FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Liu, Y Ma, QF AF Liu, Yang Ma, Qiufu TI Generation of somatic sensory neuron diversity and implications on sensory coding SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID ROOT GANGLION NEURONS; REGULATES DEVELOPMENT; NOCICEPTIVE NEURONS; AXONAL PROJECTIONS; NEUROPATHIC PAIN; DRG NEURONS; DIFFERENTIATION; MECHANISMS; EXPRESSION; RUNX1 AB Neurons in the dorsal root ganglia (DRG) are composed of a variety of sensory modalities, three of which are pain-sensing nociceptors, temperature-sensing thermoceptors, and itch-sensing pruriceptors. All these neurons are emerged from a common pool of embryonic DRG neurons that are marked by the expression of the neurotrophin receptor TrkA. Here we discuss how intrinsic transcription factors interface with target-derived signals to specify these functionally distinct sensory neurons. We will also discuss how this control mechanism provides a developmental perspective for the coding of somatic sensations. C1 [Ma, Qiufu] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Dept Neurobiol, Boston, MA 02115 USA. RP Ma, QF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM Qiufu_Ma@dfci.harvard.edu FU NIDCR [1R01DE018025]; NINDS [5P01NS047572, R01NS047710] FX We thank Dr Aziz Moqrich for his critical comments on this manuscript and for sharing a key manuscript before publication. We also thank our labmates for helpful discussions. Q.M. is supported by the NIH grants from NIDCR (1R01DE018025) and NINDS (5P01NS047572 and R01NS047710). NR 43 TC 54 Z9 55 U1 0 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2011 VL 21 IS 1 BP 52 EP 60 DI 10.1016/j.conb.2010.09.003 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 741PN UT WOS:000288876100008 PM 20888752 ER PT J AU Benichou, G Yamada, Y Aoyama, A Madsen, JC AF Benichou, Gilles Yamada, Yohei Aoyama, Akihiro Madsen, Joren C. TI Natural killer cells in rejection and tolerance of solid organ allografts SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE chronic allograft vasculopathy; innate immunity; NK cells; solid organ transplantation; tolerance; transplant; transplant rejection ID ADAPTIVE IMMUNE-RESPONSES; I ALLOANTIGEN SPECIFICITY; APOPTOSIS-INDUCING LIGAND; MOLONEY LEUKEMIA-CELLS; NK CELLS; T-CELL; GRAFT-REJECTION; CARDIAC MYOSIN; MACROPHAGE ACTIVATION; HEART-TRANSPLANTATION AB Purpose of review A series of recent studies defy conventional wisdom by showing that natural killer (NK) cells exert a powerful and long-lasting influence on the immune response to whole organ allografts. The early activation of NK cells following transplantation is associated with killing of allogeneic target cells and release of immunomodulatory chemokines and cytokines, which can contribute to either rejection or tolerance. Here, we review findings describing NK cell receptors, potential mediators and mechanisms underlying the dual influence of NK cells in solid organ transplantation. Recent findings New studies show that NK cells can discriminate between self and foreign tissues and play a key role in the initiation and regulation of adaptive immune responses after solid organ transplantation. Depending upon the types of NK cell receptors engaged and the nature of cytokines released, early NK cell activation can promote either rejection or tolerance. Summary Solid organ transplantation is associated with the early activation of NK cells, which are then licensed to kill allogeneic target cells directly or via antibody-dependent cellular cytotoxicity and release various chemokines and immunomodulatory cytokines. Depending upon the nature of NK cell subsets activated and their ability to kill allogeneic target cells and release certain types of cytokines, NK cells can promote the activation/expansion of pro-inflammatory Th1 cells or regulatory Th2/Treg cells thus tilting the balance of alloimmunity towards rejection or tolerance. An in-depth understanding of these mechanisms will be necessary in order to design therapies targeting NK cells in human transplantation. C1 [Madsen, Joren C.] Massachusetts Gen Hosp, Transplant Ctr, Div Cardiac Surg, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplant Ctr, Div Abdominal Transplantat, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, Transplant Ctr, Div Cardiac Surg, Dept Surg, Cox 654,55 Fruit St, Boston, MA 02114 USA. EM jcmadsen@partners.org FU MGH ECOR; NIAID [AI066705]; NIH [U191066705, PO1HL18646, ROTRF 313867044] FX The work was supported by grants from the MGH ECOR and NIAID AI066705 grants to G.B. and NIH U191066705, PO1HL18646 and ROTRF 313867044 to J.C.M. NR 84 TC 9 Z9 14 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1087-2418 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD FEB PY 2011 VL 16 IS 1 BP 47 EP 53 DI 10.1097/MOT.0b013e32834254cf PG 7 WC Transplantation SC Transplantation GA 705ZY UT WOS:000286181200008 PM 21157342 ER PT J AU Bauer, DE Orkin, SH AF Bauer, Daniel E. Orkin, Stuart H. TI Update on fetal hemoglobin gene regulation in hemoglobinopathies SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE BCL11A; epigenetics; fetal hemoglobin; gamma-globin; KLF1 ID BETA-GLOBIN GENE; SICKLE-CELL-ANEMIA; KRUPPEL-LIKE FACTOR; GENOME-WIDE ASSOCIATION; HUMAN GAMMA-GLOBIN; TRANSGENIC MICE; DEFINITIVE ERYTHROPOIESIS; TRANSCRIPTION FACTOR; ERYTHROID-CELLS; PRIMITIVE ERYTHROPOIESIS AB Purpose of review The developmental switch from fetal to adult hemoglobin has long fascinated biologists and attracted hematologists given its importance for patients with hemoglobin disorders. New discoveries have reinvigorated the field of globin gene regulation. These results hold promise for improved treatment of the major hemoglobinopathies. Recent findings Both genome-wide association studies and traditional linkage studies have identified several genetic loci involved in silencing fetal hemoglobin. BCL11A is a potent silencer of fetal hemoglobin in both mouse and humans. It controls the beta-globin gene cluster in concert with other factors. KLF1, a vital erythroid transcription factor, activates BCL11A and assists in coordinating the switch from fetal to adult hemoglobin. A regulatory network of cell-intrinsic and cell-extrinsic factors maintains the epigenetic homeostasis of the beta-globin cluster and accounts for the precise lineage-specific and developmental stage-specific regulation of the globin genes. Summary With an improved understanding of pathways involved in the switch from fetal to adult hemoglobin, new targets have emerged for the treatment of the common hemoglobin disorders, sickle cell anemia and beta-thalassemia. C1 [Bauer, Daniel E.; Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Bauer, Daniel E.; Orkin, Stuart H.] Dana Farber Canc Inst, Boston, MA USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Bauer, DE (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU NIH FX Work from the authors' laboratory was supported in part by grants from the NIH. S.H.O. is an Investigator of the Howard Hughes Medical Institute. The authors thank members of the laboratory for helpful discussions and J. Desimini for graphical assistance. NR 91 TC 44 Z9 48 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD FEB PY 2011 VL 23 IS 1 BP 1 EP 8 DI 10.1097/MOP.0b013e3283420fd0 PG 8 WC Pediatrics SC Pediatrics GA 706LQ UT WOS:000286220300001 PM 21157349 ER PT J AU Bauer, AM Bonilla, P Grover, MW Meyer, F Riselli, C White, L AF Bauer, Amy M. Bonilla, Pedro Grover, Matthew W. Meyer, Fremonta Riselli, Carleen White, Laura TI The Role of Psychosomatic Medicine in Global Health Care SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Psychosomatic medicine; Global mental health; Consultation-liaison psychiatry; Health care personnel; Primary care ID RANDOMIZED CONTROLLED-TRIAL; CONSULTATION-LIAISON PSYCHIATRY; MIDDLE-INCOME COUNTRIES; MENTAL-HEALTH; SELF-MANAGEMENT; CHRONIC DISEASE; DEPRESSION; DISORDERS; CHALLENGE; TELEPSYCHIATRY AB This article reviews the principles and skills involved with psychosomatic medicine and their potential ability to improve global health care. New awareness of the escalating global public health impact of noncommunicable diseases, including chronic medical conditions and mental disorders, has stimulated interest in determining how best to organize health services. Home to the biopsychosocial model, the field of psychosomatic medicine is well-suited to inform such efforts by virtue of its emphasis on cross-disciplinary collaboration and specialized knowledge at the interface of medicine and psychiatry that takes into account individual and contextual influences on health. Consistent with the principles of psychosomatic medicine, promising strategies to improve global health care include integrating mental health care into primary care, applying the chronic care model in programs aimed at enhancing disease self-management, and using innovative models such as Internet-based therapy and telemedicine to increase access to quality care. C1 [Bauer, Amy M.; Bonilla, Pedro; Grover, Matthew W.; Meyer, Fremonta; Riselli, Carleen; White, Laura] Cambridge Hlth Alliance, Dept Psychiat, Cambridge, MA 02140 USA. [Meyer, Fremonta] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Meyer, Fremonta] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Bauer, AM (reprint author), Cambridge Hlth Alliance, Dept Psychiat, 1493 Cambridge St, Cambridge, MA 02140 USA. EM abauer@challiance.org NR 51 TC 4 Z9 4 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD FEB PY 2011 VL 13 IS 1 BP 10 EP 17 DI 10.1007/s11920-010-0162-2 PG 8 WC Psychiatry SC Psychiatry GA 752ZP UT WOS:000289734300003 PM 20978952 ER PT J AU Shear, MK Simon, N Wall, M Zisook, S Neimeyer, R Duan, N Reynolds, C Lebowitz, B Sung, S Ghesquiere, A Gorscak, B Clayton, P Ito, M Nakajima, S Konishi, T Melhem, N Meert, K Schiff, M O'Connor, MF First, M Sareen, J Bolton, J Skritskaya, N Mancini, AD Keshaviah, A AF Shear, M. Katherine Simon, Naomi Wall, Melanie Zisook, Sidney Neimeyer, Robert Duan, Naihua Reynolds, Charles Lebowitz, Barry Sung, Sharon Ghesquiere, Angela Gorscak, Bonnie Clayton, Paula Ito, Masaya Nakajima, Satomi Konishi, Takako Melhem, Nadine Meert, Kathleen Schiff, Miriam O'Connor, Mary-Frances First, Michael Sareen, Jitender Bolton, James Skritskaya, Natalia Mancini, Anthony D. Keshaviah, Aparna TI COMPLICATED GRIEF AND RELATED BEREAVEMENT ISSUES FOR DSM-5 SO DEPRESSION AND ANXIETY LA English DT Review DE complicated grief; DSM-5; diagnostic criteria; dimensional assessment; stress response disorder ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; INTENSIVE-CARE-UNIT; TRAUMATIC GRIEF; DIAGNOSTIC-CRITERIA; SUICIDAL IDEATION; UNRESOLVED GRIEF; MAJOR DEPRESSION; TRIPARTITE MODEL; PSYCHIATRIC OUTPATIENTS AB Bereavement is a severe stressor that typically incites painful and debilitating symptoms of acute grief that commonly progresses to restoration of a satisfactory, if changed, life. Normally, grief does not need clinical intervention. However, sometimes acute grief can gain a foothold and become a chronic debilitating condition called complicated grief Moreover, the stress caused by bereavement, like other stressors, can increase the likelihood of onset or worsening of other physical or mental disorders. Hence, some bereaved people need to be diagnosed and treated. A clinician evaluating a bereaved person is at risk for both over-and under-diagnosis, either pathologizing a normal condition or neglecting to treat an impairing disorder. The authors of DSM IV focused primarily on the problem of over-diagnosis, and omitted complicated grief because of insufficient evidence. We revisit bereavement considerations in light of new research findings. This article focuses primarily on a discussion of possible inclusion of a new diagnosis and dimensional assessment of complicated grief We also discuss modifications in the bereavement V code and refinement of bereavement exclusions in major depression and other disorders. Depression and Anxiety 28:103-117, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Shear, M. Katherine; Ghesquiere, Angela; Skritskaya, Natalia] Columbia Univ, Sch Social Work, New York, NY 10027 USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Simon, Naomi; Sung, Sharon] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi; Sung, Sharon] Massachusetts Gen Hosp, Complicated Grief Program, Boston, MA 02114 USA. [Wall, Melanie; Duan, Naihua] Columbia Univ, Dept Biostat, New York, NY 10027 USA. [Wall, Melanie; Duan, Naihua] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Wall, Melanie; Duan, Naihua] New York State Psychiat Inst & Hosp, Div Biostat & Data Coordinat, New York, NY 10032 USA. [Zisook, Sidney; Lebowitz, Barry] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Zisook, Sidney] Vet Affairs San Diego Hlth Care Syst, La Jolla, CA USA. [Neimeyer, Robert] Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. [Reynolds, Charles] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Reynolds, Charles] Univ Pittsburgh, Sch Publ Hlth, Western Psychiat Inst & Clin, Dept Community & Behav Hlth Sci, Pittsburgh, PA 15260 USA. [Clayton, Paula] Amer Fdn Suicide Prevent, New York, NY USA. [Ito, Masaya; Nakajima, Satomi] Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Dept Adult Mental Hlth, Tokyo, Japan. [Konishi, Takako] Musashino Univ, Dept Human Studies, Tokyko, Japan. [Meert, Kathleen] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Schiff, Miriam] Hebrew Univ Jerusalem, Paul Baerwald Sch Social Work, Jerusalem, Israel. [O'Connor, Mary-Frances] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [First, Michael] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, New York, NY 10027 USA. [Sareen, Jitender; Bolton, James] Univ Manitoba, Winnipeg, MB, Canada. [Mancini, Anthony D.] Pace Univ, Dept Psychol, Pleasantville, NY USA. [Keshaviah, Aparna] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Shear, MK (reprint author), Columbia Univ, Sch Social Work, 1255 Amsterdam Ave, New York, NY 10027 USA. EM ks2394@columbia.edu RI Melhem, Nadine/G-1510-2013 FU National Institute of Mental Health [R01MH070741, R01MH060783, R01MH085308, R01MH085288, R01MH085297, R25MH084786, P30MH071944]; National Institutes of Health; American Foundation of Suicide Prevention; UPMC Endowment in Geriatric Psychiatry; Canadian Institutes of Health [102682, 152348]; Manitoba Health Research Council [200730011B]; Japanese Scientific Research Ministry of Health, Labour, and Welfare; Japanese Research Foundation for Safe Society FX The authors disclose the following financial relationships within the past 3 years: Contract grant sponsor: National Institute of Mental Health; Contract grant numbers: R01MH070741; R01MH060783; R01MH085308; R01MH085288; R01MH085297; R25MH084786; P30MH071944; Contract grant sponsors: National Institutes of Health Loan Repayment Program; American Foundation of Suicide Prevention; UPMC Endowment in Geriatric Psychiatry; Canadian Institutes of Health; Contract grant numbers: 102682; 152348; Contract grant sponsor: Manitoba Health Research Council Chair Award; Contract grant number: 200730011B; Contract grant sponsors: Japanese Scientific Research Ministry of Health, Labour, and Welfare; Japanese Research Foundation for Safe Society. NR 158 TC 208 Z9 215 U1 12 U2 58 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 FEB PY 2011 VL 28 IS 2 BP 103 EP 117 DI 10.1002/da.20780 PG 15 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 716WV UT WOS:000287005100002 PM 21284063 ER PT J AU Simon, NM Wall, MM Keshaviah, A Dryman, MT LeBlanc, NJ Shear, MK AF Simon, Naomi M. Wall, Melanie M. Keshaviah, Aparna Dryman, M. Taylor LeBlanc, Nicole J. Shear, M. Katherine TI INFORMING THE SYMPTOM PROFILE OF COMPLICATED GRIEF SO DEPRESSION AND ANXIETY LA English DT Article DE complicated grief; symptoms; grief; loss; DSM; diagnostic criteria; factor analyses; IRT ID AVOIDANCE; MISINTERPRETATIONS AB Background: Complicated Grief (CG) is under consideration as a new diagnosis in DSM5. We sought to add empirical support to the current dialogue by examining the commonly used Inventory of Complicated Grief (ICG) scale completed by 782 bereaved individuals. Methods: We employed IRT analyses, factor analyses, and sensitivity and specificity analyses utilizing our full sample (n = 782), and also compared confirmed CG cases (n = 288) to noncases (n = 377). Confirmed CG cases were defined as individuals bereaved at least 6 months who were seeking care for CG, had an ICG >= 30, and received a structured clinical interview for CG by a certified clinician confirming CG as their primary illness. Noncases were bereaved individuals who did not present with CG as a primary complaint (including those with depression, bipolar disorder, anxiety disorders, and controls) and had an ICG<25. Results: IRT analyses provided guidance about the most informative individual items and their association with CG severity. Factor analyses demonstrated a single factor solution when the full sample was considered, but within CG cases, six symptom clusters emerged: (1) yearning and preoccupation with the deceased, (2) anger and bitterness, (3) shock and disbelief (4) estrangement from others, (5) hallucinations of the deceased, and (6) behavior change, including avoidance and proximity seeking. The presence of at least one symptom from three different symptom clusters optimized sensitivity (94.8%) and specificity (98.1%). Conclusions: These data, derived from a diverse and predominantly clinical help seeking population, add an important perspective to existing suggestions for DSM5 criteria for CG. Depression and Anxiety 28:118-126, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Simon, Naomi M.; Keshaviah, Aparna; Dryman, M. Taylor; LeBlanc, Nicole J.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi M.; Keshaviah, Aparna; Dryman, M. Taylor; LeBlanc, Nicole J.] Massachusetts Gen Hosp, Complicated Grief Program, Boston, MA 02114 USA. [Wall, Melanie M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Shear, M. Katherine] Columbia Univ, Sch Social Work, New York, NY USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM nsimon@partners.org FU Massachusetts General Hospital; National Institute of Mental Health [1R01MH077700, MH60783, MH70741]; Highland Street Foundation; American Foundation for Suicide Prevention; Astra Zeneca; Cephalon; Forest Laboratories; NARSAD; NIMH; Glaxo SmithKline; Janssen; Lilly; Pfizer; Sepracor; UCB-Pharma; NIH; ADEC webinar; University of Manitoba; Winnipeg; University of Memphis FX The authors disclose the following financial relationships within the past 3 years: Contract grant sponsors: Massachusetts General Hospital Claflin Distinguished Scholar Award; National Institute of Mental Health; Contract grant numbers: 1R01MH077700; MH60783; MH70741; Contract grant sponsor: Highland Street Foundation.; Naomi M. Simon: Research grants (American Foundation for Suicide Prevention, Astra Zeneca, Cephalon, Highland Street Foundation, Forest Laboratories, NARSAD, NIMH, Glaxo SmithKline, Janssen, Lilly, Pfizer, Sepracor, UCB-Pharma), payment for manuscript preparation (Astra Zeneca), payment for the development of educational presentations (Pfizer), Melanie M. Wall: None; Aparna Keshaviah: None; M. Taylor Dryman: None; Nicole J. LeBlanc: None; M. Katherine Shear: Research grants (NIH), support for travel (NIH), and payment for the development of educational materials (ADEC webinar, the University of Manitoba, Winnipeg, & the University of Memphis). NR 21 TC 39 Z9 39 U1 2 U2 11 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 FEB PY 2011 VL 28 IS 2 BP 118 EP 126 DI 10.1002/da.20775 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 716WV UT WOS:000287005100003 PM 21284064 ER PT J AU Huang, P Yeku, O Zong, HH Tsang, P Su, WJ Yu, XA Teng, SZ Osisami, M Kanaho, Y Pessin, JE Frohman, MA AF Huang, Ping Yeku, Oladapo Zong, Haihong Tsang, Phyllis Su, Wenjuan Yu, Xiao Teng, Shuzhi Osisami, Mary Kanaho, Yasunori Pessin, Jeffrey E. Frohman, Michael A. TI Phosphatidylinositol-4-Phosphate-5-Kinase alpha Deficiency Alters Dynamics of Glucose-Stimulated Insulin Release to Improve Glucohomeostasis and Decrease Obesity in Mice SO DIABETES LA English DT Article ID SENSITIVE POTASSIUM CHANNELS; DEPENDENT MEMBRANE-FUSION; PANCREATIC BETA-CELLS; K-ATP CHANNELS; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; NUCLEOTIDE SENSITIVITY; BINDING-PROTEIN; ACTIN DYNAMICS; SECRETION; EXOCYTOSIS AB OBJECTIVE-Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP(2)). We sought to examine the role of the a isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS-The response of PI4P5K alpha(-/-) mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5K alpha(-/-) pancreatic islets and beta-cells were characterized in culture. RESULTS-We show that PI4P5K alpha(-/-) mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5K alpha(-/-) pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP(2) depletion occurred on the plasma membrane of the PI4P5K alpha(-/-) pancreatic beta-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5K alpha(-/-) beta-cells under resting conditions. CONCLUSIONS-Our findings suggest that PI4P5K alpha plays a complex role in restricting insulin release from pancreatic beta-cells through helping to maintain plasma membrane PIP(2) levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen hi type 2 diabetes-like model systems. Diabetes 60:454-463, 2011 C1 [Huang, Ping; Yeku, Oladapo; Tsang, Phyllis; Su, Wenjuan; Yu, Xiao; Osisami, Mary; Frohman, Michael A.] SUNY Stony Brook, Ctr Dev Genet, Stony Brook, NY 11794 USA. [Huang, Ping; Zong, Haihong; Tsang, Phyllis; Yu, Xiao; Pessin, Jeffrey E.; Frohman, Michael A.] SUNY Stony Brook, Dept Pharmacol, Stony Brook, NY 11794 USA. [Yeku, Oladapo; Su, Wenjuan; Frohman, Michael A.] SUNY Stony Brook, Program Mol & Cellular Pharmacol, Stony Brook, NY 11794 USA. [Yeku, Oladapo] SUNY Stony Brook, Med Scientist Training Program, Stony Brook, NY 11794 USA. [Osisami, Mary; Frohman, Michael A.] SUNY Stony Brook, Program Genet, Stony Brook, NY 11794 USA. [Teng, Shuzhi] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kanaho, Yasunori] Univ Tsukuba, Dept Physiol Chem, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan. [Kanaho, Yasunori] Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. RP Frohman, MA (reprint author), SUNY Stony Brook, Ctr Dev Genet, Stony Brook, NY 11794 USA. EM michael@pharm.stonybrook.edu RI Tsang, Siu Wai/O-2748-2013 OI Tsang, Siu Wai/0000-0001-6099-6696 FU American Heart Association; National Institutes of Health [GM-071520, DK-64166, DK-55811]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Turner Foundation FX This work was supported by an award from the American Heart Association to P.H. and National Institutes of Health awards GM-071520 and DK-64166 to M.A.F. and DK-55811 to J.E.P. O.Y. was supported by a National Institute of General Medical Sciences Medical Scientist Training Program T32 training award, an individual F31 National Research Service Award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Turner Foundation. M.O. was supported by an individual F31 National Research Service Award from NIDDK. P.T. was supported by an NIDDK postdoctoral fellow T32 training award. NR 45 TC 7 Z9 7 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2011 VL 60 IS 2 BP 454 EP 463 DI 10.2337/db10-0614 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 719AR UT WOS:000287172100014 PM 21270258 ER PT J AU Wang, P Yigit, MV Medarova, Z Wei, LL Dai, GP Schuetz, C Moore, A AF Wang, Ping Yigit, Mehmet V. Medarova, Zdravka Wei, Lingling Dai, Guangping Schuetz, Christian Moore, Anna TI Combined Small Interfering RNA Therapy and In Vivo Magnetic Resonance Imaging in Islet Transplantation SO DIABETES LA English DT Article ID BETA-CELL MASS; PANCREATIC-ISLETS; APOPTOSIS; GRAFTS; LIVER; TERM AB OBJECTIVE-Recent advances in human islet transplantation are hampered by significant graft loss shortly after transplantation and inability to follow islet fate directly. Both issues were addressed by utilizing a dual-purpose therapy/imaging small interfering RNA (siRNA)-nanoparticle probe targeting apoptotic-related gene caspase-3. We expect that treatment with the probe would result in significantly better survival of transplanted islets, which could be monitored by in vivo magnetic resonance imaging (MRI). RESEARCH DESIGN AND METHODS-We synthesized a probe consisting of therapeutic (siRNA to human caspase-3) and imaging (magnetic iron oxide nanoparticles, MN) moieties. In vitro testing of the probe included serum starvation of the islets followed by treatment with the probe. Caspase-3 gene silencing and protein expression were determined by RT-PCR and Western blot, respectively. In vivo studies included serial MRI of NOD-SCID mice transplanted with MN-small interfering (si)Caspase-3-labeled human islets under the left kidney capsule and MN-treated islets under the right kidney capsule. RESULTS-Treatment with MN-siCaspase-3 probe resulted in decrease of mRNA and protein expression in serum-starved islets compared wit h controls. In vivo MRI showed that there were significant differences in the relative volume change between MN-siCaspase-3-treated grafts and MN-labeled grafts. Histology revealed decreased caspase-3 expression and cell apoptosis in MN-siCaspase-3-treated grafts compared with the control side. CONCLUSIONS-Our data show the feasibility of combining siRNA therapy and in vivo monitoring of transplanted islets in mice. We observed a protective effect of MN-siCaspase-3 in treated islets both in vitro and in vivo. This study could potentially aid in increasing the success of clinical islet transplantation. Diabetes 60:565-571, 2011 C1 [Wang, Ping; Yigit, Mehmet V.; Medarova, Zdravka; Dai, Guangping; Moore, Anna] Harvard Univ, Sch Med, Dept Radiol,Massachusetts Gen Hosp, Mol Imaging Lab,MGH MIT HMS Athinoula A Martinos, Boston, MA 02115 USA. [Wei, Lingling; Schuetz, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02115 USA. RP Moore, A (reprint author), Harvard Univ, Sch Med, Dept Radiol,Massachusetts Gen Hosp, Mol Imaging Lab,MGH MIT HMS Athinoula A Martinos, Boston, MA 02115 USA. EM amoore@helix.mgh.harvard.edu RI Wang, Ping/E-4381-2011; Schuetz, Christian/K-5234-2013; OI Schuetz, Christian/0000-0002-6828-4543; Wang, Ping/0000-0001-6712-8939 FU National Institutes of Health [5R01-DK080784] FX This study was supported by National Institutes of Health [Grant 5R01-DK080784] (to A.M.). NR 20 TC 19 Z9 19 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2011 VL 60 IS 2 BP 565 EP 571 DI 10.2337/db10-1400 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 719AR UT WOS:000287172100025 PM 21270267 ER PT J AU Lopes-Virella, MF Hunt, KJ Baker, NL Lachin, J Nathan, DM Virella, G AF Lopes-Virella, Maria F. Hunt, Kelly J. Baker, Nathaniel L. Lachin, John Nathan, David M. Virella, G. CA Diabet Control Complications Trial TI Levels of Oxidized LDL and Advanced Glycation End Products Modified LDL in Circulating Immune Complexes Are Strongly Associated With Increased Levels of Carotid Intima-Media Thickness and Its Progression in Type 1 Diabetes SO DIABETES LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; CORONARY-ARTERY-DISEASE; ATHEROSCLEROTIC LESIONS; COMPLICATIONS TRIAL; ANTIBODIES; AUTOANTIBODIES; ATHEROGENESIS; MACROPHAGES; RABBIT; CELLS AB OBJECTIVE-High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products-modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors. RESEARCH DESIGN AND METHODS-Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC. RESULTS-OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51-14.8] and a 6.4-fold (CI 2.53-16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C. CONCLUSIONS-OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes. Diabetes 60:582-589, 2011 C1 [Lopes-Virella, Maria F.; Hunt, Kelly J.; Baker, Nathaniel L.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Lopes-Virella, Maria F.] Ralph A Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Lachin, John] George Washington Univ, Ctr Biostat, Washington, DC USA. [Nathan, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Nathan, David M.] Massachusetts Gen Hosp, Dept Microbiol & Immunol, Boston, MA 02114 USA. [Virella, G.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Lopes-Virella, MF (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM virellam@musc.edu OI Lachin, John/0000-0001-9838-2841 FU National Institutes of Health (NIH) National Heart, Lung, and Blood Institute [PO1-HL55782]; NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK081352, R01-DK088778]; Juvenile Diabetes Research Foundation [2006-49]; Research Service of the Ralph H. Johnson Department of Veterans Affairs Medical Center; Division of Diabetes, Endocrinology and Metabolic Diseases (NIDDK) of the NIH; National Center for Research Resources; Genentech; NIDDK FX This work was supported by a program project funded by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute Grant PO1-HL55782; by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK081352 and R01-DK088778; and by Juvenile Diabetes Research Foundation Grant 2006-49. This work was also supported by the Research Service of the Ralph H. Johnson Department of Veterans Affairs Medical Center.; The DCCT/EDIC was sponsored through research contracts from the Division of Diabetes, Endocrinology and Metabolic Diseases (NIDDK) of the NIH. Additional support was provided by the National Center for Research Resources through the GCRC program and by Genentech through a Cooperative Research and Development Agreement with the NIDDK. The DCCT/EDIC group provided the samples to be analyzed and the clinical data used in data analysis. No other potential conflicts of interest relevant to this article were reported. NR 38 TC 46 Z9 49 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2011 VL 60 IS 2 BP 582 EP 589 DI 10.2337/db10-0915 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 719AR UT WOS:000287172100028 PM 20980456 ER PT J AU Polak, JF Backlund, JYC Cleary, PA Harrington, AP O'Leary, DH Lachin, JM Nathan, DM AF Polak, Joseph F. Backlund, Jye-Yu C. Cleary, Patricia A. Harrington, Anita P. O'Leary, Daniel H. Lachin, John M. Nathan, David M. CA DCCT EDIC Res Grp TI Progression of Carotid Artery Intima-Media Thickness During 12 Years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study SO DIABETES LA English DT Article ID INSULIN-RESISTANCE ATHEROSCLEROSIS; PRACTICE RESEARCH DATABASE; SKIN COLLAGEN GLYCATION; CARDIOVASCULAR-DISEASE; SUBCLINICAL ATHEROSCLEROSIS; INTENSIVE TREATMENT; WALL THICKNESS; FOLLOW-UP; TYPE-1; MELLITUS AB OBJECTIVE-This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis, measured as common carotid artery intima-media thickness (IMT). RESEARCH DESIGN AND METHODS-A total of 1,116 participants (52% men) in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial, a long-term follow-up of the Diabetes Control and Complications Trial (DCCT), had carotid IMT measurements at EDIC years 1, 6, and 12. Mean age was 46 years, with diabetes duration of 24.5 years at EDIC year 12. Differences in IMT progression between DCCT intensive and conventional treatment groups were examined, controlling for clinical characteristics, IMT reader, and imaging device. RESULTS-Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional (P < 0.0001), and from years 1 to 12 was 0.014 ram less (P = 0.048); but change from years 6 to 12 was similar (intensive - conventional = 0.005 mm, P = 0.379). Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT, explaining most of the differences in IMT progression between DCCT treatment groups. Albuminuria, older age, male sex, smoking, and higher systolic blood pressure were significant predictors of IMT progression. CONCLUSIONS-Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter (6-12 years). A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended. These differences were attenuated but not negated after adjusting for blood pressure. These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis. Diabetes 60:607-613, 2011 C1 [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA 02163 USA. [Polak, Joseph F.; Harrington, Anita P.; O'Leary, Daniel H.] Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA. [Backlund, Jye-Yu C.; Cleary, Patricia A.; Lachin, John M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. RP Nathan, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA 02163 USA. EM dnathan@partners.org OI Lachin, John/0000-0001-9838-2841 FU Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers; Clinical and Translation Science Centers, National Center for Research Resources; Genentech; National Institute of Diabetes and Digestive and Kidney Diseases FX The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, National Eye Institute, National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program and the Clinical and Translation Science Centers Program, National Center for Research Resources, and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. NR 41 TC 70 Z9 73 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2011 VL 60 IS 2 BP 607 EP 613 DI 10.2337/db10-0296 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 719AR UT WOS:000287172100031 PM 21270271 ER PT J AU Wang, CP Hazuda, HP AF Wang, Chen-Pin Hazuda, Helen P. TI Better Glycemic Control Is Associated With Maintenance of Lower-Extremity Function Over Time in Mexican American and European American Older Adults With Diabetes SO DIABETES CARE LA English DT Article ID WOMENS HEALTH; US ADULTS; DISABILITY; MORTALITY; DISEASE; GLUCOSE AB OBJECTIVE-Diabetes is a major cause of functional decline among older adults, but the role of glycemic control remains unclear. This article assesses whether better glycemic control is associated with better maintenance of lower-extremity function over time in older adults with diabetes. RESEARCH DESIGN AND METHODS-Participants (n = 119) in the San Antonio Longitudinal Study of Aging, ages 71-85, who met American Diabetes Association diabetes criteria were followed over a 36-month period. Seven measures of A1C (HbA(1c)) were obtained at 6-month intervals; three measures of lower-extremity function were obtained at 18-month intervals using the Short Physical Performance Battery (SPPB). A two-step analytic approach was used, first, to identify distinct glycemic control classes using latent growth mixture modeling and, second, to examine trajectories of lower-extremity function based on these classes using path analysis. RESULTS-Two glycemic control classes were identified: a poorer control class with higher means (all >7%) and higher within-subject variability in HbA(1c) and a better control class with lower means (all <7%) and lower within-subject variability. The short-term and long-term maintenance of lower-extremity function, assessed by the association between the first and second SPPB measures and the first and third SPPB measures, were both greater in the better control class than in the poorer control class. CONCLUSIONS-Among older adults with diabetes, better glycemic control may improve both short-term and long-term maintenance of lower-extremity function. C1 [Hazuda, Helen P.] Audie Murphy Med Ctr, Dept Vet Affairs, Res Serv, San Antonio, TX USA. [Wang, Chen-Pin] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Hazuda, Helen P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. RP Hazuda, HP (reprint author), Audie Murphy Med Ctr, Dept Vet Affairs, Res Serv, San Antonio, TX USA. EM hazuda@uthscsa.edu FU National Institute on Aging (NIA) [1-R01-AG10444, 1-R01-AG16518]; National Institute of Diabetes and Digestive and Kidney Diseases [1-K25 DK075092]; National Center for Research Resources [M01-RR01346] FX This study was supported by National Institute on Aging (NIA) Grant 1-R01-AG10444 (SALSA), NIA Grant 1-R01-AG16518 (Disablement in an Aging, Bi-ethnic Cohort), National Institute of Diabetes and Digestive and Kidney Diseases Grant 1-K25 DK075092, and National Center for Research Resources Grant M01-RR01346 (Fredrick C. Bartter General Clinical Research Center). This material is the result of work supported with resources and the use of facilities at the Audie Murphy VA Medical Center, San Antonio, TX. NR 24 TC 14 Z9 14 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2011 VL 34 IS 2 BP 268 EP 273 DI 10.2337/dc10-1405 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 722LO UT WOS:000287433900004 PM 21216857 ER PT J AU Jacobson, AM Ryan, CM Cleary, PA Waberski, BH Weinger, K Musen, G Dahms, W AF Jacobson, A. M. Ryan, C. M. Cleary, P. A. Waberski, B. H. Weinger, K. Musen, G. Dahms, W. CA DCCT EDIC Res Grp TI Biomedical risk factors for decreased cognitive functioning in type 1 diabetes: an 18 year follow-up of the Diabetes Control and Complications Trial (DCCT) cohort SO DIABETOLOGIA LA English DT Article DE Cognition; Macrovascular; Microvascular; Psychomotor efficiency; Renal; Retinopathy; Type 1 diabetes ID RETINAL MICROVASCULAR ABNORMALITIES; ATHEROSCLEROSIS RISK; CEREBRAL INFARCTION; NORMATIVE DATA; MELLITUS; PERFORMANCE; DECLINE; BRAIN; INTERVENTIONS; HYPERTENSION AB In patients with type 1 diabetes, there has been concern about the effects of recurrent hypoglycaemia and chronic hyperglycaemia on cognitive function. Because other biomedical factors may also increase the risk of cognitive decline, this study examined whether macrovascular risk factors (hypertension, smoking, hypercholesterolaemia, obesity), sub-clinical macrovascular disease (carotid intima-media thickening, coronary calcification) and microvascular complications (retinopathy, nephropathy) were associated with decrements in cognitive function over an extended time period. Type 1 diabetes patients (n = 1,144) who had completed a comprehensive cognitive test battery at entry into the Diabetes Control and Complications Trial were re-assessed at a mean of 18.5 (range: 15-23) years later. Univariate and multivariable models examined the relationship between cognitive change and the presence of micro- and macrovascular complications and risk factors. Univariate modelling showed that smoking history was modestly associated with decrements in learning, memory, spatial information-processing and psychomotor efficiency; hypertension was associated with only psychomotor slowing. Multivariable modelling demonstrated that HbA(1c) level, and retinal and renal complications were each independently associated with decrements in psychomotor efficiency. In contrast, no macrovascular risk factors were significant after correcting for multiple comparisons. No interactions were found between these predictors and sex, severe hypoglycaemic events or presence of the APOE epsilon 4 allele. In relatively healthy, middle-aged adults with type 1 diabetes who had been followed for an average of 18.5 years, long-term metabolic control and microvascular factors are independently associated with a decline in cognitive function specifically affecting measures of psychomotor efficiency. ClinicalTrials.gov NCT00360893 This study is supported by NIH grant number 5RO1 DK062218-02. The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program, the Clinical and Translational Science Awards Program, the National Center for Research Resources and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. C1 [Jacobson, A. M.] Winthrop Univ Hosp, Mineola, NY 11501 USA. [Jacobson, A. M.; Weinger, K.; Musen, G.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Ryan, C. M.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Cleary, P. A.; Waberski, B. H.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Dahms, W.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Jacobson, AM (reprint author), Winthrop Univ Hosp, Suite 300,222 Stn Plaza N, Mineola, NY 11501 USA. EM amjacobson@winthrop.org FU Bayer; NIH [5RO1 DK062218-02]; Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers; Clinical and Translational Science Awards; National Center for Research Resources; Genentech; National Institute of Diabetes and Digestive and Kidney Diseases; GlaxoSmithkline FX A complete list of participants in the DCCT/EDIC research group is included in Electronic supplementary material (ESM). We thank H. Chen for providing thoughtful comments on the statistical analyses described in this manuscript. We thank the following for providing free or discounted supplies and/or equipment: Lifescan, Roche, Aventis, Eli Lilly, OmniPod, Can-Am, B-D, Animas, Medtronic, Medtronic Minimed, Bayer (one donation in 2008) and Omron. This study is supported by NIH grant number 5RO1 DK062218-02. The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program, the Clinical and Translational Science Awards Program, the National Center for Research Resources and by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases.; C. M. Ryan is a consultant to a clinical trial sponsored by GlaxoSmithkline. He has received an honorarium from NovoNordisk for his role as Associate Editor of the on-line journal, Diabetic Hypoglycaemia. He has also received an honorarium from Eli Lilly as a speaker in their 'Peaks and Valleys' program. A. M. Jacobson received travel expenses and an honorarium from Eli Lilly for a lecture on quality of life issues in diabetes. All other authors declare that there is no duality of interest associated with this manuscript. NR 50 TC 52 Z9 54 U1 2 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD FEB PY 2011 VL 54 IS 2 BP 245 EP 255 DI 10.1007/s00125-010-1883-9 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 703SO UT WOS:000286001800008 PM 20803190 ER PT J AU Greenstein, RJ Su, LY Brown, ST AF Greenstein, Robert J. Su, Liya Brown, Sheldon T. TI Growth of M. avium Subspecies Paratuberculosis in Culture Is Enhanced by Nicotinic Acid, Nicotinamide, and alpha and beta Nicotinamide Adenine Dinucleotide SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Mycobacterium avium subspecies paratuberculosis; Tobacco; Crohn's disease; Zoonosis; Emerging pathogens; Nicotine; Nicotinic acid; Nicotinamide; alpha and beta nicotinamide adenine dinucleotide; Inflammatory bowel disease ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; MYCOBACTERIUM-PARATUBERCULOSIS; ULCERATIVE-COLITIS; CIGARETTE-SMOKING; COWS MILK; PATHOGENS; DIAGNOSIS; COMPLEX; DRUGS AB Without known mechanisms of action, Crohn's disease is exacerbated, and ulcerative colitis is improved, by the use of tobacco. Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. We hypothesized that tobacco components might alter the growth kinetics of MAP, explaining these divergent clinical observations. The effect of nicotine, nicotinic acid, nicotinamide and alpha and beta nicotinamide adenine dinucleotide (alpha and beta NAD) were studied on eight strains of three mycobacterial species (MAP, M. avium and M. tb. complex). Data are obtained as "cumulative growth index," (cGI) and presented as "percent increase in cumulative GI" (% + Delta cGI). Nicotinic acid enhances the two human MAP isolates (Dominic; 225% + Delta cGI and UCF-4; 92% + Delta cGI) and M. avium (ATCC 25291; 175% + Delta cGI). Nicotinamide (at 6.4 A mu g/ml) enhances the human MAP isolates (Dominic; 156% + Delta cGI and UCF-4; 79% + Delta cGI) and M. avium (ATCC 25291; 144% + Delta cGI.) Both alpha and beta NAD enhance Dominic; (135 and 150 % + Delta cGI) and UCF-4; (81 and 79% + Delta cGI). At the doses tested, nicotine has no effect on any strain studied. We show enhancement of MAP growth by nicotinic acid, one of a parts per thousand yen4,000 tobacco-related molecules, its amide, nicotinamide and alpha and beta NAD. Pure nicotine has no enhancing effect at the doses studies. C1 [Greenstein, Robert J.] James J Peters VAMC, Dept Surg, Bronx, NY 10468 USA. [Greenstein, Robert J.; Su, Liya] James J Peters VAMC, Lab Mol Surg Res, Bronx, NY 10468 USA. [Brown, Sheldon T.] James J Peters VAMC, Dept Med, Bronx, NY 10468 USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. RP Greenstein, RJ (reprint author), James J Peters VAMC, Dept Surg, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM BGAxis@aol.com; LyiaSu01@aol.com; Sheldon.Brown@va.gov FU Division of Infectious Diseases at the James J. Peters VAMC, Bronx, NY FX This material is the result of work supported with resources and the use of facilities at the James J. Peters VAMC, Bronx, NY. This study was supported by the Division of Infectious Diseases at the James J. Peters VAMC, Bronx, NY. NR 50 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD FEB PY 2011 VL 56 IS 2 BP 368 EP 375 DI 10.1007/s10620-010-1301-7 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 712KF UT WOS:000286664900015 PM 20585983 ER PT J AU Worthley, DL Whitehall, VLJ Le Leu, RK Irahara, N Buttenshaw, RL Mallitt, KA Greco, SA Ramsnes, I Winter, J Hu, Y Ogino, S Young, GP Leggett, BA AF Worthley, Daniel L. Whitehall, Vicki L. J. Le Leu, Richard K. Irahara, Natsumi Buttenshaw, Ronald L. Mallitt, Kylie-Ann Greco, Sonia A. Ramsnes, Ingunn Winter, Jean Hu, Ying Ogino, Shuji Young, Graeme P. Leggett, Barbara A. TI DNA Methylation in the Rectal Mucosa Is Associated with Crypt Proliferation and Fecal Short-Chain Fatty Acids SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE DNA methylation; Epigenetics; Colorectal cancer; Carcinogenesis ID NORMAL COLONIC-MUCOSA; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; LINE-1 HYPOMETHYLATION; ULCERATIVE-COLITIS; PHENOTYPE; AGE; HYPERMETHYLATION; NEOPLASIA; GENES AB DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum. The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors. Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including "type A" markers (ESR1, GATA5, HIC1, HPP1, SFRP1), "type C" markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean "type A" and CIMP panel methylation Z-scores were calculated. Rectal proliferation was significantly correlated with methylation at ESR1 (rho = 0.81, P = 0.003) and GATA5 (rho = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with "low" and "high" fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression "type A" methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH(3) concentrations (P = 0.003). DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis. C1 [Worthley, Daniel L.; Whitehall, Vicki L. J.; Buttenshaw, Ronald L.; Greco, Sonia A.; Ramsnes, Ingunn; Leggett, Barbara A.] Queensland Inst Med Res, Bancroft Ctr, Herston, Qld 4029, Australia. [Worthley, Daniel L.; Whitehall, Vicki L. J.; Buttenshaw, Ronald L.; Greco, Sonia A.; Ramsnes, Ingunn; Leggett, Barbara A.] Royal Brisbane & Womens Hosp Res Fdn Clin Res Ctr, Conjoint Gastroenterol Lab, Brisbane, Qld, Australia. [Le Leu, Richard K.; Winter, Jean; Hu, Ying; Young, Graeme P.] Flinders Univ S Australia, Flinders Ctr Canc Prevent & Control, Adelaide, SA, Australia. [Irahara, Natsumi; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mallitt, Kylie-Ann] Queensland Inst Med Res, Stat Unit, Brisbane, Qld 4006, Australia. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. RP Worthley, DL (reprint author), Queensland Inst Med Res, Bancroft Ctr, Rm H07,PO RBH, Herston, Qld 4029, Australia. EM daniel.worthley@uqconnect.edu.au; vicki.whitehall@qimr.edu.au; richard.leleu@flinders.edu.au; mitsuna222@yahoo.co.jp; ron.buttenshaw@qimr.edu.au; kylieann.mallitt@qimr.edu.au; Sonia.greco@qimr.edu.au; ingunnramsnes@hotmail.com; jean.winter@flinders.edu.au; ying.hu@flinders.edu.au; shuji_Ogino@dfci.harvard.edu; graeme.young@flinders.edu.au; barbara_leggett@health.qld.gov.au RI Leggett, Barbara/D-3579-2011; Mallitt, Kylie-Ann/E-2240-2011; Whitehall, Vicki/B-6262-2013; Le Leu, Richard/H-4555-2013 OI Mallitt, Kylie-Ann/0000-0002-5722-7287; Whitehall, Vicki/0000-0002-8285-2391; Le Leu, Richard/0000-0003-4704-4943 FU National Health and Medical Research Council [442965]; National Starch Food Innovation; Gastroenterological Society of Australia; Royal Australasian College of Physicians; Royal Brisbane and Women's Hospital Foundation; Queensland Smart State PhD award FX Thank you to the volunteers that took part in this study. This study was part funded by a National Health and Medical Research Council project grant (442965), National Starch Food Innovation support, a Gastroenterological Society of Australia post-graduate medical scholarship (D. L. W.), the Royal Australasian College of Physicians Cottrell Fellowship (D. L. W.), a Royal Brisbane and Women's Hospital Foundation Research Grant (V. L. W, D. L. W, B. A. L) and a Queensland Smart State PhD award (D. L. W). This study was funded by a National Health and Medical Research Council project grant (442965), a Gastroenterological Society of Australia post-graduate medical scholarship (D. L. W), the Royal Australasian College of Physicians Cottrell Fellowship (D. L. W.), a Queensland Smart State PhD award (D. L. W), and the Royal Brisbane and Women's Hospital Foundation. NR 40 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD FEB PY 2011 VL 56 IS 2 BP 387 EP 396 DI 10.1007/s10620-010-1312-4 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 712KF UT WOS:000286664900017 PM 20635146 ER PT J AU Klos, CL Bordeianou, LG Sylla, P Chang, Y Berger, DL AF Klos, C. L. Bordeianou, L. G. Sylla, P. Chang, Y. Berger, D. L. TI The Prognostic Value of Lymph Node Ratio After Neoadjuvant Chemoradiation and Rectal Cancer Surgery SO DISEASES OF THE COLON & RECTUM LA English DT Article DE Rectal cancer; Chemotherapy; Colon and rectal surgery; Surgical oncology ID TOTAL MESORECTAL EXCISION; COLORECTAL-CANCER; PREOPERATIVE RADIOTHERAPY; NUMBER; CHEMORADIOTHERAPY; IMPACT; PROCTECTOMY; SPECIMENS; SURVIVAL; THERAPY AB BACKGROUND: Neoadjuvant chemotherapy decreases total lymph nodes harvested and possibly affects lymph node staging after total mesorectal excision in patients with rectal cancer. OBJECTIVE: This study aimed to compare staging by lymph node ratio with staging by absolute number of positive lymph nodes. DESIGN: This study is a retrospective cohort review. SETTING: A tertiary care referral center was the setting for this investigation. PATIENTS: A total of 281 consecutive patients who underwent neoadjuvant chemoradiation and total mesorectal excision after histologically confirmed rectal cancer between January 1, 1998 and December 31, 2008 were included in this study. MAIN OUTCOME MEASURES: Lymph node ratio is the number of positive lymph nodes divided by the total number of lymph nodes within one sample. Risk categories of low (0 to <0.09); medium (0.09 to <0.36); and high (>= 0.36) for lymph node ratio were chosen by significance with the use of Cox proportional hazards models. These categories were then used in a reclassification table and compared with positive lymph node stage: low (0 positive nodes), medium (1-3 nodes), and high (>3) by 5-year mortality rates. RESULTS: The majority (87%) of patients were concordant in risk assessment. Thirty patients were downstaged to lower risk lymph node ratio categories without showing actual lower mortality rates. Seven patients were upstaged to a high-risk lymph node ratio category with a supporting higher 5-year mortality rate. When limiting the analysis to those with fewer than 12 nodes, 136 (95%) patients were concordant in risk assessment; all 30 incorrectly downstaged patients were removed, but the 7 correctly upstaged patients remained. CONCLUSIONS: Patients who undergo neoadjuvant chemoradiation before rectal cancer surgery frequently have fewer than 12 lymph nodes harvested despite maintaining vigorous surgical standards. Lymph node ratios may provide excellent prognostic value and are possibly a better independent staging method than absolute positive lymph node counts when less than 12 lymph nodes are harvested after neoadjuvant treatment. C1 [Bordeianou, L. G.; Sylla, P.; Chang, Y.; Berger, D. L.] Massachusetts Gen Hosp, Dept Gastrointestinal Surg, Boston, MA 02114 USA. [Klos, C. L.] Univ Amsterdam, Amsterdam, Netherlands. RP Berger, DL (reprint author), 15 Parkman St,WAC 460, Boston, MA 02114 USA. EM dberger@partners.org NR 22 TC 17 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD FEB PY 2011 VL 54 IS 2 BP 171 EP 175 DI 10.1007/DCR.0b013e3181fd677d PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 705ZN UT WOS:000286180000008 PM 21228664 ER PT J AU Curhan, SG Eavey, R Shargorodsky, J Curhan, GC AF Curhan, Sharon G. Eavey, Roland Shargorodsky, Josef Curhan, Gary C. TI Prospective Study of Alcohol Use and Hearing Loss in Men SO EAR AND HEARING LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; NUTRITION EXAMINATION SURVEY; MALE HEALTH-PROFESSIONALS; DIETARY-FOLATE INTAKE; BREAST-CANCER RISK; OLDER-ADULTS; COGNITIVE DYSFUNCTION; NATIONAL-HEALTH; NOISE EXPOSURE; UNITED-STATES AB Objective: Hearing loss is a common and disabling sensory disorder, yet prospective data on potentially modifiable risk factors are limited. Previous studies suggest that alcohol consumption may influence the development of hearing loss, yet results have been inconsistent. The purpose of this study was to prospectively examine the relation between alcohol use and hearing loss in men. Design: We examined prospectively the independent association between alcohol intake and self-reported professionally diagnosed hearing loss in 26,809 men aged 40 to 74 yrs at baseline in 1986. Study participants completed detailed questionnaires at baseline and every 2 yrs thereafter. Incident cases of hearing loss were defined as those professionally diagnosed after 1986. Cox proportional hazards multivariate regression was used to adjust for potential confounding factors. Results: During 386,081 person-years of follow-up, 3447 incident cases of hearing loss were reported. Overall, there was no association between level of alcohol intake and risk of hearing loss. Compared with those who did not consume alcohol, the multivariate-adjusted hazard ratios (95% confidence interval) were 1.00 (0.89 to 1.12) for those who consumed 5.0 to 9.9 g/day, 1.08 (0.96 to 1.21) for 10.0 to 14.9 g/day, and 0.98 (0.85 to 1.13) for 30.0 to 49.9 g/day. The results did not differ by age group or folate intake. Among those with lower intake of vitamin B12, however, higher consumption of alcohol, specifically liquor, was associated with an increased risk of hearing loss. Conclusions: Our data suggest that low or moderate alcohol consumption does not influence the risk of hearing loss in older men. A possible relation between vitamin B12 intake, alcohol consumption, and hearing loss merits further investigation. C1 [Curhan, Sharon G.; Shargorodsky, Josef; Curhan, Gary C.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Eavey, Roland] Vanderbilt Univ, Sch Med, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN 37212 USA. [Shargorodsky, Josef] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA USA. [Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Curhan, SG (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM scurhan@partners.org FU NIH [P01 CA055075]; MEEI Foundation; Vanderbilt University School of Medicine FX This work was supported by NIH grant P01 CA055075, MEEI Foundation, and the Vanderbilt University School of Medicine Development Funds. NR 54 TC 9 Z9 10 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD FEB PY 2011 VL 32 IS 1 BP 46 EP 52 DI 10.1097/AUD.0b013e3181f46a2f PG 7 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 698GF UT WOS:000285581300006 PM 20802338 ER PT J AU Billings, CJ Bennett, KO Molis, MR Leek, MR AF Billings, Curtis J. Bennett, Keri O. Molis, Michelle R. Leek, Marjorie R. TI Cortical Encoding of Signals in Noise: Effects of Stimulus Type and Recording Paradigm SO EAR AND HEARING LA English DT Article ID AUDITORY-EVOKED-POTENTIALS; EVENT-RELATED POTENTIALS; BROAD-BAND NOISE; NORMAL-HEARING LISTENERS; WORD RECOGNITION; NEURAL REPRESENTATION; TEMPORAL RESOLUTION; SPEECH CUES; RISE TIME; MASKING AB Objectives: Perception-in-noise deficits have been demonstrated across many populations and listening conditions. Many factors contribute to successful perception of auditory stimuli in noise, including neural encoding in the central auditory system. Physiological measures such as cortical auditory-evoked potentials (CAEPs) can provide a view of neural encoding at the level of the cortex that may inform our understanding of listeners' abilities to perceive signals in the presence of background noise. To understand signal-in-noise neural encoding better, we set out to determine the effect of signal type, noise type, and evoking paradigm on the P1-N1-P2 complex. Design: Tones and speech stimuli were presented to nine individuals in quiet and in three background noise types: continuous speech spectrum noise, interrupted speech spectrum noise, and four-talker babble at a signal-to-noise ratio of -3 dB. In separate sessions, CAEPs were evoked by a passive homogenous paradigm (single repeating stimulus) and an active oddball paradigm. Results: The results for the N1 component indicated significant effects of signal type, noise type, and evoking paradigm. Although components P1 and P2 also had significant main effects of these variables, only P2 demonstrated significant interactions among these variables. Conclusions: Signal type, noise type, and evoking paradigm all must be carefully considered when interpreting signal-in-noise evoked potentials. Furthermore, these data confirm the possible usefulness of CAEPs as an aid to understand perception-in-noise deficits. C1 [Billings, Curtis J.; Bennett, Keri O.; Molis, Michelle R.; Leek, Marjorie R.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR 97239 USA. RP Billings, CJ (reprint author), Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd NCRAR, Portland, OR 97239 USA. EM curtis.billings2@va.gov FU National Institute on Deafness and Other Communication Disorders [R01 DC00626]; VA Rehabilitation Research and Development Service; Senior Research Career Scientist award FX This work was supported by a grant from the National Institute on Deafness and Other Communication Disorders (R01 DC00626), the VA Rehabilitation Research and Development Service as Career Development Awards (to C. J. B., M. R. M.), and a Senior Research Career Scientist award (to M. R. L.). NR 58 TC 16 Z9 18 U1 2 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD FEB PY 2011 VL 32 IS 1 BP 53 EP 60 PG 8 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 698GF UT WOS:000285581300007 PM 20890206 ER PT J AU Reavis, KM McMillan, G Austin, D Gallun, F Fausti, SA Gordon, JS Helt, WJ Konrad-Martin, D AF Reavis, Kelly M. McMillan, Garnett Austin, Donald Gallun, Frederick Fausti, Stephen A. Gordon, Jane S. Helt, Wendy J. Konrad-Martin, Dawn TI Distortion-Product Otoacoustic Emission Test Performance for Ototoxicity Monitoring SO EAR AND HEARING LA English DT Article ID CISPLATIN-INDUCED OTOTOXICITY; SENSORINEURAL HEARING-LOSS; HIGH-FREQUENCY AUDIOMETRY; CIS-DIAMMINEDICHLOROPLATINUM; AUDITORY FUNCTION; IMPAIRED SUBJECTS; CANCER-PATIENTS; DOSE CISPLATIN; RISK-FACTORS; SOUND-LEVEL AB Introduction: A nonbehavioral method for monitoring ototoxicity in patients treated with cisplatin is needed because patients enduring chemotherapy may not be well or cooperative enough to undergo repeated hearing tests. Distortion-product otoacoustic emissions (DPOAEs) provide a nonbehavioral measure of auditory function that is sensitive to cisplatin exposure. However, interpreting DPOAE findings in the context of ototoxicity monitoring requires that their accuracy be determined in relation to a clinically accepted gold standard test. Objectives: Among patients receiving cisplatin for the treatment of cancer, we sought to (1) identify the combination of DPOAE metrics and ototoxicity risk factors that best classified ears with and without ototoxic-induced hearing changes; and (2) evaluate the test performance achieved by the composite measure as well as by DPOAEs alone. Design: Odds of experiencing hearing changes at a given patient visit were determined using data collected prospectively from 24 Veterans receiving cisplatin. Pure-tone thresholds were examined within an octave of each subject's high-frequency hearing limit. DPOAE were collected as a set of four response growth (input/output) functions near the highest f(2) frequency that yielded a robust response at L(2) = L(1) = 65 dB SPL. Logistic regression modeled the risk of hearing change using several DPOAE metrics, drug treatment factors, and other patient factors as independent variables. An optimal discriminant function was derived by reducing the model so that only statistically significant variables were included. Receiver operating characteristic curve analyses were used to evaluate test performance. Results: At higher cisplatin doses, ears with better hearing at baseline were more likely to exhibit ototoxic hearing changes than those with poorer hearing. Measures of pre-exposure hearing, cumulative drug dose, and DPOAEs generated a highly accurate discriminant function with a cross-validated area under the receiver operating characteristic curve of 0.9. DPOAEs alone also provided an indication of ototoxic hearing change when measured at the highest DPOAE test frequency that yielded a robust response. Conclusions: DPOAEs alone and especially in combination with pre-exposure hearing and cisplatin dose provide an indication of whether or not hearing has changed as a result of cisplatin administration. These promising results need to be validated in a separate sample. C1 [Reavis, Kelly M.; McMillan, Garnett; Austin, Donald; Gallun, Frederick; Fausti, Stephen A.; Gordon, Jane S.; Helt, Wendy J.; Konrad-Martin, Dawn] Portland VA Med Ctr, NCRAR, VA RR&D, Portland, OR USA. [McMillan, Garnett] Oregon Hlth & Sci Univ, Dept Publ Hlth & Preventat Med, Portland, OR 97201 USA. [Austin, Donald; Gallun, Frederick; Fausti, Stephen A.; Konrad-Martin, Dawn] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. RP Reavis, KM (reprint author), Univ Calif Irvine, Hearing & Speech Lab, 364 Med Surge 2, Irvine, CA 92697 USA. EM reavisk@uci.edu RI Gallun, Frederick/G-3792-2012 OI Gallun, Frederick/0000-0002-4145-2199 FU National Center for Rehabilitative Auditory Research; Office of Rehabilitation Research and Development Service, Department of Veterans Affairs [C3213R, C4447K] FX This work was supported by the National Center for Rehabilitative Auditory Research and the Office of Rehabilitation Research and Development Service, Department of Veterans Affairs (Grants C3213R and C4447K). NR 82 TC 17 Z9 19 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD FEB PY 2011 VL 32 IS 1 BP 61 EP 74 PG 14 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 698GF UT WOS:000285581300008 PM 20625302 ER PT J AU Martindale, JL Goldstein, JN Pallin, DJ AF Martindale, Jennifer L. Goldstein, Joshua N. Pallin, Daniel J. TI Emergency Department Seizure Epidemiology SO EMERGENCY MEDICINE CLINICS OF NORTH AMERICA LA English DT Article DE Seizure; Acute symptomatic seizure; Epilepsy; Status epilepticus; Epidemiology ID NONCONVULSIVE STATUS EPILEPTICUS; PSYCHOGENIC NONEPILEPTIC SEIZURES; SERUM CHEMISTRY ABNORMALITIES; PEDIATRIC PREHOSPITAL CARE; NEW-ONSET SEIZURES; MINOR HEAD-INJURY; PSEUDOSTATUS EPILEPTICUS; BACTERIAL-MENINGITIS; GENERALIZED SEIZURE; COMPUTED-TOMOGRAPHY AB Although only 3% of people in the United States are diagnosed with epilepsy, 11% will have at least one seizure during their lifetime. Seizures account for about 1% of all emergency department (ED) visits, and about 2% of visits to children's hospital EDs. Seizure accounts for about 3% of prehospital transports. In adult ED patients, common causes of seizure are alcoholism, stroke, tumor, trauma, and central nervous system infection. In children, febrile seizures are most common. In infants younger than 6 months, hyponatremia and infection are important considerations. Epilepsy is an uncommon cause of seizures in the ED, accounting for a minority of seizure-related visits. Of ED patients with seizure, about 7% have status epilepticus, which has an age-dependent mortality averaging 22%. C1 [Martindale, Jennifer L.; Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Martindale, Jennifer L.; Pallin, Daniel J.] Childrens Hosp, Div Emergency Med, Boston, MA 02115 USA. [Martindale, Jennifer L.; Goldstein, Joshua N.; Pallin, Daniel J.] Harvard Affiliated Emergency Med Residency, Boston, MA 02115 USA. [Martindale, Jennifer L.; Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Martindale, Jennifer L.; Goldstein, Joshua N.; Pallin, Daniel J.] Harvard Univ, Sch Med, Boston, MA USA. RP Pallin, DJ (reprint author), 75 Francis St, Boston, MA 02115 USA. EM dpallin@partners.org RI Pallin, Daniel/H-6382-2013; Goldstein, Joshua/H-8953-2016 OI Pallin, Daniel/0000-0002-8517-9702; NR 91 TC 21 Z9 21 U1 0 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 0733-8627 J9 EMERG MED CLIN N AM JI Emerg. Med. Clin. N. Am. PD FEB PY 2011 VL 29 IS 1 BP 15 EP + DI 10.1016/j.emc.2010.08.002 PG 14 WC Emergency Medicine SC Emergency Medicine GA 698AE UT WOS:000285562200004 PM 21109099 ER PT J AU Astuti, D Ricketts, CJ Chowdhury, R McDonough, MA Gentle, D Kirby, G Schlisio, S Kenchappa, RS Carter, BD Kaelin, WG Ratcliffe, PJ Schofield, CJ Latif, F Maher, ER AF Astuti, Dewi Ricketts, Christopher J. Chowdhury, Rasheduzzaman McDonough, Michael A. Gentle, Dean Kirby, Gail Schlisio, Susanne Kenchappa, Rajappa S. Carter, Bruce D. Kaelin, William G., Jr. Ratcliffe, Peter J. Schofield, Christopher J. Latif, Farida Maher, Eamonn R. TI Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility SO ENDOCRINE-RELATED CANCER LA English DT Article AB Germline mutations in the von Hippel-Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-alpha subunits (and hence expression of the HIF-alpha transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC. C1 [Astuti, Dewi; Ricketts, Christopher J.; Gentle, Dean; Kirby, Gail; Latif, Farida; Maher, Eamonn R.] Univ Birmingham, Ctr Rare Dis & Personalised Med, Birmingham B15 2TT, W Midlands, England. [Astuti, Dewi; Ricketts, Christopher J.; Gentle, Dean; Kirby, Gail; Latif, Farida; Maher, Eamonn R.] Univ Birmingham, Sch Clin & Expt Med, Inst Biomed Res,Coll Med & Dent Sci, CRUK Renal Mol Oncol Grp, Birmingham B15 2TT, W Midlands, England. [Chowdhury, Rasheduzzaman; McDonough, Michael A.; Schofield, Christopher J.] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England. [Schlisio, Susanne; Kaelin, William G., Jr.] Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. [Schlisio, Susanne; Kaelin, William G., Jr.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schlisio, Susanne] Karolinska Inst, Ludwig Inst Canc Res Ltd, Oxygen Sensing & Canc Lab, SE-17177 Stockholm, Sweden. [Kenchappa, Rajappa S.; Carter, Bruce D.] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA. [Kenchappa, Rajappa S.; Carter, Bruce D.] Vanderbilt Univ, Sch Med, Ctr Mol Neurosci, Nashville, TN 37232 USA. [Ratcliffe, Peter J.] Univ Oxford, Oxford OX3 9DU, England. [Maher, Eamonn R.] Birmingham Womens Hosp, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England. RP Maher, ER (reprint author), Univ Birmingham, Sch Med, Inst Biomed Res, Ctr Rare Dis & Personalised Med, Birmingham B15 2TT, W Midlands, England. EM e.r.maher@bham.ac.uk RI McDonough, Michael/G-2744-2013; Chowdhury, Rasheduzzaman/I-7697-2014; OI McDonough, Michael/0000-0003-4664-6942; Chowdhury, Rasheduzzaman/0000-0002-8058-6149; Ratcliffe, Peter/0000-0002-2853-806X; Schlisio, Susanne/0000-0002-2605-3771; Schofield, Christopher/0000-0002-0290-6565 FU Cancer Research UK; National Institute of Health [NS038220] FX We thank Cancer Research UK and National Institute of Health (Grant NS038220 to B D Carter) for financial support. NR 59 TC 27 Z9 28 U1 0 U2 10 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2011 VL 18 IS 1 BP 73 EP 83 DI 10.1677/ERC-10-0113 PG 11 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA V30ED UT WOS:000208798400010 PM 20959442 ER PT J AU Walsh, KM Choi, M Oberg, K Kulke, MH Yao, JC Wu, CQ Jurkiewicz, M Hsu, LI Hooshmand, SM Hassan, M Janson, ET Cunningham, JL Vosburgh, E Sackler, RS Lifton, RP DeWan, AT Hoh, J AF Walsh, Kyle M. Choi, Murim Oberg, Kjell Kulke, Matthew H. Yao, James C. Wu, Chengqing Jurkiewicz, Magdalena Hsu, Ling-I Hooshmand, Susanne M. Hassan, Manal Janson, Eva T. Cunningham, Janet L. Vosburgh, Evan Sackler, Richard S. Lifton, Richard P. DeWan, Andrew T. Hoh, Josephine TI A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum SO ENDOCRINE-RELATED CANCER LA English DT Article ID COPY-NUMBER-VARIATION; CARCINOID-TUMORS; STRUCTURAL VARIATION; GENETIC ALTERATIONS; SUSCEPTIBILITY; CHROMOSOME-18; HYBRIDIZATION; MUTATIONS; DELETIONS; ABSENCE AB Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying > 300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16 x 10(-7)) at a Bonferroni-corrected level (< 1.62 x 10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in similar to 1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on ourmeta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval = 60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies. Endocrine-Related Cancer (2011) 18 171-180 C1 [Walsh, Kyle M.; Wu, Chengqing; Jurkiewicz, Magdalena; Hsu, Ling-I; DeWan, Andrew T.; Hoh, Josephine] Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Choi, Murim; Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06520 USA. [Oberg, Kjell; Janson, Eva T.; Cunningham, Janet L.] Univ Uppsala Hosp, Dept Endocrine Oncol, SE-75185 Uppsala, Sweden. [Kulke, Matthew H.; Hooshmand, Susanne M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yao, James C.; Hassan, Manal] Univ Texas Houston, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Vosburgh, Evan; Sackler, Richard S.] Verto Inst, Stamford, CT 06901 USA. RP Hoh, J (reprint author), Yale Univ, Dept Epidemiol & Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM josephine.hoh@yale.edu OI Vosburgh, Evan/0000-0002-1728-7787 FU Verto Institute FX Funding was provided by the Verto Institute. NR 36 TC 12 Z9 12 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD FEB PY 2011 VL 18 IS 1 BP 171 EP 180 DI 10.1677/ERC-10-0248 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 709LP UT WOS:000286439800017 PM 21139019 ER PT J AU German, JP Thaler, JP Wisse, BE Oh-I, S Sarruf, DA Matsen, ME Fischer, JD Taborsky, GJ Schwartz, MW Morton, GJ AF German, Jonathan P. Thaler, Joshua P. Wisse, Brent E. Oh-I, Shinsuke Sarruf, David A. Matsen, Miles E. Fischer, Jonathan D. Taborsky, Gerald J., Jr. Schwartz, Michael W. Morton, Gregory J. TI Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia SO ENDOCRINOLOGY LA English DT Article ID PROTEIN-2 MESSENGER-RNA; GLUCOSE-PRODUCTION; GENE-EXPRESSION; PROOPIOMELANOCORTIN NEURONS; PERIPHERAL-TISSUES; FOOD-INTAKE; RATS; RESISTANCE; HYPERPHAGIA; SENSITIVITY AB The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic beta-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin. (Endocrinology 152: 394-404, 2011) C1 [German, Jonathan P.; Thaler, Joshua P.; Wisse, Brent E.; Oh-I, Shinsuke; Sarruf, David A.; Matsen, Miles E.; Fischer, Jonathan D.; Schwartz, Michael W.; Morton, Gregory J.] Univ Washington, Diabet & Obes Ctr Excellence, Dept Med, Seattle, WA 98109 USA. [Taborsky, Gerald J., Jr.] Dept Vet Affairs Med Ctr, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP German, JP (reprint author), Univ Washington, Diabet & Obes Ctr Excellence, Dept Med, Seattle, WA 98109 USA. RI Schwartz, Michael/H-9950-2012 FU National Institutes of Health [DK083042, DK050154-13]; Veterans Affairs Merit review; Nutrition Obesity Research Center at the University of Washington [DK035816]; Mouse Metabolic Phenotyping Center at the University of Washington [U24 DK076126]; AstraZeneca; American Heart Association FX This work was supported by National Institutes of Health Grants DK083042 (to M. W. S.) and DK050154-13 (to G.J.T.); the Veterans Affairs Merit review (G.J.T.); the Nutrition Obesity Research Center Grant DK035816 and the Mouse Metabolic Phenotyping Center Grant U24 DK076126, at the University of Washington; research funding from AstraZeneca; and an American Heart Association Scientist Development grant (G.J.M.). NR 56 TC 63 Z9 66 U1 0 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2011 VL 152 IS 2 BP 394 EP 404 DI 10.1210/en.2010-0890 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 709FA UT WOS:000286422100010 PM 21159853 ER PT J AU Meeker, JD Yang, T Ye, XY Calafat, AM Hauser, R AF Meeker, John D. Yang, Tiffany Ye, Xiaoyun Calafat, Antonia M. Hauser, Russ TI Urinary Concentrations of Parabens and Serum Hormone Levels, Semen Quality Parameters, and Sperm DNA Damage SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE biomarker; endocrine; epidemiology; exposure; fertility; reproduction; thyroid ID MALE REPRODUCTIVE-SYSTEM; P-HYDROXYBENZOIC ACID; COMET ASSAY; HUMAN-SPERMATOZOA; TEMPORAL VARIABILITY; BUTYL PARABEN; CHO-K1 CELLS; HUMAN HEALTH; ESTERS; MEN AB BACKGROUND: Parabens are commonly used as antimicrobial preservatives in cosmetics, pharmaceuticals, and food and beverage processing. Widespread human exposure to parabens has been recently documented, and some parabens have demonstrated adverse effects on male reproduction in animal studies. However, human epidemiologic studies are lacking. OBJECTIVE: We investigated relationships between urinary concentrations of parabens and markers of male reproductive health in an ongoing reproductive epidemiology study. Methods: Urine samples collected from male partners attending an infertility clinic were analyzed for methyl paraben (MP), propyl paraben (PP), butyl paraben (BP), and bisphenol A (BPA). Associations with serum hormone levels (n = 167), semen quality parameters (n = 190), and sperm DNA damage measures (n = 132) were assessed using multivariable linear regression. RESULTS: Detection rates in urine were 100% for MP, 92% for PP, and 32% for BP. We observed no statistically significant associations between MP or PP and the outcome measures. Categories of urinary BP concentration were not associated with hormone levels or conventional semen quality parameters, but they were positively associated with sperm DNA damage (p for trend = 0.03). When urinary BPA quartiles were added to the model, BP and BPA were both positively associated with sperm DNA damage (p for trend = 0.03). Assessment of paraben concentrations measured on repeated urine samples from a subset of the men (n = 78) revealed substantial temporal variability. CONCLUSIONS: We found no evidence for a relationship between urinary parabens and hormone levels or semen quality, although intraindividual variability in exposure and a modest sample size could have limited our ability to detect subtle relationships. Our observation of a relationship between BP and sperm DNA damage warrants further investigation. C1 [Meeker, John D.; Yang, Tiffany] Univ Michigan, Dept Environm Hlth Sci, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Ye, Xiaoyun; Calafat, Antonia M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Dept Environm Hlth Sci, Sch Publ Hlth, 6635 SPH Tower,109 S Observ St, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI Meeker, John/0000-0001-8357-5085 FU National Institute of Environmental Health Sciences, National Institutes of Health [ES009718, ES00002] FX This work was supported by grants ES009718 and ES00002 from the National Institute of Environmental Health Sciences, National Institutes of Health. NR 46 TC 89 Z9 91 U1 4 U2 50 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2011 VL 119 IS 2 BP 252 EP 257 DI 10.1289/ehp.1002238 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 714IP UT WOS:000286803400029 PM 20876036 ER PT J AU Virani, SS Nambi, V Hoogeveen, R Wasserman, BA Coresh, J Gonzalez, F Chambless, LE Mosley, TH Boerwinkle, E Ballantyne, CM AF Virani, Salim S. Nambi, Vijay Hoogeveen, Ron Wasserman, Bruce A. Coresh, Josef Gonzalez, Franklyn, II Chambless, Lloyd E. Mosley, Thomas H. Boerwinkle, Eric Ballantyne, Christie M. TI Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study SO EUROPEAN HEART JOURNAL LA English DT Article DE Atherosclerosis; Magnetic resonance imaging; Inflammation; RANTES; High-sensitivity C-reactive protein ID CHEMOKINE RECEPTORS; DISEASE; INFLAMMATION; ENDOTHELIUM; PLASMA; RECRUITMENT; MECHANISMS; DEPOSITION; ARREST AB Aims To assess the relationship between regulated on activation, normal T-cell expressed and secreted (RANTES) and carotid atherosclerotic plaque burden and plaque characteristics. Methods and results Gadolinium-enhanced magnetic resonance imaging (MRI) of the carotid artery was performed in 1901 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Wall thickness and volume, lipid-core volume, and fibrous cap thickness (by MRI) and plasma RANTES levels (by ELISA) were measured. Regression analysis was performed to study the associations between MRI variables and RANTES. Among 1769 inclusive participants, multivariable regression analysis revealed that total wall volume [beta-coefficient (beta) = 0.09, P = 0.008], maximum wall thickness (beta = 0.08, P = 0.01), vessel wall area (beta = 0.07, P = 0.02), mean minimum fibrous cap thickness (beta = 0.11, P = 0.03), and high-sensitivity C-reactive protein (beta = 0.09, P = 0.01) were positively associated with RANTES. Total lipid-core volume showed positive association in unadjusted models (beta = 0.18, P = 0.02), but not in fully adjusted models (beta = 0.13, P = 0.09). RANTES levels were highest in Caucasian females followed by Caucasian males, African-American females, and African-American males (P < 0.0001). Statin use attenuated the relationship between RANTES and measures of plaque burden. Conclusion Positive associations between RANTES and carotid wall thickness and lipid-core volume (in univariate analysis) suggest that higher RANTES levels may be associated with extent of carotid atherosclerosis and high-risk plaques. Associations between fibrous cap thickness and RANTES likely reflect the lower reliability estimate for fibrous cap measurements compared with wall volume or lipid-core volume measurements. Statin use may modify the association between RANTES and carotid atherosclerosis. Furthermore, RANTES levels vary by race. C1 [Virani, Salim S.] Baylor Coll Med, Ctr Cardiovasc Dis Prevent, Methodist DeBakey Heart & Vasc Ctr, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Wasserman, Bruce A.] Johns Hopkins Med Inst, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Gonzalez, Franklyn, II; Chambless, Lloyd E.] Univ N Carolina, Chapel Hill, NC USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. RP Virani, SS (reprint author), Baylor Coll Med, Ctr Cardiovasc Dis Prevent, Methodist DeBakey Heart & Vasc Ctr, Michael E DeBakey Vet Affairs Med Ctr, 6565 Fannin,Suite B157B,MS BCMA601, Houston, TX 77030 USA. EM virani@bcm.tmc.edu OI Virani, Salim/0000-0001-9541-6954 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, U01HL075572-01]; Department of Veterans Affairs Health Services Research and Development Service (HSRD) [CDA-09-028] FX This work was supported by the National Heart, Lung, and Blood Institute [Contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 (The Atherosclerosis Risk in Communities study) and U01HL075572-01 (the ARIC Carotid MRI examination)]. S. S. V. is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (grant number: CDA-09-028). NR 30 TC 27 Z9 31 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD FEB PY 2011 VL 32 IS 4 BP 459 EP 468 DI 10.1093/eurheartj/ehq367 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 723HD UT WOS:000287496500018 PM 20943669 ER PT J AU Karlo, C Lauber, A Gotti, RP Baumuller, S Stolzmann, P Scheffel, H Desbiolles, L Schmidt, B Marincek, B Alkadhi, H Leschka, S AF Karlo, Christoph Lauber, Arno Goetti, Robert Paul Baumueller, Stephan Stolzmann, Paul Scheffel, Hans Desbiolles, Lotus Schmidt, Bernhard Marincek, Borut Alkadhi, Hatem Leschka, Sebastian TI Dual-energy CT with tin filter technology for the discrimination of renal lesion proxies containing blood, protein, and contrast-agent. An experimental phantom study SO EUROPEAN RADIOLOGY LA English DT Article DE Dual-energy CT; DECT; Renal cysts; Kidney lesions; Tin filter ID COMPUTED-TOMOGRAPHY; INITIAL-EXPERIENCE; CELL CARCINOMA; MASSES; CYSTS; DIFFERENTIATION; PERFORMANCE; ABDOMEN; STONES; REPAIR AB Purpose To differentiate proxy renal cystic lesions containing protein, blood, iodine contrast or saline solutions using dual-energy CT (DECT) equipped with a new tin filter technology (TFT). Materials and methods 70 proxies (saline, protein, blood and contrast agent) were placed in unenhanced and contrast-enhanced kidney phantoms. DECT was performed at 80/140 kV with and without tin filtering. Two readers measured the CT attenuation values in all proxies twice. An 80/140 kV ratio was calculated. Results All intra-and interobserver agreements were excellent (r=0.93-0.97; p<0.001). All CT attenuation values were significantly higher in the enhanced than in the unenhanced setting (p<0.05; average increase, 12.5 +/- 3.6HU), while the ratios remained similar (each, p>0.05). The CT attenuation of protein, blood and contrast agent solution differed significantly with tin filtering (p<0.01-0.05). Significant differences were found between the ratios of protein and blood compared to contrast medium solution (each, p<0.05) and between the ratios of protein and blood in both phantoms with tin filtering (each, p<0.05). Conclusion DECT allows discrimination between a proxy renal lesion containing contrast agent and lesions containing protein and blood through their different attenuation at 80 kV and 140 kV. Further discrimination between protein and blood containing proxies is possible when using a tin filter. C1 [Karlo, Christoph; Lauber, Arno; Goetti, Robert Paul; Baumueller, Stephan; Stolzmann, Paul; Scheffel, Hans; Desbiolles, Lotus; Marincek, Borut; Alkadhi, Hatem; Leschka, Sebastian] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Schmidt, Bernhard] Siemens Healthcare, Forchheim, Germany. [Alkadhi, Hatem] Massachusetts Gen Hosp, Cardiac MR PET CT Grp, Boston, MA 02114 USA. [Alkadhi, Hatem] Harvard Univ, Sch Med, Boston, MA USA. RP Karlo, C (reprint author), Univ Zurich Hosp, Inst Diagnost Radiol, Raemistr 100, CH-8091 Zurich, Switzerland. EM christoph.karlo@usz.ch RI Goetti, Robert/I-8961-2012 NR 26 TC 17 Z9 19 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD FEB PY 2011 VL 21 IS 2 BP 385 EP 392 DI 10.1007/s00330-010-1926-0 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 717WX UT WOS:000287079300021 PM 20711733 ER PT J AU Jang, YC Van Remmen, H AF Jang, Youngmok C. Van Remmen, Holly TI Age-associated alterations of the neuromuscular junction SO EXPERIMENTAL GERONTOLOGY LA English DT Article; Proceedings Paper CT 10th International Symposium on the Neurobiology and Neuroendocrinology of Aging CY JUL 25-30, 2010 CL Bregenz, AUSTRIA DE Sarcopenia; Neuromuscular junction; Oxidative stress; Mitochondria; Aging ID RAT MEDIAL GASTROCNEMIUS; SKELETAL-MUSCLE FIBERS; MOTOR UNITS; OXIDATIVE STRESS; NEUROTROPHIC FACTORS; CALORIE RESTRICTION; PERIPHERAL-NERVES; MOUSE MUSCLE; SARCOPENIA; DEGENERATION AB Age-related loss of muscle mass and function greatly affects quality of life in the elderly population. Several hypotheses have been proposed but accumulating evidence point to alterations in neuromuscular system during aging as a key event that leads to functional denervation, muscle wasting, and weakness. Over the past few decades, age-associated degeneration of the neuromuscular junction (NMJ) and its components have been well documented. With advancing age, pre-terminal portions of motor axons exhibit regions of abnormal thinning, distension, and sprouting whereas postsynaptic endplates decrease in size and reduce in number, length, and density of postsynaptic folds. Although the exact underlying mechanisms are still lacking, recent studies provided direct evidence that age-associated increase in oxidative stress plays a crucial role in NMJ degeneration and progression of sarcopenia. Homozygous deletion of an important antioxidant enzyme, Cu,Zn superoxide dismutase (CuZnSOD, SOD1) leads to acceleration of age-dependent muscle atrophy, with a significant NMJ degeneration similar to that seen in old wild-type sarcopenic animals. In this short review, we briefly summarize the current understanding of some of the cellular and molecular changes in the NMJ during aging and suggest a role for oxidative stress and mitochondrial dysfunction in age-related changes in the maintenance of neuromuscular innervation. (C) 2010 Elsevier Inc. All rights reserved. C1 [Jang, Youngmok C.; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular, San Antonio, TX 78229 USA. [Jang, Youngmok C.; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Biol Struct, San Antonio, TX 78229 USA. [Jang, Youngmok C.; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Van Remmen, Holly] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Van Remmen, H (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM vanremmen@uthscsa.edu FU NIA NIH HHS [P01 AG020591, P01 AG020591-080005, P01AG020591] NR 55 TC 54 Z9 56 U1 1 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD FEB-MAR PY 2011 VL 46 IS 2-3 SI SI BP 193 EP 198 DI 10.1016/j.exger.2010.08.029 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 720OQ UT WOS:000287290400020 PM 20854887 ER PT J AU Jung, YH Shiozawa, Y Wang, JC Patel, LR Havens, AM Song, JH Krebsbach, PH Roodman, GD Taichman, RS AF Jung, Younghun Shiozawa, Yusuke Wang, Jingcheng Patel, Lalit R. Havens, Aaron M. Song, Junhui Krebsbach, Paul H. Roodman, G. David Taichman, Russell S. TI Annexin-2 is a regulator of stromal cell-derived factor-1/CXCL12 function in the hematopoietic stem cell endosteal niche SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID FACTOR-I; BONE-MARROW; HUMAN OSTEOBLASTS; G-CSF; PROGENITOR CELLS; N-CADHERIN; CXCR4; SDF-1; MOBILIZATION; MAINTENANCE AB Objective. Previously, we reported that annexin-2 (anxa2) plays an important role in hematopoietic stem cell (HSC) localization to the endosteal/osteoblastic marrow niche. This study explored the role that annexin-2 plays in presenting stromal cell-derived factor - 1 (or CXCL12) to HSCs. Materials and Methods. Competitive long-term bone marrow transplant assays were used to determine if HSC engraftment is altered in annexin-2 - deficient animals. Colony-forming cell assays, CXCL12 enzyme-linked immunosorbent assay, and real-time reverse transcription polymerase chain reaction analyses were used to determine stem or progenitor cell mobilization by granulocyte colony-stimulating factor. Immunohistochemistry, immunoprecipitation, binding assays, and chemotactic assays were employed to determine if annexin-2 is associated with CXCL12. Degradation assays were also used to determine if annexin-2 and CXCL12 protect each other from proteolytic degradation. Results. Anxa2(-/-) animals had fewer HSCs in their marrow, and the HSCs in anxa2(-/-) animals express less CXCR4 and CXCR7, suggesting a cell intrinsic defect. Transplantation studies of wild-type marrow into anxa2(-/-) animals demonstrated a cell-extrinsic defect in the anxa2(-/-) animals. CXCL12 binds directly to annexin-2, and this interaction facilitates presentation of CXCL12 to HSCs. Yet the binding of CXCL12 to annexin-2 did not protect CXCL12 from proteolytic cleavage after stem or progenitor cell mobilization by granulocyte colony-stimulating factor. Conclusions. These results suggest that annexin-2 serves as an anchor for CXCL12 to help in the localization of HSCs to the niche. