart Health Study (SHHS): Johns Hopkins University (U01 HL064360), Case Western University (U01 HL063463), University of California, Davis (U01 HL053916), University of Arizona (U01 HL053938), University of Minnesota (relocating in 2006 to Univ Arizona) (U01 HL053934), University of Pittsburgh (U01 HL077813), Boston University (U01 HL053941), MedStar Research Institute (U01 HL063429), Johns Hopkins University (U01 HL053937). GENOA: The GENOA Study genome-wide association study was funded by NHLBI R01-HL087660. HABC: This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Howard University Family Study: The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. We thank the participants of the Howard University Family Study.; The contents of this publicationare solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HANDLS: This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (Intramural Project # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff, and study participants in creating this resource for biomedical research. The authors wish to thank Andrea Calhoun and Dr. Susan Hagen at the Electron Microscopy Core Facility at Beth Israel Deaconess Medical Center for expert assistance with electron microscopy and Drs. Dirk Hentschel and Helmut Rennke at Brigham and Women's Hospital for advice on electron microscopy images. We thank Dr. Iain Drummond at Massachusetts General Hospital and Dr. Rebecca Wingert at the University of Notre Dame for in situ probes. NR 42 TC 57 Z9 58 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2011 VL 7 IS 9 AR e1002264 DI 10.1371/journal.pgen.1002264 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100018 PM 21931561 ER PT J AU Rizki, G Iwata, TN Li, J Riedel, CG Picard, CL Jan, M Murphy, CT Lee, SS AF Rizki, Gizem Iwata, Terri Naoko Li, Ji Riedel, Christian G. Picard, Colette Lafontaine Jan, Max Murphy, Coleen T. Lee, Siu Sylvia TI The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO SO PLOS GENETICS LA English DT Article ID ELEGANS LIFE-SPAN; FOXO TRANSCRIPTION FACTORS; CAENORHABDITIS-ELEGANS; C-ELEGANS; EXPRESSION PATTERNS; PROTEIN INTERACTS; FAMILY-MEMBER; CELL-CYCLE; MLL FAMILY; FAT-BODY AB The conserved DAF-16/FOXO transcription factors and SIR-2.1/SIRT1 deacetylases are critical for diverse biological processes, particularly longevity and stress response; and complex regulation of DAF-16/FOXO by SIR-2.1/SIRT1 is central to appropriate biological outcomes. Caenorhabditis elegans Host Cell Factor 1 (HCF-1) is a longevity determinant previously shown to act as a co-repressor of DAF-16. We report here that HCF-1 represents an integral player in the regulatory loop linking SIR-2.1/SIRT1 and DAF-16/FOXO in both worms and mammals. Genetic analyses showed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response in C. elegans. Gene expression profiling revealed a striking 80% overlap between the DAF-16 target genes responsive to hcf-1 mutation and sir-2.1 overexpression. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16-mediated transcription particularly important for aging and stress responses. Analogous to its role in regulating DAF-16/SIR-2.1 target genes in C. elegans, the mammalian HCF-1 also repressed the expression of several FOXO/SIRT1 target genes. Protein-protein association studies demonstrated that SIR-2.1/SIRT1 and HCF-1 form protein complexes in worms and mammalian cells, highlighting the conservation of their regulatory relationship. Our findings uncover a conserved interaction between the key longevity determinants SIR-2.1/SIRT1 and HCF-1, and they provide new insights into the complex regulation of FOXO proteins. C1 [Rizki, Gizem; Iwata, Terri Naoko; Lee, Siu Sylvia] Cornell Univ, Dept Mol Biol & Genet, Field Comparat Biomed Sci, Ithaca, NY 14853 USA. [Riedel, Christian G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Simches Res Ctr, Boston, MA 02114 USA. [Jan, Max; Murphy, Coleen T.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Rizki, G (reprint author), Cornell Univ, Dept Mol Biol & Genet, Field Comparat Biomed Sci, Ithaca, NY 14853 USA. EM sylvia.lee@cornell.edu OI Riedel, Christian/0000-0002-3689-8022 FU National Institute on Aging [AG024425]; Ellison Medical Foundation; Cornell Center of Vertebrate Genomics; Juvenile Diabetes Research Foundation; National Institute of Child Health and Human Development [T32HD052471]; European Molecular Biology Organization; Human Frontier Science Program FX This work was supported by R01 grant AG024425 from the National Institute on Aging, a Senior Scholar in Aging award from the Ellison Medical Foundation, a seed grant from the Cornell Center of Vertebrate Genomics, and an innovation award from the Juvenile Diabetes Research Foundation awarded to SSL. TNI was supported by a Reproductive Genomic Training grant T32HD052471 from the National Institute of Child Health and Human Development. CGR was supported by long-term fellowships from the European Molecular Biology Organization and the Human Frontier Science Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 48 Z9 52 U1 2 U2 10 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 SEP PY 2011 VL 7 IS 9 AR e1002235 DI 10.1371/journal.pgen.1002235 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 827HH UT WOS:000295419100004 PM 21909281 ER PT J AU Wei, MH Querques, J Stern, TA AF Wei, Marlynn H. Querques, John Stern, Theodore A. TI Teaching Trainees about the Practice of Consultation-Liaison Psychiatry in the General Hospital SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Consultation-Liaison Psychiatry; Psychosomatic Medicine; Teaching Psychiatry; Education; Teaching Rounds ID ADULT LEARNING-THEORY; MEDICAL-EDUCATION; RANDOMIZED-TRIAL; CYNICAL HUMOR; GUIDELINES; EFFICACY; ROUNDS; PERCEPTIONS; SERVICES; FEEDBACK AB Teaching trainees about the practice of consultation-liaison (C-L) psychiatry involves formal didactics, bedside rounds, reviewing the literature, and the demonstration of specific skills (eg, critical thinking and self-awareness [autognosis]). Effective teaching (based on adult learning theory) about psychosomatic medicine uses problem-oriented approaches, integrates knowledge into real-life situations, and makes trainees responsible for their decisions. Discussions of differential diagnoses, work-ups, formulations (that involve biological, psychological, sociocultural, and existential perspectives) and treatment of myriad conditions seen in the general hospital create a solid foundation. Teaching C-L psychiatry is most effective with a layered approach, tailored to specific teaching forums and learning styles of trainees. C1 [Wei, Marlynn H.; Querques, John; Stern, Theodore A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Stern, TA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Warren Bldg,Room 605, Boston, MA 02114 USA. EM TStern@Partners.org NR 53 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X EI 1558-3147 J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2011 VL 34 IS 3 BP 689 EP + DI 10.1016/j.psc.2011.05.009 PG 20 WC Psychiatry SC Psychiatry GA 829RL UT WOS:000295601900014 PM 21889687 ER PT J AU Theurl, I Schroll, A Sonnweber, T Nairz, M Theurl, M Willenbacher, W Eller, K Wolf, D Lin, H Weiss, G AF Theurl, Igor Schroll, Andrea Sonnweber, Thomas Nairz, Manfred Theurl, Milan Willenbacher, Wolfgang Eller, Kathrin Wolf, Dominik Lin, Herbert Weiss, Guenter TI Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Theurl, Igor; Schroll, Andrea; Sonnweber, Thomas; Nairz, Manfred; Theurl, Milan; Weiss, Guenter] Med Univ Innsbruck, Ctr Internal Med, Dept Internal Med 1, Innsbruck, Austria. [Willenbacher, Wolfgang; Wolf, Dominik] Med Univ Innsbruck, Ctr Internal Med, Dept Internal Med Hematol & Oncol 5, Innsbruck, Austria. [Eller, Kathrin] Med Univ Innsbruck, Ctr Internal Med, Dept Internal Med Nephrol & Hypertensiol 4, Innsbruck, Austria. [Lin, Herbert] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Nephrol, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD SEP PY 2011 VL 123 IS 17-18 BP A71 EP A71 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 833HZ UT WOS:000295875800176 ER PT J AU Hagan, MP Saleh, H Moore, M Williamson, J AF Hagan, Michael P. Saleh, Habeeb Moore, Mary Williamson, Jeffrey TI Regulatory evaluation of prostate volume implants: Pitfalls of a retrospective assessment SO BRACHYTHERAPY LA English DT Article DE Prostate; Brachytherapy; Volume implant; Evaluation; Medical event ID POSTIMPLANT DOSIMETRY; COMPUTED-TOMOGRAPHY; TREATMENT DELIVERY; SEED LOCALIZATION; BRACHYTHERAPY; ULTRASOUND; CANCER; EDEMA; RECOMMENDATIONS; QUALITY AB PURPOSE: Evaluate for regulatory compliance the prostate implants from the Philadelphia Veterans Medical Center applying both an activity-based and volume-corrected D(90) (the maximum dose delivered to 90% of the prostate volume) metrics. METHODS AND MATERIALS: Dosimetry from 107 prostate implants performed at the Philadelphia Veterans Medical Center used immediate postprocedural CT image sets. D(90) values were adjusted for volume differences from planning volumes. Medical events (MEs) determined from the volume-corrected data were compared with an activity-based metric. RESULTS: Examination of images using original and third-party reviewed prostate contours revealed 56 and 62 cases with D(90) values <80% of the prescription close, respectively. Because postprocedural prostate volumes were on average 55.7% larger than the planned volume, clinical nomogram-based doses using the implanted activity and actual volumes found 34-47 implants failing to achieve closes greater than 80% of the prescription dose. Volume correction identified 20 MEs, 9 cases with D(90) values within 4% of the ME threshold and 11 significantly inferior cases with median D(90) values <52% of the prescribed dose. Eleven implants also had 20% or more seeds beyond the treatment site according to an activity metric recommended by the VHA Blue Ribbon Panel. Ten of these 11 cases were also identified by volume-corrected D(90) metric. The remaining 96 cases, however, had 95% (+/-6%) of seeds placed within the treatment site. CONCLUSIONS: Of the cases reported to the United States Nuclear Regulatory Commission (NRC) on the basis of Day-1 D(90) values, many appear to have been acceptable implants relative to standard-of-practice clinical criteria. The activity-based dose metric, endorsed by the NRC Advisory Committee on the Medical Uses of Isotopes in 2005 and recommended by the VHA Blue Ribbon Panel for Prostate Brachytherapy yields a more robust determination of ME for this population of implants. Published by Elsevier Inc. All rights reserved. C1 [Hagan, Michael P.; Saleh, Habeeb; Williamson, Jeffrey] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA 23298 USA. [Hagan, Michael P.] Vet Hlth Agcy, Dept Vet Affairs, Natl Radiat Oncol Program Off, Richmond, VA USA. [Moore, Mary] Philadelphia VA Med Ctr, Radiat Safety Off, Philadelphia, PA USA. RP Hagan, MP (reprint author), Virginia Commonwealth Univ, Dept Radiat Oncol, 401 Coll St, Richmond, VA 23298 USA. EM michael.hagan@va.gov NR 35 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 J9 BRACHYTHERAPY JI Brachytherapy PD SEP-OCT PY 2011 VL 10 IS 5 BP 385 EP 394 DI 10.1016/j.brachy.2011.01.005 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 826IB UT WOS:000295346700007 PM 21349777 ER PT J AU MacConaill, LE Van Hummelen, P Meyerson, M Hahn, WC AF MacConaill, Laura E. Van Hummelen, Paul Meyerson, Matthew Hahn, William C. TI Clinical Implementation of Comprehensive Strategies to Characterize Cancer Genomes: Opportunities and Challenges SO CANCER DISCOVERY LA English DT Review ID CELL LUNG-CANCER; GASTROINTESTINAL STROMAL TUMORS; METASTATIC COLORECTAL-CANCER; GROWTH-FACTOR RECEPTOR; CHRONIC MYELOID-LEUKEMIA; IN-SITU HYBRIDIZATION; TYROSINE KINASE JAK2; BREAST-CANCER; GENE-EXPRESSION; ONCOGENIC MUTATIONS AB An increasing number of anticancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Recent evidence suggests that the selection of patients whose tumors harbor specific genetic alterations identifies the subset of patients who are most likely to benefit from the use of such agents. As the number of genetic alterations that provide diagnostic and/or therapeutic information increases, the comprehensive characterization of cancer genomes will be necessary to understand the spectrum of distinct genomic alterations in cancer, to identify patients who are likely to respond to particular therapies, and to facilitate the selection of treatment modalities. Rapid developments in new technologies for genomic analysis now provide the means to perform comprehensive analyses of cancer genomes. In this article, we review the current state of cancer genome analysis and discuss the challenges and opportunities necessary to implement these technologies in a clinical setting. Significance: Rapid advances in sequencing technologies now make it possible to contemplate the use of genome scale interrogation in clinical samples, which is likely to accelerate efforts to match treatments to patients. However, major challenges in technology, clinical trial design, legal and social implications, healthcare information technology, and insurance and reimbursement remain. Identifying and addressing these challenges will facilitate the implementation of personalized cancer medicine. Cancer Discovery; 1(4): 297-311. (C) 2011 AACR. C1 [MacConaill, Laura E.; Van Hummelen, Paul; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [MacConaill, Laura E.; Van Hummelen, Paul; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [MacConaill, Laura E.; Van Hummelen, Paul; Meyerson, Matthew; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA USA. [MacConaill, Laura E.; Meyerson, Matthew] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Meyerson, Matthew; Hahn, William C.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Meyerson, Matthew; Hahn, William C.] MIT, Cambridge, MA 02139 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM william_hahn@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012 FU Novartis FX No potential conflicts of interest were disclosed by L. E. MacConaill and P. Van Hummelen. M. Meyerson is a consultant for and received research support from Novartis; the founding advisor of, consultant for, and equity holder in Foundation Medicine; a coinventor and patent holder on the use of EGFR mutations for lung cancer diagnosis, licensed to Genzyme Genetics/Labcorp. W. C. Hahn is a consultant for Novartis and Thermo-Fisher and has received research support from Novartis. NR 161 TC 25 Z9 25 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD SEP PY 2011 VL 1 IS 4 BP 297 EP 311 DI 10.1158/2159-8290.CD-11-0110 PG 15 WC Oncology SC Oncology GA 832ET UT WOS:000295785800017 PM 21935500 ER PT J AU Faber, AC Corcoran, RB Ebi, H Sequist, LV Waltman, BA Chung, EH Incio, J Digumarthy, SR Pollack, SF Song, YC Muzikansky, A Lifshits, E Roberge, S Coffman, EJ Benes, CH Gomez, HL Baselga, J Arteaga, CL Rivera, MN Dias-Santagata, D Jain, RK Engelman, JA AF Faber, Anthony C. Corcoran, Ryan B. Ebi, Hiromichi Sequist, Lecia V. Waltman, Belinda A. Chung, Euiheon Incio, Joao Digumarthy, Subba R. Pollack, Sarah F. Song, Youngchul Muzikansky, Alona Lifshits, Eugene Roberge, Sylvie Coffman, Erik J. Benes, Cyril H. Gomez, Henry L. Baselga, Jose Arteaga, Carlos L. Rivera, Miguel N. Dias-Santagata, Dora Jain, Rakesh K. Engelman, Jeffrey A. TI BIM Expression in Treatment-Naive Cancers Predicts Responsiveness to Kinase Inhibitors SO CANCER DISCOVERY LA English DT Article ID CELL LUNG-CANCER; GROWTH-FACTOR-RECEPTOR; MET AMPLIFICATION; INDUCED APOPTOSIS; BREAST-CANCER; PHASE-II; GEFITINIB; EGFR; MUTATIONS; ACTIVATION AB Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naive tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. SIGNIFICANCE: In several oncogene-addiction paradigms, assessment of BIM RNA levels identifies those cancers that fail to have substantial apoptotic responses to kinase inhibitors. BIM RNA levels may be assessed in diagnostic cancer specimens to predict which patients will receive less benefit from single-agent kinase inhibitors. Cancer Discovery: 1(4); 352-65. (C) 2011 AACR. C1 [Faber, Anthony C.; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Coffman, Erik J.; Benes, Cyril H.; Baselga, Jose; Rivera, Miguel N.; Dias-Santagata, Dora; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Rivera, Miguel N.; Dias-Santagata, Dora] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. [Digumarthy, Subba R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [Faber, Anthony C.; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Lifshits, Eugene; Coffman, Erik J.; Benes, Cyril H.; Baselga, Jose; Rivera, Miguel N.; Dias-Santagata, Dora; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Chung, Euiheon; Incio, Joao; Roberge, Sylvie; Jain, Rakesh K.] Massachusetts Gen Hosp, Steele Lab Tumor Biol, Charlestown, MA USA. [Chung, Euiheon; Incio, Joao; Roberge, Sylvie; Jain, Rakesh K.] Harvard Univ, Sch Med, Charlestown, MA USA. [Arteaga, Carlos L.] Vanderbilt Univ, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Arteaga, Carlos L.] Vanderbilt Univ, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Gomez, Henry L.] Inst Nacl Enfermedades Neoplas, Lima, Peru. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Boston, MA 02129 USA. EM jengelman@partners.org OI Incio, Joao/0000-0002-0259-1356; Gomez, Henry/0000-0003-2660-1843; Ebi, Hiromichi/0000-0003-3155-7576 FU National Institutes of Health NIH [R01CA137008-01, R01CA140594, R01CA135257-01]; National Cancer Institute Lung SPORE [P50CA090578]; DF/HCC Gastrointestinal Cancer SPORE [P50 CA127003]; American Lung Cancer Association; V Foundation; Ellison Foundation; Aid for Cancer Research Postdoctoral Fellowship; [CA120060-01] FX This study is supported by grants from the National Institutes of Health NIH R01CA137008-01 (J.A. Engelman), R01CA140594 (J.A. Engelman), R01CA135257-01 (J.A. Engelman), National Cancer Institute Lung SPORE P50CA090578 (J.A. Engelman), DF/HCC Gastrointestinal Cancer SPORE P50 CA127003 (J.A. Engelman), K08 grant CA120060-01 (J.A. Engelman), the American Lung Cancer Association Lung Cancer Discovery Award (J.A. Engelman), the V Foundation (J.A. Engelman), the Ellison Foundation Scholar (J.A. Engelman), and an Aid for Cancer Research Postdoctoral Fellowship (A.C. Faber). NR 53 TC 124 Z9 130 U1 2 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD SEP PY 2011 VL 1 IS 4 BP 352 EP 365 DI 10.1158/2159-8290.CD-11-0106 PG 14 WC Oncology SC Oncology GA 832ET UT WOS:000295785800021 PM 22145099 ER PT J AU Chen, WY AF Chen, Wendy Y. TI Postmenopausal Hormone Therapy and Breast Cancer Risk: Current Status and Unanswered Questions SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Menopause; Hormone therapy; Breast cancer; Estrogen ID ESTROGEN-PLUS-PROGESTIN; RANDOMIZED CONTROLLED-TRIAL; REPLACEMENT THERAPY; MILLION WOMEN; EQUINE ESTROGEN; FAMILY-HISTORY; MENOPAUSE; HEALTH; COHORT; MAMMOGRAPHY AB Many women take hormone therapy (HT) for menopausal symptom relief. Studies have tried to clarify whether various factors can modify the risk of HT, such as the age at initiation, dose, duration, or type of HT, or characteristics of the individual, such as family history or body mass index. The relative risks of breast cancer associated with HT across various subgroups of women should be considered similar, but absolute risks can vary significantly among women and this may inform individual decision making. For breast cancer survivors, systemic HT should be discouraged. C1 [Chen, Wendy Y.] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Wendy Y.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chen, WY (reprint author), Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, 181 Longwood Ave, Boston, MA 02115 USA. EM wendy.chen@channing.harvard.edu FU NCI NIH HHS [P01 CA087969, P01 CA087969-11] NR 49 TC 5 Z9 6 U1 1 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 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD SEP PY 2011 VL 40 IS 3 BP 509 EP + DI 10.1016/j.ecl.2011.05.006 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 829RN UT WOS:000295602100006 PM 21889717 ER PT J AU Ibarra, JM Quinones, MP Estrada, CA Jimenez, F Martinez, HG Ahuja, SS AF Ibarra, Jessica M. Quinones, Marlon P. Estrada, Carlos A. Jimenez, Fabio Martinez, Hernan G. Ahuja, Seema S. TI CD8 alpha(+) dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice SO IMMUNOBIOLOGY LA English DT Article DE CCR2; Dendritic cells; CD8 alpha(+) DC; Arthritis; SKG ID REGULATORY T-CELLS; RHEUMATOID-ARTHRITIS; AUTOIMMUNE ARTHRITIS; TRANSPLANT TOLERANCE; DIFFERENT MECHANISMS; LEISHMANIA-MAJOR; LIGAND; DIFFERENTIATION; CYTOKINES; RESPONSES AB Objective: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3(+) regulatory T cells (T g), which in turn exert immunosuppression by increasing TGF beta-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2(-/-)) mice had impaired DCs migration and reduced CD8 alpha(+) DCs in the C57B1/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2(-/-)mice, we tested the hypothesis that CD8 alpha(+) DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8 alpha(+) DCs in Ccr2(-/-) and SKG mice. Methods: To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8 alpha(+) DCs. Results: Flt3L-mediated expansion of endogenous CD8 alpha(+) DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8 alpha(+) DCs ameliorated arthritis in Ccr2(-/-) mice and enhanced TGF beta 1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. Conclusion: CD8 alpha(+) DCs were tolerogenic to the development of arthritis. CD8 alpha(+) DCs deficiency heightened the sensitivity to arthritis in Ccr2(-/-) mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2(-/-) mice was T cell-independent. Published by Elsevier GmbH. C1 [Ibarra, Jessica M.; Quinones, Marlon P.; Estrada, Carlos A.; Jimenez, Fabio; Martinez, Hernan G.; Ahuja, Seema S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Quinones, Marlon P.; Estrada, Carlos A.; Jimenez, Fabio; Martinez, Hernan G.; Ahuja, Seema S.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, Vet Adm Ctr Res AIDS & HIV Infect 1, San Antonio, TX USA. RP Ahuja, SS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, MC7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ahuja@uthscsa.edu FU National Institutes of Health (NIH) [AI48644, AR052755] FX This work was supported in part by the National Institutes of Health (NIH)grants (AI48644 and AR052755) and VA Merit to S.S.A. NR 30 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0171-2985 J9 IMMUNOBIOLOGY JI Immunobiology PD SEP PY 2011 VL 216 IS 9 BP 971 EP 978 DI 10.1016/j.imbio.2011.03.012 PG 8 WC Immunology SC Immunology GA 829TG UT WOS:000295606600001 PM 21531476 ER PT J AU Ford, L Bloom, K Nowak-Wegrzyn, A Shreffler, W Masilamani, M Sampson, H AF Ford, Lara Bloom, Katherine Nowak-Wegrzyn, Anna Shreffler, Wayne Masilamani, Madhan Sampson, Hugh TI IDENTIFICATION OF BIOMARKERS TO DISTINGUISH VARIOUS LEVELS OF COW'S MILK TOLERANCE SO INTERNAL MEDICINE JOURNAL LA English DT Meeting Abstract C1 [Ford, Lara; Bloom, Katherine; Nowak-Wegrzyn, Anna; Masilamani, Madhan; Sampson, Hugh] Mt Sinai Sch Med, New York, NY USA. [Shreffler, Wayne] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM lford@med.usyd.edu.au NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1444-0903 J9 INTERN MED J JI Intern. Med. J. PD SEP PY 2011 VL 41 SU 4 SI SI BP 7 EP 7 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 828RQ UT WOS:000295520600022 ER PT J AU McNulty, EJ Ng, W Spertus, JA Zaroff, JG Yeh, RW Ren, XSM Lundstrom, RJ AF McNulty, Edward J. Ng, William Spertus, John A. Zaroff, Jonathan G. Yeh, Robert W. Ren, Xiushi M. Lundstrom, Robert J. TI Surgical Candidacy and Selection Biases in Nonemergent Left Main Stenting Implications for Observational Studies SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE bias; bypass; comparative effectiveness; risk factors; stents ID PERCUTANEOUS CORONARY INTERVENTION; DRUG-ELUTING STENTS; ARTERY-BYPASS SURGERY; LONG-TERM OUTCOMES; HEART-ASSOCIATION GUIDELINES; CARDIAC-SURGERY; AMERICAN-COLLEGE; FOLLOW-UP; REVASCULARIZATION REGISTRY; GRAFTING SURGERY AB Objectives This study sought to characterize reasons for surgical ineligibility in patients undergoing nonemergent unprotected left main (ULM) percutaneous coronary intervention (PCI) and to assess the potential for these reasons to confound comparative effectiveness studies of coronary revascularization. Background Although both PCI and coronary artery bypass graft surgery are treatments for ULM disease, some patients are not eligible for both treatments, which may result in treatment selection biases. Methods In 101 consecutive patients undergoing nonemergent ULM PCI, mixed methods were used to determine the prevalence of treatment selection dictated by surgical ineligibility and to identify the reasons cited for avoiding coronary artery bypass graft surgery. We then determined whether these reasons were captured by the ACC-NCDR (American College of Cardiology-National Cardiovascular Data Registry) Cath-PCI dataset to assess the ability of this registry to account for biases in treatment selection. Finally, the association of surgical eligibility with long-term outcomes after ULM PCI was assessed. Results Treatment selection was dictated by surgical ineligibility in over half the ULM PCI cohort with the majority having reasons for ineligibility not captured by the ACC-NCDR. Surgical ineligibility was a significant predictor of mortality after adjustment for Society of Thoracic Surgeons (hazard ratio [HR]: 5.4, 95% confidence interval [CI]: 1.2 to 25), EuroSCORE (European System for Cardiac Operative Risk Evaluation) (HR: 5.9, 95% CI: 1.3 to 27), or NCDR mortality scores (HR: 6.2, 95% CI: 1.4 to 27). Conclusions Surgical ineligibility dictating treatment selection is common in patients undergoing nonemergent ULM PCI, occurs on the basis of risk factors not captured by the ACC-NCDR, and is independently associated with worse long-term outcomes after adjusting for standard risk scores. (J Am Coll Cardiol Intv 2011;4:1020-7) (C) 2011 by the American College of Cardiology Foundation C1 [McNulty, Edward J.; Ng, William; Zaroff, Jonathan G.; Lundstrom, Robert J.] Kaiser Permanente Med Ctr, Div Cardiol, San Francisco, CA 94115 USA. [McNulty, Edward J.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA USA. [Ren, Xiushi M.] Kaiser Permanente Med Ctr, Div Cardiol, Redwood City, CA USA. [Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. [Spertus, John A.] St Lukes Mid Amer Heart Inst, Div Cardiol, Kansas City, MO USA. [Yeh, Robert W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP McNulty, EJ (reprint author), Kaiser Permanente Med Ctr, Div Cardiol, 2350 Geary Blvd, San Francisco, CA 94115 USA. EM edward.j.mcnulty@kp.org FU Community Benefits Grant; Kaiser Foundation Research Institute; Graduate Medical Education Program; Northern California Kaiser Permanente; National Institutes of Health; American Heart Association; Amgen; Johnson , Johnson; Atherotech; Roche Diagnostics FX From the *Division of Cardiology, Kaiser Permanente Medical Center, San Francisco, California; dagger Department of Medicine, University of California, San Francisco School of Medicine, San Francisco, California; double dagger Division of Cardiology, Kaiser Permanente Medical Center, Redwood City, California; Division of Cardiology, Saint Luke's Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, Missouri; and the parallel to Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. This study was supported by grants from the Community Benefits Grant, Kaiser Foundation Research Institute (to Dr. Lundstrom) and Graduate Medical Education Program, Northern California Kaiser Permanente (to Dr. Ng). Drs. McNulty, Ng, Ren, and Lundstrom are employees of The Permanente Medical Group, Inc. Dr. McNulty receives grant support from the National Institutes of Health. Dr. Sperms has a research contract with American College of Cardiology Foundation; has received grants from American Heart Association, Amgen, Johnson &, Johnson, and National Institutes of Health; has received grant support from Atherotech and Roche Diagnostics; and is a consultant for Novartis, United Healthcare, and St. Jude Medical. Drs. Zaroff and Lundstrom receive grant support from the Kaiser Foundation Research Institute. Dr. Yeh is a consultant for the Kaiser Permanente Division of Research and the Harvard Clinical Research Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 48 TC 26 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD SEP PY 2011 VL 4 IS 9 BP 1020 EP 1027 DI 10.1016/j.jcin.2011.06.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 829RU UT WOS:000295602800011 PM 21939943 ER PT J AU Kong, YCM Brown, NK Flynn, JC McCormick, DJ Brusic, V Morris, GP David, CS AF Kong, Yi-chi M. Brown, Nicholas K. Flynn, Jeffrey C. McCormick, Daniel J. Brusic, Vladimir Morris, Gerald P. David, Chella S. TI Efficacy of HLA-DRB1*03:01 and H2E transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for autoimmune thyroiditis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Autoimmune thyroiditis; HLA-DR3; H2E; Transgenic mice; Thyroglobulin peptides ID CLASS-II TRANSGENES; REGULATORY T-CELLS; HLA-DR; PEPTIDE-BINDING; E-ALPHA; MURINE THYROIDITIS; MICE LACKING; MOLECULES; SUSCEPTIBILITY; GENES AB Thyroglobulin (Tg), a homodimer of 660 kD comprising 2748 amino acids, is the largest autoantigen known. The prevalence of autoimmune thyroid disease, including Hashimoto's thyroiditis and Graves' disease, has provided the impetus for identifying pathogenic T cell epitopes from human Tg over two decades. With no known dominant epitopes, the search has long been a challenge for investigators. After identifying HLA-DRB1*03:01 (HLA-DR3) and H2E(b) as susceptibility alleles for Tg-induced experimental autoimmune thyroiditis in transgenic mouse strains, we searched for naturally processed T cell epitopes with MHC class II-binding motif anchors and tested the selected peptides for pathogenicity in these mice. The thyroiditogenicity of one peptide, hTg2079, was confirmed in DR3 transgenic mice and corroborated in clinical studies. In H2E(b)-expressing transgenic mice, we identified three T cell epitopes from mouse Tg, mTg179, mTg409 and mTg2342, based on homology to epitopes hTg179, hTg410 and hTg2344, respectively, which we and others have found stimulatory or pathogenic in both DR3- and H2E-expressing mice. The high homology among these peptides with shared presentation by DR3. H2E(b) and H2E(k) molecules led us to examine the binding pocket residues of these class II molecules. Their similar binding characteristics help explain the pathogenic capacity of these T cell epitopes. Our approach of using appropriate human and murine MHC class II transgenic mice, combined with the synthesis and testing of potential pathogenic Tg peptides predicted from computational models of MHC-binding motifs, should continue to provide insights into human autoimmune thyroid disease. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kong, Yi-chi M.; Brown, Nicholas K.; Flynn, Jeffrey C.; Morris, Gerald P.] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. [McCormick, Daniel J.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Brusic, Vladimir] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [David, Chella S.] Mayo Clin, Coll Med, Dept Immunol, Rochester, MN 55905 USA. RP Kong, YCM (reprint author), Wayne State Univ, Sch Med, Dept Immunol & Microbiol, 540 E Canfield Ave, Detroit, MI 48201 USA. EM ykong@med.wayne.edu RI Morris, Gerald/I-3680-2016 OI Morris, Gerald/0000-0002-1097-4453 FU NIDDK [DK45950]; DOD [BC098075] FX This work was supported by DK45950 from NIDDK and DOD BC098075 (YMK). NR 77 TC 4 Z9 4 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD SEP PY 2011 VL 37 IS 2 SI SI BP 63 EP 70 DI 10.1016/j.jaut.2011.05.010 PG 8 WC Immunology SC Immunology GA 831UE UT WOS:000295755800002 PM 21683551 ER PT J AU Hasturk, H Kantarci, A Ghattas, M Schmidt, M Giordano, RA Ashman, A Diekwisch, TG Van Dyke, T AF Hasturk, Hatice Kantarci, Alpdogan Ghattas, Mazen Schmidt, Marcella Giordano, Russell A. Ashman, Arthur Diekwisch, Thomas G. Van Dyke, Thomas TI The Use of Light/Chemically Hardened Polymethylmethacrylate, Polyhydroxyethylmethacrylate, and Calcium Hydroxide Graft Material in Combination With Polyanhydride Around Implants in Minipigs: Part I: Immediate Stability and Function SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Alveolar ridge augmentation; bone replacement material; dental implants; models; animal; tooth extraction ID CONTROLLED CLINICAL-TRIALS; ALVEOLAR BONE LOSS; DENTAL IMPLANTS; FOLLOW-UP; EXTRACTION SOCKETS; RESORBABLE MEMBRANE; OSTEOTOME TECHNIQUE; BARRIER MEMBRANES; TITANIUM IMPLANTS; MOLAR FURCATIONS AB Background: The present study is designed as a proof-of-concept study to evaluate light/chemical hardening technology and a newly formulated polymethylmethacrylate, polyhydroxyethylmethacrylate, and calcium hydroxide (PPCH) plus polyanhydride (PA) (PPCH-PA) composite graft material as a bone substitute compared to positive and negative controls in a minipig model. Methods: PPCH-PA (composite graft); PPCH alone (positive control), PA alone (positive control), and no graft (negative control) were compared. Four mandibular premolar teeth per quadrant were extracted; a total of 48 implants were placed into sockets in three minipigs. Abutments were placed protruding into the oral cavity 4 mm in height for immediate loading. Crestal areas and intrabony spaces were filled with PPCH-PA, PPCH, or PA using a three-phase delivery system in which all graft materials were hardened by a light cure. In the negative control group, implant sites were left untreated. At 12 weeks, block sections containing implants were obtained. Evaluations included periodontal probing, pullout-force load, and stability measurements to determine implant stability, radiographs to examine bone levels, and scanning electron microscopy (SEM)-energy-dispersed spectroscopy to determine bone-to-implant contact. Results: Probing measurements did not reveal any pathologic pocket formation or bone loss. Radiographs revealed that immediate implant placement and loading resulted in bone at or slightly apical to the first thread of the implant in all groups at 12 weeks. Stability test values showed a relative clinical stability for all implants (range: -7 to +1); however, implants augmented with PPCH-PA exhibited a statistically significantly greater stability compared to all other groups (P <0.05). The newly formed bone in PPCH-PA-treated sites was well organized with less marrow spaces and well-distributed osteocytes. SEM revealed a tighter implant-socket interface in the PPCH-PA group compared to other groups with reduced microfissures and implant-bone interface fractures during pullout testing, whereas implants treated with PA or no graft showed approximate to 10-mu m microfissures between the implant and bone with fractures of the intrathread bone. Conclusions: The newly formulated chemically hardened graft material PPCH-PA was useful in immediate implant placement after tooth extraction and resulted in greater stability and a well-organized implant-bone interface with immediate loading, especially in those areas where cancellous bone was present. The results of this proof-of-concept study warranted further research investigating different healing times and longer durations. J Periodontol 2011;82:1339-1352. C1 [Hasturk, Hatice; Kantarci, Alpdogan; Van Dyke, Thomas] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [Ghattas, Mazen] Boston Univ, Dept Periodontol & Oral Biol, Sch Dent Med, Boston, MA 02215 USA. [Giordano, Russell A.] Boston Univ, Dept Restorat Sci Biomat, Boston, MA 02215 USA. [Schmidt, Marcella; Diekwisch, Thomas G.] Univ Illinois, Coll Dent, Dept Oral Biol, Brodie Lab Craniofacial Genet, Chicago, IL USA. [Ashman, Arthur] NYU, Coll Dent, Dept Periodontol & Implant Dent, New York, NY USA. RP Hasturk, H (reprint author), Forsyth Inst, Dept Periodontol, 245 1st St,Suite 1757, Cambridge, MA 02142 USA. EM hhasturk@forsyth.org FU Bioplant R&D, Westport, Connecticut; United States Public Health Service, NIH, Bethesda, Maryland [DE019938] FX This study was supported, in part, by Bioplant R&D, Westport, Connecticut and the United States Public Health Service, NIH, Bethesda, Maryland (grant DE019938; to Dr. Van Dyke). The authors thank Dr. Devon A. Shipp, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, New York; the veterinary and animal care personnel, Mimi Crowley, Sharron Kirchain, Michelle Callihan, Rosa Yip, and Sergio Maura at the BUMC LASC; and Ronald L'Herault, laboratory supervisor, Boston University School of Dental Medicine Biomaterials Laboratory, Boston, Massachusetts, for their technical assistance during the study. Implants and the implant equipment were kindly donated by Biomet 3i, Palm Beach Gardens, Florida. Specialty surgical instruments were a gift from Hu-Friedy, Chicago, Illinois. Dr. Ashman, chief executive officer of Bioplant R&D, is the inventor of and has issued patents on the light and chemically cured materials (PPCH-PA [composite graft of hard tissue replacement and polyanhydride with light/chemical hardening technology]) tested in this study. Drs. Hasturk, Kantarci, Ghattas, Schmidt, Giordano, Diekwisch, and Van Dyke declare no financial interests related to this study. NR 66 TC 5 Z9 6 U1 0 U2 7 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD SEP PY 2011 VL 82 IS 9 BP 1339 EP 1352 DI 10.1902/jop.2011.100617 PG 14 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 831JI UT WOS:000295726000013 PM 21342001 ER PT J AU Parikh, CR Devarajan, P Zappitelli, M Sint, K Thiessen-Philbrook, H Li, S Kim, RW Koyner, JL Coca, SG Edelstein, CL Shlipak, MG Garg, AX Krawczeski, CD AF Parikh, Chirag R. Devarajan, Prasad Zappitelli, Michael Sint, Kyaw Thiessen-Philbrook, Heather Li, Simon Kim, Richard W. Koyner, Jay L. Coca, Steven G. Edelstein, Charles L. Shlipak, Michael G. Garg, Amit X. Krawczeski, Catherine D. CA TRIBE-AKI Consortium TI Postoperative Biomarkers Predict Acute Kidney Injury and Poor Outcomes after Pediatric Cardiac Surgery SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; ACUTE-RENAL-FAILURE; CONGENITAL HEART-DISEASE; ROC CURVE; NGAL; CHILDREN; MARKERS; INCREASES; DIALYSIS; THERAPY AB Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery. C1 [Parikh, Chirag R.; Sint, Kyaw; Coca, Steven G.] Yale Univ, Sch Med, Nephrol Sect, New Haven, CT USA. [Parikh, Chirag R.; Sint, Kyaw; Coca, Steven G.] Vet Affairs Med Ctr, Clin Epidemiol Res Ctr, West Haven, CT 06516 USA. [Devarajan, Prasad; Krawczeski, Catherine D.