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Jung, Younghun; Shiozawa, Yusuke; Wang, Jingcheng; Havens, Aaron M.; Taichman, Russell S.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. [Patel, Lalit R.] Univ Michigan, Sch Dent, Dept Internal Med, Ann Arbor, MI 48109 USA. [Patel, Lalit R.] Univ Michigan, Sch Dent, Dept Urol, Ann Arbor, MI 48109 USA. [Havens, Aaron M.] Univ Michigan, Sch Dent, Dept Orthodont & Pediat Dent, Ann Arbor, MI 48109 USA. [Song, Junhui; Krebsbach, Paul H.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Roodman, G. David] Vet Affairs Pittsburgh Healthcare Syst, Dept Med Hematol Oncol, Pittsburgh, PA USA. [Roodman, G. David] Univ Pittsburgh, Dept Med Hematol Oncol, Pittsburgh, PA USA. RP Taichman, RS (reprint author), Univ Michigan, Sch Dent, Dept Periodont, 1011 N Univ Ave, Ann Arbor, MI 48109 USA. EM rtaich@umich.edu OI Taichman, Russell S./0000-0002-7890-0020 FU Pediatric Oncology Research Fellowship; Department of Defense [PC073952]; National Institutes of health [DK082481, DE020721, 1RC1DE020721, CA141426, CA09 3900] FX We thank Dr. Katherine A. Hajjar (Weill Medical College of Cornell University, New York, NY) for the anxa2-/- mice. This work was directly supported by a Pediatric Oncology Research Fellowship (Y.S.). This study was supported by grants from the Department of Defense (PC073952) and National Institutes of health (DK082481, DE020721, 1RC1DE020721, CA141426 and CA09 3900). No financial interest/relationships to the topic of this article have been declared. NR 46 TC 16 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2011 VL 39 IS 2 BP 151 EP 166 DI 10.1016/j.exphem.2010.11.007 PG 16 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 716JE UT WOS:000286964100003 PM 21108988 ER PT J AU Laubach, JP Schlossman, RL Mitsiades, CS Anderson, KC Richardson, PG AF Laubach, Jacob P. Schlossman, Robert L. Mitsiades, Constantine S. Anderson, Kenneth C. Richardson, Paul G. TI Thalidomide, lenalidomide and bortezomib in the management of newly diagnosed multiple myeloma SO EXPERT REVIEW OF HEMATOLOGY LA English DT Review DE bortezomib; lenalidomide; multiple myeloma; stem cell transplantation; thalidomide ID STEM-CELL TRANSPLANTATION; PROTEASOME INHIBITOR PS-341; PREDNISONE PLUS THALIDOMIDE; COOPERATIVE-ONCOLOGY-GROUP; HIGH-DOSE THERAPY; ELDERLY-PATIENTS; RANDOMIZED-TRIAL; PHASE-III; PERIPHERAL NEUROPATHY; INITIAL THERAPY AB The field of multiple myeloma therapeutics has been an active one for many years, but perhaps no more so than in the past decade. The introduction of thalidomide, lenalidomide and bortezomib in the treatment of this disease highlights clinical advances made during this period. While these agents were initially utilized in the setting of relapsed and refactory disease, they are now part of the therapeutic armamentarium for transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma. The principles of management applied in the care of newly diagnosed multiple myeloma are reviewed in this article, along with the clinical studies supporting the use of thalidomide, lenalidomide and bortezomib in newly diagnosed multiple myeloma. Management of treatment-related side effects is also discussed, since it constitutes a critical element in the successful management of patients with this disease. Combination regimens utilizing thalidomide, lenalidomide and bortezomib are also highlighted, as these regimens are likely to play an increasingly important role in myeloma therapy in the future. C1 [Laubach, Jacob P.; Schlossman, Robert L.; Mitsiades, Constantine S.; Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Laubach, JP (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM jacobp_laubach@dfci.harvard.edu NR 95 TC 20 Z9 23 U1 0 U2 0 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4086 J9 EXPERT REV HEMATOL JI Expert Rev. Hematol. PD FEB PY 2011 VL 4 IS 1 BP 51 EP 60 DI 10.1586/EHM.10.83 PG 10 WC Hematology SC Hematology GA 731YM UT WOS:000288146700012 PM 21322778 ER PT J AU Topcuoglu, MA Arsava, EM Ay, H AF Topcuoglu, Mehmet Akif Arsava, Ethem Murat Ay, Hakan TI Antiplatelet resistance in stroke SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE antiplatelet; aspirin; clopidogrel; ischemic stroke; non-response; platelet function assay; point of care; resistance; stroke ID CORONARY-ARTERY-DISEASE; LOW-DOSE ASPIRIN; CALCIUM-CHANNEL BLOCKERS; PLATELET-FUNCTION TESTS; PROTON PUMP INHIBITORS; LIGHT TRANSMISSION AGGREGOMETRY; ACUTE ISCHEMIC-STROKE; HIGH-RISK PATIENTS; CARDIOVASCULAR EVENTS; CLOPIDOGREL RESISTANCE AB Although the exact prevalence of antiplatelet resistance in ischemic stroke is not known, estimates about the two most widely used antiplatelet agents aspirin and clopidogrel suggest that the resistance rate is high, irrespective of the definition used and parameters measured. Inadequate antiplatelet responsiveness correlates with an increased risk of recurrent ischemic vascular events in patients with stroke and acute coronary syndrome. It is not currently known whether tailoring antiplatelet therapy based on platelet function test results translates into a more effective strategy to prevent secondary vascular events after stroke. Large-scale clinical trials using a universally accepted definition and standardized measurement techniques for antiplatelet resistance are needed to demonstrate whether a 'platelet-function test-guided antiplatelet treatment' strategy translates into improved stroke care. This article gives an overview of the clinical importance of laboratory antiplatelet resistance, describes the challenges for platelet-function test-guided antiplatelet treatment and discusses practical issues about the management of patients with aspirin and/or clopidogrel resistance. C1 [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Stroke Serv,Dept Neurol, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02129 USA. [Topcuoglu, Mehmet Akif; Arsava, Ethem Murat] Hacettepe Univ Hosp, Dept Neurol, Ankara, Turkey. RP Ay, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Stroke Serv,Dept Neurol, AA Martinos Ctr Biomed Imaging,Dept Radiol, CNY 149-2301, Boston, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013 OI Arsava, Ethem Murat/0000-0002-6527-4139 FU NIH [R01-NS059710] FX Hakan Ay has been supported by NIH grant R01-NS059710. 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 125 TC 26 Z9 28 U1 0 U2 5 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD FEB PY 2011 VL 11 IS 2 BP 251 EP 263 DI 10.1586/ERN.10.203 PG 13 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 727TB UT WOS:000287823400014 PM 21306212 ER PT J AU Mills, JC Shivdasani, RA AF Mills, Jason C. Shivdasani, Ramesh A. TI Gastric Epithelial Stem Cells SO GASTROENTEROLOGY LA English DT Review DE Stomach Stem Cells; Epithelial Self-Renewal; Tissue Metaplasia ID POLYPEPTIDE-EXPRESSING METAPLASIA; MOUSE SMALL-INTESTINE; TRANSGENIC MICE; PARIETAL-CELLS; HELICOBACTER-PYLORI; ZYMOGENIC CELLS; MOLECULAR CHARACTERIZATION; ANTRAL EPITHELIUM; DYNAMIC HISTOLOGY; PROGENITOR-CELL AB Advances in our understanding of stem cells in the gastrointestinal tract include the identification of molecular markers of stem and early progenitor cells in the small intestine. Although gastric epithelial stem cells have been localized, little is known about their molecular biology. Recent reports describe the use of inducible Cre recombinase activity to indelibly label candidate stem cells and their progeny in the distal stomach, (ie, the antrum and pylorus). No such lineage labeling of epithelial stem cells has been reported in the gastric body (corpus). Among stem cells in the alimentary canal, those of the adult corpus are unique in that they lie close to the lumen and increase proliferation following loss of a single mature progeny lineage, the acid-secreting parietal cell. They are also unique in that they neither depend on Wnt signaling nor express the surface marker Lgr5. Because pathogenesis of gastric adenocarcinoma has been associated with abnormal patterns of gastric differentiation and with chronic tissue injury, there has been much research on the response of stomach epithelial stem cells to inflammation. Chronic inflammation, as induced by infection with Helicobacter pylori, affects differentiation and promotes metaplasias. Several studies have identified cellular and molecular mechanisms in spasmolytic polypeptide-expressing (pseudopyloric) metaplasia. Researchers have also begun to identify signaling pathways and events that take place during embryonic development that eventually establish the adult stem cells to maintain the specific features and functions of the stomach mucosa. We review the cytologic, molecular, functional, and developmental properties of gastric epithelial stem cells. C1 [Mills, Jason C.] Washington Univ, Sch Med, Div Gastroenterol, Dept Med, St Louis, MO 63110 USA. [Mills, Jason C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Mills, Jason C.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA USA. RP Mills, JC (reprint author), Washington Univ, Sch Med, Div Gastroenterol, Dept Med, Box 8124,660 S Euclid Ave, St Louis, MO 63110 USA. EM jmills@wustl.edu; ramesh_shivdasani@dfci.harvard.edu FU NIDDK NIH HHS [R01 DK079798, R01 DK079798-01A2, R01 DK079798-02, R01 DK079798-03] NR 93 TC 60 Z9 62 U1 2 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2011 VL 140 IS 2 BP 412 EP 424 DI 10.1053/j.gastro.2010.12.001 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 711LR UT WOS:000286593600020 PM 21144849 ER PT J AU Patierno, S Anselmi, L Jaramillo, I Scott, D Garcia, R Sternini, C AF Patierno, Simona Anselmi, Laura Jaramillo, Ingrid Scott, David Garcia, Rachel Sternini, Catia TI Morphine Induces mu Opioid Receptor Endocytosis in Guinea Pig Enteric Neurons Following Prolonged Receptor Activation SO GASTROENTEROLOGY LA English DT Article DE G-Protein-Coupled Receptors; Opioid Peptides; Opiate Drugs; Tolerant and Naive Animals ID PROTEIN-COUPLED RECEPTORS; MEMBRANE TRAFFICKING; ABDOMINAL-SURGERY; BOWEL DYSFUNCTION; BETA-ARRESTIN; OPIATE DRUGS; SPINAL-CORD; IN-VIVO; INTERNALIZATION; DESENSITIZATION AB BACKGROUND & AIMS: The mu opioid receptor (mu OR) undergoes rapid endocytosis after acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of mu OR affects morphine's ability to induce receptor endocytosis in enteric neurons. METHODS: We compared the effects of morphine, a poor mu OR-internalizing opiate, and (D-Ala2,MePhe4,Gly-ol5) enkephalin (DAMGO), a potent mu OR-internalizing agonist, on mu OR trafficking in enteric neurons and on the expression of dynamin and beta-arrestin immunoreactivity in the ileum of guinea pigs rendered tolerant by chronic administration of morphine. RESULTS: Morphine (100 mu mol/L) strongly induced endocytosis of mu OR in tolerant but not naive neurons (55.7% +/- 9.3% vs 24.2% +/- 7.3%; P < .001) whereas DAMGO (10 mu mol/L) strongly induced internalization of mu OR in neurons from tolerant and naive animals (63.6% +/- 8.4% and 66.5% +/- 3.6%). Morphine-or DAMGO-induced mu OR endocytosis resulted from direct interactions between the ligand and the mu OR because endocytosis was not affected by tetrodotoxin, a blocker of endogenous neurotransmitter release. Ligand-induced mu OR internalization was inhibited by pretreatment with the dynamin inhibitor, dynasore. Chronic morphine administration resulted in a significant increase and translocation of dynamin immunoreactivity from the intracellular pool to the plasma membrane, but did not affect beta-arrestin immunoreactivity. CONCLUSIONS: Chronic activation of mu ORs increases the ability of morphine to induce mu OR endocytosis in enteric neurons, which depends on the level and cellular localization of dynamin, a regulatory protein that has an important role in receptor-mediated signal transduction in cells. C1 [Patierno, Simona; Anselmi, Laura; Scott, David; Garcia, Rachel; Sternini, Catia] Vet Adm Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. [Patierno, Simona; Anselmi, Laura; Jaramillo, Ingrid; Scott, David; Sternini, Catia] Univ Calif Los Angeles, Dept Med, Div Digest Dis, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Scott, David] Univ Calif Los Angeles, Dept Physiol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Sternini, Catia] Univ Calif Los Angeles, Dept Neurobiol, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Sternini, C (reprint author), Vet Adm Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Bldg 115,Room 224,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM csternin@ucla.edu FU National Institutes of Health-National Institute on Drug Abuse Center for Study of Opioid Receptors and Drugs of Abuse [DK54155, DK41301, P50 DA05010] FX This research was supported by the National Institutes of Health grants DK54155 (C. S.), DK41301 (Morphology/Imaging subsection, to C. S.), and a pilot grant (to C. S.) from the National Institutes of Health-National Institute on Drug Abuse Center for Study of Opioid Receptors and Drugs of Abuse (P50 DA05010). NR 54 TC 21 Z9 21 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2011 VL 140 IS 2 BP 618 EP 626 DI 10.1053/j.gastro.2010.11.005 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 711LR UT WOS:000286593600040 PM 21070774 ER PT J AU Kim, AY Kuntzen, T Timm, J Nolan, BE Baca, MA Reyor, LL Berical, AC Feller, AJ Johnson, KL Zur Wiesch, JS Robbins, GK Chung, RT Walker, BD Carrington, M Allen, TM Lauer, GM AF Kim, Arthur Y. Kuntzen, Thomas Timm, Joerg Nolan, Brian E. Baca, Melanie A. Reyor, Laura L. Berical, Andrew C. Feller, Andrea J. Johnson, Kristin L. Zur Wiesch, Julian Schulze Robbins, Gregory K. Chung, Raymond T. Walker, Bruce D. Carrington, Mary Allen, Todd M. Lauer, Georg M. TI Spontaneous Control of HCV Is Associated With Expression of HLA-B*57 and Preservation of Targeted Epitopes SO GASTROENTEROLOGY LA English DT Article DE CD8 T Cell; HLA-B57; Spontaneous Clearance; Viral Escape ID C VIRUS-INFECTION; T-CELL RESPONSES; ANTIGEN CLASS-I; DISEASE PROGRESSION; IMMUNE-RESPONSES; HIV-INFECTION; P24 GAG; EVOLUTION; HLA; ALLELES AB BACKGROUND & AIMS: HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses. METHODS: In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes. RESULTS: Carriage of HLA-B*57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2-3.4), while HLA-B*08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1-0.9]. Two HLA-B*57-restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B*57 harbored HCV strains with a high frequency of mutations in key residues. HLAB*57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B*57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B*57-mediated immune pressure. CONCLUSIONS: Our data indicate a role of HLA-B*57-restricted CD8(+) T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B*57. The finding that HLAB*57-mediated antiviral immunity is associated with control of both human immunodeficiency virus-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses. C1 [Kim, Arthur Y.; Reyor, Laura L.; Johnson, Kristin L.; Robbins, Gregory K.; Walker, Bruce D.; Allen, Todd M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Nolan, Brian E.; Reyor, Laura L.; Chung, Raymond T.; Lauer, Georg M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Kim, Arthur Y.; Kuntzen, Thomas; Baca, Melanie A.; Berical, Andrew C.; Feller, Andrea J.; Walker, Bruce D.; Carrington, Mary; Allen, Todd M.] Ragon Inst MGH Massachusetts Inst Technol & Harva, Boston, MA USA. [Timm, Joerg] Univ Essen Gesamthsch, Inst Virol, Essen, Germany. [Zur Wiesch, Julian Schulze] Univ Med Ctr Hamburg Eppendorf, Div Med, Hamburg, Germany. [Zur Wiesch, Julian Schulze; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Kim, AY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, GRB-504, Boston, MA 02114 USA. EM akim1@partners.org RI Robbins, Gregory/F-7988-2011; Allen, Todd/F-5473-2011 FU National Institutes of Health [AI 054379, AI 066345, AI 031563, AI 042851, AI 067926, AI 069939, DK 078772, AI 062435]; Harvard Medical School Center for AIDS Research [P30 AI060354]; Campbell Foundation; Liver Foundation; Doris Duke Charitable Foundation; Howard Hughes Medical Institute; Deutsche Forschungsgemeinschaft [DFG KU2250/1-1] FX This work was funded by the National Institutes of Health (AI 054379 to AYK, AI 066345 to AYK, GML, TMA, BDW; AI 031563, AI 042851 and AI 054379 to BDW; AI 067926 to TMA; AI 069939 and DK 078772 to RTC, AI 062435 to GKR), the Harvard Medical School Center for AIDS Research (P30 AI060354), the Campbell Foundation (GML), the Liver Foundation (GML), the Doris Duke Charitable Foundation and Howard Hughes Medical Institute (BDW), Deutsche Forschungsgemeinschaft grant DFG KU2250/1-1 (TK). NR 32 TC 66 Z9 72 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2011 VL 140 IS 2 BP 686 EP U434 DI 10.1053/j.gastro.2010.09.042 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 711LR UT WOS:000286593600047 PM 20875418 ER PT J AU Giardino, WJ Pastor, R Anacker, AMJ Spangler, E Cote, DM Li, J Stenzel-Poore, MP Phillips, TJ Ryabinin, AE AF Giardino, W. J. Pastor, R. Anacker, A. M. J. Spangler, E. Cote, D. M. Li, J. Stenzel-Poore, M. P. Phillips, T. J. Ryabinin, A. E. TI Dissection of corticotropin-releasing factor system involvement in locomotor sensitivity to methamphetamine SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Addiction; amphetamine; amygdala; corticotropin-releasing hormone; urocortin ID LONG-TERM POTENTIATION; ANXIETY-LIKE BEHAVIOR; TYPE-1 RECEPTOR ANTAGONIST; EDINGER-WESTPHAL NUCLEUS; PITUITARY-ADRENAL AXIS; VENTRAL TEGMENTAL AREA; CENTRAL-NERVOUS-SYSTEM; CRF-BINDING PROTEIN; RAT-BRAIN; COCAINE WITHDRAWAL AB Sensitivity to the euphoric and locomotor-activating effects of drugs of abuse may contribute to risk for excessive use and addiction. Repeated administration of psychostimulants such as methamphetamine (MA) can result in neuroadaptive consequences that manifest behaviorally as a progressive escalation of locomotor activation, termed psychomotor sensitization. The present studies addressed the involvement of specific components of the corticotropin-releasing factor (CRF) system in locomotor activation and psychomotor sensitization induced by MA (1, 2 mg/kg) by utilizing pharmacological approaches, as well as a series of genetic knockout (KO) mice, each deficient for a single component of the CRF system: CRF-R1, CRF-R2, CRF, or the CRF-related peptide Urocortin 1 (Ucn1). CRF-R1 KO mice did not differ from wild-type mice in sensitization to MA, and pharmacological blockade of CRF-R1 with CP-154,526 (15, 30 mg/kg) in DBA/2J mice did not selectively attenuate either the acquisition or expression of MA-induced sensitization. Deletion of either of the endogenous ligands of CRF-R1 (CRF, Ucn1) either enhanced or had no effect on MA-induced sensitization, providing further evidence against a role for CRF-R1 signaling. Interestingly, deletion of CRF-R2 attenuated MA-induced locomotor activation, elucidating a novel contribution of the CRF system to MA sensitivity, and suggesting the participation of the endogenous urocortin peptides Ucn2 and Ucn3. Immunohistochemistry for Fos was used to visualize neural activation underlying CRF-R2-dependent sensitivity to MA, identifying the basolateral and central nuclei of the amygdala as neural substrates involved in this response. Our results support further examination of CRF-R2 involvement in neural processes associated with MA addiction. C1 [Giardino, W. J.; Pastor, R.; Anacker, A. M. J.; Spangler, E.; Cote, D. M.; Li, J.; Phillips, T. J.; Ryabinin, A. E.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. [Giardino, W. J.; Pastor, R.; Anacker, A. M. J.; Spangler, E.; Cote, D. M.; Li, J.; Phillips, T. J.; Ryabinin, A. E.] Oregon Hlth & Sci Univ, Methamphetamine Abuse Res Ctr, Portland, OR 97201 USA. [Pastor, R.] Univ Jaume 1, Area Psicobiol, Castellon de La Plana, Spain. [Stenzel-Poore, M. P.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Phillips, T. J.] Portland VA Med Ctr, Res Serv, R&D32, Portland, OR USA. RP Ryabinin, AE (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, L-470,3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. EM ryabinin@ohsu.edu FU NIH [P50DA018165, RO3DA02854, T32DA007262] FX This research was supported by NIH grants P50DA018165 (A. E. R., T.J.P.), RO3DA02854 (A. E. R.) and T32DA007262 (W.J.G.), and resources were also provided by the Department of Veterans Affairs (T.J.P.). We are grateful to Pfizer for their donation of their drug, CP-154,526, for use in our work. NR 80 TC 18 Z9 18 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD FEB PY 2011 VL 10 IS 1 BP 78 EP 89 DI 10.1111/j.1601-183X.2010.00641.x PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 709VG UT WOS:000286468900009 PM 20731720 ER PT J AU Liu, T Rechtsteiner, A Egelhofer, TA Vielle, A Latorre, I Cheung, MS Ercan, S Ikegami, K Jensen, M Kolasinska-Zwierz, P Rosenbaum, H Shin, HJ Taing, S Takasaki, T Iniguez, AL Desai, A Dernburg, AF Kimura, H Lieb, JD Ahringer, J Strome, S Liu, XS AF Liu, Tao Rechtsteiner, Andreas Egelhofer, Thea A. Vielle, Anne Latorre, Isabel Cheung, Ming-Sin Ercan, Sevinc Ikegami, Kohta Jensen, Morten Kolasinska-Zwierz, Paulina Rosenbaum, Heidi Shin, Hyunjin Taing, Scott Takasaki, Teruaki Iniguez, A. Leonardo Desai, Arshad Dernburg, Abby F. Kimura, Hiroshi Lieb, Jason D. Ahringer, Julie Strome, Susan Liu, X. Shirley TI Broad chromosomal domains of histone modification patterns in C. elegans SO GENOME RESEARCH LA English DT Article ID CAENORHABDITIS-ELEGANS; EPIGENETIC REGULATION; METHYLATION STATES; X-CHROMOSOMES; HUMAN GENOME; CHROMATIN; SYNAPSIS; REPRESSION; METHYLTRANSFERASE; HETEROCHROMATIN AB Chromatin immunoprecipitation identifies specific interactions between genomic DNA and proteins, advancing our understanding of gene-level and chromosome-level regulation. Based on chromatin immunoprecipitation experiments using validated antibodies, we define the genome-wide distributions of 19 histone modifications, one histone variant, and eight chromatin-associated proteins in Caenorhabditis elegans embryos and L3 larvae. Cluster analysis identified five groups of chromatin marks with shared features: Two groups correlate with gene repression, two with gene activation, and one with the X chromosome. The X chromosome displays numerous unique properties, including enrichment of monomethylated H4K20 and H3K27, which correlate with the different repressive mechanisms that operate in somatic tissues and germ cells, respectively. The data also revealed striking differences in chromatin composition between the autosomes and between chromosome arms and centers. Chromosomes I and III are globally enriched for marks of active genes, consistent with containing more highly expressed genes, compared to chromosomes II, IV, and especially V. Consistent with the absence of cytological heterochromatin and the holocentric nature of C. elegans chromosomes, markers of heterochromatin such as H3K9 methylation are not concentrated at a single region on each chromosome. Instead, H3K9 methylation is enriched on chromosome arms, coincident with zones of elevated meiotic recombination. Active genes in chromosome arms and centers have very similar histone mark distributions, suggesting that active domains in the arms are interspersed with heterochromatin-like structure. These data, which confirm and extend previous studies, allow for in-depth analysis of the organization and deployment of the C. elegans genome during development. C1 [Vielle, Anne; Latorre, Isabel; Cheung, Ming-Sin; Kolasinska-Zwierz, Paulina; Ahringer, Julie] Univ Cambridge, Gurdon Inst, Cambridge CB2 1QN, England. [Vielle, Anne; Latorre, Isabel; Cheung, Ming-Sin; Kolasinska-Zwierz, Paulina; Ahringer, Julie] Univ Cambridge, Dept Genet, Cambridge CB2 1QN, England. [Liu, Tao; Shin, Hyunjin; Taing, Scott; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Liu, Tao; Shin, Hyunjin; Taing, Scott; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Rechtsteiner, Andreas; Egelhofer, Thea A.; Takasaki, Teruaki; Strome, Susan] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Ercan, Sevinc; Ikegami, Kohta; Jensen, Morten; Lieb, Jason D.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Biol, Chapel Hill, NC 27599 USA. [Ercan, Sevinc; Ikegami, Kohta; Jensen, Morten; Lieb, Jason D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Rosenbaum, Heidi; Iniguez, A. Leonardo] Roche NimbleGen Inc, Madison, WI 53719 USA. [Desai, Arshad] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92037 USA. [Desai, Arshad] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92037 USA. [Dernburg, Abby F.] Univ Calif Berkeley, Calif Inst Quantitat Biosci, Berkeley, CA 94720 USA. [Dernburg, Abby F.] Univ Calif Berkeley, Dept Mol & Cell Biol, HHMI, Berkeley, CA 94720 USA. [Dernburg, Abby F.] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. RP Ahringer, J (reprint author), Univ Cambridge, Gurdon Inst, Cambridge CB2 1QN, England. EM ja219@cam.ac.uk; sstrome@ucsc.edu; xsliu@jimmy.harvard.edu RI Liu, Tao/G-3585-2010; OI Dernburg, Abby/0000-0001-8037-1079; Latorre, Isabel/0000-0003-0638-1783; Liu, Tao/0000-0002-8818-8313; Liu, Tao/0000-0003-0446-9001 FU NIH National Center for Research Resources; modENCODE [U01 HG004270] FX We thank Hiroshi Kimura and Kirsten Hagstrom for antibodies. C. elegans was provided by the Caenorhabditis Genetics Center (University of Minnesota), which is funded by the NIH National Center for Research Resources. This research is supported by modENCODE grant U01 HG004270 to the modENCODE consortium headed by J.D.L., with J.A., A.D., A.F.D., A.L.I., X.S.L., and S.S. as co-investigators. NR 56 TC 115 Z9 116 U1 1 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD FEB PY 2011 VL 21 IS 2 BP 227 EP 236 DI 10.1101/gr.115519.110 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 714IU UT WOS:000286804100008 PM 21177964 ER PT J AU Drouin-Ouellet, J Brownell, AL Saint-Pierre, M Fasano, C Emond, V Trudeau, LE Levesque, D Cicchetii, F AF Drouin-Ouellet, Janelle Brownell, Anna-Liisa Saint-Pierre, Martine Fasano, Caroline Emond, Vincent Trudeau, Louis-Eric Levesque, Daniel Cicchetii, Francesca TI Neuroinflammation Is Associated with Changes in Glial mGluR5 Expression and the Development of Neonatal Excitotoxic Lesions SO GLIA LA English DT Article DE neonatal ventral hippocampal lesion; metabotropic glutamate; receptor type 5 (mGluR5), ibotenic acid; activated microglia; minocycline; astrocytes ID METABOTROPIC GLUTAMATE RECEPTORS; GROUP-I; NEURONAL DEGENERATION; REACTIVE ASTROCYTES; HUNTINGTONS-DISEASE; UP-REGULATION; ANIMAL-MODEL; MOUSE MODEL; RAT BRAIN; MINOCYCLINE AB It has been hypothesized that neuroinflammation triggered during brain development can alter brain functions later in life. We investigated the contribution of inflammation to the alteration of normal brain circuitries in the context of neuro-excitotoxicity following neonatal ventral hippocampal lesions in rats with ibotenic acid, an NMDA glutamate receptor agonist. Excitotoxic ibotenic acid lesions led to a significant and persistent astrogliosis and microglial activation, associated with the production of inflammatory mediators. This response was accompanied by a significant increase in metabotropic glutamate receptor type 5 (mGluR5) expression within two distinct neuroinflammatory cell types; astrocytes and microglia. The participation of inflammation to the neurotoxin-induced lesion was further supported by the prevention of hippocampal neuronal loss, glial mGluR5 expression and some of the behavioral perturbations associated to the excitotoxic lesion by concurrent anti-inflammatory treatment with minocycline. These results indicate that neuroinflammation significantly contributes to long-lasting excitotoxic effects of the neurotoxin and to some behavioral phenotypes associated with this model. Thus, the control of the inflammatory response may prevent the deleterious effects of excitotoxic processes that are triggered during brain development, limiting the risk to develop some of the behavioral manifestations related to these processes in adulthood. (C) 2010 Wiley-Liss, Inc. C1 [Drouin-Ouellet, Janelle; Saint-Pierre, Martine; Emond, Vincent; Cicchetii, Francesca] Ctr Rech CHUL CHUQ, Quebec City, PQ G1V 4G2, Canada. [Brownell, Anna-Liisa] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Expt PET Lab, Boston, MA 02114 USA. [Fasano, Caroline; Trudeau, Louis-Eric] Univ Montreal, Fac Med, Dept Pharmacol, Grp Rech Syst Nerveux Cent, Montreal, PQ H3C 3J7, Canada. [Levesque, Daniel] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada. [Cicchetii, Francesca] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ G1K 0A6, Canada. RP Cicchetii, F (reprint author), Ctr Rech CHUL CHUQ, RC-9800,2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada. EM Francesca.Cicchetti@crchul.ulaval.ca OI Trudeau, Louis-Eric/0000-0003-4684-1377 FU NIMH [5R01MH091684]; NIBIB [1R01EB1850]; NARSAD; Canadian Foundation for Innovation (CFI); Canadian Institutes of Health Research; Canada Frederick Banting and Charles Best doctoral scholarship FX Grant sponsor: NIMH; Grant number: 5R01MH091684 (to A.L. Brownell and F. Cicchetti); Grant sponsor: NIBIB; Grant number: 1R01EB1850 (to A.L. Brownell); NARSAD (to F. Cicchetti), the Canadian Foundation for Innovation (CFI) (to F. Cicchetti); Canadian Institutes of Health Research (to L.E. Trudeau), Canada Frederick Banting and Charles Best doctoral scholarship (to J. Drain-Ouellet). NR 49 TC 32 Z9 33 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD FEB PY 2011 VL 59 IS 2 BP 188 EP 199 DI 10.1002/glia.21086 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 707MR UT WOS:000286291200002 PM 21125661 ER PT J AU Groeneveld, PW Epstein, AJ Yang, FF Yang, L Polsky, D AF Groeneveld, Peter W. Epstein, Andrew J. Yang, Feifei Yang, Lin Polsky, Daniel TI Medicare's Policy On Carotid Stents Limited Use To Hospitals Meeting Quality Guidelines Yet Did Not Hurt Disadvantaged SO HEALTH AFFAIRS LA English DT Article; Proceedings Paper CT Annual Research Meeting of the Academy-Health CY JUN 28, 2010 CL Boston, MA SP Acad Hlth ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; ENDARTERECTOMY; COVERAGE; TECHNOLOGIES; POPULATION; TRIAL; COMPLICATIONS; DIFFUSION; STENOSIS; OUTCOMES AB Medicare began covering the use of carotid stents to treat arterial blockages in 2005 under an innovative policy requiring hospitals to meet quality-of-care benchmarks before seeking reimbursement. By restricting carotid stent provision to a smaller subset of US hospitals than those typically adopting new cardiovascular technologies, this policy could have disproportionately reduced the availability of this technology for minority, low-income, and rural patients. Such patients are often served by hospitals less able than others to meet increasingly stringent quality requirements. However, our analysis of hospitals that provided stents during 2005-07 demonstrated that although 21-38 percent fewer hospitals offered stents than offered other types of interventional cardiovascular procedures, such as heart bypass grafts, stents were no less available in localities with substantial poor, black, or rural populations than they were in other areas. Our study provides important evidence that the carotid stent coverage policy met its goal of limiting the adoption of the technology by hospitals that weren't well prepared to provide it-while still maintaining equitable availability of the technology. Therefore, it may be a useful model for future Medicare coverage decisions. C1 [Groeneveld, Peter W.; Epstein, Andrew J.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Yang, Feifei; Yang, Lin] Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Polsky, Daniel] Penns Wharton Sch, Philadelphia, PA USA. [Polsky, Daniel] Whartons Leonard Davis Inst Hlth Econ, Philadelphia, PA USA. RP Groeneveld, PW (reprint author), Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. EM petergro@mail.med.upenn.edu FU AHRQ HHS [R01 HS018403, 1R01HS018403]; NHLBI NIH HHS [R01 HL086919, R01 HL086919-03, 1R01HL086919] NR 36 TC 6 Z9 6 U1 0 U2 1 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD FEB PY 2011 VL 30 IS 2 BP 312 EP 321 DI 10.1377/hlthaff.2010.0320 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 715KR UT WOS:000286883900016 PM 21289353 ER PT J AU Jones, SM Robertson, NG Given, S Giersch, ABS Liberman, MC Morton, CC AF Jones, Sherri M. Robertson, Nahid G. Given, Shelly Giersch, Anne B. S. Liberman, M. Charles Morton, Cynthia C. TI Hearing and vestibular deficits in the Coch(-/-) null mouse model: Comparison to the Coch(G88E/G88E) mouse and to DFNA9 hearing and balance disorder SO HEARING RESEARCH LA English DT Article ID COCH GENE; MENIERES-DISEASE; VWFA2 DOMAIN; MUTATION; MICE; DYSFUNCTION; DEAFNESS; INHERITANCE; POTENTIALS; FAMILIES AB Two mouse models, the Coch(G88E/G88E) or "knock-in" and the Coch(-/-) or "knock-out" (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch(-/-) and Coch(G88E/G88E) mouse models. Both Coch(-/-) and Coch(G88E/G88E) mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch(-/-) mice and 4 of 8 Coch(G88E/G88E) mice have absent ABRs. Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch(-/-) mice at 13 and 21 months, the two ages tested, and as early as seven months in the coch(G88E/G88E) mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies. (C) 2010 Elsevier B.V. All rights reserved. C1 [Jones, Sherri M.] E Carolina Univ, Dept Commun Sci & Disorders, Greenville, NC USA. [Robertson, Nahid G.; Morton, Cynthia C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Given, Shelly] E Carolina Univ, Brody Sch Med, Greenville, NC USA. [Giersch, Anne B. S.; Morton, Cynthia C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Liberman, M. Charles] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol,Eaton Peabody Lab, Boston, MA 02115 USA. RP Morton, CC (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Ob Gyn, 77 Ave Louis Pasteur,NRB 160, Boston, MA 02115 USA. EM cmorton@partners.org FU National Institutes of Health [R01 DC006443, R01 DC03402, R01 DC00188, P30 DC05209] FX The authors would like to thank T. Lever, K. Mills, and J. Pierce for assistance with data collection and tissue preparation. This research was supported by the National Institutes of Health (R01 DC006443 to S.M.J., R01 DC03402 to C.C.M., and R01 DC00188 and P30 DC05209 to M.C.L.). NR 32 TC 14 Z9 14 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD FEB PY 2011 VL 272 IS 1-2 BP 42 EP 48 DI 10.1016/j.heares.2010.11.002 PG 7 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 735ME UT WOS:000288418100006 PM 21073934 ER PT J AU Zhu, AX Hezel, AF AF Zhu, Andrew X. Hezel, Aram F. TI Development of Molecularly Targeted Therapies in Biliary Tract Cancers: Reassessing the Challenges and Opportunities SO HEPATOLOGY LA English DT Review ID GROWTH-FACTOR-RECEPTOR; INTRAHEPATIC CHOLANGIOCELLULAR CARCINOMA; ACTIVATED PROTEIN-KINASE; CELL LUNG-CANCER; K-RAS MUTATION; GALLBLADDER CARCINOMA; BETA-CATENIN; BILE-DUCT; MICROSATELLITE INSTABILITY; HEPATOCELLULAR-CARCINOMA AB Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are a genetically diverse collection of cancers. Most patients with BTC will present with unresectable or metastatic disease. Although the standard systemic chemotherapy approaches are emerging, the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. Recent early-stage clinical trials with targeted therapies appear promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here we summarize the relevant molecular pathogenesis, recent and ongoing clinical trials with targeted agents, and the key issues in clinical trial design in BTC. (HEPATOLOGY 2011;53:695-704) C1 [Zhu, Andrew X.] Harvard Univ, Ctr Canc, Tucker Gosnell Ctr Gastrointestinal Canc, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Hezel, Aram F.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY USA. RP Zhu, AX (reprint author), Harvard Univ, Ctr Canc, Tucker Gosnell Ctr Gastrointestinal Canc, Massachusetts Gen Hosp,Med Sch, 55 Fruit St, Boston, MA 02114 USA. EM azhu@partners.org FU Augen FX Dr. Zhu advises Novartis, Pfizer, and Bayer. Dr. Hezel serves on the speaker's bureau of Augen and Bayer and receives grants from Augen. NR 80 TC 38 Z9 39 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2011 VL 53 IS 2 BP 695 EP 704 DI 10.1002/hep.24145 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 715BO UT WOS:000286855600036 PM 21274890 ER PT J AU Hsu, HE Rydzak, CE Cotich, KL Wang, B Sax, PE Losina, E Freedberg, KA Goldie, SJ Lu, Z Walensky, RP AF Hsu, H. E. Rydzak, C. E. Cotich, K. L. Wang, B. Sax, P. E. Losina, E. Freedberg, K. A. Goldie, S. J. Lu, Z. Walensky, R. P. CA CEPAC Investigators TI Quantifying the risks and benefits of efavirenz use in HIV-infected women of childbearing age in the USA SO HIV MEDICINE LA English DT Article DE efavirenz; HIV/AIDS; teratogenicity; women ID HUMAN-IMMUNODEFICIENCY-VIRUS; PNEUMOCYSTIS-CARINII-PNEUMONIA; ACTIVE ANTIRETROVIRAL THERAPY; AVIUM COMPLEX INFECTION; MULTIPLE VIROLOGICAL FAILURES; PRIMARY PROPHYLAXIS; RANDOMIZED-TRIAL; AEROSOLIZED PENTAMIDINE; HIV-1-INFECTED PATIENTS; COST-EFFECTIVENESS AB Objectives The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz-related teratogenicity) associated with using efavirenz in HIV-infected women of childbearing age in the USA. Methods We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz-based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor-based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100 000 women, we incorporated literature-based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women. Results Survival for HIV-infected women who received an efavirenz-based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non-efavirenz-based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100 000 exposed women, compared with 72.46/100 000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS-related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz-exposed women. Conclusions Use of non-efavirenz-based initial ART in HIV-infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision-making regarding efavirenz use presents a trade-off between these two risks; this study can inform discussions between patients and health care providers. C1 [Hsu, H. E.; Wang, B.; Losina, E.; Freedberg, K. A.; Lu, Z.; Walensky, R. P.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Hsu, H. E.; Rydzak, C. E.; Freedberg, K. A.; Walensky, R. P.] Harvard Univ, Sch Med, Boston, MA USA. [Rydzak, C. E.; Cotich, K. L.; Freedberg, K. A.; Goldie, S. J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Sax, P. E.; Walensky, R. P.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Losina, E.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Losina, E.; Freedberg, K. A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, E.; Freedberg, K. A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, K. A.; Walensky, R. P.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X; Lipsitch, Marc/0000-0003-1504-9213 FU National Institute of Allergy and Infectious Diseases [K24AI062476, R37AI42006]; National Cancer Institute; National Institute on Drug Abuse [U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993, U01-AI-42590]; National Institute of Child Health and Human Development [U01-HD-32632]; National Center for Research Resources [M01-RR-00071, M01-RR-00079, M01-RR-00083] FX This research was supported in part by the National Institute of Allergy and Infectious Diseases (grants K24AI062476 and R37AI42006). Data in this manuscript were collected by the Women's Interagency HIV Study at the following centres: New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Analysis Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute, and the National Institute on Drug Abuse (grants U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-AI-34989, U01-AI-34993 and U01-AI-42590). Funding is also provided by the National Institute of Child Health and Human Development (U01-HD-32632) and the National Center for Research Resources (M01-RR-00071, M01-RR-00079 and M01-RR-00083). NR 54 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-2662 J9 HIV MED JI HIV Med. PD FEB PY 2011 VL 12 IS 2 BP 97 EP 108 DI 10.1111/j.1468-1293.2010.00856.x PG 12 WC Infectious Diseases SC Infectious Diseases GA 700PH UT WOS:000285755900004 PM 20561082 ER PT J AU Wahab, F Ullah, F Chan, YM Seminara, SB Shahab, M AF Wahab, F. Ullah, F. Chan, Y. -M. Seminara, S. B. Shahab, M. TI Decrease in Hypothalamic Kiss1 and Kiss1r Expression: A Potential Mechanism for Fasting-induced Suppression of the HPG Axis in the Adult Male Rhesus Monkey (Macaca mulatta) SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE fasting; HPG axis; GnRH1; Kiss1; Kiss1r; testosterone; monkey ID LUTEINIZING-HORMONE SECRETION; PROTEIN-COUPLED RECEPTOR; STRESS-INDUCED SUPPRESSION; MESSENGER-RNA EXPRESSION; PITUITARY-GONADAL AXIS; FEMALE RAT; GONADOTROPIN-SECRETION; FOOD RESTRICTION; GENE-EXPRESSION; DOWN-REGULATION AB Fasting suppresses functioning of the hypothalamic-pituitary-gonadal (HPG) axis by mechanisms that are incompletely understood. In 2003, hypothalamic kisspeptin-Kiss1r signaling was discovered to play a significant role in regulating the HPG axis. We have recently shown that in adult male macaques, short-term fasting attenuates the response of the HPG axis to an exogenous kisspeptin challenge. In the present study, we explored the mechanism underlying this attenuated response by examining the modulation of the hypothalamic expression of Kiss1 and Kiss1r under short-term fasting and normal feeding conditions in the adult male macaques. Hypothalamic mRNA was extracted from normal fed (n = 3) and 48-h fasted (n = 3) monkeys. Kiss1, Kiss1r, and GnRH1 mRNA were quantified by reverse transcription followed by real-time polymerase chain reaction. In addition, blood samples were collected for measurement of plasma concentrations of glucose, cortisol, leptin, and testosterone. In contrast to fed animals, plasma glucose, leptin, and testosterone levels decreased and cortisol levels increased in fasted animals. The hypothalamic expression of Kiss1 and Kiss1r mRNA was significantly lower (p < 0.05) in fasted monkeys compared to fed monkeys while hypothalamic GnRH1 mRNA expression was comparable between the 2 groups. Thus, our results demonstrate that expression of hypothalamic Kiss1 and Kiss1r decrease after a short-term fasting in monkeys. This decrease may contribute to the suppression of the HPG axis during fasting conditions in primates. In addition, our finding of lower expression of Kiss1r in fasted monkeys provides an explanation for the attenuation in the HPG axis response to peripheral kisspeptin challenge during short-term fasting. C1 [Wahab, F.; Ullah, F.; Shahab, M.] Quaid I Azam Univ, Fac Biol Sci, Dept Anim Sci, Reprod Neuroendocrinol Lab, Islamabad, Pakistan. [Wahab, F.; Chan, Y. -M.; Seminara, S. B.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Wahab, F.; Chan, Y. -M.; Seminara, S. B.] Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. RP Shahab, M (reprint author), Quaid I Azam Univ, Fac Biol Sci, Dept Anim Sci, Reprod Neuroendocrinol Lab, Islamabad, Pakistan. EM Shahab@qau.edu.pk RI Shahab, Muhammad/F-9132-2015; Wahab, Fazal/G-2478-2012 FU Higher Education Commission (HEC) of Pakistan; NICHD/NIH SCCPRR [U54 5U54HD028138] FX The work presented here was funded by IRSIP program of Higher Education Commission (HEC) of Pakistan and NICHD/NIH SCCPRR grant [U54 5U54HD028138]. F. W. is an indigenous Ph.D. fellow of HEC. NR 43 TC 27 Z9 27 U1 0 U2 7 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD FEB PY 2011 VL 43 IS 2 BP 81 EP 85 DI 10.1055/s-0030-1269852 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 715HT UT WOS:000286874700002 PM 21154197 ER PT J AU Won, J de Evsikova, CM Smith, RS Hicks, WL Edwards, MM Longo-Guess, C Li, TS Naggert, JK Nishina, PM AF Won, Jungyeon de Evsikova, Caralina Marin Smith, Richard S. Hicks, Wanda L. Edwards, Malia M. Longo-Guess, Chantal Li, Tiansen Naggert, Juergen K. Nishina, Patsy M. TI NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development SO HUMAN MOLECULAR GENETICS LA English DT Article ID PIGMENTOSA GTPASE REGULATOR; CYSTIC KIDNEY-DISEASE; BARDET-BIEDL-SYNDROME; RETINAL DEGENERATION; MOUSE MODEL; CAENORHABDITIS-ELEGANS; JOUBERT-SYNDROME; ALSTROM-SYNDROME; MECKEL-SYNDROME; CAUSE OBESITY AB Nephronophthisis (NPHP) is an autosomal recessive kidney disease that is often associated with vision and/or brain defects. To date, 11 genes are known to cause NPHP. The gene products, while structurally unrelated, all localize to cilia or centrosomes. Although mouse models of NPHP are available for 9 of the 11 genes, none has been described for nephronophthisis 4 (Nphp4). Here we report a novel, chemically induced mutant, nmf192, that bears a nonsense mutation in exon 4 of Nphp4. Homozygous mutant Nphp4(nmf192/nmf192) mice do not exhibit renal defects, phenotypes observed in human patients bearing mutations in NPHP4, but they do develop severe photoreceptor degeneration and extinguished rod and cone ERG responses by 9 weeks of age. Photoreceptor outer segments (OS) fail to develop properly, and some OS markers mislocalize to the inner segments and outer nuclear layer in the Nphp4(nmf192/nmf192) mutant retina. Despite NPHP4 localization to the transition zone in the connecting cilia (CC), the CC appear to be normal in structure and ciliary transport function is partially retained. Likewise, synaptic ribbons develop normally but then rapidly degenerate by P14. Finally, Nphp4(nmf192/nmf192) male mutants are sterile and show reduced sperm motility and epididymal sperm counts. Although Nphp4(nmf192/nmf192) mice fail to recapitulate the kidney phenotype of NPHP, they will provide a valuable tool to further elucidate how NPHP4 functions in the retina and male reproductive organs. C1 [Won, Jungyeon; de Evsikova, Caralina Marin; Smith, Richard S.; Hicks, Wanda L.; Edwards, Malia M.; Longo-Guess, Chantal; Naggert, Juergen K.; Nishina, Patsy M.] Jackson Lab, Bar Harbor, ME 04609 USA. [Li, Tiansen] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Nishina, PM (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM patsy.nishina@jax.org RI Marin de Evsikova, Caralina/G-8189-2012 FU National Institutes of Health [EY016501, AA017244]; TJL institutional core grant [CA34196]; Foundation for Fighting Blindness FX This study was supported by National Institutes of Health grants (EY016501 to P.M.N., AA017244 to C.M.); a TJL institutional core grant (CA34196) and the Foundation for Fighting Blindness. NR 53 TC 30 Z9 30 U1 2 U2 7 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 FEB PY 2011 VL 20 IS 3 BP 482 EP 496 DI 10.1093/hmg/ddq494 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 703UH UT WOS:000286006300008 PM 21078623 ER PT J AU Kahle, JJ Gulbahce, N Shaw, CA Lim, J Hill, DE Barabasi, AL Zoghbi, HY AF Kahle, Juliette J. Gulbahce, Natali Shaw, Chad A. Lim, Janghoo Hill, David E. Barabasi, Albert-Laszlo Zoghbi, Huda Y. TI Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROTEIN INTERACTION NETWORK; DOMINANT CEREBELLAR-ATAXIA; CONE-ROD DYSTROPHY; AREOLAR CHOROIDAL DYSTROPHY; PURKINJE-CELL DEGENERATION; OPTIC DISK ANOMALIES; EXPRESSION ANALYSIS; RETINAL DYSTROPHY; REPEAT EXPANSION; CALCIUM-CHANNEL AB Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 x 10(-5)) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7(266Q/+) mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia. C1 [Kahle, Juliette J.; Shaw, Chad A.; Lim, Janghoo; Zoghbi, Huda Y.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Zoghbi, Huda Y.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Zoghbi, Huda Y.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Zoghbi, Huda Y.] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. [Gulbahce, Natali; Hill, David E.; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, CCSB, Boston, MA 02115 USA. [Gulbahce, Natali] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Gulbahce, Natali] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Univ Notre Dame, Ctr Complex Network Res, Notre Dame, IN 46556 USA. [Barabasi, Albert-Laszlo] Univ Notre Dame, Dept Phys, Notre Dame, IN 46556 USA. RP Zoghbi, HY (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza, Houston, TX 77030 USA. EM hzoghbi@bcm.tmc.edu RI Hill, David/B-6617-2011; OI Shaw, Chad/0000-0001-7267-5398 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development [P30HD024064]; Ellison Foundation; National Eye Institute [T32 EY07102]; Howard Hughes Medical Institute FX This work was supported by Award Number P30HD024064 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (to H.Y.Z.) and by the Ellison Foundation (to DFCI CCSB, M Vidal, Director). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health. J.J.K. was supported by a training grant from the National Eye Institute (T32 EY07102), and the research on SCA6 was supported by a generous gift from a foundation that asked that its identity not be disclosed (to H.Y.Z.). H.Y.Z. is an investigator with the Howard Hughes Medical Institute. Funding to pay the Open Access publication charges for this article was provided by Howard Hughes Medical Institute. NR 125 TC 23 Z9 24 U1 0 U2 7 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 FEB PY 2011 VL 20 IS 3 BP 510 EP 527 DI 10.1093/hmg/ddq496 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 703UH UT WOS:000286006300010 PM 21078624 ER PT J AU Groom, JR Luster, AD AF Groom, Joanna R. Luster, Andrew D. TI CXCR3 ligands: redundant, collaborative and antagonistic functions SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE CXCR3; CXCL9; CXCL10; chemokines; T-cell trafficking ID CHEMOKINE RECEPTOR CXCR3; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GAMMA-INDUCIBLE PROTEIN; T-CELL RECRUITMENT; CENTRAL-NERVOUS-SYSTEM; CHRONIC HEPATITIS-C; CARDIAC ALLOGRAFT-REJECTION; MURINE CEREBRAL MALARIA; NECROSIS-FACTOR-ALPHA; IFN-GAMMA AB CXCR3 is a chemokine receptor that is rapidly induced on naive T cells following activation, and preferentially remains highly expressed on type-1 helper (Th1)-type CD4(+) T cells, effector CD8(+) T cells and innate-type lymphocytes, such as natural killer (NK) and NKT cells. CXCR3 is activated by three interferon (IFN)-gamma-inducible ligands CXCL9 (monokine induced by gamma-interferon), CXCL10 (interferon-induced protein-10) and CXCL11 (interferon-inducible T-cell alpha chemoattractant). Although some studies have revealed that these ligands have redundant functions in vivo, other studies have demonstrated that the three CXCR3 ligands can also collaborate and even compete with each other. Differential regulation of the three ligands at specific times in defined anatomically restricted locations in vivo likely participates in the fine control of T-cell trafficking over the course of an immune response. Among the differences in regulation, CXCL10 is induced by a variety of innate stimuli that induce IFN-alpha/beta as well as the adaptive immune cell cytokine IFN-gamma, whereas CXCL9 induction is restricted to IFN-gamma. In this review, we will discuss how the balance, timing and pattern of CXCR3 ligand expression appears to regulate the generation of effector T cells in the lymphoid compartment and subsequent migration into peripheral sites of Th1-type inflammation in which the CXCR3 ligands also then regulate the interactions and migratory behavior of effector T cells in an inflamed peripheral tissue. Immunology and Cell Biology (2011) 89, 207-215; doi:10.1038/icb.2010.158; published online 11 January 2011 C1 [Groom, Joanna R.; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02129 USA. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02129 USA. EM aluster@mgh.harvard.edu FU NHMRC; Overseas Biomedical Based Fellowship; NIH [CA69212] FX JRG was supported by NH&MRC and Overseas Biomedical Based Fellowship and ADL was supported by NIH Grant CA69212. NR 174 TC 267 Z9 275 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD FEB PY 2011 VL 89 IS 2 BP 207 EP 215 DI 10.1038/icb.2010.158 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 722OY UT WOS:000287445400009 PM 21221121 ER PT J AU Lin, XP Han, XZ Kawai, T Taubman, MA AF Lin, Xiaoping Han, Xiaozhe Kawai, Toshihisa Taubman, Martin A. TI Antibody to Receptor Activator of NF-kappa B Ligand Ameliorates T Cell-Mediated Periodontal Bone Resorption SO INFECTION AND IMMUNITY LA English DT Article ID ACTINOMYCETEMCOMITANS SEROTYPE B; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; POSTMENOPAUSAL WOMEN; IMMUNE-RESPONSE; PORPHYROMONAS-GINGIVALIS; MINERAL DENSITY; HOST RESPONSES; DISEASE; LYMPHOCYTE; DENOSUMAB AB Activated T and B lymphocytes in periodontal disease lesions express receptor activator of NF-kappa B ligand (RANKL), which induces osteoclastic bone resorption. The objective of this study was to evaluate the effects of anti-RANKL antibody on periodontal bone resorption in vitro and in vivo. Aggregatibacter actinomycetemcomitans outer membrane protein 29 (Omp29) and A. actinomycetemcomitans lipopolysaccharide (LPS) were injected into 3 palatal gingival sites, and Omp29-specific T clone cells were transferred into the tail veins of rats. Rabbit anti-RANKL IgG antibody or F(ab')(2) antibody fragments thereof were injected into the palatal sites in each rat (days -1, 1, and 3). Anti-RANKL IgG antibody significantly inhibited soluble RANKL (sRANKL)-induced osteoclastogenesis in vitro, in a dose-dependent manner, but also gave rise to a rat antibody response to rabbit IgG in vivo, with no significant inhibition of periodontal bone resorption detected. Lower doses (1.5 and 0.15 mu g/3 sites) of F(ab')(2) antibody were not immunogenic in the context of the experimental model. Periodontal bone resorption was inhibited significantly by injection of the anti-RANKL F(ab')(2) antibody into gingivae. The sRANKL concentrations for the antibody-treated groups were decreased significantly compared to those for the untreated group. Osteoclasts on the alveolar bone surface were also diminished significantly after antibody injection. Gingival sRANKL concentration and bone loss showed a significant correlation with one another in animals receiving anti-RANKL F(ab')(2) antibody. These results suggest that antibody to RANKL can inhibit A. actinomycetemcomitans-specific T cell-induced periodontal bone resorption by blockade and reduction of tissue sRANKL, providing an immunological approach to ameliorate immune cell-mediated periodontal bone resorption. C1 [Lin, Xiaoping; Han, Xiaozhe; Kawai, Toshihisa; Taubman, Martin A.] Forsyth Inst, Dept Immunol, Cambridge, MA 02142 USA. [Lin, Xiaoping] China Med Univ, Shengjing Hosp, Dept Stomatol, Shenyang 110004, Liaoning Prov, Peoples R China. RP Han, XZ (reprint author), Forsyth Inst, Dept Immunol, 245 1st St, Cambridge, MA 02142 USA. EM xhan@forsyth.org FU National Institute of Dental and Craniofacial Research [DE-03420, DE-07327, DE-018499, DE-19917] FX This work was supported by NIH grants DE-03420, DE-07327, DE-018499, and DE-19917 from the National Institute of Dental and Craniofacial Research. NR 34 TC 23 Z9 29 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2011 VL 79 IS 2 BP 911 EP 917 DI 10.1128/IAI.00944-10 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 709SP UT WOS:000286462000038 PM 21078845 ER PT J AU Ramasamy, S Nguyen, DD Eston, MA Alam, SN Moss, AK Ebrahimi, F Biswas, B Mostafa, G Chen, KT Kaliannan, K Yammine, H Narisawa, S Millan, JL Warren, HS Hohmann, EL Mizoguchi, E Reinecker, HC Bhan, AK Snapper, SB Malo, MS Hodin, RA AF Ramasamy, Sundaram Nguyen, Deanna D. Eston, Michelle A. Alam, Sayeda Nasrin Moss, Angela K. Ebrahimi, Farzad Biswas, Brishti Mostafa, Golam Chen, Kathryn T. Kaliannan, Kanakaraju Yammine, Halim Narisawa, Sonoko Millan, Jose Luis Warren, H. Shaw Hohmann, Elizabeth L. Mizoguchi, Emiko Reinecker, Hans-Christian Bhan, Atul K. Snapper, Scott B. Malo, Madhu S. Hodin, Richard A. TI Intestinal Alkaline Phosphatase Has Beneficial Effects in Mouse Models of Chronic Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE DSS-induced chronic colitis; WASP-KO; spontaneous chronic colitis; inflammatory bowel disease; gut mucosal defense; lipopolysaccharides ID WISKOTT-ALDRICH-SYNDROME; INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; SYNDROME PROTEIN; DEXTRAN SULFATE; MURINE DSS; IN-VITRO; MICE; WASP; DEFICIENT AB Background: The brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation. Methods: The wildtype (WT) and TAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation. Results: Microscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52 +/- 3.8 versus 28.8 +/- 6.6, respectively, P < 0.0001). cIAP treatment attenuated the disease in both groups (KO = 30.7 +/- 6.01, WT = 18.7 +/- 5.0, P < 0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3 +/- 0.52 versus 6.2 +/- 0.34, respectively, P < 0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment. Conclusions: Endogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD. C1 [Ramasamy, Sundaram; Alam, Sayeda Nasrin; Moss, Angela K.; Ebrahimi, Farzad; Biswas, Brishti; Mostafa, Golam; Chen, Kathryn T.; Kaliannan, Kanakaraju; Yammine, Halim; Malo, Madhu S.; Hodin, Richard A.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med, Boston, MA 02114 USA. [Nguyen, Deanna D.; Eston, Michelle A.; Mizoguchi, Emiko; Reinecker, Hans-Christian; Snapper, Scott B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Nguyen, Deanna D.; Eston, Michelle A.; Mizoguchi, Emiko; Reinecker, Hans-Christian; Bhan, Atul K.; Snapper, Scott B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Narisawa, Sonoko; Millan, Jose Luis] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. [Warren, H. Shaw] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat,Infect Dis Unit, Boston, MA 02114 USA. [Hohmann, Elizabeth L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Infect Dis Div, Boston, MA 02114 USA. [Bhan, Atul K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Malo, MS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med, Jackson 812,55 Fruit St, Boston, MA 02114 USA. EM mmalo@partners.org RI kaliannan, kanakaraju/P-9094-2014; OI Kuhnen, Angela/0000-0003-4944-9143 FU National Institutes of Health (NIH) [R01DK050623, R01DK047186, RO1AI50950, K08DK083430]; Crohn's and Colitis Foundation of America [2193]; MGH Department of Surgery; Bill and Melinda Gates Foundation FX Supported by National Institutes of Health (NIH) grants R01DK050623, R01DK047186 (to R.A.H.), RO1AI50950 (to S.B.S.), K08DK083430 (to D.D.N.); Crohn's and Colitis Foundation of America Career Development Award 2193 (to D.D.N.); Junior Faculty Award from the MGH Department of Surgery (to M.S.M.); Grand Challenge Exploration Grant from the Bill and Melinda Gates Foundation (to M.S.M.). NR 44 TC 33 Z9 35 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2011 VL 17 IS 2 BP 532 EP 542 DI 10.1002/ibd.21377 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 718JF UT WOS:000287116500005 PM 20645323 ER PT J AU Lopez-Posadas, R Gonzalez, R Ballester, I Martinez-Moya, P Romero-Calvo, I Suarez, MD Zarzuelo, A Martinez-Augustin, O de Medina, FS AF Lopez-Posadas, Rocio Gonzalez, Raquel Ballester, Isabel Martinez-Moya, Patricia Romero-Calvo, Isabel Dolores Suarez, Maria Zarzuelo, Antonio Martinez-Augustin, Olga Sanchez de Medina, Fermin TI Tissue-nonspecific Alkaline Phosphatase Is Activated in Enterocytes by Oxidative Stress Via Changes in Glycosylation SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE alkaline phosphatase; oxidative stress; inflammatory bowel disease; glycosylation ID EPITHELIAL-CELL LINE; INDUCED RAT COLITIS; MESSENGER-RNA; SINGLE-GENE; IN-VIVO; LIVER; KIDNEY; BONE; EXPRESSION; SERUM AB Background: Intestinal inflammation produces an induction of alkaline phosphatase (AP) activity that is attributable in part to augmented expression, accompanied by a change in isoform, in epithelial cells. Methods: This study focuses on induction of AP in intestinal epithelial cells in vitro. Results: Treatment with the oxidants H(2)O(2), monochloramine, or tButOOH increases AP activity in vitro in Caco-2, HT29, and IEC18 cells. We selected IEC18 cells for further testing. Basal AP activity in IEC18 cells is of the tissue-nonspecific (bone-liver-kidney) type, as indicated by Northern and Western blot analysis. Oxidative stress augments AP activity and the sensitivity of the enzyme to levamisole, homoarginine, and heat in IEC18 cells. Increased immunoreactivity to tissue-nonspecific AP antibodies suggests an isoform shift from liver to either kidney or bone type. This effect occurs without changes at the mRNA level and is sensitive to tunicamycin, an inhibitor of N-glycosylation, and neuraminidase digestion. Saponin and deoxycholate produce similar effects to oxidants. Butyrate but not proinflammatory cytokines or LPS can induce a similar effect but without toxicity. The AP increase is not prevented by modulators of the MAPK, NF-kappa B, calcium, and cyclic adenosine monophosphate (cAMP) pathways, and is actually enhanced by actinomycin D via higher cell stress. Conclusions: Oxidative stress causes a distinct increase in enterocyte AP activity together with cell toxicity via changes in the glycosylation of the enzyme that correspond to a shift in isotype within the tissue-nonspecific paradigm. We speculate that this may have physiological implication for gut defense. C1 [Lopez-Posadas, Rocio; Gonzalez, Raquel; Romero-Calvo, Isabel; Zarzuelo, Antonio; Sanchez de Medina, Fermin] Univ Granada, Sch Pharm, Dept Pharmacol, Ctr Invest Biomed Red Enfermedades Hepat & Digest, E-18071 Granada, Spain. [Ballester, Isabel] Massachusetts Gen Hosp, Gastrointestinal Unit GRJ716, Boston, MA 02114 USA. [Martinez-Moya, Patricia; Dolores Suarez, Maria; Martinez-Augustin, Olga] Univ Granada, Sch Pharm, Dept Biochem & Mol Biol, Ctr Invest Biomed Red Enfermedades Hepat & Digest, E-18071 Granada, Spain. RP de Medina, FS (reprint author), Univ Granada, Sch Pharm, Dept Pharmacol, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Campus Cartuja S-N, E-18071 Granada, Spain. EM fsanchez@ugr.es RI Zarzuelo, Antonio/L-2840-2014; Lorente, M Dolores/N-1313-2014; Suarez Ortega, Maria Dolores/H-1240-2015; Martinez Augustin, Olga/K-6720-2014; OI Suarez Ortega, Maria Dolores/0000-0003-3197-2518; Martinez Augustin, Olga/0000-0001-8291-3468; Romero Calvo, Isabel/0000-0003-2868-1568; Sanchez de Medina, Fermin/0000-0002-4516-5824 FU Instituto de Investigacion Carlos III [PI051651, PI051625]; Ministerio de Ciencia e Innovacion [SAF2008-01432, AGL2008-04332]; CIBERehd; Instituto de Salud Carlos III FX Supported by the Instituto de Investigacion Carlos III (PI051651 and PI051625) and the Ministerio de Ciencia e Innovacion (SAF2008-01432 and AGL2008-04332). R.L.P., I.B., P.M.M., and I.R.C. are funded by Ministerio de Ciencia e Innovacion. RG is funded by CIBERehd. CIBERehd is funded by the Instituto de Salud Carlos III. NR 57 TC 21 Z9 21 U1 0 U2 9 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2011 VL 17 IS 2 BP 543 EP 556 DI 10.1002/ibd.21381 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 718JF UT WOS:000287116500006 PM 20645320 ER PT J AU Baumgart, DC Bernstein, CN Abbas, Z Colombel, JF Day, AS D'Haens, G Dotan, I Goh, KL Hibi, T Kozarek, RA Quigley, EMM Reinisch, W Sands, BE Sollano, JD Steinhart, H Steinwurz, F Vatn, MH Yamamoto-Furusho, JK AF Baumgart, Daniel C. Bernstein, Charles N. Abbas, Zaigham Colombel, Jean F. Day, Andrew S. D'Haens, Geert Dotan, Iris Goh, Khean L. Hibi, Toshifumi Kozarek, Richard A. Quigley, Eamonn M. M. Reinisch, Walter Sands, Bruce E. Sollano, Jose D. Steinhart, Hillary Steinwurz, Flavio Vatn, Morten H. Yamamoto-Furusho, Jesus K. TI IBD Around the world: Comparing the epidemiology, diagnosis, and treatment: Proceedings of the World Digestive Health Day 2010 - Inflammatory bowel disease task force meeting SO INFLAMMATORY BOWEL DISEASES LA English DT Article; Proceedings Paper CT WGO Task Force meeting CY MAY, 2010 CL New Orleans, LA AB Every May 29th the World Gastroenterology Organization (WGO) celebrates World Digestive Health Day (WDHD) and initiates a worldwide public health campaign through its 110 national societies and 50,000 members. Each year focuses on a particular digestive disorder in order to increase general public awareness of prevention and therapy. 2010 is dedicated to inflammatory bowel disease (IBD). Upon this occasion a WGO IBD task force was compiled from leading international specialists and researchers. The task force also included members of the American Gastroenterological Association (AGA), International Organization for the Study of Inflammatory Diseases (IOIBD) and the European Crohn's and Colitis Organization (ECCO) of the United European Gastroenterology Federation (UEGF). The goal of the task force was to bring together IBD specialists from around the world to discuss the epidemiology, diagnosis, and management of IBD within different regions. This is a summary of the WGO task force meeting at the American Gastroenterological Association's (AGA) Digestive Disease Week, held in New Orleans, Louisiana, USA, May, 2010. The expert panel identified the most pressing issues in IBD worldwide: reliable epidemiological data, global collaboration in clinical and basic research, the approach to distinguishing intestinal tuberculosis from Crohn's disease, access to specialist care and access to the latest diagnostic and therapeutic strategies. C1 [Baumgart, Daniel C.] Humboldt Univ, Virchow Hosp, Charite Med Sch, D-13344 Berlin, Germany. [Bernstein, Charles N.] Univ Manitoba, Winnipeg, MB, Canada. [Abbas, Zaigham] Sindh Inst Urol & Transplantat, Karachi, Pakistan. [Colombel, Jean F.] Univ Otago, Christchurch, New Zealand. [Day, Andrew S.] Univ Lille, Lille, France. [D'Haens, Geert] Imelda Clin Res Ctr, Bonheiden, Belgium. [Dotan, Iris] Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. [Goh, Khean L.] Univ Malaya, Kuala Lumpur, Malaysia. [Hibi, Toshifumi] Keio Univ, Sch Med, Tokyo, Japan. [Kozarek, Richard A.] Virginia Mason Med Ctr, Seattle, WA USA. [Quigley, Eamonn M. M.] Natl Univ Ireland, Cork, Ireland. [Reinisch, Walter] Med Univ, Vienna, Austria. [Sands, Bruce E.] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA USA. [Sollano, Jose D.] Univ Santo Tomas, Manila, Philippines. [Steinhart, Hillary] Mt Sinai Hosp, Toronto, ON, Canada. [Steinwurz, Flavio] Hosp Israelita Albert Einstein, Sao Paulo, Brazil. [Vatn, Morten H.] Univ Oslo, Oslo, Norway. [Yamamoto-Furusho, Jesus K.] Natl Inst Med Sci & Nutr, Mexico City, DF, Mexico. RP Baumgart, DC (reprint author), Humboldt Univ, Virchow Hosp Med Sch, Charite Med Ctr, Div Gastroenterol & Hepatol,Dept Med, D-13344 Berlin, Germany. EM daniel.baumgart@charite.de RI Goh, Khean-Lee/B-6404-2009 FU IOIBD FX The WGO IBD Task Force was supported by a grant from the IOIBD. NR 0 TC 37 Z9 41 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD FEB PY 2011 VL 17 IS 2 BP 639 EP 644 DI 10.1002/ibd.21409 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 718JF UT WOS:000287116500028 PM 20725944 ER PT J AU Finfer, S Ranieri, VM Thompson, BT Barie, PS Dhainaut, JF Douglas, IS Gardlund, B Marshall, JC Rhodes, A AF Finfer, Simon Ranieri, V. Marco Thompson, B. Taylor Barie, Philip S. Dhainaut, Jean-Francois Douglas, Ivor S. Gardlund, Bengt Marshall, John C. Rhodes, Andrew TI Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock (vol 34, pg 1935, 2008) SO INTENSIVE CARE MEDICINE LA English DT Correction C1 [Finfer, Simon] Univ Sydney, George Inst Int Hlth, Sydney, NSW 2050, Australia. [Ranieri, V. Marco] Univ Turin, Osped S Giovanni Battista Molinette, Turin, Italy. [Thompson, B. Taylor] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Barie, Philip S.] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA. [Dhainaut, Jean-Francois] Paris Descartes Univ, Cochin Port Royal Hosp, Paris, France. [Douglas, Ivor S.] Denver Hlth & Univ Colorado, Denver, CO USA. [Gardlund, Bengt] Karolinska Univ Hosp, Dept Infect Dis, S-14186 Stockholm, Sweden. [Marshall, John C.] St Michaels Hosp, Dept Surg, Toronto, ON M5B 1W8, Canada. [Marshall, John C.] St Michaels Hosp, Dept Crit Care Med, Toronto, ON M5B 1W8, Canada. [Rhodes, Andrew] St George Hosp, Dept Intens Care Med & Anaesthesia, London SW17 0QT, England. RP Finfer, S (reprint author), Univ Sydney, George Inst Int Hlth, POB M201,Missenden Rd, Sydney, NSW 2050, Australia. EM sfinfer@george.org.au NR 1 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD FEB PY 2011 VL 37 IS 2 BP 372 EP 372 DI 10.1007/s00134-010-2081-4 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 712AF UT WOS:000286633500032 ER PT J AU Keszei, M Latchman, YE Vanguri, VK Brown, DR Detre, C Morra, M Arancibia, CV Paul, E Calpe, S Castro, W Wang, NH Terhorst, C Sharpe, AH AF Keszei, Marton Latchman, Yvette E. Vanguri, Vijay K. Brown, Daniel R. Detre, Cynthia Morra, Massimo Arancibia, Carolina V. Paul, Elahna Calpe, Silvia Castro, Wilson Wang, Ninghai Terhorst, Cox Sharpe, Arlene H. TI Auto-antibody production and glomerulonephritis in congenic Slamf1(-/-) and Slamf2(-/-) [B6.129] but not in Slamf1(-/-) and Slamf2(-/-) [BALB/c.129] mice SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE CD48; congenic; lupus; SLAM; SLE ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; T-CELL-ACTIVATION; SUSCEPTIBILITY LOCUS; GENETIC DISSECTION; GENOME SCAN; IN-VIVO; CHROMOSOME-1; LINKAGE; TOLERANCE; ASSOCIATION AB Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9-14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus. C1 [Keszei, Marton] Harvard Univ, Sch Med, Div Immunol, Beth Israel Deaconess Med Ctr,Ctr Life Sci, Boston, MA 02115 USA. [Latchman, Yvette E.; Vanguri, Vijay K.; Brown, Daniel R.; Arancibia, Carolina V.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Paul, Elahna] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Keszei, M (reprint author), Harvard Univ, Sch Med, Div Immunol, Beth Israel Deaconess Med Ctr,Ctr Life Sci, Room CLS 928,3 Blackfan Circle, Boston, MA 02115 USA. EM mkeszei@bidmc.harvard.edu RI Keszei, Marton/F-3295-2014 OI Keszei, Marton/0000-0002-1158-2179 FU National Institutes of Health [AI-065687, T32 HL007627, K08AR057861] FX National Institutes of Health (AI-065687 to C.T., A.H.S. and Y.E.L.; T32 HL007627 to Brigham and Women's Hospital for V.K.V; K08AR057861 to D.B.). NR 26 TC 16 Z9 17 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD FEB PY 2011 VL 23 IS 2 BP 149 EP 158 DI 10.1093/intimm/dxq465 PG 10 WC Immunology SC Immunology GA 716SP UT WOS:000286994100008 PM 21278219 ER PT J AU Dahi, S Karliner, JS Sarkar, R Lovett, DH AF Dahi, Sia Karliner, Joel S. Sarkar, Rajabrata Lovett, David H. TI Transgenic expression of matrix metalloproteinase-2 induces coronary artery ectasia SO INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY LA English DT Article DE aneurysm; coronary artery ectasia; elastin; matrix metalloproteinase-2; transgenic ID ABDOMINAL AORTIC-ANEURYSM; CLINICAL-IMPLICATIONS; VASCULAR-DISEASE; PROMOTER; MATRIX-METALLOPROTEINASE-2; POLYMORPHISMS; INFLAMMATION; DYSFUNCTION; MMP-2 AB P>Coronary artery ectasia (CAE) is generally diagnosed in patients undergoing arteriography for presumptive atherosclerotic coronary artery disease. CAE is commonly considered as a variant of atherosclerotic disease; however, recent studies suggest that CAE is the result of a systemic vascular disorder. There is increasing evidence that aneurysmal vascular disease is a systemic disorder characterized by enhanced expression of pro-inflammatory cytokines and increased synthesis of enzymes capable of degrading elastin and other components of the vascular wall. Matrix metalloproteinase-2 degrades a number of extracellular substrates, including elastin and has been shown to play a critical role in the development of abdominal aortic aneurysms. This study characterizes the development of CAE in a unique murine transgenic model with cardiac-specific expression of active MMP-2. Transgenic mice were engineered to express an active form of MMP-2 under control of the alpha-myosin heavy chain promoter. Coronary artery diameters were quantified, along with studies of arterial structure, elastin integrity and vascular expression of the MMP-2 transgene. Latex casts quantified total coronary artery volumes and arterial branching. Mid-ventricular coronary luminal areas were increased in the MMP-2 transgenics, coupled with foci of aneurysmal dilation, ectasia and perivascular fibrosis. There was no evidence for atherogenesis. Coronary vascular elastin integrity was compromised and coupled with inflammatory cell infiltration. Latex casts of the coronary arteries displayed ectasia with fusiform dilatation. The MMP-2 transgenic closely replicates human CAE and supports a critical and initiating role for this enzyme in the pathogenesis of this disorder. C1 [Dahi, Sia; Sarkar, Rajabrata] Univ Calif San Francisco, Vet Affairs Med Ctr, Dept Surg, San Francisco, CA 94121 USA. [Karliner, Joel S.; Lovett, David H.] Univ Calif San Francisco, Vet Affairs Med Ctr, Dept Med, San Francisco Dept, San Francisco, CA 94121 USA. No Calif Inst Res & Educ, San Francisco, CA USA. RP Lovett, DH (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med 111J, 4150 Clement St, San Francisco, CA 94121 USA. EM david.lovett@va.gov FU National Heart, Lung and Blood Institute [PO-1-HL-68738] FX This work was supported by National Heart, Lung and Blood Institute Grant PO-1-HL-68738 to J. S. Karliner and D. H. Lovett. NR 24 TC 10 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0959-9673 J9 INT J EXP PATHOL JI Int. J. Exp. Pathol. PD FEB PY 2011 VL 92 IS 1 BP 50 EP 56 DI 10.1111/j.1365-2613.2010.00744.x PG 7 WC Pathology SC Pathology GA 712MP UT WOS:000286671200006 PM 21039989 ER PT J AU Deitiker, PR Oshima, M Smith, RG Mosier, D Atassi, MZ AF Deitiker, P. R. Oshima, M. Smith, R. G. Mosier, D. Atassi, M. Z. TI Association with HLA DQ of early onset myasthenia gravis in Southeast Texas region of the United States SO INTERNATIONAL JOURNAL OF IMMUNOGENETICS LA English DT Article ID HIGH-RESOLUTION; ALLELES; DQB1-ASTERISK-0502; IDENTIFICATION; POPULATION; HAPLOTYPES; ANTIBODY; JAPAN AB P>Forty-four Caucasian American myasthenia gravis (MG) patients from Southeast Texas underwent high resolution HLA DQ analysis. For the majority of patients who were late onset or male, no significant associations with DQ were observed. However, associations with DQ increased in female patients and early onset patients. At the allele level, DQB1 *0503, *0604, *0502 and *0402 collectively contributed to a positive association of the DQ locus with early onset MG (EOMG), while individually failing to show significant association. At DQ level, the novel haplotype DQA1*0401:DQB1*0201 was the primary factor in the association of combined DQ loci with early onset. In addition, *0104:*0503, *0102:*0604, *0102:*0502 and *0303:*0402 collectively contributed to the positive association of the haplotype loci. DR3-DQ2.5cis, a well known risk factor for MG in Western Eurasia, was not found associated with disease in any group. For typical EOMG [early onset, no thymoma, anti-acetylcholine receptor (AChR) antibody (Ab) positive] no association with DQA1 locus was found, however DQB1*0604 demonstrated an 'uncorrected' positive association. A few DQ haplotype (DQA1:DQB1) were positively associated with typical EOMG; a positive individual association for *0401:*0201 was complimented by the contributions of *0102:*0604 and *0303:*0402 haplotypes. A small minority of patients that were atypical and EOMG had a strong genetic association with DQA1*0104:DQB1*0503, the group included an anti-MuSK Ab positive and an anti-AChR negative patient. This report finds common ground with European studies regarding MuSK association; however similarities in association for typical early onset disease resembled HLA risk factors in East Asia and Southern Europe. C1 [Deitiker, P. R.; Oshima, M.; Atassi, M. Z.] Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. [Deitiker, P. R.; Oshima, M.; Atassi, M. Z.] Baylor Coll Med, Dept Mol Biol, Houston, TX 77030 USA. [Mosier, D.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Atassi, M. Z.] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. [Smith, R. G.] Univ Texas Med Branch, Dept Neurol, Galveston, TX USA. [Mosier, D.] ME DeBakey VA Med Ctr, Neurol & Med Res Serv, Houston, TX USA. RP Atassi, MZ (reprint author), Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. EM matassi@bcm.edu FU Welch Foundation; Muscular Dystrophy Association FX The work was supported by the Welch Foundation due to the award of the Robert A Welch Chair of Chemistry to MZ Atassi. This study was partly supported by a grant from the Muscular Dystrophy Association. The authors thank Dr. Maki Otani, Gerrit Heetderks, Laura Ouch, Lucy Tea and Masooma Naqvi for their excellent technical assistance. NR 18 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1744-3121 J9 INT J IMMUNOGENET JI Int. J. Immunogenet. PD FEB PY 2011 VL 38 IS 1 BP 55 EP 62 DI 10.1111/j.1744-313X.2010.00979.x PG 8 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 702FV UT WOS:000285880900010 PM 21108743 ER PT J AU West, DS Gorin, AA Subak, LL Foster, G Bragg, C Hecht, J Schembri, M Wing, RR AF West, D. S. Gorin, A. A. Subak, L. L. Foster, G. Bragg, C. Hecht, J. Schembri, M. Wing, R. R. CA Program Reduce Incontinence Diet E TI A motivation-focused weight loss maintenance program is an effective alternative to a skill-based approach SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE weight maintenance; motivation; obesity treatment; autonomy; motivational interviewing ID DIABETES-PREVENTION-PROGRAM; SELF-DETERMINATION THEORY; LIFE-STYLE INTERVENTION; PHYSICAL-ACTIVITY; WOMEN; SATISFACTION; OVERWEIGHT; REDUCTION; GOALS; TRIAL AB Objective: Maintaining weight loss is a major challenge in obesity treatment. Individuals often indicate that waning motivation prompts cessation of effective weight management behaviors. Therefore, a novel weight loss maintenance program that specifically targets motivational factors was evaluated. Design: Overweight women (N = 338; 19% African American) with urinary incontinence were randomized to lifestyle obesity treatment or control and followed for 18 months. All participants in lifestyle (N = 226) received the same initial 6-month group behavioral obesity treatment and were then randomized to (1) a novel motivation-focused maintenance program (N = 113) or (2) a standard skill-based maintenance approach (N - 113). Main Outcome Measure: Weight assessed at baseline, 6 and 18 months. Results: Both treatment groups (motivation-focused and skill-based) achieved comparable 18-month weight losses (-5.48% for motivation-focused vs -5.55% in skill-based, P = 0.98), and both groups lost significantly more than controls (-1.51%; P = 0.0012 in motivation-focused and P = 0.0021 in skill-based). Conclusions: A motivation-focused maintenance program offers an alternative, effective approach to weight maintenance expanding available evidence-based interventions beyond traditional skill-based programs. C1 [West, D. S.] Univ Arkansas Med Sci, Coll Publ Hlth, Little Rock, AR USA. [Gorin, A. A.] Univ Connecticut, Dept Psychol, Storrs, CT USA. [Subak, L. L.; Schembri, M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Subak, L. L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Foster, G.] Temple Univ, Dept Med, Philadelphia, PA 19122 USA. [Foster, G.] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Bragg, C.] Univ Alabama, Dept Prevent Med, Birmingham, AL USA. [Hecht, J.] Miriam Hosp, Providence, RI 02906 USA. [Wing, R. R.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP West, DS (reprint author), Univ Arkansas Med Sci, Dept Hlth Behav & Hlth Educ, Fay W Boozman Coll Publ Hlth, 4301 W Markham St,Mail Slot 820, Little Rock, AR USA. EM WestDelia@uams.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK067860, U01 DK067861, U01 DK067862]; Office of Research on Women's Health FX This research was supported in part by grants U01DK067860, U01 DK067861 and U01 DK067862 from the National Institute of Diabetes and Digestive and Kidney Diseases. Funding was also provided by the Office of Research on Women's Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. See online Supplementary materials for full author acknowledgements. NR 42 TC 45 Z9 46 U1 5 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2011 VL 35 IS 2 BP 259 EP 269 DI 10.1038/ijo.2010.138 PG 11 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 721LD UT WOS:000287355000011 PM 20680012 ER PT J AU Fuller, CD Nijkamp, J Duppen, JC Rasch, CRN Thomas, CR Wang, SJ Okunieff, P Jones, WE Baseman, D Patel, S Demandante, CGN Harris, AM Smith, BD Katz, AW McGann, C Harper, JL Chang, DT Smalley, S Marshall, DT Goodman, KA Papanikolaou, N Kachnic, LA AF Fuller, Clifton D. Nijkamp, Jasper Duppen, Joop C. Rasch, Coen R. N. Thomas, Charles R., Jr. Wang, Samuel J. Okunieff, Paul Jones, William E., III Baseman, Daniel Patel, Shilpen Demandante, Carlo G. N. Harris, Anna M. Smith, Benjamin D. Katz, Alan W. McGann, Camille Harper, Jennifer L. Chang, Daniel T. Smalley, Stephen Marshall, David T. Goodman, Karyn A. Papanikolaou, Niko Kachnic, Lisa A. CA Radiation Oncology Comm SW Oncolog TI PROSPECTIVE RANDOMIZED DOUBLE-BLIND PILOT STUDY OF SITE-SPECIFIC CONSENSUS ATLAS IMPLEMENTATION FOR RECTAL CANCER TARGET VOLUME DELINEATION IN THE COOPERATIVE GROUP SETTING SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Target volume delineation; Cooperative group; Conformal radiotherapy; Atlas; Consensus guideline ID HEAD-AND-NECK; CONFORMAL RADIOTHERAPY; RADIATION ONCOLOGY; LUNG-CANCER; IMAGE REGISTRATION; OBSERVER VARIATION; BREAST-CANCER; DUMMY RUN; DEFINITION; IMPACT AB Purpose: Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes. Methods and Materials: A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement). Results: Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure. Conclusion: Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT. (C) 2011 Elsevier Inc. C1 [Fuller, Clifton D.; Jones, William E., III; Baseman, Daniel; Demandante, Carlo G. N.; Harris, Anna M.; Papanikolaou, Niko] Univ Texas San Antonio, Hlth Sci Ctr San Antonio, Dept Radiat Oncol, San Antonio, TX USA. [Fuller, Clifton D.; Papanikolaou, Niko] Univ Texas San Antonio, Grad Div Radiol Sci, Dept Radiol, San Antonio, TX USA. [Fuller, Clifton D.; Thomas, Charles R., Jr.; Wang, Samuel J.] Oregon Hlth & Sci Univ, Dept Radiat Med, Portland, OR 97201 USA. [Nijkamp, Jasper; Duppen, Joop C.; Rasch, Coen R. N.] Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. [Okunieff, Paul; Katz, Alan W.] Univ Rochester, Dept Radiat Oncol, Rochester, NY USA. [Patel, Shilpen] Univ Washington, Med Ctr, Dept Radiat Oncol, Seattle, WA 98195 USA. [Demandante, Carlo G. N.] Wilford Hall USAF Med Ctr, San Antonio, TX 78236 USA. [Smith, Benjamin D.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Smith, Benjamin D.; McGann, Camille] Brooke Army Med Ctr, Dept Radiat Oncol, San Antonio, TX USA. [Harper, Jennifer L.; Marshall, David T.] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Chang, Daniel T.] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. [Smalley, Stephen] Univ Kansas, Dept Radiat Oncol, Kansas City, KS USA. [Smalley, Stephen] Radiat Oncol Ctr Olathe, Olathe, KS USA. [Goodman, Karyn A.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Kachnic, Lisa A.] Boston Univ, Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Kachnic, Lisa A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Fuller, CD (reprint author), Univ Texas San Antonio, Hlth Sci Ctr San Antonio, Dept Radiat Oncol, 7703 Floyd Curl Dr,MSC7889, San Antonio, TX USA. EM fullercd@uthscsa.edu OI Nijkamp, Jasper/0000-0001-7523-5881; Fuller, Clifton/0000-0002-5264-3994; Smith, Benjamin/0000-0001-7866-1093 FU National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering [5T32EB000817-04]; European Society for Therapeutic Radiology and Oncology; Society for Imaging Informatics in Medicine FX C. D. Fuller was supported by a training grant from the National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering, "Multidisciplinary Training Program in Human Imaging" (Grant 5T32EB000817-04), a Technology Transfer Grant from the European Society for Therapeutic Radiology and Oncology, and the Product Support Development Grant from the Society for Imaging Informatics in Medicine. NR 42 TC 22 Z9 22 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2011 VL 79 IS 2 BP 481 EP 489 DI 10.1016/j.ijrobp.2009.11.012 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 709OW UT WOS:000286451000023 PM 20400244 ER PT J AU Gahramanov, S Raslan, AM Muldoon, LL Hamilton, BE Rooney, WD Varallyay, CG Njus, JM Haluska, M Neuwelt, EA AF Gahramanov, Seymur Raslan, Ahmed M. Muldoon, Leslie L. Hamilton, Bronwyn E. Rooney, William D. Varallyay, Csanad G. Njus, Jeffrey M. Haluska, Marianne Neuwelt, Edward A. TI POTENTIAL FOR DIFFERENTIATION OF PSEUDOPROGRESSION FROM TRUE TUMOR PROGRESSION WITH DYNAMIC SUSCEPTIBILITY-WEIGHTED CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING USING FERUMOXYTOL VS. GADOTERIDOL: A PILOT STUDY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Blood-brain barrier; Dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging; Glioblastoma multiforme; Pseudoprogression; Radiochemotherapy ID CEREBRAL BLOOD-VOLUME; CENTRAL-NERVOUS-SYSTEM; POSITRON-EMISSION-TOMOGRAPHY; CONCOMITANT RADIOCHEMOTHERAPY; RADIATION NECROSIS; GRADE GLIOMAS; MR; PERFUSION; GLIOBLASTOMA; RADIOTHERAPY AB Purpose: We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol, in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT). Methods and Materials: Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on Day 1 and ferumoxytol on Day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions. Results: In seven MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in three and high rCBV in four, whereas ferumoxytol-DSC showed high rCBV in all seven sessions (p = 0.002). After RCT, seven MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p = 0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation, four patterns of response to RCT were observed: regression, pseudoprogression, true progression, and mixed response. Conclusion: We conclude that DSC-MRI with a blood pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV are likely exhibiting pseudoprogression, whereas high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression and warrant further investigation. (C) 2011 Elsevier Inc. C1 [Gahramanov, Seymur; Muldoon, Leslie L.; Varallyay, Csanad G.; Haluska, Marianne; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Raslan, Ahmed M.; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97239 USA. [Rooney, William D.; Njus, Jeffrey M.] Oregon Hlth & Sci Univ, Dept Radiol, Portland, OR 97239 USA. [Rooney, William D.; Njus, Jeffrey M.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97239 USA. [Varallyay, Csanad G.] Univ Klinikum Wurzburg, Dept Neuroradiol, Wurzburg, Germany. [Neuwelt, Edward A.] Portland VA Med Ctr, Portland, OR USA. RP Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,L603, Portland, OR 97239 USA. EM neuwelte@ohsu.edu FU Veterans Administration; National Institute of Health [CA 137488, NS53468, NS44687]; AMAG Pharmaceuticals FX Supported by a Veterans Administration merit review grant and by National Institute of Health grants CA 137488, NS53468, and NS44687 to EAN. Imaging efforts supported in part by the Oregon opportunity. There is a sponsored research agreement to OHSU from AMAG Pharmaceuticals. NR 31 TC 72 Z9 72 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2011 VL 79 IS 2 BP 514 EP 523 DI 10.1016/j.ijrobp.2009.10.072 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 709OW UT WOS:000286451000028 PM 20395065 ER PT J AU Engelsman, M DeLaney, TF Hong, TS AF Engelsman, Martijn DeLaney, Thomas F. Hong, Theodore S. TI PROTON RADIOTHERAPY: THE BIOLOGICAL EFFECT OF TREATING ALTERNATING SUBSETS OF FIELDS FOR DIFFERENT TREATMENT FRACTIONS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Proton therapy; Fractionation; Normalized total dose ID RADIATION-THERAPY AB Purpose: Common practice in proton radiotherapy is to deliver a subset of all fields in the treatment plan on any given treatment day. We investigate using biological modeling if the resulting variation in daily dose to normal tissues has a relevant detrimental biological effect. Methods and Materials: For four patient groups, the cumulative normalized total dose (NTD) was determined for normal tissues (OARs) of each patient using the clinically delivered fractionation schedule (FS(clin)), and for hypothetical fractionation schedules delivering all fields every day (FS(all)) or only a single field each day (FS(single)). Cumulative three-dimensional NTD distributions were summarized using the generalized equivalent uniform dose (gEUD) model. Results: For the skull base/cervical spine chordoma group, the largest effect is a 4-Gy increase in gEUD of the chiasm when treating only a subset of fields on any day. For lung cancer and pancreatic cancer patients, the variation in the gEUD of normal tissues is <0.2 Gy. For the prostate group, FSclin increases the gEUD of the femoral heads by 9 Gy compared with FS(all). Use of FS(single) resulted in the highest NTD to normal tissues for any patient. FS(all) resulted in an integral NTD to the patient that is on average 5% lower than FS(clin) and 10% lower than FS(single). Conclusion: The effects of field set of the day treatment delivery depend on the tumor site and number of fields treated each day. Modeling these effects may be important for accurate risk assessment. (C) 2011 Elsevier Inc. C1 [Engelsman, Martijn; DeLaney, Thomas F.; Hong, Theodore S.] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02139 USA. [Engelsman, Martijn; DeLaney, Thomas F.; Hong, Theodore S.] Harvard Univ, Sch Med, Boston, MA USA. RP Engelsman, M (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02139 USA. EM mengelsman@partners.org FU NCI NIH HHS [C06 CA059267-01] NR 12 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2011 VL 79 IS 2 BP 616 EP 622 DI 10.1016/j.ijrobp.2010.03.051 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 709OW UT WOS:000286451000041 PM 20675067 ER PT J AU Anastario, M Manzanero, R Blanco, R Reyes, E Jaramillo, R Black, L Dann, GE Leonard, E Boryc, K Chun, H AF Anastario, M. Manzanero, R. Blanco, R. Reyes, E. Jaramillo, R. Black, L. Dann, G. E. Leonard, E. Boryc, K. Chun, H. TI HIV infection, sexual risk behaviour and condom use in the Belize defense force SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE sexual risk behaviour; military personnel; condom use; mental health; HIV; Belize AB This study is the first Biological and Behavioral Surveillance Survey to be conducted among personnel in the Belize Defense Force. The purpose of the study was to understand the prevalence of HIV infection and risk behaviours, and to identify key correlates of sexual risk behaviours. A representative sample of personnel underwent serological testing and an Audio Computer-Assisted Self Interview. Of those sampled, 351 completed a blood test and 334 completed a behavioural interview. The prevalence of HIV was 1.14%. Twelve percent had ever reported being diagnosed with a sexually transmitted infection (STI) or screened positive for HIV infection. The odds of ever having an STI/HIV were higher among those who had less education, those who had sex with a commercial sex worker (CSW), those who ever engaged in receptive anal sex and those with post-traumatic stress disorder (PTSD). Alcohol abuse and PTSD were prevalent and associated with HIV risk behaviours. These results are being used to inform current prevention efforts. C1 [Anastario, M.; Dann, G. E.; Leonard, E.; Boryc, K.] Cicatelli Associates Inc, New York, NY 10003 USA. [Manzanero, R.; Blanco, R.; Reyes, E.] Belize Def Force, Ladyville, Belize. [Jaramillo, R.; Black, L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Chun, H.] HIVAIDS Prevent Program, Dept Def, San Diego, CA USA. RP Anastario, M (reprint author), Cicatelli Associates Inc, 505 8th Ave,Suite 1600, New York, NY 10003 USA. EM manastario@gmail.com NR 15 TC 15 Z9 15 U1 1 U2 3 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD FEB PY 2011 VL 22 IS 2 BP 73 EP 79 DI 10.1258/ijsa.2010.010274 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 757ZF UT WOS:000290127700003 PM 21427427 ER PT J AU Hankey, GJ Johnston, SC Easton, JD Hacke, W Mas, JL Brennan, D Mak, KH Bhatt, DL Fox, KAA Topol, EJ AF Hankey, Graeme J. Johnston, S. Claiborne Easton, J. Donald Hacke, Werner Mas, Jean-Louis Brennan, Danielle Mak, Koon Hou Bhatt, Deepak L. Fox, Keith A. A. Topol, Eric J. CA CHARISMA Trial Investigators TI Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE antiplatelet therapy; aspirin; atherothrombotic; CHARISMA; clinical trial; clopidogrel; ischaemic stroke ID ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; ASPIRIN; ATTACK; RISK; PREVENTION; MANAGEMENT; THERAPY AB Background The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease. However, a subanalysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke, myocardial infarction of symptomatic peripheral arterial disease. We aimed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be 'front-loaded', and maximal within the first 30-days of randomisation, without being unduly hazardous. Methods This was a subanalysis of a randomised, double-blind, placebo-controlled trial of clopidogrel vs. placebo, in addition to background therapy with low-dose acetylsalicylic acid (CHARISMA trial), restricted to all patients with transient ischaemic attack or ischaemic stroke. The primary efficacy outcome was stroke, and safety outcome severe bleeding, during the follow-up period. Results Among all transient ischaemic attack and ischaemic stroke patients randomised to placebo (n=2163), 131 (6 center dot 1%) experienced a stroke during follow-up compared with 105 (4 center dot 9%) of 2157 patients assigned clopidogrel (hazard ratio: 0 center dot 80, 95% confidence intervals: 0 center dot 62-1 center dot 03). There was no significant difference in severe bleeding (1 center dot 7% placebo vs. 1 center dot 9% clopidogrel, hazard ratio: 1 center dot 11, 95% confidence intervals: 0 center dot 71-1 center dot 73). Among all patients randomised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo (n=667), 46 (6 center dot 9%) experienced a stroke compared with 34 (5 center dot 1%) of 664 patients assigned clopidogrel (hazard ratio: 0 center dot 74, 0 center dot 46-1 center dot 16). There was no significant difference in severe bleeding (1 center dot 6% placebo vs. 1 center dot 4% clopidogrel, hazard ratio: 0 center dot 83, 95% confidence intervals: 0 center dot 34-2 center dot 01). Conclusion The data are consistent with, but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone. Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed. C1 [Hankey, Graeme J.] Royal Perth Hosp, Dept Neurol, Stroke Unit, Perth, WA 6000, Australia. [Johnston, S. Claiborne] UCSF Neurol, San Francisco, CA USA. [Easton, J. Donald] Brown Univ, Providence, RI 02912 USA. [Hacke, Werner] Dept Neurol, Heidelberg, Germany. [Mas, Jean-Louis] Hop St Anne, Serv Neurol, F-75674 Paris, France. [Brennan, Danielle] Cleveland Clin, Cleveland, OH 44106 USA. [Mak, Koon Hou] Gleneagles Med Ctr, Singapore, Singapore. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Topol, Eric J.] Scripps Hlth, La Jolla, CA USA. [Topol, Eric J.] Scripps Translat Sci Inst, La Jolla, CA USA. RP Hankey, GJ (reprint author), Royal Perth Hosp, Dept Neurol, Stroke Unit, 197 Wellington St, Perth, WA 6000, Australia. EM gjhankey@cyllene.uwa.edu.au RI Hankey, Graeme /H-4968-2014; OI Hankey, Graeme /0000-0002-6044-7328; Topol, Eric/0000-0002-1478-4729 FU Sanofi-Aventis; Bristol-Myers Squibb; Bayer and Boehringer Ingelheim; Astra Zeneca; Eisai; Ethicon; Heartscape; Sanofi Aventis; Abraxis; Alexion Pharma; AstraZeneca; Atherogenics; Aventis; Biosense Webster; Biosite; Boehringer Ingelheim; Boston Scientific; Cardionet; Centocor; Converge Medical Inc.; Cordis; Dr. Reddy's; Edwards Lifesciences; Esperion; GE Medical; Genentech; Gilford; GSK; Guidant; JJ; Kensey-Nash; Lilly; Medtronic; Merck; Mytogen; Novartis; Novo Nordisk; Orphan Therapeutics; PG Pharma; Pfizer; Roche; Sankyo; Schering-Plough,; Scios; St. Jude Medical; Takeda; TMC; VasoGenix; Viacor FX Graeme J. Hankey: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Bayer and Boehringer Ingelheim and lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Bayer and Boehringer Ingelheim; S. Claiborne Johnston: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: None; J. Donald Easton: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Werner Hacke: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: Member of the executive Committee of CHARISMA, Consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Jean-Louis Mas: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: Consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Danielle Brennan: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: None; Koon-Hou Mak: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: research support from Sanofi-Aventis and Bristol-Myers Squibb; Deepak L. Bhatt: I declare that I participated in the design, execution of the study, the data analysis and review of the manuscript. I have seen and approved the final version. Dr. Bhatt discloses the following relationships: research grants (directly to the institution) - Astra Zeneca, Bristol Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company; Honoraria (donated to non-profits for >2 years) - Astra Zeneca, Bristol Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Millennium, Paringenix, PDL, Sanofi Aventis, Schering Plough, The Medicines Company, tns Healthcare; Speaker's bureau (42 years ago) - Bristol Myers Squibb, Sanofi Aventis, The Medicines Company; Consultant/Advisory Board (any honoraria donated to non-profits) - Astra Zeneca, Bristol Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Johnson & Johnson, McNeil, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi Aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex; Expert testimony regarding clopidogrel (the compensation was donated to a non-profit organisation); Cleveland Clinic Coordinating Center currently receives or has received research funding from: Abraxis, Alexion Pharma, AstraZeneca, Atherogenics, Aventis, Biosense Webster, Biosite, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardionet, Centocor, Converge Medical Inc., Cordis, Dr.; Reddy's, dwards Lifesciences, Esperion, GE Medical, Genentech, Gilford, GSK, Guidant, J&J, Kensey-Nash, Lilly, Medtronic, Merck, Mytogen, Novartis, Novo Nordisk, Orphan Therapeutics, P&G Pharma, Pfizer, Roche, Sankyo, Sanofi-Aventis, Schering-Plough, Scios, St. Jude Medical, Takeda, TMC, VasoGenix, Viacor; Keith A. A. Fox: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis; lecture fees from Sanofi-Aventis and Bristol-Myers Squibb; and grant support from Sanofi-Aventis. Eric J. Topol: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: research support from Sanofi-Aventis and Bristol-Myers Squibb. NR 14 TC 28 Z9 32 U1 6 U2 11 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1747-4930 J9 INT J STROKE JI Int. J. Stroke PD FEB PY 2011 VL 6 IS 1 BP 3 EP 9 DI 10.1111/j.1747-4949.2010.00535.x PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 702UX UT WOS:000285922500003 PM 21205234 ER PT J AU Oral, E Muratoglu, OK AF Oral, Ebru Muratoglu, Orhun K. TI Vitamin E diffused, highly crosslinked UHMWPE: a review SO INTERNATIONAL ORTHOPAEDICS LA English DT Review ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; ELECTRON-SPIN-RESONANCE; ALPHA-TOCOPHEROL; MECHANICAL-PROPERTIES; FREE-RADICALS; PROPAGATION RESISTANCE; POLYOLEFIN OXIDATION; ANTIOXIDANT ACTIVITY; GAMMA-STERILIZATION AB Highly crosslinked UHMWPE has become the bearing surface of choice in total hip arthroplasty. First generation crosslinked UHMWPEs, clinically introduced in the 1990s, show significant improvements compared to gamma sterilised, conventional UHMWPE in decreasing wear and osteolysis. These crosslinked UHMWPEs were thermally treated (annealed or melted) after irradiation to improve their oxidation resistance. While annealing resulted in the retention of some oxidation potential, post-irradiation melted UHMWPEs had reduced fatigue strength due to the crystallinity loss during melting. Thus, the stabilisation of radiation crosslinked UHMWPEs by the diffusion of the antioxidant vitamin E was developed to obtain oxidation resistance with improved fatigue strength by avoiding post-irradiation melting. A two-step process was developed to incorporate vitamin E into irradiated UHMWPE by diffusion to obtain a uniform concentration profile. Against accelerated and real-time aging in vitro, this material showed superior oxidation resistance to UHMWPEs with residual free radicals. The fatigue strength was improved compared to irradiated and melted UHMWPEs crosslinked using the same irradiation dose. Several adverse testing schemes simulating impingement showed satisfactory behaviour. Peri-prosthetic tissue reaction to vitamin E was evaluated in rabbits and any effects of vitamin E on device fixation were evaluated in a canine model, both of which showed no detrimental effects of the inclusion of vitamin E in crosslinked UHMWPE. Irradiated, vitamin E-diffused, and gamma sterilised UHMWPEs have been in clinical use in hips since 2007 and in knees since 2008. The clinical outcome of this material will be apparent from the results of prospective, randomised clinical studies. C1 [Oral, Ebru; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Oral, Ebru; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA USA. RP Oral, E (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St,GRJ 1206, Boston, MA 02114 USA. EM eoral@partners.org FU NIH/NIAMS [AR051142]; Biomet, Inc. (Warsaw, IN); Zimmer, Inc (Warsaw, IN); William H. Harris Foundation; Zimmer, Inc.; Biomet, Inc. FX The studies discussed here were performed by research funding in part from NIH/NIAMS AR051142, research grants from Biomet, Inc. (Warsaw, IN) and Zimmer, Inc (Warsaw, IN) and the William H. Harris Foundation. The laboratory and the department also received funding from royalties from Zimmer, Inc. and Biomet, Inc. Dr. Muratoglu received royalties from Biomet, Inc. and Zimmer, Inc. Dr. Oral received royalties from Zimmer, Inc. NR 74 TC 59 Z9 63 U1 5 U2 60 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 EI 1432-5195 J9 INT ORTHOP JI Int. Orthop. PD FEB PY 2011 VL 35 IS 2 BP 215 EP 223 DI 10.1007/s00264-010-1161-y PG 9 WC Orthopedics SC Orthopedics GA 716DJ UT WOS:000286945100011 PM 21120476 ER PT J AU Uthamalingam, S Zheng, H Leavitt, M Pomerantsev, E Ahmado, I Gurm, GS Gewirtz, H AF Uthamalingam, Shanmugam Zheng, Hui Leavitt, Marcia Pomerantsev, Eugene Ahmado, Imad Gurm, Gagandeep S. Gewirtz, Henry TI Exercise-Induced ST-Segment Elevation in ECG Lead aVR Is a Useful Indicator of Significant Left Main or Ostial LAD Coronary Artery Stenosis SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE exercise treadmill test; lead aVR; left main coronary artery disease; myocardial perfusion imaging ID HEART-ASSOCIATION ELECTROCARDIOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; OF-CARDIOLOGY-FOUNDATION; REST ANGINA-PECTORIS; AMERICAN-COLLEGE; ARRHYTHMIAS COMMITTEE; SCIENTIFIC STATEMENT; CLINICAL CARDIOLOGY; PERFUSION SPECT; RHYTHM-SOCIETY AB OBJECTIVES The authors tested the hypothesis that exercise treadmill testing (ETT)-induced ST-segment elevation (STE) in electrocardiographic lead aVR is an important indicator of significant left main coronary artery (LMCA) or ostial left anterior descending coronary artery (LAD) stenosis. BACKGROUND Although STE in lead aVR is an indicator of LMCA or very proximal LAD occlusion in acute coronary syndromes, its predictive power in the setting of ETT is uncertain. METHODS Rest and stress electrocardiograms, clinical and stress test parameters, and single photon-emission computed tomographic myocardial perfusion imaging (MPI) data, when available, were obtained in 454 subjects (378 with MPI) who underwent cardiac catheterization and standard Bruce ETT <= 6 months before catheterization. Patients were selected for LMCA or ostial LAD disease (>= 50% stenosis) with or without other coronary artery disease (CAD), CAD (>= 70% stenosis) without significant LMCA or ostial LAD, or no significant CAD. Univariate followed by multivariate logistic regression analyses of clinical, electrocardiographic, stress test, and single photon-emission computed tomographic MPI variables were used to identify significant correlates of LMCA or ostial LAD stenosis. Bayesian analysis of the data also was performed. RESULTS LMCA (n = 38) or ostial LAD (n = 42) stenosis occurred in 75 patients (5 patients had both). The remainder had CAD without LMCA or ostial LAD stenosis (n = 276) or no CAD (n = 103). In multivariate analysis, the strongest predictor was stress-induced STE in lead aVR (p < 0.0001, area under the curve 0.82). Both left ventricular ejection fraction (after stress) and percent reversible LAD ischemia on single photon-emission computed tomographic MPI also contributed significantly in multivariate analysis (p < 0.005 and p < 0.05, respectively, areas under the curve 0.60 and 0.64, respectively). Although additional electrocardiographic, stress test, and MPI variables were significant univariate predictors, none was statistically significant in multivariate analysis. At 1-mm STE in lead aVR, sensitivity for LMCA or ostial LAD stenosis was 75%, specificity was 81%, overall predictive accuracy was 80%, and post-test probability increased nearly 3 times from 17% to 45%. CONCLUSIONS Stress (ETT)-induced STE in lead aVR is an important indicator of significant LMCA or ostial LAD stenosis and should not be ignored. (J Am Coll Cardiol Img 2011;4:176-86) (C) 2011 by the American College of Cardiology Foundation C1 [Gewirtz, Henry] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Unit, Boston, MA 02114 USA. [Zheng, Hui] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA 02114 USA. RP Gewirtz, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Unit, Yawkey 5E, Boston, MA 02114 USA. EM hgewirtz@partners.org FU Harvard Catalyst The Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 RR 025758]; Harvard University; FluoroPharma FX This work was conducted with support from Harvard Catalyst 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). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. Dr. Gewirtz has received a research grant from FluoroPharma unrelated to this topic. All other authors have reported that they have no relationships to disclose. NR 30 TC 20 Z9 21 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD FEB PY 2011 VL 4 IS 2 BP 176 EP 186 DI 10.1016/j.jcmg.2010.11.014 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 731LU UT WOS:000288109100010 PM 21329903 ER PT J AU Gray, WA Rosenfield, KA Jaff, MR Chaturvedi, S Peng, L Verta, P AF Gray, William A. Rosenfield, Kenneth A. Jaff, Michael R. Chaturvedi, Seemant Peng, Lei Verta, Patrick CA CAPTURE 2 Investigators Executive TI Influence of Site and Operator Characteristics on Carotid Artery Stent Outcomes Analysis of the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) Clinical Study SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE angioplasty; carotid; risk factors; stenosis; stents; stroke ID MULTISPECIALTY CONSENSUS RECOMMENDATIONS; AMERICAN-HEART-ASSOCIATION; HOSPITAL VOLUME; COMPETENCE STATEMENT; EMBOLIC PROTECTION; STATEWIDE ANALYSIS; ISCHEMIC LESIONS; ENDARTERECTOMY; RISK; PREDICTORS AB Objectives The aim of this study was to analyze the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) study for physician- or site-related variables associated with differential outcomes for carotid artery stenting (CAS). Background The CAPTURE 2 trial is an ongoing, prospective, nonrandomized, independently adjudicated, multicenter clinical study enrolling high-surgical-risk patients undergoing CAS. Methods In this assessment of the CAPTURE 2 study, the American Heart Association carotid endarterectomy guideline limits were used to define acceptable site and physician CAS outcomes; therefore, the resulting population of nonoctogenarian, asymptomatic subjects in this analysis is confined to 3,388 (of the total 5,297) subjects treated at 180 U.S. hospitals by 459 operators between March 2006 and January 2009. Results The rates of death, stroke, and myocardial infarction and death and stroke (DS) at 30 days were 3.5% and 3.3%, respectively, for the full CAPTURE 2 study cohort and 2.9% and 2.7%, respectively, for the asymptomatic, nonoctogenarian subgroup. In this subgroup, two-thirds of sites (118 of 180, 66%) had no DS events. Within the remaining sites, an inverse relationship between event rates and hospital patient volume,as well as between event rates and individual operator volume was observed. The DS rates trended lower for interventional cardiologists compared with other specialties. Conclusions Outcomes from the largest prospectively gathered, independently adjudicated, multicenter CAS study indicate that CAS can be safely performed in a variety of hospital settings by physicians with various specialties. The most important determinant of perioperative CAS outcomes was both site and operator CAS volume. A threshold of 72 cases was found to be necessary for consistently achieving a DS rate below 3% in this later-phase single arm study; background era and non-study operator experience will affect this determination. (Second Phase of "Carotid RX ACCULINK/RX ACCUNET Post-Approval Trial to Uncover Unanticipated or Rare Events"; NCT00302237) (J Am Coll Cardiol Intv 2011;4:235-46) (C) 2011 by the American College of Cardiology Foundation C1 [Gray, William A.] Columbia Univ, Dept Med, Ctr Intervent Vasc Therapy, New York, NY 10027 USA. [Rosenfield, Kenneth A.; Jaff, Michael R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chaturvedi, Seemant] Wayne State Univ, Dept Neurol, Detroit, MI USA. [Peng, Lei; Verta, Patrick] Abbott Labs, Santa Clara, CA USA. RP Gray, WA (reprint author), Columbia Univ, Dept Med, Ctr Intervent Vasc Therapy, 161 Ft Washington Ave,5th Floor, New York, NY 10027 USA. EM wg2131@columbia.edu NR 27 TC 56 Z9 56 U1 0 U2 1 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 FEB PY 2011 VL 4 IS 2 BP 235 EP 246 DI 10.1016/j.jcin.2010.10.009 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 731WP UT WOS:000288141400014 PM 21349464 ER PT J AU Powis, KM Smeaton, L Ogwu, A Lockman, S Dryden-Peterson, S van Widenfelt, E Leidner, J Makhema, J Essex, M Shapiro, RL AF Powis, Kathleen M. Smeaton, Laura Ogwu, Anthony Lockman, Shahin Dryden-Peterson, Scott van Widenfelt, Erik Leidner, Jean Makhema, Joseph Essex, Max Shapiro, Roger L. TI Effects of in Utero Antiretroviral Exposure on Longitudinal Growth of HIV-Exposed Uninfected Infants in Botswana SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE prevention of mother-to-child transmission; HIV; growth ID LOW-BIRTH-WEIGHT; CHILDREN BORN; INFECTED WOMEN; THERAPY; PREGNANCY; MORTALITY; TRANSMISSION; TANZANIA; MOTHERS; UNDERNUTRITION AB Background: The impact of in utero exposure to highly active antiretroviral therapy (HAART) on longitudinal growth of HIV-uninfected infants is unknown. Methods: The Mashi and Mma Bana PMTCT intervention trials enrolled HIV-infected pregnant women at four sites in Botswana. Breast-fed (BF), HIV-uninfected infants born at 37 weeks or greater were included in this analysis. Weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores were calculated using World Health Organization Child Growth Standards. Mean z-scores were compared between in utero antiretroviral exposure groups using Student t test, response profiles analysis, and general linear mixed effects modeling. Results: Growth of 619 HAART-exposed and 440 zidovudine-exposed, HIV-uninfected infants was evaluated. Mean birth weights were 3.01 kg for HAART and 3.15 kg for zidovudine-exposed infants (P < 0.001) with lower mean birth WAZ, length-for-age (LAZ), and weight-for-length (WLZ) among HAART-exposed infants (all P < 0.001). HAART-exposed infants had greater improvement in WAZ and weight-for-length (WLZ) from birth through 2 months (P = 0.03, P < 0.001, respectively). The WAZ did not differ between groups from 3 through 6 months (P = 0.26). Length-for-age (LAZ) remained lower in HAART-exposed infants but the incidence of wasting or stunting did not differ between exposure groups. Conclusions: Lower weights in HAART-exposed uninfected infants at birth were rapidly corrected during the first 6 months of life. C1 [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Internal Med & Pediat, Boston, MA 02114 USA. [Smeaton, Laura; Leidner, Jean] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Powis, Kathleen M.; Ogwu, Anthony; Lockman, Shahin; Dryden-Peterson, Scott] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Lockman, Shahin; Dryden-Peterson, Scott; van Widenfelt, Erik; Makhema, Joseph; Essex, Max] Brigham & Womens Hosp, Infect Dis Unit, Boston, MA 02115 USA. [Powis, Kathleen M.; Lockman, Shahin; Dryden-Peterson, Scott; Essex, Max; Shapiro, Roger L.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Roger L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Powis, KM (reprint author), Massachusetts Gen Hosp, Dept Internal Med & Pediat, 175 Cambridge St 5th Floor, Boston, MA 02114 USA. EM kpowis@partners.org FU Harvard University Center for AIDS Research; Harvard Institute for Global Health; National Institutes of Health, National Institute of Child Health and Human Development [R01 HD37793]; Oak Foundation; Boehringer Ingelheim; GlaxoSmithKline; United Nations Children's Fund; National Institute of Allergy and Infectious Diseases [U01-AI066454]; Fogarty International Center [TW00004]; Brigham and Women's Global Women's Health Fellowship; National Institutes of Health: National Institute of Allergy and Infectious Diseases [UO1 AI066454]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [RO1 HD37793]; Central CFAR Statistics [2P30AI060354-06]; Global Infections Diseases Program FX The Longitudinal Infant Growth Study was supported by a grant from the Harvard University Center for AIDS Research, the Global Infections Diseases Program, and the Global Health Scholars Program at the Harvard Institute for Global Health (K. M. P.). The Mashi study was supported by a grant from the National Institutes of Health, National Institute of Child Health and Human Development (R01 HD37793); a grant from the Oak Foundation; Boehringer Ingelheim (which provided nevirapine); by GlaxoSmithKline (which provided zidovudine); and the United Nations Children's Fund, which provided funds to assist with ongoing mentoring of the study participants. The Mma Bana study was supported by a grant (U01-AI066454) from the National Institute of Allergy and Infectious Diseases. The Fogarty International Center (TW00004) supported several study trainees for both the Mashi and Mma Bana studies. Funding support from Brigham and Women's Global Women's Health Fellowship supported K.M.P.'s salary during the Mma Bana study. Research grants from the National Institutes of Health: National Institute of Allergy and Infectious Diseases (UO1 AI066454) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (RO1 HD37793) support S.D.P.'s salary for the current study. Central CFAR Statistics Grant award #2P30AI060354-06 supported L.S.' salary for the current study. NR 25 TC 28 Z9 30 U1 0 U2 0 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 FEB 1 PY 2011 VL 56 IS 2 BP 131 EP 138 DI 10.1097/QAI.0b013e3181ffa4f5 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 714KE UT WOS:000286807700016 PM 21124227 ER PT J AU Hooker, CI Tully, LM Verosky, SC Fisher, M Holland, C Vinogradov, S AF Hooker, Christine I. Tully, Laura M. Verosky, Sara C. Fisher, Melissa Holland, Christine Vinogradov, Sophia TI Can I Trust You? Negative Affective Priming Influences Social Judgments in Schizophrenia SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE schizophrenia; paranoia; person perception; trustworthiness; social cognition ID EMOTIONAL FACIAL EXPRESSIONS; RECOGNITION; COGNITION; MOOD; IDENTIFICATION; AMYGDALA; STATES; PERFORMANCE; PERCEPTION; DEPRESSION AB Successful social interactions rely on the ability to make accurate judgments based on social cues as well as the ability to control the influence of internal or external affective information on those judgments. Prior research suggests that individuals with schizophrenia misinterpret social stimuli and this misinterpretation contributes to impaired social functioning. We tested the hypothesis that for people with schizophrenia, social judgments are abnormally influenced by affective information. Twenty-three patients with schizophrenia and 35 healthy control participants rated the trustworthiness of faces following the presentation of neutral, negative (threat-related), or positive affective primes. Results showed that all participants rated faces following negative affective primes as less trustworthy than faces following neutral or positive primes. Importantly, this effect was significantly more pronounced for participants with schizophrenia, suggesting that schizophrenia may be characterized by an exaggerated influence of negative affective information on social judgment. Furthermore, the extent that the negative affective prime influenced trustworthiness judgments was significantly associated with patients' severity of positive symptoms, particularly feelings of persecution. These findings suggest that for people with schizophrenia, negative affective information contributes to an interpretive bias, consistent with paranoid ideation, when judging the trustworthiness of others. This bias may contribute to social impairments in schizophrenia. C1 [Hooker, Christine I.; Tully, Laura M.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Verosky, Sara C.] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Fisher, Melissa; Holland, Christine; Vinogradov, Sophia] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Fisher, Melissa; Holland, Christine; Vinogradov, Sophia] San Francisco VA Med Ctr, San Francisco, CA USA. RP Hooker, CI (reprint author), Harvard Univ, Dept Psychol, 820 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM chooker@wjh.harvard.edu OI Tully, Laura/0000-0002-2751-9887 FU NIMH NIH HHS [MH71746, MH68725-02, R01 MH068725, K08 MH071746-01, K08 MH071746] NR 61 TC 23 Z9 24 U1 1 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD FEB PY 2011 VL 120 IS 1 BP 98 EP 107 DI 10.1037/a0020630 PG 10 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA 717VB UT WOS:000287074400009 PM 20919787 ER PT J AU Dykes, PC Carroll, D McColgan, K Hurley, AC Lipsitz, SR Colombo, L Zuyev, L Middleton, B AF Dykes, Patricia C. Carroll, Diane McColgan, Kerry Hurley, Ann C. Lipsitz, Stuart R. Colombo, Lisa Zuyev, Lyubov Middleton, Blackford TI Scales for assessing self-efficacy of nurses and assistants for preventing falls SO JOURNAL OF ADVANCED NURSING LA English DT Article DE falls; hospital; instrument development; nursing; safety; self-efficacy ID HOSPITALIZED-PATIENTS; BEHAVIORAL CHANGE; CARE HOSPITALS; RISK; INJURIES; PROGRAM; SATISFACTION; METAANALYSIS; INITIATIVES; MANAGEMENT AB P>Aim. This paper is a report of the development and testing of the Self-Efficacy for Preventing Falls Nurse and Assistant scales. Background. Patient falls and fall-related injuries are traumatic ordeals for patients, family members and providers, and carry a toll for hospitals. Self-efficacy is an important factor in determining actions persons take and levels of performance they achieve. Performance of individual caregivers is linked to the overall performance of hospitals. Scales to assess nurses and certified nursing assistants' self-efficacy to prevent patients from falling would allow for targeting resources to increase SE, resulting in improved individual performance and ultimately decreased numbers of patient falls. Method. Four phases of instrument development were carried out to (1) generate individual items from eight focus groups (four each nurse and assistant conducted in October 2007), (2) develop prototype scales, (3) determine content validity during a second series of four nurse and assistant focus groups (January 2008) and (4) conduct item analysis, paired t-tests, Student's t-tests and internal consistency reliability to refine and confirm the scales. Data were collected during February-December, 2008. Results. The 11-item Self-Efficacy for Preventing Falls Nurse had an alpha of 0 center dot 89 with all items in the range criterion of 0 center dot 3-0 center dot 7 for item total correlation. The 8-item Self-Efficacy for Preventing Falls Assistant had an alpha of 0 center dot 74 and all items had item total correlations in the 0 center dot 3-0 center dot 7 range. Conclusions. The Self-Efficacy for Preventing Falls Nurse and Self-Efficacy for Preventing Falls Assistant scales demonstrated psychometric adequacy and are recommended to measure bedside staff's self-efficacy beliefs in preventing patient falls. C1 [Dykes, Patricia C.; McColgan, Kerry; Middleton, Blackford] Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. [Carroll, Diane] Massachusetts Gen Hosp, Munn Ctr Nursing Res, Boston, MA 02114 USA. [Hurley, Ann C.] Brigham & Womens Hosp, Ctr Nursing Excellence, Boston, MA 02115 USA. [Lipsitz, Stuart R.; Middleton, Blackford] Brigham & Womens Hosp, Dept Gen Med, Boston, MA 02115 USA. [Lipsitz, Stuart R.] Harvard Univ, Sch Med, Boston, MA USA. [Colombo, Lisa] Hlth Alliance Hosp, Milton, MA USA. RP Dykes, PC (reprint author), Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. EM pdykes@partners.org OI Middleton, Blackford/0000-0002-1819-1234 FU Brigham and Women's Hospital Center for Nursing Excellence; Brigham and Women's Hospital; Brigham and Women's Hospital Department of General Medicine; Robert Wood Johnson Foundation Interdisciplinary Nursing Quality Research Initiative FX This study was supported by the Brigham and Women's Hospital Center for Nursing Excellence, the Brigham and Women's Hospital Lily Kravitz Nursing Studies Award, Brigham and Women's Hospital Department of General Medicine, and the Robert Wood Johnson Foundation Interdisciplinary Nursing Quality Research Initiative. NR 53 TC 1 Z9 1 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-2402 J9 J ADV NURS JI J. Adv. Nurs. PD FEB PY 2011 VL 67 IS 2 BP 438 EP 449 DI 10.1111/j.1365-2648.2010.05501.x PG 12 WC Nursing SC Nursing GA 706IK UT WOS:000286211400021 PM 21073506 ER PT J AU Brown, TE Holdnack, J Saylor, K Adler, L Spencer, T Williams, DW Padival, AK Schuh, K Trzepacz, PT Kelsey, D AF Brown, Thomas E. Holdnack, James Saylor, Keith Adler, Lenard Spencer, Thomas Williams, David W. Padival, Anoop K. Schuh, Kory Trzepacz, Paula T. Kelsey, Douglas TI Effect of Atomoxetine on Executive Function Impairments in Adults With ADHD SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE ADHD; atomoxetine; adults; Brown ADD Scale for Adults; executive functioning ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ONCE-DAILY ATOMOXETINE; DEFICIT HYPERACTIVITY DISORDER; DOUBLE-BLIND; ANXIETY DISORDER; CHILDREN; ADOLESCENTS; STABILITY; TRIAL; GIRLS AB Objective: To assess the effect of atomoxetine on ADHD-related executive functions over a 6-month period using the Brown Attention-Deficit Disorder Scale (BADDS) for Adults, a normed, 40-item, self-report scale in a randomized, double-blind, placebo-controlled clinical trial. Method: In a randomized, double-blind clinical trial, adults with ADHD received either atomoxetine 25 to 100 mg/day or placebo for 6 months. Patients completed the BADDS to report their current daily functioning in 5 clusters of ADHD-related impairments of executive functioning: ( I) Organizing and Activating to Work; (2) Focusing for Tasks; (3) Regulating Alertness and Effort; (4) Modulating Emotions; and (5) Utilizing Working Memory. Results: Mean scores were significantly more improved in the atomoxetine group compared to the placebo group: total score, -27.0 versus -19.0 (p<.001); all 5 cluster scores, p<.01. Conclusions: Once-daily atomoxetine can improve executive function impairments in adults with ADHD as assessed by the BADDS. (J. of Att. Dis.2011;15(2) 130-138) C1 [Brown, Thomas E.] Yale Univ, Sch Med, Hamden, CT 06517 USA. [Holdnack, James] Psychological Corp, San Antonio, TX USA. [Saylor, Keith] NeuroScience Inc, Herndon, VA USA. [Adler, Lenard] NYU, Sch Med, New York, NY 10003 USA. [Adler, Lenard] New York VA Harbor Healthcare Syst, Psychiat Serv, New York, NY USA. [Spencer, Thomas] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Williams, David W.; Padival, Anoop K.; Schuh, Kory; Kelsey, Douglas] Lilly USA LLC, Indianapolis, IN USA. [Trzepacz, Paula T.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Trzepacz, Paula T.] Univ Mississippi, Sch Med, Jackson, MS 39216 USA. [Trzepacz, Paula T.] Indiana Univ Sch Med, Indianapolis, IN USA. [Trzepacz, Paula T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Brown, TE (reprint author), Yale Univ, Sch Med, 1188 Whitney Ave, Hamden, CT 06517 USA. EM tebrownyu@aol.com OI Adler, Len/0000-0002-9812-8234 FU Lilly USA, LLC; Eli Lilly and Company; Shire; Pfizer; Abbott; AstraZeneca; Bristol-Myers Squibb; Johnson Johnson; Supernus; PGX Health; Otsuka; Wyeth; Cephalon; Novartis; Abbott Laboratories; Cortex Pharmaceuticals; Major League Baseball; Merck Co; Mindsite; National Institute on Drug Abuse; New River Pharmaceuticals; Novartis Pharmaceuticals; Organon; Ortho McNeil/Jannsen/Johnson and Johnson; Psychogenics; Sanofi-Aventis Pharmaceuticals; GlaxoSmithKline; Janssen; McNeil; National Institute of Mental Health FX This research was funded by Lilly USA, LLC, a wholly owned subsidiary of Eli Lilly and Company. Dr. Brown is an investigator and Advisory Board member for Lilly USA, LLC and/or Eli Lilly and Company and receives royalties on the sale of the Brown Scales and books from the Yale University Press and the American Psychiatric Press. Dr. Holdnack is a paid consultant for Lilly USA, LLC and/or Eli Lilly and Company and is an employee of Pearson, the publisher of the test for the Brown Attention-Deficit Disorder Scale (BADDS). Dr. Saylor is a principal investigator or coinvestigator for studies sponsored by Lilly USA, LLC and/or Eli Lilly and Company, Shire, Pfizer, Abbott, AstraZeneca, Bristol-Myers Squibb, Johnson & Johnson, Supernus, PGX Health, Otsuka, Wyeth, Cephalon, and Novartis. In the prior year, Dr. Adler was a consultant, Advisory Board member, Speakers' Bureau member, and/or recipient of research grants from Abbott Laboratories, Bristol-Myers Squibb, Cephalon, Cortex Pharmaceuticals, Lilly USA, LLC and/or Eli Lilly and Company, Major League Baseball, Merck & Co, Mindsite, National Institute on Drug Abuse, New River Pharmaceuticals, Novartis Pharmaceuticals, Organon,Ortho McNeil/Jannsen/Johnson and Johnson, Pfizer, Psychogenics, Sanofi-Aventis Pharmaceuticals, and Shire. Dr. Spencer receives research support from, is a speaker for, or is on the Advisory Board of the following sources: Shire, Lilly USA, LLC and/or Eli Lilly and Company, GlaxoSmithKline, Janssen, McNeil, Novartis, Cephalon, Pfizer, and the National Institute of Mental Health. Dr. Padival is a Publications Manager with Abbott Laboratories. Drs. Kelsey, Schuh, and Trzepacz, and Mr. Williams are employees of Lilly USA, LLC or Eli Lilly and Company and minor shareholders of Eli Lilly and Company. The authors thank Martin Paczkowski, MPH, for protocol and Statistical Analysis Plan development. NR 36 TC 24 Z9 25 U1 3 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 J9 J ATTEN DISORD JI J. Atten. Disord. PD FEB PY 2011 VL 15 IS 2 BP 130 EP 138 DI 10.1177/1087054709356165 PG 9 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA 714XZ UT WOS:000286846300005 PM 20026871 ER PT J AU Wu, GF Shindler, KS Allenspach, EJ Stephen, TL Thomas, HL Mikesell, RJ Cross, AH Laufer, TM AF Wu, Gregory F. Shindler, Kenneth S. Allenspach, Eric J. Stephen, Tom L. Thomas, Hannah L. Mikesell, Robert J. Cross, Anne H. Laufer, Terri M. TI Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Dendritic cells; Experimental autoimmune; encephalomyelitis/MS; Autoimmunity; Neuroimmunology; Immunopathology; Antigen presenting cells ID B T-CELLS; MULTIPLE-SCLEROSIS; IN-VIVO; OPTIC NEURITIS; CNS AUTOIMMUNITY; TRANSGENIC MICE; TH17 CELLS; ENCEPHALOMYELITIS; DEPLETION; PEPTIDES AB Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Wu, Gregory F.; Mikesell, Robert J.; Cross, Anne H.] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Wu, Gregory F.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19004 USA. [Shindler, Kenneth S.] Univ Penn, Sch Med, Dept Ophthalmol, Philadelphia, PA 19004 USA. [Allenspach, Eric J.; Stephen, Tom L.; Thomas, Hannah L.; Laufer, Terri M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19004 USA. [Laufer, Terri M.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19004 USA. RP Wu, GF (reprint author), Washington Univ, Dept Neurol, Box 8111,600 S Euclid Ave, St Louis, MO 63110 USA. EM wug@neuro.wustl.edu; tlaufer@mail.med.upenn.edu OI Allenspach, Eric/0000-0001-7346-5835 FU NIH; National Multiple Sclerosis Society; Penn Center for Clinical Immunology FX The authors would like to thank Gary Koretzky, Avinash Bhandoola, and Taku Kambayashi for helpful discussions and Angela Archambault, Taku Kambayashi and Michael Racke for critical review of the manuscript. The authors appreciate the technical expertise of Hua Ding from the Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia protein core of Children's hospital of Philadelphia for generating MOG protein. This research was supported by grants from the NIH and a Pilot Research Award from the National Multiple Sclerosis Society to TML. GFW was supported by a postdoctoral fellowship from the National Multiple Sclerosis Society and a Penn Center for Clinical Immunology Jackson-Wade Fellowship. These sponsors had no role in the study design, collection, analysis and interpretation of data, writing of the manuscript or decision to submit the paper for publication. NR 50 TC 20 Z9 21 U1 1 U2 1 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 FEB PY 2011 VL 36 IS 1 BP 56 EP 64 DI 10.1016/j.jaut.2010.10.006 PG 9 WC Immunology SC Immunology GA 727WB UT WOS:000287832500008 PM 21095100 ER PT J AU Toyoda, T An, D Witczak, CA Koh, HJ Hirshman, MF Fujii, N Goodyear, LJ AF Toyoda, Taro An, Ding Witczak, Carol A. Koh, Ho-Jin Hirshman, Michael F. Fujii, Nobuharu Goodyear, Laurie J. TI Myo1c Regulates Glucose Uptake in Mouse Skeletal Muscle SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MYOSIN I-BETA; GLUT4 TRANSLOCATION; INSULIN-RECEPTOR; CORTICAL ACTIN; GLYCOGEN-SYNTHASE; TRANSPORT; CONTRACTION; EXERCISE; DISRUPTION; MEMBRANE AB Contraction and insulin promote glucose uptake in skeletal muscle through GLUT4 translocation to cell surface membranes. Although the signaling mechanisms leading to GLUT4 translocation have been extensively studied in muscle, the cellular transport machinery is poorly understood. Myo1c is an actin-based motor protein implicated in GLUT4 translocation in adipocytes; however, the expression profile and role of Myo1c in skeletal muscle have not been investigated. Myo1c protein abundance was higher in more oxidative skeletal muscles and heart. Voluntary wheel exercise (4 weeks, 8.2 +/- 0.8 km/day), which increased the oxidative profile of the triceps muscle, significantly increased Myo1c protein levels by similar to 2-fold versus sedentary controls. In contrast, high fat feeding (9 weeks, 60% fat) significantly reduced Myo1c by 17% in tibialis anterior muscle. To study Myo1c regulation of glucose uptake, we expressed wild-type Myo1c or Myo1c mutated at the ATPase catalytic site (K111A-Myo1c) in mouse tibialis anterior muscles in vivo and assessed glucose uptake in vivo in the basal state, in response to 15 min of in situ contraction, and 15 min following maximal insulin injection (16.6 units/kg of body weight). Expression of wild-type Myo1c or K111A-Myo1c had no effect on basal glucose uptake. However, expression of wild-type Myo1c significantly increased contraction- and insulin-stimulated glucose uptake, whereas expression of K111A-Myo1c decreased both contraction-stimulated and insulin-stimulated glucose uptake. Neither wild-type nor K111A-Myo1c expression altered GLUT4 expression, and neither affected contraction- or insulin-stimulated signaling proteins. Myo1c is a novel mediator of both insulin-stimulated and contraction- stimulated glucose uptake in skeletal muscle. C1 [Toyoda, Taro; An, Ding; Witczak, Carol A.; Koh, Ho-Jin; Hirshman, Michael F.; Fujii, Nobuharu; Goodyear, Laurie J.] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Goodyear, Laurie J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Goodyear, Laurie J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Goodyear, LJ (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. EM goodyear@joslin.harvard.edu RI Fujii, Nobuharu/J-2724-2014 OI Fujii, Nobuharu/0000-0002-0974-3033 FU National Institutes of Health [R01 AR45670, R01 AR42238, F32AR051663, K99AR056298]; Diabetes and Endocrinology Research Center [P30 DK36836]; Joslin Diabetes Center; Japan Society for the Promotion of Science Kakenhi [21240063]; Nakatomi Foundation; Naito Foundation; Uehara Memorial Foundation; American Diabetes Association; Canadian Institute for Health Research [MFE-83802]; Canadian Diabetes Association [PF-3-07-2255-DA]; American Physiological Society (APS); Japan Society for the Promotion of Science FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 AR45670 and R01 AR42238 (to L. J. G.), F32AR051663 and K99AR056298 (to C. A. W.), and the Diabetes and Endocrinology Research Center grant P30 DK36836 (to the Joslin Diabetes Center). This work was also supported by funding from the Graetz Challenge Grant Program of the Joslin Diabetes Center (to L. J. G.); the Japan Society for the Promotion of Science Kakenhi 21240063 (to N. F.); grants from the Nakatomi Foundation, the Naito Foundation, the Uehara Memorial Foundation, and the Japan Society for the Promotion of Science (to T. T.); an American Diabetes Association Mentor-based Award (to L. J. G.); a fellowship from the Canadian Institute for Health Research (MFE-83802) and a Canadian Diabetes Association Incentive Award PF-3-07-2255-DA (to D. A.); and the American Physiological Society (APS) Fellowship in Physiological Genomics (to H.-J. K.). NR 58 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4133 EP 4140 DI 10.1074/jbc.M110.174938 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700012 PM 21127070 ER PT J AU Novgorodov, SA Chudakova, DA Wheeler, BW Bielawski, J Kindy, MS Obeid, LM Gudz, TI AF Novgorodov, Sergei A. Chudakova, Daria A. Wheeler, Brian W. Bielawski, Jacek Kindy, Mark S. Obeid, Lina M. Gudz, Tatyana I. TI Developmentally Regulated Ceramide Synthase 6 Increases Mitochondrial Ca2+ Loading Capacity and Promotes Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PERMEABILITY TRANSITION PORE; NERVE GROWTH-FACTOR; BRAIN MITOCHONDRIA; CELL-DEATH; CYSTINE/GLUTAMATE ANTIPORTER; (DIHYDRO)CERAMIDE SYNTHASE; SUBSTRATE-SPECIFICITY; N-ACYLTRANSFERASE; CALPAIN INHIBITOR; CNS MITOCHONDRIA AB Ceramides, which are membrane sphingolipids and key mediators of cell-stress responses, are generated by a family of (dihydro) ceramide synthases (Lass1-6/CerS1-6). Here, we report that brain development features significant increases in sphingomyelin, sphingosine, and most ceramide species. In contrast, C-16:0-ceramide was gradually reduced and CerS6 was down-regulated in mitochondria, thereby implicating CerS6 as a primary ceramide synthase generating C-16:0-ceramide. Investigations into the role of CerS6 in mitochondria revealed that ceramide synthase down-regulation is associated with dramatically decreased mitochondrial Ca2+-loading capacity, which could be rescued by addition of ceramide. Selective CerS6 complexing with the inner membrane component of the mitochondrial permeability transition pore was detected by immunoprecipitation. This suggests that CerS6-generated ceramide could prevent mitochondrial permeability transition pore opening, leading to increased Ca2+ accumulation in the mitochondrial matrix. We examined the effect of high CerS6 expression on cell survival in primary oligodendrocyte (OL) precursor cells, which undergo apoptotic cell death during early postnatal brain development. Exposure of OLs to glutamate resulted in apoptosis that was prevented by inhibitors of de novo ceramide biosynthesis, myriocin and fumonisin B1. Knockdown of CerS6 with siRNA reduced glutamate-triggered OL apoptosis, whereas knockdown of CerS5 had no effect: the pro-apoptotic role of CerS6 was not stimulus-specific. Knockdown of CerS6 with siRNA improved cell survival in response to nerve growth factor-induced OL apoptosis. Also, blocking mitochondrial Ca2+ uptake or decreasing Ca2+-dependent protease calpain activity with specific inhibitors prevented OL apoptosis. Finally, knocking down CerS6 decreased calpain activation. Thus, our data suggest a novel role for CerS6 in the regulation of both mitochondrial Ca2+ homeostasis and calpain, which appears to be important in OL apoptosis during brain development. C1 [Obeid, Lina M.; Gudz, Tatyana I.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Chudakova, Daria A.; Wheeler, Brian W.; Kindy, Mark S.; Gudz, Tatyana I.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Novgorodov, Sergei A.; Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Novgorodov, Sergei A.; Bielawski, Jacek; Obeid, Lina M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Gudz, TI (reprint author), 114 Doughty St, Charleston, SC 29425 USA. EM gudz@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health for NCCR COBRE in Lipidomics and Pathobiology [P20 RR 17677, AG16583]; Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health Grant P20 RR 17677 for NCCR COBRE in Lipidomics and Pathobiology (to T. I. G.), Grant AG16583 (to L. M. O.), and Veterans Affairs Rehabilitation Research and Development Merit Awards (to T. I. G. and M. S. K.). NR 79 TC 31 Z9 33 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB PY 2011 VL 286 IS 6 BP 4644 EP 4658 DI 10.1074/jbc.M110.164392 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 716MW UT WOS:000286975700064 PM 21148554 ER PT J AU Hajjarian, Z Xi, JQ Jaffer, FA Tearney, GJ Nadkarni, SK AF Hajjarian, Zeinab Xi, Jingqun Jaffer, Farouc A. Tearney, Guillermo J. Nadkarni, Seemantini K. TI Intravascular laser speckle imaging catheter for the mechanical evaluation of the arterial wall SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE Atherosclerosis; viscoelasticity; intracoronary; catheter; laser speckle imaging ID CORONARY ATHEROSCLEROTIC PLAQUES; FIBROUS CAP THICKNESS; VULNERABLE PLAQUE; ULTRASOUND; RUPTURE; STRESS; LESION AB Laser speckle imaging (LSI) is a novel technique for measuring the mechanical properties of atherosclerotic plaques. In LSI, the decorrelation time constant of speckle intensity fluctuations provides an index of viscoelasticity that is closely related to plaque microstructure and composition. Here, we demonstrate for the first time, the feasibility of conducting LSI in vivo using a prototype 1.5 mm (4.5 Fr) diameter intravascular catheter. Investigation of the catheter performance using human arterial samples ex vivo shows that plaque time constants measured by the LSI catheter correlate well with those measured using a free-space bulk optics system. To demonstrate LSI in vivo, the catheter is interfaced with a portable console for intravascular evaluation in the aorta of a living rabbit. Distinct differences in arterial time constants are identified at normal aortic and stented sites in vivo with intravascular LSI. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3533322] C1 [Nadkarni, Seemantini K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Massachusetts Gen Hosp BAR 7, Boston, MA 02114 USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Nadkarni, SK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Massachusetts Gen Hosp BAR 7, Boston, MA 02114 USA. EM seemantini_nadkarni@hms.harvard.edu OI Jaffer, Farouc/0000-0001-7980-384X FU NIH [R21 HL 088306, ARRA R21 HL 088306-02S1] FX The authors thank Jose-Luiz Guerrero and Adam Mauskapf for their assistance in conducting in vivo animal studies. This work was supported in part by the NIH Grant Nos. R21 HL 088306 (S.N) and the ARRA R21 HL 088306-02S1 (S.N.). NR 30 TC 15 Z9 17 U1 0 U2 7 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD FEB PY 2011 VL 16 IS 2 AR 026005 DI 10.1117/1.3533322 PG 7 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 742JW UT WOS:000288939200034 PM 21361689 ER PT J AU Imitola, J Cote, D Rasmussen, S Xie, XS Liu, YR Chitnis, T Sidman, RL Lin, CP Khoury, SJ AF Imitola, Jaime Cote, Daniel Rasmussen, Stine Xie, X. Sunney Liu, Yingru Chitnis, Tanuja Sidman, Richard L. Lin, Charles. P. Khoury, Samia J. TI Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE confocal; reflectance; coherent anti-Stokes Raman scattering; live imaging; CX(3)CR1-green fluorescence protein; microglia; neurodegeneration ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; NERVE-FIBER LAYER; IN-VIVO; MICROTUBULE CONTRIBUTION; NEURONAL DYSFUNCTION; CONFOCAL MICROSCOPY; INJURY; REFLECTANCE; PATHWAY; DEMYELINATION AB Myelin loss and axonal degeneration predominate in many neurological disorders; however, methods to visualize them simultaneously in live tissue are unavailable. We describe a new imaging strategy combining video rate reflectance and fluorescence confocal imaging with coherent anti-Stokes Raman scattering (CARS) microscopy tuned to CH(2) vibration of myelin lipids, applied in live tissue of animals with chronic experimental autoimmune encephalomyelitis (EAE). Our method allows monitoring over time of demyelination and neurodegeneration in brain slices with high spatial resolution and signal-to-noise ratio. Local areas of severe loss of lipid signal indicative of demyelination and loss of the reflectance signal from axons were seen in the corpus callosum and spinal cord of EAE animals. Even in myelinated areas of EAE mice, the intensity of myelin lipid signals is significantly reduced. Using heterozygous knock-in mice in which green fluorescent protein replaces the CX(3)CR1 coding sequence that labels central nervous system microglia, we find areas of activated microglia colocalized with areas of altered reflectance and CARS signals reflecting axonal injury and demyelination. Our data demonstrate the use of multimodal CARS microscopy for characterization of demyelinating and neurodegenerative pathology in a mouse model of multiple sclerosis, and further confirm the critical role of microglia in chronic inflammatory neurodegeneration. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI:10.1117/1.3533312] C1 [Imitola, Jaime; Rasmussen, Stine; Liu, Yingru; Chitnis, Tanuja; Khoury, Samia J.] Harvard Univ, Partner Multiple Sclerosis Ctr, Brigham & Womens Hosp, Ctr Neurol Dis,Sch Med,Dept Neurol, Boston, MA 02115 USA. [Cote, Daniel; Xie, X. Sunney; Lin, Charles. P.] Massachusetts Gen Hosp, Adv Microscopy Program, Ctr Syst Biol, Boston, MA 02114 USA. [Cote, Daniel; Xie, X. Sunney; Lin, Charles. P.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Sidman, Richard L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Cote, Daniel] Univ Laval, Ctr Rech Univ Laval Robert Giffard, Quebec City, PQ G1J 2G3, Canada. [Cote, Daniel] Ctr Opt Photon & Laser, Quebec City, PQ G1J 2G3, Canada. RP Khoury, SJ (reprint author), Harvard Univ, Partner Multiple Sclerosis Ctr, Brigham & Womens Hosp, Ctr Neurol Dis,Sch Med,Dept Neurol, 77 Ave Louis Pasteur,HIM 712, Boston, MA 02115 USA. EM skhoury@rics.bwh.harvard.edu RI Cote, Daniel/D-5185-2011; imitola, jaime/J-8478-2015; OI khoury, samia/0000-0003-3198-6063 FU NMSS [RG2988, RG35041, 1239]; NIAID [AI043496, AI058680]; NIBIB [EB000664]; NSERC Canada; NINDS [KO8 NS 047669-01]; University of Southern Denmark; Horslev Fonden in Denmark FX This study was funded through the following: Grant Nos. RG2988 and RG35041 from NMSS, Grant Nos. AI043496 and AI058680 from NIAID to S.J.K.; Grant No. EB000664 from NIBIB to C.P.L.; NSERC Canada Research Chairs to D.C.; Grant No. KO8 NS 047669-01 from NINDS to T.C.; NMSS Pilot Project No. 1239 to J.I.; and a faculty PhD scholarship from University of Southern Denmark and a grant from Horslev Fonden in Denmark to S.R.. The authors thank Dr. Bing Zhu, MD, PhD, for critical reading of the manuscript and suggestions. NR 31 TC 28 Z9 28 U1 0 U2 25 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD FEB PY 2011 VL 16 IS 2 AR 021109 DI 10.1117/1.3533312 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 742JW UT WOS:000288939200016 PM 21361672 ER PT J AU Khuman, J Meehan, WP Zhu, XX Qiu, JH Hoffmann, U Zhang, J Giovannone, E Lo, EH Whalen, MJ AF Khuman, Jugta Meehan, William P., III Zhu, Xiaoxia Qiu, Jianhua Hoffmann, Ulrike Zhang, Jimmy Giovannone, Eric Lo, Eng H. Whalen, Michael J. TI Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE cognition; concussion; inflammation; mice; traumatic brain injury; tumor necrosis factor ID CLOSED-HEAD INJURY; HIPPOCAMPAL SYNAPTIC PLASTICITY; NEURONAL LOSS; TNF-ALPHA; RAT; MEMORY; INVOLVEMENT; IMPAIRMENT; EXPRESSION; MODEL AB Tumor necrosis factor alpha (TNF alpha) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNF alpha/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-alpha mRNA, Fas mRNA, and TNF alpha protein were increased in the brain at 3 to 6 hours after injury (P < 0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P = 0.009) and probe deficits (P = 0.001) in the Morris water maze versus sham. Surprisingly, injured TNF alpha/Fas knockout (KO) mice performed worse in hidden platform trials (P = 0.036) but better in probe trials than did WT mice (P = 0.0001). Administration of recombinant TNF alpha to injured TNF alpha/Fas KO mice reduced probe trial performance to that of WT. Thus, TNF alpha/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNF alpha/Fas together may be inappropriate for patients with concussive TBI. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 778-789; doi:10.1038/jcbfm.2010.172; published online 13 October 2010 C1 [Khuman, Jugta; Zhang, Jimmy; Giovannone, Eric; Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. [Khuman, Jugta; Meehan, William P., III; Zhu, Xiaoxia; Qiu, Jianhua; Hoffmann, Ulrike; Zhang, Jimmy; Giovannone, Eric; Lo, Eng H.; Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA 02129 USA. [Meehan, William P., III] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Emergency Med,Dept Med, Boston, MA USA. [Meehan, William P., III] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Sports Med,Dept Orthoped,Sports Concuss Clin, Boston, MA USA. [Zhu, Xiaoxia] Fudan Univ, Huashan Hosp, Dept Rheumatol, Shanghai 200433, Peoples R China. [Qiu, Jianhua; Hoffmann, Ulrike; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. RP Whalen, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. EM mwhalen@partners.org FU NICHD [T32 HD040128-06]; NINDS [5RO1NS047447]; MGH Center for the Integration of Medicine and Technology (CIMIT) FX This work was supported by grants from NICHD T32 HD040128-06 (WM), NINDS 5RO1NS047447 (MJW), and MGH Center for the Integration of Medicine and Technology (CIMIT) (MJW). NR 37 TC 28 Z9 30 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD FEB PY 2011 VL 31 IS 2 BP 778 EP 789 DI 10.1038/jcbfm.2010.172 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 715XY UT WOS:000286930100038 PM 20940727 ER PT J AU Page, ST Lin, DW Mostaghel, EA Marck, BT Wright, JL Wu, J Amory, JK Nelson, PS Matsumoto, AM AF Page, Stephanie T. Lin, Daniel W. Mostaghel, Elahe A. Marck, Brett T. Wright, Jonathan L. Wu, Jennifer Amory, John K. Nelson, Peter S. Matsumoto, Alvin M. TI Dihydrotestosterone Administration Does Not Increase Intraprostatic Androgen Concentrations or Alter Prostate Androgen Action in Healthy Men: A Randomized-Controlled Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LATE-ONSET HYPOGONADISM; TESTOSTERONE REPLACEMENT; OLDER MEN; TRANSDERMAL DIHYDROTESTOSTERONE; SERUM TESTOSTERONE; DOUBLE-BLIND; CANCER; FINASTERIDE; CASTRATION; HYPERPLASIA AB Context: Concern exists that androgen treatment might adversely impact prostate health in older men. Dihydrotestosterone (DHT), derived from local conversion of testosterone to DHT by 5 alpha-reductase enzymes, is the principal androgen within the prostate. Exogenous androgens raise serum DHT concentrations, but their effects on the prostate are not clear. Objective: To determine the impact of large increases in serum DHT concentrations on intraprostatic androgen concentrations and androgen action within the prostate. Design: Double-blind, randomized, placebo-controlled. Setting: Single academic medical center. Participants: 31 healthy men ages 35-55. Intervention: Daily transdermal DHT or placebo gel. Main Outcome Measures: Serum and prostate tissue androgen concentrations and prostate epithelial cell gene expression after 4 wk of treatment. Results: Twenty-seven men completed all study procedures. Serum DHT levels increased nearly sevenfold, while testosterone levels decreased in men treated with daily transdermal DHT gel but were unchanged in the placebo-treated group (P < 0.01 between groups). In contrast, intraprostatic DHT and testosterone concentrations on d 28 were not different between groups (DHT: placebo = 2.8 +/- 0.2 vs. DHT gel = 3.1 +/- 0.5 ng/g; T: placebo = 0.6 +/- 0.2 vs. DHT gel = 0.4 +/- 0.1, mean +/- SE). Similarly, prostate volume, prostate-specific antigen, epithelial cell proliferation, and androgen-regulated gene expression were not different between groups. Conclusions: Robust supraphysiologic increases in serum DHT, associated with decreased serum T, do not significantly alter intraprostatic levels of DHT, testosterone, or prostate epithelial cell androgen-regulated gene expression in healthy men. Changes in circulating androgen concentrations are not necessarily mimicked within the prostate microenvironment, a finding with implications for understanding the impact of androgen therapies in men. (J Clin Endocrinol Metab 96: 430-437, 2011) C1 [Page, Stephanie T.] Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98195 USA. [Lin, Daniel W.; Wright, Jonathan L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Lin, Daniel W.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Mostaghel, Elahe A.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol & Clin Res, Seattle, WA 98109 USA. VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Marck, Brett T.; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA 98108 USA. RP Page, ST (reprint author), Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Box 357138,1959 NE Pacific St, Seattle, WA 98195 USA. EM page@u.washington.edu FU National Institute of Aging [K23-AG027238]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54-HD-42454]; Pacific Northwest Prostate Cancer SPORE [P50-CA097186]; Endocrine Society; BHR Pharma LLC; Prostate Cancer Foundation FX This work was supported by the National Institute of Aging (K23-AG027238), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54-HD-42454), the Pacific Northwest Prostate Cancer SPORE (P50-CA097186), an Endocrine Society Clinical Research Award, an investigator-initiated grant from BHR Pharma LLC, and the Prostate Cancer Foundation. S.T.P. received grant support from BHR Pharma LLC. NR 36 TC 27 Z9 27 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2011 VL 96 IS 2 BP 430 EP 437 DI 10.1210/jc.2010-1865 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 716MG UT WOS:000286972500047 PM 21177791 ER PT J AU Huang, Q Fan, XS Feng, AN Lauwers, GY Yu, CC AF Huang, Q. Fan, X. S. Feng, A. N. Lauwers, G. Y. Yu, C. C. TI Distal Esophageal Columnar Metaplasia is Common in Chinese Patients: A Histopathologic Study of 151 Surgical Resection Cases SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Meeting Abstract C1 [Huang, Q.; Fan, X. S.; Feng, A. N.] Nanjing Drum Tower Hosp, Dept Pathol, Nanjing, Peoples R China. [Yu, C. C.] Nanjing Drum Tower Hosp, Dept Gastroenterol, Nanjing, Peoples R China. [Huang, Q.] Vet Affairs Boston Healthcare Syst, Dept Pathol, W Roxbury, MA USA. [Huang, Q.; Lauwers, G. Y.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Lauwers, G. Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD FEB PY 2011 VL 45 IS 2 BP 192 EP 193 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 707SY UT WOS:000286309600052 ER PT J AU Ory, B Ramsey, MR Wilson, C Vadysirisack, DD Forster, N Rocco, JW Rothenberg, SM Ellisen, LW AF Ory, Benjamin Ramsey, Matthew R. Wilson, Catherine Vadysirisack, Douangsone D. Forster, Nicole Rocco, James W. Rothenberg, S. Michael Ellisen, Leif W. TI A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID P53 FAMILY; DNA-DAMAGE; P73-DEPENDENT APOPTOSIS; TP53 MUTATIONS; NECK-CANCER; P63; P73; EXPRESSION; CISPLATIN; HEAD AB The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions - p73 mediates chemosensitivity while p63 promotes proliferation and cell survival - and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors. C1 [Ory, Benjamin; Ramsey, Matthew R.; Wilson, Catherine; Vadysirisack, Douangsone D.; Forster, Nicole; Rothenberg, S. Michael; Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ory, Benjamin; Ramsey, Matthew R.; Wilson, Catherine; Vadysirisack, Douangsone D.; Forster, Nicole; Rothenberg, S. Michael; Ellisen, Leif W.] Harvard Univ, Sch Med, Boston, MA USA. [Rocco, James W.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Rocco, James W.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, GRJ 904,55 Fruit St, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu RI ory, benjamin/K-8231-2015; OI Ramsey, Matthew/0000-0003-2402-8502 FU NIH [RO1 DE-015945, K08 DE-020139]; Fondation pour la Recherche Medicale; Susan G. Komen for the Cure [KG091277] FX We thank Alea Mills for the gift of the p63lox mice; Peter M. Sadow For pathological review of HNSCC specimens; Philippe Hulin, Nantes University, IFR 26, PICell, for time lapse microscopy; Zachary Nash for technical assistance; and Lee Zou, Shobha Vasudevan, and members of the Ellisen laboratory for critical review of the manuscript. This work was supported by NIH RO1 DE-015945 (to L.W. Ellisen), by NIH K08 DE-020139 (to S.M. Rothenberg), and by Fondation pour la Recherche Medicale and Susan G. Komen for the Cure KG091277 (to B. Ory). NR 50 TC 38 Z9 39 U1 0 U2 3 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2011 VL 121 IS 2 BP 809 EP 820 DI 10.1172/JCI43897 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 715UO UT WOS:000286913800041 PM 21293058 ER PT J AU Ehrenfeld, JM Rehman, MA AF Ehrenfeld, Jesse M. Rehman, Mohamed A. TI ANESTHESIA INFORMATION MANAGEMENT SYSTEMS: A REVIEW OF FUNCTIONALITY AND INSTALLATION CONSIDERATIONS SO JOURNAL OF CLINICAL MONITORING AND COMPUTING LA English DT Article DE anesthesia; information systems; AIMS; informatics; software ID NONCARDIAC SURGERY; OPERATING-ROOM; RECORD; DOCUMENTATION; CARE; IMPLEMENTATION; REIMBURSEMENT; PERFORMANCE; QUALITY; EVENTS AB The functionality and rate of implementation of Anesthesia Information Management Systems (AIMS) has markedly risen over the past decade. These systems have now become much more than the generic automated record keepers, originally proposed and developed in the 1980s. AIMS have now become complex integrated systems, which have been shown to improve patient care and, in some cases, the financial performance of a department. Although the underlying technology has improved greatly over the past 5 years, the process of selecting and completing an AIMS installation still presents a number of challenges, and must be approached carefully in order to maximize the benefits provided by these systems. C1 [Ehrenfeld, Jesse M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Rehman, Mohamed A.] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Rehman, Mohamed A.] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. RP Ehrenfeld, JM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Jackson 458, Boston, MA 02114 USA. EM jehrenfe@post.harvard.edu; Rehman@email.chop.edu OI Ehrenfeld, Jesse/0000-0003-3427-0140 FU Foundation for Anesthesia Education and Research; National Institute of Health [5T32GM007592]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital FX Financial support for the preparation of this manuscript was provided from a Research Fellowship Grant from the Foundation for Anesthesia Education and Research, 5T32GM007592 from the National Institute of Health, as well as by department funds of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital. There are no conflicts of interest. Portions of the article were adapted from "Anesthesia Information Management Systems: A Guide to Their Successful Installation and Use" Anesthesiology News, September 2009. NR 35 TC 16 Z9 16 U1 1 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1387-1307 J9 J CLIN MONIT COMPUT JI J. Clin. Monitor. Comp. PD FEB PY 2011 VL 25 IS 1 BP 71 EP 79 DI 10.1007/s10877-010-9256-y PG 9 WC Anesthesiology SC Anesthesiology GA 872IP UT WOS:000298803000004 PM 20734117 ER PT J AU Isakoff, SJ Baselga, J AF Isakoff, Steven J. Baselga, Jose TI Trastuzumab-DM1: Building a Chemotherapy-Free Road in the Treatment of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID MONOCLONAL-ANTIBODY; ADJUVANT CHEMOTHERAPY; INHIBITOR; PLUS; COMBINATION; PERTUZUMAB; LAPATINIB; EFFICACY; THERAPY; COMPLEX C1 [Isakoff, Steven J.; Baselga, Jose] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Isakoff, SJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. NR 30 TC 19 Z9 21 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 FEB 1 PY 2011 VL 29 IS 4 BP 351 EP 354 DI 10.1200/JCO.2010.31.6679 PG 4 WC Oncology SC Oncology GA 717XR UT WOS:000287081800019 PM 21172881 ER PT J AU Crawford, ED Grubb, R Black, A Andriole, GL Chen, MH Izmirlian, G Berg, CD D'Amico, AV AF Crawford, E. David Grubb, Robert, III Black, Amanda Andriole, Gerald L., Jr. Chen, Ming-Hui Izmirlian, Grant Berg, Christine D. D'Amico, Anthony V. TI Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; COMPETING RISK; RADIOTHERAPY; COMPLICATIONS; FAILURE; DEATH AB Purpose Estimates of prostate cancer-specific mortality (PCSM) were similar for men randomly assigned to intervention compared with usual care on the Prostate, Lung, Colorectal and Ovarian PC screening study. However, results analyzed by comorbidity strata remain unknown. Patients and Methods Between 1993 and 2001, of 76,693 men who were randomly assigned to usual care or intervention at 10 US centers, 73,378 (96%) completed a questionnaire that inquired about comorbidity and prostate-specific antigen (PSA) testing before random assignment. Fine and Gray's multivariable analysis was performed to assess whether the randomized screening arm was associated with the risk of PCSM in men with no or minimal versus at least one significant comorbidity, adjusting for age and prerandomization PSA testing. Results After 10 years of follow-up, 9,565 deaths occurred, 164 from PC. A significant decrease in the risk of PCSM ( 22 v 38 deaths; adjusted hazard ratio [AHR], 0.56; 95% CI, 0.33 to 0.95; P = .03) was observed in men with no or minimal comorbidity randomly assigned to intervention versus usual care, and the additional number needed to treat to prevent one PC death at 10 years was five. Among men with at least one significant comorbidity, those randomly assigned to intervention versus usual care did not have a decreased risk of PCSM ( 62 v 42 deaths; AHR, 1.43; 95% CI, 0.96 to 2.11; P = .08). Conclusion Selective use of PSA screening for men in good health appears to reduce the risk of PCSM with minimal overtreatment. J Clin Oncol 29: 355-361. (c) 2010 by American Society of Clinical Oncology C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Washington Univ, Sch Med, St Louis, MO USA. NCI, Rockville, MD USA. Univ Connecticut, Storrs, CT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,,L-2 Level, Boston, MA 02115 USA. EM adamico@partners.org RI Berg , Christine/K-1047-2014 FU National Cancer Institute; University of Colorado [N01-CN-25514]; Georgetown University [N01-CN-25522]; Pacific Health Research Institute [N01-CN-25515]; Henry Ford Health System [N01-CN-25512]; University of Minnesota [N01-CN-25513]; Washington University [N01-CN-25516]; University of Pittsburgh Medical Center [N01-CN-25511]; University of Utah [N01-CN-25524]; Marshfield Clinic Research Foundation [N01-CN-25518]; University of Alabama at Birmingham [N01-CN-75022]; Westat [N01-CN-25476]; University of California at Los Angeles Immunogenetics Center [N01-CN-25404]; GlaxoSmithKline; Aeterna Zentaris; Antigenics; Ferring Pharmaceuticals FX Supported by the National Cancer Institute and Grants No. N01-CN-25514, University of Colorado; N01-CN-25522, Georgetown University; N01-CN-25515, Pacific Health Research Institute; N01-CN-25512, Henry Ford Health System; N01-CN-25513, University of Minnesota; N01-CN-25516, Washington University; N01-CN-25511, University of Pittsburgh Medical Center; N01-CN-25524, University of Utah; N01-CN-25518, Marshfield Clinic Research Foundation; N01-CN-75022, University of Alabama at Birmingham; N01-CN-25476, Westat; and N01-CN-25404, University of California at Los Angeles Immunogenetics Center.; Robert Grubb III, GlaxoSmithKline; Gerald L. Andriole Jr, Aeterna Zentaris, Antigenics, Ferring Pharmaceuticals, Veridex Expert Testimony: None Other Remuneration: None NR 25 TC 75 Z9 76 U1 0 U2 2 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 FEB 1 PY 2011 VL 29 IS 4 BP 355 EP 361 DI 10.1200/JCO.2010.30.5979 PG 7 WC Oncology SC Oncology GA 717XR UT WOS:000287081800020 PM 21041707 ER PT J AU Burris, HA Rugo, HS Vukelja, SJ Vogel, CL Borson, RA Limentani, S Tan-Chiu, E Krop, IE Michaelson, RA Girish, S Amler, L Zheng, MX Chu, YW Klencke, B O'Shaughnessy, JA AF Burris, Howard A., III Rugo, Hope S. Vukelja, Svetislava J. Vogel, Charles L. Borson, Rachel A. Limentani, Steven Tan-Chiu, Elizabeth Krop, Ian E. Michaelson, Richard A. Girish, Sandhya Amler, Lukas Zheng, Maoxia Chu, Yu-Waye Klencke, Barbara O'Shaughnessy, Joyce A. TI Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) -Positive Breast Cancer After Prior HER2-Directed Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MAYTANSINE; INHIBITOR; PLUS; CHEMOTHERAPY; PERTUZUMAB; TRIAL AB Purpose The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. Patients and Methods This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. Results With a follow-up of >= 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed >= median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade >= 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). Conclusion T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose. J Clin Oncol 29: 398-405. (C) 2010 by American Society of Clinical Oncology C1 [Burris, Howard A., III] Sarah Cannon Res Inst, Nashville, TN 37203 USA. Univ Calif San Francisco, San Francisco Helen Diller Family Comprehens Canc, San Francisco, CA USA. US Oncol, Tyler Canc Ctr, Texas Oncol, Tyler, TX USA. US Oncol, Baylor Sammons Canc Ctr, Dallas, TX USA. Lynn Canc Inst, Boca Raton, FL USA. Florida Canc Care, Davie, FL USA. St Louis Canc & Breast Inst, St Louis, MO USA. Univ N Carolina, Blumenthal Canc Ctr, Charlotte, NC 28223 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Barnabas Hosp, Livingston, NJ USA. RP Burris, HA (reprint author), Sarah Cannon Res Inst, 250 25th Ave N,Ste 110, Nashville, TN 37203 USA. EM howard.burris@scresearch.net FU Genentech; Roche FX Hope S. Rugo, Genentech, Roche; Charles L. Vogel, Genentech; Steven Limentani, Genentech; Elizabeth Tan-Chiu, Genentech; Ian E. Krop, Genentech NR 27 TC 277 Z9 285 U1 3 U2 53 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 FEB 1 PY 2011 VL 29 IS 4 BP 398 EP 405 DI 10.1200/JCO.2010.29.5865 PG 8 WC Oncology SC Oncology GA 717XR UT WOS:000287081800026 PM 21172893 ER PT J AU Bohanes, PO Goldman, BH Benedetti, J Blanke, CD Leichman, LP Iqbal, S Thomas, CR Corless, CL Gold, PJ Lenz, H AF Bohanes, P. O. Goldman, B. H. Benedetti, J. Blanke, C. D. Leichman, L. P. Iqbal, S. Thomas, C. R., Jr. Corless, C. L. Gold, P. J. Lenz, H. TI Association of excision repair cross-complementation group 1 (ERCC1) gene expression (GE) with outcome in stage II-III esophageal adenocarcinoma (EA) patients treated with preoperative platinum-based chemoradiation (CRT) in a phase II cooperative study (SWOG 0356). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. SW Oncol Grp, Ctr Stat, Seattle, WA USA. Univ British Columbia, British Columbia Canc Agcy, Vancouver, BC V5Z 1M9, Canada. Desert Reg Med Ctr, Ctr Comprehens Canc, Palm Springs, CA USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. Swedish Canc Inst, Seattle, WA 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 2 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100003 PM 27985783 ER PT J AU George, S Lechner, T Li, S Cohen, DP Demetri, GD AF George, S. Lechner, T. Li, S. Cohen, D. P. Demetri, G. D. TI Hypertension (HTN) as a potential biomarker of efficacy in patients (pts) with gastrointestinal stromal tumor (GIST) treated with sunitinib (SU) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Pfizer Oncol, New York, NY USA. Pfizer Oncol, Shanghai, Peoples R China. Pfizer Oncol, La Jolla, CA 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 38 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100038 PM 27985734 ER PT J AU Gunderson, LL Winter, KA Ajani, JA Pedersen, JE Benson, AB Thomas, CR Mayer, RJ Haddock, MG Rich, TA Willett, CG AF Gunderson, L. L. Winter, K. A. Ajani, J. A. Pedersen, J. E. Benson, A. B. Thomas, C. R., Jr. Mayer, R. J. Haddock, M. G. Rich, T. A. Willett, C. G. TI Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: Comparison of concurrent chemoradiation with 5FU-mitomycin versus 5FU-cisplatin for disease-free and overall survival. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Arizona Canc Ctr, Scottsdale, AZ USA. RTOG Stat Ctr, Philadelphia, PA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Univ Virginia, Med Ctr, Charlottesville, VA USA. Duke Univ, Med Ctr, Durham, NC 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 367 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100365 PM 27985486 ER PT J AU Lu, J Deng, H Tang, R Hsu, C Kindler, HL Fuchs, C Gansert, J Bray, S Loh, E Zhu, M AF Lu, J. Deng, H. Tang, R. Hsu, C. Kindler, H. L. Fuchs, C. Gansert, J. Bray, S. Loh, E. Zhu, M. TI Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Amgen Inc, Thousand Oaks, CA USA. Univ Chicago, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Amgen Inc, Cambridge, England. Amgen Inc, San Francisco, CA 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 263 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100262 PM 27985584 ER PT J AU Mizukami, Y Kawamoto, T Sugiyama, Y Sasajima, J Koizumi, K Moriichi, K Fujiya, M Bardeesy, N Chung, DC Kohgo, Y AF Mizukami, Y. Kawamoto, T. Sugiyama, Y. Sasajima, J. Koizumi, K. Moriichi, K. Fujiya, M. Bardeesy, N. Chung, D. C. Kohgo, Y. TI Effect of transplantation of pro-angiogenic monocytes to pancreatic cancer-bearing mice on resistance to chemotherapy/radiotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Asahikawa Med Coll, Asahikawa, Hokkaido 078, Japan. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 212 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100212 PM 27985919 ER PT J AU Pawlik, TM Pulitano, C Alexandrescu, S Gamblin, TC Ferrone, C Sotiropoulos, G Marques, H Bauer, TW Gigot, J Montha, G AF Pawlik, T. M. Pulitano, C. Alexandrescu, S. Gamblin, T. C. Ferrone, C. Sotiropoulos, G. Marques, H. Bauer, T. W. Gigot, J. Montha, G. CA Int Intrahepatic Cholangiocarcinom TI Intrahepatic cholangiocarcinoma: An international, multi-institutional analysis of prognostic factors and lymph node assessment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Ist Sci San Raffaele, Liver Unit, I-20132 Milan, Italy. Fundeni Clin Inst Digest, Bucharest, Romania. Univ Pittsburgh, Med Ctr, Neuroendocrine Canc Treatment Ctr, Pittsburgh, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Hosp Essen, Essen, Netherlands. Curry Cabral Hosp, Lisbon, Portugal. Univ Virginia, Charlottesville, VA USA. Clin Univ St Luc, B-1200 Brussels, Belgium. Univ Hosp Geneva, Dept Visceral Surg, Geneva, Switzerland. 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 162 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100163 PM 27985653 ER PT J AU Sargent, DJ Shi, Q Bot, BM Resnick, MB Meyers, MO Goldar-Najafi, A Clancy, TE Gill, S Siemons, GO Fradet, Y AF Sargent, D. J. Shi, Q. Bot, B. M. Resnick, M. B. Meyers, M. O. Goldar-Najafi, A. Clancy, T. E. Gill, S. Siemons, G. O. Fradet, Y. TI GCC expression in lymph nodes (LNs) as a significant determinant of recurrence in stage II colon cancer (CC) patients (pts) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Rochester, MN USA. Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. Rhode Isl Hosp, Providence, RI USA. Brown Univ, Providence, RI 02912 USA. Univ N Carolina, Sch Med, Div Surg Oncol & Endocrine Surg, Chapel Hill, NC USA. Lahey Clin Fdn, Burlington, MA USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Centennial Med Ctr, Voorhees, NJ USA. DiagnoCure, Quebec City, PQ, Canada. 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 369 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100367 PM 27985505 ER PT J AU Schoenfeld, JD Mamon, HJ Blaszkowsky, LS Enzinger, PC Wo, JY Allen, JN Wadlow, RC Ryan, DP Hong, TS AF Schoenfeld, J. D. Mamon, H. J. Blaszkowsky, L. S. Enzinger, P. C. Wo, J. Y. Allen, J. N. Wadlow, R. C. Ryan, D. P. Hong, T. S. TI Gastric adenocarcinoma treated with radiation with or without epirubicin-based chemotherapy: Evaluation of radiation-induced liver disease 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. 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 110 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100110 PM 27985444 ER PT J AU Shacham, S Kauffman, M Sandanayaka, V Draetta, G Shechter, S Williams, J Nir, R AF Shacham, S. Kauffman, M. Sandanayaka, V. Draetta, G. Shechter, S. Williams, J. Nir, R. TI Preclinical development of small-molecule CRM1 inhibitors as novel therapy for the treatment of colorectal cancer (CRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Karyopharm Therapeut, Newton, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. SBH Sci, Natick, MA 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 430 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100427 PM 27985840 ER PT J AU Wadlow, RC Hezel, AF Wolpin, BM Allen, JN Blaszkowsky, LS Kwak, EL Wang, R Zhu, AX Ryan, DP Clark, JW AF Wadlow, R. C. Hezel, A. F. Wolpin, B. M. Allen, J. N. Blaszkowsky, L. S. Kwak, E. L. Wang, R. Zhu, A. X. Ryan, D. P. Clark, J. W. TI A single-arm trial of panitumumab in cetuximab refractory KRAS wild-type colorectal cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 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 FEB 1 PY 2011 VL 29 IS 4 SU S MA 428 PG 1 WC Oncology SC Oncology GA V30WW UT WOS:000208847100425 PM 27985823 ER PT J AU Daly, EJ Trivedi, MH Fava, M Shelton, R Wisniewski, SR Morris, DW Stegman, D Preskorn, SH Rush, AJ AF Daly, Ella J. Trivedi, Madhukar H. Fava, Maurizio Shelton, Richard Wisniewski, Stephen R. Morris, David W. Stegman, Diane Preskorn, Sheldon H. Rush, A. John TI The Relationship Between Adverse Events During Selective Serotonin Reuptake Inhibitor Treatment for Major Depressive Disorder and Nonremission in the Suicide Assessment Methodology Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE major depressive disorder; adverse events; remission ID STAR-ASTERISK-D; MEASUREMENT-BASED CARE; DIAGNOSTIC SCREENING QUESTIONNAIRE; SEQUENCED TREATMENT ALTERNATIVES; REPORT QIDS-SR; TRANSPORTER POLYMORPHISMS; ANTIDEPRESSANT THERAPY; RATING-SCALE; PSYCHOMETRIC PROPERTIES; SYMPTOMATOLOGY IDS AB Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d] paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2. Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with non-remission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy. C1 [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Mood Disorders Program, Dept Psychiat, Dallas, TX 75390 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. [Shelton, Richard] Vanderbilt Univ, Dept Psychiat, Nashville, TN USA. [Wisniewski, Stephen R.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Preskorn, Sheldon H.] Univ Kansas, Sch Med, Dept Psychiat, Wichita, KS 67214 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. RP Trivedi, MH (reprint author), Univ Texas SW Med Ctr Dallas, Mood Disorders Program, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM madhukar.trivedi@utsouthwestern.edu RI Preskorn, Sheldon/L-9839-2016; OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU National Institute of Mental Health [N01MH90003]; Agency for Healthcare Research and Quality; Corcept Therapeutics, Inc; Cyberonics, Inc; Merck; National Alliance for Research in Schizophrenia and Depression; National Institute on Drug Abuse; Novartis; Pharmacia Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals, Inc; Targacept; Wyeth Laboratory; Ayerst Laboratory; Abbott Laboratories; Alkermes; Aspect Medical Systems; AstraZeneca; Bristol-Myers Squibb Company; Cephalon; Eli Lilly Company; Forest Pharmaceuticals Inc; GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Organon Inc; PamLab, LLC; Pfizer Inc; Pharmavite; Roche; Sanofi/Synthelabo; Eli Lilly and Company; GlaxoSmithKline Pharmaceuticals; Janssen Pharmaceutica; Sanofi Pharmaceutica; AstraZeneca Pharmaceutica; Stanley Medical Research Institute FX This project was funded by the National Institute of Mental Health under Contract N01MH90003 to University of Texas Southwestern Medical Center at Dallas (to Dr Trivedi, principal investigator).; Dr Trivedi has been a consultant or served on speakers' bureaus for Abbott Laboratories, Inc; Abdi Brahim; Akzo (Organon Pharmaceuticals Inc); AstraZeneca; Bristol-Myers Squibb Company; Cephalon, Inc; Fabre-Kramer Pharmaceuticals, Inc; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Neuronetics; Parke-Davis Pharmaceuticals, Inc; Pfizer, Inc; Sepracor; VantagePoint; and Wyeth-Ayerst Laboratories. He has served on speakers' bureaus for Abdi Brahim; Akzo (Organon Pharmaceuticals Inc); BristolMyers Squibb Company; Cephalon, Inc; Cyberonics, Inc; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals, Inc; and Wyeth-Ayerst Laboratories. He has received research support from the Agency for Healthcare Research and Quality; Corcept Therapeutics, Inc; Cyberonics, Inc; Merck; National Alliance for Research in Schizophrenia and Depression; National Institute of Mental Health; National Institute on Drug Abuse; Novartis; Pharmacia & Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals, Inc; Targacept; and Wyeth-Ayerst Laboratories.; Dr Fava has received research support from Abbott Laboratories; Alkermes; Aspect Medical Systems; AstraZeneca; Bristol-Myers Squibb Company; Cephalon; Eli Lilly & Company; Forest Pharmaceuticals Inc; GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis; Organon Inc; PamLab, LLC; Pfizer Inc; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals, Inc; and Wyeth-Ayerst Laboratories. He has provided advisory/consulting services to Aspect Medical Systems; AstraZeneca; Bayer AG; Best Practice Project Management, Inc; Biovail Pharmaceuticals, Inc; BrainCells, Inc; Bristol-Myers Squibb Company; Cephalon; Compellis; CNS Response; Cypress Pharmaceuticals; Dov Pharmaceuticals; Eli Lilly & Company; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals, Inc; Forest Pharmaceuticals Inc; GlaxoSmithKline; Grunenthal GmBH; Janssen Pharmaceutica; Jazz Pharmaceuticals; J & J Pharmaceuticals; Knoll Pharmaceutical Company; Lundbeck; MedAvante, Inc; Merck; Neuronetics; Novartis; Nutrition 21; Organon Inc; PamLab, LLC; Pfizer Inc; PharmaStar; Pharmavite; Precision Human Biolaboratory; Roche; Sanofi/Synthelabo; Sepracor; Solvay Pharmaceuticals, Inc; Somaxon; Somerset Pharmaceuticals; Takeda; and Wyeth-Ayerst Laboratories and served on speakers bureaus with AstraZeneca; Boehringer-Ingelheim; Bristol-Myers Squibb Company; Cephalon; Eli Lilly & Company; Forest Pharmaceuticals Inc; GlaxoSmithKline; Novartis; Organon Inc; Pfizer Inc; PharmaStar; and Wyeth-Ayerst Laboratories. He has equity holdings with Compellis and MedAvante.; Dr Shelton has received grant/research support from Eli Lilly and Company; GlaxoSmithKline Pharmaceuticals; Janssen Pharmaceutica; Pfizer Inc; Sanofi Pharmaceutica; Wyeth-Ayerst Laboratories; AstraZeneca Pharmaceutica; and Abbott Laboratories; has been a paid consultant to Pfizer Inc; and Janssen Pharmaceutica. He has served on speakers' bureaus for Bristol-Myers Squibb Company; Eli Lilly and Company; Janssen Pharmaceutica; Pfizer Inc; GlaxoSmithKline Pharmaceuticals; Solvay Pharmaceuticals, Inc; Wyeth-Ayerst Laboratories; and Abbott Laboratories.; Dr Preskorn is an employee of the Clinical Research Institute, which has received grant support from Pfizer, Inc.; Dr Rush has received research support from the National Institute of Mental Health and the Stanley Medical Research Institute. He has been on the advisory boards and/or consultant for Advanced Neuromodulation Systems, Inc; AstraZeneca; Best Practice Project Management, Inc; Bristol-Myers Squibb Company; Cyberonics, Inc; Forest Pharmaceuticals; Gerson Lehman Group; GlaxoSmithKline; Jazz Pharmaceuticals; Magellan Health Services; Merck & Co., Inc; Neuronetics; Novartis Pharmaceuticals; Ono Pharmaceutical; Organon USA Inc; Otsuka Pharmaceuticals; PamLab; Pfizer Inc; Transcept Pharmaceuticals; The Urban Institute; and Wyeth-Ayerst Laboratories Inc. He has been on the speakers' bureau for Cyberonics, Inc; Forest Pharmaceuticals, Inc; and GlaxoSmithKline. He has equity holdings (excluding mutual funds/blinded trusts) in Pfizer Inc and has royalty income affiliations with Guilford Publications and Healthcare Technology Systems, Inc. NR 46 TC 8 Z9 9 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2011 VL 31 IS 1 BP 31 EP 38 DI 10.1097/JCP.0b013e318205e17b PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 700UY UT WOS:000285771000006 PM 21192140 ER PT J AU Koizumi, A Jakobs, TC Masland, RH AF Koizumi, Amane Jakobs, Tatjana C. Masland, Richard H. TI Regular Mosaic of Synaptic Contacts Among Three Retinal Neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE retina; synapse; spacing; mosaic ID CONE BIPOLAR CELLS; INNER PLEXIFORM LAYER; MULTIDENDRITIC SENSORY NEURONS; SELECTIVE GANGLION-CELLS; STARBURST AMACRINE CELLS; JACK MACKEREL RETINA; RABBIT RETINA; RECEPTIVE-FIELDS; MAMMALIAN RETINA; MOUSE RETINA AB Retinal bipolar, amacrine, and ganglion cells contact each other within precisely defined synaptic laminae, but the spatial distribution of contacts between the cells is generally treated as random. Here we show that not to be the case. Excitatory inputs to inner retinal neurons were visualized by introduction of a plasmid coding for the postsynaptic protein PSD95-GFP. Our initial finding was that synapses on the dendrites of retinal ganglion cells are regularly spaced, at 2-3-mu m intervals, along the dendrites. Thus, the presence of a PSD95 punctum creates a nearby zone from which other inputs appear to be excluded. Despite their great variation in size and different morphologies, the spacing is similar for the arbors of different retinal ganglion cell types. Regular spacing was also observed for the starburst amacrine cells. This regularity is mirrored in the spacing of axonal varicosities of the stratified bipolar cells, which have a regular, nonrandom interval consistent with that of the PSD95 puncta on ganglion cells. Thus, for each level of the inner plexiform layer all three cell types participate in a single 2D mosaic of synaptic contacts. These findings raise a new set of questions: How does the self-avoidance of synaptic sites along an individual dendrite arise and how is it physically maintained? Why is a regular spacing of inputs important for the computational function of the cells? Finally, which of the three players, if any, is developmentally responsible for the initial establishment of the pattern? J. Comp. Neurol. 519:341-357, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Jakobs, Tatjana C.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab, Boston, MA 02114 USA. RP Jakobs, TC (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab, 5th Floor,243 Charles St, Boston, MA 02114 USA. EM tatjana_jakobs@meei.harvard.edu RI Koizumi, Amane/E-7771-2011; OI Jakobs, Tatjana/0000-0002-8104-9206 FU National Institutes of Health (NIH) [RO1 017169, RO1 EY019703] FX Grant sponsor: National Institutes of Health (NIH); Grant numbers: RO1 017169 and RO1 EY019703. R.H.M. is a Senior Investigator of Research to Prevent Blindness. NR 89 TC 16 Z9 16 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD FEB 1 PY 2011 VL 519 IS 2 BP 341 EP 357 DI 10.1002/cne.22522 PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 696EW UT WOS:000285425700009 PM 21165978 ER PT J AU Ng, R Singh, F Papamanou, DA Song, XQ Patel, C Holewa, C Patel, N Klepac-Ceraj, V Fontana, CR Kent, R Pagonis, TC Stashenko, PP Soukos, NS AF Ng, Raymond Singh, Fiza Papamanou, Despina A. Song, Xiaoqing Patel, Chitrang Holewa, Colleen Patel, Niraj Klepac-Ceraj, Vanja Fontana, Carla R. Kent, Ralph Pagonis, Tom C. Stashenko, Philip P. Soukos, Nikolaos S. TI Endodontic Photodynamic Therapy Ex Vivo SO JOURNAL OF ENDODONTICS LA English DT Article DE Endodontic disinfection; ex vivo; methylene blue; photodynamic therapy ID LIGHT-ACTIVATED DISINFECTION; ROOT-CANAL TREATMENT; OF-THE-LITERATURE; ENTEROCOCCUS-FAECALIS; IN-VITRO; APICAL PERIODONTITIS; EFFICACY; PHOTOSENSITIZATION; INACTIVATION; IRRIGATION AB Introduction: The objective of this study was to evaluate the antimicrobial effects of photodynamic therapy (PDT) on infected human teeth ex vivo. Methods: Fifty-two freshly extracted teeth with pulpal necrosis and associated periradicular radiolucencies were obtained from 34 subjects. Twenty-six teeth with 49 canals received chemomechanical debridement (CMD) with 6% NaOCl, and 26 teeth with 52 canals received CMD plus PDT. For PDT, root canal systems were incubated with methylene blue (MB) at concentration of 50 mu g/mL for 5 minutes, followed by exposure to red light at 665 nm with an energy fluence of 30 J/cm(2). The contents of root canals were sampled by flushing the canals at baseline and after CMD alone or CMD+PDT and were serially diluted and cultured on blood agar. Survival fractions were calculated by counting colony-forming units (CFUs). Partial characterization of root canal species at baseline and after CMD alone or CMD+PDT was performed by using DNA probes to a panel of 39 endodontic species in the checkerboard assay. Results: The Mantel-Haenszel chi(2) test for treatment effects demonstrated the better performance of CMD+PDT over CMD (P = .026). CMD+PDT significantly reduced the frequency of positive canals relative to CMD alone (P = .0003). After CMD+PDT, 45 of 52 canals (86.5%) had no CFUs as compared with 24 of 49 canals (49%) treated with CMD (canal flush samples). The CFU reductions were similar when teeth or canals were treated as independent entities. Post-treatment detection levels for all species were markedly lower for canals treated by CMD+PDT than they were for those treated by CMD alone. Bacterial species within dentinal tubules were detected in 17 of 22 (77.3%) and 15 of 29 (51.7%) canals in the CMD and CMD+PDT groups, respectively (P = .034). Conclusions: Data indicate that PDT significantly reduces residual bacteria within the root canal system, and that PDT, if further enhanced by technical improvements, holds substantial promise as an adjunct to CMD. (J Endod 2011;37:217-222) C1 [Ng, Raymond; Singh, Fiza; Pagonis, Tom C.] Harvard Univ, Sch Dent Med, Div Endodont, Boston, MA 02115 USA. [Papamanou, Despina A.; Song, Xiaoqing; Patel, Chitrang; Holewa, Colleen; Patel, Niraj; Klepac-Ceraj, Vanja; Fontana, Carla R.; Soukos, Nikolaos S.] Forsyth Inst, Appl Mol Photomed Lab, Boston, MA USA. [Kent, Ralph] Forsyth Inst, Dept Biostat, Boston, MA USA. [Stashenko, Philip P.] Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. RP Soukos, NS (reprint author), Forsyth Inst, Appl Mol Photomed Lab, 245 1st St, Cambridge, MA 02142 USA. EM nsoukos@forsyth.org RI Fontana, Carla/C-2033-2012; OI Fontana, Carla/0000-0002-9135-3690; Klepac-Ceraj, Vanja/0000-0001-5387-5706 FU NIDCR [RO1-DE-16922] FX This work was supported by NIDCR grant RO1-DE-16922. NR 43 TC 39 Z9 43 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0099-2399 J9 J ENDODONT JI J. Endod. PD FEB PY 2011 VL 37 IS 2 BP 217 EP 222 DI 10.1016/j.joen.2010.10.008 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 722JJ UT WOS:000287428200016 PM 21238805 ER PT J AU Donelan, K Mailhot, JR Dutwin, D Barnicle, K Oo, SA Hobrecker, K Percac-Lima, S Chabner, BA AF Donelan, Karen Mailhot, Johanna R. Dutwin, David Barnicle, Kristen Oo, Sarah Abernethy Hobrecker, Karin Percac-Lima, Sanja Chabner, Bruce A. TI Patient Perspectives of Clinical Care and Patient Navigation in Follow-up of Abnormal Mammography SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE disparities; patient satisfaction; community-based interventions; evaluation; breast cancer ID UNITED-STATES; HEALTH-CARE; UNDERSERVED WOMEN; CANCER-DIAGNOSIS; URBAN-POPULATION; BREAST; DISPARITIES; PROGRAM; IMPACT; MASSACHUSETTS AB BACKGROUND: Racial and ethnic disparities in cancer care and survival are well documented. Patient navigation has been shown to improve timely follow-up of abnormal breast screenings for underserved patients. Few studies showed the impact of navigation on patient experiences of care. OBJECTIVE: We compared the experiences of patients enrolled in a patient navigator program and non-navigated patients referred to a hospital breast center for follow-up of abnormal mammogram in an underserved community health center population. DESIGN: Group comparison study using data from a mail and telephone survey to measure the experience of navigated and non-navigated patients. PARTICIPANTS: English-and Spanish-speaking patients with abnormal mammography attending the Avon Breast Center between April 1, 2005 and April 30, 2007. Seventy-two navigated patients and 181 non-navigated patients completed surveys; the survey response rate was 53.6%. MAIN MEASURES: Timeliness of care, preparation for the visit to the breast center, ease of access, quality of care, provider communication, unmet need and patient satisfaction. KEY RESULTS: Most measures of the patient experience did not differ between navigated and non-navigated patients. Overall quality of care was rated as excellent (55% vs 62%, p=0.294). Navigated patients were significantly more likely than non-navigated to 'definitely' understand what to expect at their visit (79% vs 60%, p=0.003), to receive a reminder letter or telephone call (89% vs 77%, p=0.029), and to feel welcome (89% vs 75%, p=0.012). Navigated patients were less likely than non-navigated to rate the concern shown for their cultural/religious beliefs as excellent (45% vs 54%, p=0.014). CONCLUSIONS: Assessing patient perspectives is essential to evaluate the success of quality improvement interventions. In our center, we measured few significant disparities in the perceptions of care of these two very different populations of patients, although, there are still areas in which our program needs improvement. Further research is needed to understand the effectiveness of patient navigation programs in reducing racial and ethnic disparities. C1 [Donelan, Karen; Mailhot, Johanna R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Dutwin, David] Int Commun Res, Media, PA USA. [Barnicle, Kristen] Partners Healthcare Community Benefits, Boston, MA USA. [Oo, Sarah Abernethy; Percac-Lima, Sanja] MGH Chelsea HealthCare Ctr, Chelsea, MA USA. [Hobrecker, Karin] MGH Patient Care Serv, Boston, MA USA. [Chabner, Bruce A.] MGH Canc Ctr, Boston, MA USA. RP Donelan, K (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM kdonelan@partners.org FU MGH Cancer Center; Avon Foundation FX This work was funded in part by the MGH Cancer Center and in part by the Avon Foundation. NR 39 TC 16 Z9 16 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2011 VL 26 IS 2 BP 116 EP 122 DI 10.1007/s11606-010-1436-4 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 725TK UT WOS:000287668800008 PM 20607432 ER PT J AU Atlas, SJ Grant, RW Lester, WT Ashburner, JM Chang, YC Barry, MJ Chueh, HC AF Atlas, Steven J. Grant, Richard W. Lester, William T. Ashburner, Jeffrey M. Chang, Yuchiao Barry, Michael J. Chueh, Henry C. TI A Cluster-Randomized Trial of a Primary Care Informatics-Based System for Breast Cancer Screening SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; screening; mammography; health information technology; randomized controlled trial ID PREVENTIVE SERVICES; PATIENT REMINDERS; MAMMOGRAPHY; TELEPHONE; PHYSICIAN; WOMEN; METAANALYSIS; PROGRAM; QUALITY; INTERVENTIONS AB BACKGROUND: Information technology offers the promise, as yet unfulfilled, of delivering efficient, evidence- based health care. OBJECTIVE: To evaluate whether a primary care network-based informatics intervention can improve breast cancer screening rates. DESIGN: Cluster-randomized controlled trial of 12 primary care practices conducted from March 20, 2007 to March 19, 2008. PATIENTS: Women 42-69 years old with no record of a mammogram in the prior 2 years. INTERVENTIONS: In intervention practices, a population- based informatics system was implemented that: connected overdue patients to appropriate care providers, presented providers with a Web-based list of their overdue patients in a non-visit-based setting, and enabled "one-click" mammography ordering or documented deferral reasons. Patients selected for mammography received automatically generated letters and follow-up phone calls. All practices had electronic health record reminders about breast cancer screening available during clinical encounters. MAIN MEASURES: The primary outcome was the proportion of overdue women undergoing mammography at 1-year follow-up. KEY RESULTS: Baseline mammography rates in intervention and control practices did not differ (79.5% vs 79.3%, p=0.73). Among 3,054 women in intervention practices and 3,676 women in control practices overdue for mammograms, intervention patients were somewhat younger, more likely to be non-Hispanic white, and have health insurance. Most intervention providers used the system (65 of 70 providers, 92.9%). Action was taken for 2,652 (86.8%) intervention patients [ 2,274 (74.5%) contacted and 378 (12.4%) deferred]. After 1 year, mammography rates were significantly higher in the intervention arm (31.4% vs 23.3% in control arm, p<0.001 after adjustment for baseline differences; 8.1% absolute difference, 95% CI 5.111.2%). All demographic subgroups benefited from the intervention. Intervention patients completed screening sooner than control patients (p<0.001). CONCLUSIONS: A novel population-based informatics system functioning as part of a non-visit-based care model increased mammography screening rates in intervention practices. C1 [Atlas, Steven J.; Ashburner, Jeffrey M.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Lester, William T.; Chueh, Henry C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Comp Sci Lab, Boston, MA USA. [Atlas, Steven J.; Grant, Richard W.; Chang, Yuchiao; Barry, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Div, Boston, MA USA. RP Atlas, SJ (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St, Boston, MA 02114 USA. EM satlas@partners.org OI Lester, William/0000-0003-4086-9280; Grant, Richard/0000-0002-6164-8025 FU National Cancer Institute [NCI 1 R21 CA121908]; Massachusetts General Hospital; NIDDK [K23 DK067452] FX This study was supported by a grant from the National Cancer Institute (NCI 1 R21 CA121908) and by institutional funding through the Massachusetts General Hospital Primary Care Operations Improvement program. Dr. Grant is supported by an NIDDK Career Development Award (K23 DK067452). No funding source had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 38 TC 9 Z9 9 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2011 VL 26 IS 2 BP 154 EP 161 DI 10.1007/s11606-010-1500-0 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 725TK UT WOS:000287668800014 PM 20872083 ER PT J AU Bradley, KA Rubinsky, AD Sun, HL Bryson, CL Bishop, MJ Blough, DK Henderson, WG Maynard, C Hawn, MT Tonnesen, H Hughes, G Beste, LA Harris, AHS Hawkins, EJ Houston, TK Kivlahan, DR AF Bradley, Katharine A. Rubinsky, Anna D. Sun, Haili Bryson, Chris L. Bishop, Michael J. Blough, David K. Henderson, William G. Maynard, Charles Hawn, Mary T. Tonnesen, Hanne Hughes, Grant Beste, Lauren A. Harris, Alex H. S. Hawkins, Eric J. Houston, Thomas K. Kivlahan, Daniel R. TI Alcohol Screening and Risk of Postoperative Complications in Male VA Patients Undergoing Major Non-cardiac Surgery SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE alcohol screening; surgical outcomes; AUDIT-C ID PRIMARY-CARE VALIDATION; UPPER DIGESTIVE-TRACT; SURGICAL CARE; ELECTIVE SURGERY; MALE VETERANS; USE DISORDERS; AUDIT-C; QUALITY; MORBIDITY; SCORES AB BACKGROUND: Patients who misuse alcohol are at increased risk for surgical complications. Four weeks of preoperative abstinence decreases the risk of complications, but practical approaches for early preoperative identification of alcohol misuse are needed. OBJECTIVE: To evaluate whether results of alcohol screening with the Alcohol Use Disorders Identification Test -Consumption (AUDIT-C) questionnaire-up to a year before surgery-were associated with the risk of postoperative complications. DESIGN: This is a cohort study. SETTING AND PARTICIPANTS: Male Veterans Affairs (VA) patients were eligible if they had major noncardiac surgery assessed by the VA's Surgical Quality Improvement Program (VASQIP) in fiscal years 2004-2006, and completed the AUDIT-C alcohol screening questionnaire (0-12 points) on a mailed survey within 1 year before surgery. MAIN OUTCOME MEASURE: One or more postoperative complication(s) within 30 days of surgery based on VASQIP nurse medical record reviews. RESULTS: Among 9,176 eligible men, 16.3% screened positive for alcohol misuse with AUDIT-C scores >= 5, and 7.8% had postoperative complications. Patients with AUDIT-C scores >= 5 were at significantly increased risk for postoperative complications, compared to patients who drank less. In analyses adjusted for age, smoking, and days from screening to surgery, the estimated prevalence of postoperative complications increased from 5.6% (95% CI 4.8-6.6%) in patients with AUDIT-C scores 1-4, to 7.9% (6.3-9.7%) in patients with AUDIT-Cs 5-8, 9.7% (6.6-14.1%) in patients with AUDIT-Cs 9-10 and 14.0% (8.9-21.3%) in patients with AUDIT-Cs 11-12. In fully-adjusted analyses that included preoperative covariates potentially in the causal pathway between alcohol misuse and complications, the estimated prevalence of postoperative complications increased significantly from 4.8% (4.1-5.7%) in patients with AUDIT-C scores 1-4, to 6.9% (5.5-8.7%) in patients with AUDIT-Cs 5-8 and 7.5% (5.0-11.3%) among those with AUDIT-Cs 9-10. CONCLUSIONS: AUDIT-C scores of 5 or more up to a year before surgery were associated with increased postoperative complications. C1 [Bradley, Katharine A.; Rubinsky, Anna D.; Sun, Haili; Bryson, Chris L.; Blough, David K.; Maynard, Charles; Beste, Lauren A.; Hawkins, Eric J.; Kivlahan, Daniel R.] Dept Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98101 USA. [Bradley, Katharine A.; Hawkins, Eric J.; Kivlahan, Daniel R.] Ctr Excellence Subst Abuse Treatment & Educ, Dept Vet Affairs VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Bradley, Katharine A.; Rubinsky, Anna D.; Maynard, Charles; Beste, Lauren A.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Henderson, William G.; Hughes, Grant] Dept Vet Affairs Eastern Colorado Healthcare Syst, Denver, CO USA. [Harris, Alex H. S.] Ctr Hlth Care Evaluat, Dept Vet Affairs Palo Alto Hlth Care Syst, Menlo Pk, CA USA. [Houston, Thomas K.] Bedford VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, TX USA. [Bishop, Michael J.] Anesthesia Serv, Dept Vet Affairs, Cent Off, Washington, DC USA. [Hawkins, Eric J.; Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Blough, David K.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Bishop, Michael J.] Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA. [Henderson, William G.] Univ Colorado, Hlth Outcomes Program, Aurora, CO USA. [Hawn, Mary T.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. [Tonnesen, Hanne] Bispebjerg Hosp, WHO Collaborating Ctr Evidence Based Hlth Promot, Copenhagen, Denmark. [Houston, Thomas K.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Hawn, Mary T.] Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA. RP Bradley, KA (reprint author), Dept Vet Affairs Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM willi@u.washington.edu RI Houston, Thomas/F-2469-2013; Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Health Services Research and Development [IAC 06-021] FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development and Health Services Research and Development (project IAC 06-021). Dr. Bradley is an investigator at the VA Northwest HSR&D Center of Excellence and at the Center of Excellence in Substance Abuse Treatment and Education, VA Puget Sound Health Care System, Seattle, WA. NR 52 TC 30 Z9 30 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2011 VL 26 IS 2 BP 162 EP 169 DI 10.1007/s11606-010-1475-x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 725TK UT WOS:000287668800015 PM 20878363 ER PT J AU Lyles, CR Karter, AJ Young, BA Spigner, C Grembowski, D Schillinger, D Adler, NE AF Lyles, Courtney R. Karter, Andrew J. Young, Bessie A. Spigner, Clarence Grembowski, David Schillinger, Dean Adler, Nancy E. TI Correlates of Patient-Reported Racial/Ethnic Health Care Discrimination in the Diabetes Study of Northern California (DISTANCE) SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Race/ethnicity; discrimination; diabetes care; managed care ID PERCEIVED DISCRIMINATION; RACIAL-DISCRIMINATION; PUBLIC-HEALTH; MENTAL-HEALTH; SOCIAL-STATUS; DISPARITIES; POPULATION; ADULTS; PERSONALITY; ASSOCIATION AB Objectives. We examined possible determinants of self-reported health care discrimination. Methods. We examined survey data from the Diabetes Study of Northern California (DISTANCE), a race-stratified sample of Kaiser diabetes patients. Respondents reported perceived discrimination, and regression models examined socioeconomic, acculturative, and psychosocial correlates. Results. Subjects (n=17,795) included 20% Blacks, 23% Latinos, 13% East Asians, 11% Filipinos, and 27% Whites. Three percent and 20% reported health care and general discrimination. Health care discrimination was more frequently reported by minorities (ORs ranging from 2.0 to 2.9 compared with Whites) and those with poorer health literacy (OR=1.10, 95% CI: 1.04-1.16), limited English proficiency (OR=1.91, 95% CI: 1.32-2.78), and depression (OR=1.53, 95% CI: 1.10-2.13). Conclusions. In addition to race/ethnicity, health literacy and English proficiency may be bases of discrimination. Evaluation is needed to determine whether patients are treated differently or more apt to perceive discrimination, and whether depression fosters and/or follows perceived discrimination. C1 [Lyles, Courtney R.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Young, Bessie A.] Univ Washington, Dept Nephrol, Seattle, WA 98195 USA. [Young, Bessie A.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Schillinger, Dean] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schillinger, Dean] San Francisco Gen Hosp, Ctr Vulnerable Populat, San Francisco, CA USA. RP Lyles, CR (reprint author), Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Box 359455, Seattle, WA 98195 USA. EM crees@u.washington.edu FU AHRQ HHS [T32 HS013853, HS013853]; NICHD NIH HHS [R01 HD46113, R01 HD046113-02, R01 HD046113, R01 HD046113-01, R01 HD046113-04, R01 HD046113-03]; NIDDK NIH HHS [RC1 DK086178-02, RC1 DK086178, R01 DK081796-02, R01 DK081796-01A1, R01 DK081796, R01 DK065664-03, R01 DK065664-04, R01 DK081796-03, R01 DK65664, R01 DK081796-04, R01 DK065664-05, R01 DK065664-02, R01 DK065664-01A1, R01 DK065664] NR 53 TC 16 Z9 16 U1 2 U2 9 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD FEB PY 2011 VL 22 IS 1 BP 211 EP 225 PG 15 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 718ZK UT WOS:000287165100016 PM 21317516 ER PT J AU Xia, Y Cortez-Retamozo, V Niederkofler, V Salie, R Chen, SZ Samad, TA Hong, CC Arber, S Vyas, JM Weissleder, R Pittet, MJ Lin, HY AF Xia, Yin Cortez-Retamozo, Virna Niederkofler, Vera Salie, Rishard Chen, Shanzhuo Samad, Tarek A. Hong, Charles C. Arber, Silvia Vyas, Jatin M. Weissleder, Ralph Pittet, Mikael J. Lin, Herbert Y. TI Dragon (Repulsive Guidance Molecule b) Inhibits IL-6 Expression in Macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MORPHOGENETIC PROTEIN CORECEPTOR; REGULATES HEPCIDIN EXPRESSION; GROWTH IMPAIRMENT; MESSENGER-RNA; SMOOTH-MUSCLE; BONE; CELLS; RECEPTORS; PATHWAY; DISEASE AB Repulsive guidance molecule (RGM) family members RGMa, RGMb/Dragon, and RGMc/hemojuvelin were found recently to act as bone morphogenetic protein (BMP) coreceptors that enhance BMP signaling activity. Although our previous studies have shown that hemojuvelin regulates hepcidin expression and iron metabolism through the BMP pathway, the role of the BMP signaling mediated by Dragon remains largely unknown. We have shown previously that Dragon is expressed in neural cells, germ cells, and renal epithelial cells. In this study, we demonstrate that Dragon is highly expressed in macrophages. Studies with RAW264.7 and J774 macrophage cell lines reveal that Dragon negatively regulates IL-6 expression in a BMP ligand-dependent manner via the p38 MAPK and Erk1/2 pathways but not the Smad1/5/8 pathway. We also generated Dragon knockout mice and found that IL-6 is upregulated in macrophages and dendritic cells derived from whole lung tissue of these mice compared with that in respective cells derived from wild-type littermates. These results indicate that Dragon is an important negative regulator of IL-6 expression in immune cells and that Dragon-deficient mice may be a useful model for studying immune and inflammatory disorders. The Journal of Immunology, 2011, 186: 1369-1376. C1 [Xia, Yin; Cortez-Retamozo, Virna; Chen, Shanzhuo; Weissleder, Ralph; Pittet, Mikael J.; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Xia, Yin; Chen, Shanzhuo; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol, Boston, MA 02114 USA. [Xia, Yin; Chen, Shanzhuo; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA 02114 USA. [Niederkofler, Vera; Salie, Rishard; Arber, Silvia] Univ Basel, Biozentrum, Dept Cell Biol, Basel, Switzerland. [Niederkofler, Vera; Salie, Rishard; Arber, Silvia] Friedrich Miescher Inst Biomed Res, Basel, Switzerland. [Samad, Tarek A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neural Plast Res Unit,Dept Anesthesia, Boston, MA 02114 USA. [Hong, Charles C.] Vet Affairs Tennessee Valley Healthcare Syst, Res Med, Nashville, TN 37212 USA. [Hong, Charles C.] Vanderbilt Univ, Div Cardiovasc Med, Sch Med, Nashville, TN 37232 USA. [Vyas, Jatin M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Dept Med, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Xia, Y (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, CPZN 8150,185 Cambridge St, Boston, MA 02114 USA. EM Xia.Yin@mgh.harvard.edu; Lin.Herbert@mgh.harvard.edu RI Vyas, Jatin/Q-1627-2016 OI Vyas, Jatin/0000-0002-9985-9565 FU National Institutes of Health [R01 DK-071837, R01 DK-069533, R03 HD60641, K01 DK084081, U01 HL080731, P50 CA86355, U54 CA126515] FX This work was supported by National Institutes of Health Grants R01 DK-071837 and R01 DK-069533 (to H.Y.L.), R03 HD60641 and K01 DK084081 (to Y.X.), and U01 HL080731, P50 CA86355, and U54 CA126515 (to V.C.R., M.J.P., and R.W.). NR 32 TC 26 Z9 27 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2011 VL 186 IS 3 BP 1369 EP 1376 DI 10.4049/jimmunol.1002047 PG 8 WC Immunology SC Immunology GA 708RE UT WOS:000286381200014 PM 21187450 ER PT J AU de Weers, M Tai, YT van der Veer, MS Bakker, JM Vink, T Jacobs, DCH Oomen, LA Peipp, M Valerius, T Slootstra, JW Mutis, T Bleeker, WK Anderson, KC Lokhorst, HM van de Winkel, JGJ Parren, PWHI AF de Weers, Michel Tai, Yu-Tzu van der Veer, Michael S. Bakker, Joost M. Vink, Tom Jacobs, Danielle C. H. Oomen, Lukas A. Peipp, Matthias Valerius, Thomas Slootstra, Jerry W. Mutis, Tuna Bleeker, Wim K. Anderson, Kenneth C. Lokhorst, Henk M. van de Winkel, Jan G. J. Parren, Paul W. H. I. TI Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; COMPLEMENT-DEPENDENT CYTOTOXICITY; CHRONIC LYMPHOCYTIC-LEUKEMIA; IN-VIVO; BONE-MARROW; FOLLICULAR LYMPHOMA; HUMAN CD20; RITUXIMAB; CELL; OFATUMUMAB AB CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors. The Journal of Immunology, 2011, 186: 1840-1848. C1 [de Weers, Michel; Bakker, Joost M.; Vink, Tom; Jacobs, Danielle C. H.; Oomen, Lukas A.; Bleeker, Wim K.; van de Winkel, Jan G. J.; Parren, Paul W. H. I.] Genmab, NL-3584 CM Utrecht, Netherlands. [Tai, Yu-Tzu; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Tai, Yu-Tzu; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA 02115 USA. [van der Veer, Michael S.; Mutis, Tuna] Univ Med Ctr, Dept Clin Chem & Hematol, NL-3584 CX Utrecht, Netherlands. [Lokhorst, Henk M.] Univ Med Ctr, Dept Hematol, NL-3584 CX Utrecht, Netherlands. [Peipp, Matthias; Valerius, Thomas] Univ Kiel, Div Stem Cell Transplantat & Immunotherapy, D-24105 Kiel, Germany. [Slootstra, Jerry W.] Pepscan Syst, NL-8243 RC Lelystad, Netherlands. [van de Winkel, Jan G. J.] Univ Med Ctr, Dept Immunol, Immunotherapy Lab, NL-3584 EA Utrecht, Netherlands. RP Parren, PWHI (reprint author), Genmab, Yalelaan 60, NL-3584 CM Utrecht, Netherlands. EM p.parren@genmab.com RI Valerius, Thomas/A-3086-2011; Peipp, Matthias/A-8775-2013; OI Parren, Paul/0000-0002-4365-3859 FU Genmab FX M.d.W., J.M.B., T.V., D.C.H.J., LAO., W.K.B., J.G.J.v.d.W., and P.W.H.I.P. are employees of Genmab and own stock and/or stock options. M.d.W., T.V., W.K.B., J.G.J.v.d.W., and P.W.H.I.P. also own patents related to ongoing research. Y.-T.T. has received a Genmab-sponsored fellowship. M.S.v.d.V., T.M., and H.M.L. have received Genmab-sponsored research grants. T.V. is a Genmab board member. NR 51 TC 181 Z9 182 U1 7 U2 22 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2011 VL 186 IS 3 BP 1840 EP 1848 DI 10.4049/jimmunol.1003032 PG 9 WC Immunology SC Immunology GA 708RE UT WOS:000286381200064 PM 21187443 ER PT J AU Niessner, H Beck, D Sinnberg, T Lasithiotakis, K Maczey, E Gogel, J Venturelli, S Berger, A Mauthe, M Toulany, M Flaherty, K Schaller, M Schadendorf, D Proikas-Cezanne, T Schittek, B Garbe, C Kulms, D Meier, F AF Niessner, Heike Beck, Daniela Sinnberg, Tobias Lasithiotakis, Konstantinos Maczey, Evelyn Gogel, Jeannette Venturelli, Sascha Berger, Alexander Mauthe, Mario Toulany, Mahmoud Flaherty, Keith Schaller, Martin Schadendorf, Dirk Proikas-Cezanne, Tassula Schittek, Birgit Garbe, Claus Kulms, Dagmar Meier, Friedegund TI The Farnesyl Transferase Inhibitor Lonafarnib Inhibits mTOR Signaling and Enforces Sorafenib-Induced Apoptosis in Melanoma Cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID DOWN-REGULATION; HUMAN CANCER; PATHWAYS; DEATH; EXPRESSION; GROWTH; TRIAL; MCL-1; STIMULATION; BAY-43-9006 AB Farnesyl transferase inhibitors (FTIs) inhibit the farnesylation of proteins, including RAS and RHEB (Ras homolog enriched in brain). RAS signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways, which have a major role in melanoma progression. RHEB positively regulates mammalian target of rapamycin (mTOR). We investigated the effects of the FTI lonafarnib alone and in combination with MAPK (mitogen-activated protein kinase) or AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma) pathway inhibitors on proliferation, survival, and invasive tumor growth of melanoma cells. Lonafarnib alone did not sufficiently inhibit melanoma cell growth. Combinations of lonafarnib with AKT pathway inhibitors did not significantly increase melanoma cell growth inhibition. In contrast, combinations of lonafarnib with MAPK pathway inhibitors yielded additional growth-inhibiting effects. In particular, the combination of the FTI lonafarnib with the pan-RAF inhibitor sorafenib synergistically inhibited melanoma cell growth, significantly enhanced sorafenib-induced apoptosis, and completely suppressed invasive tumor growth in monolayer and organotypic cultures, respectively. Apoptosis induction was associated with upregulation of the endoplasmic reticulum stress-related transcription factors p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), and downregulation of the antiapoptotic Bcl-2 (B-cell lymphoma-2) family protein Mcl-1(myeloid cell leukemia 1). Lonafarnib did not affect MAPK and AKT but did affect mTOR signaling. Together, these findings suggest that the FTI lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells and may therefore represent an effective alternative for melanoma treatment. C1 [Niessner, Heike; Beck, Daniela; Sinnberg, Tobias; Lasithiotakis, Konstantinos; Maczey, Evelyn; Gogel, Jeannette; Schaller, Martin; Schittek, Birgit; Garbe, Claus; Meier, Friedegund] Univ Tubingen, Div Dermatol Oncol, Dept Dermatol, D-72076 Tubingen, Germany. [Venturelli, Sascha; Berger, Alexander] Med Univ Clin, Dept Internal Med 1, Tubingen, Germany. [Mauthe, Mario; Proikas-Cezanne, Tassula] Univ Tubingen, Dept Mol Biol, Interfacultary Inst Cell Biol, Autophagy Lab, D-72076 Tubingen, Germany. [Toulany, Mahmoud] Univ Tubingen, Div Radiobiol & Mol Environm Res, Dept Radiat Oncol, D-72076 Tubingen, Germany. [Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Schadendorf, Dirk] Univ Essen Gesamthsch, Dept Dermatol, Essen, Germany. [Kulms, Dagmar] Univ Stuttgart, Inst Cell Biol & Immunol, Stuttgart, Germany. RP Meier, F (reprint author), Univ Tubingen, Div Dermatol Oncol, Dept Dermatol, Liebermeisterstr 25, D-72076 Tubingen, Germany. EM friedegund.meier@t-online.de RI Kulms, Dagmar/H-1653-2014; OI Mauthe, Mario/0000-0003-0049-7961 FU Deutsche Forschungsgemeinschaft [SFB 773] FX We acknowledge Essex Pharma GmbH for donation of lonafarnib, Bayer Vital GmbH for donation of sorafenib, and Plexxikon for donation of PLX4032. We also acknowledge Helga Moeller, Hannelore Bischof, Renate Nordin, and Birgit Fehrenbacher for excellent assistance in electron microscopy. This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 773). NR 38 TC 26 Z9 26 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2011 VL 131 IS 2 BP 468 EP 479 DI 10.1038/jid.2010.297 PG 12 WC Dermatology SC Dermatology GA 705YU UT WOS:000286177500028 PM 20944654 ER PT J AU Lang, JM Shennan, M Njauw, JCN Luo, S Bishop, JN Harland, M Hayward, NK Tucker, MA Goldstein, AM Landi, MT Puig, S Gruis, NA Bergman, W Bianchi-Scarra, G Ghiorzo, P Hogg, D Tsao, H AF Lang, Julie M. Shennan, Michael Njauw, Jenny C. -N. Luo, Su Bishop, Julia N. Harland, Mark Hayward, Nicholas K. Tucker, Margaret A. Goldstein, Alisa M. Landi, Maria T. Puig, Susana Gruis, Nelleke A. Bergman, Wilma Bianchi-Scarra, Giovanna Ghiorzo, Paola Hogg, David Tsao, Hensin TI A Flexible Multiplex Bead-Based Assay for Detecting Germline CDKN2A and CDK4 Variants in Melanoma-Prone Kindreds SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID NEURAL SYSTEM TUMORS; MALIGNANT-MELANOMA; UVEAL MELANOMA; MUTATIONS; FAMILIES; VALIDATION; GENOMEL; GENES AB The presence of recurrent high-risk mutations in cyclin-dependent kinase inhibitor 2A/cyclin-dependent kinase 4 (CDKN2A/CDK4) among melanoma-prone families suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. To this end, we have developed a multiplex bead-based assay for high-throughput CDKN2A/CDK4 genotyping in the context of familial melanoma. Genomic DNA from 1,603 subjects (1,005 in training set and 598 in validation set) were amplified by multiplex PCR using five CDKN2A/CDK4 primer sets followed by multiplex allele-specific primer extension for 39 distinct germline variants. The products were then sorted and analyzed using the Luminex xMAP system. Genotypes were compared with previously determined sequence data. In the Toronto training cohort, all 145 samples with known variants were detected by the bead assay (100% concordance). Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77%). Overall, the bead assay correctly genotyped 1,540/1,603 (96.07%) of all individuals in the study and 1,540/1,545 (99.68%) of individuals whose variants were represented in the probe set. Out of a total of 62,517 allelic calls, 62,512 (99.99%) were correctly assigned. The multiplex bead-based assay is an accurate method for genotyping CDKN2A/CDK4 variants and is potentially useful in genotyping low-to-moderate melanoma risk single-nucleotide polymorphisms. C1 [Njauw, Jenny C. -N.; Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Njauw, Jenny C. -N.; Luo, Su; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Lang, Julie M.; Shennan, Michael; Hogg, David] Univ Toronto, Dept Med, Toronto, ON, Canada. [Lang, Julie M.; Shennan, Michael; Hogg, David] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Bishop, Julia N.; Harland, Mark] Univ Leeds, St James Hosp, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Hayward, Nicholas K.] Queensland Inst Med Res, Oncogenom Lab, Brisbane, Qld 4006, Australia. [Tucker, Margaret A.; Goldstein, Alisa M.; Landi, Maria T.] NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Puig, Susana] Hosp Clin Barcelona, Melanoma Unit, Dept Dermatol, IDIBAPS, Barcelona, Spain. [Puig, Susana] CIBER Enfermedades Raras, Barcelona, Spain. [Gruis, Nelleke A.; Bergman, Wilma] Leiden Univ, Dept Dermatol, Med Ctr, Leiden, Netherlands. [Bianchi-Scarra, Giovanna; Ghiorzo, Paola] Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. [Bianchi-Scarra, Giovanna] San Martino Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org RI Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; hayward, nicholas/0000-0003-4760-1033; Puig, Susana/0000-0003-1337-9745; Gruis, Nelleke/0000-0002-5210-9150 FU American Cancer Society [RSG-07-085-01-MGO]; National Cancer Institute [P50 CA93683, K24 CA149202]; National Health and Medical Research Council of Australia; National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health (NIH); NIH [RO1 CA83115]; EU [LSHC-CT-2006-018702]; Fondo de Investigaciones Sanitarias, Spain; MGH Millennium Melanoma Fund; [PRIN-2008-W8JTPA] FX This work was supported by the American Cancer Society (RSG-07-085-01-MGO) and the National Cancer Institute (P50 CA93683 and K24 CA149202; all to HT), the National Health and Medical Research Council of Australia (to NKH), PRIN-2008-W8JTPA (to GBS), the National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health (NIH) (AMG, MTL, MAT), the NIH (RO1 CA83115), the EU FP6 contract LSHC-CT-2006-018702 (to GenoMEL), the Fondo de Investigaciones Sanitarias, Spain (to SP), and the generous donors of the MGH Millennium Melanoma Fund. NR 19 TC 11 Z9 12 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2011 VL 131 IS 2 BP 480 EP 486 DI 10.1038/jid.2010.331 PG 7 WC Dermatology SC Dermatology GA 705YU UT WOS:000286177500029 PM 21085193 ER PT J AU Johansen, CT Kathiresan, S Hegele, RA AF Johansen, Christopher T. Kathiresan, Sekar Hegele, Robert A. TI Thematic Review Series: Genetics of Human Lipid Diseases Genetic determinants of plasma triglycerides SO JOURNAL OF LIPID RESEARCH LA English DT Review DE hypertriglyceridemia; hypotriglyceridemia; dyslipidemias; genetic variation; genomics; lipoproteins; resequencing ID HIGH-DENSITY-LIPOPROTEIN; FAMILIAL COMBINED HYPERLIPIDEMIA; PHOSPHOLIPID-TRANSFER-PROTEIN; GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-A-V; UPSTREAM STIMULATORY FACTORS; COMBINED LIPASE DEFICIENCY; CORONARY-ARTERY-DISEASE; AMINO-ACID SUBSTITUTION; TYPE-2 DIABETES RISK AB Plasma triglyceride (TG) concentration is re-emerging as an important cardiovascular disease risk factor. More complete understanding of the genes and variants that modulate plasma TG should enable development of markers for risk prediction, diagnosis, prognosis, and response to therapies and might help specify new directions for therapeutic interventions. Recent genome-wide association studies (GWAS) have identified both known and novel loci associated with plasma TG concentration. However, genetic variation at these loci explains only similar to 10% of overall TG variation within the population. As the GWAS approach may be reaching its limit for discovering genetic determinants of TG, alternative genetic strategies, such as rare variant sequencing studies and evaluation of animal models, may provide complementary information to flesh out knowledge of clinically and biologically important pathways in TG metabolism. Herein, we review genes recently implicated in TG metabolism and describe how some of these genes likely modulate plasma TG concentration. We also discuss lessons regarding plasma TG metabolism learned from various genomic and genetic experimental approaches. Treatment of patients with moderate to severe hypertriglyceridemia with existing therapies is often challenging; thus, gene products and pathways found in recent genetic research studies provide hope for development of more effective clinical strategies.-Johansen, C. T., S. Kathiresan, and R. A. Hegele. Genetic determinants of plasma triglycerides. J. Lipid Res. 2011. 52: 189-206. C1 [Johansen, Christopher T.; Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, Dept Biochem, London, ON N6A 5K8, Canada. [Johansen, Christopher T.; Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, Dept Med, London, ON N6A 5K8, Canada. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Hegele, RA (reprint author), Univ Western Ontario, Robarts Res Inst, Dept Biochem, London, ON N6A 5K8, Canada. EM hegele@robarts.ca RI Hegele, Robert/G-3301-2011 FU Canadian Institutes of Health Research (CIHR) [MOP-13430, MOP-79523, CTP-79853]; Heart and Stroke Foundation of Ontario [NA-6059, T-6018, PRG-4854]; Pfizer; Genome Canada through the Ontario Genomics Institute FX This work was supported by a Canadian Institutes of Health Research (CIHR) Banting and Best Canada Graduate Scholarship Doctoral Research Award (CTJ); by operating grants from CIHR (MOP-13430, MOP-79523, CTP-79853) and the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854) (RAH), and by a Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award and Genome Canada through the Ontario Genomics Institute. C. T. J. is a University of Western Ontario MD/PhD student and a CIHR fellow in vascular research. R. A. H. is the Jacob J. Wolfe Distinguished Medical Research Chair, University of Western Ontario, the Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I), and the Martha G. Blackburn Chair in Cardiovascular Research. NR 170 TC 95 Z9 99 U1 3 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2011 VL 52 IS 2 BP 189 EP 206 DI 10.1194/jlr.R009720 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705ZZ UT WOS:000286181400002 PM 21041806 ER PT J AU Bousquet, M Gue, K Emond, V Julien, P Kang, JX Cicchetti, F Calon, F AF Bousquet, Melanie Gue, Karl Emond, Vincent Julien, Pierre Kang, Jing X. Cicchetti, Francesca Calon, Frederic TI Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease SO JOURNAL OF LIPID RESEARCH LA English DT Article DE docosahexaenoic acid; dopamine; fatty acids; dopaminergic neurons; catecholamines; brain lipids ID POLYUNSATURATED FATTY-ACIDS; RAT FRONTAL-CORTEX; DOCOSAHEXAENOIC ACID; FAT-1 MICE; NEURONAL DEGENERATION; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; BRAIN; INFLAMMATION; CELLS AB We have recently identified a neuroprotective role for omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a toxin-induced mouse model of Parkinson's disease (PD). Combined with epidemiological data, these observations suggest that low n-3 PUFA intake is a modifiable environmental risk factor for PD. In order to strengthen these preclinical findings as prerequisite to clinical trials, we further investigated the neuroprotective role of n-3 PUFAs in Fat-1 mice, a transgenic model expressing an n-3 fatty acid desaturase converting n-6 PUFAs into n-3 PUFAs. Here, we report that the expression of the fat-1 transgene increased cortical n-3:n-6 PUFA ratio (+28%), but to a lesser extent than dietary supplementation (92%). Such a limited endogenous production of n-3 PUFAs in the Fat-1 mouse was insufficient to confer neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity as assessed by dopamine levels, tyrosine hydroxylase (TH)-positive neurons and fibers, as well as nigral Nurr1 and dopamine transporter (DAT) mRNA expression. Nevertheless, higher cortical docosahexaenoic acid (DHA) concentrations were positively correlated with markers of nigral dopaminergic neurons such as the number of TH-positive cells, in addition to Nurr1 and DAT mRNA levels. These associations are consistent with the protective role of DHA in a mouse model of PD. Taken together, these data suggest that dietary intake of a preformed DHA supplement is more effective in reaching the brain and achieving neuroprotection in an animal model of PD.-Bousquet, M., K. Gue, V. Emond, P. Julien, J. X. Kang, F. Cicchetti, and F. Calon. Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease. J. Lipid Res. 2011. 52: 263-271. C1 [Bousquet, Melanie; Gue, Karl; Emond, Vincent; Cicchetti, Francesca; Calon, Frederic] Axe Neurosci, Ctr Rech CHUL CHUQ, Quebec City, PQ, Canada. [Bousquet, Melanie; Calon, Frederic] Univ Laval, Fac Pharm, Quebec City, PQ, Canada. [Cicchetti, Francesca] Univ Laval, Fac Med, Dept Psychiat & Neurosci, Quebec City, PQ G1K 7P4, Canada. [Julien, Pierre] CHUL CHUQ, Ctr Rech Malad Lipid, Quebec City, PQ, Canada. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Sch Med, Boston, MA USA. RP Cicchetti, F (reprint author), Axe Neurosci, Ctr Rech CHUL CHUQ, Quebec City, PQ, Canada. EM Francesca.Cicchetti@crchul.ulaval.ca; Frederic.Calon@crchul.ulaval.ca FU Parkinson Society Canada; Institute of Nutrition, Metabolism and Diabetes (INMD) of the Canadian Institutes of Health Research (CIHR); Canada Foundation for Innovation; CIHR; Clinical Research Initiative; CIHR Institute of Aging [CAN-76833] FX This study was supported by Parkinson Society Canada, and by the Institute of Nutrition, Metabolism and Diabetes (INMD) of the Canadian Institutes of Health Research (CIHR) and the Canada Foundation for Innovation (F. Cicchetti and F. Calon). M. Bousquet was supported by a Vanier Canada Graduate Scholarship from the CIHR. The work of F. Calon was supported by a New Investigator Award from the Clinical Research Initiative and the CIHR Institute of Aging (CAN-76833). The work of F. Cicchetti was supported by a New Investigator Award from the CIHR. NR 55 TC 33 Z9 36 U1 4 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2011 VL 52 IS 2 BP 263 EP 271 DI 10.1194/jlr.M011692 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705ZZ UT WOS:000286181400008 PM 21115966 ER PT J AU Hou, Q Jin, JF Zhou, H Novgorodov, SA Bielawska, A Szulc, ZM Hannun, YA Obeid, LM Hsu, YT AF Hou, Qi Jin, Junfei Zhou, Hui Novgorodov, Sergei A. Bielawska, Alicja Szulc, Zdzislaw M. Hannun, Yusuf A. Obeid, Lina M. Hsu, Yi-Te TI Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ceramide; Bax; mitochondria ID CYTOCHROME-C RELEASE; NECROSIS-FACTOR-ALPHA; BCL-X-L; PROTEIN-KINASE; CONFORMATIONAL-CHANGE; ACID SPHINGOMYELINASE; BAX TRANSLOCATION; CARCINOMA-CELLS; HUMAN HEAD; IN-VIVO AB C(6)-pyridinium (D-erythro -2-N-[6'-(1 '' -pyridinium)hexanoyl]sphingosine bromide [LCL29]) is a cationic mitochondrion-targeting ceramide analog that promotes mitochondrial permeabilization and cancer cell death. In this study, we compared the biological effects of that compound with those of D -erythro-C(6)-ceramide, its non-mitochondrion-targeting analog. In MCF7 cells it was found that C(6) -pyridinium ceramide preferentially promoted autophagosome formation and retarded cell growth more extensively than its uncharged analog. This preferential inhibition of cell growth was also observed in breast epithelial cells and other breast cancer cells. In addition, this compound could promote Bax translocation to mitochondria. This redistribution of Bax in MCF7 cells could be blocked by the pan-caspase inhibitor zVAD-fmk but via a Bid-independent signaling pathway. Moreover, C(6) -pyridinium ceramide-induced translocation of Bax to mitochondria led to mitochondrial permeabilization and cell death. Overall, we show that mitochondrial targeting of C(6) -pyridinium ceramide significantly enhances cellular response to this compound.-Hou, Q., J. Jin, H. Zhou, S. A. Novgorodov, A. Bielawska, Z. M. Szulc, Y. A. Hannun, L. M. Obeid, and Y-T. Hsu. Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J. Lipid Res. 2011. 52: 278-288. C1 [Hou, Qi; Jin, Junfei; Zhou, Hui; Bielawska, Alicja; Szulc, Zdzislaw M.; Hannun, Yusuf A.; Hsu, Yi-Te] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Novgorodov, Sergei A.; Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Hou, Qi] Peking Union Med Coll, Inst Mat Med, Dept Pharmacol, Beijing 100050, Peoples R China. Chinese Acad Med Sci, Beijing 100050, Peoples R China. [Jin, Junfei] Univ S China, Res Ctr Life Sci, Hengyang 421001, Hunan, Peoples R China. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Hsu, YT (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. EM hsuy@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [NS-40932, AG-16583]; Office of Research and Development, US Department of Veterans Affairs FX This research was supported in part by National Institutes of Health Grants NS-40932 (Y-T.H.) and AG-16583 (L. M. O.) and a MERIT Award (L. M. O.) from the Office of Research and Development, US Department of Veterans Affairs. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies. NR 48 TC 24 Z9 27 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2011 VL 52 IS 2 BP 278 EP 288 DI 10.1194/jlr.M012161 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 705ZZ UT WOS:000286181400010 PM 21081756 ER PT J AU Faughnan, ME Palda, VA Garcia-Tsao, G Geisthoff, UW McDonald, J Proctor, DD Spears, J Brown, DH Buscarini, E Chesnutt, MS Cottin, V Ganguly, A Gossage, JR Guttmacher, AE Hyland, RH Kennedy, SJ Korzenik, J Mager, JJ Ozanne, AP Piccirillo, JF Picus, D Plauchu, H Porteous, MEM Pyeritz, RE Ross, DA Sabba, C Swanson, K Terry, P Wallace, MC Westermann, CJJ White, RI Young, LH Zarrabeitia, R AF Faughnan, M. E. Palda, V. A. Garcia-Tsao, G. Geisthoff, U. W. McDonald, J. Proctor, D. D. Spears, J. Brown, D. H. Buscarini, E. Chesnutt, M. S. Cottin, V. Ganguly, A. Gossage, J. R. Guttmacher, A. E. Hyland, R. H. Kennedy, S. J. Korzenik, J. Mager, J. J. Ozanne, A. P. Piccirillo, J. F. Picus, D. Plauchu, H. Porteous, M. E. M. Pyeritz, R. E. Ross, D. A. Sabba, C. Swanson, K. Terry, P. Wallace, M. C. Westermann, C. J. J. White, R. I. Young, L. H. Zarrabeitia, R. TI International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PULMONARY ARTERIOVENOUS-MALFORMATIONS; HEPATIC VASCULAR MALFORMATIONS; ND-YAG LASER; ARGON PLASMA COAGULATION; OSLER-WEBER-SYNDROME; QUALITY-OF-LIFE; ROW HELICAL CT; TO-LEFT SHUNT; CONTRAST ECHOCARDIOGRAPHY; GASTROINTESTINAL-TRACT AB Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations. C1 [Faughnan, M. E.; Hyland, R. H.] Univ Toronto, St Michaels Hosp, Div Respirol, Dept Med, Toronto, ON M5B 1W8, Canada. [Faughnan, M. E.] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Palda, V. A.] Univ Toronto, Dept Hlth Policy, Toronto, ON M5B 1W8, Canada. [Palda, V. A.] Univ Toronto, Dept Management & Evaluat, Toronto, ON M5B 1W8, Canada. [Garcia-Tsao, G.] Yale Univ, Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT 06510 USA. [Geisthoff, U. W.] Univ Saarland, Fac Med, D-6650 Homburg, Germany. [Geisthoff, U. W.] City Hosp, Dept Otorhinolaryngol, Holweide Hosp, Cologne, Germany. [McDonald, J.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Spears, J.] Univ Toronto, St Michaels Hosp, Dept Surg, Toronto, ON M5B 1W8, Canada. [Brown, D. H.] Univ Toronto, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5B 1W8, Canada. [Buscarini, E.] Osped Maggiore Crema, UO Gastroenterol & Endoscopia Digest, Crema, Italy. [Chesnutt, M. S.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, HHT Ctr Excellence, Dotter Intervent Inst, Portland, OR 97201 USA. [Cottin, V.] Univ Lyon, Hosp Civils Lyon, Natl Reference Ctr Rare Pulm Dis, Lyon, France. [Ganguly, A.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Gossage, J. R.] Med Coll Georgia, Augusta, GA 30912 USA. [Guttmacher, A. E.] NHGRI, NIH, Bethesda, MD 20892 USA. [Kennedy, S. J.] Childrens Hosp Eastern Ontario, Ontario Newborn Screening Program, Ottawa, ON K1H 8L1, Canada. [Kennedy, S. J.] Childrens Hosp Eastern Ontario, Reg Genet Program, Ottawa, ON K1H 8L1, Canada. [Korzenik, J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Mager, J. J.; Westermann, C. J. J.] St Antonius Hosp, Nieuwegein, Netherlands. [Ozanne, A. P.] Hop Bicetre, Paris, France. [Piccirillo, J. F.] Washington Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, St Louis, MO 63110 USA. [Picus, D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Plauchu, H.] Hosp Civils Lyon, Natl Reference Ctr HHT Dis, Hotel Dieu Hosp, Lyon, France. [Porteous, M. E. M.] Western Gen Hosp, SE Scotland Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Ross, D. A.] St Vincents Med Ctr, Dept Surg, Bridgeport, CT USA. [Sabba, C.] Univ Bari, Dept Internal Med & Publ Hlth, Bari, Italy. [Swanson, K.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Terry, P.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Wallace, M. C.] Univ Hlth Network, Div Neurosurg, Krembil Neurosci Ctr, Toronto, ON, Canada. [White, R. I.] Yale Univ, Sch Med, Yale Vasc Malformat Ctr, New Haven, CT USA. [Young, L. H.] Yale Univ, Sch Med, Sect Cardiovasc Med, New Haven, CT USA. [Zarrabeitia, R.] Hosp Sierrallana, Med Interna Serv, Unidad HHT, Serv Cantabro Salud, Torrelavega, Cantabria, Spain. RP Faughnan, ME (reprint author), Univ Toronto, St Michaels Hosp, Div Respirol, Dept Med, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM faughnanm@smh.ca OI Sabba', Carlo/0000-0002-9874-8740 FU Argosy Foundation; HHT Foundation International Inc; Canadian Institutes of Health Research; St Michael's Hospital Department of Medicine; Nelson Arthur Hyland Foundation; Li Ka Shing Knowledge Institute of St Michael's Hospital; Ethek F Donahue Foundation FX John Abele on behalf of the Argosy Foundation, HHT Foundation International Inc, Canadian Institutes of Health Research, St Michael's Hospital Department of Medicine. Financial support for MEF: Nelson Arthur Hyland Foundation, Li Ka Shing Knowledge Institute of St Michael's Hospital.; VP received an honorarium for attending the HHT Guidelines Conference. DP received a grant (completed) from the Ethek F Donahue Foundation to study hormonal therapy in HHT. NR 131 TC 248 Z9 268 U1 3 U2 31 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 FEB PY 2011 VL 48 IS 2 BP 73 EP 87 DI 10.1136/jmg.2009.069013 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 711WM UT WOS:000286622100001 PM 19553198 ER PT J AU Nakano, H Williams, E Hoshijima, M Sasaki, M Minamisawa, S Chien, KR Nakano, A AF Nakano, Haruko Williams, Estrelania Hoshijima, Masahiko Sasaki, Mika Minamisawa, Susumu Chien, Kenneth R. Nakano, Atsushi TI Cardiac origin of smooth muscle cells in the inflow tract SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Cardiogenesis; Myogenic progenitor; Smooth muscle; Great vessel; Plasticity ID CARDIOVASCULAR PROGENITOR CELLS; ATRIAL-FIBRILLATION; HEART FIELD; VENOUS POLE; EMBRYONIC-DEVELOPMENT; MAMMALIAN HEART; SECONDARY HEART; ARTERIAL POLE; EXPRESSION; MYOCARDIUM AB Multipotent Isl1(+) heart progenitors give rise to three major cardiovascular cell types: cardiac, smooth muscle, and endothelial cells, and play a pivotal role in lineage diversification during cardiogenesis. A critical question is pinpointing when this cardiac-vascular lineage decision is made, and how this plasticity serves to coordinate cardiac chamber and vessel growth. The posterior domain of the Isl1-positive second heart field contributes to the SLN-positive atrial myocardium and myocardial sleeves in the cardiac inflow tract, where myocardial and vascular smooth muscle layers form anatomical and functional continuity. Herein, using a new atrial specific SLN-Cre knockin mouse line, we report that bipotent Isl1(+)/SLN+ transient cell population contributes to cardiac as well as smooth muscle cells at the heart-vessel junction in cardiac inflow tract. The Isl1(+)/SLN+ cells are capable of giving rise to cardiac and smooth muscle cells until late gestational stages. These data suggest that the cardiac and smooth muscle cells in the cardiac inflow tract share a common developmental origin. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". (C) 2010 Elsevier Ltd. All rights reserved. C1 [Sasaki, Mika; Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Nakano, Haruko; Williams, Estrelania; Nakano, Atsushi] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Nakano, Haruko; Williams, Estrelania; Nakano, Atsushi] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Hoshijima, Masahiko] Univ Calif San Diego, Ctr Res Biol Syst, Dept Med, La Jolla, CA 92093 USA. [Sasaki, Mika; Chien, Kenneth R.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Sasaki, Mika; Chien, Kenneth R.] Harvard Stem Cell Inst, Boston, MA 02114 USA. [Minamisawa, Susumu] Waseda Univ, Dept Sci & Engn, Tokyo 1698555, Japan. RP Chien, KR (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM kchien@partners.org; anakano@ucla.edu FU NIH; Jean Le Ducq foundation; Harvard Stem Cell Institute; Massachusetts General Hospital; UCLA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research FX This work is supported by NIH, Jean Le Ducq foundation, Harvard Stem Cell Institute, Massachusetts General Hospital, UCLA, and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. We thank Marianne Cilluffo at the Electron Microscopic Lab in Brain Research Institute, UCLA. NR 41 TC 9 Z9 11 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD FEB PY 2011 VL 50 IS 2 SI SI BP 337 EP 345 DI 10.1016/j.yjmcc.2010.10.009 PG 9 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 719BU UT WOS:000287175200013 PM 20974149 ER PT J AU Freeman, DK Fried, SI AF Freeman, Daniel K. Fried, Shelley I. TI Multiple components of ganglion cell desensitization in response to prosthetic stimulation SO JOURNAL OF NEURAL ENGINEERING LA English DT Article ID HIGH-FREQUENCY STIMULATION; RETINAL ELECTRICAL-STIMULATION; SUBTHALAMIC NEURONS; STEADY DISCHARGES; MECHANISMS; ACTIVATION; CAT; THRESHOLDS; ADAPTATION; CONTRAST AB Retinal prostheses aim to restore functional vision to those blinded by outer retinal diseases using electric stimulation of surviving neurons. Previous work indicates that repetitive stimulation with stimuli that activate the synaptic network reduces the sensitivity of retinal neurons to further stimulation. Such desensitization may contribute to the fading of visual percepts over time reported by human subjects. Here, we show that desensitization may be more complex than previously considered. We recorded spike trains from rabbit retinal ganglion cells and found that desensitization persists in the presence of inhibitory blockers (strychnine and picrotoxin), indicating amacrine cell inhibition is not solely responsible for reducing sensitivity in response to electric stimulation. The threshold for direct activation of the ganglion cell changes little during the simultaneous desensitization of the synaptically mediated response, indicating that desensitization likely occurs upstream of the spike generator. In addition to rapid desensitization acting over hundreds of milliseconds (tau = 176.4 +/- 8.8 ms), we report the presence of slow acting desensitization with a time course of seconds (tau = 14.0 +/- 1.1 s). The time courses of the two components of desensitization that we found are similar to the two phases of brightness fading seen in human subjects. This suggests that the reduction in ganglion cell firing due to desensitization may be responsible for the fading of visual percepts over time in response to prosthetic stimulation. C1 [Freeman, Daniel K.; Fried, Shelley I.] Boston VA Healthcare Syst, Ctr Innovat Visual Rehabil, Boston, MA 02130 USA. [Freeman, Daniel K.; Fried, Shelley I.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Freeman, Daniel K.; Fried, Shelley I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Freeman, DK (reprint author), Boston VA Healthcare Syst, Ctr Innovat Visual Rehabil, 150 S Huntington Ave, Boston, MA 02130 USA. EM Fried.Shelley@mgh.harvard.edu FU VA Healthcare System [CDA-1]; National Eye Institute [R01 EY-019967-01] FX We thank Angelica Perez-Fornos for helpful discussions on data from human trials, as well as Donald Eddington, Richard Masland and Joseph Rizzo for their contributions. This work was funded in part by the VA Healthcare System Career Development Award (CDA-1) to D Freeman and a National Eye Institute Grant (R01 EY-019967-01) to S Fried. NR 39 TC 28 Z9 29 U1 1 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 J9 J NEURAL ENG JI J. Neural Eng. PD FEB PY 2011 VL 8 IS 1 AR 016008 DI 10.1088/1741-2560/8/1/016008 PG 14 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 726KR UT WOS:000287721700010 PM 21248379 ER PT J AU Norden, AD Drappatz, J Wen, PY Claus, EB AF Norden, Andrew D. Drappatz, Jan Wen, Patrick Y. Claus, Elizabeth B. TI Survival among patients with primary central nervous system lymphoma, 1973-2004 SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Primary central nervous system lymphoma; Surveillance; Epidemiology; End Results (SEER); Survival ID PRIMARY CNS LYMPHOMA; NON-HODGKINS-LYMPHOMA; MARITAL-STATUS; BRAIN; TRENDS; RADIOTHERAPY; PROGNOSIS; PATTERNS; THERAPY; OLDER AB Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma that occurs in immunocompetent and human immunodeficiency virus (HIV) patients. Despite treatment advances, previous reports have produced conflicting information about survival trends over time. Using the Surveillance, Epidemiology, and End Results (SEER) data, 2,557 patients diagnosed with PCNSL between 1973 and 2004 were identified and classified by HIV status. Potential predictors of survival were evaluated using log-rank tests. Hazard ratios and 95% confidence intervals (CIs) were computed using a Cox proportional hazards regression model. The cohort included 1,732 (67.7%) HIV-negative patients and 825 (32.3%) HIV-positive patients. Median overall survival was 12 months (95% CI 10, 13) among HIV-negative patients. In this group, median survival increased over time, from 7.5 months (95% CI 6, 14) for patients diagnosed in the 1970s, to 14 months (95% CI 11, 20) for patients diagnosed in the 2000s. Independent predictors of mortality included older age (hazard ratio [HR] 1.03 [95% CI 1.02, 1.03]), earlier year of diagnosis (HR 0.98 [95% CI 0.98, 0.99]), male sex (HR 1.20 [95% CI 1.08, 1.34), married status (HR 0.70 [95% CI 0.63, 0.78]), and receipt of radiation therapy (HR 0.69 [95% CI 0.61, 0.77]). HIV positivity was a powerful adverse prognostic factor in the overall cohort (HR 4.55 [95% CI 4.01, 5.16]). Despite treatment advances, survival among PCNSL patients in the United States remains poor. However, in the subset of PCNSL patients who are HIV-negative, survival has improved over time. C1 [Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.; Claus, Elizabeth B.] Harvard Univ, Sch Med, Boston, MA USA. [Claus, Elizabeth B.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Claus, Elizabeth B.