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Zappitelli, Michael] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pediat,Div Nephrol, Montreal, PQ H3H 1P3, Canada. [Thiessen-Philbrook, Heather; Garg, Amit X.] Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. [Li, Simon] Yale Univ, Sch Med, Dept Pediat, Div Pediat Crit Care Med, New Haven, CT 06510 USA. [Kim, Richard W.] Yale Univ, Sch Med, Div Pediat Cardiac Surg, New Haven, CT USA. [Koyner, Jay L.] Univ Chicago, Pritzker Sch Med, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Edelstein, Charles L.] Univ Colorado, Div Renal Dis, Denver, CO 80202 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. RP Parikh, CR (reprint author), Yale Univ, Nephrol Sect, 950 Campbell Ave,Mail Code 151B,Bldg 35 A,Room 21, West Haven, CT 06516 USA. EM chirag.parikh@yale.edu FU American Heart Association; National Heart, Lung, and Blood Institute [R01 HL-085757]; National Center for Research Resources [UL1 RR024139] FX The research reported in this article was supported by the American Heart Association Clinical Development Award, Grant R01 HL-085757 from the National Heart, Lung, and Blood Institute. The study was also supported by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources. This work is Clinical Trials.gov number NCT00774137. The urine biomarker assays were donated by Abbott Diagnostics. Plasma NGAL was donated by Biosite, Inc. NR 36 TC 140 Z9 141 U1 1 U2 7 PU AMER SOC 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 SEP PY 2011 VL 22 IS 9 BP 1737 EP 1747 DI 10.1681/ASN.2010111163 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 831CH UT WOS:000295705800021 PM 21836147 ER PT J AU Parikh, CR Coca, SG Thiessen-Philbrook, H Shlipak, MG Koyner, JL Wang, Z Edelstein, CL Devarajan, P Patel, UD Zappitelli, M Krawczeski, CD Passik, CS Swaminathan, M Garg, AX AF Parikh, Chirag R. Coca, Steven G. Thiessen-Philbrook, Heather Shlipak, Michael G. Koyner, Jay L. Wang, Zhu Edelstein, Charles L. Devarajan, Prasad Patel, Uptal D. Zappitelli, Michael Krawczeski, Catherine D. Passik, Cary S. Swaminathan, Madhav Garg, Amit X. CA TRIBE-AKI Consortium TI Postoperative Biomarkers Predict Acute Kidney Injury and Poor Outcomes after Adult Cardiac Surgery SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; ACUTE-RENAL-FAILURE; ACUTE CORONARY SYNDROMES; MORTALITY; RISK; RECLASSIFICATION; ASSOCIATION; DYSFUNCTION; MARKERS; MICE AB Acute kidney injury (AKI) is a frequent complication of cardiac surgery and increases morbidity and mortality. The identification of reliable biomarkers that allow earlier diagnosis of AKI in the postoperative period may increase the success of therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 1219 adults undergoing cardiac surgery to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse patient outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. After multivariable adjustment, the highest quintiles of urine IL-18 and plasma NGAL associated with 6.8-fold and 5-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine and plasma NGAL levels associated with longer length of hospital stay, longer intensive care unit stay, and higher risk for dialysis or death. The clinical prediction model for AKI had an area under the receiver-operating characteristic curve (AUC) of 0.69. Urine IL-18 and plasma NGAL significantly improved the AUC to 0.76 and 0.75, respectively. Urine IL-18 and plasma NGAL significantly improved risk prediction over the clinical models alone as measured by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). In conclusion, urine IL-18, urine NGAL, and plasma NGAL associate with subsequent AKI and poor outcomes among adults undergoing cardiac surgery. (Clinical Trials.gov number, NCT00774137). C1 [Parikh, Chirag R.; Coca, Steven G.; Wang, Zhu] Yale Univ, Sch Med, Nephrol Sect, New Haven, CT USA. [Parikh, Chirag R.; Coca, Steven G.; Wang, Zhu] Vet Affairs Med Ctr, Clin Epidemiol Res Ctr, West Haven, CT USA. [Thiessen-Philbrook, Heather; Garg, Amit X.] Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. [Shlipak, Michael G.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco Vet Adm Med Ctr, San Francisco, CA 94143 USA. [Koyner, Jay L.] Univ Chicago, Pritzker Sch Med, Dept Med, Nephrol Sect, Chicago, IL 60637 USA. [Edelstein, Charles L.] Univ Colorado, Div Renal Dis, Denver, CO 80202 USA. [Devarajan, Prasad; Krawczeski, Catherine D.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Patel, Uptal D.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Swaminathan, Madhav] Duke Univ, Sch Med, Dept Anesthesiol, Div Cardiothorac Anesthesiol & Crit Care Med, Durham, NC USA. [Zappitelli, Michael] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pediat,Div Nephrol, Montreal, PQ H3H 1P3, Canada. [Passik, Cary S.] Danbury Hosp, Dept Cardiothorac Surg, Danbury, CT USA. [Passik, Cary S.] Univ Vermont, Coll Med, Burlington, VT USA. RP Parikh, CR (reprint author), Yale Univ, Nephrol Sect, 950 Campbell Ave,Mail Code 151B,Bldg 35 A,Room 21, West Haven, CT 06516 USA. EM chirag.parikh@yale.edu FU American Heart Association from the National Heart, Lung, and Blood Institute [R01 HL-085757]; National Center for Research Resources [UL1 RR024139]; Abbott Diagnostics; Biosite, Inc. FX We would also like to thank the nursing and support staff of the preadmission clinic, anesthesia units, and the cardiac care units at all of the participating centers. The research reported in this article was supported by the American Heart Association Clinical Development award (grant R01 HL-085757) from the National Heart, Lung, and Blood Institute. The study was also supported by a Clinical and Translational Science Award grant (UL1 RR024139) from the National Center for Research Resources. The urine biomarker assays were donated by Abbott Diagnostics, and plasma NGAL was donated by Biosite. The granting agencies, Abbott Diagnostics and Biosite, Inc., did not participate in the protocol development, analysis, or interpretation of the results. NR 36 TC 188 Z9 190 U1 1 U2 12 PU AMER SOC 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 SEP PY 2011 VL 22 IS 9 BP 1748 EP 1757 DI 10.1681/ASN.2010121302 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 831CH UT WOS:000295705800022 PM 21836143 ER PT J AU Vladutiu, GD Isackson, PJ Kaufman, K Harley, JB Cobb, B Christopher-Stine, L Wortmann, RL AF Vladutiu, Georgirene D. Isackson, Paul J. Kaufman, Kenneth Harley, John B. Cobb, Beth Christopher-Stine, Lisa Wortmann, Robert L. TI Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Malignant hyperthermia; Statin myopathy; RYR1 gene mutations; Metabolic muscle disease; Coexisting genetic risk ID DEPENDENT CALCIUM-CHANNEL; CENTRAL CORE DISEASE; SKELETAL-MUSCLE; RYANODINE RECEPTOR; EXERTIONAL RHABDOMYOLYSIS; SUSCEPTIBILITY LOCUS; CONGENITAL MYOPATHY; MOLECULAR-BASIS; RYR1 MUTATIONS; FAMILIES AB Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n = 197), mild statin myopathy (n = 163), statin-tolerant controls (n = 133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n = 392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease-causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology. (C) 2011 Elsevier Inc. All rights reserved. C1 [Vladutiu, Georgirene D.; Isackson, Paul J.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pediat, Buffalo, NY 14203 USA. [Vladutiu, Georgirene D.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Neurol, Buffalo, NY 14203 USA. [Vladutiu, Georgirene D.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Pathol & Anat Sci, Buffalo, NY 14203 USA. [Kaufman, Kenneth] Univ Oklahoma, Oklahoma Med Res Fdn, Hlth Sci Ctr, Oklahoma City, OK USA. [Kaufman, Kenneth] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Harley, John B.; Cobb, Beth] Cincinnati Childrens Hosp, Dept Med, Cincinnati, OH USA. [Christopher-Stine, Lisa] Johns Hopkins Univ, Dept Med, Johns Hopkins Sch Med, Myositis Ctr, Baltimore, MD USA. [Wortmann, Robert L.] Dartmouth Hitchcock Med Ctr, Dept Med, Lebanon, NH 03766 USA. RP Vladutiu, GD (reprint author), SUNY Buffalo, Sch Med & Biomed Sci, Dept Pediat, 100 High St, Buffalo, NY 14203 USA. EM gdv@buffalo.edu FU NHLBI [1R41HL093956-01, RO1HL085800]; UB Office of the Vice President for Research FX This work was supported by grants from the NHLBI (1R41HL093956-01 and RO1HL085800; GDV) and an Interdisciplinary Research and Creative Activities Award from the UB Office of the Vice President for Research (GDV). We are especially grateful to Dr. Nyamkhishig Sambuughin for her assistance in the interpretation of RYR1 gene variant data. We thank Dr. Henry Rosenberg for his helpful comments during the preparation of this manuscript. We thank Ms. Shanping Huang for technical assistance with preparation, organization and individual genotyping of genomic DNA samples and Ms. Catherine Kern for coordination of collaborating centers and maintenance of the participant database. We also are grateful to physicians and their patients from medical centers including the Mayo Clinic, Rochester, MN; Cedars Sinai Medical Center, Los Angeles, CA; Texas Children's Hospital, Houston, TX; Walter Reed Army Medical Center, Washington, DC; the Oregon Health 8: Science University, Portland, OR; Yale-New Haven Medical Center, New Haven, CT; McMaster University, Hamilton, Ontario, Canada; and the VA Western New York Healthcare System, Buffalo, NY. NR 38 TC 24 Z9 24 U1 0 U2 8 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 SEP-OCT PY 2011 VL 104 IS 1-2 SI SI BP 167 EP 173 DI 10.1016/j.ymgme.2011.07.001 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 823UF UT WOS:000295151300027 PM 21795085 ER PT J AU Arar, N Seo, J Abboud, HE Parchman, M Noel, P AF Arar, Nedal Seo, Joann Abboud, Hanna E. Parchman, Michael Noel, Polly TI Veterans' experience in using the online Surgeon General's family health history tool SO PERSONALIZED MEDICINE LA English DT Article DE family health history; genomic services; Surgeon General's online tool ID GENOMIC MEDICINE; PRIMARY-CARE; SATISFACTION; INFORMATION; DISEASE; POPULATION; PREVENTION; COMMUNITY; INTERNET; DELIVERY AB Aim: To assess veterans' experience and satisfaction in using the Surgeon General's (SG) online family health history (FHH) tool, and determine the perceived facilitators and barriers to using the online SG-FHH tool. Materials & methods: A mixed-method using both qualitative and quantitative approaches was employed in this study. A total of 35 veterans at the VA Medical Center in San Antonio, Texas, USA were invited to enter their FHH information using the online SG-FHH tool, complete the study's satisfaction survey and participate in a short semi-structured interview. The goal of the semi-structured interviews was to assess participants perceived facilitators and barriers to using the online SG-FHH tool. All participants were also provided with a printed copy of their pedigree, which was generated by the SG-FHH tool and were encouraged to share it with their relatives and providers. Results: The majority of participants (91%) said that they had access to a computer with internet capability and 77% reported that they knew how to use a computer. More than two-thirds of the participants felt that items on the SG-FHH tool were easy to read and felt that FHH categories were relevant to their family's health. Approximately 94% of participants viewed the SG-FHH tool as useful, and the majority of participants (97%) indicated that they were likely to recommend the tool to others. Content analysis of the semi-structured interviews highlighted several barriers to veterans' use of the SG-FHH tool and their FHH information. These included: lack of patients' knowledge regarding their relatives' FHH, and privacy and confidentiality concerns. Conclusion: This study provides information on the performance and functionality of an inexpensive and widely accessible method for FHH collection. Furthermore, our findings highlight several opportunities and challenges facing the utilization of FHH information as a clinical and genomic tool at the Veterans Health Administration (VHA). The results suggest that strategies that improve veterans' knowledge regarding the importance of their FHH information and that address their concerns about privacy and confidentiality may enhance the successful implementation of FHH information into VHA clinical practice. Implications: identifying a locally accepted method for FHH collection and documentation which can be conducted outside of the patient visit will reduce time burdens for providers and patients and allow for a focus on other important topics during clinic visits. Improvement in familial risk screening and assessment will enable the VHA to be prepared for personalized medicine and focus their resources on promoting critically important health behaviors for populations with the highest risk of developing chronic diseases and their complications. C1 [Arar, Nedal; Seo, Joann; Abboud, Hanna E.; Parchman, Michael; Noel, Polly] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Arar, Nedal; Seo, Joann; Abboud, Hanna E.; Parchman, Michael; Noel, Polly] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Arar, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ararn@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 FU VHA-HSR and D [DNA 08-129, PPO 09-241]; NIH [UL1RR025767] FX This work was supported by the VHA-HSR and D (DNA 08-129 and PPO 09-241, PI: Nedal Arar). This study was partly funded by the Clinical and Translational Science Award (CTSA) - NIH grant (UL1RR025767). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 35 TC 7 Z9 7 U1 1 U2 1 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 SEP PY 2011 VL 8 IS 5 BP 523 EP 532 DI 10.2217/PME.11.53 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 832JX UT WOS:000295802100010 PM 22076122 ER PT J AU Dileepan, T Linehan, JL Moon, JJ Pepper, M Jenkins, MK Cleary, PP AF Dileepan, Thamotharampillai Linehan, Jonathan L. Moon, James J. Pepper, Marion Jenkins, Marc K. Cleary, Patrick P. TI Robust Antigen Specific Th17 T Cell Response to Group A Streptococcus Is Dependent on IL-6 and Intranasal Route of Infection SO PLOS PATHOGENS LA English DT Article ID LYMPHOID-TISSUE; HOST-DEFENSE; M1 PROTEIN; IN-VITRO; PATHOGENESIS; PYOGENES; HYALURONAN; GENERATION; PLASTICITY; INDUCTION AB Group A streptococcus (GAS, Streptococcus pyogenes) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to quantify pMHCII-specific CD4(+) helper T cells and evaluate their contribution to both protective immunity and autoimmune complications induced by specific bacterial pathogens. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4(+) helper T cell response in C57BL/6 mice that express the I-A(b) MHCII molecule. Following intranasal inoculation with GAS-2W, antigen-experienced 2W:I-A(b)-specific CD4(+) T cells were identified in the nasal-associated lymphoid tissue (NALT) that produced IL-17A or IL-17A and IFN-gamma if infection was recurrent. The dominant Th17 response was also dependent on the intranasal route of inoculation; intravenous or subcutaneous inoculations produced primarily IFN-gamma(+) 2W:I-A(b+) CD4(+) T cells. The acquisition of IL-17A production by 2W: I-A(b)-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-gamma-producing 2W:I-A(b)-specific CD4(+) T cells. Our results suggest that an imbalance between IL-17- and IFN-gamma-producing CD4(+) T cells could contribute to GAS carriage in humans. C1 [Dileepan, Thamotharampillai; Linehan, Jonathan L.; Pepper, Marion; Jenkins, Marc K.] Univ Minnesota, Sch Med, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. [Moon, James J.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Cambridge, MA USA. RP Dileepan, T (reprint author), Univ Minnesota, Sch Med, Dept Microbiol, Ctr Immunol, Minneapolis, MN 55455 USA. EM dile0003@umn.edu RI Jenkins, Marc/G-1063-2012 OI Jenkins, Marc/0000-0001-8009-7655 FU National Institutes of Health [AI059533, AI39614]; [P30 CA77598] FX This work was supported by National Institutes of Health Grant AI059533 to P. P. C and National Institutes of Health Grant AI39614 to M.K.J. We would like to acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 33 Z9 33 U1 0 U2 5 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 SEP PY 2011 VL 7 IS 9 AR e1002252 DI 10.1371/journal.ppat.1002252 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 827DY UT WOS:000295409000052 PM 21966268 ER PT J AU Gnanakaran, S Bhattacharya, T Daniels, M Keele, BF Hraber, PT Lapedes, AS Shen, TY Gaschen, B Krishnamoorthy, M Li, H Decker, JM Salazar-Gonzalez, JF Wang, SY Jiang, CL Gao, F Swanstrom, R Anderson, JA Ping, LH Cohen, MS Markowitz, M Goepfert, PA Saag, MS Eron, JJ Hicks, CB Blattner, WA Tomaras, GD Asmal, M Letvin, NL Gilbert, PB DeCamp, AC Magaret, CA Schief, WR Ban, YEA Zhang, M Soderberg, KA Sodroski, JG Haynes, BF Shaw, GM Hahn, BH Korber, B AF Gnanakaran, S. Bhattacharya, Tanmoy Daniels, Marcus Keele, Brandon F. Hraber, Peter T. Lapedes, Alan S. Shen, Tongye Gaschen, Brian Krishnamoorthy, Mohan Li, Hui Decker, Julie M. Salazar-Gonzalez, Jesus F. Wang, Shuyi Jiang, Chunlai Gao, Feng Swanstrom, Ronald Anderson, Jeffrey A. Ping, Li-Hua Cohen, Myron S. Markowitz, Martin Goepfert, Paul A. Saag, Michael S. Eron, Joseph J. Hicks, Charles B. Blattner, William A. Tomaras, Georgia D. Asmal, Mohammed Letvin, Norman L. Gilbert, Peter B. DeCamp, Allan C. Magaret, Craig A. Schief, William R. Ban, Yih-En Andrew Zhang, Ming Soderberg, Kelly A. Sodroski, Joseph G. Haynes, Barton F. Shaw, George M. Hahn, Beatrice H. Korber, Bette TI Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY-RESPONSES; N-LINKED GLYCOSYLATION; SUBTYPE-C INFECTION; CYTOPLASMIC TAIL; CROSS-VALIDATION; IMMUNE EVASION; HETEROSEXUAL TRANSMISSION; SELECTIVE TRANSMISSION; VACCINE DEVELOPMENT AB Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response. C1 [Gnanakaran, S.; Bhattacharya, Tanmoy; Daniels, Marcus; Hraber, Peter T.; Lapedes, Alan S.; Shen, Tongye; Gaschen, Brian; Krishnamoorthy, Mohan; Zhang, Ming; Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Bhattacharya, Tanmoy; Korber, Bette] Santa Fe Inst, Santa Fe, NM 87501 USA. [Keele, Brandon F.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Keele, Brandon F.; Li, Hui; Decker, Julie M.; Salazar-Gonzalez, Jesus F.; Wang, Shuyi; Goepfert, Paul A.; Saag, Michael S.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Keele, Brandon F.; Li, Hui; Decker, Julie M.; Salazar-Gonzalez, Jesus F.; Wang, Shuyi; Goepfert, Paul A.; Saag, Michael S.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Shen, Tongye] Univ Tennessee, Ctr Biophys Mol, Knoxville, TN USA. [Shen, Tongye] Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN USA. [Jiang, Chunlai] Jilin Univ, Sch Life Sci, Natl Engn Lab AIDS Vaccine, Changchun 130023, Peoples R China. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Jiang, Chunlai; Gao, Feng; Hicks, Charles B.; Tomaras, Georgia D.; Soderberg, Kelly A.; Haynes, Barton F.] Duke Univ, Duke Human Vaccine Inst, Durham, NC USA. [Swanstrom, Ronald; Anderson, Jeffrey A.; Ping, Li-Hua; Cohen, Myron S.; Eron, Joseph J.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Swanstrom, Ronald; Anderson, Jeffrey A.; Ping, Li-Hua; Cohen, Myron S.; Eron, Joseph J.] Univ N Carolina, Div Infect Dis, Ctr AIDS Res, Chapel Hill, NC USA. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Blattner, William A.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Asmal, Mohammed; Letvin, Norman L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Letvin, Norman L.] Harvard Univ, Sch Med, Dept Med, Div Viral Pathogenesis, Boston, MA USA. [Gilbert, Peter B.; DeCamp, Allan C.; Magaret, Craig A.] Fred Hutchinson Canc Res Ctr, Vaccine Infect Dis Div, Seattle, WA 98104 USA. [Schief, William R.; Ban, Yih-En Andrew] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Ban, Yih-En Andrew] Arzeda Corp, Seattle, WA USA. [Zhang, Ming] Univ Georgia, Coll Publ Hlth, Dept Epidemiol & Biostat, Athens, GA 30602 USA. [Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Gnanakaran, S (reprint author), Los Alamos Natl Lab, Los Alamos, NM USA. EM btk@lanl.gov RI Shen, Tongye/A-9718-2008; Bhattacharya, Tanmoy/J-8956-2013; Tomaras, Georgia/J-5041-2016; OI Shen, Tongye/0000-0003-1495-3104; Bhattacharya, Tanmoy/0000-0002-1060-652X; Gnanakaran, S/0000-0002-9368-3044; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU Division of AIDS, NIAID, NIH for the Center for HIV/AIDS Vaccine Immunology (CHAVI) [AI06785] FX This work was funded by the a grant from the Division of AIDS, NIAID, NIH for the Center for HIV/AIDS Vaccine Immunology (CHAVI) AI06785. This study was undertaken as part of our response to the CHAVI call, however, and in this sense it was at the request of the NIH that we initiated this work, but it was implemented, details were designed, and the specific experiments and analyses undertaken by CHAVI consortium. The supercomputing facility at Los Alamos National Laboratory also contributed computational resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 122 TC 63 Z9 64 U1 3 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2011 VL 7 IS 9 AR e1002209 DI 10.1371/journal.ppat.1002209 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 827DY UT WOS:000295409000017 PM 21980282 ER PT J AU Jain, FA Brooks, JO Larsen, KA Kelly, SE Bode, RH Sweeney, GA Stern, TA AF Jain, Felipe A. Brooks, John O., III Larsen, Kenneth A. Kelly, Susan E. Bode, Robert H. Sweeney, Gerard A. Stern, Theodore A. TI Individual Risk Profiles for Postoperative Delirium after Joint Replacement Surgery SO PSYCHOSOMATICS LA English DT Article ID MENTAL-STATE-EXAMINATION; ELDERLY-PATIENTS; HIP FRACTURE; BIPOLAR DISORDER; PREDICTIVE MODEL; CONTROLLED-TRIAL; BLOOD-PRESSURE; PREVENTION; VALIDATION; DONEPEZIL AB Background: Delirium occurs in nearly half of older patients after joint replacement surgery. However, risk profiles for developing delirium have not been established. Objective: We sought to identify risk profiles for delirium in patients following joint replacement surgery. Method: Based on data from a randomized, double-blind, placebo-controlled trial of olanzapine (10 mg) as delirium prophylaxis in 400 patients (67-81 years old) undergoing hip or knee replacement surgery, we performed a signal detection analysis to develop risk profiles for postsurgical delirium (using baseline patient characteristics, iatrogenic factors, and physiologic response parameters). Results: Olanzapine reduced the incidence of delirium by 63% relative to placebo. Among patients receiving placebo, those with an ASA class = 3 and age >= 74 years had a 64% risk of delirium. Those with ASA class < 3 still had a 67% risk of delirium if postoperative oxygen saturation was < 95%. Patients who received olanzapine had an 83% risk of developing delirium if they received >= 42.5 mg equivalents of intra-operative morphine, were a 74 years old, and had a mean arterial pressure (MAP) < 90 mm Hg at the presurgical screening visit. Patients with the lowest risk (6%) of developing delirium received olanzapine had a hematocrit >= 28%, and a presurgical MAP >= 90. Conclusion: Although use of prophylactic olanzapine reduced the incidence of delirium, subsets of patients remained likely to develop delirium. The risk of developing delirium may be reduced through prophylactic dispensation of olanzapine, maintaining optimal perfusion and oxygenation, and limiting intra-operative opioids. (Psychosomatics 2011; 52:410-416) C1 [Jain, Felipe A.; Brooks, John O., III] UCLA Semel Inst Neurosci & Human Behav, Dept Psychiat, Boston, MA USA. New England Baptist Hosp, Boston, MA USA. [Larsen, Kenneth A.; Kelly, Susan E.; Sweeney, Gerard A.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Bode, Robert H.] Beth Israel Deaconess Med Ctr, Dept Anesthesiol, Boston, MA 02215 USA. [Kelly, Susan E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Brooks, JO (reprint author), 760 Westwood Plaza,B8-267, Los Angeles, CA 90024 USA. EM john.brooks@ucla.edu FU Doris Duke Charitable Foundation; Pfizer FX This work was supported by a grant from the Doris Duke Charitable Foundation to Harvard Medical School to fund a Clinical Research Fellowship awarded to FAJ. TAS has been a consultant to, and has been on the speaker's bureau of; Eli Lilly and has been a consultant to, and shareholder of WiFiMed, the company that designed the Tablet PC data management software. JOB is on the speaker's bureau for Merck, Sunovion, and Pfizer, and has received research funding from Pfizer. No other authors reported conflicts of interest. NR 36 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2011 VL 52 IS 5 BP 410 EP 416 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 825BD UT WOS:000295245000002 PM 21907058 ER PT J AU Greer, JA Solis, JM Temel, JS Lennes, IT Prigerson, HG Maciejewski, PK Pirl, WF AF Greer, Joseph A. Solis, Jessica M. Temel, Jennifer S. Lennes, Inga T. Prigerson, Holly G. Maciejewski, Paul K. Pirl, William F. TI Anxiety Disorders in Long-Term Survivors of Adult Cancers SO PSYCHOSOMATICS LA English DT Article ID NATIONAL-COMORBIDITY-SURVEY; POSTTRAUMATIC-STRESS-DISORDER; SUPPORTIVE CARE NEEDS; SURVEY REPLICATION; DEPRESSION; DIAGNOSIS; SAMPLE AB Background: Little is known about the prevalence of anxiety disorders among long-term survivors of adult cancers. Using data from the National Comorbidity Survey Replication (NCS-R), we compared rates of anxiety disorders between long-term cancer survivors and individuals without a histoty of cancer. Methods: A nationally representative sample of 9282 adults participated in a household survey to assess the prevalence of DSM-IV psychiatric disorders, a subset of whom also answered questions about medical comorbidities, including cancer. Long-term survivors were defined as those who received an adult cancer diagnosis at least 5 years before the survey. Multiple logistic regression analyses were used to examine associations between cancer histoty and anxiety disorders in the past year. Results: The NCS-R sample consisted of 225 long-term cancer survivors and 5337 people without a history of cancer. Controlling for socio-demographic variables, long-term cancer survivors were more likely to have an anxiety disorder (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.04-2.13), including specific phobia (OR: 1.59, 95% CI: 1.06-2.44) and medical phobia (OR: 3.45, 95% CI: 1.15-10.0), during the past 12 months compared with those without cancer histories. Rates for social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, panic disorder, and agoraphobia were not significantly different between groups. Conclusion: Longterm survivors of adult cancers were more likely to have an anxiety disorder diagnosis, namely specific phobia, in the past 12 months compared with the general public. Further longitudinal study is needed to clarify the timing and course of anxiety relative to the cancer diagnosis. (Psychosomatics 2011; 52:417-423) C1 [Greer, Joseph A.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Canc, Boston, MA 02114 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Prigerson, Holly G.; Maciejewski, Paul K.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Greer, JA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Canc, WACC 812,15 Parkman St, Boston, MA 02114 USA. EM jgreer2@partners.org FU NIH/NCI [R03 CA 128478, K23 CA 115908] FX This study was supported by NIH/NCI R03 CA 128478 (Greet) and K23 CA 115908 (Pin). NR 23 TC 8 Z9 8 U1 3 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2011 VL 52 IS 5 BP 417 EP 423 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 825BD UT WOS:000295245000003 PM 21907059 ER PT J AU Legesse, B Freudenreich, O Murray, E Price, B AF Legesse, Benalfew Freudenreich, Oliver Murray, Evan Price, Bruce TI A Case Report of Confusional Psychosis with Abrupt Onset and Rapid Resolution of Symptoms SO PSYCHOSOMATICS LA English DT Article ID CYCLOID PSYCHOSES; CONCORDANCE C1 [Legesse, Benalfew; Murray, Evan; Price, Bruce] Harvard Univ, Sch Med, McLean Hosp, Dept Neurol, Belmont, MA 02478 USA. [Freudenreich, Oliver] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Legesse, B (reprint author), Harvard Univ, Sch Med, McLean Hosp, Dept Neurol, 115 Mill St, Belmont, MA 02478 USA. EM blegesse@partners.org NR 16 TC 1 Z9 1 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2011 VL 52 IS 5 BP 468 EP 471 PG 4 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 825BD UT WOS:000295245000012 PM 21907068 ER PT J AU Moore, MA Wallace, EC Westra, SJ AF Moore, Michael A. Wallace, E. Christine Westra, Sjirk J. TI Chest Trauma in Children: Current Imaging Guidelines and Techniques SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Trauma; Chest; Pediatric; CT; Radiography; Ultrasound; Algorithms; Techniques ID BLUNT THORACIC TRAUMA; SEVERELY INJURED PATIENTS; COMPUTED-TOMOGRAPHY; PULMONARY CONTUSION; RIB FRACTURES; PEDIATRIC-PATIENTS; X-RAY; BRONCHIAL RUPTURE; AORTIC RUPTURE; HELICAL CT AB Given the heterogeneous nature of pediatric chest trauma, the optimal imaging approach is tailored to the specific patient. Chest radiography remains the most important imaging modality for initial triage. The decision to perform a chest computed tomography scan should be based on the nature of the trauma, the child's clinical condition, and the initial radiographic findings, taking the age-related pretest probabilities of serious injury into account. The principles of as low as reasonably achievable and Image Gently should be followed. The epidemiology and pathophysiology, imaging techniques, characteristic findings, and evidence-based algorithms for pediatric chest trauma are discussed. C1 [Westra, Sjirk J.] Harvard Univ, Sch Med, Div Pediat Radiol, Dept Radiol,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moore, Michael A.] Cork Univ Hosp, Dept Radiol, Cork, Ireland. [Wallace, E. Christine] Univ Massachusetts, Sch Med, UMass Mem Med Ctr, Dept Radiol, Worcester, MA 01655 USA. RP Westra, SJ (reprint author), Harvard Univ, Sch Med, Div Pediat Radiol, Dept Radiol,Massachusetts Gen Hosp, 55 Fruit St,White 246, Boston, MA 02114 USA. EM swestra@partners.org NR 114 TC 4 Z9 4 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2011 VL 49 IS 5 BP 949 EP + DI 10.1016/j.rcl.2011.06.002 PG 21 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 826WY UT WOS:000295387500008 PM 21889016 ER PT J AU Kurth, J DeFeo, E Cheng, LL AF Kurth, Johannes DeFeo, Elita Cheng, Leo L. TI Magnetic resonance spectroscopy: A promising tool for the diagnostics of human prostate cancer? SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Human prostate cancer; Metabolomics; Spectroscopy; MRS; MRSI; HRMAS ID HR-MAS SPECTROSCOPY; PROTON NMR; PERIPHERAL ZONE; RESOLUTION; TISSUE; OUTCOMES; MR; OVERDIAGNOSIS; METABOLITES; SPERMINE AB Background: Prostate Cancer (CaP) is one of the topmost diagnosed malignant diseases worldwide. In developed countries, early cancer detection methods have led to an increase of incidence rates over the last decades; however, with great variance of the prognosis. There is no diagnostic tool for an exact prediction of tumor aggressiveness, thus there is a lack of adequate and optimal treatment planning. Methods: Electronic databases (Medline, PubMed) were scanned for scientific literature. Basic concepts of magnetic resonance spectroscopy (MRS), important results and its clinical applications were extracted and reviewed in this article. Conclusions: MRS provides crucial information about the metabolic status of human prostate samples while preserving the specimens for further investigations. Single metabolites and metabolomic profiles can be quantified to distinguish benign from malignant tissue and to predict aggressiveness, such as the recurrence rates of CaP. Studies are also anticipating that MRS might be beneficially applicable for in vivo investigations in the future. (C) 2011 Elsevier Inc. All rights reserved. C1 [DeFeo, Elita; Cheng, Leo L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. [DeFeo, Elita; Cheng, Leo L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. [Kurth, Johannes] Charite, D-13353 Berlin, Germany. RP Cheng, LL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. EM cheng@nmr.mgh.harvard.edu FU NIH [CA 115746, CA115746S2, CA141139] FX This work was supported in part by NIH grants (CA 115746, CA115746S2, and CA141139). NR 37 TC 2 Z9 3 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD SEP-OCT PY 2011 VL 29 IS 5 BP 562 EP 571 DI 10.1016/j.urolonc.2011.05.016 PG 10 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 829UE UT WOS:000295609000016 PM 21930088 ER PT J AU Robinson, CM Rajaiya, J Zhou, XH Singh, G Dyer, DW Chodosh, J AF Robinson, Christopher M. Rajaiya, Jaya Zhou, Xiaohong Singh, Gurdeep Dyer, David W. Chodosh, James TI The E3 CR1-gamma gene in human adenoviruses associated with epidemic keratoconjunctivitis SO VIRUS RESEARCH LA English DT Article DE Human adenovirus type 37; CR1-gamma; 31.6K; E3 transcription unit; Epidemic keratoconjunctivitis ID BIOINFORMATICS ANALYSIS; GENITAL INFECTIONS; DOWN-MODULATE; SUBGROUP-D; PROTEIN; APOPTOSIS; IDENTIFICATION; RECEPTOR; TYPE-2; REGION AB Human adenovirus species D type 37 (HAdV-D37) is an important etiologic agent of epidemic keratoconjunctivitis. Annotation of the whole genome revealed an open reading frame (ORF) in the E3 transcription unit predicted to encode a 31.6 kDa protein. This ORF, also known as CR1-gamma, is predicted to be an integral membrane protein containing N-terminal signal sequence, luminal, transmembrane, and cytoplasmic domains. HAdV-D19 (C), another viral pathogen causing epidemic keratoconjunctivitis, contains an ORF 100% identical to its HAdV-D37 homologue but only 66% identical to other HAdV-D homologues. Kinetics of RNA expression and confirmation of splicing to the adenovirus tripartite leader sequence suggest a role for the protein product of CR1-gamma in the late stages of the viral replication cycle. Confocal microscopy is consistent with expression in the cytoplasm. Sequence analysis reveals a hypervariable luminal domain and a conserved cytoplasmic domain. The luminal domain is predicted to contain multiple N-glycosylation sites. The cytoplasmic domain contains a putative protein kinase C phosphorylation site and potential YXX phi and dileucine (LL) motifs suggesting a potential role in modification of host proteins. (C) 2011 Elsevier B.V. All rights reserved. C1 [Robinson, Christopher M.; Rajaiya, Jaya; Zhou, Xiaohong; Singh, Gurdeep; Chodosh, James] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Howe Lab, Boston, MA 02114 USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Chodosh, J (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Howe Lab, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU NIH [EY013124, P30EY014104]; Department of Ophthalmology, Harvard Medical School from Research to Prevent Blindness, Inc. FX Supported by NIH grants EY013124 and P30EY014104, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School from Research to Prevent Blindness, Inc. The funding sponsors played no role in any aspect of the study. NR 38 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD SEP PY 2011 VL 160 IS 1-2 BP 120 EP 127 DI 10.1016/j.virusres.2011.05.022 PG 8 WC Virology SC Virology GA 826HQ UT WOS:000295345600015 PM 21683743 ER PT J AU Verma, P Randhawa, I Klaustermeyer, WB AF Verma, Prashant Randhawa, Inderpal Klaustermeyer, William B. TI Clinical efficacy of omalizumab in an elderly veteran population with severe asthma SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article ID SEVERE ALLERGIC-ASTHMA; ANTIIMMUNOGLOBULIN-E THERAPY; SEVERE PERSISTENT ASTHMA; E ANTIBODY OMALIZUMAB; IGE ANTIBODY; ADULTS; EXACERBATIONS; TOLERABILITY; MANAGEMENT; VALIDITY AB Severe asthma in elderly patients is underdiagnosed, difficult to treat, and often accompanied by atopy. This study was designed to compare clinical outcomes of omalizumab therapy in an elderly veteran population with severe allergic asthma. A retrospective, observational data analysis was performed over 2 years. Cohort outcome measures 1 year before omalizumab therapy were compared with 1 year of active treatment. Statistical analysis included two sample t-tests. The total number of patients enrolled was 17 with median age of 60 years. Omalizumab therapy was associated with a significant reduction in acute asthma exacerbations requiring prednisone treatment (p < 0.01), a significant improvement in forced expiratory volume in 1 second of 0.28 L (p < 0.01), and significantly higher Asthma Control Test (ACT) scores at 3 (p = 0.043), 6 (p = 0.039), and 12 months of therapy (p < 0.01). Two of five patients on daily prednisone for >6 months were able to discontinue systemic steroid use within 3 months of omalizumab treatment. Our study suggests elderly patients with severe atopic asthma show a significant positive clinical response to oinalizumab. (Allergy Asthma Proc 32:346-350, 2011; doi: 10.2500/aap.2011.32.3467) C1 [Verma, Prashant; Randhawa, Inderpal; Klaustermeyer, William B.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Med, Div Allergy Immunol, Los Angeles, CA 90073 USA. RP Verma, P (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Med, Div Allergy Immunol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM verma.allergy@gmail.com NR 36 TC 14 Z9 15 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD SEP-OCT PY 2011 VL 32 IS 5 BP 346 EP 350 DI 10.2500/aap.2011.32.3467 PG 5 WC Allergy SC Allergy GA 828JN UT WOS:000295497400004 PM 22195686 ER PT J AU Konstantinidis, IT Warshaw, AL Lauwers, GY Sahani, DV Gan, SI Ferrone, CR AF Konstantinidis, Ioannis T. Warshaw, Andrew L. Lauwers, Gregory Y. Sahani, Dushyant V. Gan, S. Ian Ferrone, Cristina R. TI A Duodenal Duplication Cyst Causing Recurrent Pancreatitis in a Young Patient SO AMERICAN SURGEON LA English DT Article C1 [Konstantinidis, Ioannis T.; Warshaw, Andrew L.; Lauwers, Gregory Y.; Sahani, Dushyant V.; Ferrone, Cristina R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gan, S. Ian] Virginia Mason Med Ctr, Seattle, WA 98101 USA. RP Konstantinidis, IT (reprint author), Univ Arizona, 1500 N Campbell Ave,POB 245058, Tucson, AZ 85724 USA. EM ikonstan@email.arizona.edu NR 5 TC 0 Z9 0 U1 0 U2 2 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD SEP PY 2011 VL 77 IS 9 BP 1267 EP 1269 PG 3 WC Surgery SC Surgery GA 826GX UT WOS:000295343700024 PM 21944639 ER PT J AU Almashat, S Sepehr, A AF Almashat, Salwan Sepehr, Alireza TI Obstructive and Inflammatory Gastric Heterotopic Pancreatic Tissue SO ARCHIVES OF IRANIAN MEDICINE LA English DT Article DE heterotopic pancreas AB Heterotopic pancreas is defined as pancreatic tissue arising ectopically with no vascular or anatomic contiguity with the pancreas proper and is believed to arise embryologically during rotation of the foregut and fusion of the dorsal and ventral pancreatic buds. We report a case of gastric heterotopic pancreas presenting as an obstructive inflammatory mass with the clinical differential diagnosis of gastric carcinoma. A 54 year-old woman presented with a history of four days of severe, acute-onset abdominal pain. Abdominal ultrasound showed a gastric antral mass. This was confirmed on computerized tomography, which revealed a hypo-dense mass with heterogeneous enhancement in the gastric antrum and multiple ill-defined hypo-dense areas in the liver suspicious for metastases. A preoperative diagnosis of malignant neoplasm was strongly favored, and a subtotal gastrectomy was performed. Microscopic examination of the specimen revealed submucosal and deeply seated intra-muscular and mural heterotopic pancreatic tissue, comprised of both ductal and acinar structures, surrounded by exuberant acute and chronic inflammation. The ducts were inflamed and showed marked cytologic atypia, favored to be of reactive nature. There was overlying mucosal ulceration with marked acute and chronic full-thickness gastric mural inflammatory response with abscess formation. This is the second reported case of obstructive gastric heterotopic pancreas, presenting as an inflammatory mural gastric mass. C1 [Almashat, Salwan; Sepehr, Alireza] Harvard Univ, Sch Med, BIDMC, Dept Pathol, Boston, MA 02215 USA. RP Sepehr, A (reprint author), Harvard Univ, Sch Med, BIDMC, Dept Pathol, East Campus,330 Brookline Ave E1061, Boston, MA 02215 USA. EM asepehr@bidmc.harvard.edu NR 6 TC 5 Z9 6 U1 0 U2 1 PU ACAD MEDICAL SCIENCES I R IRAN PI TEHRAN PA PO BOX 19395-5655, TEHRAN, 00000, IRAN SN 1029-2977 J9 ARCH IRAN MED JI Arch. Iran. Med. PD SEP PY 2011 VL 14 IS 5 BP 357 EP 358 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 828FJ UT WOS:000295486600012 PM 21888463 ER PT J AU Holmes, LB Westgate, MN AF Holmes, Lewis B. Westgate, Marie-Noel TI Inclusion and Exclusion Criteria for Malformations in Newborn Infants Exposed to Potential Teratogens SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE exclusion criteria; malformations; teratogens ID PRENATAL-DIAGNOSIS; CONGENITAL-MALFORMATIONS; MINOR ANOMALIES; PREDICTIVE VALUE; MOTHERS; COHORT; TRENDS AB BACKGROUND: The surveillance of newborn infants exposed to potential teratogens often relies on the findings in routine physicians' examinations to identify malformations. Exposed newborn infants can have a wide variety of physical features, including malformations, birth marks, positional deformities, and minor anomalies. The routine physician's findings are not standardized. Some physicians record a wide variety of physical features and others do not. The purpose of this study was to develop criteria and definitions for identifying malformations and for identifying the more common and less severe physical features that would be excluded as not being malformations. METHODS: The physical features recorded by the examining pediatricians were obtained from a review of the medical records of a consecutive sample of 1000 liveborn and stillborn infants and elective terminations for fetal anomalies. RESULTS: A malformation, defined as a structural abnormality with surgical, medical or cosmetic importance, was present in 18 (2.8%) of the infants; 222 other recorded features were identified and excluded: malformations attributed to dominant or recessive genes (4) or chromosome abnormalities (6), minor anomalies and normal variations (65), birth marks (110), positional deformities (6), prematurity-related features (5), physiologic findings (4) and findings identified by prenatal ultrasound (but not by the examining pediatrician) (20), functional abnormalities (1) and findings in newborn screening (1). CONCLUSIONS: Investigators should establish, in advance, the exclusion criteria to be used in programs, such as malformation surveillance programs or pregnancy registries, whose findings are based on a review of the routine examinations in medical records. It is essential that the same criteria be used in evaluating the drug-exposed and the unexposed comparison group. Birth Defects Research (Part A) 91:807-812, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Holmes, Lewis B.] Harvard Univ, Genet Unit, MassGen Hosp Children, Med Sch,Dept Pediat, Boston, MA 02114 USA. Harvard Univ, Active Malformat Surveillance Program, Dept Newborn Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02114 USA. RP Holmes, LB (reprint author), Harvard Univ, Genet Unit, MassGen Hosp Children, Med Sch,Dept Pediat, 175 Cambridge St,5th Floor, Boston, MA 02114 USA. EM holmes.lewis@mgh.harvard.edu FU Center for Birth Defects Research and Prevention in the Massachusetts Department of Public Health FX The authors received salary support from a subcontract from the Center for Birth Defects Research and Prevention in the Massachusetts Department of Public Health. The funding agency had no role in the conduction of the study or in the analysis of the findings. NR 32 TC 12 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD SEP PY 2011 VL 91 IS 9 BP 807 EP 812 DI 10.1002/bdra.20842 PG 6 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 827BP UT WOS:000295400900001 PM 21800414 ER PT J AU Danzer, KM McLean, PJ AF Danzer, Karin M. McLean, Pamela J. TI Drug Targets from Genetics: Alpha-Synuclein SO CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS LA English DT Article DE Alpha-synuclein; Parkinson's disease; chaperones; oligomers; heat shock proteins; oxidative stress; degradation; neurodegeneration ID HEAT-SHOCK PROTEINS; CHAPERONE-MEDIATED AUTOPHAGY; DELAYS DISEASE PROGRESSION; SOLUBLE AMYLOID OLIGOMERS; INCLUSION-BODY FORMATION; DOPAMINERGIC NEURON LOSS; A-BETA BURDEN; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LEWY BODIES AB One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (alpha syn) or multiplication of the SNCA gene encoding alpha syn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing alpha syn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded alpha syn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of alpha syn are the toxic moieties, then cellular mechanisms that degrade misfolded alpha syn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying alpha syn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt alpha syn induced pathogenesis in PD. C1 [Danzer, Karin M.; McLean, Pamela J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. RP McLean, PJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. EM pmclean@partners.org FU NIH [NS063963]; Michael J. Fox Foundation for Parkinson's Disease research FX PJM is supported by NIH NS063963 and research grants from the Michael J. Fox Foundation for Parkinson's Disease research. NR 200 TC 6 Z9 6 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5273 J9 CNS NEUROL DISORD-DR JI CNS Neurol. Disord.-Drug Targets PD SEP PY 2011 VL 10 IS 6 BP 712 EP 723 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 827CO UT WOS:000295404000009 PM 21838671 ER PT J AU Dollinger, M Kobler, J Berry, DA Mehta, DD Luegmair, G Bohr, C AF Doellinger, Michael Kobler, James Berry, David A. Mehta, Daryush D. Luegmair, Georg Bohr, Christopher TI Experiments on Analysing Voice Production: Excised (Human, Animal) and In Vivo (Animal) Approaches SO CURRENT BIOINFORMATICS LA English DT Article DE Larynx; hemilarynx; vocal fold; dynamics; laryngeal flow; acoustics ID VOCAL FOLD VIBRATION; INVIVO CANINE MODEL; LARYNGEAL NERVE-STIMULATION; PHONATION THRESHOLD FLOW; MEDIAL SURFACE DYNAMICS; FUNDAMENTAL-FREQUENCY; LAMINA PROPRIA; AIR-FLOW; VIDEOSTROBOSCOPIC ANALYSIS; EMPIRICAL EIGENFUNCTIONS AB Experiments on human and on animal excised specimens as well as in vivo animal preparations are so far the most realistic approaches to simulate the in vivo process of human phonation. These experiments do not have the disadvantage of limited space within the neck and enable studies of the actual organ necessary for phonation, i.e., the larynx. The studies additionally allow the analysis of flow, vocal fold dynamics, and resulting acoustics in relation to well-defined laryngeal alterations. Purpose of Review: This paper provides an overview of the applications and usefulness of excised (human/animal) specimen and in vivo animal experiments in voice research. These experiments have enabled visualization and analysis of dehydration effects, vocal fold scarring, bifurcation and chaotic vibrations, three-dimensional vibrations, aerodynamic effects, and mucosal wave propagation along the medial surface. Quantitative data will be shown to give an overview of measured laryngeal parameter values. As yet, a full understanding of all existing interactions in voice production has not been achieved, and thus, where possible, we try to indicate areas needing further study. Recent Findings: A further motivation behind this review is to highlight recent findings and technologies related to the study of vocal fold dynamics and its applications. For example, studies of interactions between vocal tract airflow and generation of acoustics have recently shown that airflow superior to the glottis is governed by not only vocal fold dynamics but also by subglottal and supraglottal structures. In addition, promising new methods to investigate kinematics and dynamics have been reported recently, including dynamic optical coherence tomography, X-ray stroboscopy and three-dimensional reconstruction with laser projection systems. Finally, we touch on the relevance of vocal fold dynamics to clinical laryngology and to clinically-oriented research. C1 [Doellinger, Michael; Luegmair, Georg] Univ Hosp Erlangen, Sch Med, Lab Computat Med, Dept Phoniatr & Pediat Audiol, D-91054 Erlangen, Germany. [Kobler, James; Mehta, Daryush D.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Berry, David A.] Univ Calif Los Angeles, Sch Med, Laryngeal Dynam Lab, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Bohr, Christopher] Univ Hosp Erlangen, Sch Med, ENT Hosp, D-91054 Erlangen, Germany. RP Dollinger, M (reprint author), Univ Hosp Erlangen, Sch Med, Lab Computat Med, Dept Phoniatr & Pediat Audiol, Bohlenpl 21, D-91054 Erlangen, Germany. EM Michael.doellinger@uk-erlangen.de FU Deutsche Forschungsgemeinschaft (DFG) [FOR 894/2]; NIH [R01 DC03072, R01 DC007640]; Institute for Laryngology and Voice Restoration; Eugene B. Casey Foundation FX This work was made possible by Deutsche Forschungsgemeinschaft (DFG) grant no. FOR 894/2 "Stromungsphysikalische Grundlagen der Menschlichen Stimmgebung". Dr. Berry's contributions to this investigation were supported by NIH grant no. R01 DC03072. Drs. Kobler and Mehta acknowledge support from the Institute for Laryngology and Voice Restoration, the Eugene B. Casey Foundation and NIH grant no. R01 DC007640. We thank all colleagues for providing the figures. NR 119 TC 12 Z9 12 U1 1 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-8936 J9 CURR BIOINFORM JI Curr. Bioinform. PD SEP PY 2011 VL 6 IS 3 BP 286 EP 304 PG 19 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 827ET UT WOS:000295411100003 PM 26581597 ER PT J AU Isci, S Ozturk, C Jones, J Otu, H AF Isci, Senol Ozturk, Cengihan Jones, Jon Otu, Hasan TI Bayesian network based pathway analysis of microarray data SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Congress CY SEP 28-OCT 01, 2011 CL Istanbul, TURKEY SP European Biotechnol Themat Network Assoc C1 [Isci, Senol; Ozturk, Cengihan] Bogazici Univ, Inst Biomed Engn, TR-34342 Istanbul, Turkey. [Jones, Jon] Johannes Gutenberg Univ Mainz, Dept Urol, D-55131 Mainz, Germany. [Otu, Hasan] Harvard Univ, Sch Med, Dept Med, BIDMC Genom Ctr, Boston, MA USA. [Otu, Hasan] Istanbul Bilgi Univ, Dept Bioengn, Istanbul, Turkey. EM hotu@bidmc.harvard.edu RI isci, senol/E-7024-2012; Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 NR 0 TC 0 Z9 0 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD SEP PY 2011 VL 22 SU 1 BP S22 EP S22 DI 10.1016/j.copbio.2011.05.034 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 825VS UT WOS:000295310800029 ER PT J AU Friedman, MJ Resick, PA Bryant, RA Strain, J Horowitz, M Spiegel, D AF Friedman, Matthew J. Resick, Patricia A. Bryant, Richard A. Strain, James Horowitz, Mardi Spiegel, David TI CLASSIFICATION OF TRAUMA AND STRESSOR-RELATED DISORDERS IN DSM-5 SO DEPRESSION AND ANXIETY LA English DT Review DE trauma; stress; stressor; dissociation; dissociative disorders; anxiety disorders; adjustment disorders; PTSD; ASD; posttraumatic stress disorder ID DISSOCIATIVE IDENTITY DISORDER; MENTAL-HEALTH PROBLEMS; COMBAT-RELATED PTSD; POSTTRAUMATIC-STRESS; LIFE EVENTS; PANIC DISORDER; PERITRAUMATIC DISSOCIATION; PSYCHIATRIC OUTPATIENTS; INTERNALIZING SUBTYPES; TERRORIST ATTACKS AB This review examines the question of whether there should be a cluster of disorders, including the adjustment disorders (ADs), acute stress disorder (ASD), posttraumatic stress disorder (PTSD), and the dissociative disorders (DDs), in a section devoted to abnormal responses to stress and trauma in the DSM-5. Environmental risk factors, including the individual's developmental experience, would thus become a major diagnostic consideration. The relationship of these disorders to one another is examined and also their relationship to other anxiety disorders to determine whether they are better grouped with anxiety disorders or a new specific grouping of trauma and stressor-related disorders. First how stress responses have been classified since DSM-III is reviewed. The major focus is on PTSD because it has received the most attention, regarding its proper placement among the psychiatric diagnoses. It is discussed whether PTSD should be considered an anxiety disorder, a stress-induced fear circuitry disorder, an internalizing disorder, or a trauma and stressor-related disorder. Then, ASD, AD, and DD are considered from a similar perspective. Evidence is examined pro and con, and a concision is offered recommending inclusion of this cluster of disorders in a section entitled "Trauma and Stressor-Related Disorders." The recommendation to shift ASD and PTSD out of the anxiety disorders section reflects increased recognition of trauma as a precipitant, emphasizing common etiology over common phenomenology. Similar considerations are addressed with regard to AD and DD. Depression and Anxiety 28:737-749, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Spiegel, David] Dept Psychiat & Behav Sci, Stanford, CA USA. [Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, VA Med Ctr, White River Jct, VT USA. [Friedman, Matthew J.] Dartmouth Med Sch, Dept Psychiat, Hanover, NH USA. [Friedman, Matthew J.] Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH USA. [Resick, Patricia A.] VA Ctr Natl Ctr PTSD, White River Jct, VT USA. [Resick, Patricia A.] Boston Univ, Boston, MA 02215 USA. [Bryant, Richard A.] Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. [Strain, James] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Horowitz, Mardi] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Spiegel, D (reprint author), Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. EM dspiegel@stanford.edu OI Bryant, Richard/0000-0002-9607-819X NR 114 TC 72 Z9 74 U1 10 U2 52 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD SEP PY 2011 VL 28 IS 9 SI SI BP 737 EP 749 DI 10.1002/da.20845 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 823EK UT WOS:000295105100002 PM 21681870 ER PT J AU Friedman, MJ Resick, PA Bryant, RA Brewin, CR AF Friedman, Matthew J. Resick, Patricia A. Bryant, Richard A. Brewin, Chris R. TI CONSIDERING PTSD FOR DSM-5 SO DEPRESSION AND ANXIETY LA English DT Review DE PTSD; DSM-IV; DSM-V; diagnostic criteria; posttraumatic; syndromes ID POSTTRAUMATIC-STRESS-DISORDER; CONFIRMATORY FACTOR-ANALYSIS; COGNITIVE-PROCESSING THERAPY; MOTOR-VEHICLE ACCIDENTS; SEPTEMBER-11 TERRORIST ATTACKS; VIETNAM COMBAT VETERANS; CHILDHOOD SEXUAL-ABUSE; FEMALE CRIME VICTIMS; TRAUMA-RELATED GUILT; MENTAL-HEALTH AB This is a review of the relevant empirical literature concerning the DSM-IV-TR diagnostic criteria for PTSD. Most of this work has focused on Criteria A1 and A2, the two components of the A (Stressor) Criterion. With regard to A1, the review considers: (a) whether A1 is etiologically or temporally related to the PTSD symptoms; (b) whether it is possible to distinguish "traumatic" from "non-traumatic" stressors; and (c) whether A1 should be eliminated from DSM-5. Empirical literature regarding the utility of the A2 criterion indicates that there is little support for keeping the A2 criterion in DSM-5. The B (reexperiencing), C (avoidance/numbing) and D (hyperarousal) criteria are also reviewed. Confirmatory factor analyses suggest that the latent structure of PTSD appears to consist of four distinct symptom clusters rather than the three-cluster structure found in DSM-IV. It has also been shown that in addition to the fear-based symptoms emphasized in DSM-IV; traumatic exposure is also followed by dysphoric, anhedonic symptoms, aggressive/externalizing symptoms, guilt/shame symptoms, dissociative symptoms, and negative appraisals about oneself and the world. A new set of diagnostic criteria is proposed for DSM-5 that: (a) attempts to sharpen the A1 criterion; (b) eliminates the A2 criterion; (c) proposes four rather than three symptom clusters; and (d) expands the scope of the B-E criteria beyond a fear-based context. The final sections of this review consider: (a) partial/subsyndromal PTSD; (b) disorders of extreme stress not otherwise specified (DESNOS)/complex PTSD; (c) cross- cultural factors; (d) developmental factors; and (e) subtypes of PTSD. Depression and Anxiety 28:750-769, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, VA Med Ctr, White River Jct, VT 05009 USA. [Friedman, Matthew J.] Dartmouth Med Sch, Hanover, NH USA. [Resick, Patricia A.] VA Boston Healthcare Syst, Boston, MA USA. [Resick, Patricia A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Bryant, Richard A.] Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. [Brewin, Chris R.] UCL, London, England. RP Friedman, MJ (reprint author), US Dept Vet Affairs, Natl Ctr PTSD, VA Med Ctr, 215 N Main St, White River Jct, VT 05009 USA. EM Matthew.Friedman@Dartmouth.edu RI Brewin, Chris/C-4566-2008; OI Brewin, Chris/0000-0002-7462-4460; Bryant, Richard/0000-0002-9607-819X NR 185 TC 186 Z9 187 U1 16 U2 111 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD SEP PY 2011 VL 28 IS 9 SI SI BP 750 EP 769 DI 10.1002/da.20767 PG 20 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 823EK UT WOS:000295105100003 PM 21910184 ER PT J AU Hinton, DE Lewis-Fernandez, R AF Hinton, Devon E. Lewis-Fernandez, Roberto TI THE CROSS-CULTURAL VALIDITY OF POSTTRAUMATIC STRESS DISORDER: IMPLICATIONS FOR DSM-5 SO DEPRESSION AND ANXIETY LA English DT Review DE DSM-5; culture; classification diagnostic criteria; PTSD; trauma ID ATAQUES-DE-NERVIOS; NATIONAL COMORBIDITY SURVEY; DOSE-EFFECT RELATIONSHIPS; COMMON MENTAL-DISORDERS; FOCUSED PANIC-ATTACKS; CAMBODIAN REFUGEES; 12-MONTH PREVALENCE; TIBETAN REFUGEES; VIETNAM VETERANS; PSYCHIATRIC-DISORDERS AB Background: There is considerable debate about the cross-cultural applicability of the posttraumatic stress disorder (PTSD) category as currently specified. Concerns include the possible status of PTSD as a Western culture-bound disorder and the validity of individual items and criteria thresholds. This review examines various types of cross-cultural validity of the PTSD criteria as defined in DSM-IV-TR, and presents options and preliminary recommendations to be considered for DSM-5. Methods: Searches were conducted of the mental health literature, particularly since 1994, regarding cultural-, race-, or ethnicity-related factors that might limit the universal applicability of the diagnostic criteria of PTSD in DSM-IV-TR and the possible criteria for DSM-5 Results: Substantial evidence of the cross-cultural validity of PTSD was found. However, evidence of cross-cultural variability in certain areas suggests the need for further research: the relative salience of avoidance/numbing symptoms, the role of the interpretation of trauma-caused symptoms in shaping symptomatology, and the prevalence of somatic symptoms. This review also indicates the need to modify certain criteria, such as the items on distressing dreams and on foreshortened future, to increase their cross-cultural applicability. Text additions are suggested to increase the applicability of the manual across cultural contexts: specifying that cultural syndromes-such as those indicated in the DSM-IV-TR Glossary-may be a prominent part of the trauma response in certain cultures, and that those syndromes may influence PTSD symptom salience and comorbidity. Conclusions: The DSM-IV-TR PTSD category demonstrates various types of validity. Criteria modification and textual clarifications are suggested to further improve its cross-cultural applicability. Depression and Anxiety 28:783-801, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Hinton, Devon E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Lewis-Fernandez, Roberto] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Lewis-Fernandez, Roberto] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Hinton, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu; rlewis@nyspi.cpmc.columbia.edu NR 171 TC 83 Z9 84 U1 12 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD SEP PY 2011 VL 28 IS 9 SI SI BP 783 EP 801 DI 10.1002/da.20753 PG 19 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 823EK UT WOS:000295105100005 PM 21910185 ER PT J AU Strain, JJ Friedman, MJ AF Strain, James J. Friedman, Matthew J. TI CONSIDERING ADJUSTMENT DISORDERS AS STRESS RESPONSE SYNDROMES FOR DSM-5 SO DEPRESSION AND ANXIETY LA English DT Review ID NATIONAL COMORBIDITY SURVEY; MAJOR DEPRESSION; MODERATION; RELEVANCE; ANXIETY; GENE C1 [Strain, James J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Friedman, Matthew J.] US Dept Vet Affairs, Natl Ctr PTSD, Washington, DC USA. [Friedman, Matthew J.] Dartmouth Med Sch, Hanover, NH USA. RP Friedman, MJ (reprint author), VA Med Ctr, Natl Ctr PTSD 116D, 215 N Main St, White River Jct, VT 05009 USA. EM matthew.friedman@dartmouth.edu NR 33 TC 27 Z9 27 U1 1 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD SEP PY 2011 VL 28 IS 9 SI SI BP 818 EP 823 DI 10.1002/da.20782 PG 6 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 823EK UT WOS:000295105100007 PM 21254314 ER PT J AU Ling, MF Luster, AD AF Ling, Morris F. Luster, Andrew D. TI Novel approach to inhibiting chemokine function SO EMBO MOLECULAR MEDICINE LA English DT Editorial Material DE CCL2; chemokine; glutaminyl cyclase; inflammatory disease; MCP-1; monocyte ID PROGRESSION; RECEPTORS; ARTHRITIS; DISEASE; CCR2 C1 [Ling, Morris F.; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02115 USA. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02115 USA. EM aluster@mgh.harvard.edu OI Ling, Morris/0000-0002-9657-8960 NR 12 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD SEP PY 2011 VL 3 IS 9 BP 510 EP 512 DI 10.1002/emmm.201100161 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 827KK UT WOS:000295427200003 PM 21882341 ER PT J AU Pittet, MJ Swirski, FK AF Pittet, Mikael J. Swirski, Filip K. TI Monocytes link atherosclerosis and cancer SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Atherosclerosis; Cancer; Monocyte ID TUMOR-ASSOCIATED MACROPHAGES; SUPPRESSOR-CELLS; LESION FORMATION; CCR2(-/-) MICE; INFLAMMATION; SUBSETS; ATHEROGENESIS; ACCUMULATION; HYPERCHOLESTEROLEMIA; INTERLEUKIN-1 AB From many perspectives, cardiovascular diseases and cancers are fundamentally different. On the one hand, atherosclerosis is a disease of lipid accumulation driven by diet and lifestyle, whereas cancer is an attack "from within'' driven by mutations. Nevertheless, studies over the past 20 years have forced us to re-evaluate such a view. We are learning that, among other factors, the immune system is indispensable for the development and progression of both diseases. Its components are not only reactive but can also orchestrate both tumor and atherosclerotic lesion growth. In this Viewpoint, we explore how monocytes, which are key constituents of the immune system, forge links between cardiovascular diseases and cancers. C1 [Pittet, Mikael J.; Swirski, Filip K.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pittet, Mikael J.; Swirski, Filip K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Swirski, FK (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu; fswirski@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL095612]; NIAID NIH HHS [R01 AI084880] NR 48 TC 15 Z9 16 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2011 VL 41 IS 9 BP 2519 EP 2522 DI 10.1002/eji.201141727 PG 4 WC Immunology SC Immunology GA 825HC UT WOS:000295260800014 PM 21952809 ER PT J AU Luteijn, R Sciaranghella, G van Lunzen, J Nolting, A Dugast, AS Ghebremichael, MS Altfeld, M Alter, G AF Luteijn, Rutger Sciaranghella, Gaia van Lunzen, Jan Nolting, Anne Dugast, Anne-Sophie Ghebremichael, Musie S. Altfeld, Marcus Alter, Galit TI Early viral replication in lymph nodes provides HIV with a means by which to escape NK-cell-mediated control SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE HIV; Innate immunity; Lymph nodes; NK cells ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-KILLER-CELLS; EXPOSED UNINFECTED INDIVIDUALS; CD8 T-CELLS; RECEPTOR EXPRESSION; DENDRITIC CELLS; IN-VIVO; CHEMOKINE RECEPTORS; TYPE-1 INFECTION; PD-1 EXPRESSION AB Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little is known about the location of their antiviral control. Given that HIV replicates profusely in LNs during early infection, we sought to define whether changes occurred in the NK cell infiltrate within these sites during the first year of HIV infection. Surprisingly, NK cell numbers and distribution were unaltered during early HIV infection. LN NK cells expressed decreased inhibitory receptors, were more highly activated, and expressed elevated TRAIL, potentially conferring a superior capacity for NK cells to become activated and control infection. Most noticeably, KIR(+) NK cells were rarely detected in the LN during HIV infection, associated with diminished migratory capacity in the setting of reduced expression of CX3CR1 and CXCR1. Thus, incomplete control of HIV viral replication during early disease may be due to the inefficient recruitment of KIR(+) NK cells to this vulnerable site, providing HIV a niche where it can replicate unabated by early NK-cell-mediated innate pressure. C1 [Luteijn, Rutger; Sciaranghella, Gaia; Nolting, Anne; Dugast, Anne-Sophie; Ghebremichael, Musie S.; Altfeld, Marcus; Alter, Galit] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. [van Lunzen, Jan] Univ Klinikum Hamburg Eppendorf, Sekt Infektiol, Med Klin 1, Hamburg, Germany. [van Lunzen, Jan] Univ Klinikum Hamburg Eppendorf, Ambulanzzentrum UKE, Hamburg, Germany. [Ghebremichael, Musie S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ghebremichael, Musie S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Alter, G (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, 149 13th St, Boston, MA 02129 USA. EM galter@partners.org RI Dugast, AnneSophie/L-9541-2015 FU NIAID NIH HHS [R01 AI080289] NR 63 TC 13 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD SEP PY 2011 VL 41 IS 9 BP 2729 EP 2740 DI 10.1002/eji.201040886 PG 12 WC Immunology SC Immunology GA 825HC UT WOS:000295260800038 PM 21630248 ER PT J AU Gros, DF Frueh, BC Magruder, KM AF Gros, Daniel F. Frueh, B. Christopher Magruder, Kathryn M. TI Prevalence and features of panic disorder and comparison to posttraumatic stress disorder in VA primary care SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Panic disorder; Posttraumatic stress disorder; Veterans; Comorbidity; Health care utilization ID US VETERANS; DSM-IV; PTSD; COMORBIDITY; SYMPTOMS; CLINICS AB Objective: Although panic disorder (PD) is a highly prevalent condition in both community and community primary care settings, little is known about PD in veteran populations, especially in comparison to posttraumatic stress disorder (PTSD). The present study investigated prevalence, comorbidity, physical and mental health impairment, and health care utilization of veterans with PD and PTSD. Method: A total of 884 veterans participated in a cross-sectional investigation in primary care clinics in four Veteran Affairs Medical Centers (VAMCs). Participants completed diagnostic interviews and self-report questionnaires, and a chart review was completed to assess their VAMC health care utilization. Results: A large number of veterans (8.3%) met the diagnostic criteria for PD and reported significantly more severe physical health impairment (pain, general health), mental health impairment (emotional well-being, role limitations) and social functioning than veterans without PD. Veterans with PD also had increased health care utilization for mental health. Further, PD was highly comorbid with PTSD, with similar symptoms across all measures. Conclusions: These findings demonstrate the high prevalence and severe impairment associated with PD in veterans and highlight the need for improved recognition, assessment and specialized treatments for PD in VAMCs and other care settings. Published by Elsevier Inc. C1 [Gros, Daniel F.] Ralph H Johnson VAMC, Mental Hlth Serv 116, Charleston, SC 29401 USA. [Gros, Daniel F.; Magruder, Kathryn M.] Med Univ S Carolina, Charleston, SC 29403 USA. [Frueh, B. Christopher] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. [Frueh, B. Christopher] Menninger Clin, Houston, TX 77080 USA. RP Gros, DF (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv 116, Charleston, SC 29401 USA. EM grosd@musc.edu RI Schueter, nicos/A-3625-2014 FU Veterans Affairs Health Services Research and Development [VCR-99-010-2]; Ralph H. Johnson VAMC Research Enhancement Award Program [REA08-261] FX This work was partially supported by a grant from Veterans Affairs Health Services Research and Development (VCR-99-010-2). In addition, the authors are members of the Ralph H. Johnson VAMC Research Enhancement Award Program (REA08-261; principal investigator: Leonard Egede, M.D.). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. There are no conflicts of interest to disclose. NR 25 TC 24 Z9 24 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD SEP-OCT PY 2011 VL 33 IS 5 BP 482 EP 488 DI 10.1016/j.genhosppsych.2011.06.005 PG 7 WC Psychiatry SC Psychiatry GA 824MP UT WOS:000295206300012 PM 21816481 ER PT J AU Huffman, JC Chang, TE Durham, LE Weiss, AP AF Huffman, Jeff C. Chang, Trina E. Durham, Lauren E. Weiss, Anthony P. TI Antipsychotic polytherapy on an inpatient psychiatric unit: how does clinical practice coincide with Joint Commission guidelines? SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Antipsychotics; Polypharmacy; Quality; Inpatient; Psychosis ID ATYPICAL ANTIPSYCHOTICS; DOUBLE-BLIND; SCHIZOPHRENIA; QUETIAPINE; DISORDER; POLYPHARMACY; ANTIDEPRESSANTS; AUGMENTATION; METAANALYSIS; RISPERIDONE AB Objective: A recently developed quality measure set for inpatient psychiatric care includes measurement of antipsychotic polytherapy at discharge. Our objective was to use detailed chart reviews to assess the use of antipsychotic polytherapy and place this use in the context of these measures. Methods: Patients (N=75) discharged on multiple antipsychotics and a comparable set (N=114) of comparison patients (a randomly selected set of all admitted inpatients) were identified from consecutive admissions to a psychiatric inpatient unit. Medical records were reviewed to ascertain the clinical rationale for antipsychotic polytherapy and assess differences in characteristics between these groups. Results: Patients discharged on antipsychotic polytherapy were more likely to have public insurance, longer lengths of stay, psychotic illness, more prior admissions, and state-funded services for persons with chronic mental illness. We identified subgroups of patients based on the clinical rationale for the antipsychotic co-prescription (refractory illness, regimen unchanged from admission and use of antipsychotic for nonpsychosis symptoms). Some, but not all, such rationales appeared to be clinically justified. Conclusions: The majority of patients discharged on antipsychotic polytherapy had justifiable clinical rationales that were concordant with the new quality measures. However, two additional subsets were identified, one where quality improvement efforts may be warranted and another where revision of existing quality measure definitions should be considered. Given the implications of public reporting of quality measures, further study and refinement of these measures are required to provide meaningful information to all concerned stakeholders. (C) 2011 Elsevier Inc. All rights reserved. C1 [Huffman, Jeff C.; Chang, Trina E.; Durham, Lauren E.; Weiss, Anthony P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Huffman, Jeff C.; Chang, Trina E.; Weiss, Anthony P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM jhuffman@partners.org NR 23 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD SEP-OCT PY 2011 VL 33 IS 5 BP 501 EP 508 DI 10.1016/j.genhosppsych.2011.05.012 PG 8 WC Psychiatry SC Psychiatry GA 824MP UT WOS:000295206300014 PM 21762994 ER PT J AU Tischkowitz, M Bahubeshi, A Hamel, N Pasini, B Asioli, S Baynam, G Overkov, A Frieder, RP Dishop, M Graf, N Ekim, M Bouron-Dal Soglio, D Arseneau, J Young, RH Sabbaghian, N Srivastava, A Priest, JR Foulkes, WD AF Tischkowitz, Marc Bahubeshi, A. Hamel, N. Pasini, B. Asioli, S. Baynam, G. Overkov, A. Frieder, R. P. Dishop, M. Graf, N. Ekim, M. Bouron-Dal Soglio, D. Arseneau, J. Young, R. H. Sabbaghian, N. Srivastava, A. Priest, J. R. Foulkes, W. D. TI Extending the Benign and Malignant Phenotypes Associated with Germline DICER1 Mutations SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract CT British Human Genetics Conference CY SEP 05-07, 2011 CL Univ Warwick, Coventry, ENGLAND HO Univ Warwick C1 [Tischkowitz, Marc; Bahubeshi, A.; Hamel, N.; Sabbaghian, N.; Srivastava, A.; Foulkes, W. D.] McGill Univ, Program Canc Genet, Dept Oncol, Montreal, PQ, Canada. [Tischkowitz, Marc; Bahubeshi, A.; Hamel, N.; Sabbaghian, N.; Srivastava, A.; Foulkes, W. D.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Tischkowitz, Marc; Bahubeshi, A.; Sabbaghian, N.; Srivastava, A.; Foulkes, W. D.] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Hamel, N.; Foulkes, W. D.] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada. [Pasini, B.] Univ Turin, Dept Genet Biol & Biochem, I-10124 Turin, Italy. [Asioli, S.] Univ Turin, Dept Biomed Sci & Human Oncol, I-10124 Turin, Italy. [Baynam, G.; Overkov, A.] Univ Western Australia, Sch Pediat & Child Hlth, Nedlands, WA 6009, Australia. [Frieder, R. P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Dishop, M.] Childrens Hosp, Dept Pathol, Aurora, CO USA. [Graf, N.] Childrens Hosp Westmead, Dept Pathol, Sydney, NSW, Australia. [Ekim, M.] Ankara Univ, Sch Med, Dept Pediat Nephrol, TR-06100 Ankara, Turkey. [Bouron-Dal Soglio, D.] CHU St Justine, Dept Pathol, Montreal, PQ, Canada. [Arseneau, J.] McGill Univ, Dept Pathol, Montreal, PQ, Canada. [Young, R. H.] Harvard Univ, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Priest, J. R.] Childrens Hosp & Clin Minnesota, Int Pleuropulm Blastoma Registry, Minneapolis, MN USA. EM marc.tischkowitz@mcgill.ca RI Ekim, Mesiha/L-9398-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2011 VL 48 SU 1 BP S103 EP S103 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 823DY UT WOS:000295103800225 ER PT J AU Hutt, E Ruscin, JM Linnebur, SA Fish, DN Oman, KS Fink, RM Radcliff, TA Van Dorsten, B Liebrecht, D Fish, R McNulty, MC AF Hutt, Evelyn Ruscin, J. Mark Linnebur, Sunny A. Fish, Douglas N. Oman, Kathleen S. Fink, Regina M. Radcliff, Tiffany A. Van Dorsten, Brent Liebrecht, Debra Fish, Ron McNulty, Monica C. TI A Multifaceted Intervention to Implement Guidelines Did Not Affect Hospitalization Rates for Nursing Home-Acquired Pneumonia SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Nursing home; pneumonia; hospitalization; guidelines; care processes ID RANDOMIZED CONTROLLED-TRIAL; TERM-CARE FACILITIES; RESIDENTS; MANAGEMENT; PROGRAM; REDUCE; IMPACT AB Objective: Determine whether a comprehensive approach to implementing national consensus guidelines for nursing home acquired pneumonia (NHAP) affected hospitalization rates. Design: Quasi-experimental, mixed-methods, multifaceted, unblinded intervention trial. Setting: Sixteen nursing homes (NHs) from 1 corporation: 8 in metropolitan Denver, CO; 8 in Kansas and Missouri during 3 influenza seasons, October to April 2004 to 2007. Participants: Residents with 2 or more signs and symptoms of systemic lower respiratory tract infection (LRTI); NH staff and physicians were eligible. Intervention: Multifaceted, including academic detailing to clinicians, within-facility nurse change agent, financial incentives, and nursing education. Measurements: Subjects' NH medical records were reviewed for resident characteristics, disease severity, and care processes. Bivariate analysis compared hospitalization rates for subjects with stable and unstable vital signs between intervention and control NHs and time periods. Qualitative interviews were analyzed using content coding. Results: Hospitalization rates for stable residents in both NH groups remained low throughout the study. Few critically ill subjects in the intervention NHs were hospitalized in either the baseline or intervention period. In control NHs, 8.7% of subjects with unstable vital signs were hospitalized during the baseline and 33% in intervention year 2, but the difference was not statistically significant (P = .10). Interviews with nursing staff and leadership confirmed there were significant pressures for, and enablers of, avoiding hospitalization for treatment of acute infections. Conclusions: Secular pressures to avoid hospitalization and the challenges of reaching NH physicians via academic detailing are likely responsible for the lack of intervention effect on hospitalization rates for critically ill NH residents. (J Am Med Dir Assoc 2011; 12: 499-507) C1 [Hutt, Evelyn; Radcliff, Tiffany A.] Univ Colorado Denver, Denver VA Med Ctr, Denver, CO 80220 USA. [Hutt, Evelyn; Ruscin, J. Mark; Linnebur, Sunny A.; Fish, Douglas N.; Oman, Kathleen S.; Fink, Regina M.; Radcliff, Tiffany A.; Van Dorsten, Brent; Liebrecht, Debra; Fish, Ron; McNulty, Monica C.] Univ Colorado Denver, Aurora, CO USA. RP Hutt, E (reprint author), Univ Colorado Denver, Denver VA Med Ctr, 1055 Clermont St,151, Denver, CO 80220 USA. EM evelyn.hutt@ucdenver.edu NR 20 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD SEP PY 2011 VL 12 IS 7 BP 499 EP 507 DI 10.1016/j.jamda.2010.03.011 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 827QJ UT WOS:000295442700005 PM 21450174 ER PT J AU Shofner, JD Lipworth, A Tannous, Z Avram, MM AF Shofner, Joshua D. Lipworth, Adam Tannous, Zeina Avram, Mathew M. TI When Not to Treat Cutaneous Vascular Lesions With the Pulsed Dye Laser SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE pulsed dye laser; telangiectasia; petechiae ID TELANGIECTASIA; DERMATOMYOSITIS; MELANOMA; ERYTHEMA; ROSACEA; DISEASE; UPDATE; NM AB The availability of effective laser treatment for cutaneous vascular lesions has risen dramatically in recent years. At the same time, there has been a proliferation of laser providers with varying amounts of training-both medical and nonmedical. We report a series of four cases where patients presented for cosmetic evaluation of vascular lesions and were discovered to have more significant pathologic disease. In presenting these cases, we hope to illuminate a basic differential diagnosis that exists for cutaneous vascular lesions and remind healthcare providers that not all "cosmetic" concerns are benign in origin. There is a differential diagnosis that exists for cutaneous vascular lesions that is worth reviewing, and it should be considered in all patients presenting for laser treatment. Lasers Surg. Med. 43:792-796, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Avram, Mathew M.] Harvard Univ, Massachusetts Gen Hosp, Dept Dermatol, MGH Laser & Cosmet Ctr,Med Sch, Boston, MA 02114 USA. [Lipworth, Adam] Harvard Univ, Brigham & Womens Hosp, Dept Dermatol, Sch Med, Boston, MA 02114 USA. RP Avram, MM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Dermatol, MGH Laser & Cosmet Ctr,Med Sch, 50 Staniford St,250, Boston, MA 02114 USA. EM mavram@partners.org NR 27 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD SEP PY 2011 VL 43 IS 8 BP 792 EP 796 DI 10.1002/lsm.21119 PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA 824WG UT WOS:000295232300002 PM 21956626 ER PT J AU Haedersdal, M Katsnelson, J Sakamoto, FH Farinelli, WA Doukas, AG Tam, J Anderson, RR AF Haedersdal, M. Katsnelson, J. Sakamoto, F. H. Farinelli, W. A. Doukas, A. G. Tam, J. Anderson, R. R. TI Enhanced Uptake and Photoactivation of Topical Methyl Aminolevulinate After Fractional CO2 Laser Pretreatment SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE drug delivery; fractional laser ablation; methyl 5-aminolevulinic acid; photodynamic therapy; photosensitizer; porphyrins ID BASAL-CELL CARCINOMA; NONMELANOMA SKIN-CANCER; PROTOPORPHYRIN-IX FLUORESCENCE; ACID-PHOTODYNAMIC THERAPY; ACTINIC KERATOSIS; ENDOGENOUS PROTOPORPHYRIN; 5-AMINOLEVULINIC ACID; PHOTOTHERMOLYSIS; PHOTOSENSITIZER; EPIDEMIOLOGY AB Background and Objectives: Photodynamic therapy (PDT) of thick skin lesions is limited by topical drug uptake. Ablative fractional resurfacing (AFR) creates vertical channels that may facilitate topical PDT drug penetration and improve PDT-response in deep skin layers. The purpose of this study was to evaluate whether pre-treating the skin with AFR before topically applied methyl aminolevulinate (MAL) could enable a deep PDT-response. Materials and Methods: Yorkshire swine were treated under general anesthesia with a fractional CO2 laser using stacked single pulses of 3 milliseconds, 91.6 mJ per pulse and subsequent topical MAL application for 3 hours (Metvix (R)). Red light (LED arrays) was then delivered at fluences of 37 and 200 J/cm(2). Fluorescent photography and microscopy was used to quantify MAL-induced porphyrin distribution and PDT-induced photobleaching at the skin surface and five specific depths down to 1,800 mu m. Results: Laser-ablated channels were approximately 1,850 mu m deep, which significantly increased topical MAL-induced porphyrin fluorescence (hair follicles, dermis, P < 0.0001) and PDT response, both superficially and deep, versus topical MAL application alone. The fraction of porphyrin fluorescence lost by photobleaching was slightly less after 37 J/cm(2) than after 200 J/cm(2) (overall median values 67-90%; 37 vs. 200 J/cm(2), P > 0.05 for all but one comparison). Photobleaching was steady throughout skin layers and did not vary significantly with skin depth at either LED fluence (P > 0.05). Conclusions: AFR greatly facilitates topical MAL-induced porphyrins and the fraction of photobleached porphyrins is similar for superficial and deep skin. These observations are consistent with AFR-enhanced uptake of MAL, increased porphyrin synthesis, and photodynamic activation of deep porphyrins even at the lower fluence of 37 J/cm(2), widely used in clinical practice. AFR appears to be a clinically practical means for improving PDT deep into the skin. Clinical studies are suggested to evaluate selectivity in targeting dysplastic cell types. Lasers Surg. Med. 43:804-813, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Haedersdal, M.; Katsnelson, J.; Sakamoto, F. H.; Farinelli, W. A.; Doukas, A. G.; Tam, J.; Anderson, R. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Haedersdal, M.] Univ Copenhagen, Bispebjerg Hosp, Dept Dermatol, DK-2400 Copenhagen, Denmark. [Sakamoto, F. H.] Univ Fed Sao Paulo, Escola Paulista Med, Dept Dermatol, BR-04023900 Sao Paulo, Brazil. RP Haedersdal, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, BHX 630-55 Fruit St, Boston, MA 02114 USA. EM mhaedersdal@dadlnet.dk FU Photocure/Galderma; Danish Council for Independent Research/Medical Sciences (FSS); Aage Bang Foundation; A.P Moller Foundation for the Advancement of Medical Science FX M.H. has received fee from Photocure/Galderma for speaking and is on the advisory board for Galderma International regarding photodynamic therapy of organ transplant recipients. None of the other listed authors have any conflict of interest regarding this publication.; Contract grant sponsor: Danish Council for Independent Research/Medical Sciences (FSS); Contract grant sponsor: Aage Bang Foundation; Contract grant sponsor: A.P Moller Foundation for the Advancement of Medical Science. NR 32 TC 55 Z9 56 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD SEP PY 2011 VL 43 IS 8 BP 804 EP 813 DI 10.1002/lsm.21096 PG 10 WC Dermatology; Surgery SC Dermatology; Surgery GA 824WG UT WOS:000295232300004 PM 21956628 ER PT J AU Sharma, SK Kharkwal, GB Sajo, M Huang, YY De Taboada, L McCarthy, T Hamblin, MR AF Sharma, Sulbha K. Kharkwal, Gitika B. Sajo, Mari Huang, Ying-Ying De Taboada, Luis McCarthy, Thomas Hamblin, Michael R. TI Dose Response Effects of 810 nm Laser Light on Mouse Primary Cortical Neurons SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE low level laser therapy; LLLT; photobiomodulation; cultured cortical neurons; near-infra red laser; reactive oxygen species; nitric oxide; mitochondrial membrane potential; intracellular calcium; ATP; biphasic dose response ID HELIUM-NEON LASER; TERM NEUROLOGICAL DEFICITS; TRAUMATIC BRAIN-INJURY; HUMAN SKIN FIBROBLASTS; NITRIC-OXIDE; PROMOTES REGENERATION; FUNCTIONAL RECOVERY; ISCHEMIC-STROKE; INFRARED LIGHT; ATP SYNTHESIS AB Background and Objectives: In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from embryonic mouse brains. Study Design/Materials and Methods: Neurons were irradiated with fluences of 0.03, 0.3, 3, 10, or 30 J/cm(2) of 810-nm laser delivered over varying times at 25 mW/cm(2) and intracellular levels of reactive oxygen species (ROS), nitric oxide and calcium were measured using fluorescent probes within 5 minutes of the end of irradiation. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Results: Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluences. ROS was significantly induced at low fluences, followed by a decrease and a second larger increase at 30 J/cm(2). Nitric oxide levels showed a similar pattern of a double peak but values were less significant compared to ROS. Conclusions: The results suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling processes which in turn may be responsible for the beneficial stimulatory effects of the low level laser. At higher fluences beneficial mediators are reduced and high levels of Janus-type mediators such as ROS and NO (beneficial at low concentrations and harmful at high concentrations) may be responsible for the damaging effects of high-fluence light and the overall biphasic dose response. Lasers Surg. Med. 43:851-859, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Sharma, Sulbha K.; Kharkwal, Gitika B.; Sajo, Mari; Huang, Ying-Ying; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Sharma, Sulbha K.; Kharkwal, Gitika B.; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Sajo, Mari] Univ Tokyo, Grad Sch Pharmaceut, Tokyo, Japan. [Huang, Ying-Ying] Guangxi Med Univ, Aesthet & Plast Ctr, Nanning, Peoples R China. [De Taboada, Luis; McCarthy, Thomas] Photothera Inc, Carlsbad, CA USA. [Hamblin, Michael R.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Huang, Ying-ying/G-3153-2011; OI Huang, Ying-ying/0000-0003-3066-6981; Hamblin, Michael/0000-0001-6431-4605 FU Photothera, Inc.; Photothera; NIH [R01AI050875]; Center for Integration of Medicine and Innovative Technology [DAMD17-02-2-0006]; CDMRP Program in TBI [W81XWH-09-1-0514]; Air Force Office of Scientific Research [FA9950-04-1-0079] FX This study was partly supported by a sponsored research agreement from Photothera, Inc. Luis De Taboada and Thomas McCarthy are employees and stockholders in Photothera, Inc. Michael R Hamblin has received research support, loan of equipment and consulting fees from Photothera.; Contract grant sponsor: NIH; Contract grant number: R01AI050875; Contract grant sponsor: Center for Integration of Medicine and Innovative Technology; Contract grant number: DAMD17-02-2-0006; Contract grant sponsor: CDMRP Program in TBI; Contract grant number: W81XWH-09-1-0514; Contract grant sponsor: Air Force Office of Scientific Research; Contract grant number: FA9950-04-1-0079. NR 63 TC 40 Z9 41 U1 1 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD SEP PY 2011 VL 43 IS 8 BP 851 EP 859 DI 10.1002/lsm.21100 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 824WG UT WOS:000295232300010 PM 21956634 ER PT J AU Mershon-Shier, KL Vasuthasawat, A Takahashi, K Morrison, SL Beenhouwer, DO AF Mershon-Shier, Kileen L. Vasuthasawat, Alex Takahashi, Kazue Morrison, Sherie L. Beenhouwer, David O. TI In vitro C3 deposition on Cryptococcus capsule occurs via multiple complement activation pathways SO MOLECULAR IMMUNOLOGY LA English DT Article DE Cryptococcus; Complement ID MANNAN-BINDING LECTINS; CLASSICAL PATHWAY; MICE DEFICIENT; COMPONENT C3; NEOFORMANS; INFECTION; SERUM; PROTECTION; INNATE; GATTII AB Complement can be activated via three pathways: classical, alternative, and lectin. Cryptococcus gattii and Cryptococcus neoformans are closely related fungal pathogens possessing a polysaccharide capsule composed mainly of glucuronoxylomannan (GXM), which serves as a site for complement activation and deposition of complement components. We determined 0 deposition on Cryptococcus spp. by flow cytometry and confocal microscopy after incubation with serum from C57BL/6J mice as well as mice deficient in complement components C4, C3, factor B, and mannose binding lectin (MBL). C. gattii and C. neoformans activate complement in EGTA-treated serum indicating that they can activate the alternative pathway. However, complement activation was seen with factor B(-/-) serum suggesting activation could also take place in the absence of a functional alternative pathway. Furthermore, we uncovered a role for C4 in the alternative pathway activation by Cryptococcus spp. We also identified an unexpected and complex role for MBL in complement activation by Cryptococcus spp. No complement activation occurred in the absence of MBL-A and -C proteins although activation took place when the lectin binding activity of MBL was disrupted by calcium chelation. In addition, alternative pathway activation by C. neoformans required both MBL-A and -C, while either MBL-A or -C was sufficient for alternative pathway activation by C. gattii. Thus, complement activation by Cryptococcus spp. can take place through multiple pathways and complement activation via the alternative pathway requires the presence of C4 and MBL proteins. Published by Elsevier Ltd. C1 [Beenhouwer, David O.] Vet Affairs Greater Angeles Healthcare Syst, Div Infect Dis 111F, Los Angeles, CA 90073 USA. [Mershon-Shier, Kileen L.; Vasuthasawat, Alex; Morrison, Sherie L.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. [Mershon-Shier, Kileen L.; Vasuthasawat, Alex; Morrison, Sherie L.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Takahashi, Kazue] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Morrison, Sherie L.; Beenhouwer, David O.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Beenhouwer, DO (reprint author), Vet Affairs Greater Angeles Healthcare Syst, Div Infect Dis 111F, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM dbeenhou@ucla.edu FU Ford Foundation; NIH [R01 AI51415, R01 AI071025, CA-16042, AI-28697]; Veterans Affairs Merit Award; Jonsson Cancer Center; UCLA AIDS Institute; UCLA School of Medicine; UCLA MIMG Department; UCLA Muscular Dystrophy Translational Research Consortium FX This work was supported by a Ford Foundation Pre-Doctoral Fellowship awarded to K.L.M.-s., NIH grants R01 AI51415 (S.L.M.) and R01 AI071025 (D.O.B.), and a Veterans Affairs Merit Award (D.O.B.). Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Cytometry Core Facility that is supported by the National Institutes of Health Awards CA-16042 and AI-28697, by the Jonsson Cancer Center, the UCLA AIDS Institute, and the UCLA School of Medicine. Flow cytometry was also supported through funds provided by UCLA MIMG Department and the UCLA Muscular Dystrophy Translational Research Consortium. NR 34 TC 6 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD SEP PY 2011 VL 48 IS 15-16 BP 2009 EP 2018 DI 10.1016/j.molimm.2011.06.215 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 826ZY UT WOS:000295395300033 PM 21723612 ER PT J AU Landau, M Kurella-Tamura, M Shlipak, MG Kanaya, A Strotmeyer, E Koster, A Satterfield, S Simsonick, EM Goodpaster, B Newman, AB Fried, LF AF Landau, Michael Kurella-Tamura, Manjula Shlipak, Michael G. Kanaya, Alka Strotmeyer, Elsa Koster, Annemarie Satterfield, Suzanne Simsonick, Eleanor M. Goodpaster, Bret Newman, Anne B. Fried, Linda F. CA Hlth Aging Body Composition Study TI Correlates of insulin resistance in older individuals with and without kidney disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic kidney disease; cystatin C; insulin resistance; subcutaneous fat ID CHRONIC-RENAL-FAILURE; GLOMERULAR-FILTRATION-RATE; METABOLIC SYNDROME; ADIPOSE-TISSUE; PLASMA ADIPONECTIN; MUSCLE COMPOSITION; ABDOMINAL OBESITY; BODY-COMPOSITION; VISCERAL FAT; SENSITIVITY AB Background. Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ. Methods. Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70-79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m(2) based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD. Results. Individuals with IR had a lower eGFR (80.7 +/- 20.9 versus 75.6 +/- 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73m(2) 0.92, 95% confidence interval 0.87-0.98) and CKD (1.41, 1.04-1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04), where adiponectin was associated with IR in those without CKD but not in those with CKD. Conclusions. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD. C1 [Strotmeyer, Elsa; Newman, Anne B.; Fried, Linda F.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Landau, Michael] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Kurella-Tamura, Manjula] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Shlipak, Michael G.] San Francisco VA, Gen Internal Med Sect, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA. [Shlipak, Michael G.; Kanaya, Alka] Univ Calif San Francisco, Dept Biostat, San Francisco, CA USA. [Koster, Annemarie] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Koster, Annemarie] Sch Publ Hlth & Primary Care CAPHRI, Maastricht, Netherlands. [Koster, Annemarie] Maastricht Univ, Dept Internal Med, Maastricht, Netherlands. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simsonick, Eleanor M.] NIA, NIH, Baltimore, MD 21224 USA. [Goodpaster, Bret; Newman, Anne B.; Fried, Linda F.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Fried, Linda F.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. RP Fried, LF (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. EM linda.fried@va.gov RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; Strotmeyer, Elsa/F-3015-2014; Kurella Tamura, Manjula/C-8284-2014; OI Newman, Anne/0000-0002-0106-1150; Kurella Tamura, Manjula/0000-0001-5227-2479; Strotmeyer, Elsa/0000-0002-4093-6036 FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIH, National Institute on Aging FX The Health, Aging and Body Composition Study is supported by NIA contract numbers of all participating centers (N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. The results presented in this paper have not been published previously in whole or part. NR 45 TC 19 Z9 19 U1 0 U2 0 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 SEP PY 2011 VL 26 IS 9 BP 2814 EP 2819 DI 10.1093/ndt/gfq817 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600016 PM 21248294 ER PT J AU O'Seaghdha, CM Hwang, SJ Muntner, P Melamed, ML Fox, CS AF O'Seaghdha, Conall M. Hwang, Shih-Jen Muntner, Paul Melamed, Michal L. Fox, Caroline S. TI Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE CKD; ESRD; phosphorus ID GLOMERULAR-FILTRATION-RATE; DIETARY-PROTEIN; CARDIOVASCULAR-DISEASE; RISK-FACTOR; PHOSPHATE; INSUFFICIENCY; PROGRESSION; MORTALITY; INJURY; HYPERTENSION AB Background. Elevations in serum phosphorus are associated with renal decline in animal models and progression of established chronic kidney disease (CKD) in human observational studies. We examined whether serum phosphorus levels increase the risk of incident CKD or end-stage renal disease (ESRD) in two population-based prospective cohort studies. Methods. Overall, 2269 participants free of CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73(2)] from the Framingham Heart Study (FHS; mean age 42 years; 53% women) and 13 372 participants from the Third National Health and Nutrition Examination Survey (NHANES III; mean age 44.3 years, 52% women) contributed to the present study. In the FHS, we evaluated the relationship between baseline phosphorus category (< 2.5 mg/dL, 2.5-3.49 mg/dL, 3.5-3.99 mg/dL and >= 4 mg/dL) and incident CKD (n 267). In NHANES, we examined the relationship between phosphorus below and above 4 mg/dL in relation to incident ESRD (n 65). Results. FHS participants in the highest phosphorus category had an increased risk of CKD [odds ratio 2.14; 95% confidence interval (CI), 1.07-4.28; P = 0.03] in multivariable-adjusted models when compared to the referent group (2.5-3.49 mg/dL). Similarly, NHANES III participants with phosphorus levels >= 4 mg/dL demonstrated an increased risk of incident ESRD compared to those < 4 mg/dL (relative risk 1.90; 95% CI 1.03-3.53; P = 0.04). Conclusions. In prospective studies of the general population, serum phosphorus levels in the upper-normal range were associated with a doubling in the risk of developing incident CKD and ESRD. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Div Renal, Boston, MA 02114 USA. [O'Seaghdha, Conall M.] Harvard Univ, Sch Med, Boston, MA USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. [Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35294 USA. [Melamed, Michal L.] Albert Einstein Coll Med, Dept Med, Div Nephrol, Bronx, NY 10467 USA. [Melamed, Michal L.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute [N01-HC-25195]; [K23- DK 078774] FX The Framingham Offspring Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195). M.L.M. is supported by grant K23- DK 078774. NR 47 TC 30 Z9 31 U1 0 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2011 VL 26 IS 9 BP 2885 EP 2890 DI 10.1093/ndt/gfq808 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 824VZ UT WOS:000295231600025 PM 21292817 ER PT J AU Pirl, WF Traeger, L Greer, JA Bemis, H Gallagher, E Lennes, I Sequist, L Heist, R Temel, JS AF Pirl, William F. Traeger, Lara Greer, Joseph A. Bemis, Heather Gallagher, Emily Lennes, Inga Sequist, Lecia Heist, Rebecca Temel, Jennifer S. TI Tumor Epidermal Growth Factor Receptor Genotype and Depression in Stage IV Non-Small Cell Lung Cancer SO ONCOLOGIST LA English DT Article DE Non-small cell; Genotyping; Epidermal growth factor receptor; Depression; Major depressive disorder ID FACTOR-ALPHA; CLINICAL-TRIALS; MAJOR DEPRESSION; EGFR MUTATIONS; DOUBLE-BLIND; GENE; AMPHIREGULIN; GEFITINIB; SYMPTOMS; BEHAVIOR AB Introduction. Depression appears to be associated with worse survival from cancer, but underlying mechanisms for this association are unknown. In the present study, we explored the degree to which tumor genotype may be associated with depression in patients with non-small cell lung cancer (NSCLC). We examined differences in depression severity and rates of positive screens for major depressive disorder among newly diagnosed patients with stage IV NSCLC and known epidermal growth factor receptor (EGFR) genotype. Methods. Newly diagnosed patients (n = 53) with metastatic NSCLC attending an initial thoracic oncology consultation completed self-report questionnaires regarding demographics, smoking behavior, and depression before meeting with their oncologist. Biopsy samples were subsequently genotyped, including screening for EGFR mutations. We conducted a retrospective chart review to obtain clinical data, including tumor stage, performance status, and EGFR genotype. Results. Twelve patients (22.6%) tested positive for EGFR mutation. No EGFR mutation-positive cases met the screening criteria for major depressive disorder, in comparison with 29.3% of patients with wild-type EGFR (p = .03). Mutations of EGFR were also associated with lower depression severity than with wild-type EGFR, independent of gender, performance status, and smoking history (p < .05). This finding persisted for both the cognitive-affective and somatic domains of depression symptoms. Conclusions. EGFR mutations were associated with lower depression severity and lower rates of probable major depressive disorder in patients with metastatic NSCLC, based on mood screening performed before results of genotyping were known. Findings support further work to explore the directionality of the associations and potential biological pathways to depression. The Oncologist 2011;16:1299-1306 C1 [Pirl, William F.; Traeger, Lara; Greer, Joseph A.; Bemis, Heather] Massachusetts Gen Hosp, Ctr Canc, Ctr Psychiat Oncol & Behav Sci, Boston, MA 02114 USA. [Gallagher, Emily; Lennes, Inga; Sequist, Lecia; Heist, Rebecca; Temel, Jennifer S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Thorac Oncol, Boston, MA 02114 USA. RP Pirl, WF (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Psychiat Oncol & Behav Sci, Yawkey 9A,55 Fruit St, Boston, MA 02114 USA. EM wpirl@partners.org RI Inov Farmaceutica, Inct/K-2313-2013 FU NIH [CA115908] FX This work was supported by NIH grant CA115908 (Pirl). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 6 Z9 6 U1 0 U2 2 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD SEP PY 2011 VL 16 IS 9 BP 1299 EP 1306 DI 10.1634/theoncologist.2011-0116 PG 8 WC Oncology SC Oncology GA 825EP UT WOS:000295254100011 PM 21807767 ER PT J AU Schorge, JO Garrett, LA Goodman, A AF Schorge, John O. Garrett, Leslie A. Goodman, Annekathryn TI Cytoreductive Surgery for Advanced Ovarian Cancer: Quo Vadis? SO ONCOLOGY-NEW YORK LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; NEOADJUVANT CHEMOTHERAPY; SURGICAL CYTOREDUCTION; STAGE-III; PROGNOSTIC-FACTORS; DEBULKING SURGERY; IMPROVES SURVIVAL; RESIDUAL DISEASE; PROGRESSION-FREE; STEM-CELLS AB Two-thirds of women who are newly diagnosed with invasive epithelial ovarian cancer present with stage III or IV disease. The preferred initial treatment has traditionally consisted of primary surgical debulking followed by platinum-based chemotherapy. However, recent data suggesting comparable efficacy for neoadjuvant Chemotherapy and interval debulking have challenged this conventional dogma. Most patients with advanced ovarian cancer will achieve remission regardless of initial treatment, but 80% to 90% of patients will ultimately relapse. The timing and clinical benefit of a second debulking operation for recurrent disease is even more contentious. This article focuses on the recent debate regarding when-or whether-patients with ovarian cancer should undergo aggressive surgical resection. C1 [Schorge, John O.; Garrett, Leslie A.; Goodman, Annekathryn] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv,Div Gynecol Oncol, Boston, MA 02114 USA. RP Schorge, JO (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv,Div Gynecol Oncol, Boston, MA 02114 USA. NR 45 TC 12 Z9 14 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD SEP PY 2011 VL 25 IS 10 BP 928 EP 934 PG 7 WC Oncology SC Oncology GA 826KI UT WOS:000295352600009 PM 22010391 ER PT J AU Heidel, FH Wang, Z Feng, Z Armstrong, SA AF Heidel, F. H. Wang, Z. Feng, Z. Armstrong, S. A. TI Genetic and pharmacologic inhibition of beta-Catenin (Ctnnb1) targets imatinib resistant leukemia stem cells in CML SO ONKOLOGIE LA English DT Meeting Abstract C1 [Heidel, F. H.] Univ Magdeburg, Klin Haematol Onkol, D-39106 Magdeburg, Germany. [Heidel, F. H.; Wang, Z.; Feng, Z.; Armstrong, S. A.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. [Armstrong, S. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Armstrong, S. A.] Harvard Stem Cell Inst HSCI, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD SEP PY 2011 VL 34 SU 6 BP 29 EP 30 PG 2 GA 823XG UT WOS:000295160600070 ER PT J AU Koch, R Diering, N Lahmann, M Demant, M Aung, T Chapuy, B Becker, S Sinzig, U Trumper, L Wulf, G AF Koch, R. Diering, N. Lahmann, M. Demant, M. Aung, T. Chapuy, B. Becker, S. Sinzig, U. Truemper, L. Wulf, G. TI Homeostasis of lymphoma side population cells in aggressive B-cell lymphoma SO ONKOLOGIE LA English DT Meeting Abstract C1 [Koch, R.; Diering, N.; Lahmann, M.; Demant, M.; Aung, T.; Becker, S.; Sinzig, U.; Truemper, L.; Wulf, G.] Univ Med Gottingen, Gottingen, Germany. [Chapuy, B.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD SEP PY 2011 VL 34 SU 6 BP 190 EP 190 PG 1 GA 823XG UT WOS:000295160600502 ER PT J AU Rummel, M Kuter, D Mandanas, R Giagounidis, A Wang, X Matthias, SD Deuson, R AF Rummel, M. Kuter, D. Mandanas, R. Giagounidis, A. Wang, X. Matthias, S. D. Deuson, R. TI Quality of Life (QOL) in nonsplenectomized Immune Thrombocytopenia (ITP) patients receiving romiplostim or Standard of Care (SOC) SO ONKOLOGIE LA English DT Meeting Abstract C1 [Rummel, M.] Klinikum Justus Liebig Univ, Giessen, Germany. [Kuter, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mandanas, R.] Integris Canc Inst Oklahoma, Oklahoma City, OK USA. [Giagounidis, A.] St Johannes Hosp, Duisburg, Germany. [Wang, X.; Deuson, R.] Amgen Inc, Thousand Oaks, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X J9 ONKOLOGIE JI Onkologie PD SEP PY 2011 VL 34 SU 6 BP 239 EP 240 PG 2 GA 823XG UT WOS:000295160600640 ER PT J AU Desai, KH Tan, CS Leek, JT Maier, RV Tompkins, RG Storey, JD AF Desai, Keyur H. Tan, Chuen Seng Leek, Jeffrey T. Maier, Ronald V. Tompkins, Ronald G. Storey, John D. CA Inflammation Host Response Injury TI Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study SO PLOS MEDICINE LA English DT Article ID NF-KAPPA-B; MULTIPLE ORGAN FAILURE; RESPONSE SYNDROME; SYSTEMIC INFLAMMATION; NOSOCOMIAL INFECTION; DR EXPRESSION; SEPTIC SHOCK; TRAUMA; SEPSIS; MORTALITY AB Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition. Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring,400 clinical variables and longitudinally profiling leukocyte gene expression with similar to 800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury. Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions. C1 [Desai, Keyur H.; Tan, Chuen Seng; Storey, John D.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Leek, Jeffrey T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Maier, Ronald V.] Univ Washington, Harborview Med Ctr, Dept Surg, Seattle, WA 98104 USA. [Tompkins, Ronald G.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Storey, John D.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Desai, KH (reprint author), Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. EM jstorey@princeton.edu RI Tan, Chuen Seng/K-1078-2013; OI Tan, Chuen Seng/0000-0002-6513-2309; Leek, Jeffrey/0000-0002-2873-2671 FU NIH [U54 GM-62119] FX This research is supported in part by NIH grant U54 GM-62119 (PI: Ronald Tompkins). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 21 Z9 23 U1 0 U2 5 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 SEP PY 2011 VL 8 IS 9 AR e1001093 DI 10.1371/journal.pmed.1001093 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 825ZW UT WOS:000295321900009 PM 21931541 ER PT J AU King, BS Sturtevant, OJ Kao, G AF King, B. S. Sturtevant, O. J. Kao, G. TI Using Novel Parameters in Predicting Stem Cell Mobilization SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting and CTTXPO CY OCT 22-25, 2011 CL San Diego, CA SP AABB C1 [Sturtevant, O. J.; Kao, G.] Dana Farber Canc Inst, Cell Manipulat Core Facil, Boston, MA 02115 USA. EM bking3@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2011 VL 51 SU 3 SI SI BP 220A EP 220A PG 1 WC Hematology SC Hematology GA 822YC UT WOS:000295085500565 ER EF