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Norden, AD (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, 44 Binney St, Boston, MA 02115 USA. EM anorden@partners.org NR 23 TC 19 Z9 21 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD FEB PY 2011 VL 101 IS 3 BP 487 EP 493 DI 10.1007/s11060-010-0269-7 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 709VI UT WOS:000286469100014 PM 20556477 ER PT J AU Paintlia, MK Paintlia, AS Singh, AK Singh, I AF Paintlia, Manjeet K. Paintlia, Ajaib S. Singh, Avtar K. Singh, Inderjit TI Synergistic activity of interleukin-17 and tumor necrosis factor-alpha enhances oxidative stress-mediated oligodendrocyte apoptosis SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis and multiple sclerosis; interleukin-17; oligodendrocyte; tumor necrosis factor ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; ACTIVATED PROTEIN-KINASE; BRAIN-BARRIER DISRUPTION; KAPPA-B ACTIVATION; INDUCED CELL-DEATH; MULTIPLE-SCLEROSIS; PROGENITOR CELLS; TNF-ALPHA; DEMYELINATING DISEASES AB P>Th1 cytokine-induced loss of oligodendrocytes (OLs) is associated with axonal loss in CNS demyelinating diseases such as multiple sclerosis (MS)that contributes to neurological disabilities in affected individuals. Recent studies indicated that, in addition to Th1-phenotype cytokines including tumor necrosis factor (TNF)-alpha, Th17 phenotype cytokine, interleukin (IL)-17 also involved in the development of MS. In this study, we investigated the direct effect of IL-17 on the survival of OLs in the presence of TNF-alpha and individually in vitro settings. Our findings suggest that IL-17 alone, however, was not able to affect the survival of OLs, but it exacerbates the TNF-alpha-induced OL apoptosis as compared with individual TNF-alpha treatment. This effect of cytokines was ascribed to an inhibition of cell-survival mechanisms, co-localization of Bid/Bax proteins in the mitochondrial membrane and caspase 8 activation mediated release of apoptosis inducing factor from mitochondria in treated OLs. In addition, cytokine treatment disturbed the mitochondrial membrane potential in OLs with corresponding increase in the generation of reactive oxygen species, which were attenuated by N-acetyl cysteine treatment. In addition, combining of these cytokines induced cell-cycle arrest at G1/S phases in OL-like cells and inhibited the maturation of OL progenitor cells that was attenuated by peroxisome proliferator-activated receptor-gamma/-beta agonists. Collectively, these data provide initial evidence that IL-17 exacerbates TNF-alpha-induced OL loss and inhibits the differentiation of OL progenitor cells suggesting that antioxidant- or peroxisome proliferator-activated receptor agonist-based therapies have potential to limit CNS demyelination in MS or other related demyelinating disorders. C1 [Paintlia, Manjeet K.; Paintlia, Ajaib S.; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Darby Childrens Res Inst, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Dept Pathol & Lab Med, Charleston, SC USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, Darby Childrens Res Inst, 173 Ashley Ave, Charleston, SC 29425 USA. EM singhi@musc.edu OI Paintlia, Ajaib/0000-0003-4525-5333 FU NIH [NS-22576, NS-34741, NS-37766, C06-RR015455, C06-RR018823] FX We thank Dr Jennifer G. Schnellmann for critical reading of this manuscript and Ms Joyce Bryan and Ms Carrie Barnes for their technical assistance. We would like to thank Dr. Shailendra Giri for performing EMSA and DNA ladder analyses. This study was supported by grants from the NIH (NS-22576, NS-34741, NS-37766, C06-RR015455, and C06-RR018823). NR 66 TC 38 Z9 39 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2011 VL 116 IS 4 BP 508 EP 521 DI 10.1111/j.1471-4159.2010.07136.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 715MK UT WOS:000286888400005 PM 21143599 ER PT J AU Offner, H Sinha, S Burrows, GG Ferro, AJ Vandenbark, AA AF Offner, Halina Sinha, Sushmita Burrows, Gregory G. Ferro, Adolph J. Vandenbark, Arthur A. TI RTL therapy for multiple sclerosis: A Phase I clinical study SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Experimental autoimmune encephalomyelitis (EAE); Multiple sclerosis (MS); Recombinant T cell receptor ligand (RTL); Neuroprotection; Clinical trial ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CELL-RECEPTOR LIGANDS; ENCEPHALITOGENIC T-CELLS; CENTRAL-NERVOUS-SYSTEM; CHEMOKINE RECEPTORS; PROMOTES RECOVERY; CYTOKINE SWITCH; MYELIN; CXCR2; ACTIVATION AB A human recombinant T cell receptor ligand (RTL1000) consisting of DR2 alpha 1 and beta 1 domains linked covalently to MOG-35-55 peptide can reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), and was evaluated for safety in a Phase 1 randomized, placebo-controlled, escalating dose study in 34 subjects with multiple sclerosis (MS). RTL1000 was safe and well tolerated at a dose of <= 60 mg that is well within the effective dose range for EAE and did not cause worsening of MS disease at doses <= 200 mg. RTL1000 represents a novel approach for the treatment of MS that promises potent immunoregulation and CNS repair without global immunosuppression. (C) 2010 Elsevier B.V. All rights reserved. C1 [Offner, Halina; Sinha, Sushmita; Vandenbark, Arthur A.] Vet Affairs Med Ctr, Portland, OR 97239 USA. [Offner, Halina; Sinha, Sushmita; Burrows, Gregory G.; Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Burrows, Gregory G.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Burrows, Gregory G.; Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Tykeson MS Res Lab, Portland, OR 97239 USA. [Ferro, Adolph J.] Artielle ImmunoTherapeut Inc, Portland, OR 97223 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. RP Offner, H (reprint author), Portland VA Med Ctr, Neuroimmunol Res R&D31, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU National Multiple Sclerosis Society [RG3794B, RG3794A, RG3468A]; NIH [NS47661, AI43960, NS41965, NS46877]; Biomedical Laboratory RD Service; Department of Veterans Affairs FX This work was supported by the National Multiple Sclerosis Society Grants RG3794B, RG3794A and RG3468A, NIH Grants NS47661, AI43960, NS41965, and NS46877, and by the Biomedical Laboratory R&D Service, Department of Veterans Affairs. The authors wish to thank Ms. Eva Niehaus for assistance in preparing the manuscript and acknowledge the contributions of Chunhe Wang and Shayne Andrew. Dr. Offner, Dr. Burrows and Dr. Vandenbark have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the result of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU and VAMC Conflict of Interest in Research Committees. NR 22 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD FEB PY 2011 VL 231 IS 1-2 SI SI BP 7 EP 14 DI 10.1016/j.jneuroim.2010.09.013 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 744YT UT WOS:000289131800003 PM 20965577 ER PT J AU Camelo-Piragua, S Jansen, M Ganguly, A Kim, JC Cosper, AK Dias-Santagata, D Nutt, CL Iafrate, AJ Louis, DN AF Camelo-Piragua, Sandra Jansen, Michael Ganguly, Aniruddha Kim, James ChulMin Cosper, Arjola K. Dias-Santagata, Dora Nutt, Catherine L. Iafrate, A. John Louis, David N. TI A Sensitive and Specific Diagnostic Panel to Distinguish Diffuse Astrocytoma From Astrocytosis: Chromosome 7 Gain With Mutant Isocitrate Dehydrogenase 1 and p53 SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Astrocytoma; Astrocytosis; Chromosome 7; FISH; IDH1; Immunohistochemistry; p53 ID MONOCLONAL-ANTIBODY KI-67; IN-SITU HYBRIDIZATION; HUMAN-BRAIN-TUMORS; LOW-GRADE; MUTATIONAL ANALYSIS; IDH1 MUTATIONS; GLIOBLASTOMAS; PROTEIN; GLIOMAS; OLIGODENDROGLIOMAS AB One of the major challenges of surgical neuropathology is the distinction of diffuse astrocytoma (World Health Organization grade II) from astrocytosis. The most commonly used ancillary tool to solve this problem is p53 immunohistochemistry (IHC), but this is neither sensitive nor specific. Isocitrate dehydrogenase 1 (IDH1) mutations are common in lower-grade gliomas, with most causing a specific amino acid change (R132H) that can be detected with a monoclonal antibody. IDH2 mutations are rare, but they also occur in gliomas. In addition, gains of chromosome 7 are common in gliomas. In this study, we assessed the status of p53, IDH1/2, and chromosome 7 to determine the most useful panel to distinguish astrocytoma from astrocytosis. We studied biopsy specimens from 21 World Health Organization grade II diffuse astrocytomas and 20 reactive conditions. The single most sensitive test to identify astrocytoma is fluorescence in situ hybridization for chromosome 7 gain (76.2%). The combination of p53 and mutant IDH1 IHC provides a higher sensitivity (71.4%) than either test alone (47.8%); this combination offers a practical initial approach for the surgical pathologist. The best overall sensitivity (95%) is achieved when fluorescence in situ hybridization for chromosome 7 gain is added to the p53-mutant IDH1 IHC panel. C1 [Louis, David N.] Massachusetts Gen Hosp, Pathol Serv, James Homer Wright Pathol Labs, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Iafrate, A. John; Louis, David N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. RP Louis, DN (reprint author), Massachusetts Gen Hosp, Pathol Serv, James Homer Wright Pathol Labs, Dept Pathol, WRN225, Boston, MA 02114 USA. EM dlouis@partners.org RI Nutt, Catherine/K-8794-2012 FU National Institutes of Health [CA57683] FX This work was supported by the National Institutes of Health grant CA57683 (DNL). NR 25 TC 38 Z9 40 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD FEB PY 2011 VL 70 IS 2 BP 110 EP 115 DI 10.1097/NEN.0b013e31820565f9 PG 6 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 709EU UT WOS:000286421500002 PM 21343879 ER PT J AU Duhaime, AC AF Duhaime, Ann-Christine TI Traumatic brain injuries SO JOURNAL OF NEUROSURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Duhaime, AC (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 2011 VL 114 IS 2 BP 543 EP 543 DI 10.3171/2010.4.JNS10409 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 710WU UT WOS:000286548500041 PM 21087201 ER PT J AU Wang, YG Neumann, M Hansen, K Hong, SM Kim, S Noble-Haeusslein, LJ Liu, JL AF Wang, Yonggang Neumann, Melanie Hansen, Katharina Hong, Shuwhey M. Kim, Sharon Noble-Haeusslein, Linda J. Liu, Jialing TI Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE controlled cortical impact; histone acetylation; memory; methyl-CpG binding domain 1; selective serotonin reuptake inhibitor ID FOCAL CEREBRAL-ISCHEMIA; HISTONE H3 ACETYLATION; LONG-TERM-MEMORY; SYNAPTIC PLASTICITY; COGNITIVE DEFICITS; GENE-EXPRESSION; MOTOR RECOVERY; ANIMAL-MODEL; WATER MAZE; CELL-DEATH AB The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. C1 [Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.; Liu, Jialing] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94121 USA. [Noble-Haeusslein, Linda J.] Univ Calif San Francisco, Dept Phys Therapy Rehabil Sci, San Francisco, CA 94121 USA. [Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Liu, Jialing] San Francisco VA Med Ctr, San Francisco, CA USA. [Wang, Yonggang] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurol Surg, Beijing, Peoples R China. [Neumann, Melanie] Univ Klinikum Hamburg Eppendorf, Hamburg, Germany. RP Liu, JL (reprint author), Univ Calif San Francisco, Dept Neurol Surg 112C, 4150 Clement St, San Francisco, CA 94121 USA. EM jialing.liu@ucsf.edu RI Liu, Jialing/A-8627-2012 OI Liu, Jialing/0000-0003-4420-4382 FU VA Merit award; Department of Defense collaborative in Neuroscience Center of Excellence FX This work was supported by a VA Merit award (to J.L.), and a Department of Defense collaborative in Neuroscience Center of Excellence (to J.L.). NR 57 TC 35 Z9 36 U1 2 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD FEB PY 2011 VL 28 IS 2 BP 259 EP 268 DI 10.1089/neu.2010.1648 PG 10 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 719UE UT WOS:000287234700009 PM 21175261 ER PT J AU Caban-Martinez, AJ Lee, DJ Goodman, E Davila, EP Fleming, LE LeBlanc, WG Arheart, KL McCollister, KE LeBlanc, WG Arheart, KL McCollister, KE Christ, SL Zimmerman, FJ Muntaner, C Hollenbeck, JA AF Caban-Martinez, Alberto J. Lee, David J. Goodman, Elizabeth Davila, Evelyn P. Fleming, Lora E. LeBlanc, William G. Arheart, Kristopher L. McCollister, Kathryn E. LeBlanc, William G. Arheart, Kristopher L. McCollister, Kathryn E. Christ, Sharon L. Zimmerman, Frederick J. Muntaner, Carles Hollenbeck, Julie A. TI Health Indicators Among Unemployed and Employed Young Adults SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID RISK BEHAVIORS; PHYSICAL-ACTIVITY; UNITED-STATES; SOCIOECONOMIC POSITION; INTERVIEW SURVEY; CHRONIC ILLNESS; BLOOD-PRESSURE; PITT COUNTY; LIFE-STYLE; ADOLESCENTS AB Objective: Research on the prevalence of health indicators by employment status among young US adults is limited. Methods: We analyzed data from a nationally representative sample of young adults aged 18 to 24 years to document the prevalence of five health behaviors (cigarette smoking, risky drinking, leisure-time physical activity, and fruit and French fries consumption) by employment status. Results: Unemployed young adults reported higher levels of risky drinking and nonengagement in leisure-time physical activity, while employed young adults had higher levels of smoking, French fries consumption, and low fruit/vegetable consumption. Transportation/material-moving young adult workers reported the highest level of risky drinking (13.5%), and precision production/craft/repair workers reported the highest smoking rates (39.7%). Conclusions: We found an elevated prevalence of risk factors, which places young workers at increased risk for the development of chronic conditions later in life. C1 [Caban-Martinez, Alberto J.; Lee, David J.; Davila, Evelyn P.; Fleming, Lora E.; LeBlanc, William G.; Arheart, Kristopher L.; McCollister, Kathryn E.; Hollenbeck, Julie A.] Univ Miami, Dept Epidemiol & Publ Hlth, Miller Sch Med, Miami, FL 33136 USA. [Goodman, Elizabeth] MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA USA. [Christ, Sharon L.] Univ N Carolina, Ctr Dev Sci, Chapel Hill, NC USA. [Zimmerman, Frederick J.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Muntaner, Carles] Univ Toronto, Bloomberg Fac Nursing, Toronto, ON, Canada. [Muntaner, Carles] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Caban-Martinez, AJ (reprint author), Univ Miami, Dept Epidemiol & Publ Hlth, Miller Sch Med, Clin Res Bldg,Room 1073,1120 NW,14th St,10th Floo, Miami, FL 33136 USA. EM acaban@med.miami.edu OI Caban-Martinez, Alberto/0000-0002-5960-1308; Zimmerman, Frederick/0000-0002-4163-9893 FU NIAMS NIH HHS [F31 AR057687, F31 AR057687-01, F31 AR057687-02]; NICHD NIH HHS [T32 HD007376]; NIOSH CDC HHS [OH003915, OH003915-06A1, R01 OH003915]; None [R01 OH003915-06A1] NR 58 TC 4 Z9 4 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD FEB PY 2011 VL 53 IS 2 BP 196 EP 203 DI 10.1097/JOM.0b013e318209915e PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 718OF UT WOS:000287133100015 PM 21270653 ER PT J AU Volandes, AE Ferguson, LA Davis, AD Hull, NC Green, MJ Chang, YC Deep, K Paasche-Orlow, MK AF Volandes, Angelo E. Ferguson, Laurie Anne Davis, Aretha D. Hull, Nathan C. Green, Michael J. Chang, Yuchiao Deep, Kristy Paasche-Orlow, Michael K. TI Assessing End-of-Life Preferences for Advanced Dementia in Rural Patients Using an Educational Video: A Randomized Controlled Trial SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID NURSING-HOME RESIDENTS; COGNITIVE IMPAIRMENT; URBAN DIFFERENCES; DECISION-MAKING; SUSTAINING TREATMENTS; HEALTH LITERACY; CARE; SUPPORT; COMMUNICATION; DIRECTIVES AB Objective: Few studies have evaluated the end-of-life preferences of elderly patients in rural communities and whether preferences are associated with level of health literacy. Design: Randomized controlled trial of a goals-of-care video decision aid of advanced dementia. Participants: Elderly subjects (65 years or older) at a primary care clinic in rural Louisiana. Methods: Half of subjects heard a verbal description of advanced dementia and the goals of care; the other half heard the same verbal description and then viewed the video decision aid. End points were the preferred goal of care in advanced dementia: life-prolonging care (cardiopulmonary resuscitation [CPR], etc.), limited care (hospitalization but not CPR), or comfort care (symptom relief). The principal category for analysis was the difference in proportions of subjects preferring comfort care for each characteristic including randomization group and health literacy level. Results: Seventy-six subjects were randomized to the verbal (n = 43) or video (n = 33) arms of the study. Among subjects receiving the verbal description of advanced dementia and the goals of care, 31 (72%) preferred comfort; 5 (12%) chose limited; and 7 (16%) desired life-prolonging. In the video group, 30 (91%) preferred comfort; 3 (9%) chose limited; and none desired life-prolonging (chi(2) = 6.3, df = 2, p = 0.047). Factors associated with greater likelihood of opting for comfort included greater health literacy (unadjusted odds ratio [OR] 12.1; 95% confidence interval [CI], 2.4-62.6) and randomization to the video (unadjusted OR 3.9; 95% CI, 1.0-15.1). Conclusion: Rural subjects with higher health literacy were more likely to want comfort care compared to those with lower levels of health literacy. Furthermore, subjects who viewed a video decision aid were more likely to opt for comfort compared to those who solely listened to a verbal description. These findings suggest that video can help elicit preferences and that interventions to empower such patients need to be designed in a manner that is sensitive to health literacy. C1 [Volandes, Angelo E.; Chang, Yuchiao] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. [Volandes, Angelo E.; Davis, Aretha D.; Chang, Yuchiao] Harvard Univ, Sch Med, Boston, MA USA. [Ferguson, Laurie Anne] Univ Texas Hlth Sci Ctr, Sch Nursing, Houston, TX USA. [Hull, Nathan C.; Green, Michael J.] Penn State Coll Med, Hershey, PA USA. [Deep, Kristy] Univ Kentucky, Dept Med, Lexington, KY 40506 USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Volandes, AE (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM avolandes@partners.org OI Paasche-Orlow, Michael/0000-0002-9276-7190 FU Foundation for Informed Medical Decision Making; Alzheimer's Association FX Dr. Volandes was supported by a George Bennett Fellowship from the Foundation for Informed Medical Decision Making and a New Investigator Research Grant from the Alzheimer's Association. NR 40 TC 21 Z9 21 U1 3 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD FEB PY 2011 VL 14 IS 2 BP 169 EP 177 DI 10.1089/jpm.2010.0299 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 719UM UT WOS:000287236200012 PM 21254815 ER PT J AU Rudders, SA Banerji, A Clark, S Camargo, CA AF Rudders, Susan A. Banerji, Aleena Clark, Sunday Camargo, Carlos A., Jr. TI Age-Related Differences in the Clinical Presentation of Food-Induced Anaphylaxis SO JOURNAL OF PEDIATRICS LA English DT Article ID MANAGEMENT; ALLERGY AB Food-induced anaphylaxis may be more difficult to recognize in younger children. We describe age-related patterns in the clinical presentation of children with anaphylaxis, which may facilitate the early recognition and treatment of this potentially life-threatening condition. (J Pediatr 2011; 158:326-8) C1 [Rudders, Susan A.; Banerji, Aleena; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Banerji, Aleena; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Rudders, Susan A.] Childrens Hosp Boston, Div Allergy & Immunol, Boston, MA USA. [Clark, Sunday] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org FU NIH [NRSA T32-AI-007512]; Dey Pharma (Basking Ridge, NJ) FX Supported by NIH training grant NRSA T32-AI-007512 (S.R.) and investigator-initiated research grant from Dey Pharma (Basking Ridge, NJ) (C.C. is Principal Investigator). C.C. has consulted for Dey Pharma and Sanofi-Aventis. The other authors declare no conflicts of interest. NR 9 TC 31 Z9 32 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD FEB PY 2011 VL 158 IS 2 BP 326 EP 328 DI 10.1016/j.jpeds.2010.10.017 PG 3 WC Pediatrics SC Pediatrics GA 706DC UT WOS:000286196300035 PM 21094954 ER PT J AU Biederman, J Petty, CR Clarke, A Lomedico, A Faraone, SV AF Biederman, Joseph Petty, Carter R. Clarke, Allison Lomedico, Alexandra Faraone, Stephen V. TI Predictors of persistent ADHD: An 11-year follow-up study SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE ADHD; Persistence; Predictors; Longitudinal; Young adult ID ATTENTION-DEFICIT HYPERACTIVITY; AGE-DEPENDENT DECLINE; PSYCHIATRIC STATUS; DEFICIT/HYPERACTIVITY DISORDER; RISK-FACTORS; BOYS; CHILDREN; COMORBIDITY; CHILDHOOD; ADOLESCENCE AB Objective: Despite the existence of several follow-up studies of children with ADHD followed up into adulthood, there is limited information on whether patterns of persistence and remission in ADHD can be predicted over the long term. The main aim of this study was to evaluate predictors of persistence of ADHD in a large sample of boys with and without ADHD followed prospectively for 11 years into young adulthood. Method: Subjects were Caucasian, non-Hispanic boys with (N = 110) and without (N = 105) ADHD who were 6-17 years old at the baseline assessment (mean age 11 years) and 15 to 31 years old at the follow-up assessment (mean age 22 years). Subjects were comprehensively and blindly assessed with structured diagnostic interviews and assessments of cognitive, social, school, and family functioning. Results: At the 11-year follow-up, 78% of children with ADHD continued to have a full (35%) or a partial persistence (subsyndromal (22%), impaired functioning (15%), or remitted but treated (6%)). Predictors of persistence were severe impairment of ADHD, psychiatric comorbidity, and exposure to maternal psychopathology at baseline. Conclusions: These findings prospectively confirm that persistence of ADHD over the long term is predictable from psychosocial adversity and psychiatric comorbidity ascertained 11 years earlier. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Biederman, Joseph; Petty, Carter R.; Clarke, Allison; Lomedico, Alexandra] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Biederman, Joseph; Petty, Carter R.; Clarke, Allison; Lomedico, Alexandra] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,YAW 6A-6900, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Child Health and Human Development (NICHD) [5R01HD036317-10]; Lilly Foundation Fund; Pediatric Psychopharmacology Philanthropic Fund; Alza; AstraZeneca; Bristol Myers Squibb; Eli Lilly and Co.; Janssen Pharmaceuticals Inc.; McNeil; Merck; Organon; Otsuka; Shire; NIMH; NICHD; Fundacion Areces; Medice Pharmaceuticals; Spanish Child Psychiatry Association; Abbott; Celltech; Cephalon; Esai; Forest; Glaxo; Gliatech; Janssen; NARSAD; NIDA; New River; Novartis; Noven; Neurosearch; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma, Inc.; Wyeth; Eli Lilly; Ortho-McNeil; Shire Development; National Institutes of Health FX This work was supported, in part, by National Institute of Child Health and Human Development (NICHD) grant 5R01HD036317-10, the Lilly Foundation Fund, and the Pediatric Psychopharmacology Philanthropic Fund.; Dr. Joseph Biederman is currently receiving research support from the following sources: Alza, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Co., Janssen Pharmaceuticals Inc., McNeil, Merck, Organon, Otsuka, Shire, NIMH, and NICHD. In 2009, Dr. Joseph Biederman received a speaker's fee from the following sources: Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, NARSAD, NIDA, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc. and Wyeth.; In the past year, Dr. Stephen Faraone has received consulting fees and has been on Advisory Boards for Eli Lilly, Ortho-McNeil and Shire Development and has received research support from Eli Lilly, Pfizer, Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on Advisory Boards or has been a speaker for the following sources: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. In previous years he has received research support from Eli Lilly, Shire, Pfizer and the National Institutes of Health. NR 35 TC 96 Z9 98 U1 1 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD FEB PY 2011 VL 45 IS 2 BP 150 EP 155 DI 10.1016/j.jpsychires.2010.06.009 PG 6 WC Psychiatry SC Psychiatry GA 728WZ UT WOS:000287906500002 PM 20656298 ER PT J AU Mehta, DD Deliyski, DD Quatieri, TF Hillman, RE AF Mehta, Daryush D. Deliyski, Dimitar D. Quatieri, Thomas F. Hillman, Robert E. TI Automated Measurement of Vocal Fold Vibratory Asymmetry From High-Speed Videoendoscopy Recordings SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE vocal fold; assessment; endoscopy; voice ID VOICE QUALITY; MUCOSAL WAVE; VIDEOKYMOGRAPHY; VISUALIZATION; VIBRATIONS; DYNAMICS AB Purpose: In prior work, a manually derived measure of vocal fold vibratory phase asymmetry correlated to varying degrees with visual judgments made from laryngeal high-speed videoendoscopy (HSV) recordings. This investigation extended this work by establishing an automated HSV-based framework to quantify 3 categories of vocal fold vibratory asymmetry. Method: HSV-based analysis provided for cycle-to-cycle estimates of left-right phase asymmetry, left-right amplitude asymmetry, and axis shift during glottal closure for 52 speakers with no vocal pathology producing comfortable and pressed phonation. An initial cross-validation of the automated left-right phase asymmetry measure was performed by correlating the measure with other objective and subjective assessments of phase asymmetry. Results: Vocal fold vibratory asymmetry was exhibited to a similar extent in both comfortable and pressed phonations. The automated measure of left-right phase asymmetry strongly correlated with manually derived measures and moderately correlated with visual-perceptual ratings. Correlations with the visual-perceptual ratings remained relatively consistent as the automated measure was derived from kymograms taken at different glottal locations. Conclusions: An automated HSV-based framework for the quantification of vocal fold vibratory asymmetry was developed and initially validated. This framework serves as a platform for investigating relationships between vocal fold tissue motion and acoustic measures of voice function. C1 [Mehta, Daryush D.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Hillman, Robert E.] MIT, Cambridge, MA 02139 USA. [Mehta, Daryush D.; Quatieri, Thomas F.] MIT, Lincoln Lab, Lexington, MA 02173 USA. [Deliyski, Dimitar D.] Univ S Carolina, Columbia, SC 29208 USA. [Hillman, Robert E.] Harvard Univ, Sch Med, Boston, MA USA. RP Mehta, DD (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM daryush.mehta@alum.mit.edu FU NIDCD NIH HHS [R01 DC007640, T32 DC000038, T32 DC00038]; NIEHS NIH HHS [27304C0002, 27306C0002] NR 22 TC 35 Z9 35 U1 0 U2 5 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD FEB 1 PY 2011 VL 54 IS 1 BP 47 EP 54 DI 10.1044/1092-4388(2010/10-0026) PG 8 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 714IY UT WOS:000286804500010 PM 20699347 ER PT J AU Wiedemann-Bidlack, FB Kwak, SY Beniash, E Yamakoshi, Y Simmer, JP Margolis, HC AF Wiedemann-Bidlack, Felicitas B. Kwak, Seo-Young Beniash, Elia Yamakoshi, Yasuo Simmer, James P. Margolis, Henry C. TI Effects of phosphorylation on the self-assembly of native full-length porcine amelogenin and its regulation of calcium phosphate formation in vitro SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Amelogenin; Biomineralization; Calcium phosphates; Dynamic light scattering; Enamel; Self-assembly ID DYNAMIC LIGHT-SCATTERING; ENAMEL MATRIX PROTEINS; RECOMBINANT AMELOGENIN; CRYSTAL-GROWTH; OCTACALCIUM PHOSPHATE; SECRETORY-STAGE; MOUSE AMELOGENINS; RAT INCISOR; HYDROXYAPATITE; SUBUNIT AB The self-assembly of the predominant extracellular enamel matrix protein amelogenin plays an essential role in regulating the growth and organization of enamel mineral during early stages of dental enamel formation. The present study describes the effect of the phosphorylation of a single site on the full-length native porcine amelogenin P173 on self-assembly and on the regulation of spontaneous calcium phosphate formation in vitro. Studies were also conducted using recombinant non-phosphorylated (rP172) porcine amelogenin, along with the most abundant amelogenin cleavage product (P148) and its recombinant form (rP147). Amelogenin self-assembly was assessed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Using these approaches, we have shown that self-assembly of each amelogenin is very sensitive to pH and appears to be affected by both hydrophilic and hydrophobic interactions. Furthermore, our results suggest that the phosphorylation of the full-length porcine amelogenin P173 has a small but potentially important effect on its higher-order self-assembly into chain-like structures under physiological conditions of pH, temperature, and ionic strength. Although phosphorylation has a subtle effect on the higher-order assembly of full-length amelogenin, native phosphorylated P173 was found to stabilize amorphous calcium phosphate for extended periods of time, in sharp contrast to previous findings using non-phosphorylated rP172. The biological relevance of these findings is discussed. (C) 2010 Elsevier Inc. All rights reserved. C1 [Wiedemann-Bidlack, Felicitas B.; Kwak, Seo-Young; Margolis, Henry C.] Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. [Beniash, Elia] Univ Pittsburgh, Dept Oral Biol, Pittsburgh, PA 15261 USA. [Yamakoshi, Yasuo; Simmer, James P.] Univ Michigan, Dent Res Lab, Ann Arbor, MI 48109 USA. RP Margolis, HC (reprint author), Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. EM hmargolis@forsyth.org FU National Institute of Dental and Craniofacial Research [DE-016376]; [T32 DE-007327] FX This work was supported by grant DE-016376 (HCM) from the National Institute of Dental and Craniofacial Research. S-YK was also partially supported by grant T32 DE-007327. NR 60 TC 29 Z9 32 U1 0 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD FEB PY 2011 VL 173 IS 2 BP 250 EP 260 DI 10.1016/j.jsb.2010.11.006 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 714YD UT WOS:000286846700007 PM 21074619 ER PT J AU Wilens, TE Martelon, M Fried, R Petty, C Bateman, C Biederman, J AF Wilens, Timothy E. Martelon, MaryKate Fried, Ronna Petty, Carter Bateman, Clancey Biederman, Joseph TI Do Executive Function Deficits Predict Later Substance Use Disorders Among Adolescents and Young Adults? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; executive function; substance-use disorders; longitudinal follow-up ID HYPERACTIVITY DISORDER; FOLLOW-UP; DEFICIT/HYPERACTIVITY DISORDER; ADHD; ATTENTION; CHILDREN; RISK; AGE; PERFORMANCE; CHILDHOOD AB Objective: There is increasing interest regarding the risk and overlap of executive function deficits (EFDs) in stable cigarette smoking and substance use disorders (SUD). Therefore, we examined whether earlier EFD was a risk factor for subsequent cigarette smoking and SUD and further explored the relationship between EFD and SUD. Method: We assessed 435 subjects at the 5-year follow-up (232 subjects with attention-deficit/hyperactivity disorder [ADHD], mean age +/- SD: 15.4 +/- 3.43 years; and 203 controls: 16.3 +/- 3.42 years) and again 4 to 5 years later as part of a prospective family study of youth with ADHD. Individuals were assessed by structured psychiatric interview for psychopathology and SUD. EFD was categorically defined in an individual who had abnormal results on at least two of six neuropsychological tests of executive functioning. Results: At the final follow-up period, ADHD was found to be a significant predictor of stable cigarette smoking (p < .01) and SUD into late adolescence and young adult years (p < .01). However, EFDs were not associated with an increase in subsequent substance use outcomes. New-onset stable cigarette smoking, but not SUD, was associated with subsequent EFD (p < .01). Conclusions: Our results do not support the hypothesis that EFDs predicts later stable cigarette smoking or SUD in children with ADHD growing up. However, stable cigarette smoking is associated with subsequent EFD. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(2):141-149. C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin & Res Program Pediat Psychopharmacol, 55 Parkman St,YAW 6A, Boston, MA 02114 USA. EM twilens@partners.org FU U.S. Public Health Service Commissioned Corps (National Institute of Child Health and Human Development) [5RO1 HD-36317-07]; Eli Lilly and Co. Foundation; Pediatric Psychopharmacology Philanthropy Fund; Abbott; McNeil; Eli Lilly and Co.; National Institutes of Health National Institute on Drug Abuse; Merck; Shire; Alza; AstraZeneca; Bristol-Myers Squibb; Celltech; Cephalon; GlaxoSmithKline; Janssen; National Alliance for Research on Schizophrenia and Depression; National Institute of Child Health and Human Development; National Institute of Mental Health; National Institute on Drug Abuse; New River; Novartis; Noven; Neurosearch; Organon; Otsuka; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; USB Pharma; Wyeth; [K24 DA016264] FX This study was funded by K24 DA016264 (T.W.) as well as in part, by a grant from the U.S. Public Health Service Commissioned Corps (National Institute of Child Health and Human Development), grant 5RO1 HD-36317-07 (J.B.), and in part by a grant from the Eli Lilly and Co. Foundation and the Pediatric Psychopharmacology Philanthropy Fund.; Dr. Wilens has received grant support from Abbott, McNeil, Eli Lilly and Co., the National Institutes of Health National Institute on Drug Abuse, Merck, and Shire. He has served on the speakers' bureau for Eli Lilly and Co., McNeil, Novartis, and Shire. He has served as a consultant for Abbott, AstraZeneca, McNeil, Eli Lilly and Co., the National Institutes of Health National Institute on Drug Abuse, Novartis, Merck, and Shire. He receives royalties from Guilford Press. Dr. Biederman has received research support from Alza, AstraZeneca, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., GlaxoSmithKline, Janssen, McNeil, Merck, National Alliance for Research on Schizophrenia and Depression, the National Institute of Child Health and Human Development, the National Institute of Mental Health, the National Institute on Drug Abuse, New River, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, the Prechter Foundation, Shire, the Stanley Foundation, USB Pharma, and Wyeth. Dr. Fried, Ms. Martelon, Mr. Petty, and Ms. Bateman report no biomedical financial interests or potential conflicts of interest. NR 53 TC 17 Z9 17 U1 0 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2011 VL 50 IS 2 BP 141 EP 149 DI 10.1016/j.jaac.2010.11.010 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 712ZL UT WOS:000286704700006 PM 21241951 ER PT J AU Fett, N Werth, VP AF Fett, Nicole Werth, Victoria P. TI Update on morphea Part II. Outcome measures and treatment SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE autoimmune connective tissue disorder; fibrosing disorders; localized scleroderma; morphea; scleroderma; systemic sclerosis ID LOCALIZED SCLERODERMA MORPHEA; ULTRAVIOLET A1 PHOTOTHERAPY; PUVA BATH PHOTOCHEMOTHERAPY; LOW-DOSE METHOTREXATE; 1ST CASE SERIES; BROAD-BAND UVA; SYSTEMIC-SCLEROSIS; MYCOPHENOLATE-MOFETIL; LINEAR SCLERODERMA; DOUBLE-BLIND AB Morphea is a rare fibrosing disorder of the skin and underlying tissues. The underlying pathogenesis of morphea is not completely understood at this time, but ultimately results in an imbalance of collagen production and destruction. Evidence-based treatment options of morphea are limited secondary to the rarity of the disease, and the lack of universally used validated outcome measures. The most commonly used outcome measures are skin scores, computerized surface area measurement, durometer, cutometer, thermography, and ultrasound measurements. The Localized Scleroderma Cutaneous Assessment Tool is a promising recently validated skin scoring tool that allows differentiation between activity and damage, is sensitive to change, and requires no additional equipment. The most robust data in the treatment of morphea exists for methotrexate in combination with systemic steroids and ultraviolet A1. (J Am Acad Dermatol 2011;64:231-42.) C1 [Fett, Nicole] Univ Penn, Sch Med, Dept Dermatol, Perelman Ctr Adv Med, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Fett, N (reprint author), Univ Penn, Sch Med, Dept Dermatol, Perelman Ctr Adv Med, Ste 1-330A,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Nicole.Fett@uphs.upenn.edu FU Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; National Institutes of Health [NIH K24-AR 02207] FX Supported in part by a Merit Review Grant from the Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, and by the National Institutes of Health (grant NIH K24-AR 02207) to Dr Werth. NR 66 TC 48 Z9 51 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2011 VL 64 IS 2 BP 231 EP 242 DI 10.1016/j.jaad.2010.05.046 PG 12 WC Dermatology SC Dermatology GA 714AX UT WOS:000286780400002 PM 21238824 ER PT J AU Kimball, AB Gordon, KB Langley, RG Menter, A Perdok, RJ Valdes, J AF Kimball, Alexa B. Gordon, Kenneth B. Langley, Richard G. Menter, Alan Perdok, Renee J. Valdes, Joaquin CA ABT-874 Study Investigators TI Efficacy and safety of ABT-874, a monoclonal anti-interleukin 12/23 antibody, for the treatment of chronic plaque psoriasis: 36-week observation/retreatment and 60-week open-label extension phases of a randomized phase II trial SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE ABT-874; interleukin-12; interleukin-23; plaque; psoriasis; Psoriasis Area and Severity Index; retreatment ID DOUBLE-BLIND; USTEKINUMAB AB Background: ABT-874, an anti-interleukin-12 and -23 antibody, was previously shown to be significantly more effective compared with placebo during a 12-week phase II study of psoriasis. We report here safety and efficacy data of ABT-874 during subsequent phases of this study. Objective: We sought to examine the preliminary efficacy and safety of ABT-874 for moderate to severe psoriasis beyond 12 weeks, Methods: Patients with chronic plaque psoriasis who responded to ABT-874 during the initial randomized, placebo-controlled, 12-week study phase were eligible for a 36-week observation/retreatment phase. During the subsequent 60-week, open-label extension phase, eligible patients were retreated with one of two ABT-874 dosages. Efficacy was measured using Psoriasis Area and Severity Index and physician global assessment scores; safety was monitored by adverse events (AEs), laboratory parameters, and vital signs. Results: During the observation/retreatment phase, 130 of 180 patients were eligible for retreatment. After 12-week retreatment with ABT-874, 55% to 94% of retreated patients (n = 58) achieved a 75% or greater reduction in Psoriasis Area and Severity Index score. Among patients receiving ABT-874 through the first 48 weeks, there were no deaths and 4 patients with serious AEs; one patient discontinued because of an AE. During the open-label extension (N = 105), there were no deaths or serious infections, and 3 serious AEs. Limitations: Lack of placebo or active comparator groups limited statistical analysis in later study phases. Dosing differences existed between groups, and only week-12 responders were eligible for retreatment. Conclusion: ABT-874 continued to show good efficacy and safety during withdrawal and reinitiation of therapy. (J Am Acad Dermatol 2011;64:263-74.) C1 [Kimball, Alexa B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Unit Res Trials Skin, Boston, MA 02114 USA. [Gordon, Kenneth B.] N Shore Univ HealthSyst, Div Dermatol, Evansville, IN USA. [Gordon, Kenneth B.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Langley, Richard G.] Dalhousie Univ, Dept Med, Div Dermatol, Halifax, NS, Canada. [Menter, Alan] Baylor Res Inst, Dept Internal Med, Div Dermatol, Dallas, TX USA. [Perdok, Renee J.] Abbott, Clin Stat, Abbott Pk, IL USA. [Valdes, Joaquin] Abbott, Immunol Dev, Abbott Pk, IL USA. RP Kimball, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Unit Res Trials Skin, 50 Staniford St,246, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU Abbott; Amgen/Wyeth; Astellas Pharma Inc; Centocor; Genentech; Novartis; Amgen; Astellas; Galderma; Wyeth FX Financial support for the study and for editorial assistance was provided by Abbott.; Disclosure: Dr Kimball has been a consultant and investigator for Amgen, Abbott, and Centocor; and investigator for Pfizer, Genzyme, Novartis, and Boehringer Ingelheim. Dr Gordon has been an investigator and consultant for Abbott and Amgen; investigator for Centocor and Nova Nordisk; and consultant for Galderma. Dr Langley has been an investigator for Abbott, Amgen, Astellas Pharma Inc, Boehringer Ingelheim, Celgene, Centocor, Genentech, Novartis, Ortho Biotech, Pfizer, and Schering-Plough; served on the scientific advisory board for Abbott, Amgen, Astellas Pharma Inc, Boehringer Ingelheim, Centocor, Genentech, and Ortho Biotech; and received lecture fees from Abbott, Amgen/Wyeth, Astellas Pharma Inc, Centocor, Genentech, and Novartis. Dr Menter has been an investigator for Abbott, Allergan, Amgen, Astellas, Asubio, Celgene, Centocor, DUSA, Eli Lilly, Genentech, Novartis, Novo Nordisk, Pfizer, Promius, Stiefel, Warner Chilcott, and Wyeth; served on the scientific advisory board for Abbott, Amgen, Astellas, Centocor, Galderma, Genentech, and Warner Chilcott; and received lecture fees from Abbott, Amgen, Astellas, Centocor, Galderma, Genentech, and Wyeth. Ms Perdok and Dr Valdes are employees of Abbott Laboratories. NR 17 TC 12 Z9 13 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2011 VL 64 IS 2 BP 263 EP 274 DI 10.1016/j.jaad.2010.01.030 PG 12 WC Dermatology SC Dermatology GA 714AX UT WOS:000286780400005 PM 21145618 ER PT J AU Emmons, KM Geller, AC Puleo, E Savadatti, SS Hu, SW Gorham, S Werchniak, AE AF Emmons, Karen M. Geller, Alan C. Puleo, Elaine Savadatti, Sanghamitra S. Hu, Stephanie W. Gorham, Susan Werchniak, Andrew E. CA Dana-Farber Skin Canc Screening Gr TI Skin cancer education and early detection at the beach: A randomized trial of dermatologist examination and biometric feedback SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE skin cancer prevention; skin examinations; sun protection ID SUN PROTECTION BEHAVIORS; PUBLIC-HEALTH CAMPAIGNS; ULTRAVIOLET-RADIATION; SCREENING-PROGRAM; OUTDOOR RECREATION; AMERICAN-ACADEMY; FEAR APPEALS; MELANOMA; EXPOSURE; PREVENTION AB Background: There are limited data on the effectiveness of skin cancer prevention education and early detection programs at beaches. Objectives: We evaluate 4 strategies for addressing skin cancer prevention in beach settings. Methods: This prospective study at 4 beaches included 4 intervention conditions: (1) education only; (2) education plus biometric feedback; (3) education plus dermatologist skin examination; or (4) education plus biometric feedback and dermatologist skin examination. Outcomes included sun protection behaviors, sunburns, and skin self-examinations. Results:There was a significant increase in hat wearing, sunscreen use, and a reduction in sunburns in the education plus biometric feedback group (odds ratio = 1.97, 1.94, and 1.07, respectively), and greater improvements in knowing what to look for in skin-self examinations (odds ratio = 1.13); there were no differences in frequency of self-examinations. Skin examinations plus biometric feedback led to greater reductions in sunburns. The dermatologist examinations identified atypical moles in 28% of participants. Limitations: Inclusion of only one beach per condition, use of self-report data, and a limited intervention period are limitations. Conclusions: Education and biometric feedback may be more effective than education alone for impacting sun protective attitudes and behaviors in beachgoing, high-risk populations. (J Am Acad Dermatol 2011;64:282-9.) C1 [Emmons, Karen M.; Geller, Alan C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Geller, Alan C.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Gorham, Susan] SHADE Fdn Amer, Phoenix, AZ USA. [Puleo, Elaine] Univ Massachusetts, Amherst, MA 01003 USA. [Hu, Stephanie W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Emmons, KM (reprint author), Harvard Univ, Sch Publ Hlth, 44 Binney St, Boston, MA 02115 USA. EM Karen_M_Emmons@dfci.harvard.edu FU SHADE Foundation of America FX Supported by an unrestricted grant from the SHADE Foundation of America. NR 39 TC 14 Z9 14 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2011 VL 64 IS 2 BP 282 EP 289 DI 10.1016/j.jaad.2010.01.040 PG 8 WC Dermatology SC Dermatology GA 714AX UT WOS:000286780400007 PM 21163550 ER PT J AU Patti, JA AF Patti, John A. TI Transparency in Leadership 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 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD FEB PY 2011 VL 8 IS 2 BP 79 EP 79 DI 10.1016/j.jacr.2010.12.016 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FG UT WOS:000305448900001 PM 21292177 ER PT J AU Krishnaraj, A AF Krishnaraj, Arun TI Boston Med: The Untold Stories SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Krishnaraj, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. EM akrishnaraj@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD FEB PY 2011 VL 8 IS 2 BP 82 EP 83 DI 10.1016/j.jacr.2010.10.006 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FG UT WOS:000305448900003 PM 21292179 ER PT J AU Carlos, RJ Weinreb, JC Sherry, CS Patti, JA Sunshine, J Ellenbogen, PH Hillman, BJ AF Carlos, Ruth J. Weinreb, Jeffrey C. Sherry, Cynthia S. Patti, John A. Sunshine, Jonathan Ellenbogen, Paul H. Hillman, Bruce J. TI Managing Hospital-Radiologist Relationships: Proceedings of the Tenth Annual ACR Forum SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE ACR Forum; radiologist-hospital relationships; independent radiologic practice AB The annual ACR Forum brings together a multidisciplinary group to discuss a topic of present and future importance to radiologists. The 2010 gathering was dedicated to radiologist-hospital relationships. This article summarizes the dons and and details the advice of attendees to the ACR as to what actions might best benefit radiologists and the specialty. C1 [Carlos, Ruth J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Weinreb, Jeffrey C.] Yale Univ, New Haven, CT USA. [Sherry, Cynthia S.; Ellenbogen, Paul H.] Presbyterian Med Ctr, Dallas, TX USA. [Patti, John A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sunshine, Jonathan] Amer Coll Radiol, Reston, VA USA. [Hillman, Bruce J.] Univ Virginia, Charlottesville, VA USA. RP Hillman, BJ (reprint author), UVA Radiol Res, Box 801339, Charlottesville, VA 22908 USA. EM bjh8a@virginia.edu NR 0 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 FEB PY 2011 VL 8 IS 2 BP 95 EP 98 DI 10.1016/j.jacr.2010.10.012 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FG UT WOS:000305448900007 PM 21292183 ER PT J AU Whitson, HE Thielke, S Diehr, P O'Hare, AM Chaves, PHM Zakai, NA Arnold, A Chaudhry, S Ives, D Newman, AB AF Whitson, Heather E. Thielke, Stephen Diehr, Paula O'Hare, Ann M. Chaves, Paulo H. M. Zakai, Neil A. Arnold, Alice Chaudhry, Sarwat Ives, Diane Newman, Anne B. TI Patterns and Predictors of Recovery from Exhaustion in Older Adults: The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE symptoms; frailty; fatigue; transition analysis ID STUDIES DEPRESSION SCALE; CRITERION VALIDITY; FRAILTY CRITERIA; WOMENS HEALTH; CES-D; DISABILITY; FATIGUE; DISEASE; CARE; PHENOTYPE AB OBJECTIVES To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults. DESIGN Secondary analysis of a cohort study. SETTING Six annual examinations in four U.S. communities. PARTICIPANTS Four thousand five hundred eighty-four men and women aged 69 and older. MEASUREMENTS Exhaustion was considered present when a participant responded "a moderate amount" or "most of the time" to either of two questions: "How often have you had a hard time getting going?" and "How often does everything seem an effort?" RESULTS Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion free at least once during follow-up. When data from all time points were considered, 48% of those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease. CONCLUSION Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being. C1 [Whitson, Heather E.] Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA. [Whitson, Heather E.; Arnold, Alice] Duke Univ, Med Ctr, Dept Med, Div Geriatr, Durham, NC 27710 USA. [Thielke, Stephen; Diehr, Paula; Arnold, Alice] Univ Washington Hlth Syst, Dept Psychiat, Seattle, WA USA. [Thielke, Stephen; Diehr, Paula] Univ Washington Hlth Syst, Dept Biostat, Seattle, WA USA. [Thielke, Stephen; O'Hare, Ann M.] Univ Washington, Dept Med, Seattle, WA USA. [Thielke, Stephen; O'Hare, Ann M.] Vet Affairs Puget Sound Healthcare Syst, Seattle, WA USA. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Med, Inst Med, Baltimore, MD USA. [Chaves, Paulo H. M.] Johns Hopkins Univ, Dept Epidemiol, Inst Med, Baltimore, MD USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Zakai, Neil A.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Chaudhry, Sarwat] Yale Univ, Sch Med, Dept Internal Med, Med Genet Sect, New Haven, CT 06510 USA. [Ives, Diane; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. RP Whitson, HE (reprint author), DUMC 3003, Durham, NC 27710 USA. EM heather.whitson@duke.edu RI Kim, Hyung Woo /G-7525-2011; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health [AG-023629]; National Heart, Lung, and Blood Institute [N01-HC-85079-N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295]; National Institute on Aging [R01-AG-023629, R01 AG-15928, R01 AG-20098, AG-027058]; National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute; University of Pittsburgh Pepper Center [P30-AG-02482]; American Federation for Aging Research; Duke Pepper Center [P30-AG-028716, K23-AG-032867]; John A. Hartford Foundation; [K23 AG038345]; [K23-AG-030986] FX This work was supported by the National Institutes of Health (AG-023629, CHS was supported by Contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133; Grant U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute on Aging (R01-AG-023629); National Institute of Neurological Disorders and Stroke; R01 AG-15928, R01 AG-20098, and AG-027058 from the National Institute on Aging; R01 HL-075366 from the National Heart, Lung and Blood Institute; University of Pittsburgh Pepper Center P30-AG-02482). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Dr. Whitson is supported by the American Federation for Aging Research, the Duke Pepper Center (P30-AG-028716) and K23-AG-032867. Dr. Thielke received support from the John A. Hartford Foundation and K23 AG038345. Dr. Chaudhry is supported by K23-AG-030986. NR 39 TC 9 Z9 9 U1 2 U2 3 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 FEB PY 2011 VL 59 IS 2 BP 207 EP 213 DI 10.1111/j.1532-5415.2010.03238.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 719VX UT WOS:000287240700003 PM 21288229 ER PT J AU Lee, CG Boyko, EJ Nielson, CM Stefanick, ML Bauer, DC Hoffman, A Dam, TTL Lapidus, JA Cawthon, PM Ensrud, KE Orwoll, ES AF Lee, Christine G. Boyko, Edward J. Nielson, Carrie M. Stefanick, Marcia L. Bauer, Douglas C. Hoffman, AndrewR. Dam, Thuy-Tien L. Lapidus, Jodi A. Cawthon, Peggy Mannen Ensrud, Kristine E. Orwoll, Eric S. CA Osteoporotic Fractures Men Study G TI Mortality Risk in Older Men Associated with Changes in Weight, Lean Mass, and Fat Mass SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE mortality; older men; body composition; lean mass; fat mass ID ALL-CAUSE MORTALITY; X-RAY ABSORPTIOMETRY; MIDDLE-AGED MEN; BODY-COMPOSITION; MUSCLE MASS; LONGITUDINAL CHANGES; FOLLOW-UP; OSTEOPOROTIC FRACTURES; PHYSICAL-ACTIVITY; ELDERLY-MEN AB OBJECTIVES To evaluate risk of all-cause mortality associated with changes in body weight, total lean mass, and total fat mass in older men. DESIGN Longitudinal cohort study. SETTING Six U.S. clinical centers. PARTICIPANTS Four thousand three hundred thirty-one ambulatory men aged 65 to 93 at baseline. MEASUREMENTS Repeated measurements of body weight and total lean and fat mass were taken using dual-energy X-ray absorptiometry 4.6 +/- 0.4 years apart. Percentage changes in these measures were categorized as gain (+5%), loss (-5%), or stable (-5% to +5%). Deaths were verified centrally according to death certificate reviews, and proportional hazard models were used to estimate the risk of mortality. RESULTS After accounting for baseline lifestyle factors and medical conditions, a higher risk of mortality was found for men with weight loss (hazard rat (HR)=1.84, 95% confidence interval (CI)=1.50-2.26), total lean mass loss (HR=1.78, 95% CI=1.45-2.19), and total fat mass loss (HR=1.72, 95% CI=1.34-2.20) than for men who were stable for each body composition measure. Men with total fat mass gain had a slightly greater mortality risk (HR=1.29, 95% CI=0.99-1.67) than those who remained stable. These associations did not differ according to baseline age, obesity, or self-reported health status (P for interactions >.10), although self-reported weight loss intent altered mortality risks with total fat mass (P for interaction=.04) and total lean mass (P for interaction=.09) change. CONCLUSION Older men who lost weight, total lean mass, or total fat mass had a higher risk of mortality than men who remained stable. C1 [Lee, Christine G.; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97239 USA. [Nielson, Carrie M.] Oregon Hlth & Sci Univ, Div Epidemiol, Portland, OR 97239 USA. [Lapidus, Jodi A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Div Biostat, Portland, OR 97239 USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Stefanick, Marcia L.; Hoffman, AndrewR.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Dam, Thuy-Tien L.] Columbia Univ, Dept Med, Med Ctr, Div Geriatr Med & Aging, New York, NY USA. [Cawthon, Peggy Mannen] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Ensrud, Kristine E.] Vet Affairs Med Ctr, Dept Med, Gen Internal Med Sect, Minneapolis, MN 55417 USA. RP Lee, CG (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet & Clin Nutr, 3181 SW Sam Jackson Pk Rd,CR113, Portland, OR 97239 USA. EM leechr@ohsu.edu OI Orwoll, Eric/0000-0002-8520-7355 FU National Institutes of Health [AG05394]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Aging; National Center for Research Resources; NIH roadmap for Medical Research [U01AR45580, U01AR45614, U01AR45632, U01AR45647, U01AR45654, U01AR45583, U01AG18197, U01AG027810, UL1RR 024140]; Department of Veterans Affairs FX MrOS is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Center for Research Resources, and the NIH roadmap for Medical Research under the following grants: U01AR45580, U01AR45614, U01AR45632, U01AR45647, U01AR45654, U01AR45583, U01AG18197, U01AG027810, and UL1RR 024140. Dr. Ensrud has received funding from the NIH (AG05394). Dr. Boyko is supported by the Department of Veterans Affairs. NR 49 TC 42 Z9 45 U1 3 U2 10 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 FEB PY 2011 VL 59 IS 2 BP 233 EP 240 DI 10.1111/j.1532-5415.2010.03245.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 719VX UT WOS:000287240700006 PM 21288234 ER PT J AU Lee, SJ Steinman, MA Tan, EJ AF Lee, Sei J. Steinman, Michael A. Tan, Erwin J. TI Volunteering, Driving Status, and Mortality in US Retirees SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE mortality; volunteerism; driving ID OLDER-ADULTS; SOCIAL INTEGRATION; EXPERIENCE CORPS; PROPENSITY SCORE; PUBLIC-HEALTH; LATER LIFE; COMMUNITY; CESSATION; BENEFITS; SUPPORT AB OBJECTIVES To evaluate how accounting for driving status altered the relationship between volunteering and mortality in U.S. retirees. DESIGN Observational prospective cohort. SETTING Nationally representative sample from the Health and Retirement Study in 2000 and 2002 followed to 2006. PARTICIPANTS Retirees aged 65 and older (N=6,408). MEASUREMENTS Participants self-reported their volunteering, driving status, age, sex, race or ethnicity, presence of chronic conditions, geriatric syndromes, socioeconomic factors, functional limitations, and psychosocial factors. Death by December 31, 2006, was the outcome. RESULTS For drivers, mortality in volunteers (9%) and nonvolunteers (12%) was similar; for limited or non-drivers, mortality for volunteers (15%) was markedly lower than for nonvolunteers (32%). Adjusted results showed that, for drivers, the volunteering-mortality odds ratio (OR) was 0.90 (95% confidence interval (CI)=0.66-1.22), whereas for limited or nondrivers, the OR was 0.62 (95% CI=0.49-0.78) (interaction P=.05). The effect of driving status was greater for rural participants, with greater differences between rural drivers and rural limited or nondrivers (interaction P=.02) and between urban drivers and urban limited or nondrivers (interaction P=.81). CONCLUSION The influence of volunteering in decreasing mortality seems to be stronger in rural retirees who are limited or nondrivers. This may be because rural or nondriving retirees are more likely to be socially isolated and thus receive more benefit from the greater social integration from volunteering. C1 [Lee, Sei J.; Steinman, Michael A.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA 94121 USA. [Lee, Sei J.; Steinman, Michael A.] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Tan, Erwin J.] Corp Natl & Community Serv, Washington, DC USA. RP Lee, SJ (reprint author), San Francisco VA Med Ctr, Div Geriatr, 4150 Clement St,Bldg 1,Rm 211A,Box 181G, San Francisco, CA 94121 USA. EM sei.lee@ucsf.edu FU Hartford Geriatric Health Outcomes Research Scholars Award; Hellman Family Foundation at the University of California at San Francisco; National Center for Research Resources, NIH [KL2RR024130]; National Institute of Aging (NIA); American Federation for Aging Research [K23 AG030999]; NIA Johns Hopkins Older Americans Independence Center [P30-AG02133]; John A. Hartford Foundation FX Dr. Lee was supported by the Hartford Geriatric Health Outcomes Research Scholars Award, Hellman Family Foundation Award for Young Faculty Scholars at the University of California at San Francisco and KL2RR024130 from the National Center for Research Resources, a component of the National Institutes of Health. Dr. Steinman was supported by a Beeson Career Development Award from the National Institute of Aging (NIA) and the American Federation for Aging Research (K23 AG030999). Dr. Tan was supported by the NIA Johns Hopkins Older Americans Independence Center (Contract P30-AG02133) and the John A. Hartford Foundation. NR 48 TC 4 Z9 4 U1 3 U2 6 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 FEB PY 2011 VL 59 IS 2 BP 274 EP 280 DI 10.1111/j.1532-5415.2010.03265.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 719VX UT WOS:000287240700011 PM 21314648 ER PT J AU Velagapudi, C Bhandari, BS Abboud-Werner, S Simone, S Abboud, HE Habib, SL AF Velagapudi, Chakradhar Bhandari, Basant S. Abboud-Werner, Sherry Simone, Sinnona Abboud, Hanna E. Habib, Samy L. TI The Tuberin/mTOR Pathway Promotes Apoptosis of Tubular Epithelial Cells in Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID OXIDATIVE DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; MAMMALIAN TARGET; RHEB; ACTIVATION; RAPAMYCIN; COMPLICATIONS; GLYCOSYLASE; INHIBITION; EXPRESSION AB Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose (HG) induces apoptosis is not fully understood. Because the tuberin/mTOR pathway can modulate apoptosis, we studied the role of this pathway in apoptosis in type I diabetes and in cultured proximal tubular epithelial (PTE) cells exposed to HG. Compared with control rats, diabetic rats had more apoptotic cells in the kidney cortex. Induction of diabetes also increased phosphorylation of tuberin in association with mTOR activation (measured by p70S6K phosphorylation), inactivation of Bcl-2, increased cytosolic cytochrome c expression, activation of caspase 3, and cleavage of PARP; insulin treatment prevented these changes. In vitro, exposure of PTE cells to HG increased phosphorylation of tuberin and p70S6K, phosphorylation of Bcl-2, expression of cytosolic cytochrome c, and caspase 3 activity. High glucose induced translocation of the caspase substrate YY1 from the cytoplasm to the nucleus and enhanced cleavage of PARP. Pretreatment the cells with the mTOR inhibitor rapamycin reduced the number of apoptotic cells induced by HG and the downstream effects of mTOR activation noted above. Furthermore, gene silencing of tuberin with siRNA decreased cleavage of PARP. These data show that the tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes, mediated in part by cleavage of PARP by YY1. C1 [Habib, Samy L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Abboud-Werner, Sherry] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Simone, Sinnona] Univ Bari, Dept Emergency & Transplantat, Bari, Italy. [Habib, Samy L.] S Texas Vet Healthcare Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. RP Habib, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med MSC 7882, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM habib@uthscsa.edu RI Velagapudi, Chakradhar/F-9750-2015 FU UTHSCSA; San Antonio Cancer Institute; VA merit review award; NIH [RO1 (DK 078971)]; Italian Society of Nephrology; American Heart Association; South Texas Veterans Healthcare System FX Confocal fluorescence microscopy and FAGS analysis were performed in the core optical imaging facility supported by UTHSCSA and San Antonio Cancer Institute and the immunostaining at the Morphology core of the George O' Brien Kidney Research Center. We thank Dan Riley, M.D., for reading the manuscript. This work was supported in part by grants from a VA merit review award and NIH RO1 (DK 078971) (to H.E.A.), a Research Scholar Award from The Italian Society of Nephrology (to S.S.), and the American Heart Association, New Investigator Award and Merit Review Award from South Texas Veterans Healthcare System (to S.L.H.). NR 33 TC 32 Z9 47 U1 1 U2 4 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 FEB PY 2011 VL 22 IS 2 BP 262 EP 273 DI 10.1681/ASN.2010040352 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 725VF UT WOS:000287673600013 PM 21289215 ER PT J AU Carlson, RW Allred, C Anderson, BO Burstein, HJ Carter, WB Edge, SB Erban, JK Farrar, WB Forero, A Giordano, SH Goldstein, LJ Gradishar, WJ Hayes, DF Hudis, CA Ljung, BM Mankoff, DA Marcom, PK Mayer, IA McCormick, B Pierce, LJ Reed, EC Sachdev, J Smith, ML Somlo, G Ward, JH Wolff, AC Zellars, R AF Carlson, Robert W. Allred, Craig Anderson, Benjamin O. Burstein, Harold J. Carter, W. Bradford Edge, Stephen B. Erban, John K. Farrar, William B. Forero, Andres Giordano, Sharon Hermes Goldstein, Lori J. Gradishar, William J. Hayes, Daniel F. Hudis, Clifford A. Ljung, Britt-Marie Mankoff, David A. Marcom, P. Kelly Mayer, Ingrid A. McCormick, Beryl Pierce, Lori J. Reed, Elizabeth C. Sachdev, Jasgit Smith, Mary Lou Somlo, George Ward, John H. Wolff, Antonio C. Zellars, Richard TI Invasive Breast Cancer SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article DE NCCN Clinical Practice Guidelines; NCCN Guidelines; breast cancer; chemotherapy; breast-conserving therapy; adjuvant therapy; mastectomy; endocrine therapy; radiation; therapy; lobular carcinoma in situ; ductal carcinoma in situ ID RANDOMIZED CONTROLLED-TRIAL; SKIN-SPARING MASTECTOMY; SURGICAL ADJUVANT BREAST; GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; SENTINEL-NODE BIOPSY; QUALITY-OF-LIFE; PLACEBO-CONTROLLED TRIAL; IN-SITU HYBRIDIZATION; FIRST-LINE THERAPY C1 [Carlson, Robert W.] Stanford Comprehens Canc Ctr, Stanford, CA USA. [Allred, Craig] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Allred, Craig] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Anderson, Benjamin O.; Mankoff, David A.] Univ Washington Seattle Canc Care Alliance, Seattle, WA USA. [Burstein, Harold J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Carter, W. Bradford] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Edge, Stephen B.] Roswell Pk Canc Inst, Buffalo, NY USA. [Erban, John K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Farrar, William B.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Forero, Andres] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Giordano, Sharon Hermes] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Gradishar, William J.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Hayes, Daniel F.; Pierce, Lori J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Hudis, Clifford A.; McCormick, Beryl] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Mayer, Ingrid A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Reed, Elizabeth C.] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. [Sachdev, Jasgit] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Somlo, George] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Ward, John H.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Wolff, Antonio C.; Zellars, Richard] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Carlson, RW (reprint author), Stanford Comprehens Canc Ctr, Stanford, CA USA. NR 377 TC 77 Z9 81 U1 0 U2 8 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD FEB PY 2011 VL 9 IS 2 BP 136 EP 222 PG 87 WC Oncology SC Oncology GA 729IU UT WOS:000287942900002 PM 21310842 ER PT J AU Zenati, MA Shroyer, AL Collins, JF Hattler, B Ota, T Almassi, GH Amidi, M Novitzky, D Grover, FL Sonel, AF AF Zenati, Marco A. Shroyer, A. Laurie Collins, Joseph F. Hattler, Brack Ota, Takeyoshi Almassi, G. Hossein Amidi, Morteza Novitzky, Dimitri Grover, Frederick L. Sonel, Ali F. TI Impact of endoscopic versus open saphenous vein harvest technique on late coronary artery bypass grafting patient outcomes in the ROOBY (Randomized On/Off Bypass) Trial SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID OFF-PUMP; ON-PUMP; SURGERY; PATENCY AB Objective: In the Randomized On/Off Bypass (ROOBY) Trial, the efficacy of on-pump versus off-pump coronary artery bypass grafting was evaluated. This ROOBY Trial planned subanalysis compared the effects on postbypass patient clinical outcomes and graft patency of endoscopic vein harvesting and open vein harvesting. Methods: From April 2003 to April 2007, the technique used for saphenous vein graft harvesting was recorded in 1471 cases. Of these, 894 patients (341 endoscopic harvest and 553 open harvest) also underwent coronary angiography 1 year after coronary artery bypass grafting. Univariate and multivariable analyses were used to compare patient outcomes in the endoscopic and open groups. Results: Preoperative patient characteristics were statistically similar between the endoscopic and open groups. Endoscopic vein harvest was used in 38% of the cases. There were no significant differences in both short-term and 1-year composite outcomes between the endoscopic and open groups. For patients with 1-year catheterization follow-up (n = 894), the saphenous vein graft patency rate for the endoscopic group was lower than that in the open harvest group (74.5% vs 85.2%, P < .0001), and the repeat revascularization rate was significantly higher (6.7% vs 3.4%, P < .05). Multivariable regression documented no interaction effect between endoscopic approach and off-pump treatment. Conclusions: In the ROOBY Trial, endoscopic vein harvest was associated with lower 1-year saphenous vein graft patency and higher 1-year revascularization rates, independent of the use of off-pump or on-pump cardiac surgical approach. (J Thorac Cardiovasc Surg 2011;141:338-44) C1 [Zenati, Marco A.] Vet Affairs Boston Healthcare Syst, W Roxbury, MA USA. [Zenati, Marco A.] Harvard Univ, Brigham & Womens Hosp, Div Cardiac Surg, Boston, MA 02115 USA. [Shroyer, A. Laurie; Hattler, Brack; Grover, Frederick L.] Eastern Colorado Healthcare Syst, Dept Vet Affairs, Denver, CO USA. [Shroyer, A. Laurie] Northport Vet Affairs Med Ctr, Northport, NY USA. [Collins, Joseph F.] Vet Affairs Med Ctr, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Ota, Takeyoshi; Amidi, Morteza; Sonel, Ali F.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Ota, Takeyoshi] Univ Pittsburgh, Med Ctr, Heart Lung & Esophageal Surg Inst, Pittsburgh, PA USA. [Almassi, G. Hossein] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Almassi, G. Hossein] Zablocki Vet Affairs Med Ctr, Milwaukee, WI USA. [Novitzky, Dimitri] Univ S Florida, Dept Surg, Tampa, FL 33620 USA. RP Zenati, MA (reprint author), BHS, Div Cardiac Surg, 1400 VFW Pkwy 112, W Roxbury, MA 02132 USA. EM Marco_Zenati@hms.harvard.edu RI Shroyer, Annie Laurie/B-8836-2016 OI Shroyer, Annie Laurie/0000-0001-6461-0623 FU Department of Veterans Affairs, Office of Research and Development; Department of Veterans Affairs Central Office, Office of Patient Care Services, Washington, DC FX Supported by the Cooperative Studies Program of the Department of Veterans Affairs, Office of Research and Development, and by the Department of Veterans Affairs Central Office, Office of Patient Care Services, Washington, DC. NR 24 TC 53 Z9 60 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD FEB PY 2011 VL 141 IS 2 BP 338 EP 344 DI 10.1016/j.jtcvs.2010.10.004 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 706MP UT WOS:000286222800009 PM 21130476 ER PT J AU Suvak, MK Barrett, LF AF Suvak, Michael K. Barrett, Lisa Feldman TI Considering PTSD From the Perspective of Brain Processes: A Psychological Construction Approach SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MEDIAL PREFRONTAL CORTEX; HUMAN AMYGDALA; FUNCTIONAL CONNECTIVITY; DEFAULT MODE; ORBITOFRONTAL CORTEX; SOCIAL COGNITION; TRAUMATIC STRESS; CONTEXTUAL FEAR; INDIVIDUAL-DIFFERENCES AB Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that involves symptoms from various domains that appear to be produced by the combination of several mechanisms. The authors contend that existing neural accounts fail to provide a viable model that explains the emergence and maintenance of PTSD and the associated heterogeneity in the expression of this disorder (cf. Garfinkel & Liberzon, 2009). They introduce a psychological construction approach as a novel framework to probe the brain basis of PTSD, where distributed networks within the human brain are thought to correspond to the basic psychological ingredients of the mind. The authors posit that it is the combination of these ingredients that produces the heterogeneous symptom clusters in PTSD. Their goal is show that a constructionist approach has significant heuristic value in understanding the emergence and maintenance of PTSD symptoms, and leads to different and perhaps more useful conjectures about the origins and maintenance of the syndrome than the traditional hyperreactive fear account. C1 [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Suvak, Michael K.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Cambridge, MA 02138 USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. EM l.barrett@neu.edu FU NIA NIH HHS [R01 AG030311, AG030311]; NIH HHS [DP1OD003312, DP1 OD003312-04, DP1 OD003312] NR 253 TC 32 Z9 32 U1 7 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2011 VL 24 IS 1 BP 3 EP 24 DI 10.1002/jts.20618 PG 22 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 727GR UT WOS:000287786600002 PM 21298725 ER PT J AU Rosenfeld, L Chew, GL Rudd, R Emmons, K Acosta, L Perzanowski, M Acevedo-Garcia, D AF Rosenfeld, Lindsay Chew, Ginger L. Rudd, Rima Emmons, Karen Acosta, Luis Perzanowski, Matt Acevedo-Garcia, Dolores TI Are Building-Level Characteristics Associated with Indoor Allergens in the Household? SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE Asthma; Buildings; Building size; Indoor allergens; Public housing ID NEW-YORK-CITY; MULTIFAMILY RESIDENTIAL BUILDINGS; PUERTO-RICAN CHILDREN; 1ST NATIONAL-SURVEY; COCKROACH ALLERGEN; MOUSE ALLERGEN; RISK-FACTORS; ASTHMA MORBIDITY; LOW-INCOME; DUST-MITE AB Building-level characteristics are structural factors largely beyond the control of those who live in them. We explored whether building-level characteristics and indoor allergens in the household are related. We examined the relationship between building-level characteristics and indoor allergens: dust mite, cat, cockroach, and mouse. Building-level characteristics measured were presence of pests (seeing cockroaches and rodents), building type (public housing, buildings zoned commercially and residentially, and building size), and building condition (building age and violations). Allergen cutpoints were used for categorical analyses and defined as follows: dust mite: 90.25 mu g/g; cat: 91 mu g/g; cockroach: 91 U/g; mouse: 91.6 mu g/g. In fully adjusted linear analyses, neither dust mite nor cat allergen were statistically significantly associated with any building-level characteristics. Cockroach allergen was associated with the presence of cockroaches (2.07; 95% CI, 1.23, 3.49) and living in public housing (2.14; 95% CI, 1.07, 4.31). Mouse allergen was associated with the presence of rodents (1.70; 95% CI, 1.29, 2.23), and building size: living in a low-rise (<8 floors; 0.60; 95% CI, 0.42, 0.87) or high-rise (8+floors; 0.50; 95% CI, 0.29, 0.88; compared with house/duplex). In fully adjusted logistic analyses, cat allergen was statistically significantly associated with living in a high-rise (6.29; 95% CI, 1.51, 26.21; compared with a house/duplex). Mouse allergen was associated with living in public housing (6.20; 95% CI, 1.01, 37.95) and building size: living in a low-rise (0.16; 95% CI, 0.05, 0.52) or high-rise (0.06; 95% CI, 0.01, 0.50; compared with a house/duplex). Issues concerning building size and public housing may be particularly critical factors in reducing asthma morbidity. We suggest that future research explore the possible improvement of these factors through changes to building code and violations adherence, design standards, and incentives for landlords. C1 [Rosenfeld, Lindsay; Acevedo-Garcia, Dolores] Northeastern Univ, Inst Urban Hlth Res, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Chew, Ginger L.; Acosta, Luis; Perzanowski, Matt] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Rosenfeld, Lindsay; Rudd, Rima; Emmons, Karen; Acevedo-Garcia, Dolores] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Emmons, Karen] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Rosenfeld, L (reprint author), Northeastern Univ, Inst Urban Hlth Res, Bouve Coll Hlth Sci, Boston, MA 02115 USA. EM l.rosenfeld@neu.edu FU NIEHS [R01 ES 10922, P30 ES 009089] FX We thank the Puerto Rican Asthma Project research participants and staff for their time and effort. We also thank Jeff Blossom for creating variables and maps in ArcGIS 9.2 and Amy Cohen for her SAS programming expertise. This work was supported by NIEHS grants R01 ES 10922 and P30 ES 009089. NR 88 TC 11 Z9 12 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD FEB PY 2011 VL 88 IS 1 BP 14 EP 29 DI 10.1007/s11524-010-9527-4 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 724PU UT WOS:000287589500002 PM 21274646 ER PT J AU Karam, JA Rini, BI Varella, L Garcia, JA Dreicer, R Choueiri, TK Jonasch, E Matin, SF Campbell, SC Wood, CG Tannir, NM AF Karam, Jose A. Rini, Brian I. Varella, Leticia Garcia, Jorge A. Dreicer, Robert Choueiri, Toni K. Jonasch, Eric Matin, Surena F. Campbell, Steven C. Wood, Christopher G. Tannir, Nizar M. TI Metastasectomy After Targeted Therapy in Patients With Advanced Renal Cell Carcinoma SO JOURNAL OF UROLOGY LA English DT Article DE kidney; carcinoma; renal cell; neoplasm metastasis; drug therapy; reoperation ID PHASE-III TRIAL; INTERFERON-ALPHA; SURGICAL RESECTION; DOUBLE-BLIND; NEPHRECTOMY; BEVACIZUMAB; SORAFENIB; SUNITINIB; EFFICACY; SURGERY AB Purpose: Metastasectomy is often incorporated in overall treatment in patients with metastatic renal cell carcinoma. While this approach was studied in the immunotherapy era, only a few cases have been described in the targeted therapy era. Thus, we evaluated the role of metastasectomy in patients with metastatic renal cell carcinoma who received prior targeted therapy. Materials and Methods: We retrospectively evaluated the records of patients who underwent consolidative metastasectomy after targeted therapy at 3 institutions from 2004 to 2009. All patients received at least 1 cycle of targeted therapy before surgical resection of all visible disease. Results: We identified 22 patients. Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain and inferior venal caval thrombus in 1 each. A total of 6 postoperative complications were observed in 4 patients within 12 weeks after surgery, which resolved with appropriate management. Postoperatively 9 patients received at least 1 targeted therapy. In 11 patients recurrence developed a median of 42 weeks after metastasectomy and another 11 experienced no recurrence at a median of 43 weeks. At a median followup of 109 weeks 21 patients were alive and 1 died of renal cell carcinoma 105 weeks after metastasectomy. Conclusions: In a cohort of select patients with a limited tumor burden after treatment with targeted agents consolidative metastasectomy is feasible with acceptable morbidity. Significant time off targeted therapy and long-term tumor-free status are possible with this approach. C1 [Rini, Brian I.; Varella, Leticia; Garcia, Jorge A.; Dreicer, Robert] Cleveland Clin, Dept Solid Tumor Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. [Campbell, Steven C.] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Urol, Cleveland, OH 44106 USA. [Karam, Jose A.; Matin, Surena F.; Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Jonasch, Eric; Tannir, Nizar M.] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Rini, BI (reprint author), Cleveland Clin, Dept Solid Tumor Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. EM ntannir@mdanderson.org FU Pfizer; Bayer; Genentech; GlaxoSmithKline; Novartis; Bayer/Onyx FX Financial interest and/or other relationship with Pfizer, Bayer and Genentech.; Financial interest and/or other relationship with GlaxoSmithKline, Pfizer, Novartis, Genentech and Bayer/Onyx. NR 28 TC 55 Z9 56 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2011 VL 185 IS 2 BP 439 EP 444 DI 10.1016/j.juro.2010.09.086 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 704JH UT WOS:000286047500018 PM 21167518 ER PT J AU Sonpavde, G Khan, MM Lerner, SP Svatek, RS Novara, G Karakiewicz, PI Skinner, E Tilki, D Kassouf, W Fradet, Y Dinney, CP Fritsche, HM Izawa, JI Bastian, PJ Ficarra, V Schoenberg, M Sagalowsky, AI Lotan, Y Shariat, SF AF Sonpavde, Guru Khan, Myrna M. Lerner, Seth P. Svatek, Robert S. Novara, Giacomo Karakiewicz, Pierre I. Skinner, Eila Tilki, Derya Kassouf, Wassim Fradet, Yves Dinney, Colin P. Fritsche, Hans-Martin Izawa, Jonathan I. Bastian, Patrick J. Ficarra, Vincenzo Schoenberg, Mark Sagalowsky, Arthur I. Lotan, Yair Shariat, Shahrokh F. TI Disease-Free Survival at 2 or 3 Years Correlates With 5-Year Overall Survival of Patients Undergoing Radical Cystectomy for Muscle Invasive Bladder Cancer SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder neoplasms; cystectomy; disease-free survival ID TRANSITIONAL-CELL CARCINOMA; 18 RANDOMIZED-TRIALS; NEOADJUVANT CHEMOTHERAPY; PERIOPERATIVE CHEMOTHERAPY; ADJUVANT CHEMOTHERAPY; COLON-CANCER; END-POINTS; METAANALYSIS; GUIDELINES; OUTCOMES AB Purpose: The conventional primary end point in trials of perioperative systemic therapy for muscle invasive bladder cancer is 5-year overall survival. We identified an association between disease-free survival at 2 to 3 years and 5-year overall survival. Materials and Methods: We retrospectively analyzed a multicenter database containing records of 2,724 patients treated with radical cystectomy for muscle invasive bladder cancer with negative margins. Of these patients 844 had received adjuvant chemotherapy. We evaluated the association of disease-free survival at 2 and 3 years with overall survival at 5 years using Cox proportional hazards modeling and the kappa statistic. Results: Overall 2-year/3-year disease-free survival was 0.63/0.57 and 5-year overall survival was 0.47. The overall agreement between 2-year disease-free survival and 5-year overall survival was 79%, and between 3-year disease-free survival and 5-year overall survival was 81%. Agreements were similar when analyzed within pathological substages, radical cystectomy decades and adjuvant chemotherapy subgroups. The kappa statistic was 0.57 (95% CI 0.53-0.60) for 2-year disease-free survival/5-year overall survival and 0.61 (95% CI 0.58-0.64) for 3-year disease-free survival/5-year overall survival, indicating moderate agreement. The hazard ratio for disease-free survival as a time dependent variable was 12.7 (95% CI 11.60-13.90), indicating a strong relationship between disease-free and overall survival. Conclusions: Disease-free survival rates at 2 and 3 years correlate with and are potential intermediate surrogates for 5-year overall survival in patients treated with radical cystectomy for muscle invasive bladder cancer regardless of adjuvant chemotherapy. These data warrant external validation and may expedite the development of adjuvant systemic therapy. In addition, they may be applicable to the neoadjuvant setting. C1 [Sonpavde, Guru; Khan, Myrna M.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Sonpavde, Guru; Khan, Myrna M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Svatek, Robert S.; Dinney, Colin P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sagalowsky, Arthur I.; Lotan, Yair] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Novara, Giacomo; Ficarra, Vincenzo] Univ Padua, Padua, Italy. [Karakiewicz, Pierre I.] Univ Montreal, Montreal, PQ, Canada. [Kassouf, Wassim] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Fradet, Yves] Univ Laval, Quebec City, PQ, Canada. [Izawa, Jonathan I.] Univ Western Ontario, London, ON, Canada. [Skinner, Eila] Univ So Calif, Los Angeles, CA USA. [Tilki, Derya; Bastian, Patrick J.] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Fritsche, Hans-Martin] Univ Regensburg, Regensburg, Germany. [Schoenberg, Mark] Johns Hopkins Univ, Baltimore, MD USA. [Shariat, Shahrokh F.] Weill Cornell Med Ctr, Dept Urol, New York, NY USA. RP Sonpavde, G (reprint author), 501 Med Ctr Blvd, Webster, TX 77598 USA. EM gurus@bcm.edu RI Izawa, Jonathan/C-1111-2015 FU Sanofi-Aventis; Novartis; Pfizer-Wyeth; Bioniche/Parexel; Abbott; Inverness FX Financial interest and/or other relationship with Sanofi-Aventis, Novartis and Pfizer-Wyeth.; Financial interest and/or other relationship with Bioniche/Parexel.; Financial interest and/or other relationship with Abbott and Inverness. NR 30 TC 32 Z9 32 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2011 VL 185 IS 2 BP 456 EP 461 DI 10.1016/j.juro.2010.09.110 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 704JH UT WOS:000286047500021 PM 21167527 ER PT J AU Ganguli, S Stecker, MS Pyne, D Baum, RA Fan, CM AF Ganguli, Suvranu Stecker, Michael S. Pyne, Deveraj Baum, Richard A. Fan, Chieh-Min TI Uterine Artery Embolization in the Treatment of Postpartum Uterine Hemorrhage SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID OBSTETRIC HEMORRHAGE; CERVICAL PREGNANCY; MANAGEMENT; HYSTERECTOMY; OCCLUSION AB Purpose: To evaluate the clinical effectiveness and safety of uterine artery embolization (UAE) in the treatment of primary postpartum hemorrhage (PPH), secondary PPH, and PPH associated with cesarean section. Materials and Methods: All women who underwent UAE for obstetric-related hemorrhage during a 52-month period culminating in April 2009 were included. Clinical success was defined as obviation of hysterectomy. Blood product requirements before and after UAE were calculated. Statistically significant associations between subject characteristics and clinical success were evaluated. The two subgroups of women with uterine artery pseudoaneurysms and women who underwent cesarean section were examined separately as well. Results: Sixty-six women (mean age, 33 years; range, 17-47 y) underwent UAE, with an overall clinical success rate of 95% (98% for primary PPH, 88% for secondary PPH, and 94% for PPH associated with cesarean section) and an overall complication rate of 4.5%. Mean pre- and postembolization transfusion requirements were 3.1 U and 0.4 U of packed red blood cells, respectively. The only significant characteristic identified for the cases that necessitated hysterectomy was an increased transfusion requirement after UAE (increase of 1.0 U +/- 0.5; P = .02). Uterine artery pseudoaneurysms were associated with secondary PPH (P = .01) and cesarean section (P = .03). Conclusions: The threshold for UAE in women with PPH should be low, as it is associated with a high clinical effectiveness rate and a low complication rate. Uterine artery pseudoaneurysms should be suspected in women presenting with secondary PPH after cesarean section. C1 [Ganguli, Suvranu; Stecker, Michael S.; Pyne, Deveraj; Baum, Richard A.; Fan, Chieh-Min] Brigham & Womens Hosp, Dept Radiol, Div Angiog & Intervent Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ganguli, Suvranu] Massachusetts Gen Hosp, Dept Imaging, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ganguli, S (reprint author), Brigham & Womens Hosp, Dept Radiol, Div Angiog & Intervent Radiol, 75 Francis St,SR-340, Boston, MA 02115 USA. EM sganguli@partners.org OI Stecker, Mark/0000-0002-9632-168X NR 35 TC 32 Z9 34 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2011 VL 22 IS 2 BP 169 EP 176 DI 10.1016/j.jvir.2010.09.031 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 718ZU UT WOS:000287166600009 PM 21183360 ER PT J AU Miller, RA Harrison, DE Astle, CM Baur, JA Boyd, AR de Cabo, R Fernandez, E Flurkey, K Javors, MA Nelson, JF Orihuela, CJ Pletcher, S Sharp, ZD Sinclair, D Starnes, JW Wilkinson, JE Nadon, NL Strong, R AF Miller, Richard A. Harrison, David E. Astle, C. M. Baur, Joseph A. Boyd, Angela Rodriguez de Cabo, Rafael Fernandez, Elizabeth Flurkey, Kevin Javors, Martin A. Nelson, James F. Orihuela, Carlos J. Pletcher, Scott Sharp, Zelton Dave Sinclair, David Starnes, Joseph W. Wilkinson, J. Erby Nadon, Nancy L. Strong, Randy TI Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE TOR; Rapamycin; Life span; Resveratrol ID CANCER-THERAPY; C-ELEGANS; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; REDUCTASE INHIBITOR; DIETARY RESTRICTION; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; DWARF MICE; MTOR AB Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging. C1 [Miller, Richard A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, Richard A.; Pletcher, Scott] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Miller, Richard A.] Ann Arbor VA Med Ctr, Grad Res Educ & Clin Ctr, Ann Arbor, MI USA. [Harrison, David E.; Astle, C. M.; Flurkey, Kevin] Jackson Lab, Bar Harbor, ME 04609 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Baur, Joseph A.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Boyd, Angela Rodriguez; Orihuela, Carlos J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Fernandez, Elizabeth; Javors, Martin A.; Nelson, James F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Fernandez, Elizabeth; Javors, Martin A.; Nelson, James F.; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Pletcher, Scott] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, San Antonio, TX 78229 USA. [Sharp, Zelton Dave] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Sinclair, David] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Starnes, Joseph W.] Univ N Carolina, Dept Kinesiol, Greensboro, NC 27412 USA. [Wilkinson, J. Erby] Univ Michigan, Sch Med, Unit Lab Anim Med, Ann Arbor, MI USA. [Nadon, Nancy L.] NIA, Biol Aging Program, Bethesda, MD 20892 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX 78229 USA. [Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. RP Miller, RA (reprint author), Univ Michigan, Dept Pathol, BSRB Room 3001,Box 2200,109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA. EM millerr@umich.edu RI Baur, Joseph/D-8163-2011; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Baur, Joseph/0000-0001-8262-6549; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693 FU National Institute on Aging at the National Institutes of Health [U01-AG022303, U01-AG025707, U01-AG022308, R21-AG029313, U01-AG022307, R01-AG13319]; Department of Veterans Affairs; National Institute on Aging FX This work was supported by the National Institute on Aging at the National Institutes of Health (U01-AG022303 to R.A.M., U01-AG025707 and U01-AG022308 to D.E.H., R21-AG029313 to C.J.O., and U01-AG022307 and R01-AG13319 to R.S.); and the Department of Veterans Affairs (R.A.M. and R.S.). R.d.C. is supported by the Intramural Research Program of the National Institute on Aging. NR 51 TC 350 Z9 355 U1 2 U2 40 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD FEB PY 2011 VL 66 IS 2 BP 191 EP 201 DI 10.1093/gerona/glq178 PG 11 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 710TZ UT WOS:000286541200005 PM 20974732 ER PT J AU Uygun, BE Price, G Saeidi, N Izamis, ML Berendsen, T Yarmush, M Uygun, K AF Uygun, Basak E. Price, Gavrielle Saeidi, Nima Izamis, Maria-Louisa Berendsen, Tim Yarmush, Martin Uygun, Korkut TI Decellularization and Recellularization of Whole Livers SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Bioengineering; Issue 48; Liver extracellular matrix; decellularization; recellularization; hepatocytes; bioreactor AB The liver is a complex organ which requires constant perfusion for delivery of nutrients and oxygen and removal of waste in order to survive(1). Efforts to recreate or mimic the liver microstructure with grounds up approach using tissue engineering and microfabrication techniques have not been successful so far due to this design challenge. In addition, synthetic biomaterials used to create scaffolds for liver tissue engineering applications have been limited in inducing tissue regeneration and repair in large part due to the lack of specific cell binding motifs that would induce the proper cell functions(2). Decellularized native tissues such blood vessels(3)and skin(4)on the other hand have found many applications in tissue engineering, and have provided a practical solution to some of the challenges. The advantage of decellularized native matrix is that it retains, to an extent, the original composition, and the microstructure, hence enhancing cell attachment and reorganization(5). In this work we describe the methods to perform perfusion-decellularization of the liver, such that an intact liver bioscaffold that retains the structure of major blood vessels is obtained. Further, we describe methods to recellularize these bioscaffolds with adult primary hepatocytes, creating a liver graft that is functional in vitro, and has the vessel access necessary for transplantation in vivo. C1 [Uygun, Basak E.; Price, Gavrielle; Saeidi, Nima; Izamis, Maria-Louisa; Berendsen, Tim; Yarmush, Martin; Uygun, Korkut] Harvard Univ, Sch Med, Shriners Hosp Children, Massachusetts Gen Hosp,Ctr Engn Med, Cambridge, MA 02138 USA. RP Yarmush, M (reprint author), Harvard Univ, Sch Med, Shriners Hosp Children, Massachusetts Gen Hosp,Ctr Engn Med, Cambridge, MA 02138 USA. EM ireis@sbi.org; kuygun@partners.org OI Uygun, Basak/0000-0002-2600-7900 FU US NIH [R01DK59766, R01DK084053, R00DK080942]; US NSF [CBET-0853569]; Shriners Hospitals for Children [8503] FX The authors would like to thank Jack Milwid for the design of the in vitro perfusion chamber. This work was supported by grants from the US NIH, R01DK59766 and R01DK084053 to M.Y., R00DK080942 to K.U., US NSF CBET-0853569 to K.U. and the Shriners Hospitals for Children to B.E.U. (grant no. 8503). We also acknowledge support and the Shriners Hospitals for Children. NR 6 TC 5 Z9 5 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 FEB PY 2011 IS 48 AR UNSP e2394 DI 10.3791/2394 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36LG UT WOS:000209212900014 ER PT J AU Komers, R Oyama, TT Beard, DR Tikellis, C Xu, B Lotspeich, DF Anderson, S AF Komers, Radko Oyama, Terry T. Beard, Douglas R. Tikellis, Chris Xu, Bei Lotspeich, Daniel F. Anderson, Sharon TI Rho kinase inhibition protects kidneys from diabetic nephropathy without reducing blood pressure SO KIDNEY INTERNATIONAL LA English DT Article DE connective tissue growth factor; diabetic nephropathy; fasudil; glomerulosclerosis; Rho-associated kinases (ROCK); transforming growth factor-beta ID EPITHELIAL-MESENCHYMAL TRANSITION; MESSENGER-RNA TRANSLATION; SPONTANEOUSLY HYPERTENSIVE-RATS; PROXIMAL TUBULAR CELLS; E-CADHERIN EXPRESSION; INDUCED RENAL INJURY; SMOOTH-MUSCLE-CELLS; GROWTH-FACTOR-BETA; ANGIOTENSIN-II; HIGH GLUCOSE AB Rho-associated kinases (ROCK) are activated in the kidney as well as in cultured cells of diabetic models and have been implicated in renal pathophysiology. To explore whether inhibition of ROCK is protective, we studied its role in a model of accelerated diabetic nephropathy where uninephrectomized rats were made diabetic by streptozotocin. After establishing diabetes, rats were treated with the ROCK inhibitor fasudil continuously or for the final 6 weeks of an 18-week experimental period. The results were compared to similar rats given losartan, an established treatment of clinical and experimental diabetic nephropathy, or a combination of both agents. Vehicle-treated diabetic and non-diabetic uninephrectomized rats served as controls. Diabetes resulted in a rapid development of albuminuria, higher glomerulosclerosis and interstitial fibrosis scores, lower glomerular filtration rates, and increased expression of several molecular markers of diabetic nephropathy. Eighteen weeks of fasudil treatment reduced renal ROCK activity, and ameliorated diabetes-induced structural changes in the kidney and expression of the molecular markers in association with a modest anti-proteinuric effect but no change in blood pressure. Late intervention with fasudil reduced glomerulosclerosis, but did not influence proteinuria. Most effects of fasudil were comparable to those of losartan, although losartan lowered blood pressure and further lowered proteinuria. The combination of both treatments was no different than losartan alone. Thus, ROCK inhibition protected the kidney from diabetic nephropathy even though it did not reduce the blood pressure. Kidney International (2011) 79, 432-442; doi:10.1038/ki.2010.428; published online 20 October 2010 C1 [Komers, Radko; Oyama, Terry T.; Xu, Bei; Lotspeich, Daniel F.; Anderson, Sharon] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Portland, OR 97239 USA. [Beard, Douglas R.; Anderson, Sharon] Portland VA Med Ctr, Portland, OR USA. [Tikellis, Chris] Juvenile Diabet Res Fdn, Danielle Alberti Mem Ctr Diabet Complicat, Baker Med Res Inst, Melbourne, Vic, Australia. RP Komers, R (reprint author), Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, PP262,3314 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM komersr@ohsu.edu FU Juvenile Diabetes Research Foundation [RK 1-2008-314] FX These studies were supported by the Juvenile Diabetes Research Foundation (RK 1-2008-314). NR 62 TC 47 Z9 54 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2011 VL 79 IS 4 BP 432 EP 442 DI 10.1038/ki.2010.428 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 713HL UT WOS:000286726500009 PM 20962741 ER PT J AU Vaidya, VS Niewczas, MA Ficociello, LH Johnson, AC Collings, FB Warram, JH Krolewski, AS Bonventre, JV AF Vaidya, Vishal S. Niewczas, Monika A. Ficociello, Linda H. Johnson, Amanda C. Collings, Fitz B. Warram, James H. Krolewski, Andrzej S. Bonventre, Joseph V. TI Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-beta-D-glucosaminidase SO KIDNEY INTERNATIONAL LA English DT Article DE chronic kidney disease; diabetic nephropathy; renal proximal tubule cell; tubular epithelium ID PROXIMAL TUBULE; GLYCOSYLATED HEMOGLOBIN; NEPHROPATHY; PROTEINURIA; PREDICTOR; KIM-1; CELLS; PROGRESSION; MELLITUS; DISEASE AB Elevated urinary albumin excretion in patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy. Kidney International (2011) 79, 464-470; doi:10.1038/ki.2010.404; published online 27 October 2010 C1 [Niewczas, Monika A.; Ficociello, Linda H.; Johnson, Amanda C.; Warram, James H.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Bonventre, Joseph V.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Renal,Dept Med,Harvard Inst Med, Boston, MA 02115 USA. RP Krolewski, AS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, 1 Joslin Pl,Room 368, Boston, MA 02115 USA. EM Andrzej.krolewski@joslin.harvard.edu; joseph_bonventre@hms.harvard.edu FU NIH [ES016723, DK74099, DK72381, DK41526, DK67638]; ADA [7-03-MN-28] FX This work was supported by NIH grants ES016723 (to VSV), DK74099 and DK72381 (to JVB), DK41526 and DK67638 (to ASK), and by ADA Grant 7-03-MN-28 (to MAN). NR 39 TC 83 Z9 92 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2011 VL 79 IS 4 BP 464 EP 470 DI 10.1038/ki.2010.404 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 713HL UT WOS:000286726500012 PM 20980978 ER PT J AU Reddy, MM Fernandes, MS Salgia, R Levine, RL Griffin, JD Sattler, M AF Reddy, M. M. Fernandes, M. S. Salgia, R. Levine, R. L. Griffin, J. D. Sattler, M. TI NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases SO LEUKEMIA LA English DT Article DE Myeloid neoplasia; tyrosine kinase oncogene; signal transduction; NADPH oxidase; migration ID REACTIVE OXYGEN; PATHWAY; DOMAIN; ACTIVATION; NOX; CONTRIBUTES; METABOLISM; EXPRESSION; PROTEINS; PROMOTES AB Transformation by tyrosine kinase oncogenes (TKOs) in myeloid malignancies, including BCR-ABL in chronic myeloid leukemia, FLT3ITD in acute myeloid leukemia or JAK2V617F in myeloproliferative neoplasms, is associated with increased growth and cytoskeletal abnormalities. Using targeted approaches against components of the superoxide-producing NADPH-oxidases, including NADPH oxidase 2 (NOX2), NOX4 and the common p22(phox) subunit of NOX1-4, myeloid cells were found to display reduced cell growth and spontaneous migration. Consistent with a role of NOXs as regulators of membrane proximal signaling events in nonphagocytic cells, NOX2 and NOX4 were not involved in the excess production of intracellular reactive oxygen species and did not significantly increase oxygen consumption. All NOX family members are controlled in part through levels of the rate-limiting substrate NADPH, which was found to be significantly elevated in TKO-transformed cells. Also, reduced phosphorylation of the actin filament crosslinking protein myristoylated alanine-rich C-kinase substrate (MARCKS) in response to suppression of p22(phox) hints at a novel effector of NOX signaling. MARCKS was also found to be required for increased migration. Overall, these data suggest a model whereby NOX links metabolic NADPH production to cellular events that directly contribute to transformation. Leukemia (2011) 25, 281-289; doi:10.1038/leu.2010.263; published online 12 November 2010 C1 [Reddy, M. M.; Fernandes, M. S.; Griffin, J. D.; Sattler, M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Reddy, M. M.; Fernandes, M. S.; Griffin, J. D.; Sattler, M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Reddy, M. M.; Fernandes, M. S.; Griffin, J. D.; Sattler, M.] Harvard Univ, Sch Med, Boston, MA USA. [Salgia, R.] Univ Chicago, Dept Med, Pritzker Sch Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Levine, R. L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Levine, R. L.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. RP Sattler, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM martin_sattler@dfci.harvard.edu FU National Institutes of Health [5R01CA134660-03, 5R01CA129501-02, 5R01CA125541-03, 5P01CA66996-12]; Leukemia and Lymphoma Society; American Cancer Society; US Department of Defense; Innovative Cancer Research FX This work is supported in part by National Institutes of Health Grants (5R01CA134660-03, MS), (5R01CA129501-02 and 5R01CA125541-03, RS) and (5P01CA66996-12, JDG), a Leukemia and Lymphoma Society SCOR grant (JDG) and by grants from the American Cancer Society, the US Department of Defense and the Adams Barr Program in Innovative Cancer Research (MS). NR 32 TC 43 Z9 45 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2011 VL 25 IS 2 BP 281 EP 289 DI 10.1038/leu.2010.263 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 719GC UT WOS:000287188600012 PM 21072051 ER PT J AU Witzig, TE Reeder, CB LaPlant, BR Gupta, M Johnston, PB Micallef, IN Porrata, LF Ansell, SM Colgan, JP Jacobsen, ED Ghobrial, IM Habermann, TM AF Witzig, T. E. Reeder, C. B. LaPlant, B. R. Gupta, M. Johnston, P. B. Micallef, I. N. Porrata, L. F. Ansell, S. M. Colgan, J. P. Jacobsen, E. D. Ghobrial, I. M. Habermann, T. M. TI A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma SO LEUKEMIA LA English DT Article DE lymphoma; mantle cell lymphoma; large cell lymphoma; everolimus; mTOR ID MANTLE CELL LYMPHOMA; SINGLE-AGENT TEMSIROLIMUS; CANCER-TREATMENT-GROUP; NON-HODGKINS-LYMPHOMA; MAMMALIAN TARGET; CLINICAL-TRIALS; RAPAMYCIN; RITUXIMAB; SURVIVAL; ACTIVATION AB The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant. Leukemia (2011) 25, 341-347; doi:10.1038/leu.2010.226; published online 7 December 2010 C1 [Witzig, T. E.; Gupta, M.; Johnston, P. B.; Micallef, I. N.; Porrata, L. F.; Ansell, S. M.; Colgan, J. P.; Habermann, T. M.] Mayo Clin, Coll Med, Dept Med, Div Hematol, Rochester, MN 55905 USA. [Witzig, T. E.; LaPlant, B. R.; Gupta, M.; Johnston, P. B.; Micallef, I. N.; Porrata, L. F.; Ansell, S. M.; Colgan, J. P.; Habermann, T. M.] Mayo Fdn, Rochester, MN 55905 USA. [Reeder, C. B.] Mayo Clin, Dept Med, Div Hematol Oncol, Phoenix, AZ USA. [LaPlant, B. R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Jacobsen, E. D.; Ghobrial, I. M.] Dana Farber Canc Ctr, Boston, MA USA. RP Witzig, TE (reprint author), Mayo Clin, Coll Med, Dept Med, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM Witzig@mayo.edu FU NIH [CA127433, CA112904, CA97274]; Predolin Foundation FX Research supported in part by the NIH grants CA127433, CA112904 and CA97274, and the Predolin Foundation. NR 31 TC 154 Z9 157 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD FEB PY 2011 VL 25 IS 2 BP 341 EP 347 DI 10.1038/leu.2010.226 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 719GC UT WOS:000287188600019 PM 21135857 ER PT J AU Sun, PZ Cheung, JS Wang, EF Benner, T Sorensen, AG AF Sun, Phillip Zhe Cheung, Jerry S. Wang, Enfeng Benner, Thomas Sorensen, A. Gregory TI Fast Multislice pH-Weighted Chemical Exchange Saturation Transfer (CEST) MRI With Unevenly Segmented RF Irradiation SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE acute ischemia; amide proton transfer (APT); chemical exchange saturation transfer (CEST); pH; stroke ID PROTON-EXCHANGE; PARACEST AGENTS; IN-VIVO; QUANTITATIVE DESCRIPTION; TRANSFER CONTRAST; ISCHEMIA; SYSTEMS; WATER; POWER; 3T AB Chemical exchange saturation transfer (CEST) MRI is a versatile imaging technique for measuring microenvironment properties via dilute CEST labile groups. Conventionally, CEST MRI is implemented with a long radiofrequency irradiation module, followed by fast image acquisition to obtain the steady state CEST contrast. Nevertheless, the sensitivity, scan time, and spatial coverage of the conventional CEST MRI method may not be optimal. Our study proposed a segmented radiofrequency labeling scheme that includes a long primary radiofrequency irradiation module to generate the steady state CEST contrast and repetitive short secondary radiofrequency irradiation module immediately after the image acquisition so as to maintain the steady state CEST contrast for multislice acquisition and signal averaging. The proposed CEST MRI method was validated experimentally with a tissue-like pH phantom and optimized for the maximal contrast-to-noise ratio. In addition, the proposed sequence was evaluated for imaging ischemic acidosis via pH-weighted endogenous amide proton transfer MRI, which showed similar contrast as conventional amide proton transfer MRI. In sum, a fast multislice relaxation self-compensated CEST MRI sequence was developed, with significantly improved sensitivity and suitable for in vivo applications. Magn Reson Med 65:588-594, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Sun, Phillip Zhe; Cheung, Jerry S.; Wang, Enfeng; Benner, Thomas; Sorensen, A. Gregory] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Sun, Phillip Zhe; Cheung, Jerry S.; Wang, Enfeng; Benner, Thomas; Sorensen, A. Gregory] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Wang, Enfeng] Zhengzhou Univ, Dept Radiol, Affiliated Hosp 3, Zhengzhou, Peoples R China. RP Sun, PZ (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Rm 2301,149 13th St, Charlestown, MA 02129 USA. EM pzhesun@nmr.mgh.harvard.edu FU AHA [SDG 0835384N]; NIH [NIBIB 1K01EB009771, 1R21NS061119, NCRR-P41RR14075] FX Grant sponsor: AHA; Grant number: SDG 0835384N; Grant sponsor: NIH; Grant numbers: NIBIB 1K01EB009771, 1R21NS061119, NCRR-P41RR14075. NR 29 TC 21 Z9 23 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2011 VL 65 IS 2 BP 588 EP 594 DI 10.1002/mrm.22628 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712CT UT WOS:000286643000034 PM 20872859 ER PT J AU Ostrosky-Zeichner, L Kullberg, BJ Bow, EJ Hadley, S Leon, C Nucci, M Patterson, TF Perfect, JR AF Ostrosky-Zeichner, Luis Kullberg, Bart Jan Bow, Eric J. Hadley, Susan Leon, Cristobal Nucci, Marcio Patterson, Thomas F. Perfect, John R. TI Early treatment of candidemia in adults: a review SO MEDICAL MYCOLOGY LA English DT Review DE antifungals; candidemia; invasive candidiasis; empirical therapy; pre-emptive therapy ID INTENSIVE-CARE-UNIT; INVASIVE FUNGAL-INFECTIONS; BETA-D-GLUCAN; ILL SURGICAL-PATIENTS; PLACEBO-CONTROLLED TRIAL; BLOOD-STREAM INFECTION; HUMAN SEPTIC SHOCK; ANTIFUNGAL THERAPY; FLUCONAZOLE PROPHYLAXIS; TRANSPLANT RECIPIENTS AB Invasive candidiasis is associated with high mortality, particularly in adults. Retrospective studies show that shorter times to treatment are correlated with a lower risk of death. A number of factors can be used to predict which patients would benefit from antifungal prophylaxis or early (pre-emptive or empirical) therapy. Detection of the fungal cell wall component (1 -> 3)-beta-D-glucan (BDG) shows promise as an early biomarker of invasive fungal infection and may be useful in identifying patients who would benefit from early antifungal treatment. To date, no consistent early treatment strategy has evolved. Proof-of-concept studies are needed to assess the role of pre-emptive and empirical therapy in ICU patients and the relevance of BDG as an early marker of infection. C1 [Ostrosky-Zeichner, Luis] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Kullberg, Bart Jan] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Bow, Eric J.] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Bow, Eric J.] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Hadley, Susan] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Leon, Cristobal] Univ Seville, Univ Hosp Valme, Seville, Spain. [Nucci, Marcio] Univ Fed Rio de Janeiro, Univ Hosp, Rio De Janeiro, Brazil. [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Perfect, John R.] Duke Univ, Sch Med, Durham, NC USA. RP Ostrosky-Zeichner, L (reprint author), Univ Texas Houston, Sch Med, 6431 Fannin,MSB 2-112, Houston, TX 77030 USA. EM Luis.Ostrosky-Zeichner@uth.tmc.edu RI Nucci, Marcio/G-4515-2012; Kullberg, Bart Jan/C-8520-2013 OI Nucci, Marcio/0000-0003-4867-0014; FU Pfizer Inc.; Merck; Astellas; Basilea; Gilead; Associates of Cape Cod; Merck-Frosst; Amgen; Wyeth Pharmaceuticals; Schering-Plough; Bayer; Enzon; Pfizer FX This manuscript summarizes the proceedings of a clinical advisory board on early antifungal therapy sponsored by Pfizer Inc. Editorial support was provided by D. Wolf, MSc, of PAREXEL, and was funded by Pfizer Inc.; Dr Ostrosky-Zeichner has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, Basilea, Gilead, and Associates of Cape Cod; Dr Kullberg has received research grants from Pfizer and has been a consultant or speaker for the following companies: Astellas, Basilea, and Pfizer; Dr Bow has received research grants and served as a consultant or speaker for the following companies: Pfizer, Merck-Frosst, Astellas, Amgen, Wyeth Pharmaceuticals, and Schering-Plough; Dr Hadley received research support, consulting fees or speaker honoraria from Pfizer, Schering-Plough, Merck and Astellas; Dr Leon has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, and Gilead; Dr Nucci has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, Gilead, and Bayer; Dr Patterson has received research grants to the University of Texas Health Science Center at San Antonio from Basilea, Merck, Pfizer, and Schering-Plough, and consulting fees or honoraria from Basilea and Pfizer; Dr Perfect has received research support, consulting fees, and honoraria from Pfizer, Schering-Plough, Merck, Astellas, Enzon, and Basilea. NR 54 TC 29 Z9 31 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD FEB PY 2011 VL 49 IS 2 BP 113 EP 120 DI 10.3109/13693786.2010.512300 PG 8 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 722RH UT WOS:000287451500001 PM 20818922 ER PT J AU Shah, P Nanduri, B Swiatlo, E Ma, YF Pendarvis, K AF Shah, Pratik Nanduri, Bindu Swiatlo, Edwin Ma, Yinfa Pendarvis, Ken TI Polyamine biosynthesis and transport mechanisms are crucial for fitness and pathogenesis of Streptococcus pneumoniae SO MICROBIOLOGY-SGM LA English DT Article ID ESCHERICHIA-COLI; PROTEIN IDENTIFICATIONS; VIRULENCE FACTORS; COLONIZATION; METABOLISM; RESISTANCE; SEQUEST; STRESS; GROWTH; MICE AB Polyamines such as cadaverine, putrescine and spermidine are polycationic molecules that have pleiotropic effects on cells via their interaction with nucleic acids. Streptococcus pneumoniae (the pneumococcus) is a Gram-positive pathogen capable of causing pneumonia, septicaemia, otitis media and meningitis. Pneumococci have a polyamine transport operon (potABCD) responsible for the binding and transport of putrescine and spermidine, and can synthesize cadaverine and spermidine using their lysine decarboxylase (cad) and spermidine synthase (speE) enzymes. Previous studies from our laboratory have shown that an increase in PotD expression is seen following exposure to various stresses, while during infection, potD inactivation significantly attenuates pneumococcal virulence, and anti-PotD immune responses are protective in mice. In spite of their relative importance, not much is known about the global contribution of polyamine biosynthesis and transport pathways to pneumococcal disease. Mutants deficient in polyamine biosynthesis (Delta speE or Delta cad) or transport genes (Delta potABCD) were constructed and were found to be attenuated in murine models of pneumococcal colonization and pneumonia, either alone or in competition with the wild-type strain. The Delta speE mutant was also attenuated during invasive disease, while the potABCD and cad genes seemed to be dispensable. HPLC analyses showed reduced intracellular polyamine levels in all mutant strains compared with wild-type bacteria. High-throughput proteomic analyses indicated reduced expression of growth, replication and virulence factors in mutant strains. Thus, polyamine biosynthesis and transport mechanisms are intricately linked to the fitness, survival and pathogenesis of the pneumococcus in host microenvironments, and may represent important targets for prophylactic and therapeutic interventions. C1 [Shah, Pratik] Univ Mississippi, Med Ctr, Dept Microbiol, Jackson, MS 39216 USA. [Nanduri, Bindu; Pendarvis, Ken] Mississippi State Univ, Coll Vet Med, Mississippi State, MS 39762 USA. [Swiatlo, Edwin] Vet Affairs Med Ctr, Res Serv, Jackson, MS 39216 USA. [Ma, Yinfa] Missouri Univ Sci & Technol, Dept Chem, Rolla, MO 65409 USA. RP Shah, P (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. EM pratikshah@molbio.mgh.harvard.edu OI Shah, Pratik/0000-0002-1255-9325 NR 61 TC 21 Z9 23 U1 0 U2 8 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD FEB PY 2011 VL 157 BP 504 EP 515 DI 10.1099/mic.0.042564-0 PN 2 PG 12 WC Microbiology SC Microbiology GA 736HW UT WOS:000288483200019 PM 20966092 ER PT J AU Johnson, DC Polusny, MA Erbes, CR King, D King, L Litz, BT Schnurr, PP Friedman, M Pietrzak, RH Southwick, SM AF Johnson, Douglas C. Polusny, Melissa A. Erbes, Christopher R. King, Daniel King, Lynda Litz, Brett T. Schnurr, Paula P. Friedman, Matthew Pietrzak, Robert H. Southwick, Steven M. TI Development and Initial Validation of the Response to Stressful Experiences Scale SO MILITARY MEDICINE LA English DT Article ID DAVIDSON RESILIENCE SCALE; PSYCHOLOGICAL RESILIENCE; CONSTRUCT-VALIDITY; JOB-SATISFACTION; SOCIAL SUPPORT; LIFE EVENTS; CD-RISC; HARDINESS; PREDICTORS; MODEL AB This report describes the development and initial validation of the Response to Stressful Experiences Scale (RSES), a measure of individual differences in cognitive, emotional, and behavioral responses to stressful life events. We validated this instrument with active-duty and reserve components of military and veterans samples (N = 1,014). The resulting 22-item scale demonstrated sound internal consistency (alpha = 0.91-0.93) and good test-retest reliability (r = 0.87). Factor analysis suggested 5 protective factors: (a) meaning-making and restoration, (b) active coping, (c) cognitive flexibility, (d) spirituality, and (e) self-efficacy. Associations with other measures supported convergent, discriminant, and concurrent validity. In separate military samples, the RSES accounted for unique variance in posttraumatic stress disorder symptoms above and beyond existing scales measuring resilience-related constructs, thereby demonstrating incremental validity. The RSES provides a brief, reliable, and valid measure of individual differences in cognitive, emotional, and behavioral responses to life's most stressful events. C1 [Johnson, Douglas C.] USN, Hlth Res Ctr, San Diego, CA 92106 USA. [Johnson, Douglas C.] Univ Calif San Diego, Sch Med, Dept Psychiat, La Jolla, CA 92037 USA. [Polusny, Melissa A.] Minneapolis VA Med Ctr, Posttraumat Stress Recovery Program, Minneapolis, MN 55417 USA. [Polusny, Melissa A.] Minneapolis VA Med Ctr, Ctr Chron Dis Outcome Res, Minneapolis, MN 55417 USA. [Polusny, Melissa A.; Erbes, Christopher R.] Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55454 USA. [King, Daniel; Litz, Brett T.] VA Boston Healthcare Syst 116B2, Natl Ctr Posttraumat Stress Disorder, Behav Sci Div, Boston, MA 02130 USA. [King, Daniel; King, Lynda; Litz, Brett T.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [King, Lynda] VA Boston Healthcare Syst 116B3, Natl Ctr Posttraumat Stress Disorder, Womens Hlth Sci Div, Boston, MA 02130 USA. [Schnurr, Paula P.; Friedman, Matthew] VA Med Ctr, Natl Ctr Posttraumat Stress Disorder, Execut Div, White River Jct, VT 05009 USA. [Schnurr, Paula P.; Friedman, Matthew] Dartmouth Med Sch, Dept Psychiat, Hanover, NH 03755 USA. [Friedman, Matthew] Dartmouth Med Sch, Dept Pharmacol, Hanover, NH 03755 USA. [Pietrzak, Robert H.; Southwick, Steven M.] Vet Adm Med Ctr, Natl Ctr Posttratimat Stress Disorder, Clin Neurosci Div, West Haven, CT 06516 USA. [Pietrzak, Robert H.; Southwick, Steven M.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. RP Johnson, DC (reprint author), USN, Hlth Res Ctr, 140 Sylvester Rd,Bldg 328, San Diego, CA 92106 USA. FU Department of Defense [W81XWH-07-2-003] FX This material is the result of work supported with resources and the use of facilities at the Minneapolis VA Medical Center, Minneapolis, MN; VA Connecticut Healthcare System, West Haven, CT; and VA Boston Healthcare System, Boston, MA. This research was supported in part by a grant from the Department of Defense Congressionally Directed Medical Research Program (CDMRP; W81XWH-07-2-003). NR 35 TC 19 Z9 19 U1 4 U2 9 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD FEB PY 2011 VL 176 IS 2 BP 161 EP 169 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 825BL UT WOS:000295245800011 PM 21366078 ER PT J AU Ryan, RJH Nitta, M Borger, D Lafrate, AJ Zukerberg, L Sohani, A Le, L AF Ryan, R. J. H. Nitta, M. Borger, D. Lafrate, A. J. Zukerberg, L. Sohani, A. Le, L. TI EZH2 Codon 641 Mutations Are Common in BCL2-Rearranged B Cell Lymphomas SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP United States Canadian Acad Pathol C1 [Ryan, R. J. H.; Nitta, M.; Borger, D.; Lafrate, A. J.; Zukerberg, L.; Sohani, A.; Le, L.] Mass Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2011 VL 24 SU 1 MA 1355 BP 319A EP 319A PG 1 WC Pathology SC Pathology GA 720LN UT WOS:000287282301510 ER PT J AU Lukason, M DuFresne, E Rubin, H Pechan, P Li, QH Kim, I Kiss, S Flaxel, C Collins, M Miller, J Hauswirth, W MacLachlan, T Wadsworth, S Scaria, A AF Lukason, Michael DuFresne, Elizabeth Rubin, Hillard Pechan, Peter Li, Qiuhong Kim, Ivana Kiss, Szilard Flaxel, Christina Collins, Margaret Miller, Joan Hauswirth, William MacLachlan, Timothy Wadsworth, Samuel Scaria, Abraham TI Inhibition of Choroidal Neovascularization in a Nonhuman Primate Model by Intravitreal Administration of an AAV2 Vector Expressing a Novel Anti-VEGF Molecule SO MOLECULAR THERAPY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PHASE-I TRIAL; LEBERS CONGENITAL AMAUROSIS; GENE-THERAPY; MACULAR DEGENERATION; RETINAL NEOVASCULARIZATION; PARKINSONS-DISEASE; OPEN-LABEL; SAFETY; TOLERABILITY AB Inhibition of vascular endothelial growth factor (VEGF) for the management of the pathological ocular neovascularization associated with diseases such as neovascular age-related macular degeneration is a proven paradigm; however, monthly intravitreal injections are required for optimal treatment. We have previously shown that a novel, secreted anti-VEGF molecule sFLT01 delivered by intravitreal injection of an AAV2 vector (AAV2-sFLT01) gives persistent expression and is efficacious in a murine model of retinal neovascularization. In the present study, we investigate transduction and efficacy of an intravitreally administered AAV2-sFLT01 in a nonhuman primate (NHP) model of choroidal neovascularization (CNV). A dose-dependent and persistent expression of sFLT01 was observed by collecting samples of aqueous humor at different time points over 5 months. The location of transduction as elucidated by in situ hybridization was in the transitional epithelial cells of the pars plana and in retinal ganglion cells. AAV2-sFLT01 was able to effectively inhibit laser-induced CNV in a dose-dependent manner as determined by comparing the number of leaking CNV lesions in the treated versus control eyes using fluorescein angiography. Our data suggest that intravitreal delivery of AAV2-sFLT01 may be an effective long-term treatment for diseases caused by ocular neovascularization. C1 [Lukason, Michael; DuFresne, Elizabeth; Rubin, Hillard; Pechan, Peter; MacLachlan, Timothy; Wadsworth, Samuel; Scaria, Abraham] Genzyme Corp, Framingham, MA 01701 USA. [Li, Qiuhong; Hauswirth, William] Univ Florida, Dept Ophthalmol, Gainesville, FL USA. [Kim, Ivana; Kiss, Szilard; Miller, Joan] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Flaxel, Christina] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Collins, Margaret] Charles River Labs Preclin Serv Nevada, Reno, NV USA. RP Scaria, A (reprint author), Genzyme Corp, 49 New York Ave, Framingham, MA 01701 USA. EM abraham.scaria@genzyme.com OI Pechan, Peter/0000-0001-9663-8743 FU NEI NIH HHS [P30 EY021721] NR 20 TC 38 Z9 40 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2011 VL 19 IS 2 BP 260 EP 265 DI 10.1038/mt.2010.230 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 715WM UT WOS:000286923000009 PM 20978476 ER PT J AU Kourkoumpetis, TK Velmahos, GC Ziakas, PD Tampakakis, E Manolakaki, D Coleman, JJ Mylonakis, E AF Kourkoumpetis, Themistoklis K. Velmahos, George C. Ziakas, Panayiotis D. Tampakakis, Emmanouil Manolakaki, Dimitra Coleman, Jeffrey J. Mylonakis, Eleftherios TI The Effect of Cumulative Length of Hospital Stay on the Antifungal Resistance of Candida Strains Isolated from Critically Ill Surgical Patients SO MYCOPATHOLOGIA LA English DT Article DE Candida; Risk factor; Fluconazole; Emergency surgery; Resistance; Candidiasis ID BLOOD-STREAM INFECTIONS; NON-ALBICANS-CANDIDA; INTENSIVE-CARE-UNIT; RISK-FACTORS; FLUCONAZOLE RESISTANCE; INTERPRETIVE BREAKPOINTS; INVASIVE CANDIDIASIS; AZOLE RESISTANCE; SUSCEPTIBILITY; GLABRATA AB Fluconazole is the first line of therapy for the management of candidiasis. However, fluconazole-resistant strains pose an emerging challenge in everyday clinical practice. In this study, we sought to determine whether cumulative length of hospital stay (CLOS) is a predictive factor for the acquisition of non-susceptible Candida strains to fluconazole. Thirty-three critically ill emergency surgery patients with 56 Candida isolates were enrolled in this prospective study. We divided our isolates according to their minimum inhibitory concentration (MIC) to fluconazole using 8 mcg/ml as a cutoff. We then compared the two groups with respect to basic demographics, antifungal agents prescribed, number of wide-spectrum antibiotics, duration of central venous catheter placement, elapsed time to positive culture, duration of prior hospital stay, and length of hospital stay. Non-susceptible fluconazole samples belonged to patients with a significantly longer prior hospital stay and a longer CLOS (P = 0.02 and 0.01, respectively). The difference between the 2 groups regarding non-albicans strains was statistically significant (P < 0.001). By fitting a non-parametric receiver-operating characteristics (ROC) curve into our analysis, a CLOS a parts per thousand yen 29 days predicted the occurrence of non-susceptible strains with 90% sensitivity and 79.6% specificity (correct classification 81.5%). A CLOS a parts per thousand yen 29 days is a strong predictor for the isolation of non-susceptible Candida isolates to fluconazole among critically ill emergency surgery patients. Clinicians should consider the duration of previous hospital stay when deciding on empiric antifungal therapy. C1 [Kourkoumpetis, Themistoklis K.; Tampakakis, Emmanouil; Coleman, Jeffrey J.; Mylonakis, Eleftherios] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Infect Dis Div, Boston, MA 02114 USA. [Velmahos, George C.; Manolakaki, Dimitra] Harvard Univ, Sch Med, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Ziakas, Panayiotis D.] Univ Athens, Sch Med, Dept Pathophysiol, GR-11527 Athens, Greece. RP Mylonakis, E (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Infect Dis Div, Gray Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM tkourkoumpetis@partners.org; gvelmahos@partners.org; zpanos@otenet.gr; etampakakis@partners.org; dimanolakaki@gmail.com; jjcoleman@partners.org; emylonakis@partners.org RI Coleman, Jeffrey/E-2981-2015; OI Coleman, Jeffrey/0000-0001-8579-1996 FU Astellas Pharma, Inc. FX The study was supported by an unrestricted research grant from Astellas Pharma, Inc. NR 42 TC 5 Z9 5 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X J9 MYCOPATHOLOGIA JI Mycopathologia PD FEB PY 2011 VL 171 IS 2 BP 85 EP 91 DI 10.1007/s11046-010-9369-3 PG 7 WC Mycology SC Mycology GA 705BN UT WOS:000286103500001 PM 20927595 ER PT J AU Zhang, F Cong, L Lodato, S Kosuri, S Church, GM Arlotta, P AF Zhang, Feng Cong, Le Lodato, Simona Kosuri, Sriram Church, George M. Arlotta, Paola TI Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription SO NATURE BIOTECHNOLOGY LA English DT Article ID III EFFECTORS; HOMING ENDONUCLEASE; DNA RECOGNITION; PROTEINS; GENOME; GENE; LIBRARIES; PROMOTER; BINDING; AVRBS3 AB The ability to direct functional proteins to specific DNA sequences is a long-sought goal in the study and engineering of biological processes. Transcription activator-like effectors (TALEs) from Xanthomonas sp. are site-specific DNA-binding proteins that can be readily designed to target new sequences. Because TALEs contain a large number of repeat domains, it can be difficult to synthesize new variants. Here we describe a method that overcomes this problem. We leverage codon degeneracy and type IIs restriction enzymes to generate orthogonal ligation linkers between individual repeat monomers, thus allowing full-length, customized, repeat domains to be constructed by hierarchical ligation. We synthesized 17 TALEs that are customized to recognize specific DNA-binding sites, and demonstrate that they can specifically modulate transcription of endogenous genes (SOX2 and KLF4) in human cells. C1 [Zhang, Feng; Cong, Le; Kosuri, Sriram; Church, George M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Zhang, Feng; Cong, Le; Kosuri, Sriram; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Cong, Le] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA. [Zhang, Feng; Lodato, Simona; Arlotta, Paola] Harvard Univ, Sch Med, Dept Stem Cell & Regenerat Biol, Boston, MA USA. [Lodato, Simona; Arlotta, Paola] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Lodato, Simona; Arlotta, Paola] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. RP Zhang, F (reprint author), MIT & Harvard, Broad Inst, Cambridge, MA USA. EM zhang_f@mit.edu; paola_arlotta@hms.harvard.edu RI Cong, Le/M-9981-2013; Lodato, Simona/A-3525-2017; OI Cong, Le/0000-0003-4725-8714; Lodato, Simona/0000-0001-6498-2590; Kosuri, Sriram/0000-0002-4661-0600 FU Harvard Society of Fellows; National Human Genome Research Institute Center for Excellence in Genomics Science [P50 HG003170]; Department of Energy Genomes to Life [DE-FG02-02ER63445]; Defense Advanced Research Projects Agency [W911NF-08-1-0254]; Wyss Institute for Biologically Inspired Engineering; National Institutes of Health [R01 NS073124-01]; European School of Molecular Medicine; Church and Arlotta laboratories FX This work was supported by the Harvard Society of Fellows (F.Z.), National Human Genome Research Institute Center for Excellence in Genomics Science (P50 HG003170, G.M.C.), Department of Energy Genomes to Life (DE-FG02-02ER63445, G.M.C.), Defense Advanced Research Projects Agency (W911NF-08-1-0254, G.M.C.), the Wyss Institute for Biologically Inspired Engineering (G.M.C.) and National Institutes of Health Transformative R01 (R01 NS073124-01, F.Z. and P.A.). S.L. was partially supported by a predoctoral fellowship from the European School of Molecular Medicine (S.E.M.M.). We thank the entire Church and Arlotta laboratories for discussion and support. NR 28 TC 366 Z9 407 U1 10 U2 112 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2011 VL 29 IS 2 BP 149 EP U90 DI 10.1038/nbt.1775 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 717DJ UT WOS:000287023000022 PM 21248753 ER PT J AU Balaj, L Lessard, R Dai, LX Cho, YJ Pomeroy, SL Breakefield, XO Skog, J AF Balaj, Leonora Lessard, Ryan Dai, Lixin Cho, Yoon-Jae Pomeroy, Scott L. Breakefield, Xandra O. Skog, Johan TI Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences SO NATURE COMMUNICATIONS LA English DT Article ID BREAST-CANCER; DIAGNOSTIC BIOMARKERS; REVERSE-TRANSCRIPTASE; HORIZONTAL TRANSFER; ENDOTHELIAL-CELLS; APOPTOTIC BODIES; DOUBLE MINUTES; MESSENGER-RNA; HERV-K; GENE AB Tumour cells release an abundance of microvesicles containing a selected set of proteins and RNAs. Here, we show that tumour microvesicles also carry DNA, which reflects the genetic status of the tumour, including amplification of the oncogene c-Myc. We also find amplified c-Myc in serum microvesicles from tumour-bearing mice. Further, we find remarkably high levels of retrotransposon RNA transcripts, especially for some human endogenous retroviruses, such as LINE-1 and Alu retrotransposon elements, in tumour microvesicles and these transposable elements could be transferred to normal cells. These findings expand the nucleic acid content of tumour microvesicles to include: elevated levels of specific coding and non-coding RNA and DNA, mutated and amplified oncogene sequences and transposable elements. Thus, tumour microvesicles contain a repertoire of genetic information available for horizontal gene transfer and potential use as blood biomarkers for cancer. C1 [Balaj, Leonora; Lessard, Ryan; Breakefield, Xandra O.; Skog, Johan] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02129 USA. [Balaj, Leonora; Lessard, Ryan; Breakefield, Xandra O.; Skog, Johan] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Balaj, Leonora; Lessard, Ryan; Pomeroy, Scott L.; Breakefield, Xandra O.; Skog, Johan] Massachusetts Gen Hosp, Boston, MA 02129 USA. [Balaj, Leonora; Lessard, Ryan; Pomeroy, Scott L.; Breakefield, Xandra O.; Skog, Johan] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02129 USA. [Balaj, Leonora] Vrije Univ Amsterdam, Dept Neurosurg, NL-1081 HV Amsterdam, Netherlands. [Dai, Lixin] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Dai, Lixin] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA. [Cho, Yoon-Jae; Pomeroy, Scott L.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Skog, J (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02129 USA. EM Skog.Johan@mgh.harvard.edu FU Wenner-Gren Foundation; Hyugens Scholarship NL; Stiftelsen Olle Engkvist Byggmastare [NCI CA86355, NCI CA69246, CA141226 NCI, CA141150, CA109467] FX We thank Ms Suzanne McDavitt for skilled editorial assistance, Dr Mikkel Noerholm, Jens Magnusson and Tobias Limperg for editing of the manuscript, and Drs Tom Wurdinger and David Noske in the Neuro-Oncology Research Group (NRG), Cancer Center Amsterdam, Amsterdam NL for continuous support. We also thank Dr Leileata Russo for insightful discussions, Dr Kristan van der Vos for valuable assistance with microvesicle quantification and Dr Kathleen Burns and Dr Jef Boeke for advice on the RT assay. This work was kindly supported by the Wenner-Gren Foundation (J.S.), Hyugens Scholarship NL (L. B.), Stiftelsen Olle Engkvist Byggmastare (J.S.), NCI CA86355 (X.O.B.), NCI CA69246 (X.O.B./J.S.), and CA141226 NCI (X.O.B.), CA141150 (X.O.B./J.S.), CA109467 (S.L.P., J.C.). NR 60 TC 255 Z9 261 U1 5 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2011 VL 2 AR 180 DI 10.1038/ncomms1180 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732YP UT WOS:000288225900009 PM 21285958 ER PT J AU Lausch, E Janecke, A Bros, M Trojandt, S Alanay, Y De Laet, C Hubner, CA Meinecke, P Nishimura, G Matsuo, M Hirano, Y Tenoutasse, S Kiss, A Rosa, RFM Unger, SL Renella, R Bonafe, L Spranger, J Unger, S Zabel, B Superti-Furga, A AF Lausch, Ekkehart Janecke, Andreas Bros, Matthias Trojandt, Stefanie Alanay, Yasemin De Laet, Corinne Huebner, Christian A. Meinecke, Peter Nishimura, Gen Matsuo, Mari Hirano, Yoshiko Tenoutasse, Sylvie Kiss, Andrea Machado Rosa, Rafael Fabiano Unger, Sharon L. Renella, Raffaele Bonafe, Luisa Spranger, Juergen Unger, Sheila Zabel, Bernhard Superti-Furga, Andrea TI Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity SO NATURE GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DENDRITIC CELLS; MULTIPLE-SCLEROSIS; T-CELLS; OSTEOPONTIN EXPRESSION; STAPHYLOCOCCUS-AUREUS; ACP 5; SPONDYLOENCHONDRODYSPLASIA; SURVIVAL; DISEASE AB Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders. C1 [Lausch, Ekkehart; Spranger, Juergen; Unger, Sheila; Zabel, Bernhard; Superti-Furga, Andrea] Univ Freiburg, Freiburg Univ Hosp, Ctr Pediat & Adolescent Med, Freiburg, Germany. [Janecke, Andreas] Innsbruck Med Univ, Dept Pediat 2, Innsbruck, Austria. [Janecke, Andreas] Innsbruck Med Univ, Div Human Genet, Innsbruck, Austria. [Bros, Matthias; Trojandt, Stefanie] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Dermatol, Mainz, Germany. [Alanay, Yasemin] Hacettepe Univ, Fac Med, Dept Pediat, Pediat Genet Unit, TR-06100 Ankara, Turkey. [De Laet, Corinne; Tenoutasse, Sylvie] Queen Fabiola Childrens Univ Hosp, Nutr & Metab Unit, Brussels, Belgium. [Huebner, Christian A.] Univ Jena, Univ Hosp Jena, Inst Human Genet, Jena, Germany. [Meinecke, Peter] Childrens Hosp Altona, Clin Genet Unit, Hamburg, Germany. [Nishimura, Gen] Tokyo Metropolitan Childrens Med Ctr, Dept Pediat Imaging, Tokyo, Japan. [Matsuo, Mari; Hirano, Yoshiko] Tokyo Womens Med Univ, Dept Pediat, Tokyo, Japan. [Kiss, Andrea; Machado Rosa, Rafael Fabiano] Univ Fed Ciencias Saude Porto Alegre, Div Clin Genet, Porto Alegre, RS, Brazil. [Kiss, Andrea; Machado Rosa, Rafael Fabiano] Univ Fed Ciencias Saude Porto Alegre, Grad Program Pathol, Porto Alegre, RS, Brazil. [Unger, Sharon L.] Univ Toronto, Mt Sinai Hosp, Div Neonatol, Toronto, ON M5G 1X5, Canada. [Renella, Raffaele] Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Renella, Raffaele] Dana Farber Canc Inst, Boston, MA 02115 USA. [Renella, Raffaele; Bonafe, Luisa; Superti-Furga, Andrea] CHU Vaudois, Dept Pediat, CH-1011 Lausanne, Switzerland. [Unger, Sheila] CHU Vaudois, Dept Med Genet, CH-1011 Lausanne, Switzerland. RP Superti-Furga, A (reprint author), Univ Freiburg, Freiburg Univ Hosp, Ctr Pediat & Adolescent Med, Freiburg, Germany. EM asuperti@unil.ch RI unger, sheila/E-9177-2015; superti-furga, andrea/E-9162-2015; Hubner, Christian/A-2950-2017; OI superti-furga, andrea/0000-0002-3543-7531; Hubner, Christian/0000-0002-1030-4943; Renella, Raffaele/0000-0002-5041-2308; Janecke, Andreas/0000-0001-7155-0315 FU Deutsche Forschungsgemeinschaft [La 1381/1-3]; German Bundesministerium fur Bildung und Forschung; Leenaards Foundation (Lausanne, Switzerland) FX We thank our cases and their families for participation in this study. We are also grateful to T. Velten and to the Lausch/Zabel lab for excellent technical assistance and to M. Osawa and H. Katumori, Tokyo, for clinical information. S. Ehl and his group at the Centre for Chronic Immunodeficiency in Freiburg were most helpful in discussing immunological aspects and experimental strategies. This work was made possible by continuous grant support from the Deutsche Forschungsgemeinschaft to E. L. and B.Z. (La 1381/1-3). B.Z. is also supported by the German Bundesministerium fur Bildung und Forschung (SKELNET project), and A.S.-F. is supported by the Leenaards Foundation (Lausanne, Switzerland). The paper is dedicated to Celine and Sinai. NR 50 TC 67 Z9 69 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2011 VL 43 IS 2 BP 132 EP U79 DI 10.1038/ng.749 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 711XD UT WOS:000286623800011 PM 21217752 ER PT J AU Islam, SA Chang, DS Colvin, RA Byrne, MH McCully, ML Moser, B Lira, SA Charo, IF Luster, AD AF Islam, Sabina A. Chang, Daniel S. Colvin, Richard A. Byrne, Mike H. McCully, Michelle L. Moser, Bernhard Lira, Sergio A. Charo, Israel F. Luster, Andrew D. TI Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5(+) T(H)2 cells SO NATURE IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR CCR8; T-CELLS; DENDRITIC CELLS; AIRWAY INFLAMMATION; IMMUNE-RESPONSES; CUTTING EDGE; TH1 CELLS; IN-VIVO; EXPRESSION; DIFFERENTIATION AB Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation. C1 [Islam, Sabina A.; Chang, Daniel S.; Colvin, Richard A.; Byrne, Mike H.; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02163 USA. [McCully, Michelle L.; Moser, Bernhard] Cardiff Univ, Dept Infect Immun & Biochem, Cardiff, S Glam, Wales. [Lira, Sergio A.] Mt Sinai Sch Med, Inst Immunol, New York, NY USA. [Charo, Israel F.] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94143 USA. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02163 USA. EM aluster@mgh.harvard.edu RI McCully, Michelle/A-7705-2013 OI McCully, Michelle/0000-0003-1543-3629 FU US National Institutes of Health (Harvard Skin Disease Research Center Pilot & Feasibility Study) [K08-AI556663, P30AR042689, R37-AI040618]; Infectious Diseases Society of America FX This work is funded by US National Institutes of Health grants K08-AI556663 and P30AR042689 (Harvard Skin Disease Research Center Pilot & Feasibility Study) to S. A. I. and R37-AI040618 to A. D. L., and the Infectious Diseases Society of America Young Investigator Award to S. A. I. The authors thank P. Murphy (National Institutes of Health) for 4DE4 cells, J. Pease (Imperial College London) for human CCR8 receptor transfectants, P. Shrikant (Roswell Park Cancer Institute) for transgenic Thy1.1 OTII mice, L. Lefrancois (University of Connecticut School of Medicine) for transgenic Thy1.2 OTII mice, C. Sanderson (National Institute for Medical Research, London) for Il5-transgenic mice, S. Thomas for assistance with calcium flux studies and T. Means for assistance with design and validation of QPCR primers. NR 50 TC 93 Z9 98 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2011 VL 12 IS 2 BP 167 EP U86 DI 10.1038/ni.1984 PG 13 WC Immunology SC Immunology GA 708QF UT WOS:000286378400011 PM 21217759 ER PT J AU Liu, J Gao, BB Clermont, AC Blair, P Chilcote, TJ Sinha, S Flaumenhaft, R Feener, EP AF Liu, Jia Gao, Ben-Bo Clermont, Allen C. Blair, Price Chilcote, Tamie J. Sinha, Sukanto Flaumenhaft, Robert Feener, Edward P. TI Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein SO NATURE MEDICINE LA English DT Article ID SPONTANEOUS INTRACEREBRAL HEMORRHAGE; RECEPTOR GLYCOPROTEIN-VI; ACUTE STROKE; ADMISSION HYPERGLYCEMIA; VASCULAR-PERMEABILITY; PLATELET-COLLAGEN; ISCHEMIC-STROKE; MANAGEMENT; MORTALITY; GLUCOSE AB Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia auguments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis. C1 [Liu, Jia; Gao, Ben-Bo; Clermont, Allen C.; Feener, Edward P.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Liu, Jia; Gao, Ben-Bo; Clermont, Allen C.; Feener, Edward P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Blair, Price; Flaumenhaft, Robert] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Div Hemostasis & Thrombosis, Boston, MA 02215 USA. [Chilcote, Tamie J.; Sinha, Sukanto] ActiveSite Pharmaceut Inc, Berkeley, CA USA. RP Feener, EP (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM edward.feener@joslin.harvard.edu FU US National Institutes of Health [EY19029, DK36836, HL090132, HL87203, HL07917]; American Heart Association [0855905D, 0840043N] FX This work was supported in part by the US National Institutes of Health (grants EY19029, DK36836, HL090132, HL87203 and HL07917) and the American Heart Association (0855905D and 0840043N). NR 40 TC 43 Z9 45 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2011 VL 17 IS 2 BP 206 EP U99 DI 10.1038/nm.2295 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 716LK UT WOS:000286969900029 PM 21258336 ER PT J AU Wang, MC Min, W Freudiger, CW Ruvkun, G Xie, XS AF Wang, Meng C. Min, Wei Freudiger, Christian W. Ruvkun, Gary Xie, X. Sunney TI RNAi screening for fat regulatory genes with SRS microscopy SO NATURE METHODS LA English DT Article ID ELEGANS; OBESITY; SEIPIN AB Identification of genes regulating fat accumulation is important for basic and medical research; genetic screening for those genes in Caenorhabditis elegans, a widely used model organism, requires in vivo quantification of lipids. We demonstrated RNA interference screening based on quantitative imaging of lipids with label-free stimulated Raman scattering (SRS) microscopy, which overcomes major limitations of coherent anti-Stokes Raman scattering microscopy. Our screening yielded eight new genetic regulators of fat storage. C1 [Min, Wei; Freudiger, Christian W.; Xie, X. Sunney] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Wang, Meng C.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wang, Meng C.] Baylor Coll Med, Huffington Ctr Aging, Houston, TX 77030 USA. [Wang, Meng C.; Ruvkun, Gary] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA USA. [Wang, Meng C.; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Freudiger, Christian W.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. RP Xie, XS (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM wmeng@bcm.tmc.edu; wm2256@columbia.edu; xie@chemistry.harvard.edu FU US National Institutes of Health [AG034988, EB010244]; Boehringer Ingelheim Fonds FX We thank members of the H. Hutter laboratory (Simon Fraser University) for providing the nre-1(hd20)lin-15b(hd126) strain, members of the C. Sztalryd lab (University of Maryland School of Medicine) for providing perilipin A, ADFP and LSDP5 plasmids, J. Melo and Y. Hao for helping with the membrane receptor RNAi library, A. Soukas and H. Mak for helping with the nuclear hormone receptor RNAi library, Z. Shi for helping with RNAi clone sequencing, X. Zhang and B. Saar for helping on imaging instrumentation, P. Iakova and A. Folick for helping with mammalian cell transfection and C. He and J. Kang for gas chromatography analysis. This work was supported by US National Institutes of Health grants AG034988 (M. C. W.) and EB010244 (X. S. X.) and a predoctoral fellowship from Boehringer Ingelheim Fonds (C.W.F.). NR 15 TC 77 Z9 83 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD FEB PY 2011 VL 8 IS 2 BP 135 EP U52 DI 10.1038/NMETH.1556 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 712GQ UT WOS:000286654600009 PM 21240281 ER PT J AU Bickart, KC Wright, CI Dautoff, RJ Dickerson, BC Barrett, LF AF Bickart, Kevin C. Wright, Christopher I. Dautoff, Rebecca J. Dickerson, Bradford C. Barrett, Lisa Feldman TI Amygdala volume and social network size in humans SO NATURE NEUROSCIENCE LA English DT Article ID BRAIN; PRIMATES AB We found that amygdala volume correlates with the size and complexity of social networks in adult humans. An exploratory analysis of subcortical structures did not find strong evidence for similar relationships with any other structure, but there were associations between social network variables and cortical thickness in three cortical areas, two of them with amygdala connectivity. These findings indicate that the amygdala is important in social behavior. C1 [Wright, Christopher I.; Dautoff, Rebecca J.; Dickerson, Bradford C.; Barrett, Lisa Feldman] Massachusetts Gen Hosp, Psychiat Neuroimaging Res Program, Charlestown, MA 02129 USA. [Wright, Christopher I.; Dautoff, Rebecca J.; Dickerson, Bradford C.; Barrett, Lisa Feldman] Harvard Univ, Sch Med, Charlestown, MA USA. [Bickart, Kevin C.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Wright, Christopher I.; Dautoff, Rebecca J.; Dickerson, Bradford C.; Barrett, Lisa Feldman] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dickerson, Bradford C.] Harvard Univ, Sch Med, Boston, MA USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. RP Barrett, LF (reprint author), Massachusetts Gen Hosp, Psychiat Neuroimaging Res Program, Charlestown, MA 02129 USA. EM l.barrett@neu.edu FU US National Institutes of Health [DP1OD003312]; US National Institute on Aging [R01-AG030311, R01-AG029411, R21-AG29840] FX The authors thank Michael Brickhouse for assistance with morphometric analyses. This study was supported by grants from the US National Institutes of Health Director's Pioneer Award (DP1OD003312) and the US National Institute on Aging (R01-AG030311, R01-AG029411 and R21-AG29840). NR 15 TC 129 Z9 130 U1 4 U2 41 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2011 VL 14 IS 2 BP 163 EP 164 DI 10.1038/nn.2724 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 711MJ UT WOS:000286595400012 PM 21186358 ER PT J AU Blackburn, JS Liu, SL Raimondi, AR Ignatius, MS Salthouse, CD Langenau, DM AF Blackburn, Jessica S. Liu, Sali Raimondi, Aubrey R. Ignatius, Myron S. Salthouse, Christopher D. Langenau, David M. TI High-throughput imaging of adult fluorescent zebrafish with an LED fluorescence macroscope SO NATURE PROTOCOLS LA English DT Article ID VISIBLE IMPLANT ELASTOMER; TRANSGENIC ZEBRAFISH; CLONAL ZEBRAFISH; DANIO-RERIO; NEW-MODELS; CANCER; TRANSPLANTATION; SENSITIVITY; LEUKEMIA; DISEASE AB Zebrafish are a useful vertebrate model for the study of development, behavior, disease and cancer. A major advantage of zebrafish is that large numbers of animals can be economically used for experimentation; however, high-throughput methods for imaging live adult zebrafish had not been developed. Here, we describe protocols for building a light-emitting diode (LELED) fluorescence macroscope and for using it to simultaneously image up to 30 adult animals that transgenically express a fluorescent protein, are transplanted with fluorescently labeled tumor cells or are tagged with fluorescent elastomers. These protocols show that the LELED fluorescence macroscope is capable of distinguishing five fluorescent proteins and can image unanesthetized swimming adult zebrafish in multiple fluorescent channels simultaneously. The macroscope can be built and used for imaging within 1 day, whereas creating fluorescently labeled adult zebrafish requires 1 hour to several months, depending on the method chosen. The LELED fluorescence macroscope provides a low-cost, high-throughput method to rapidly screen adult fluorescent zebrafish and it will be useful for imaging transgenic animals, screening for tumor engraftment, and tagging individual fish for long-term analysis. C1 [Blackburn, Jessica S.; Liu, Sali; Raimondi, Aubrey R.; Ignatius, Myron S.; Langenau, David M.] Massachusetts Gen Hosp, Dept Mol Pathol, Boston, MA 02114 USA. [Blackburn, Jessica S.; Liu, Sali; Raimondi, Aubrey R.; Ignatius, Myron S.; Langenau, David M.] Massachusetts Gen Canc Ctr, Boston, MA USA. [Blackburn, Jessica S.; Liu, Sali; Raimondi, Aubrey R.; Ignatius, Myron S.; Langenau, David M.] Harvard Stem Cell Inst, Boston, MA USA. [Salthouse, Christopher D.] Univ Massachusetts, Dept Elect & Comp Engn, Amherst, MA 01003 USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Dept Mol Pathol, Boston, MA 02114 USA. EM dlangenau@partners.org FU National Institutes of Health (NIH) [5T32CA09216-26, K01 AR055619-01A1, 3 K01 AR055619-03S1]; Dev and Linda Gupta Fund; Alex's Lemonade Stand Foundation; Sarcoma Foundation of America; Leukemia Research Foundation; Harvard Stem Cell Institute FX J.S.B. is supported by National Institutes of Health (NIH) grant 5T32CA09216-26. C.D.S. is supported by the Dev and Linda Gupta Fund. D.M.L. is supported by NIH grants K01 AR055619-01A1 and 3 K01 AR055619-03S1, the Alex's Lemonade Stand Foundation, the Sarcoma Foundation of America, the Hollis Brownstein Research Grant from the Leukemia Research Foundation and by a grant from the Harvard Stem Cell Institute. We thank Northwest Marine Technology for expert technical advice and for providing visible implant elastomers for our pilot experiments. NR 24 TC 19 Z9 19 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 J9 NAT PROTOC JI Nat. Protoc. PD FEB PY 2011 VL 6 IS 2 BP 229 EP 241 DI 10.1038/nprot.2010.170 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 716BR UT WOS:000286940400010 PM 21293462 ER PT J AU Mathis, D Shoelson, SE AF Mathis, Diane Shoelson, Steven E. TI Foreword Immunometabolism: an emerging frontier SO NATURE REVIEWS IMMUNOLOGY LA English DT Editorial Material ID HEMATOPOIETIC STEM-CELLS; INSULIN-RESISTANCE; SALSALATE; OBESITY; INFLAMMATION; ANTAGONIST; METABOLISM; DISEASE AB Immunometabolism is an emerging field of investigation at the interface between the historically distinct disciplines of immunology and metabolism. Accelerating interest in this area is being fuelled by the obesity epidemic and the relatively recent realization that obesity affects the immune system and promotes inflammation, and that obesity-induced inflammation potentially promotes a variety of chronic conditions and diseases. The multilevel interactions between the metabolic and immune systems suggest pathogenic mechanisms that may underlie many of the downstream complications of obesity and offer substantial therapeutic promise. C1 [Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Shoelson, Steven E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM dm@hms.harvard.edu; steven.shoelson@joslin.harvard.edu FU NHLBI NIH HHS [P50 HL083813]; NIDDK NIH HHS [P30 DK036836, R01 DK045943, R01 DK051729, R01 DK073547, R01 DK095327, R37 DK051729, RC4 DK090792, U01 DK074556] NR 15 TC 113 Z9 118 U1 4 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD FEB PY 2011 VL 11 IS 2 BP 81 EP 83 DI 10.1038/nri2922 PG 3 WC Immunology SC Immunology GA 711KD UT WOS:000286589300012 PM 21469396 ER PT J AU Donath, MY Shoelson, SE AF Donath, Marc Y. Shoelson, Steven E. TI Type 2 diabetes as an inflammatory disease SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID BETA-CELL DYSFUNCTION; NECROSIS-FACTOR-ALPHA; MONOCYTE CHEMOATTRACTANT PROTEIN-1; ENDOPLASMIC-RETICULUM STRESS; INDUCED INSULIN-RESISTANCE; DIET-INDUCED OBESITY; REGULATORY T-CELLS; NF-KAPPA-B; CHRONIC GRANULOMATOUS-DISEASE; ACTIVATED SIGNALING PATHWAYS AB Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease. C1 [Donath, Marc Y.] Univ Basel Hosp, Clin Endocrinol Diabet & Metab, CH-4031 Basel, Switzerland. [Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Donath, MY (reprint author), Univ Basel Hosp, Clin Endocrinol Diabet & Metab, CH-4031 Basel, Switzerland. EM MDonath@uhbs.ch; steven.shoelson@joslin.harvard.edu NR 143 TC 921 Z9 965 U1 41 U2 309 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD FEB PY 2011 VL 11 IS 2 BP 98 EP 107 DI 10.1038/nri2925 PG 10 WC Immunology SC Immunology GA 711KD UT WOS:000286589300014 PM 21233852 ER PT J AU Nombela-Arrieta, C Ritz, J Silberstein, LE AF Nombela-Arrieta, Cesar Ritz, Jerome Silberstein, Leslie E. TI The elusive nature and function of mesenchymal stem cells SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Article ID HUMAN BONE-MARROW; THERAPY POSITION STATEMENT; STROMAL CELLS; HEMATOPOIETIC STEM; IN-VITRO; PROGENITOR CELLS; OSTEOGENESIS IMPERFECTA; STEM/PROGENITOR CELLS; INTERNATIONAL-SOCIETY; EXPRESSION ANALYSIS AB Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered. C1 [Ritz, Jerome; Silberstein, Leslie E.] Childrens Hosp, Div Mol & Cellular Med, Ctr Human Cell Therapy, Boston, MA 02115 USA. [Ritz, Jerome] Dana Farber Canc Inst, Div Haematol Malignancies, Boston, MA 02115 USA. RP Silberstein, LE (reprint author), Childrens Hosp, Div Mol & Cellular Med, Ctr Human Cell Therapy, Karp Res Bldg,1 Blackfan Circle, Boston, MA 02115 USA. EM leslie.silberstein@childrens.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669; Nombela-Arrieta, Cesar/0000-0003-0415-259X FU National Heart Lung and Blood Institute, USA [P01 HL095489, R01 HL093139, HHSN268201000009C]; National Cancer Institute, USA [P01 CA78378]; National Heart Lung and Blood Institute [HHSN268201000009C, P01 CA142106]; Human Frontiers in Science Program [00194/2008-L] FX L.E.S. is supported by grants P01 HL095489 and R01 HL093139, and contract HHSN268201000009C from the National Heart Lung and Blood Institute, USA. J.R. is supported by grant P01 CA78378 from the National Cancer Institute, USA, and grant P01 CA142106 and contract HHSN268201000009C from the National Heart Lung and Blood Institute. C.N-A. is a recipient of Human Frontiers in Science Program long-term fellowship 00194/2008-L. NR 82 TC 173 Z9 189 U1 6 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD FEB PY 2011 VL 12 IS 2 BP 126 EP 131 DI 10.1038/nrm3049 PG 6 WC Cell Biology SC Cell Biology GA 709TZ UT WOS:000286465600016 PM 21253000 ER PT J AU Isakova, T Gutierrez, OM Smith, K Epstein, M Keating, LK Juppner, H Wolf, M AF Isakova, Tamara Gutierrez, Orlando M. Smith, Kelsey Epstein, Michael Keating, Leigh K. Jueppner, Harald Wolf, Myles TI Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE chronic kidney disease; FGF23; phosphate; phosphate binders ID PHOSPHATE; FIBROBLAST-GROWTH-FACTOR-23; FGF23; FGF-23; MEN; HOMEOSTASIS; DEFICIENCY; METABOLISM; DIALYSIS; INTACT AB Background. High levels of fibroblast growth factor 23 (FGF23) are associated with mortality and progression of chronic kidney disease (CKD). Reducing dietary phosphorus intake lowers FGF23 secretion in healthly individuals, but there is little data on its effects in patients with pre-dialysis CKD. Methods. Using a 2 x 2 factorial design, we randomly assigned 16 normophosphataemic CKD stage 3-4 patients to receive a 2-week treatment with either lanthanum carbonate 1000 mg three times daily or placebo, and to ingest a tightly controlled diet containing 750 or 1500 mg of dietary phosphorus daily. We analysed serial measurements of FGF23, parathyroid hormone, serum phosphate and calcium, and 24-h urinary phosphate and calcium excretion using repeated-measures analyses. Results. Compared with the 1500-mg phosphorus diet, patients assigned to the 750-mg diet had greater reduction in 24-h urinary phosphate excretion (66% vs. 29%; P < 0.0001). Lanthanum-treated patients experienced a significant reduction in 24-h urinary phosphate excretion compared with baseline (64%; P < 0.0001), but the difference compared with placebo did not reach significance (64% vs. 31%). Despite the significant reductions in 24-h urinary phosphate excretion, no group demonstrated a significant reduction in FGF23 levels; FGF23 levels actually increased significantly in the 1500-mg diet plus placebo group, suggesting dietary phosphorus loading. Conclusions. Although dietary phosphorus restriction and lanthanum lowered urinary phosphate excretion consistent with a rapid decrease in phosphorus absorption, inducing a reduction in FGF23 levels in CKD patients may require interventions with a longer duration than in healthy volunteers. C1 [Isakova, Tamara; Gutierrez, Orlando M.; Smith, Kelsey; Wolf, Myles] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Epstein, Michael; Keating, Leigh K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mallinckrodt Gen Clin Res Ctr, Boston, MA USA. [Jueppner, Harald] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit,Dept Med, Boston, MA USA. RP Isakova, T (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. EM tisakova@med.miami.edu FU Shire Pharmaceuticals; American Kidney Fund Clinical Scientist in Nephrology; National Institutes of Health [K23DK081673, RO1DK076116, R01DK081374]; National Institutes of Health National Center for Research Resources [UL1RR025758-01, M01RR01066] FX This study was supported by a grant from Shire Pharmaceuticals, a grant from the American Kidney Fund Clinical Scientist in Nephrology Fellowship (T.I.), grants from the National Institutes of Health: K23DK081673 (O.M.G.), RO1DK076116 (M.W.) and R01DK081374 (M.W.), and grants UL1RR025758-01 and M01RR01066 from the National Institutes of Health National Center for Research Resources. Shire Pharmaceuticals gave full rights of publication to the investigators. Shire did review the manuscript but did not participate in the conceptual design, data analysis, interpretation of the results or writing of the manuscript. Parts of this manuscript were presented in abstract form at the National Kidney Foundation Spring Clinical Meeting in Orlando, FL, USA, 14-17 April 2010. NR 26 TC 84 Z9 89 U1 0 U2 14 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 FEB PY 2011 VL 26 IS 2 BP 584 EP 591 DI 10.1093/ndt/gfq419 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 712OF UT WOS:000286675400029 PM 20631407 ER PT J AU Dosa, E Guillaume, DJ Haluska, M Lacy, CA Hamilton, BE Njus, JM Rooney, WD Kraemer, DF Muldoon, LL Neuwelt, EA AF Dosa, Edit Guillaume, Daniel J. Haluska, Marianne Lacy, Cynthia A. Hamilton, Bronwyn E. Njus, Jeffrey M. Rooney, William D. Kraemer, Dale F. Muldoon, Leslie L. Neuwelt, Edward A. TI Magnetic resonance imaging of intracranial tumors: intra-patient comparison of gadoteridol and ferumoxytol SO NEURO-ONCOLOGY LA English DT Article DE brain tumors; ferumoxyrol; magnetic resonance imaging; ultrasmall superparamagnetic iron oxide nanoparticles ID SUPERPARAMAGNETIC IRON-OXIDES; NEPHROGENIC SYSTEMIC FIBROSIS; BLOOD-VOLUME MAPS; BRAIN-TUMORS; MALIGNANT GLIOMAS; MR; PERFUSION; NANOPARTICLES; CHEMOTHERAPY; PROGRESSION AB This study aims to compare gadoteridol with ferumoxytol for contrast-enhanced and perfusion-weighted (PW) MR1 of intracranial tumors. The final analysis included 26 patients, who underwent 3 consecutive days of 3T MRI. Day 1 consisted of anatomical pre- and postcontrast images, and PW MRI was acquired using gadoteridol (0.1 mmol/kg). On Day 2, the same MRI sequences were obtained with ferumoxytol (510 mg) and on Day 3, the anatomical images were repeated to detect delayed ferumoxytol-induced signal changes. The T(1)-weighted images were evaluated qualitatively and quantitatively for enhancement volume and signal intensity (SI) changes; PW data were used to estimate the relative cerebral blood volume (rCBV). All 26 lesions showed 24-hour T(1)-weighted ferumoxytol enhancement; 16 also had T(2)-weighted hypointensities. In 6 patients, ferumoxytol-induced signal changes were noted in areas with no gadoteridol enhancement. Significantly greater (P < .0001) SI changes were seen with gadoteridol, and qualitative analyses (lesion border delineation, internal morphology, contrast enhancement) also showed significant preferences (P = .0121; P = .0015; P < .0001, respectively) for this agent. There was no significant difference in lesion enhancement volumes between contrast materials. The ferumoxytol-rCBV values were significantly higher (P = .0016) compared with the gadoteridol-rCBV values. In conclusion, ferumoxytol provides important information about tumor biology that complements gadoteridol imaging. The rCBV measurements indicate areas of tumor undergoing rapid growth, whereas the 24-hour scans mark the presence of inflammatory cells. Both of these functions provide useful information about tumor response to treatment. We suggest that dynamic and anatomical imaging with ferumoxytol warrant further assessment in brain tumor therapy. C1 [Dosa, Edit; Haluska, Marianne; Lacy, Cynthia A.; Muldoon, Leslie L.; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Guillaume, Daniel J.; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97239 USA. [Hamilton, Bronwyn E.] Oregon Hlth & Sci Univ, Dept Radiol, Portland, OR 97239 USA. [Kraemer, Dale F.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Kraemer, Dale F.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. [Njus, Jeffrey M.; Rooney, William D.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97239 USA. [Kraemer, Dale F.] Oregon State Univ, Dept Pharm Practice, Portland, OR USA. [Neuwelt, Edward A.] Portland VA Med Ctr, Portland, OR USA. RP Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,L603, Portland, OR 97239 USA. EM neuwelte@ohsu.edu FU AMAG Pharmaceuticals FX OHSU has received a sponsored research agreement from AMAG Pharmaceuticals to conduct clinical trials of MRI with ferumoxytol. None of the authors has financial interest in this agent or in its developer AMAG Pharmaceuticals. NR 29 TC 21 Z9 21 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD FEB PY 2011 VL 13 IS 2 BP 251 EP 260 DI 10.1093/neuonc/noq172 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 716VX UT WOS:000287002700011 PM 21163809 ER PT J AU Liu, H Li, WJ Ahmad, M Miller, TM Rose, ME Poloyac, SM Uechi, G Balasubramani, M Hickey, RW Graham, SH AF Liu, Hao Li, Wenjin Ahmad, Muzamil Miller, Tricia M. Rose, Marie E. Poloyac, Samuel M. Uechi, Guy Balasubramani, Manimalha Hickey, Robert W. Graham, Steven H. TI Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Ubiquitin-proteasome pathway; Ubiquitin-C-terminal hydrolase L1; Cyclopentenone prostaglandins; Protein post-translational modification; Arachidonic acid; Hypoxic neuronal injury ID PROLIFERATOR-ACTIVATED RECEPTOR; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); PARKINSONS-DISEASE; PROTEIN AGGREGATION; NEURONAL APOPTOSIS; ENDOGENOUS ELECTROPHILE; NEUROBLASTOMA-CELLS; CEREBRAL-ISCHEMIA; PROTEASOME SYSTEM; UCH-L1 AB Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Delta(12,14) -prostaglandin J(2) (15d-PGJ(2)), are active prostaglandin metabolites exerting a variety of biological effects that may be important in the pathogenesis of neurological diseases. Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain specific deubiquitinating enzyme whose aberrant function has been linked to neurodegenerative disorders. We report that [15d-PGJ(2)] detected by quadrapole mass spectrometry (MS) increases in rat brain after temporary focal ischemia, and that treatment with 15d-PGJ(2) induces accumulation of ubiquitinated proteins and exacerbates cell death in normoxic and hypoxic primary neurons. 15d-PGJ(2) covalently modifies UCH-L1 and inhibits its hydrolase activity. Pharmacologic inhibition of UCH-L1 exacerbates hypoxic neuronal death while transduction with a TAT-UCH-L1 fusion protein protects neurons from hypoxia. These studies indicate that UCH-L1 function is important in hypoxic neuronal death and that excessive production of CyPGs after stroke may exacerbate ischemic injury by modification and inhibition of UCH-L1. Published by Elsevier Inc. C1 [Liu, Hao; Li, Wenjin; Ahmad, Muzamil; Rose, Marie E.; Graham, Steven H.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. [Liu, Hao; Li, Wenjin; Ahmad, Muzamil; Rose, Marie E.; Graham, Steven H.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [Miller, Tricia M.; Poloyac, Samuel M.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA. [Uechi, Guy; Balasubramani, Manimalha] Univ Pittsburgh, Genom & Prote Core Labs, Pittsburgh, PA 15260 USA. [Hickey, Robert W.] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15260 USA. RP Graham, SH (reprint author), VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr GR H 00, Highland Dr, Pittsburgh, PA 15206 USA. EM sgra@pitt.edu FU NIH NINDS [R0137549]; VA Merit Review program FX This work was supported by NIH NINDS R0137549 and the VA Merit Review program (SHG). The authors thank Pat Strickler for secretarial support, Drs. Jun Chen and Guodong Cao (University of Pittsburgh, Pittsburgh) for providing the TAT-containing plasmid, and Dr. Billy W. Day (University of Pittsburgh, Pittsburgh) for helpful discussions. NR 53 TC 20 Z9 21 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2011 VL 41 IS 2 BP 318 EP 328 DI 10.1016/j.nbd.2010.09.020 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 705QZ UT WOS:000286154300010 PM 20933087 ER PT J AU Perez, SE He, B Muhammad, N Oh, KJ Fahnestock, M Ikonomovic, MD Mufson, EJ AF Perez, Sylvia E. He, Bin Muhammad, Nadeem Oh, Kwang-Jin Fahnestock, Margaret Ikonomovic, Milos D. Mufson, Elliott J. TI Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Alzheimer's disease; Amyloid; Cholinergic; Nerve growth factor; ChAT; proNGF; p75(NTR); Transgenic mice; TrkA; Aging ID NERVE GROWTH-FACTOR; AMYLOID PRECURSOR PROTEIN; MILD COGNITIVE IMPAIRMENT; NICOTINIC ACETYLCHOLINE-RECEPTOR; CHOLINE-ACETYLTRANSFERASE ACTIVITY; ALZHEIMERS-DISEASE; MOUSE MODEL; A-BETA; NUCLEUS BASALIS; PRESYNAPTIC BOUTONS AB The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However. nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying A beta, plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2-4 months), middle-aged (13-15 months) and old (18-20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal-subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75(NTR) protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by A beta plaque pathology. (C) 2010 Elsevier Inc. All rights reserved. C1 [Perez, Sylvia E.; He, Bin; Muhammad, Nadeem; Oh, Kwang-Jin; Mufson, Elliott J.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Fahnestock, Margaret] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada. [Ikonomovic, Milos D.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Ikonomovic, Milos D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Ikonomovic, Milos D.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. RP Mufson, EJ (reprint author), Rush Univ, Med Ctr, Alla V & Solomon Jesmer Chair Aging, 1735 W Harrison St,Suite 300, Chicago, IL 60612 USA. EM sylvia_e_perez@rush.edu; binhe_2000@yahoo.com; Muhammad_Nadeem@rush.edu; sp8472@gmail.com; fahnest@mcmaster.ca; ikonomovicmd@upmc.edu; emufson@rush.edu OI Fahnestock, Margaret/0000-0002-6815-0529 FU Shapiro Foundation; [AG10688] FX This work was supported by the Shapiro Foundation and AG10688. The authors thank K. Schafernak for editing the manuscript. NR 91 TC 27 Z9 29 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2011 VL 41 IS 2 BP 338 EP 352 DI 10.1016/j.nbd.2010.10.002 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 705QZ UT WOS:000286154300012 PM 20937383 ER PT J AU Shi, S Hoogaars, WMH de Gorter, DJJ van Heiningen, SH Lin, HY Hong, CC Kernaladewi, DU Aartsma-Rus, A ten Dijke, P 't Hoen, PAC AF Shi, SongTing Hoogaars, Willem M. H. de Gorter, David J. J. van Heiningen, Sandra H. Lin, Herbert Y. Hong, Charles C. Kernaladewi, Dwi U. Aartsma-Rus, Annemieke ten Dijke, Peter 't Hoen, Peter A. C. TI BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model SO NEUROBIOLOGY OF DISEASE LA English DT Article DE DMD; BMP signaling; Myogenic differentiation ID DUCHENNE-MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE; TGF-BETA; MDX MICE; HETEROTOPIC OSSIFICATION; MOLECULAR SIGNATURE; SATELLITE CELLS; EXPRESSION; GENE; REGENERATION AB Duchenne Muscular Dystrophy (DMD) is an X-linked lethal muscle wasting disease characterized by muscle fiber degeneration and necrosis. The progressive pathology of DMD can be explained by an insufficient regenerative response resulting in fibrosis and adipose tissue formation. BMPs are known to inhibit myogenic differentiation and in a previous study we found an increased expression of a BMP family member BMP4 in DMD myoblasts. The aim of the current study was therefore to investigate whether inhibition of BMP signaling could be beneficial for myoblast differentiation and muscle regeneration processes in a DMD context. All tested BMP inhibitors, Noggin, dorsomorphin and LDN-193189, were able to accelerate and enhance myogenic differentiation. However, dorsomorphin repressed both BMP and TG beta signaling and was found to be toxic to primary myoblast cell cultures. In contrast, Noggin was found to be a potent and selective BMP inhibitor and was therefore tested in vivo in a DMD mouse model. Local adenoviral-mediated overexpression of Noggin in muscle resulted in an increased expression of the myogenic regulatory genes Myog and Myod1 and improved muscle histology. In conclusion, our results suggest that repression of BMP signaling may constitute an attractive adjunctive therapy for DMD patients. (C) 2010 Elsevier Inc. All rights reserved. C1 [Hoogaars, Willem M. H.; van Heiningen, Sandra H.; Kernaladewi, Dwi U.; Aartsma-Rus, Annemieke; 't Hoen, Peter A. C.] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. [Shi, SongTing; de Gorter, David J. J.; van Heiningen, Sandra H.; ten Dijke, Peter] Dept Mol Cell Biol, Leiden, Netherlands. [Shi, SongTing; de Gorter, David J. J.; van Heiningen, Sandra H.; ten Dijke, Peter] Ctr Biomed Genet, Leiden, Netherlands. [Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, Boston, MA USA. [Hong, Charles C.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. RP Hoogaars, WMH (reprint author), Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. EM w.m.h.hoogaars@lumc.nl RI 't Hoen, Peter/A-4857-2012 FU Dutch Organization for Scientific Research (Zon-MW) [NWO 918.66.606]; Dutch Ministry for Economic Affairs [IGE7001]; Dutch Parent Project; Centre for Biomedical Genetics FX We thank Dr. Aris Economides and Dr. Paschalis Sideras for providing us with the Noggin protein and the Noggin adenovirus. This work was financially supported by the Dutch Organization for Scientific Research (Zon-MW) (VICI Grant NWO 918.66.606), the Dutch Ministry for Economic Affairs (IOP Genomics grant IGE7001), the Dutch Parent Project and the Centre for Biomedical Genetics. NR 48 TC 14 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2011 VL 41 IS 2 BP 353 EP 360 DI 10.1016/j.nbd.2010.10.003 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 705QZ UT WOS:000286154300013 PM 20940052 ER PT J AU Rossetti, AO Milligan, TA Vulliemoz, S Michaelides, C Bertschi, M Lee, JW AF Rossetti, Andrea O. Milligan, Tracey A. Vulliemoz, Serge Michaelides, Costas Bertschi, Manuel Lee, Jong Woo TI A Randomized Trial for the Treatment of Refractory Status Epilepticus SO NEUROCRITICAL CARE LA English DT Article DE Propofol; Thiopental; Pentobarbital; Burst-suppression; Outcome; Complications ID PROPOFOL INFUSION SYNDROME; INTENSIVE-CARE-UNIT; PHARMACOKINETICS; NEUROLOGISTS; MANAGEMENT; PROGNOSIS AB Refractory status epilepticus (RSE) has a mortality of 16-39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36-48 h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. The trial was terminated after 3 years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm (P = 0.40). Mortality (43 vs. 34%; P = 1.00) and return to baseline clinical conditions at 3 months (36 vs. 44%; P = 1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation (P = 0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidence. C1 [Rossetti, Andrea O.] CHUV, Dept Neurol, CH-1011 Lausanne, Switzerland. [Rossetti, Andrea O.] Univ Lausanne, CHUV BH07, CH-1011 Lausanne, Switzerland. [Milligan, Tracey A.; Lee, Jong Woo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Vulliemoz, Serge] HUG, Dept Neurol, Geneva, Switzerland. [Michaelides, Costas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Bertschi, Manuel] Univ Bern, Inselspital, Dept Neurol, CH-3010 Bern, Switzerland. RP Rossetti, AO (reprint author), CHUV, Dept Neurol, CH-1011 Lausanne, Switzerland. EM andrea.rossetti@chuv.ch RI Rossetti, Andrea/A-6712-2008 OI Rossetti, Andrea/0000-0002-7878-172X FU UCB (Switzerland); Swiss League against Epilepsy; AstraZeneca (Switzerland) FX The study was supported in part by grants from the Swiss League against Epilepsy, AstraZeneca (Switzerland) and UCB (Switzerland). The six authors do not have any other financial disclosures or conflict of interest. The authors wish to thank Dr Jan Novy (CHUV Lausanne), Katherine Gleason, and Sonia Replansky (BWH Boston, MA) for their help in data acquisition, and Dr Nathan B. Fountain (Charlottesville, VA) for his inputs on the study design. We confirm that we have read the Journal's position on issues involved in ethical publications and affirm that this report is consistent with those guidelines. NR 26 TC 72 Z9 76 U1 0 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD FEB PY 2011 VL 14 IS 1 BP 4 EP 10 DI 10.1007/s12028-010-9445-z PG 7 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 708WF UT WOS:000286394300002 PM 20878265 ER PT J AU Salat, DH Chen, JJ van der Kouwe, AJ Greve, DN Fischl, B Rosas, HD AF Salat, D. H. Chen, J. J. van der Kouwe, A. J. Greve, D. N. Fischl, B. Rosas, H. D. TI Hippocampal degeneration is associated with temporal and limbic gray matter/white matter tissue contrast in Alzheimer's disease SO NEUROIMAGE LA English DT Article DE Alzheimer's disease; Cerebral cortex; Cortical thickness; Gray matter; Cortical surface; Tissue contrast; Pathology; Aging; Medial temporal; Entorhinal; Hippocampus ID HUMAN CEREBRAL-CORTEX; AGE-RELATED-CHANGES; MILD COGNITIVE IMPAIRMENT; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; WHITE-MATTER; CORTICAL THICKNESS; DIFFUSION TENSOR; HUMAN BRAIN; IN-VIVO AB Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimer's disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD. Published by Elsevier Inc. C1 [Salat, D. H.; Chen, J. J.; van der Kouwe, A. J.; Greve, D. N.; Fischl, B.; Rosas, H. D.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Salat, D. H.; Chen, J. J.; van der Kouwe, A. J.; Greve, D. N.; Fischl, B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Salat, D. H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Fischl, B.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Rosas, H. D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Salat, DH (reprint author), MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, MGH Dept Radiol, Bldg 149,13th St,Mail Code 149 2301, Charlestown, MA 02129 USA. EM salat@nmr.mgh.harvard.edu RI Chen, J. Jean/A-2846-2013 OI Chen, J. Jean/0000-0001-5469-7542 FU National Institutes of Health [K01AG024898, R01NR010827, P41RR14075, BIRN002, U24RR021382, R01EB001550, R01EB006758, R01NS052585, U54EB005149]; Canadian Institutes of Health Research; Athinoula A. Martinos Center for Biomedical Imaging; Mental Illness and Neuroscience Discovery (MIND) Institute; Ellison Medical Foundation; [P50 AG05681]; [P01 AG03991]; [R01 AG021910]; [P50 MH071616]; [U24 RR021382]; [R01 MH56584] FX This work was supported by the National Institutes of Health [K01AG024898, R01NR010827, P41RR14075, BIRN002, U24RR021382, R01EB001550, R01EB006758, R01NS052585, U54EB005149]; a postdoctoral fellowship from the Canadian Institutes of Health Research; the Athinoula A. Martinos Center for Biomedical Imaging, the Mental Illness and Neuroscience Discovery (MIND) Institute, and The Autism & Dyslexia Project funded by the Ellison Medical Foundation. We are grateful to Dr. Randy Buckner for his comments on this work, and for his support in the use of the OASIS dataset: Grants P50 AG05681, P01 AG03991, R01 AG021910, P50 MH071616, U24 RR021382, R01 MH56584. NR 51 TC 23 Z9 23 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2011 VL 54 IS 3 BP 1795 EP 1802 DI 10.1016/j.neuroimage.2010.10.034 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 707QV UT WOS:000286302000004 PM 20965261 ER PT J AU Brown, GG Mathalon, DH Stern, H Ford, J Mueller, B Greve, DN McCarthy, G Voyvodic, J Glover, G Diaz, M Yetter, E Ozyurt, IB Jorgensen, KW Wible, CG Turner, JA Thompson, WK Potkin, SG AF Brown, Gregory G. Mathalon, Daniel H. Stern, Hal Ford, Judith Mueller, Bryon Greve, Douglas N. McCarthy, Gregory Voyvodic, James Glover, Gary Diaz, Michele Yetter, Elizabeth Ozyurt, I. Burak Jorgensen, Kasper W. Wible, Cynthia G. Turner, Jessica A. Thompson, Wesley K. Potkin, Steven G. CA Function Biomed Informatics Res Ne TI Multisite reliability of cognitive BOLD data SO NEUROIMAGE LA English DT Article ID MULTICENTER FMRI; MOTOR-PERFORMANCE; FIELD STRENGTHS; FUNCTIONAL MRI; REPRODUCIBILITY; ACTIVATION; BEHAVIOR; SYSTEMS; DESIGNS; BRAIN AB Investigators perform multi-site functional magnetic resonance imaging studies to increase statistical power, to enhance generalizability, and to improve the likelihood of sampling relevant subgroups. Yet undesired site variation in imaging methods could off-set these potential advantages. We used variance components analysis to investigate sources of variation in the blood oxygen level-dependent (BOLD) signal across four 3-T magnets in voxelwise and region-of-interest (ROI) analyses. Eighteen participants traveled to four magnet sites to complete eight runs of a working memory task involving emotional or neutral distraction. Person variance was more than 10 times larger than site variance for five of six ROIs studied. Person-by-site interactions, however, contributed sizable unwanted variance to the total. Averaging over runs increased between-site reliability, with many voxels showing good to excellent between-site reliability when eight runs were averaged and regions of interest showing fair to good reliability. Between-site reliability depended on the specific functional contrast analyzed in addition to the number of runs averaged. Although median effect size was correlated with between-site reliability, dissociations were observed for many voxels. Brain regions where the pooled effect size was large but between-site reliability was poor were associated with reduced individual differences. Brain regions where the pooled effect size was small but between-site reliability was excellent were associated with a balance of participants who displayed consistently positive or consistently negative BOLD responses. Although between-site reliability of BOLD data can be good to excellent, acquiring highly reliable data requires robust activation paradigms, ongoing quality assurance, and careful experimental control. Published by Elsevier Inc. C1 [Brown, Gregory G.] VA San Diego Healthcare Syst, Psychol Serv 116B, San Diego, CA 92161 USA. [Brown, Gregory G.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92161 USA. [Mathalon, Daniel H.; Ford, Judith; Yetter, Elizabeth] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Mathalon, Daniel H.; Ford, Judith; Yetter, Elizabeth] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Stern, Hal] Univ Calif Irvine, Dept Stat, Irvine, CA 92697 USA. [Mueller, Bryon] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Greve, Douglas N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [McCarthy, Gregory] Yale Univ, Dept Psychol, New Haven, CT 06511 USA. [Voyvodic, James; Diaz, Michele] Duke Univ, Med Ctr, Brain Imaging & Anal Ctr, Durham, NC 27705 USA. [Glover, Gary] Stanford Univ, Radiol Sci Lab, Stanford, CA 94305 USA. [Ozyurt, I. Burak; Thompson, Wesley K.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92161 USA. [Jorgensen, Kasper W.] Univ Calif San Francisco, Brain Imaging & EEG Lab, San Francisco, CA 94121 USA. [Wible, Cynthia G.] Harvard Univ, Sch Med, Dept Psychiat, Brockton, MA 02301 USA. [Wible, Cynthia G.] Brockton VAMC, Brockton, MA 02301 USA. [Turner, Jessica A.; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat, Irvine, CA 92697 USA. RP Brown, GG (reprint author), VA San Diego Healthcare Syst, Psychol Serv 116B, 3350 La Jolla Dr, San Diego, CA 92161 USA. EM gbrown@ucsd.edu RI Turner, Jessica/H-7282-2015; Potkin, Steven/A-2021-2013 OI Turner, Jessica/0000-0003-0076-8434; Mathalon, Daniel/0000-0001-6090-4974; Potkin, Steven/0000-0003-1028-1013; Andersen, Kasper Winther/0000-0002-7643-2067; FU NCRR NIH HHS [U24 RR021992, U24 RR021992-05] NR 54 TC 30 Z9 30 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2011 VL 54 IS 3 BP 2163 EP 2175 DI 10.1016/j.neuroimage.2010.09.076 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 707QV UT WOS:000286302000040 PM 20932915 ER PT J AU Ren, JQ Jiang, Y Wang, ZH McCarthy, D Rajadhyaksha, AM Tropea, TF Kosofsky, BE Bhide, PG AF Ren, Jia-Qian Jiang, Yan Wang, Zhihui McCarthy, Deirdre Rajadhyaksha, Anjali M. Tropea, Thomas F. Kosofsky, Barry E. Bhide, Pradeep G. TI Prenatal L-DOPA exposure produces lasting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference SO NEUROPHARMACOLOGY LA English DT Article DE Dopamine; L-DOPA; Cocaine; Conditioned place preference; Locomotor activity ID NUCLEUS-ACCUMBENS; ADULT MICE; CEREBRAL-CORTEX; RECEPTOR; SCHIZOPHRENIA; ACTIVATION; EXPRESSION; STRIATUM; RATS; BEHAVIORS AB Dopamine, its receptors and transporter are present in the brain beginning from early in the embryonic period. Dopamine receptor activation can influence developmental events including neurogenesis, neuronal migration and differentiation raising the possibility that dopamine imbalance in the fetal brain can alter development of the brain and behavior. We examined whether elevated dopamine levels during gestation can produce persisting changes in brain dopamine content and dopamine-mediated behaviors. We administered L-3,4-dihydroxyphenylalanine (L-DOPA) in drinking water to timed-pregnant CD1 mice from the 11th day of gestation until the day of parturition. The prenatal L-DOPA exposure led to significantly lower cocaine conditioned place preference, a behavioral test of reward, at postnatal day 60 (P60). However, in vivo microdialysis measurements showed significant increases in cocaine-induced dopamine release in the caudate putamen of P26 and P60 mice exposed to L-DOPA prenatally, ruling out attenuated dopamine release in the caudate putamen as a contributor to decreased conditioned place preference. Although dopamine release was induced in the nucleus accumbens of prenatally L-DOPA exposed mice at P60 by cocaine, the dopamine release in the nucleus accumbens was not significantly different between the L-DOPA and control groups. However, basal dopamine release was significantly higher in the prenatally L-DOPA exposed mice at P60 suggesting that the L-DOPA exposed mice may require a higher dose of cocaine for induction of cocaine place preference than the controls. The prenatal L-DOPA exposure did not alter cocaine-induced locomotor response, suggesting dissociation between the effects of prenatal L-DOPA exposure on conditioned place preference and locomotor activity. Tissue concentration of dopamine and its metabolites in the striatum and ventral midbrain were significantly affected by the L-DOPA exposure as well as by developmental changes over the P14-P60 period. Thus, elevation of dopamine levels during gestation can produce persisting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ren, Jia-Qian; McCarthy, Deirdre; Bhide, Pradeep G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Ren, Jia-Qian; Jiang, Yan; Wang, Zhihui] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Jiang, Yan] Beijing Univ Chinese Med, Dept Med, Beijing, Peoples R China. [Rajadhyaksha, Anjali M.; Tropea, Thomas F.; Kosofsky, Barry E.] Cornell Univ, Weill Cornell Med Coll, Div Pediat Neurol, New York, NY 10021 USA. RP Bhide, PG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, 149,13th St, Charlestown, MA 02129 USA. EM bhide@helix.mgh.harvard.edu OI Bhide, Pradeep/0000-0003-4236-9415 FU USPHS [RO1DA020796, P30NS045776, KO2DA00354] FX Supported by USPHS grants RO1DA020796, P30NS045776 (PGB) and KO2DA00354 (BEK). NR 38 TC 5 Z9 5 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB-MAR PY 2011 VL 60 IS 2-3 BP 295 EP 302 DI 10.1016/j.neuropharm.2010.09.012 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 717NL UT WOS:000287054600012 PM 20854831 ER PT J AU Dunn, GP Gerrard, JL Jho, DH Ogilvy, CS AF Dunn, Gavin P. Gerrard, Jason L. Jho, David H. Ogilvy, Christopher S. TI Surgical Treatment of a Large Fusiform Distal Anterior Cerebral Artery Aneurysm With In Situ End-to-Side A3-A3 Bypass Graft and Aneurysm Trapping: Case Report and Review of the Literature SO NEUROSURGERY LA English DT Article DE Aneurysm; Bypass; Distal anterior cerebral artery; End-to-side anastomosis; Microsurgery ID ANASTOMOSIS; SURGERY AB BACKGROUND AND IMPORTANCE: Large fusiform aneurysms of the distal anterior cerebral territory are extremely rare and can be particularly challenging to treat. The circumferential pathology of fusiform lesions renders stand-alone clip or coil ablation unsatisfactory, and the deep, narrow corridor augments the difficulty of surgical approaches. In this setting, bypass procedures may be used to both treat the aneurysm definitively and preserve distal parent artery flow. We report a rare case of a large fusiform A3 aneurysm treated with trapping and concomitant end-to-side A3:A3 bypass. CLINICAL PRESENTATION: A 52-year-old man was evaluated after losing consciousness and experiencing a fall. A noncontrast computed tomography scan revealed a focal area of hemorrhage above the body of the corpus callosum, and computed tomography angiography showed a fusiform aneurysm of the right A3 artery. To treat the aneurysm definitively and preserve distal vessel flow, the patient was taken to surgery in anticipation of aneurysm ablation and cerebrovascular bypass. A large, fusiform right A3 aneurysm was identified. Intraoperative flow measurement demonstrated poor collateral circulation. The aneurysm was trapped with clips, and a right-to-left A3:A3 end-to-side in situ bypass was performed. Aneurysm occlusion and preserved distal vessel flow were confirmed with intraoperative angiography. CONCLUSION: Large fusiform aneurysms in the distal anterior cerebral artery region are rare, and the anatomy of these lesions and their vascular location render stand-alone surgical management technically challenging. End-to-side A3: A3 bypass combined with aneurysm trapping represents a feasible treatment strategy for lesions in this location. C1 [Dunn, Gavin P.; Gerrard, Jason L.; Jho, David H.; Ogilvy, Christopher S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. RP Ogilvy, CS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. EM cogilvy@partners.org NR 12 TC 5 Z9 5 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 FEB PY 2011 VL 68 IS 2 BP E587 EP E591 DI 10.1227/NEU.0b013e3182036012 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 703QJ UT WOS:000285994300014 PM 21135720 ER PT J AU De La Garza, BH Muir, ER Li, GA Shih, YYI Duong, TQ AF De La Garza, Bryan H. Muir, Eric R. Li, Guang Shih, Yen-Yu I. Duong, Timothy Q. TI Blood oxygenation level-dependent (BOLD) functional MRI of visual stimulation in the rat retina at 11.7 T SO NMR IN BIOMEDICINE LA English DT Article DE laminar specificity; high magnetic field; high-resolution fMRI; choroid; dark and light adaptation; blood flow ID GLIAL-CELLS; FLOW; EYE AB Although optically based imaging techniques provide valuable functional and physiological information of the retina, they are mostly limited to the probing of the retinal surface and require an unobstructed light path. MRI, in contrast, could offer physiological and functional data without depth limitation. Blood oxygenation level-dependent functional MRI (BOLD fMRI) of the thin rat retina is, however, challenging because of the need for high spatial resolution, and the potential presence of eye movement and susceptibility artifacts. This study reports a novel application of high-resolution (111 x 111 x 1000 mu m(3)) BOLD fMRI of visual stimulation in the anesthetized rat retina at 11.7 T. A high-field MRI scanner was utilized to improve the signal-to-noise ratio, spatial resolution and BOLD sensitivity. Visual stimuli (8 Hz diffuse achromatic light) robustly increased BOLD responses in the retina [5.0 +/- 0.8% from activated pixels and 3.1 +/- 1.1% from the whole-retina region of interest (mean +/- SD), n = 12 trials on six rats, p < 0.05 compared with baseline]. Some activated pixels were detected surrounding the pupil and ciliary muscle because of accommodation reflex to visual stimuli, and were reduced with atropine and phenylephrine eye drops. BOLD fMRI scans without visual stimulations showed no significantly activated pixels (whole-retina BOLD changes were 0.08 +/- 0.34%, n = 6 trials on five rats, not statistically different from baseline, p > 0.05). BOLD fMRI of visual stimulation has the potential to provide clinically relevant data to probe hemodynamic neurovascular coupling and dysfunction of the retina with depth resolution. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [De La Garza, Bryan H.; Muir, Eric R.; Li, Guang; Shih, Yen-Yu I.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Muir, Eric R.; Duong, Timothy Q.] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 USA. [Li, Guang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [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. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Duong, Timothy Q.] SW Natl Primate Res Ctr, 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 Li, Guang/C-9539-2011; Duong, Timothy/B-8525-2008; Muir, Eric/H-8830-2013; OI Li, Guang/0000-0002-7648-0464; Shih, Yen-Yu Ian/0000-0001-6529-911X FU National Institutes of Health [R01EY014211, R01EY018855]; VA MERIT FX The authors thank Bill Rogers of the Research Imaging Institute for building the visual stimulation unit used in this study, Dr Joseph M. Harrison of Ophthalmology for his help with luminance measurements, and Dr Carlos Rosende of Ophthalmology for helpful discussions. This work was supported by the National Institutes of Health (R01EY014211, R01EY018855) and VA MERIT. NR 30 TC 13 Z9 13 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD FEB PY 2011 VL 24 IS 2 BP 188 EP 193 DI 10.1002/nbm.1571 PG 6 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 732SG UT WOS:000288209300009 PM 21344533 ER PT J AU Burke, LE Conroy, MB Sereika, SM Elci, OU Styn, MA Acharya, SD Sevick, MA Ewing, LJ Glanz, K AF Burke, Lora E. Conroy, Molly B. Sereika, Susan M. Elci, Okan U. Styn, Mindi A. Acharya, Sushama D. Sevick, Mary A. Ewing, Linda J. Glanz, Karen TI The Effect of Electronic Self-Monitoring on Weight Loss and Dietary Intake: A Randomized Behavioral Weight Loss Trial SO OBESITY LA English DT Article ID HAND-HELD COMPUTERS; LOSS PROGRAM; OBESITY; INTERVENTION; DIARIES AB Technology may improve self-monitoring adherence and dietary changes in weight loss treatment. Our study aimed to investigate whether using a personal digital assistant (PDA) with dietary and exercise software, with and without a feedback message, compared to using a paper diary/record (PR), results in greater weight loss and improved self-monitoring adherence. Healthy adults (N = 210) with a mean BMI of 34.01 kg/m(2) were randomized to one of three self-monitoring approaches: PR (n = 72), PDA with self-monitoring software (n = 68), or PDA with self-monitoring software and daily feedback messages (PDA+FB, n = 70). All participants received standard behavioral treatment. Self-monitoring adherence and change in body weight, waist circumference, and diet were assessed at 6 months; retention was 91%. All participants had a significant weight loss (P < 0.01) but weight loss did not differ among groups. A higher proportion of PDA+FB participants (63%) achieved >= 5% weight loss in comparison to the PR group (46%) (P < 0.05) and PDA group (49%) (P = 0.09). Median percent self-monitoring adherence over the 6 months was higher in the PDA groups (PDA 80%; PDA+FB 90%) than in the PR group (55%) (P < 0.01). Waist circumference decreased more in the PDA groups than the PR group (P = 0.02). Similarly, the PDA groups reduced energy and saturated fat intake more than the PR group (P < 0.05). Self-monitoring adherence was greater in the PDA groups with the greatest weight change observed in the PDA+FB group. C1 [Burke, Lora E.; Sereika, Susan M.; Elci, Okan U.; Styn, Mindi A.; Acharya, Sushama D.] Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA 15261 USA. [Burke, Lora E.; Conroy, Molly B.; Styn, Mindi A.; Acharya, Sushama D.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Conroy, Molly B.; Sevick, Mary A.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Sereika, Susan M.; Elci, Okan U.; Sevick, Mary A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Sevick, Mary A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth & Equ Res & Promot, Pittsburgh, PA USA. [Ewing, Linda J.] Univ Pittsburgh, Sch Med, Dept Psychol, Pittsburgh, PA 15261 USA. [Ewing, Linda J.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. [Glanz, Karen] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Sch Nursing, Family & Community Hlth Div, Philadelphia, PA 19104 USA. RP Burke, LE (reprint author), Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA 15261 USA. EM lbu100@pitt.edu FU National Institutes of Health [RO1-DK71817, NR010742]; Data Management Core of the Center for Research in Chronic Disorders NIH-NINR [P30-NR03924]; General Clinical Research Center, NIH-NCRR-GCRC [5MO1-RR00056]; Clinical Translational Research Center, NIH/NCRR/CTSA, University of Pittsburgh [UL1 RR024153] FX We gratefully acknowledge the participants in this study who so willingly gave of their time to complete the assessments. This study was supported by National Institutes of Health grants #RO1-DK71817 and partial support for L.E.B. by NIH K24 Award, NR010742. The conduct of the study was also supported by the Data Management Core of the Center for Research in Chronic Disorders NIH-NINR #P30-NR03924 and the General Clinical Research Center, NIH-NCRR-GCRC #5MO1-RR00056 and the Clinical Translational Research Center, NIH/NCRR/CTSA Grant UL1 RR024153 at the University of Pittsburgh. NR 28 TC 72 Z9 72 U1 1 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD FEB PY 2011 VL 19 IS 2 BP 338 EP 344 DI 10.1038/oby.2010.208 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 712FW UT WOS:000286651400017 PM 20847736 ER PT J AU Hivert, MF Sun, Q Shrader, P Mantzoros, CS Meigs, JB Hu, FB AF Hivert, Marie-France Sun, Qi Shrader, Peter Mantzoros, Christol S. Meigs, James B. Hu, Frank B. TI Higher Adiponectin Levels Predict Greater Weight Gain in Healthy Women in the Nurses' Health Study SO OBESITY LA English DT Article ID HIGH-MOLECULAR-WEIGHT; NECROSIS-FACTOR-ALPHA; BODY-MASS INDEX; INSULIN-RESISTANCE; RISK; OBESITY; SENSITIVITY; ADIPOCYTES; EXPRESSION; GHRELIN AB Adiponectin and resistin's possible roles in weight regulation have received little attention. We tested the hypothesis that adipokine levels predict future weight gain in women in the Nurses' Health Study. Among women who provided blood samples in 1990, we studied 1,063 women who did not develop diabetes ("healthy") and 984 women who subsequently developed diabetes. Total and high-molecular-weight (HMW) adiponectin and resistin levels were measured using enzyme-linked immunosorbent assay. Women who did not developed diabetes had a mean BMI of 26.3 +/- 6.0 kg/m(2) at baseline and gained 2.0 +/- 6.1 kg over 4 years. Women who developed diabetes had a mean BMI of 30.1 +/- 5.4 kg/m(2) at baseline, and gained 2.4 +/- 7.1 kg over 4 years. In women who did not developed diabetes, higher baseline levels of total and HMW adiponectin were associated with significantly greater weight gain after adjustment for age, BMI, physical activity, diet, and other covariates: women in the highest quintile of total adiponectin gained 3.18 kg compared to women in the lowest quintile who gained 0.80 kg (fully adjusted; P for trend <0.0001). Adiponectin was not significantly associated with weight gain in women who subsequently developed diabetes. Resistin levels were not associated with weight gain in either women who did or did not develop diabetes during the follow-up. We conclude that elevated adiponectin levels are associated with higher weight gain in healthy women, independent of confounding risk factors. High adiponectin production by adipocytes might be a sign of "healthy" adipose tissue with further capacity to store fat. C1 [Hivert, Marie-France; Shrader, Peter; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Hivert, Marie-France; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sun, Qi; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sun, Qi; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mantzoros, Christol S.] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. EM fhu@hsph.harvard.edu FU National Institutes of Health (NIH) [DK58845, DK58785, DK79929, DK 081913]; American Diabetes Association; NIDDK [K24 DK080140]; GlaxoSmithKline; BIDMC FX The data used in this report were taken from the Nurses' Health Study, which is located in the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School. The National Institutes of Health provided funding for this study (NIH grant DK58845). The funding source had no role in the collection, analysis, or interpretation of the data, or the decision to submit the manuscript for publication. J.B.M. was supported by a Career Development Award from the American Diabetes Association and by NIDDK K24 DK080140. J.B.M. currently has a research grant from GlaxoSmithKline, and has a consulting agreement with Interleukin Genetics, Inc. C.S.M. is supported by NIH grants DK58785, DK79929, DK 081913, DK58845 and a discretionary grant from BIDMC. NR 20 TC 12 Z9 12 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD FEB PY 2011 VL 19 IS 2 BP 409 EP 415 DI 10.1038/oby.2010.189 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 712FW UT WOS:000286651400026 PM 20814416 ER PT J AU Shen, RR Hahn, WC AF Shen, R. R. Hahn, W. C. TI Emerging roles for the non-canonical IKKs in cancer SO ONCOGENE LA English DT Review DE NF-kappa B; cancer; IKK ID NF-KAPPA-B; INNATE IMMUNE-RESPONSE; KINASE-RELATED KINASES; TUMOR-SUPPRESSOR CYLD; INTERFERON REGULATORY FACTOR-3; UBIQUITIN-LIKE DOMAIN; BREAST-CANCER; I INTERFERON; ANTIVIRAL RESPONSE; ADAPTER PROTEIN AB The I kappa B Kinase (IKK)-related kinases TBK1 and IKK epsilon have essential roles as regulators of innate immunity by modulating interferon and NF-kappa B signaling. Recent work has also implicated these non-canonical IKKs in malignant transformation. IKK epsilon is amplified in similar to 30% of breast cancers and transforms cells through the activation of NF-kappa B. TBK1 participates in RalB-mediated inflammatory responses and cell survival, and is essential for the survival of non-small cell lung cancers driven by oncogenic KRAS. The delineation of target substrates and downstream activities for TBK1 and IKK epsilon has begun to define their role(s) in promoting tumorigenesis. In this review, we will highlight the mechanisms by which IKKe and TBK1 orchestrate pathways involved in inflammation and cancer. Oncogene (2011) 30, 631-641; doi:10.1038/onc.2010.493; published online 1 November 2010 C1 [Shen, R. R.; Hahn, W. C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hahn, W. C.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 1538, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu FU US NIH [R01 CA130988] FX We thank the members of the Hahn laboratory for advice. This work was supported in part by the US NIH (R01 CA130988). NR 112 TC 59 Z9 61 U1 5 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2011 VL 30 IS 6 BP 631 EP 641 DI 10.1038/onc.2010.493 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 719GY UT WOS:000287192000001 PM 21042276 ER PT J AU Gossec, L Paternotte, S Maillefert, JF Combescure, C Conaghan, PG Davis, AM Gunther, KP Hawker, G Hochberg, M Katz, JN Kloppenburg, M Lim, K Lohmander, LS Mahomed, NN March, L Pavelka, K Punzi, L Roos, EM Sanchez-Riera, L Singh, JA Suarez-Almazor, ME Dougados, M AF Gossec, L. Paternotte, S. Maillefert, J. F. Combescure, C. Conaghan, P. G. Davis, A. M. Gunther, K. -P. Hawker, G. Hochberg, M. Katz, J. N. Kloppenburg, M. Lim, K. Lohmander, L. S. Mahomed, N. N. March, L. Pavelka, K. Punzi, L. Roos, E. M. Sanchez-Riera, L. Singh, J. A. Suarez-Almazor, M. E. Dougados, M. CA OARSI-OMERACT Task Force Total Art TI The role of pain and functional impairment in the decision to recommend total joint replacement in hip and knee osteoarthritis: an international cross-sectional study of 1909 patients. Report of the OARSI-OMERACT Task Force on total joint replacement SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Knee; Hip; Osteoarthritis; Joint replacement; Surgery; Symptom ID RADIOGRAPHIC FEATURES; PHYSICAL-FUNCTION; OUTCOME MEASURE; ARTHROPLASTY; SEVERITY; SURGERY; TRIALS; PRIORITIZATION; ASSOCIATION; PREDICTORS AB Objective: To assess the pain and functional disability levels corresponding to an indication for total joint replacement (TJR) in hip and knee osteoarthritis (OA). Methods: Design: International cross-sectional study in 10 countries. Patients: Consecutive outpatients with definite hip or knee OA attending an orthopaedic outpatient clinic. Gold standard measure for recommendation for TJR: Surgeon's decision that TJR is justified. Outcome measures: Pain (ICOAP: intermittent and constant osteoarthritis pain, 0-100) and functional impairment (HOOS-PS/KOOS-PS: Hip/Knee injury and Osteoarthritis Outcome Score Physical function Short-form, 0-100). Analyses: Comparison of patients with vs without surgeons' indication for TJR. Receiver Operating Characteristic (ROC) curve analyses and logistic regression were applied to determine cut points of pain and disability defining recommendation for TJR. Results: In all, 1909 patients were included (1130 knee/779 hip OA). Mean age was 66.4 [standard deviation (SD) 10.9] years, 58.1% were women; 628/1130 (55.6%) knee OA and 574/779 (73.7%) hip OA patients were recommended for TJR. Although patients recommended for TJR (yes vs no) had worse symptom levels [pain, 55.5 (95% confidence interval 54.2, 56.8) vs. 44.9 (43.2, 46.6), and functional impairment, 59.8 (58.7, 60.9) vs. 50.9 (49.3, 52.4), respectively, both P < 0.0001]. there was substantial overlap in symptom levels between groups, even when adjusting for radiographic joint status. Thus, it was not possible to determine cut points for pain and function defining 'requirement for TJR'. Conclusion: Although symptom levels were higher in patients recommended for TJR, pain and functional disability alone did not discriminate between those who were and were not considered to need TJR by the orthopaedic surgeon. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Gossec, L.] Paris Descartes Univ, Hop Cochin, APHP, Fac Med,Rheumatol Dept B,Serv Rhumatol B, F-75014 Paris, France. [Maillefert, J. F.] Dijon Univ Hosp, Dept Rheumatol, F-21078 Dijon, France. [Maillefert, J. F.] Univ Burgundy, F-21079 Dijon, France. [Maillefert, J. F.] INSERM, U887, F-21079 Dijon, France. [Combescure, C.] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Conaghan, P. G.] Univ Leeds, Sect Musculoskeletal Dis, Leeds, W Yorkshire, England. [Conaghan, P. G.] NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Davis, A. M.] Toronto Western Res Inst, Div Hlth Care & Outcomes Res & Arthrit, Toronto, ON, Canada. [Davis, A. M.] Toronto Western Res Inst, Community Res & Evaluat Unit, Toronto, ON, Canada. [Davis, A. M.] Univ Toronto, Dept Rehabil Sci, Toronto, ON M5S 1A1, Canada. [Davis, A. M.] Univ Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON M5S 1A1, Canada. [Gunther, K. -P.] Univ Dresden, Dept Orthopaed Surg, Dresden, Germany. [Hawker, G.] Univ Toronto, Div Rheumatol, Dept Med, Womens Coll Hosp, Toronto, ON M5S 1A1, Canada. [Hawker, G.] Univ Toronto, Clin Epidemiol & Hlth Care Res Program, Dept Hlth Policy Management & Evaluat, Fac Med, Toronto, ON M5S 1A1, Canada. [Hochberg, M.] Univ Maryland, Sch Med, Dept Med, Div Rheumatol & Clin Immunol, Baltimore, MD 21201 USA. [Hochberg, M.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Div Gerontol, Baltimore, MD 21201 USA. [Katz, J. N.] Harvard Univ, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. [Katz, J. N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Katz, J. N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kloppenburg, M.] Leiden Univ Med Ctr, Dept Rheumatol, Leiden, Netherlands. [Kloppenburg, M.] Leiden Univ Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Lim, K.] St Vincents Hosp, Dept Rheumatol, Melbourne, Vic, Australia. [Lim, K.] Western Hosp, Melbourne, Vic, Australia. [Lohmander, L. S.] Lund Univ, Dept Orthopaed, Lund, Sweden. [Mahomed, N. N.] Univ Toronto, Toronto Western Hosp, Div Orthopaed Surg, Toronto, ON M5T 2S8, Canada. [March, L.] Univ Sydney, Royal N Shore Hosp, Inst Bone & Joint Res, St Leonards, NSW 2065, Australia. [Pavelka, K.] Charles Univ Prague, Inst Rheumatol, CR-11636 Prague 1, Czech Republic. [Punzi, L.] Univ Padua, Rheumatol Unit, Dept Clin & Expt Med, I-35100 Padua, Italy. [Roos, E. M.] Univ So Denmark, Inst Sports & Clin Biomech, Odense, Denmark. [Sanchez-Riera, L.] Univ Sydney, Inst Bone & Joint Res, Sydney, NSW 2006, Australia. [Singh, J. A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, J. A.] Univ Alabama Birmingham, Birmingham, AL USA. [Suarez-Almazor, M. E.] Univ Texas MD Anderson Canc Ctr, Rheumatol Sect, Houston, TX 77030 USA. RP Gossec, L (reprint author), Paris Descartes Univ, Hop Cochin, APHP, Fac Med,Rheumatol Dept B,Serv Rhumatol B, 27 Rue Faubourg St Jacques, F-75014 Paris, France. EM laure.gossec@cch.aphp.fr RI Roos, Ewa/A-5416-2012; Lohmander, Stefan/I-8326-2012; DOUGADOS, MAXIME/P-5287-2016; Pavelka, Karel/E-6578-2017; OI Roos, Ewa/0000-0001-5425-2199; Pavelka, Karel/0000-0003-1952-8422; PUNZI, LEONARDO/0000-0002-8853-516X; Lohmander, Stefan/0000-0002-5424-9448; singh, jasvinder/0000-0003-3485-0006 FU Servier; Allergan; Takeda; Savient; Wyeth; Amgen; URL pharmaceuticals FX Lyn March has received a speaker honorarium and travel grant from Servier.; JAS has received speaker honoraria from Abbott; research and travel grants from Allergan, Takeda, Savient, Wyeth and Amgen; and consultant fees from Savient and URL pharmaceuticals. NR 41 TC 64 Z9 65 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD FEB PY 2011 VL 19 IS 2 BP 147 EP 154 DI 10.1016/j.joca.2010.10.025 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 722YG UT WOS:000287470600002 PM 21044689 ER PT J AU Jain, S Siegle, GJ Gu, C Moore, CG Ivanco, LS Jennings, JR Steinhauer, SR Studenski, S Greenamyre, JT AF Jain, Samay Siegle, Greg J. Gu, Chen Moore, Charity G. Ivanco, Larry S. Jennings, J. Richard Steinhauer, Stuart R. Studenski, Stephanie Greenamyre, J. Timothy TI Autonomic insufficiency in pupillary and cardiovascular systems in Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Non-motor features; Parkinson's disease; Pupillography; Pupil; Cardiac physiology; Autonomic dysfunction ID HEART-RATE-VARIABILITY AB Background: In Parkinson's disease (PD), neurodegenerative changes have been observed in autonomic pathways involving multiple organ systems. We explore pupillary and cardiac autonomic measures as physiological manifestations of PD neurodegeneration. Methods: Pupil measures (pupillary unrest (spontaneous changes of pupil diameter in darkness), constriction velocity and redilation velocity) were assessed in 35 participants (17 PD, 18 controls). Simultaneous cardiac measures (respiratory sinus arrythmia during deep breathing, Valsalva ratio, resting heart rate variability (HRV), orthostatic change in blood pressure and orthostatic change in heart rate) were obtained. Nonparametric statistics were used to compare PD with control participants and to calculate correlation coefficients between pupillary and cardiac measures. Results: Pupillary unrest and orthostatic decreases in systolic blood pressure were greater in PD than controls. Respiratory sinus arrythmia during deep breathing and resting HRV were lower in PD. Among all participants, there was a negative correlation between HRV and redilation velocity and a positive correlation between orthostatic change in heart rate and pupillary unrest. A modifying effect of PD was found on the association between high frequency HRV and pupillary unrest. Conclusions: Results demonstrate simultaneous autonomic dysfunction in both pupillary and cardiac systems in PD. The correlations between pupillary and cardiac measures suggest shared central centers of autonomic integration, while the modifying effect of PD may reflect autonomic effects of PD-related pathology not present in controls. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Jain, Samay; Siegle, Greg J.; Gu, Chen; Moore, Charity G.; Ivanco, Larry S.; Jennings, J. Richard; Steinhauer, Stuart R.; Studenski, Stephanie; Greenamyre, J. Timothy] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Steinhauer, Stuart R.; Greenamyre, J. Timothy] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Jain, Samay; Greenamyre, J. Timothy] Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA. RP Jain, S (reprint author), Univ Pittsburgh, Med Ctr, Dept Neurol, 3471 5th Ave,Suite 811,Kaufmann Med Bldg, Pittsburgh, PA 15213 USA. EM jains@upmc.edu OI Moore, Charity/0000-0002-0060-0124; Greenamyre, J. Timothy/0000-0003-3468-7878 FU NIH [KL2 RR024154, KMH082998, MH55762, P30 AG-024826, UL1 RR024153]; Dept. of Veterans Affairs; American Parkinson's Disease Association Center for Advanced Research at the University of Pittsburgh FX NIH grants KL2 RR024154, KMH082998, MH55762, P30 AG-024826, UL1 RR024153, Dept. of Veterans Affairs, and the American Parkinson's Disease Association Center for Advanced Research at the University of Pittsburgh. NR 12 TC 15 Z9 16 U1 0 U2 1 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 FEB PY 2011 VL 17 IS 2 BP 119 EP 122 DI 10.1016/j.parkreldis.2010.11.005 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 736FB UT WOS:000288475000009 PM 21115264 ER PT J AU Trenor, CC Chung, RJ Michelson, AD Neufeld, EJ Gordon, CM Laufer, MR Emans, SJ AF Trenor, Cameron C., III Chung, Richard J. Michelson, Alan D. Neufeld, Ellis J. Gordon, Catherine M. Laufer, Marc R. Emans, S. Jean TI Hormonal Contraception and Thrombotic Risk: A Multidisciplinary Approach SO PEDIATRICS LA English DT Article DE contraception; thrombosis; thrombophilia; hormone ID DEEP-VEIN THROMBOSIS; ACTIVATED PROTEIN-C; NONFATAL VENOUS THROMBOEMBOLISM; COMBINED ORAL-CONTRACEPTIVES; V-LEIDEN MUTATION; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; PULMONARY-EMBOLISM; ETHINYL ESTRADIOL; MYOCARDIAL-INFARCTION AB Heightened publicity about hormonal contraception and thrombosis risk and the publication of new guidelines by the World Health Organization in 2009 and the Centers for Disease Control and Prevention in 2010 addressing this complex issue have led to multidisciplinary discussions on the special issues of adolescents cared for at our pediatric hospital. In this review of the literature and new guidelines, we have outlined our approach to the complex patients referred to our center. The relative risk of thrombosis on combined oral contraception is three-to fivefold, whereas the absolute risk for a healthy adolescent on this therapy is only 0.05% per year. This thrombotic risk is affected by estrogen dose, type of progestin, mechanism of delivery, and length of therapy. Oral progestin-only contraceptives and transdermal estradiol used for hormone replacement carry minimal or no thrombotic risk. Transdermal, vaginal, or intrauterine contraceptives and injectable progestins need further study. A personal history of thrombosis, persistent or inherited thrombophilia, and numerous lifestyle choices also influence thrombotic risk. In this summary of one hospital's approach to hormone therapies and thrombosis risk, we review relative-risk data and discuss the application of absolute risk to individual patient counseling. We outline our approach to challenging patients with a history of thrombosis, known thrombophilia, current anticoagulation, or family history of thrombosis or thrombophilia. Our multidisciplinary group has found that knowledge of the guidelines and individualized management plans have been particularly useful for informing discussions about hormonal and nonhormonal options across varied indications. Pediatrics 2011; 127:347-357 C1 [Trenor, Cameron C., III; Michelson, Alan D.; Neufeld, Ellis J.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [Chung, Richard J.; Gordon, Catherine M.; Laufer, Marc R.; Emans, S. Jean] Childrens Hosp Boston, Div Adolescent Young Adult Med, Boston, MA USA. [Gordon, Catherine M.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Laufer, Marc R.; Emans, S. Jean] Childrens Hosp Boston, Div Gynecol, Dept Med, Boston, MA USA. [Laufer, Marc R.; Emans, S. Jean] Childrens Hosp Boston, Dept Surg, Boston, MA USA. [Trenor, Cameron C., III; Michelson, Alan D.; Neufeld, Ellis J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Trenor, Cameron C., III; Michelson, Alan D.; Neufeld, Ellis J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Trenor, CC (reprint author), Childrens Hosp Boston, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM cameron.trenor@childrens.harvard.edu RI Neufeld, Ellis/F-9331-2011; OI Emans, S. Jean/0000-0002-4535-7850 FU National Institutes of Health (NIH); Health Resources and Services Administration/Maternal and Child Health Leadership Education in Adolescent [T71 MC00009]; National Institutes of Health/National Heart, Lung, and Blood Institute [K08 HL089509, K24 HL004184] FX Funded by the National Institutes of Health (NIH).; This work was supported by Health Resources and Services Administration/Maternal and Child Health Leadership Education in Adolescent Health Training grant T71 MC00009 (to Dr Emans, including funding of Dr Chung), National Institutes of Health/National Heart, Lung, and Blood Institute grant K08 HL089509 (to Dr Trenor), and National Institutes of Health/National Heart, Lung, and Blood Institute grant K24 HL004184 (to Dr Neufeld). NR 97 TC 24 Z9 25 U1 1 U2 11 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2011 VL 127 IS 2 BP 347 EP 357 DI 10.1542/peds.2010-2221 PG 11 WC Pediatrics SC Pediatrics GA 714JF UT WOS:000286805200053 PM 21199853 ER PT J AU Kentsis, A AF Kentsis, Alex TI Challenges and opportunities for discovery of disease biomarkers using urine proteomics SO PEDIATRICS INTERNATIONAL LA English DT Article DE biological marker; individualized medicine; mass spectrometry; proteomics; urine ID MASS-SPECTROMETRY; QUANTITATIVE PROTEOMICS; PROTEIN IDENTIFICATIONS; ORTHOSTATIC PROTEINURIA; DIABETIC-NEPHROPATHY; UROTHELIAL CANCER; TECHNOLOGY; VALIDATION; EXCLUSION; STRATEGY AB Modern medicine has experienced a tremendous explosion in knowledge about disease pathophysiology, gained largely from understanding the molecular biology of human disease. Recent advances in mass spectrometry and proteomics now allow for simultaneous identification and quantification of thousands of unique proteins and peptides in complex biological tissues and fluids. In particular, proteomic studies of urine benefit from urine's less complex composition as compared to serum and tissues, and have been used successfully to discover novel markers of a variety of infectious, autoimmune, oncological, and surgical conditions. This perspective discusses the challenges of such studies that stem from the compositional variability and complexity of human urine, as well as instrumental sampling limitations and the effects of noise and selection bias. Strategies for the design of observational clinical trials, physical and chemical fractionation of urine specimens, mass spectrometry analysis, and functional data annotation are outlined. Rigorous translational investigations using urine proteomics are likely to discover novel and accurate markers of both rare and common diseases. This should aid the diagnosis, improve stratification of therapy, and identify novel therapeutic targets for a variety of childhood and adult diseases, all of which will be essential for the development of personalized and predictive medicine of the future. C1 [Kentsis, Alex] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kentsis, Alex] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Kentsis, A (reprint author), 44 Binney St, Boston, MA 02115 USA. EM alex.kentsis@childrens.harvard.edu OI Kentsis, Alex/0000-0002-8063-9191 FU NCI NIH HHS [K08 CA160660] NR 54 TC 15 Z9 16 U1 0 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1328-8067 J9 PEDIATR INT JI Pediatr. Int. PD FEB PY 2011 VL 53 IS 1 BP 1 EP 6 DI 10.1111/j.1442-200X.2010.03253.x PG 6 WC Pediatrics SC Pediatrics GA 725RF UT WOS:000287662900001 PM 20840485 ER PT J AU Foo, J Leder, K Michor, F AF Foo, Jasmine Leder, Kevin Michor, Franziska TI Stochastic dynamics of cancer initiation SO PHYSICAL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENES; PROGRAMMED CELL-DEATH; STEM-CELLS; POPULATION-GENETICS; COLORECTAL-CANCER; WAITING TIME; HUMAN COLON; MULTISTAGE CARCINOGENESIS; DNA METHYLATION; MUTATION AB Most human cancer types result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Once the first change (or changes) have arisen, tumorigenesis is initiated and the subsequent emergence of additional alterations drives progression to more aggressive and ultimately invasive phenotypes. Elucidation of the dynamics of cancer initiation is of importance for an understanding of tumor evolution and cancer incidence data. In this paper, we develop a novel mathematical framework to study the processes of cancer initiation. Cells at risk of accumulating oncogenic mutations are organized into small compartments of cells and proliferate according to a stochastic process. During each cell division, an (epi)genetic alteration may arise which leads to a random fitness change, drawn from a probability distribution. Cancer is initiated when a cell gains a fitness sufficiently high to escape from the homeostatic mechanisms of the cell compartment. To investigate cancer initiation during a human lifetime, a 'race' between this fitness process and the aging process of the patient is considered; the latter is modeled as a second stochastic Markov process in an aging dimension. This model allows us to investigate the dynamics of cancer initiation and its dependence on the mutational fitness distribution. Our framework also provides a methodology to assess the effects of different life expectancy distributions on lifetime cancer incidence. We apply this methodology to colorectal tumorigenesis while considering life expectancy data of the US population to inform the dynamics of the aging process. We study how the probability of cancer initiation prior to death, the time until cancer initiation, and the mutational profile of the cancer-initiating cell depends on the shape of the mutational fitness distribution and life expectancy of the population. C1 [Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu FU NCI [U54CA143798] FX This work is supported by NCI grant U54CA143798 to establish the Dana-Farber Cancer Institute Physical Sciences Oncology Center (http://psoc.dfci.harvard.edu). NR 68 TC 15 Z9 15 U1 1 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1478-3967 J9 PHYS BIOL JI Phys. Biol. PD FEB PY 2011 VL 8 IS 1 AR 015002 DI 10.1088/1478-3975/8/1/015002 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717LE UT WOS:000287044600005 PM 21301064 ER PT J AU Capoccia, BJ Lennerz, JKM Bredemeyer, AJ Klco, JM Frater, JL Mills, JC AF Capoccia, Benjamin J. Lennerz, Jochen K. M. Bredemeyer, Andrew J. Klco, Jeffery M. Frater, John L. Mills, Jason C. TI Transcription factor MIST1 in terminal differentiation of mouse and human plasma cells SO PHYSIOLOGICAL GENOMICS LA English DT Article DE plasma cell neoplasm ID UNFOLDED PROTEIN RESPONSE; ROUGH ENDOPLASMIC-RETICULUM; SEROUS EXOCRINE CELLS; GENE-EXPRESSION; FACTOR XBP-1; BONE-MARROW; MULTIPLE-MYELOMA; ZYMOGENIC CELLS; STRESS-RESPONSE; B-LYMPHOCYTES AB Capoccia BJ, Lennerz JK, Bredemeyer AJ, Klco JM, Frater JL, Mills JC. Transcription factor MIST1 in terminal differentiation of mouse and human plasma cells. Physiol Genomics 43: 174-186, 2011. First published November 23, 2010; doi:10.1152/physiolgenomics.00084.2010.-Despite their divergent developmental ancestry, plasma cells and gastric zymogenic (chief) cells share a common function: high-capacity secretion of protein. Here we show that both cell lineages share increased expression of a cassette of 269 genes, most of which regulate endoplasmic reticulum (ER) and Golgi function, and they both induce expression of the transcription factors X-box binding protein 1 (Xbp1) and Mist1 during terminal differentiation. XBP1 is known to augment plasma cell function by establishing rough ER, and MIST1 regulates secretory vesicle trafficking in zymogenic cells. We examined morphology and function of plasma cells in wild-type and Mist1(-/-) mice and found subtle differences in ER structure but no overall defect in plasma cell function, suggesting that Mist1 may function redundantly in plasma cells. We next reasoned that MIST1 might be useful as a novel and reliable marker of plasma cells. We found that MIST1 specifically labeled normal plasma cells in mouse and human tissues, and, moreover, its expression was also characteristic of plasma cell differentiation in a cohort of 12 human plasma cell neoplasms. Overall, our results show that MIST1 is enriched upon plasma cell differentiation as a part of a genetic program facilitating secretory cell function and also that MIST1 is a novel marker of normal and neoplastic plasma cells in mouse and human tissues. C1 [Capoccia, Benjamin J.; Bredemeyer, Andrew J.; Klco, Jeffery M.; Frater, John L.; Mills, Jason C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Mills, Jason C.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Lennerz, Jochen K. M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Mills, JC (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, Box 8118,660 So Euclid Ave, St Louis, MO 63110 USA. EM jmills@pathology.wustl.edu RI di Ronza, Alberto/H-7674-2016; OI di Ronza, Alberto/0000-0002-9813-5143; Klco, Jeffery/0000-0003-2961-6960 FU National Institutes of Health [RO1 DK-079798-01, T32 CA-009547-23] FX Further support came from National Institutes of Health Grants RO1 DK-079798-01 (J. C. Mills) and T32 CA-009547-23 (B. J. Capoccia, A. J. Bredemeyer). NR 58 TC 11 Z9 11 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD FEB PY 2011 VL 43 IS 3 BP 174 EP 186 DI 10.1152/physiolgenomics.00084.2010 PG 13 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 720TB UT WOS:000287303200009 PM 21098683 ER PT J AU Aoki, H Hara, A Motohashi, T Osawa, M Kunisada, T AF Aoki, Hitomi Hara, Akira Motohashi, Tsutomu Osawa, Masatake Kunisada, Takahiro TI Functionally distinct melanocyte populations revealed by reconstitution of hair follicles in mice SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE melanocytes; hair reconstitution assay; cell lineage; kit; Endothelin3 ID CELLS IN-VITRO; STEM-CELLS; EPIDERMAL MELANOCYTES; FLUORESCENT PROTEIN; DISSOCIATED CELLS; MOUSE; DIFFERENTIATION; PIGMENTATION; EXPRESSION; MIGRATION AB P>Hair follicle reconstitution analysis was used to test the contribution of melanocytes or their precursors to regenerated hair follicles. In this study, we first confirmed the process of chimeric hair follicle regeneration by both hair keratinocytes and follicular melanocytes. Then, as first suggested from the differential growth requirements of epidermal skin melanocytes and non-cutaneous or dermal melanocytes, we confirmed the inability of the latter to be involved as follicular melanocytes to regenerate hair follicles during the hair reconstitution assay. This clear functional discrimination between non-cutaneous or dermal melanocytes and epidermal melanocytes suggests the presence of two different melanocyte cell lineages, a finding that might be important in the pathogenesis of melanocyte-related diseases and melanomas. C1 [Aoki, Hitomi; Motohashi, Tsutomu; Kunisada, Takahiro] Gifu Univ, Dept Tissue & Organ Dev Regenerat & Adv Med Sci, Grad Sch Med, Gifu, Japan. [Hara, Akira] Gifu Univ, Dept Tumor Pathol Regenerat & Adv Med Sci, Grad Sch Med, Gifu, Japan. [Osawa, Masatake] Harvard Univ, Dept Dermatol, Cutaneous Biol Res Ctr, Sch Med,Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Kunisada, T (reprint author), Gifu Univ, Dept Tissue & Organ Dev Regenerat & Adv Med Sci, Grad Sch Med, Gifu, Japan. EM tkunisad@gifu-u.ac.jp OI Kunisada, Takahiro/0000-0003-1651-2716 FU Japan Society for the Promotion of Science and Research; Japan Society for the Promotion of Science for Young Scientists; Ministry of Education, Science, Sports, and Culture of Japan FX We thank Dr. Jiro Kishimoto and Ritsuro Ideta for teaching the techniques of the hair reconstitution assay, Kyoko Takahashi for her excellent technical assistance, and Drs Tomohisa Hirobe and Hisahiro Yoshida for their thoughtful advice. We also thank Dr. J. Miyazaki for CAG-CAT-GFP mice, Dr. I. Jackson for Dct-lacZ mice, Dr. M. Okabe for CAG-EGFP mice, and Dr. F. Beermann for Dcttm1(Cre)Bee mice. This work was supported by grants from the Japan Society for the Promotion of Science and Research, a Fellowship from the Japan Society for the Promotion of Science for Young Scientists (H. A.), and a grant from the Ministry of Education, Science, Sports, and Culture of Japan. NR 44 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD FEB PY 2011 VL 24 IS 1 BP 125 EP 135 DI 10.1111/j.1755-148X.2010.00801.x PG 11 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 706IA UT WOS:000286210400021 PM 21054816 ER PT J AU Lettre, G Palmer, CD Young, T Ejebe, KG Allayee, H Benjamin, EJ Bennett, F Bowden, DW Chakravarti, A Dreisbach, A Farlow, DN Folsom, AR Fornage, M Forrester, T Fox, E Haiman, CA Hartiala, J Harris, TB Hazen, SL Heckbert, SR Henderson, BE Hirschhorn, JN Keating, BJ Kritchevsky, SB Larkin, E Li, M Rudock, ME McKenzie, CA Meigs, JB Meng, YA Mosley, TH Newman, AB Newton-Cheh, CH Paltoo, DN Papanicolaou, GJ Patterson, N Post, WS Psaty, BM Qasim, AN Qu, L Rader, DJ Redline, S Reilly, MP Reiner, AP Rich, SS Rotter, JI Liu, Y Shrader, P Siscovick, DS Tang, WHW Taylor, HA Tracy, RP Vasan, RS Waters, KM Wilks, R Wilson, JG Fabsitz, RR Gabriel, SB Kathiresan, S Boerwinkle, E AF Lettre, Guillaume Palmer, Cameron D. Young, Taylor Ejebe, Kenechi G. Allayee, Hooman Benjamin, Emelia J. Bennett, Franklyn Bowden, Donald W. Chakravarti, Aravinda Dreisbach, Al Farlow, Deborah N. Folsom, Aaron R. Fornage, Myriam Forrester, Terrence Fox, Ervin Haiman, Christopher A. Hartiala, Jaana Harris, Tamara B. Hazen, Stanley L. Heckbert, Susan R. Henderson, Brian E. Hirschhorn, Joel N. Keating, Brendan J. Kritchevsky, Stephen B. Larkin, Emma Li, Mingyao Rudock, Megan E. McKenzie, Colin A. Meigs, James B. Meng, Yang A. Mosley, Tom H., Jr. Newman, Anne B. Newton-Cheh, Christopher H. Paltoo, Dina N. Papanicolaou, George J. Patterson, Nick Post, Wendy S. Psaty, Bruce M. Qasim, Atif N. Qu, Liming Rader, Daniel J. Redline, Susan Reilly, Muredach P. Reiner, Alexander P. Rich, Stephen S. Rotter, Jerome I. Liu, Yongmei Shrader, Peter Siscovick, David S. Tang, W. H. Wilson Taylor, Herman A., Jr. Tracy, Russell P. Vasan, Ramachandran S. Waters, Kevin M. Wilks, Rainford Wilson, James G. Fabsitz, Richard R. Gabriel, Stacey B. Kathiresan, Sekar Boerwinkle, Eric TI Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project SO PLOS GENETICS LA English DT Article ID ARTERY-DISEASE; MYOCARDIAL-INFARCTION; LOCI; VARIANTS; METAANALYSIS; TRAITS AB Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture-and SNP-association to maximize power for genetic discovery in even larger African-American consortia. C1 [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Palmer, Cameron D.; Young, Taylor; Ejebe, Kenechi G.; Farlow, Deborah N.; Hirschhorn, Joel N.; Meng, Yang A.; Newton-Cheh, Christopher H.; Patterson, Nick; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Allayee, Hooman; Haiman, Christopher A.; Hartiala, Jaana; Henderson, Brian E.; Waters, Kevin M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Epidemiol, Boston, MA 02118 USA. [Benjamin, Emelia J.; Newton-Cheh, Christopher H.; Vasan, Ramachandran S.; Kathiresan, Sekar] NHLBI, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.; Newton-Cheh, Christopher H.; Vasan, Ramachandran S.; Kathiresan, Sekar] Boston Univ, Framingham, MA USA. [Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Dreisbach, Al; Fox, Ervin; Mosley, Tom H., Jr.; Taylor, Herman A., Jr.; Wilson, James G.] Univ Mississipi, Med Ctr, Dept Med, Jackson, MS USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Sch Publ Hlth, Houston, TX USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hazen, Stanley L.; Tang, W. H. Wilson] Cleveland Clin, Dept Cell Biol, Cleveland, OH 44106 USA. [Hazen, Stanley L.; Tang, W. H. Wilson] Cleveland Clin, Dept Cardiovasc Med, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44106 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA USA. [Heckbert, Susan R.; Psaty, Bruce M.; Reiner, Alexander P.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Hirschhorn, Joel N.; Meigs, James B.; Newton-Cheh, Christopher H.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Div Gerontol & Geriatr Med, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Larkin, Emma] Case Western Reserve Univ, Ctr Clin Investigat, Cleveland, OH 44106 USA. [Qasim, Atif N.; Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rudock, Megan E.; Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Kingston 7, Jamaica. [Meigs, James B.; Shrader, Peter] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher H.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Paltoo, Dina N.; Papanicolaou, George J.; Fabsitz, Richard R.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Post, Wendy S.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS USA. [Taylor, Herman A., Jr.] Tougaloo Coll, Tougaloo, MS USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Colchester, VT USA. [Wilks, Rainford] Univ W Indies, Res Inst Trop Med, Epidemiol Res Unit, Kingston 7, Jamaica. [Wilson, James G.] GV Sonny Montgomery Vet Affairs Med Ctr, Jackson, MS USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. RP Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. EM Eric.Boerwinkle@uth.tmc.edu RI Tang, Wai Hong/I-1238-2013; Newman, Anne/C-6408-2013; Ejebe, Kenechi/I-9238-2016; OI Newman, Anne/0000-0002-0106-1150; Ejebe, Kenechi/0000-0002-6090-8657; Ramachandran, Vasan/0000-0001-7357-5970; Kritchevsky, Stephen/0000-0003-3336-6781; Benjamin, Emelia/0000-0003-4076-2336 FU ADB [HHSN268200625226C, N01-HC-65226]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, 1P01HL098055-01, P01HL087018, P01HL076491, R01DK080732, R01HL103931-01]; NIH, National Institute on Aging; National Center for Research Resources [C06, RR10600-01, CA62528-01, RR14514-01] FX The grants and contracts that have supported CARe are listed at http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx, including HHSN268200625226C (ADB No. N01-HC-65226). Additional support for this work was provided by: the Fondation de l'Institut de Cardiologie de Montreal and the Centre of Excellence in Personalized Medicine (CEPMed) (to GL), NIDDK K24 DK080140 (to JBM). The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The Health ABC 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. The Health ABC research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The Cleveland Clinic GeneBank study was supported through NIH grants 1P01HL098055-01, P01HL087018, P01HL076491, R01DK080732, and R01HL103931-01. A portion of analyses for the Cleveland Clinic GeneBank was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 135 Z9 140 U1 1 U2 16 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 FEB PY 2011 VL 7 IS 2 AR e1001300 DI 10.1371/journal.pgen.1001300 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300015 PM 21347282 ER PT J AU Smith, JG Magnani, JW Palmer, C Meng, YA Soliman, EZ Musani, SK Kerr, KF Schnabel, RB Lubitz, SA Sotoodehnia, N Redline, S Pfeufer, A Muller, M Evans, DS Nalls, MA Liu, YM Newman, AB Zonderman, AB Evans, MK Deo, R Ellinor, PT Paltoo, DN Newton-Cheh, C Benjamin, EJ Mehra, R Alonso, A Heckbert, SR Fox, ER AF Smith, J. Gustav Magnani, Jared W. Palmer, Cameron Meng, Yan A. Soliman, Elsayed Z. Musani, Solomon K. Kerr, Kathleen F. Schnabel, Renate B. Lubitz, Steven A. Sotoodehnia, Nona Redline, Susan Pfeufer, Arne Mueller, Martina Evans, Daniel S. Nalls, Michael A. Liu, Yongmei Newman, Anne B. Zonderman, Alan B. Evans, Michele K. Deo, Rajat Ellinor, Patrick T. Paltoo, Dina N. Newton-Cheh, Christopher Benjamin, Emelia J. Mehra, Reena Alonso, Alvaro Heckbert, Susan R. Fox, Ervin R. CA CARe Consortium TI Genome-Wide Association Studies of the PR Interval in African Americans SO PLOS GENETICS LA English DT Article ID HEART-RATE; ATHEROSCLEROSIS RISK; GENETIC-ANALYSIS; COMMON VARIANTS; DESIGN; POPULATIONS; OBJECTIVES; CONDUCTION; DISEASE; TWINS AB The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p < 2.5 > 10(-8)) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta = 5.1 msec per minor allele, 95% CI = 4.1-6.1, p = 3 x 10(-23)). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8-3.0, p = 3 x 10(-16)) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity < 0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans. C1 [Smith, J. Gustav] Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. [Smith, J. Gustav; Palmer, Cameron; Meng, Yan A.; Newton-Cheh, Christopher] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Smith, J. Gustav; Palmer, Cameron; Meng, Yan A.; Newton-Cheh, Christopher] MIT, Cambridge, MA 02139 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Cardiovasc Sect, Boston, MA 02118 USA. [Magnani, Jared W.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Soliman, Elsayed Z.] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Ctr EPICARE, Winston Salem, NC 27109 USA. [Musani, Solomon K.; Fox, Ervin R.] Univ Mississippi, Med Ctr, Jackson Heart Study, Dept Med,Div Cardiovasc Dis, Jackson, MS 39216 USA. [Kerr, Kathleen F.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Med Clin Cardiol 2, Mainz, Germany. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.; Newton-Cheh, Christopher] Harvard Univ, Sch Med, Boston, MA USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Pfeufer, Arne] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne] Helmholtz Cent Munchen, Inst Human Genet, Neuherberg, Germany. [Mueller, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller, Martina] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [Mueller, Martina] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Evans, Daniel S.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Zonderman, Alan B.; Evans, Michele K.] NIA, NIH, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Paltoo, Dina N.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [Mehra, Reena] Case Sch Med, Dept Med, Cleveland, OH USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Smith, JG (reprint author), Lund Univ, Fac Med, Dept Cardiol, Lund, Sweden. EM gustav.smith@med.lu.se RI Kerr, Kathleen/A-2893-2013; Pfeufer, Arne/B-6634-2013; Alonso, Alvaro/A-4917-2010; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Soliman, Elsayed/D-8124-2011 OI Alonso, Alvaro/0000-0002-2225-8323; Newman, Anne/0000-0002-0106-1150; Mehra, Reena/0000-0002-6222-2675; Benjamin, Emelia/0000-0003-4076-2336; Zonderman, Alan B/0000-0002-6523-4778; Soliman, Elsayed/0000-0001-5632-8150 FU National Heart, Lung, and Blood Institute [N01-HC-55015, 268200900055C-0-0-1]; Baylor Medical College [N01-HC-55016]; University of Mississippi Medical Center [N01-HC-55021]; University of Minnesota [N01-HC-55019, N01-HC-95163]; Johns Hopkins University [N01-HC-55020, N01-HC-95162, N01-HC-95168]; University of Texas, Houston [N01-HC-55022]; University of North Carolina, Forsyth County [N01-HC-55018]; Cleveland Family Study (CFS): Case Western Reserve University (NIH) [HL 46380, M01RR00080]; 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]; Northwestern University [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 [R01-HL-071205]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, T32HL007575, 1K23HL080025, 1R01HL098283, 1R01HL092577, 1R01HL102214, 1R01 AG028321, K23 HL079114, 1RC1HL099452, 1RC1HL101056]; NIH, National Institute on Aging; National Center for Minority Health and Health Disparities; NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; Swedish Heart Lung Foundation; American Heart Association [09FTF2190028, 0530188N, 09SDG2280087]; NHLBI [268200900055C-0-0-1]; German National Genome Research Network [NGFN 01GR0803]; German Federal Ministry of Research BMBF [01EZ0874]; National Center for Research Resources [KL2RR024132]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund; Central Society of Clinical Research Award; NCI [1U54CA116867]; [1R21DA027021] FX The following four 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 database for wide dissemination to the biomedical research community. Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts to the 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); Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080); 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 University (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). The Health, Aging, and Body Composition Study (Health ABC) 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. The Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) study was in part supported by the intramural research program of the National Institute on Aging and the National Center for Minority Health and Health Disparities, National Institutes of Health. 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 (contract # 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). JGS was supported by the Swedish Heart Lung Foundation. JWM was supported by American Heart Association grant 09FTF2190028. KFK was supported by NHLBI contract 268200900055C-0-0-1. SAL was supported by NIH T32HL007575. AP was supported by the German National Genome Research Network grants NGFN 01GR0803 and the German Federal Ministry of Research BMBF 01EZ0874. RD was supported by Grant Number KL2RR024132 from the National Center for Research Resources. PTE was supported by 1R01HL092577, 1R21DA027021.; CN-C was supported by NIH 1K23HL080025, 1R01HL098283, Doris Duke Charitable Foundation Clinical Scientist Development Award, and Burrougs Wellcome Fund Career Award for Medical Scientists. EJB was supported by NIH awards 1R01HL092577, 1R01HL092577, 1R01HL102214, 1R01 AG028321. RM was supported by NIH K23 HL079114, American Heart Association National Scientist Development Award 0530188N, Central Society of Clinical Research Award, and NCI 1U54CA116867. AA was supported by NIH awards 1RC1HL099452 and 1RC1HL101056 and American Heart Association grant 09SDG2280087. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 50 Z9 51 U1 1 U2 9 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 FEB PY 2011 VL 7 IS 2 AR e1001304 DI 10.1371/journal.pgen.1001304 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300019 PM 21347284 ER PT J AU Wijsman, EM Pankratz, ND Choi, Y Rothstein, JH Faber, KM Cheng, R Lee, JH Bird, TD Bennett, DA Diaz-Arrastia, R Goate, AM Farlow, M Ghetti, B Sweet, RA Foroud, TM Mayeux, R AF Wijsman, Ellen M. Pankratz, Nathan D. Choi, Yoonha Rothstein, Joseph H. Faber, Kelley M. Cheng, Rong Lee, Joseph H. Bird, Thomas D. Bennett, David A. Diaz-Arrastia, Ramon Goate, Alison M. Farlow, Martin Ghetti, Bernardino Sweet, Robert A. Foroud, Tatiana M. Mayeux, Richard CA NIA-LOAD NCRAD Family Study Grp TI Genome-Wide Association of Familial Late-Onset Alzheimer's Disease Replicates BIN1 and CLU and Nominates CUGBP2 in Interaction with APOE SO PLOS GENETICS LA English DT Article ID AGE-AT-ONSET; HARDY-WEINBERG EQUILIBRIUM; APOLIPOPROTEIN-E GENOTYPE; ALLELE-SPECIFIC PCR; LINKAGE DISEQUILIBRIUM; CARIBBEAN HISPANICS; VASCULAR DEMENTIA; GENE; LOCI; RISK AB Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e. g., rs2075650, p = 3.2 x 10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE epsilon 4 homozygotes (e.g., rs201119, p = 1.5 x 10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. C1 [Wijsman, Ellen M.; Rothstein, Joseph H.; Bird, Thomas D.] Univ Washington, Div Med Genet, Seattle, WA 98195 USA. [Wijsman, Ellen M.; Choi, Yoonha] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Pankratz, Nathan D.; Faber, Kelley M.; Foroud, Tatiana M.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Cheng, Rong; Lee, Joseph H.; Mayeux, Richard] Columbia Univ, Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, Gertrude H Sergievsky Ctr, New York, NY USA. [Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Bennett, David A.] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA. [Diaz-Arrastia, Ramon] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Goate, Alison M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Farlow, Martin] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA. [Ghetti, Bernardino] Indiana Univ Sch Med, Div Neuropathol, Dept Pathol, Indianapolis, IN USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Wijsman, EM (reprint author), Univ Washington, Div Med Genet, Seattle, WA 98195 USA. EM wijsman@u.washington.edu RI Lee, Joseph/D-2441-2012; OI Lee, Joseph/0000-0002-2000-4821; Wijsman, Ellen/0000-0002-2725-6669 FU National Institute of Aging [U24AG026395]; National Cell Repository for Alzheimer's Disease [U24AG021886]; University of Pittsburgh [R01AG027224, P50AG005133]; Rush University Medical Center [P30AG10161]; Boston University [P30AG013846]; Columbia University [P50AG08702, P01AG07232, R37AG015473]; Duke University [P30AG028377, P50AG05128]; Indiana University [P30AG010133]; Massachusetts General Hospital [P50AG05134]; Mayo Clinic, Rochester, and Mayo Clinic, Jacksonville [P50AG165574]; Mount Sinai School of Medicine [P01AG05138, P01AG02219, P50AG05138]; Northwestern University Medical School [P30AG13854]; Oregon Health and Science University [P30AG008017]; University of Alabama at Birmingham [P50AG016582]; David Geffen School of Medicine, University of California Los Angeles [P50AG016579]; University of Kentucky, Lexington [P30AG028383]; University of Pennsylvania [P30AG10124]; University of Southern California [P50AG05142]; University of Texas Southwestern Medical Center [P30AG12300]; University of Washington [P50AG05136]; Washington University School of Medicine [P50AG05681, P01AG03991]; National Institutes of Health [HHSN268200782096C] FX This study was supported by the following federal grants from the National Institute of Aging: U24AG026395 (NIA-LOAD Family Study); U24AG021886 (National Cell Repository for Alzheimer's Disease); R01AG027224 and P50AG005133 University of Pittsburgh; P30AG10161 Rush University Medical Center; P30AG013846 Boston University; P50AG08702, P01AG07232, and R37AG015473 Columbia University; P30AG028377 and P50AG05128 Duke University; P30AG010133 Indiana University; P50AG05134 Massachusetts General Hospital; P50AG165574 Mayo Clinic, Rochester, and Mayo Clinic, Jacksonville; P01AG05138, P01AG02219, and P50AG05138 Mount Sinai School of Medicine; P30AG13854 Northwestern University Medical School; P30AG008017 Oregon Health and Science University; P50AG016582 University of Alabama at Birmingham; P50AG016579 David Geffen School of Medicine, University of California Los Angeles; P30AG028383 University of Kentucky, Lexington; P30AG10124 University of Pennsylvania; P50AG05142 University of Southern California; P30AG12300 The University of Texas Southwestern Medical Center; P50AG05136 University of Washington; and P50AG05681 and P01AG03991 Washington University School of Medicine. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, but did review the manuscript prior to submission. NR 101 TC 110 Z9 113 U1 3 U2 21 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 FEB PY 2011 VL 7 IS 2 AR e1001308 DI 10.1371/journal.pgen.1001308 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300023 PM 21379329 ER PT J AU Zhernakova, A Stahl, EA Trynka, G Raychaudhuri, S Festen, EA Franke, L Westra, HJ Fehrmann, RSN Kurreeman, FAS Thomson, B Gupta, N Romanos, J McManus, R Ryan, AW Turner, G Brouwer, E Posthumus, MD Remmers, EF Tucci, F Toes, R Grandone, E Mazzilli, MC Rybak, A Cukrowska, B Coenen, MJH Radstake, TRDJ van Riel, PLCM Li, YH de Bakker, PIW Gregersen, PK Worthington, J Siminovitch, KA Klareskog, L Huizinga, TWJ Wijmenga, C Plenge, RM AF Zhernakova, Alexandra Stahl, Eli A. Trynka, Gosia Raychaudhuri, Soumya Festen, Eleanora A. Franke, Lude Westra, Harm-Jan Fehrmann, Rudolf S. N. Kurreeman, Fina A. S. Thomson, Brian Gupta, Namrata Romanos, Jihane McManus, Ross Ryan, Anthony W. Turner, Graham Brouwer, Elisabeth Posthumus, Marcel D. Remmers, Elaine F. Tucci, Francesca Toes, Rene Grandone, Elvira Mazzilli, Maria Cristina Rybak, Anna Cukrowska, Bozena Coenen, Marieke J. H. Radstake, Timothy R. D. J. van Riel, Piet L. C. M. Li, Yonghong de Bakker, Paul I. W. Gregersen, Peter K. Worthington, Jane Siminovitch, Katherine A. Klareskog, Lars Huizinga, Tom W. J. Wijmenga, Cisca Plenge, Robert M. TI Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci SO PLOS GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SUSCEPTIBILITY LOCI; RISK LOCUS; TYROSINE-PHOSPHATASE; AUTOIMMUNE-DISEASES; GENETIC-VARIANTS; CROHNS-DISEASE; COMMON; ACTIVATION; EXPRESSION AB Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P < 5 x 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 x 10(-12)), rs864537 near CD247 (P(combined) = 2.2 x 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 x 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 x 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 x 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases. C1 [Zhernakova, Alexandra; Kurreeman, Fina A. S.; Toes, Rene; Huizinga, Tom W. J.] Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. [Zhernakova, Alexandra] Univ Med Ctr Utrecht, Complex Genet Sect, Dept Med Genet, Utrecht, Netherlands. [Zhernakova, Alexandra; Stahl, Eli A.; Raychaudhuri, Soumya; Kurreeman, Fina A. S.; de Bakker, Paul I. W.; Plenge, Robert M.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Stahl, Eli A.; Raychaudhuri, Soumya; Kurreeman, Fina A. S.; Thomson, Brian; Gupta, Namrata; de Bakker, Paul I. W.; Plenge, Robert M.] Broad Inst, Cambridge, MA USA. [Trynka, Gosia; Festen, Eleanora A.; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S. N.; Romanos, Jihane; Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Trynka, Gosia; Festen, Eleanora A.; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S. N.; Romanos, Jihane; Brouwer, Elisabeth; Posthumus, Marcel D.; Wijmenga, Cisca] Univ Groningen, Groningen, Netherlands. [Raychaudhuri, Soumya] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Raychaudhuri, Soumya; Plenge, Robert M.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Franke, Lude] Queen Mary Univ London, Blizard Inst Cell & Mol Sci, Barts & London Sch Med & Dent, London, England. [McManus, Ross; Ryan, Anthony W.; Turner, Graham] St James Hosp, Trinity Coll, Dept Clin Med, Trinity Ctr Hlth Sci, Dublin, Ireland. [McManus, Ross; Ryan, Anthony W.; Turner, Graham] St James Hosp, Trinity Coll, Inst Mol Med, Trinity Ctr Hlth Sci, Dublin, Ireland. [Brouwer, Elisabeth; Posthumus, Marcel D.] Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 AV Groningen, Netherlands. [Remmers, Elaine F.] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. [Tucci, Francesca] Univ Naples Federico 2, European Lab Food Induced Dis, Naples, Italy. [Grandone, Elvira] IRCCS Casa Sollievo Sofferenza, Unita Aterosclerosi & Trombosi, Foggia, Italy. [Mazzilli, Maria Cristina] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. [Rybak, Anna] Childrens Mem Hlth Inst, Dept Gastroenterol Hepatol & Immunol, Warsaw, Poland. [Cukrowska, Bozena] Childrens Mem Hlth Inst, Dept Pathol, Warsaw, Poland. [Coenen, Marieke J. H.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Radstake, Timothy R. D. J.; van Riel, Piet L. C. M.] Radboud Univ Nijmegen, Dept Rheumatol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Li, Yonghong] Celera, Alameda, CA USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Dept Med,Med Sch, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Gregersen, Peter K.] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Worthington, Jane] Univ Manchester, Arthrit Res Campaign Epidemiol Unit, Manchester, Lancs, England. [Siminovitch, Katherine A.] Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Univ Hlth Network, Toronto, ON, Canada. [Klareskog, Lars] Karolinska Inst, Rheumatol Unit, Dept Med, Karolinska Univ Hosp Solna, Stockholm, Sweden. RP Zhernakova, A (reprint author), Leiden Univ, Med Ctr, Dept Rheumatol, Leiden, Netherlands. EM rplenge@partners.org RI Coenen, Marieke/A-2159-2010; Fehrmann, Rudolf/E-2551-2011; Ryan, Anthony/A-1336-2010; Romanos, Jihane/F-7372-2012; de Bakker, Paul/B-8730-2009; Wijmenga, Cisca/D-2173-2009; Siminovitch, Katherine/K-1475-2013; Riel, P.L.C.M./H-8082-2014; Worthington, Jane/M-9770-2014; Brouwer, Elisabeth/A-3198-2015; Franke, Lude/P-7036-2016; Festen, Eleonora/S-3557-2016 OI Zhernakova, Alexandra/0000-0002-4574-0841; Trynka, Gosia/0000-0002-6955-9529; Wijmenga, Cisca/0000-0002-5635-1614; McManus, Ross/0000-0002-0529-9617; Klareskog, Lars/0000-0001-9601-6186; Fehrmann, Rudolf/0000-0002-7516-315X; de Bakker, Paul/0000-0001-7735-7858; Worthington, Jane/0000-0003-0544-042X; Franke, Lude/0000-0002-5159-8802; FU NIH [R01-AR057108, R01-AR056768, U01-GM092691, 1K08AR055688-01A1]; Burroughs Wellcome Fund; European Community [PIOF-GA-2009-237280, HEALTH-F2-2008-223404]; National Center for Research Resources [U54 RR020278]; Coeliac Disease Consortium; Dutch Government [BSIK03009]; Netherlands Organisation for Scientific Research (NWO) [918.66.620, 916.10.135, 825.10.002]; Netherlands Genomics Initiative [93519031]; Royal Netherlands Academy of Arts and Sciences (KNAW); Science Foundation Ireland [09/IN.1/B2640]; Canada Research Chair; Sherman Family Chair in Genomic Medicine; CIHR [MOP79321, IIN84042]; ORF [RE01061]; EU; National Institute of Arthritis and Musculoskeletal and Skin Diseases FX RMP was supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. SR is supported by an NIH Career Development Award (1K08AR055688-01A1). FK is supported by a Marie Curie International Outgoing Fellowship for Career Development from the European Community's FP7 (Grant Agreement number PIOF-GA-2009-237280). The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The work presented is made possible by grants from the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative, and partially funded by the Dutch Government (BSIK03009 to CW) and by the Netherlands Organisation for Scientific Research (NWO, VICI grant 918.66.620 to CW). LF received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). AZ received a Rubicon grant from NWO (825.10.002). GT received a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences (KNAW). RMcM is supported by a Science Foundation Ireland Grant 09/IN.1/B2640. KAS is supported by a Canada Research Chair, Sherman Family Chair in Genomic Medicine, CIHR grants MOP79321 and IIN84042, and ORF grant RE01061. This work is partly supported by Coordination Theme 1 (Health) of the European Community's FP7, Grant Agreement number HEALTH-F2-2008-223404 (MASTERSWITCH project); by the EU FP6 supported AutoCure; and by the intramural program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 165 Z9 166 U1 2 U2 27 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 FEB PY 2011 VL 7 IS 2 AR e1002004 DI 10.1371/journal.pgen.1002004 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 726CV UT WOS:000287697300036 PM 21383967 ER PT J AU Thorndike, AN Healey, E Sonnenberg, L Regan, S AF Thorndike, Anne N. Healey, Erica Sonnenberg, Lillian Regan, Susan TI Participation and cardiovascular risk reduction in a voluntary worksite nutrition and physical activity program SO PREVENTIVE MEDICINE LA English DT Article DE Obesity; Worksite; Cardiovascular risk; Weight loss; Physical activity; Nutrition; Blood pressure; Cholesterol ID HEALTH-CARE COSTS; INTERVENTIONS; OBESITY; DISEASE AB Objective. In a cohort of employees participating in a worksite nutrition and physical activity program, we compared program completion and changes in cardiovascular risk factors by baseline body mass index. Methods. In 2007, 774 employees enrolled in a 10 week program at a hospital in Boston, Massachusetts. Program completion and change in weight, cholesterol, and blood pressure were compared between obese (body mass index >= 30), overweight (body mass index = 25-29.9), and normal weight (body mass index <25) participants. Results. At baseline, 63% were obese or overweight and had higher blood pressure and cholesterol compared to normal weight participants. Program completion was 82% and did not differ by body mass index. Mean weight loss was 1.9 kg at end of program (p<0.001) and 0.4 kg at 1 year (p = 0.002). At end of program, participants with body mass index >= 30 lost 3.0% body weight vs. 2.7% for body mass index = 25-29.9 and 1.7% for body mass index<25 (p<0.001), but weight loss at 1 year did not differ by body mass index. Mean cholesterol and blood pressure were lower at end of program and 1 year (all, p<0.005) but did not differ by body mass index. Conclusions. Worksite programs can successfully initiate cardiovascular risk reduction among employees, but more intensive interventions are needed to make significant improvements in the health of higher risk obese employees. (C) 2010 Elsevier Inc. All rights reserved. C1 [Thorndike, Anne N.; Healey, Erica; Regan, Susan] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. [Sonnenberg, Lillian] Massachusetts Gen Hosp, Ambulatory Nutr Serv, Boston, MA 02114 USA. RP Thorndike, AN (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St,9th floor, Boston, MA 02114 USA. EM athorndike@partners.org; ehealey2@gmail.com; lsonnenberg@partners.org; sregan@partners.org OI Regan, Susan/0000-0003-0940-2017 FU National Institutes of Health [1K23 HL93221-01 A1] FX Dr. Thorndike is supported by the grant 1K23 HL93221-01 A1 from the National Institutes of Health. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. We thank Jeff Davis, Senior Vice President, Human Resources at Massachusetts General Hospital, for his support of the Be Fit employee wellness program. NR 16 TC 8 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD FEB PY 2011 VL 52 IS 2 BP 164 EP 166 DI 10.1016/j.ypmed.2010.11.023 PG 3 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 716IH UT WOS:000286961800014 PM 21130804 ER PT J AU Kim, HJ Wang, X Radfar, S Sproule, TJ Roopenian, DC Cantor, H AF Kim, Hye-Jung Wang, Xuan Radfar, Soroosh Sproule, Thomas J. Roopenian, Derry C. Cantor, Harvey TI CD8(+) T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Rag2-deficient mice; cell transfer; HLA-E; KIR; memory CD8 cells ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; BXSB-YAA MICE; INHIBITORY RECEPTORS; NEGATIVE SELECTION; HLA-E; LYMPHOCYTES; SUBSET; REPERTOIRE; TOLERANCE; EXPANSION AB The immune system includes a subpopulation of CD8(+) T cells equipped to inhibit the expansion of follicular T helper (T-FH) cells, resulting in suppression of autoantibody production and associated lupus-like disease. These CD8(+) T regulatory (Treg) cells recognize Qa-1/peptide complexes on target T-FH cells and depend on the IL-15 cytokine for development and function. Here we show that these CD8(+) Treg cells express a triad of surface receptors-CD44, CD122, and the class I MHC receptor Ly49-and account for <5% of CD8(+) T cells. Moreover, the development of systemic lupus erythematosus-like disease in B6-Yaa mutant mice is associated with a pronounced defect in CD8(+) Treg cell activity, suggesting that this regulatory subset may represent an effective therapeutic approach to systemic lupus erythematosus-like autoimmune disease. C1 [Kim, Hye-Jung; Wang, Xuan; Radfar, Soroosh; Cantor, Harvey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kim, Hye-Jung; Radfar, Soroosh; Cantor, Harvey] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sproule, Thomas J.; Roopenian, Derry C.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Cantor, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu FU National Institutes of Health Research [AI 037562]; National Research Service Award [T32 CA070083]; Alliance for Lupus Research Target Identification in Lupus FX We thank A. Angel for manuscript and figure preparation. This work was supported in part by National Institutes of Health Research Grant AI 037562 and a gift from the Schecter Research Foundation (to H.C.), National Research Service Award Fellowship DFCI/NCI T32 CA070083 (to H.-J.K.), and Alliance for Lupus Research Target Identification in Lupus (to D.C.R.). NR 34 TC 53 Z9 53 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 FEB 1 PY 2011 VL 108 IS 5 BP 2010 EP 2015 DI 10.1073/pnas.1018974108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714JA UT WOS:000286804700050 PM 21233417 ER PT J AU Gonzalez-Malerva, L Park, J Zou, LH Hu, YH Moradpour, Z Pearlberg, J Sawyer, J Stevens, H Harlow, E LaBaer, J AF Gonzalez-Malerva, Laura Park, Jaehong Zou, Lihua Hu, Yanhui Moradpour, Zahra Pearlberg, Joseph Sawyer, Jacqueline Stevens, Hallam Harlow, Ed LaBaer, Joshua TI High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE functional screen; estrogen receptor ID BREAST-CANCER CELLS; ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; ANTIESTROGENS TAMOXIFEN; PATIENT SURVIVAL; MECHANISMS; INHIBITORS; PATHWAYS; ESTROGEN; DEATH AB Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway to understand underlying mechanisms. Resistance can be either intrinsic or acquired. We derived a series of subcloned MCF7 cell lines that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. Gene-expression studies revealed a signature of 67 genes that differentially respond to tamoxifen in sensitive vs. resistant subclones, which also predicts disease-free survival in tamoxifen-treated patients. High-throughput cell-based screens, in which >500 human kinases were independently ectopically expressed, identified 31 kinases that conferred drug resistance on sensitive cells. One of these, HSPB8, was also in the expression signature and, by itself, predicted poor clinical outcome in one cohort of patients. Further studies revealed that HSPB8 protected MCF7 cells from tamoxifen and blocked autophagy. Moreover, silencing HSBP8 induced autophagy and caused cell death. Tamoxifen itself induced autophagy in sensitive cells but not in resistant ones, and tamoxifen-resistant cells were sensitive to the induction of autophagy by other drugs. These results may point to an important role for autophagy in the sensitivity to tamoxifen. C1 [Gonzalez-Malerva, Laura; Park, Jaehong; Hu, Yanhui; Moradpour, Zahra; Pearlberg, Joseph; Sawyer, Jacqueline; Stevens, Hallam; Harlow, Ed; LaBaer, Joshua] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Harvard Inst Prote, Boston, MA 02115 USA. [Gonzalez-Malerva, Laura; Moradpour, Zahra; LaBaer, Joshua] Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ 85287 USA. [Zou, Lihua] Dana Farber Canc Inst, Boston, MA 02115 USA. [Moradpour, Zahra] Univ Med Sci, Fac Pharm, Dept Pharmaceut Biotechnol, Shiraz 71364, Iran. RP Harlow, E (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Harvard Inst Prote, Boston, MA 02115 USA. EM eharlow@hms.harvard.edu OI Stevens, Hallam/0000-0002-9083-3131; MORADPOUR, ZAHRA/0000-0001-8179-0216 FU National Cancer Institute at Harvard; Breast Cancer Research Foundation; National Cancer Institute [P01 C080111]; Expedition Inspiration for Breast Cancer Research FX We thank Joan Brugge for providing MCF7 cells, Mauricio Fernandez for all the engineering technical support with the robot instruments, John Doench and Dorre Gruenberg for manuscript suggestions and corrections, Dorre Gruenberg for providing the shRNA construct for mammalian target of rapamycin, and Milen Vitanov for his technical support at Arizona State University. This work was supported by the National Cancer Institute Specialized Programs of Research Excellence in Breast Cancer at Harvard, the Breast Cancer Research Foundation, and the National Cancer Institute Program Project Grant P01 C080111. The Expedition Inspiration for Breast Cancer Research supported L.G.-M. NR 40 TC 33 Z9 34 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 1 PY 2011 VL 108 IS 5 BP 2058 EP 2063 DI 10.1073/pnas.1018157108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714JA UT WOS:000286804700058 PM 21233418 ER PT J AU Sharpless, BA Barber, JP AF Sharpless, Brian A. Barber, Jacques P. TI A Clinician's Guide to PTSD Treatments for Returning Veterans SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE PTSD; posttraumatic stress disorder; post-traumatic stress disorder; psychotherapy; psychopharmacology ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE PROCESSING THERAPY; EYE-MOVEMENT DESENSITIZATION; NATIONAL COMORBIDITY SURVEY; PROLONGED EXPOSURE; REPROCESSING EMDR; TRIAL; PSYCHOTHERAPY; VICTIMS; TRAUMA AB What options are available to mental health providers helping clients with posttraumatic stress disorder (PTSD)? In this paper we review many of the current pharmacological and psychological interventions available to help prevent and treat PTSD with an emphasis on combat-related traumas and veteran populations. There is strong evidence supporting the use of several therapies including prolonged exposure (PE), eye movement desensitization and reprocessing (EMDR), and cognitive processing therapies (CPT), with PE possessing the most empirical evidence in favor of its efficacy. There have been relatively fewer studies of nonexposure based modalities (e.g., psychodynamic, interpersonal, and dialectical behavior therapy perspectives), but there is no evidence that these treatments are less effective. Pharmacotherapy is promising (especially paroxetine, sertraline, and venlafaxine), but more research comparing the relative merits of medication vs. psychotherapy and the efficacy of combined treatments is needed. Given the recent influx of combat-related traumas due to ongoing conflicts in Iraq and Afghanistan, there is clearly an urgent need to conduct more randomized clinical trials research and effectiveness studies in military and Department of Veterans Affairs PTSD samples. Finally, we provide references to a number of PTSD treatment manuals and propose several recommendations to help guide clinicians' treatment selections. C1 [Sharpless, Brian A.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Barber, Jacques P.] Univ Penn, Ctr Psychotherapy Res, Philadelphia, PA 19104 USA. [Barber, Jacques P.] Philadelphia VA Med Ctr, CESATE, Philadelphia, PA USA. RP Sharpless, BA (reprint author), Penn State Univ, Dept Psychol, 314 Moore Bldg, University Pk, PA 16802 USA. EM bas171@psu.edu RI Schueter, nicos/A-3625-2014; OI barber, jacques/0000-0002-8762-2595 FU NIMH NIH HHS [R01 MH070664, R01 MH070664-01A2] NR 48 TC 13 Z9 14 U1 4 U2 25 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD FEB PY 2011 VL 42 IS 1 SI SI BP 8 EP 15 DI 10.1037/a0022351 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 733TE UT WOS:000288285100002 PM 21475611 ER PT J AU Vujanovic, AA Niles, B Pietrefesa, A Schmertz, SK Potter, CM AF Vujanovic, Anka A. Niles, Barbara Pietrefesa, Ashley Schmertz, Stefan K. Potter, Carrie M. TI Mindfulness in the Treatment of Posttraumatic Stress Disorder Among Military Veterans SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE mindfulness; posttraumatic stress disorder; treatment; military veterans ID RANDOMIZED CONTROLLED-TRIAL; DIALECTICAL BEHAVIOR-THERAPY; BORDERLINE PERSONALITY-DISORDER; COMMITMENT THERAPY; COGNITIVE THERAPY; RELAPSE PREVENTION; EXPOSURE TREATMENT; SELF-REPORT; ACCEPTANCE; DEPRESSION AB How might a practice that has its roots in contemplative traditions, seeking heightened awareness through meditation, apply to trauma-related mental health struggles among military veterans? In recent years, clinicians and researchers have observed the increasing presence of mindfulness in Western mental health treatment programs. Mindfulness is about bringing an attitude of curiosity and compassion to present experience. This review addresses the above question in a detailed manner with an emphasis on the treatment of military veterans suffering from posttraumatic stress disorder (PTSD) and related psychopathology. In addition, the integration of mindfulness with current empirically supported treatments for PTSD is discussed with specific attention to directions for future research in this area. C1 [Vujanovic, Anka A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Vujanovic, Anka A.; Niles, Barbara] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Vujanovic, AA (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, 150 S Huntington Ave 116B-2, Boston, MA 02130 USA. EM anka.vujanovic@va.gov NR 64 TC 25 Z9 26 U1 12 U2 51 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD FEB PY 2011 VL 42 IS 1 SI SI BP 24 EP 31 DI 10.1037/a0022272 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 733TE UT WOS:000288285100004 ER PT J AU Katzman, MA Copeland, A Klassen, LJ Chokka, P Brawman-Mintzer, O AF Katzman, Martin A. Copeland, Alex Klassen, Larry J. Chokka, Pratap Brawman-Mintzer, Olga TI Pharmacotherapy for Generalized Anxiety Disorder SO PSYCHIATRIC ANNALS LA English DT Article ID VENLAFAXINE EXTENDED-RELEASE; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; NATIONAL-COMORBIDITY-SURVEY; QUALITY-OF-LIFE; DOUBLE-BLIND; MAJOR DEPRESSION; BEHAVIORAL-INHIBITION; CLINICAL-TRIALS; DULOXETINE TREATMENT C1 [Katzman, Martin A.; Copeland, Alex] START Clin Mood & Anxiety Disorders, Toronto, ON M5G 1N8, Canada. [Katzman, Martin A.] Univ Toronto, Dept Psychiat, Fac Med, Toronto, ON M5S 1A1, Canada. [Katzman, Martin A.] Lakehead Univ, Dept Psychol, Thunder Bay, ON P7B 5E1, Canada. [Klassen, Larry J.] Univ Manitoba, Dept Psychiat, Fac Med, Winnipeg, MB R3T 2N2, Canada. [Chokka, Pratap] Univ Alberta, Fac Med, Edmonton, AB T6G 2M7, Canada. [Brawman-Mintzer, Olga] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Brawman-Mintzer, Olga] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Katzman, MA (reprint author), START Clin Mood & Anxiety Disorders, 900-790 Bay St, Toronto, ON M5G 1N8, Canada. EM mkatzman@startclinic.ca NR 83 TC 3 Z9 3 U1 3 U2 10 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD FEB PY 2011 VL 41 IS 2 BP 95 EP U48 DI 10.3928/00485713-20110203-08 PG 11 WC Psychiatry SC Psychiatry GA 884XT UT WOS:000299742900008 ER PT J AU Amstadter, AB Balachandar, V Bergen, SE Ceulemans, S Christensen, JH Cole, J Dagdan, E De Luca, V Ducci, F Tee, SF Hartz, S Keers, R Medland, S Melas, PA Muhleisen, TW Ozomaro, U Pidsley, R Scott, AP Sha, L Talati, A Teltsh, O Videtic, A Wang, K Wong, CCY DeLisi, LE AF Amstadter, Ananda B. Balachandar, Vellingiri Bergen, Sarah E. Ceulemans, Shana Christensen, Jane H. Cole, James Dagdan, Elif De Luca, Vincenzo Ducci, Francesca Tee, Shiau Foon Hartz, Sarah Keers, Robert Medland, Sarah Melas, Philippe A. Muehleisen, Thomas W. Ozomaro, Uzoezi Pidsley, Ruth Scott, Adrian P. Sha, Li Talati, Ardesheer Teltsh, Omri Videtic, Alja Wang, Kai Wong, Chloe C. Y. DeLisi, Lynn E. TI Selected summaries from the XVII World Congress of Psychiatric Genetics, San Diego, California, USA, 4-8 November 2009 (vol 20, pg 229, 2010) SO PSYCHIATRIC GENETICS LA English DT Correction C1 [Amstadter, Ananda B.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, Charleston, SC 29425 USA. [Bergen, Sarah E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Bergen, Sarah E.] MIT & Harvard, Broad Inst, Stanley Ctr Psychiat Res, Boston, MA USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [DeLisi, Lynn E.] VA Boston Healthcare Syst, Brockton, MA USA. [Hartz, Sarah] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Ozomaro, Uzoezi] Univ Miami, Miller Sch Med, Hussman Inst Human Genom, Miami, FL 33136 USA. [Talati, Ardesheer] Columbia Univ, Dept Psychiat, New York, NY USA. [Talati, Ardesheer] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Wang, Kai] Childrens Hosp, Ctr Appl Gen, Philadelphia, PA 19104 USA. [Balachandar, Vellingiri] Bharathiar Univ, Sch Life Sci, Human Genet Lab, Dept Zool, Coimbatore, Tamil Nadu, India. [Ceulemans, Shana] Univ Antwerp, Appl Mol Genom Grp, VIB Dept Mol Genet, B-2020 Antwerp, Belgium. [Christensen, Jane H.] Aarhus Univ, Dept Human Genet, DK-8000 Aarhus C, Denmark. [Cole, James; Pidsley, Ruth] Kings Coll London, Inst Psychiat, SGDP Res Ctr, London WC2R 2LS, England. [Keers, Robert] Kings Coll London, Inst Psychiat, MRC SGDP Res Ctr, London WC2R 2LS, England. [Wong, Chloe C. Y.] Kings Coll London, Inst Psychiat, Genet & Dev Psychiat Ctr, MRC Social, London WC2R 2LS, England. [Sha, Li] Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Edinburgh EH8 9YL, Midlothian, Scotland. [De Luca, Vincenzo] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Tee, Shiau Foon] Univ Tunku Abdul Rahman, Fac Sci & Engn, Dept Chem Engn, Kuala Lumpur, Malaysia. [Hartz, Sarah] Po Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld, Australia. [Scott, Adrian P.] Univ Western Australia, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Scott, Adrian P.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Melas, Philippe A.] Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Neurogenet Unit, Stockholm, Sweden. [Muehleisen, Thomas W.] Univ Bonn, Inst Human Genet, Life & Brain Ctr, Dept Genom, D-5300 Bonn, Germany. [Teltsh, Omri] Hadassah Hebrew Univ, Med Ctr, Dept Psychiat, Biol Psychiat Lab, Jerusalem, Israel. [Videtic, Alja] Univ Ljubljana, Fac Med, Inst Biochem, Med Ctr Mol Genet, Ljubljana 61000, Slovenia. [Dagdan, Elif] Inst Mol Med, Trinity Ctr Hlth Sci, Neuropsychiat Genet Res Grp, Dublin, Ireland. RP Amstadter, AB (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 171 Ashley Ave, Charleston, SC 29425 USA. RI Keers, Robert/C-1014-2009; Wong, Chloe/B-3679-2012; Pidsley, Ruth/D-8127-2012; Bergen, Sarah/I-8313-2012; Medland, Sarah/C-7630-2013 OI Keers, Robert/0000-0001-7954-7583; Wong, Chloe/0000-0003-4886-8506; Medland, Sarah/0000-0003-1382-380X NR 2 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD FEB PY 2011 VL 21 IS 1 BP 55 EP 55 DI 10.1097/YPG.0b013e328343171a PG 1 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 697UR UT WOS:000285544800012 ER PT J AU Bodugoz-Senturk, H Guven, O AF Bodugoz-Senturk, Hatice Guven, Olgun TI Enhancement of conductivity in polyaniline-[poly(vinylidene chloride)-co-(vinyl acetate)] blends by irradiation SO RADIATION PHYSICS AND CHEMISTRY LA English DT Article DE Poly(vinylidene chloride-co-vinyl acetate); Polyaniline; Conductive polymer; Irradiation; Polymer blends ID ELECTRICAL-CONDUCTIVITY; POLYVINYLIDENE CHLORIDE; THERMAL-DEGRADATION; POLYANILINE; COMPOSITES; POLYMERS; GAMMA; FILMS; ORIENTATION; BASE AB In this study we have prepared conductive poly(aniline), (PANI) blends with poly(vinylidene chloride-co-vinyl acetate), [P(VDC-co-VAc)] copolymer with varying compositions using gamma radiation to induce conductivity. A number of blends with different compositions were prepared by solution casting followed by irradiation in a (60)Co gamma cell to different doses up to 800 kGy. Electrical conductivity of the blends was measured before and after irradiation using a four-probe technique. Increasing radiation dose resulted in an increase of 9 orders of magnitude in the conductivity of P(VDC-co-VAc)/(PANI) films reaching 0.1 S/cm at 500 kGy and beyond this dose a decrease was observed. Effect of film thickness on conductivity of the blends was investigated and a slight increase of an order of magnitude was observed on increasing the film thickness from 50 to 200 mu m. It was also observed that PANI blends exhibited a stretch dependent small increase in conductivity. The conductivity of the irradiated films was found to be stable for up to 12 months under ambient conditions. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Guven, Olgun] Hacettepe Univ, Dept Chem, TR-06800 Ankara, Turkey. [Bodugoz-Senturk, Hatice] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Bodugoz-Senturk, Hatice] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Guven, O (reprint author), Hacettepe Univ, Dept Chem, TR-06800 Ankara, Turkey. EM guven@hacettepe.edu.tr NR 23 TC 12 Z9 12 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-806X J9 RADIAT PHYS CHEM JI Radiat. Phys. Chem. PD FEB PY 2011 VL 80 IS 2 BP 153 EP 158 DI 10.1016/j.radphyschem.2010.07.025 PG 6 WC Chemistry, Physical; Nuclear Science & Technology; Physics, Atomic, Molecular & Chemical SC Chemistry; Nuclear Science & Technology; Physics GA 692QJ UT WOS:000285169900008 ER PT J AU McLoud, TC AF McLoud, Theresa C. TI Trends in Radiologic Training Response SO RADIOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP McLoud, TC (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,POB 9657,MZ-FND 216, Boston, MA 02114 USA. EM tmcloud@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2011 VL 258 IS 2 BP 649 EP 650 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 712GH UT WOS:000286653700039 ER PT J AU Mancuso, F Horan, WP Kern, RS Green, MF AF Mancuso, Francesco Horan, William P. Kern, Robert S. Green, Michael F. TI Social cognition in psychosis: Multidimensional structure, clinical correlates, and relationship with functional outcome SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Social cognition; Neurocognition; Positive symptoms; Negative symptoms; Functional outcome ID PSYCHIATRIC RATING-SCALE; SCHIZOPHRENIA-PATIENTS; QUALITY-ASSURANCE; MIND DEFICITS; HIGH-RISK; NEUROCOGNITION; ATTRIBUTIONS; PERFORMANCE; RELEVANCE; DECEPTION AB Social cognitive impairments are common, detectable across a wide range of tasks, and appear to play a key role in explaining poor outcome in schizophrenia and related psychotic disorders. However, little is known about the underlying factor structure of social cognition in people with psychotic disorders due to a lack of exploratory factor analyses using a relatively comprehensive social cognitive assessment battery. In a sample of 85 outpatients with psychosis, we examined the factor structure and clinical/functional correlates of eight indexes derived from five social cognition tasks that span the domains of emotional processing, social perception, attributional style, and Theory of Mind. Exploratory factor analysis revealed three factors with relatively low inter-correlations that explained a total of 54% of the variance: (1) Hostile attributional style, (2) Lower-level social cue detection, and (3) Higher-level inferential and regulatory processes. None of the factors showed significant correlations with negative symptoms. Factor 1 significantly correlated with clinical symptoms (positive, depression-anxiety, agitation) but not functional outcome, whereas Factors 2 and 3 significantly correlated with functional outcome (functional capacity and real-world social and work functioning) but not clinical symptoms. Furthermore, Factor 2 accounted for unique incremental variance in functional capacity, above and beyond non-social neurocognition (measured with MATRICS Consensus Cognitive Battery) and negative symptoms. Results suggest that multiple separable dimensions of social cognition can be identified in psychosis, and these factors show distinct patterns of correlation with clinical features and functional outcome. (C) 2010 Elsevier B.V. All rights reserved. C1 [Mancuso, Francesco; Horan, William P.; Kern, Robert S.; Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mancuso, Francesco; Horan, William P.; Kern, Robert S.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, MIRECC VISN22, Los Angeles, CA USA. [Mancuso, Francesco] Univ Naples SUN, Dept Psychiat, Naples, Italy. RP Horan, WP (reprint author), Univ Calif Los Angeles, Dept Psychiat & Behav Sci, David Geffen Sch Med, 300 UCLA Med Plaza,Suite 2255, Los Angeles, CA 90095 USA. EM horan@ucla.edu FU Veterans Affairs; NIMH [MH043292]; Mental Illness Research Education Clinical Center [VA VISN-22] FX Funding for this project came from a Veterans Affairs Merit Grant and NIMH grant MH043292 (both to Dr. Green), and the VA VISN-22 Mental Illness Research Education Clinical Center. The VA had no further role in study design; 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 68 TC 94 Z9 100 U1 1 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB PY 2011 VL 125 IS 2-3 BP 143 EP 151 DI 10.1016/j.schres.2010.11.007 PG 9 WC Psychiatry SC Psychiatry GA 733ZW UT WOS:000288304000006 PM 21112743 ER PT J AU Steckling, N Boese-O'Reilly, S Gradel, C Gutschmidt, K Shinee, E Altangerel, E Badrakh, B Bonduush, I Surenjav, U Ferstl, P Roider, G Sakamoto, M Sepai, O Drasch, G Lettmeier, B Morton, J Jones, K Siebert, U Hornberg, C AF Steckling, Nadine Boese-O'Reilly, Stephan Gradel, Cornelia Gutschmidt, Kersten Shinee, Enkhtsetseg Altangerel, Enkhjargal Badrakh, Burmaa Bonduush, Ichinkhorloo Surenjav, Unursaikhan Ferstl, Philip Roider, Gabriele Sakamoto, Mineshi Sepai, Ovnair Drasch, Gustav Lettmeier, Beate Morton, Jackie Jones, Kate Siebert, Uwe Hornberg, Claudia TI Mercury exposure in female artisanal small-scale gold miners (ASGM) in Mongolia: An analysis of human biomonitoring (HBM) data from 2008 SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Mercury; Human biomonitoring; Mongolia; Artisanal small-scale gold mining; Amalgam smelting ID 1998 GERES-III; ENVIRONMENTAL-POLLUTANTS; GERMAN POPULATION; HEALTH-HAZARD; MINING AREAS; METHYLMERCURY; CHILDREN; URINE; PHILIPPINES; TANZANIA AB Background: Many poor in developing countries have turned to artisanal small-scale gold mining (ASGM) in an attempt to improve their situation. However, the mercury used to extract gold from ore is discharged in vaporized form into the environment, where it poses a hazard for human health. Methods: As part of an environmental epidemiological study in Mongolia to evaluate the burden of environmental mercury contamination urine, blood and hair samples were collected from residents of areas with or without mercury contamination. A total of 200 blood, urine and hair samples were analyzed for mercury and divided into three subgroups according to mercury content: (1) occupational exposure (high/medium); (2) environmental exposure (low); and (3) no exposure. Internal mercury distributions of the subgroups were compared using the Kruskal-Wallis and Mann-Whitney U-test. The Chi-square test and likelihood ratio proportion were used to compare the findings with threshold limits. Results: The highest values and greatest differences were seen in the urine samples (p<0.001, Kruskal-Wallis). The occupational group showing the highest exposure with a median mercury level of 4.36 mu g/l (control group: 0.10 mu g/l, p<0.001), 7.18 mu g/g creatinine and 12 results above the threshold limit HBM I (Human Biomonitoring I). Even participants from the low-exposure subgroup showed elevated mercury levels (median 2.88 mu g/l urine and 2.98 mu g/g creatinine, p<0.001), with 10 individuals above the HBM I threshold limits. Discussion: The body burden resulting from the use of mercury in artisanal gold mining is high not only in the miners themselves, an increased mercury hazard was also found for inhabitants of mining areas who were not actively involved in mining. Public health support measures are urgently needed to alleviate the situation. (C) 2010 Elsevier B.V. All rights reserved. C1 [Boese-O'Reilly, Stephan] UMIT Univ Hlth Sci Med Informat & Technol, Eduard Wallnoefer Ctr 1, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Inst Publ Hlth Med Decis Making & Hlth Technol As, A-6060 Hall In Tirol, Austria. [Steckling, Nadine; Gradel, Cornelia; Hornberg, Claudia] Univ Bielefeld, Fac Hlth Sci, Bielefeld, Germany. [Gutschmidt, Kersten] World Hlth Org, Evidence & Policy Environm Hlth EPE Dept Publ Hlt, Geneva, Switzerland. [Shinee, Enkhtsetseg] World Hlth Org, Ulaanbaatar, Mongol Peo Rep. [Altangerel, Enkhjargal] Minist Hlth, Ulaanbaatar, Mongol Peo Rep. [Badrakh, Burmaa; Bonduush, Ichinkhorloo; Surenjav, Unursaikhan] Inst Publ Hlth, Ulaanbaatar, Mongol Peo Rep. [Roider, Gabriele; Drasch, Gustav; Lettmeier, Beate] Univ Munich, Inst Forens Med, Dept Forens Toxicol, Munich, Germany. [Sakamoto, Mineshi] Natl Inst Minamata Dis, Dept Int Affairs & Environm Sci, Kumamoto, Japan. [Sepai, Ovnair] Hlth Protect Agcy, Ctr Radiat Chem & Environm Hazards, Chem Hazards & Poisons Div, Didcot, Oxon, England. [Morton, Jackie; Jones, Kate] Hlth & Safety Lab, Harpur Hill SK17 9JN, Buxton, England. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment,Cardiovasc Res Program, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Boese-O'Reilly, S (reprint author), UMIT Univ Hlth Sci Med Informat & Technol, Eduard Wallnoefer Ctr 1, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Inst Publ Hlth Med Decis Making & Hlth Technol As, A-6060 Hall In Tirol, Austria. EM stephan.boeseoreilly@umit.at RI Jones, Kate/C-8983-2009 OI Jones, Kate/0000-0001-8923-2999 NR 39 TC 15 Z9 15 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 1 PY 2011 VL 409 IS 5 BP 994 EP 1000 DI 10.1016/j.scitotenv.2010.11.029 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 721HW UT WOS:000287345200015 PM 21183207 ER PT J AU Tucker, JD Li, JZ Robbins, GK Davis, BT Lobo, AM Kunkel, J Papaliodis, GN Durand, ML Felsenstein, D AF Tucker, Joseph D. Li, Jonathan Z. Robbins, Gregory K. Davis, Benjamin T. Lobo, Ann-Marie Kunkel, Jan Papaliodis, George N. Durand, Marlene L. Felsenstein, Donna TI Ocular syphilis among HIV-infected patients: a systematic analysis of the literature SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Review ID IMMUNODEFICIENCY VIRUS-INFECTION; PENICILLIN THERAPY; SECONDARY SYPHILIS; POSTERIOR UVEITIS; MANIFESTATIONS; NEUROSYPHILIS; EPIDEMIC; DISEASE; AIDS; SEX AB Background Ocular syphilis among HIV-infected patients continues to be a problem in the highly active antiretroviral therapy (HAART) era. However, outside of case reports or small case series, little is known about the clinical, laboratory, and treatment outcomes of these patients. Objective To examine the literature on HIV-infected patients and determine the results of treatment. Methods Systematic review of cases series and case reports among HIV-infected individuals with ocular syphilis. Reviews, languages other than English and pre-1980 reports were excluded. The effect of CD4 count and virological suppression on clinical manifestations and diagnostic laboratory values was evaluated. Results A total of 101 HIV-infected individuals in case series and case reports were identified. Ocular syphilis led to the HIV diagnosis in 52% of cases, including patients with CD4 count >200 cells/mm(3). Posterior uveitis was significantly more common in individuals with CD4 count <200 cells/mm(3) (p=0.002). Three patients with confirmed ocular syphilis had negative non-treponemal tests. Ninety-seven per cent of patients with visual impairment improved following intravenous penicillin or ceftriaxone. Conclusions Non-treponemal tests may be negative in HIV-infected patients with ocular syphilis. Ocular syphilis remains an important clinical manifestation that can lead to initial HIV diagnosis. C1 [Tucker, Joseph D.; Robbins, Gregory K.; Davis, Benjamin T.; Durand, Marlene L.; Felsenstein, Donna] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Li, Jonathan Z.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Lobo, Ann-Marie; Papaliodis, George N.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Kunkel, Jan] Charite, Dept Med 1, D-13353 Berlin, Germany. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jtucker4@partners.org FU National Institutes of Health [T32 AI07387]; US NIH [R24TW007988]; American Society of Tropical Medicine and Hygiene FX Support from the National Institutes of Health (T32 AI07387, JL), US NIH Fogarty International Clinical Fellowship (R24TW007988, JT) and the American Society of Tropical Medicine and Hygiene (JT). NR 48 TC 34 Z9 36 U1 2 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD FEB PY 2011 VL 87 IS 1 BP 4 EP 8 DI 10.1136/sti.2010.043042 PG 5 WC Infectious Diseases SC Infectious Diseases GA 706MZ UT WOS:000286223800003 PM 20798396 ER PT J AU Jonker, MA Hermsen, JL Gomez, FE Sano, Y Kudsk, KA AF Jonker, Mark A. Hermsen, Joshua L. Gomez, F. Enrique Sano, Yoshifumi Kudsk, Kenneth A. TI Injury Induces Localized Airway Increases in Pro-Inflammatory Cytokines in Humans and Mice SO SURGICAL INFECTIONS LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Parenteral-and-Enteral-Nutrition CY FEB 01-04, 2009 CL New Orleans, LA SP Amer Soc Parenter & Enter ID TUMOR-NECROSIS-FACTOR; RESPIRATORY-DISTRESS-SYNDROME; FACTOR-KAPPA-B; NOSOCOMIAL PNEUMONIA; SECRETORY COMPONENT; FACTOR-ALPHA; TRAUMA; IMMUNOGLOBULIN; RECEPTOR; INTERLEUKIN-6 AB Background: Secretory immunoglobulin A (sIgA) increases in the airways of humans and mice after injury to protect against infection. The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 are linked molecularly to sIgA production and secretion and are required for sIgA increases in the airway after injury in a mouse model. We investigated the injury effect on airway and serum concentrations to determine the source of the cytokines involved in the airway IgA response. Methods: In the first experiment, TNF-alpha, IL-1 beta, and IL-6 concentrations in bronchoalveolar lavage (BAL) fluid and serum obtained from 11 ventilated trauma patients within 30 h of admission were compared with those in eight elective surgical patients. In the second experiment, male ICR mice received no injury (n=7) or injury with sham celiotomy and neck incisions (n=8) with sacrifice of all animals at 8 h for BAL fluid and serum cytokine measurements by enzyme-linked immunosorbent assay. Results: Injured patients had significantly higher BAL fluid and serum TNF-alpha, IL-1 beta, and IL-6 concentrations, with greater increases in the BAL fluid than in the serum. Injured mice had significantly increased BAL fluid concentrations of TNF-alpha, IL-1 beta, and IL-6 without significant changes in serum TNF-alpha or IL-1 beta. Serum IL-6 increased significantly. Conclusions: Injury significantly increases human and mouse airway TNF-alpha, IL-1 beta, and IL-6. Increases are greater in the airway than in serum, implying a local rather than a systemic stress response to injury. C1 [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Surg Serv, Madison, WI USA. [Jonker, Mark A.; Hermsen, Joshua L.; Sano, Yoshifumi; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Gomez, F. Enrique] Inst Nutr Salvador Zubiran, Dept Nutr Physiol, Tlalpan, DF, Mexico. RP Kudsk, KA (reprint author), 600 Highland Ave,H4-736 CSC, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU NIGMS NIH HHS [R01 GM53439] NR 38 TC 7 Z9 8 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-2964 J9 SURG INFECT JI Surg. Infect. PD FEB PY 2011 VL 12 IS 1 BP 49 EP 56 DI 10.1089/sur.2010.040 PG 8 WC Infectious Diseases; Surgery SC Infectious Diseases; Surgery GA 768LN UT WOS:000290936300008 PM 21166596 ER PT J AU Wright, CD AF Wright, Cameron D. TI Stage IVA Thymoma: Patterns of Spread and Surgical Management SO THORACIC SURGERY CLINICS LA English DT Article DE Thymoma; Pleural disease; Pleurectomy; Pleuropneumonectomy ID THYMIC TUMORS; MULTIMODALITY THERAPY; PLEURAL RECURRENCE; RESECTION; INVASION AB Stage IVA disease can be de novo disease or more commonly represent recurrent disease. The pleura is the most common site of relapse after thymoma resection. Local pleural disease is usually simply resected. This is usually combined with either induction or adjuvant chemotherapy. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy done for extensive pleural disease. This rarely performed operation is done for both stage IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again, these advanced patients with pleural spread are probably best managed by induction chemotherapy followed by resection. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Thorac Surg,Dept Surg, Boston, MA 02114 USA. RP Wright, CD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Thorac Surg,Dept Surg, Boston, MA 02114 USA. EM cdwright@partners.org NR 17 TC 3 Z9 4 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 1547-4127 J9 THORAC SURG CLIN JI Thorac. Surg. Clin. PD FEB PY 2011 VL 21 IS 1 BP 93 EP + DI 10.1016/j.thorsurg.2010.08.007 PG 6 WC Respiratory System; Surgery SC Respiratory System; Surgery GA 045AB UT WOS:000311665200010 PM 21070990 ER PT J AU Bichara, DA Zhao, X Bodugoz-Senturk, H Ballyns, FP Oral, E Randolph, MA Bonassar, LJ Gill, TJ Muratoglu, OK AF Bichara, David A. Zhao, Xing Bodugoz-Senturk, Hatice Ballyns, Fred P. Oral, Ebru Randolph, Mark A. Bonassar, Lawrence J. Gill, Thomas J. Muratoglu, Orhun K. TI Porous Poly(Vinyl Alcohol)-Hydrogel Matrix-Engineered Biosynthetic Cartilage SO TISSUE ENGINEERING PART A LA English DT Article ID ARTICULAR-CARTILAGE; NEOCARTILAGE FORMATION; HYDROGELS; POLYMER; GEL AB The objective of this study was to fabricate hydrogel matrix-engineered biosynthetic cartilage using a porous poly(vinyl alcohol) hydrogel (PVA-H) and articular chondrocytes. Chondrocytes were suspended in fibrin gel (FG) or saline carriers and injected into porous PVA-H discs and three-layered constructs (PVA-H between devitalized cartilage). After implantation in nude mice, PVA discs were explanted at 6 weeks and subjected to creep testing for a 20 h period. The three-layered constructs were explanted at 12 weeks and subjected to tensile testing to determine the strength of the interface between the engineered hydrogel and devitalized cartilage. Histological analysis revealed PVA-H porous channels occupied by chondrocytes. Extracellular matrix was identified by Safranin-O and toluidine blue stains. Immunohistochemical analysis revealed a positive stain for COL II and scant staining for COL I. Creep and relaxation response of PVA-FG-chondrocyte constructs was similar to that of native cartilage. The presence of cells and FG significantly enhanced the integration strength of layered constructs (p < 0.05). These results demonstrate that porous PVA-H in combination with FG and chondrocytes provides a favorable microenvironment for tissue engineering of articular cartilage, creating a biosynthetic construct that can adhere to native devitalized articular cartilage utilizing hydrogel matrix-engineered technology. C1 [Bichara, David A.; Zhao, Xing; Randolph, Mark A.] Harvard Univ, Massachusetts Gen Hosp, Div Plast Surg, Plast Surg Res Lab,Med Sch, Boston, MA 02114 USA. [Bodugoz-Senturk, Hatice; Oral, Ebru; Muratoglu, Orhun K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthoped Biomech & Biomat Lab, Boston, MA 02114 USA. [Ballyns, Fred P.; Bonassar, Lawrence J.] Cornell Univ, Sibley Sch Mech & Aerosp Engn, Dept Biomed Engn, Ithaca, NY 14853 USA. [Gill, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Div Sport Med,Med Sch, Boston, MA 02114 USA. RP Randolph, MA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Plast Surg, Plast Surg Res Lab,Med Sch, Room WAC 435,15 Parkman St, Boston, MA 02114 USA. EM marandolph@partners.org RI Bonassar, Lawrence/C-2103-2016 OI Bonassar, Lawrence/0000-0003-1094-6433 FU Department of Orthopaedic Surgery Academic Enrichment, Massachusetts General Hospital FX This study was supported by the Department of Orthopaedic Surgery Academic Enrichment Fund of the Massachusetts General Hospital. None of the authors are associated to financial affiliations that could have biased this study. NR 16 TC 19 Z9 19 U1 2 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD FEB PY 2011 VL 17 IS 3-4 BP 301 EP 309 DI 10.1089/ten.tea.2010.0322 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 712JB UT WOS:000286661600005 PM 20799889 ER PT J AU Thakor, DK Teng, YD Obata, H Nagane, K Saito, S Tabata, Y AF Thakor, Devang K. Teng, Yang D. Obata, Hideaki Nagane, Kentaro Saito, Shigeru Tabata, Yasuhiko TI Nontoxic Genetic Engineering of Mesenchymal Stem Cells Using Serum-Compatible Pullulan-Spermine/DNA Anioplexes SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID MARROW STROMAL CELLS; SPINAL-CORD-INJURY; STEM/PROGENITOR CELLS; PLASMID DNA; TRANSGENE EXPRESSION; CATIONIC LIPOSOMES; PALMITIC ACID; DELIVERY; ADULT; TRANSPLANTATION AB Genetic modification of stem cells could be applied to initiate/enhance their secretion of therapeutic molecules, alter their biological properties, or label them for in vivo tracking. We recently developed a negatively charged gene carrier ("anioplex") based on pullulan-spermine, a conjugate prepared from a natural polysaccharide and polyamine. In rat mesenchymal stem cells (MSCs), anioplex-derived reporter gene activity was comparable to or exceeded that obtained using a commercial cationic lipid reagent. Transfection in the growth medium with 15% serum and antibiotics was approximately sevenfold more effective than in serum-free conditions. Cytotoxicity was essentially indiscernible after 24 h of anioplex transfection with 20 mu g/mL DNA, in contrast to cationic lipid transfection that resulted in 40%-60% death of target MSCs. Anioplex-derived reporter gene activity persisted throughout the entire 3-week study, with post-transfection MSCs appearing to maintain osteogenic, adipogenic, and chondrogenic multipotency. In particular, chondrogenic pellet formation of differentiating human MSCs was significantly inhibited after lipofection but not after aniofection, which further indicates the biological inertness of pullulan-spermine/DNA anioplexes. Collectively, these data introduce a straightforward technology for genetic engineering of adult stem/progenitor cells under physiological niche-like conditions. Moreover, reporter gene activity was observed in rat spinal cords after minimally invasive intrathecal implantation, suggesting effective engraftment of donor MSCs. It is therefore plausible that anioplex-transfected MSCs or other stem/progenitor cells with autologous potential could be applied to disorders such as neurotrauma or neuropathic pain that involve the spinal cord and brain. C1 [Thakor, Devang K.; Teng, Yang D.] Boston VA Healthcare Syst, Div SCI Res, Boston, MA 02132 USA. [Thakor, Devang K.; Nagane, Kentaro; Tabata, Yasuhiko] Kyoto Univ, Inst Frontier Med Sci, Kyoto 6068507, Japan. [Thakor, Devang K.; Teng, Yang D.] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Thakor, Devang K.; Teng, Yang D.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Obata, Hideaki; Saito, Shigeru] Gunma Univ, Sch Med, Dept Anesthesiol, Maebashi, Gumma 371, Japan. RP Teng, YD (reprint author), Boston VA Healthcare Syst, Div SCI Res, 1400 VFW Pkwy,Bldg 3,Room 2B110, Boston, MA 02132 USA. EM yang_teng@hms.harvard.edu; yasuhiko@frontier.kyoto-u.ac.jp FU Japan Society for the Promotion of Science, as well as the Takanawakai; Clinical Implant Society of Japan; VA; NIH; CIMIT-DOD; State of Massachusetts FX D. K. T. has been supported by a foreign postdoctoral fellowship and grant-in-aid from the Japan Society for the Promotion of Science, as well as the Takanawakai, the Clinical Implant Society of Japan, and a VA Biomedical Merit Grant. Work at Y.D.T.'s labs are supported by VA, NIH, CIMIT-DOD, and the State of Massachusetts. We thank Dr. Jun-Ichiro Jo, Mr. Masataka Yoshida, and Mr. Norio Doi of Kyoto University for assistance in the preparation of pullulan-spermine. We thank Dr. Jyunichi Miyazaki of Osaka University for kindly providing luciferase. We thank Dr. Masaru Tobe of Gunma University for assistance with animal experiments. We thank Mr. Nirav Thakor for assistance with figure preparation. NR 56 TC 9 Z9 9 U1 3 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD FEB PY 2011 VL 17 IS 2 BP 131 EP 144 DI 10.1089/ten.tec.2010.0120 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 713GR UT WOS:000286723900002 PM 20698746 ER PT J AU Pergam, SA Forsberg, CW Boeckh, MJ Maynard, C Limaye, AP Wald, A Smith, NL Young, BA AF Pergam, S. A. Forsberg, C. W. Boeckh, M. J. Maynard, C. Limaye, A. P. Wald, A. Smith, N. L. Young, B. A. TI Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE herpes zoster; infection; liver transplantation; kidney transplantation; African American ID HEALTH-CARE-SYSTEM; VARICELLA-ZOSTER; VETERANS-AFFAIRS; LIVER-TRANSPLANTATION; RENAL-TRANSPLANTATION; ADMINISTRATIVE DATABASES; INFECTIOUS COMPLICATIONS; HEART-TRANSPLANTATION; LUNG TRANSPLANTATION; CELL TRANSPLANTATION AB Background Immunosuppressed patients are at increased risk for herpes zoster (HZ), but incidence in solid organ transplant (SOT) recipients has varied in multiple studies. To assess incidence of HZ, we examined patients who underwent SOT and received follow-up care within the large multicenter US Department of Veteran's Affairs healthcare system. Methods Incident cases of HZ were determined using ICD-9 coding from administrative databases. A multivariable Cox proportional hazards model, adjusted for a priori risk factors, was used to assess demographic factors associated with development of HZ. Results Among the 1077 eligible SOT recipients, the cohort-specific incidence rate of HZ was 22.2 per 1000 patient-years (95% confidence interval [CI], 18.1-27.4). African Americans (37.6 per 1000 [95% CI, 25.0-56.6]) and heart transplants recipients (40.0 per 1000 [95% CI, 23.2-68.9]) had the highest incidence of HZ. Patients transplanted between 2005 and 2007 had the lowest incidence (15.3 per 1000 [95% CI, 8.2-28.3]). In a multivariable model, African Americans (hazard ratio [HR] 1.88; 95% CI: 1.12, 3.17) and older transplant recipients (HR 1.13; 95% CI: 1.01, 1.27 [per 5-year increment]) had increased relative hazards of HZ. Conclusions These data demonstrate that HZ is a common infectious complication following SOT. Future studies focused on HZ prevention are needed in this high-risk population. C1 [Pergam, S. A.; Boeckh, M. J.; Limaye, A. P.; Wald, A.; Young, B. A.] Univ Washington, Dept Med, Seattle, WA USA. [Pergam, S. A.; Boeckh, M. J.; Wald, A.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Forsberg, C. W.; Maynard, C.; Smith, N. L.; Young, B. A.] Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Maynard, C.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Limaye, A. P.; Wald, A.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Wald, A.; Smith, N. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Young, B. A.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Seattle, WA USA. RP Pergam, SA (reprint author), Fred Hutchinson Canc Ctr, Vaccine & Infect Dis Div, 1100 Fairview Ave N,D3-100,POB 19024, Seattle, WA 98109 USA. EM spergam@fhcrc.org RI Pergam, Steven/C-2286-2008; Wald, Anna/B-6272-2012; Maynard, Charles/N-3906-2015 OI Pergam, Steven/0000-0002-6333-5196; Wald, Anna/0000-0003-3486-6438; Maynard, Charles/0000-0002-1644-7814 FU Office of Research and Development Cooperative Studies Program, Department of Veterans Affairs; Puget Sound VA Epidemiologic Research and Information Center, VA Research & Development, Seattle, WA; Joel Meyers Foundation; NIH [K23HL096831, CA18029, K24HL093294, RO1 DK079745]; American Society of Blood and Marrow Transplant/Viropharma, Inc.; [K24AI071113] FX The authors would like to thank Ted Gooley, PhD and Amelia Margaret, PhD for their assistance with the statistical analyses in this manuscript, and Ernie Ayers, MPTH for his administrative support. This material is based on work supported in part by the Office of Research and Development Cooperative Studies Program, Department of Veterans Affairs and the use of facilities at the VA Puget Sound Health Care System. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.; This study was supported in part by the Puget Sound VA Epidemiologic Research and Information Center, VA Research & Development, Seattle, WA. S.A.P. is supported by the Joel Meyers Foundation, NIH grant K23HL096831, and an American Society of Blood and Marrow Transplant/Viropharma, Inc. New Investigator Award. M.J.B is supported by NIH grant CA18029 (core C), and K24HL093294. A.W. is supported by K24AI071113. B.A.Y. is supported by NIH grant RO1 DK079745. NR 70 TC 20 Z9 21 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD FEB PY 2011 VL 13 IS 1 BP 15 EP 23 DI 10.1111/j.1399-3062.2010.00547.x PG 9 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 718AX UT WOS:000287093100003 PM 20636480 ER PT J AU Li, HM Rao, A Hogan, PG AF Li, Huiming Rao, Anjana Hogan, Patrick G. TI Interaction of calcineurin with substrates and targeting proteins SO TRENDS IN CELL BIOLOGY LA English DT Review ID ROOT GANGLION NEURONS; LONG-TERM DEPRESSION; T-CELL-ACTIVATION; TRANSCRIPTION FACTOR; CARDIAC-HYPERTROPHY; CYCLOSPORINE-A; IN-VIVO; INHIBITS CALCINEURIN; PHOSPHATASE-ACTIVITY; SIGNALING PATHWAYS AB Calcineurin is a calcium activated protein phosphatase with a major role in calcium signaling in diverse cells and organs and clinical importance as the target of the immunosuppressive drugs cyclosporin A and tacrolimus (FK506). Cell biology studies have focused mainly on the role of calcineurin in transcriptional signaling. Calcium entry in response to extracellular stimuli results in calcineurin activation, and signal transmission from the cytosol into the nucleus through dephosphorylation and nuclear translocation of the transcription factor nuclear factor of activated T cells (NFAT). This initiates a cascade of transcriptional events involved in physiological and developmental processes. Molecular analyses of the calcineurin-NFAT interaction have been extended recently to encompass the interaction of calcineurin with other substrates, targeting proteins and regulators of calcineurin activity. These studies have increased our understanding of how this essential calcium activated enzyme orchestrates intracellular events in cooperation with other signaling pathways, and have suggested a link between altered calcineurin signaling and the developmental anomalies of Down syndrome. C1 [Li, Huiming; Rao, Anjana; Hogan, Patrick G.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Li, Huiming; Rao, Anjana; Hogan, Patrick G.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Huiming] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rao, Anjana; Hogan, Patrick G.] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. RP Hogan, PG (reprint author), Childrens Hosp, Immune Dis Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM phogan@liai.org FU NIH [AI84167, AI40127] FX This work was funded by NIH grants AI84167 and AI40127 (to AR and PGH). NR 119 TC 121 Z9 127 U1 1 U2 22 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD FEB PY 2011 VL 21 IS 2 BP 91 EP 103 DI 10.1016/j.tcb.2010.09.011 PG 13 WC Cell Biology SC Cell Biology GA 723YZ UT WOS:000287544600004 PM 21115349 ER PT J AU Hou, J Fu, Y Zhou, J Li, W Xie, R Cao, F Gilbert, GE Shi, J AF Hou, J. Fu, Y. Zhou, J. Li, W. Xie, R. Cao, F. Gilbert, G. E. Shi, J. TI Lactadherin functions as a probe for phosphatidylserine exposure and as an anticoagulant in the study of stored platelets SO VOX SANGUINIS LA English DT Article DE lactadherin; microparticles; phosphatidylserine; procoagulant activity; stored platelets ID FLOW-CYTOMETRIC DETECTION; ANNEXIN-V; BLOOD-COAGULATION; THROMBIN GENERATION; APOPTOTIC CELLS; MICROPARTICLES; STORAGE; MEMBRANE; ACTIVATION; EXPRESSION AB Background and Objectives Annexin V, the long established standard method of measuring phosphatidylserine (PS) exposure, is not the most suitable probe for the study of stored platelets because of calcium dependence and low sensitivity under 8% PS exposure. The aim of this study was to show lactadherin as a sensitive probe for PS exposure and an effective anticoagulant for stored platelets. Materials and Methods PS exposure and the associated procoagulant activity of platelets in 20 platelet concentrate units were investigated by flow cytometry, confocal microscopy, coagulation time analysis and enzymatic assays. Annexin V and lactadherin were utilized separately in this study. Results Using lactadherin, we identified higher levels of PS exposure on the platelets and microparticles compared to detection using annexin V by flow cytometry. Lactadherin staining showed earlier PS exposure localized to platelets membrane in the earlier stage of storage. Subsequently, PS was distributed on the narrow rim of the plasma membrane and blebbing vesicles. Lactadherin or annexin V (32 nm) prolonged coagulation time 2 center dot 4 fold versus twofold. The production of thrombin and intrinsic/extrinsic factor Xase were inhibited approximately 85 similar to 90% and 65 similar to 70% by lactadherin and annexin V, respectively. Conclusion Lactadherin can provide the quantification and location of PS exposure on banked platelets in the absence of agonists. Furthermore, lactadherin is a more effective anticoagulant for inhibiting the procoagulant activity of stored platelets compared with annexin V. C1 [Hou, J.; Fu, Y.; Zhou, J.; Li, W.; Xie, R.; Cao, F.; Shi, J.] Harbin Med Coll, Affiliated Hosp 1, Dept Hematol, Harbin, Peoples R China. [Gilbert, G. E.; Shi, J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gilbert, G. E.; Shi, J.] Brigham & Womens Hosp, Dept Med, VA Boston Hlth Care Syst, Boston, MA 02115 USA. RP Shi, J (reprint author), Harbin Med Coll, Affiliated Hosp 1, Div Hematol, Dept Med, 23 Youzheng St, Harbin 150001, Peoples R China. EM jialan_shi@hms.harvard.edu FU National Natural Science Foundation of China [30871227]; National Traditional Chinese Medicine Bureau [0607LP15]; International Cooperation Foundation [WH05C01]; Scientific Foundation of Heilongjiang Province [GB08C401-02] FX This work was supported by the National Natural Science Foundation of China (30871227), the National Traditional Chinese Medicine Bureau (0607LP15), the International Cooperation Foundation (WH05C01), and the Scientific Foundation of Heilongjiang Province (GB08C401-02). We thank Xiuhua Liu, Hongjuan Yu, Chengfang Lv, Shuchuan Liu, Valerie A. Novakovic, Yingmei Zhang and Yueqiu Teng for excellent technical assistance. NR 35 TC 31 Z9 33 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD FEB PY 2011 VL 100 IS 2 BP 187 EP 195 DI 10.1111/j.1423-0410.2010.01375.x PG 9 WC Hematology SC Hematology GA 705OR UT WOS:000286146300003 PM 20738837 ER PT J AU Choi, WW Freire, MP Soukup, JR Yin, L Lipsitz, SR Carvas, F Williams, SB Hu, JC AF Choi, Wesley W. Freire, Marcos P. Soukup, Jane R. Yin, Lei Lipsitz, Stuart R. Carvas, Fernando Williams, Stephen B. Hu, Jim C. TI Nerve-sparing technique and urinary control after robot-assisted laparoscopic prostatectomy SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Radical prostatectomy; Continence; Outcomes; Nerve sparing ID RADICAL RETROPUBIC PROSTATECTOMY; QUALITY-OF-LIFE; URETHRAL SPHINCTER; RISK-FACTORS; CONTINENCE; PRESERVATION; INCONTINENCE; IMPACT; OUTCOMES; POTENCY AB To characterize determinants of 4-, 12-, and 24-month urinary control after robot-assisted laparoscopic prostatectomy (RALP). Adjusted comparative study using prospectively collected, patient self-reported urinary control for 602 consecutive RALPs. Urinary control defined as: (1) EPIC urinary function (UF) scored from 0 to 100 and (2) continence (zero pads per day). Both UF (62.8 vs. 42.4, P < 0.001) and continence rates (47.2 vs. 26.7%, P = 0.043) were better for bilateral nerve-sparing (BNS) vs. non-nerve-sparing (NNS) at 4 months, but only UF scores were significantly better at 12- (80.9 vs. 70.7, P = 0.014) and 24-month (89.2 vs. 77.4, P = 0.024) post-RALP. No difference in positive margin rates was observed. In multivariate analysis, older age (parameter estimate -0.42, 95% CI -0.80 to -0.04) and increasing gland volume (-0.13, CI -0.26 to -0.01) resulted in lower UF scores at 4 months, while higher pre-operative UF (0.25, CI 0.05-0.46), bladder neck-sparing technique (10.1, CI 3.79-16.35), BNS (19.1, CI 9.37-28.82), and unilateral nerve-sparing (19.00, CI 7.88-30.11) resulted in higher UF scores at 4 months. At 12 months, higher pre-operative UF (0.24, CI 0.083-0.40) and BNS (9.54, CI 1.92-17.16) resulted in higher UF scores. At 24 months, higher pre-operative UF (0.20, CI 0.06-0.33), bladder neck-sparing technique (7.80, CI 3.48-12.10), and BNS (7.86, CI 1.04-14.68) resulted in higher UF scores. BNS, bladder neck-sparing technique, and higher pre-operative UF score result in improved 24-month urinary control after RALP. C1 [Williams, Stephen B.; Hu, Jim C.] Brigham & Womens Hosp, Div Urol, Boston, MA 02115 USA. [Choi, Wesley W.; Freire, Marcos P.; Yin, Lei; Carvas, Fernando; Williams, Stephen B.; Hu, Jim C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg, Boston, MA 02115 USA. [Soukup, Jane R.; Lipsitz, Stuart R.; Hu, Jim C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Hu, Jim C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), Brigham & Womens Hosp, Div Urol, 45 Francis St,ASB-2, Boston, MA 02115 USA. EM swilliams22@partners.org; jhu2@partners.org FU Department of Defense [W81XWH-08-1-0283] FX This project was funded by the Department of Defense research grant to Dr. Hu (W81XWH-08-1-0283). NR 30 TC 20 Z9 20 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD FEB PY 2011 VL 29 IS 1 BP 21 EP 27 DI 10.1007/s00345-010-0601-z PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 709TX UT WOS:000286465400005 PM 20959992 ER PT J AU Tabach, Y Kogan-Sakin, I Buganim, Y Solomon, H Goldfinger, N Hovland, R Ke, XS Oyan, AM Kalland, KH Rotter, V Domany, E AF Tabach, Yuval Kogan-Sakin, Ira Buganim, Yosef Solomon, Hilla Goldfinger, Naomi Hovland, Randi Ke, Xi-Song Oyan, Anne M. Kalland, Karl-H. Rotter, Varda Domany, Eytan TI Amplification of the 20q Chromosomal Arm Occurs Early in Tumorigenic Transformation and May Initiate Cancer SO PLOS ONE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; BREAST-CANCER; PROSTATE-CANCER; COLORECTAL-CANCER; GENE-EXPRESSION; FREQUENT AMPLIFICATION; ARRAY-CGH; ANEUPLOIDY AB Duplication of chromosomal arm 20q occurs in prostate, cervical, colon, gastric, bladder, melanoma, pancreas and breast cancer, suggesting that 20q amplification may play a causal role in tumorigenesis. According to an alternative view, chromosomal imbalance is mainly a common side effect of cancer progression. To test whether a specific genomic aberration might serve as a cancer initiating event, we established an in vitro system that models the evolutionary process of early stages of prostate tumor formation; normal prostate cells were immortalized by the over-expression of human telomerase catalytic subunit hTERT, and cultured for 650 days till several transformation hallmarks were observed. Gene expression patterns were measured and chromosomal aberrations were monitored by spectral karyotype analysis at different times. Several chromosomal aberrations, in particular duplication of chromosomal arm 20q, occurred early in the process and were fixed in the cell populations, while other aberrations became extinct shortly after their appearance. A wide range of bioinformatic tools, applied to our data and to data from several cancer databases, revealed that spontaneous 20q amplification can promote cancer initiation. Our computational model suggests that 20q amplification induced deregulation of several specific cancer-related pathways including the MAPK pathway, the p53 pathway and Polycomb group factors. In addition, activation of Myc, AML, B-Catenin and the ETS family transcription factors was identified as an important step in cancer development driven by 20q amplification. Finally we identified 13 "cancer initiating genes", located on 20q13, which were significantly over-expressed in many tumors, with expression levels correlated with tumor grade and outcome suggesting that these genes induce the malignant process upon 20q amplification. C1 [Tabach, Yuval; Domany, Eytan] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Tabach, Yuval; Kogan-Sakin, Ira; Buganim, Yosef; Solomon, Hilla; Goldfinger, Naomi; Rotter, Varda] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Hovland, Randi] Haukeland Hosp, Dept Med, N-5021 Bergen, Norway. [Hovland, Randi] Univ Bergen, Dept Biomed, Bergen, Norway. [Ke, Xi-Song; Oyan, Anne M.; Kalland, Karl-H.] Univ Bergen, Gade Inst, Bergen, Norway. [Ke, Xi-Song; Oyan, Anne M.; Kalland, Karl-H.] Haukeland Hosp, Dept Microbiol, N-5021 Bergen, Norway. RP Tabach, Y (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02115 USA. EM eytan.domany@weizmann.ac.il RI DOMANY, EYTAN/K-1560-2012; Kalland, Karl-Henning/B-9445-2017 OI Kalland, Karl-Henning/0000-0003-4486-2334 FU Leir Charitable Foundation; EC; Center for Women's Health Research FX This research was supported by a grant from the Leir Charitable Foundation and by EC FP6 funding. Partial funding was provided by the Center for Women's Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 32 Z9 35 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 JAN 31 PY 2011 VL 6 IS 1 AR e14632 DI 10.1371/journal.pone.0014632 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300014 PM 21297939 ER PT J AU Yang, AC Fuh, JL Huang, NE Shia, BC Peng, CK Wang, SJ AF Yang, Albert C. Fuh, Jong-Ling Huang, Norden E. Shia, Ben-Chang Peng, Chung-Kang Wang, Shuu-Jiun TI Temporal Associations between Weather and Headache: Analysis by Empirical Mode Decomposition SO PLOS ONE LA English DT Article ID NONSTATIONARY TIME-SERIES; POPULATION-BASED SURVEY; BAROMETRIC-PRESSURE; MIGRAINE HEADACHE; CHINOOK WINDS AB Background: Patients frequently report that weather changes trigger headache or worsen existing headache symptoms. Recently, the method of empirical mode decomposition (EMD) has been used to delineate temporal relationships in certain diseases, and we applied this technique to identify intrinsic weather components associated with headache incidence data derived from a large-scale epidemiological survey of headache in the Greater Taipei area. Methodology/Principal Findings: The study sample consisted of 52 randomly selected headache patients. The weather time-series parameters were detrended by the EMD method into a set of embedded oscillatory components, i.e. intrinsic mode functions (IMFs). Multiple linear regression models with forward stepwise methods were used to analyze the temporal associations between weather and headaches. We found no associations between the raw time series of weather variables and headache incidence. For decomposed intrinsic weather IMFs, temperature, sunshine duration, humidity, pressure, and maximal wind speed were associated with headache incidence during the cold period, whereas only maximal wind speed was associated during the warm period. In analyses examining all significant weather variables, IMFs derived from temperature and sunshine duration data accounted for up to 33.3% of the variance in headache incidence during the cold period. The association of headache incidence and weather IMFs in the cold period coincided with the cold fronts. Conclusions/Significance: Using EMD analysis, we found a significant association between headache and intrinsic weather components, which was not detected by direct comparisons of raw weather data. Contributing weather parameters may vary in different geographic regions and different seasons. C1 [Yang, Albert C.] Chu Tung Vet Hosp, Dept Psychiat, Hsin Chu Cty, Taiwan. [Yang, Albert C.] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan. [Yang, Albert C.; Huang, Norden E.; Peng, Chung-Kang] Natl Cent Univ, Ctr Dynam Biomarkers & Translat Med, Chungli 32054, Taiwan. [Fuh, Jong-Ling; Wang, Shuu-Jiun] Taipei Vet Gen Hosp, Dept Neurol, Neurol Inst, Taipei, Taiwan. [Fuh, Jong-Ling; Wang, Shuu-Jiun] Natl Yang Ming Univ, Sch Med, Dept Neurol, Taipei 112, Taiwan. [Huang, Norden E.] Natl Cent Univ, Res Ctr Adapt Data Anal, Chungli 32054, Taiwan. [Shia, Ben-Chang] Fu Jen Catholic Univ, Dept Stat & Informat Sci, Taipei Cty, Taiwan. [Peng, Chung-Kang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Margret & HA Rey Inst Nonlinear Dynam Med,Beth Is, Boston, MA USA. RP Wang, SJ (reprint author), Taipei Vet Gen Hosp, Dept Neurol, Neurol Inst, Taipei, Taiwan. EM sjwang@vghtpe.gov.tw RI Peng, Chung-Kang/E-1489-2011; OI Peng, Chung-Kang/0000-0003-3666-9833; Fuh, Jong-Ling/0000-0001-9135-3351 FU Taipei-Veterans General Hospital [V97A-061, V100C-059, V100C-087, VGHUST 100-G7-1-1, VGHUST 100-G7-1-3]; National Science Council (NSC) of Taiwan [NSC 96-2314-B-075-075, 98-2314-B-010-019-MY2, NSC 99-2911-I-008-100]; Ministry of Education, Taipei, Taiwan FX The study was supported in part by a grant from Taipei-Veterans General Hospital (V97A-061, V100C-059, V100C-087, VGHUST 100-G7-1-1, VGHUST 100-G7-1-3), the National Science Council (NSC) of Taiwan (NSC 96-2314-B-075-075, 98-2314-B-010-019-MY2), NSC support for the Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 99-2911-I-008-100), and the Ministry of Education (Aim for the Top University Plan), Taipei, Taiwan. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 12 Z9 12 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 31 PY 2011 VL 6 IS 1 AR e14612 DI 10.1371/journal.pone.0014612 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300004 PM 21297940 ER PT J AU Kitchens, WH Elias, N Blaszkowsky, LS Cosimi, AB Hertl, M AF Kitchens, William H. Elias, Nahel Blaszkowsky, Lawrence S. Cosimi, A. Benedict Hertl, Martin TI Partial abdominal evisceration and intestinal autotransplantation to resect a mesenteric carcinoid tumor SO WORLD JOURNAL OF SURGICAL ONCOLOGY LA English DT Article ID EX-VIVO RESECTION; MIDGUT CARCINOIDS; SMALL-BOWEL; NEUROENDOCRINE TUMORS; COMPUTED-TOMOGRAPHY; METASTASES; MANAGEMENT; FIBROSIS; SURGERY; ROOT AB Background: Midgut carcinoids are neuroendocrine tumors that commonly metastasize to the intestinal mesentery, where they predispose to intestinal obstruction, ischemia and/or congestion. Because of their location, many mesenteric carcinoid tumors are deemed unresectable due to the risk of uncontrollable bleeding and prolonged intestinal ischemia. Case Presentation: We report the case of a 60-year-old male with a mesenteric carcinoid tumor obstructing his superior mesenteric vein, resulting in intestinal varices and severe recurrent GI bleeds. While his tumor was thought to be unresectable by conventional techniques, it was successfully resected using intestinal autotransplantation to safely gain access to the tumor. This case is the first described application of this technique to carcinoid tumors. Conclusions: Intestinal autotransplantation can be utilized to safely resect mesenteric carcinoid tumors from patients who were not previously thought to be surgical candidates. We review the literature concerning both carcinoid metastases to the intestinal mesentery and the use of intestinal autotransplantation to treat lesions involving the mesenteric root. C1 [Elias, Nahel; Cosimi, A. Benedict; Hertl, Martin] Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. [Blaszkowsky, Lawrence S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Hertl, M (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. EM mhertl@partners.org FU American Society of Transplant Surgeons FX WHK is supported by an ASTS-Roche Laboratories Scientist Scholarship from the American Society of Transplant Surgeons. NR 25 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7819 J9 WORLD J SURG ONCOL JI World J. Surg. Oncol. PD JAN 31 PY 2011 VL 9 AR 11 DI 10.1186/1477-7819-9-11 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 720UV UT WOS:000287309000001 PM 21281518 ER PT J AU Hwang, I Yoon, T Kim, C Cho, B Lee, S Song, MK AF Hwang, Inkyung Yoon, Taeho Kim, Changhoon Cho, Byungmann Lee, Sooil Song, Moon K. TI Different roles of zinc plus arachidonic acid on insulin sensitivity between high fructose- and high fat-fed rats SO LIFE SCIENCES LA English DT Article DE Insulin resistance; Diabetes; Hepatic glucose output; Hyperinsulinemic euglycemic clamp; Arachidonic acid; Zinc ID MAGNETIC-RESONANCE-SPECTROSCOPY; DEPENDENT DIABETES-MELLITUS; DEGRADING ENZYME GENE; METABOLIC SYNDROME; GLUCOSE-OXIDATION; LINOLEIC ACID; CORN SYRUP; HIS-PRO; RESISTANCE; MECHANISMS AB Aims: This study was to determine the effects of zinc plus arachidonic acid (ZA) treatment on the insulin action in the specific ZA target organs using hyperinsulinemic euglycemic clamp method. Main methods: 18 Sprague-Dawley rats weighing similar to 130 g were divided into 3 groups of 6 rats and treated them with 1) normal rat chow, 2) high fructose (60.0%) diet only, or 3) the same fructose diet plus drinking water containing 10 mg zinc plus 50 mg arachidonic acid (AA)/L In a separate study, male Wistar rats weighing similar to 250 g were fed normal rat chow (n = 4) or high fat (66.5%) diet with drinking water containing zero (n = 9) or 10 mg AA plus 20 mg zinc /L (n = 9). After 4 week treatment, insulin action was assessed using the hyperinsulinemic eguglycemic clamp technique. Key findings: High fructose feeding impaired suppression of hepatic glucose output by insulin compared to controls during the clamp procedure (4.39 vs. 2.35 mg/kg/min; p<0.05). However, ZA treatment in high fructose-fed rats showed a significant improvement of hepatic insulin sensitivity compared to non-treatment controls (4.39 vs. 2.18 mg/kg/min; p<0.05). Glucose infusion rates in Wistar rats maintained on a high fat diet (HFD) were significantly lower compared to control rats (22.8 +/- 1.3 vs. 31.9 +/- 1.4 mg/kg/min; p<0.05). ZA treatment significantly improved (similar to 43%) peripheral tissue insulin sensitivity in HFD fed animals (26.7 +/- 1.3 [n=9] vs. 22.8 +/- 1.3 mg/kg/min; p<0.05). Significance: These data demonstrate that ZA treatment is effective in improving glucose utilization in hyperglycemic rats receiving either a high-fructose or a high-fat diet. Published by Elsevier Inc. C1 [Song, Moon K.] VA Great Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Song, Moon K.] Univ Calif Los Angeles, Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Hwang, Inkyung; Yoon, Taeho; Kim, Changhoon; Cho, Byungmann; Lee, Sooil] Pusan Natl Univ, Coll Med, Dept Prevent Med, Pusan 609735, South Korea. RP Song, MK (reprint author), VA Great Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. EM mksong@earthlink.net FU Medical Research Institute; Pusan National University Hospital; Korean Scientific Foundation FX This study was supported by a Medical Research Institute Grant, Pusan National University Hospital, and the Korean Scientific Foundation. We are very grateful to Dr. Eain Cornford, Professor of Neurology at the UCLA School of Medicine, for his most valuable comments and editorial help in the preparation of this final version of manuscript. NR 66 TC 3 Z9 3 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JAN 31 PY 2011 VL 88 IS 5-6 BP 278 EP 284 DI 10.1016/j.lfs.2010.12.007 PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 714FK UT WOS:000286792700012 PM 21167181 ER PT J AU Jones, PB Adams, KW Rozkalne, A Spires-Jones, TL Hshieh, TT Hashimoto, T von Armin, CAF Mielke, M Bacskai, BJ Hyman, BT AF Jones, Phillip B. Adams, Kenneth W. Rozkalne, Anete Spires-Jones, Tara L. Hshieh, Tammy T. Hashimoto, Tadafumi von Armin, Christine A. F. Mielke, Mathew Bacskai, Brian J. Hyman, Bradley T. TI Apolipoprotein E: Isoform Specific Differences in Tertiary Structure and Interaction with Amyloid-beta in Human Alzheimer Brain SO PLOS ONE LA English DT Article ID RESONANCE ENERGY-TRANSFER; DOMAIN INTERACTION; A-BETA; TRANSGENIC MICE; TYPE-4 ALLELE; E GENOTYPE; DISEASE; APOE; BINDING; PROTEIN AB We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in A beta-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with A beta than ApoE4, but a greater proportion of A beta molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with A beta deposition. We found an increased number of ApoE N-terminal fragments in ApoE4 plaques, consistent with the observation that ApoE4 is more easily cleaved than ApoE3. In addition, we measured a small but significant isoform specific difference in ApoE domain interaction. Based on our in situ data, supported by traditional biochemical data, we propose a pathway by which isoform specific conformational differences increase the level of cleavage at the hinge region of ApoE4, leading to a loss of ApoE function to mediate clearance of A beta and thereby increase the risk of AD for carriers of the APOE epsilon 4 allele. C1 [Jones, Phillip B.; Adams, Kenneth W.; Rozkalne, Anete; Spires-Jones, Tara L.; Hshieh, Tammy T.; Hashimoto, Tadafumi; Mielke, Mathew; Bacskai, Brian J.; Hyman, Bradley T.] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, Charlestown, MA USA. [von Armin, Christine A. F.] Univ Ulm Klinikum, Neurol Klin, Ulm, Germany. RP Jones, PB (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, Charlestown, MA USA. EM bhyman@partners.org RI Hashimoto, Tadafumi/A-7723-2013; OI Jones, Phillip/0000-0003-0525-6323 FU National Institutes of Health (NIH) [AG026240, AG005134, K99 AG033670-01A1, DK048549] FX This work was supported by National Institutes of Health (NIH) grants AG026240, AG005134, K99 AG033670-01A1, and DK048549 (www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 29 Z9 29 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 JAN 31 PY 2011 VL 6 IS 1 AR e14586 DI 10.1371/journal.pone.0014586 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 714UK UT WOS:000286834300002 PM 21297948 ER PT J AU Saydam, O Ozdener, GB Senol, O Mizrak, A Prabhakar, S Stemmer-Rachamimov, AO Breakefield, XO Brenner, GJ AF Saydam, Okay Ozdener, Gokhan Baris Senol, Ozlem Mizrak, Arda Prabhakar, Shilpa Stemmer-Rachamimov, Anat O. Breakefield, Xandra O. Brenner, Gary J. TI A novel imaging-compatible sciatic nerve schwannoma model SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Schwannoma; NF2; Sciatic nerve tumor model ID NEUROFIBROMATOSIS TYPE-2; PROTEIN AB Benign schwannomas are common tumors of the cranial and peripheral nerves, causing pain and loss of function. The development of effective therapy for these tumors has been hampered by the lack of relevant experimental in vivo models for convenient testing. Here, we describe a novel schwannoma model in which an immortalized human schwannoma cell line, HEI-193, established from an neurofibromatosis type 2 patient, has been stably transduced with fluorescent protein and luciferase reporters and implanted within the sciatic nerve of nude mice. These cells reliably formed a tumor within several weeks which had pathologic characteristics of schwannoma tumors. This model system will be useful for investigation of schwannoma biology and for preclinical assessment of therapeutic agents. (C) 2010 Elsevier B.V. All rights reserved. C1 [Saydam, Okay; Ozdener, Gokhan Baris; Senol, Ozlem; Mizrak, Arda; Prabhakar, Shilpa; Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. [Saydam, Okay; Ozdener, Gokhan Baris; Senol, Ozlem; Mizrak, Arda; Prabhakar, Shilpa; Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [Saydam, Okay; Ozdener, Gokhan Baris; Senol, Ozlem; Mizrak, Arda; Prabhakar, Shilpa; Breakefield, Xandra O.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02129 USA. [Ozdener, Gokhan Baris; Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurooncol Lab, Boston, MA 02129 USA. [Ozdener, Gokhan Baris; Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. [Ozdener, Gokhan Baris; Brenner, Gary J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02129 USA. RP Saydam, O (reprint author), Med Univ Vienna, Dept Pediat, A-1090 Vienna, Austria. EM okay.saydam@meduniwien.ac.at; GJBRENNER@PARTNERS.ORG FU Children's Tumor Foundation [2007-01-043, 2007-05-011]; NINDS [NS24279]; NCI [CA69246, CA86355] FX This study was supported by the Children's Tumor Foundation "Young Investigator Award" 2007-01-043 (O.S.), Drug Discovery Initiative Award 2007-05-011 (G.J.B.), NINDS NS24279 (X.O.B., O.S. and A.S.), NCI CA69246 (X.O.B.) and CA86355 (X.O.B.). NR 11 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 30 PY 2011 VL 195 IS 1 BP 75 EP 77 DI 10.1016/j.jneumeth.2010.10.021 PG 3 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 717UR UT WOS:000287073400010 PM 21111000 ER PT J AU Holzel, BK Carmody, J Vangel, M Congleton, C Yerramsetti, SM Gard, T Lazar, SW AF Hoelzel, Britta K. Carmody, James Vangel, Mark Congleton, Christina Yerramsetti, Sita M. Gard, Tim Lazar, Sara W. TI Mindfulness practice leads to increases in regional brain gray matter density SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Meditation; Mindfulness; Voxel-based morphometry; Gray matter; Magnetic resonance imaging; Hippocampus; Posterior cingulate ID HIPPOCAMPAL INACTIVATION DISRUPTS; VENTROMEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; VOXEL-BASED MORPHOMETRY; LONG-TERM MEDITATION; LOCUS-COERULEUS; TEMPOROPARIETAL JUNCTION; INTEROCEPTIVE AWARENESS; CORTICAL THICKNESS AB Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular, but to date little is known about neural mechanisms associated with these interventions. Mindfulness-Based Stress Reduction (MBSR), one of the most widely used mindfulness training programs, has been reported to produce positive effects on psychological well-being and to ameliorate symptoms of a number of disorders. Here, we report a controlled longitudinal study to investigate pre-post changes in brain gray matter concentration attributable to participation in an MBSR program. Anatomical magnetic resonance (MR) images from 16 healthy, meditation-naive participants were obtained before and after they underwent the 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry, and compared with a waiting list control group of 17 individuals. Analyses in a priori regions of interest confirmed increases in gray matter concentration within the left hippocampus. Whole brain analyses identified increases in the posterior cingulate cortex, the temporo-parietal junction, and the cerebellum in the MBSR group compared with the controls. The results suggest that participation in MBSR is associated with changes in gray matter concentration in brain regions involved in learning and memory processes, emotion regulation, self-referential processing, and perspective taking. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Hoelzel, Britta K.; Vangel, Mark; Congleton, Christina; Yerramsetti, Sita M.; Gard, Tim; Lazar, Sara W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hoelzel, Britta K.; Gard, Tim] Univ Giessen, Bender Inst Neuroimaging, D-35390 Giessen, Germany. [Carmody, James] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Holzel, BK (reprint author), Massachusetts Gen Hosp, 120 2nd Ave, Charlestown, MA 02129 USA. EM britta@nmr.mgh.harvard.edu RI Lazar, Sara/G-3809-2012 OI Lazar, Sara/0000-0003-1126-8363 FU National Institutes of Health-NCCAM [R21-AT003425-01A2]; British Broadcasting Company; Mind and Life Institute; European Community; National Institutes of Health [K01AT00694] FX We thank our participants for their cooperation and the Center for Mindfulness for conducting the Mindfulness-Based Stress Reduction courses. We thank Daniel McCaffrey and Nik Olendzki for support in data collection, and Douglas Greve, Ulrich Ott, and Julie Bates for helpful discussions. This research was funded by the National Institutes of Health-NCCAM (R21-AT003425-01A2), the British Broadcasting Company, and the Mind and Life Institute (Varela research grant). B.K.H. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. S.W.L. was supported by the National Institutes of Health funding K01AT00694. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflicts of interest. NR 90 TC 344 Z9 361 U1 34 U2 230 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 JAN 30 PY 2011 VL 191 IS 1 BP 36 EP 43 DI 10.1016/j.pscychresns.2010.08.006 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 737TM UT WOS:000288591100006 PM 21071182 ER PT J AU Quintana, J Lee, J Marcus, M Kee, K Wong, T Yerevanian, A AF Quintana, Javier Lee, Junghee Marcus, Michael Kee, Kimmy Wong, Tiffany Yerevanian, Armen TI Brain dysfunctions during facial discrimination in schizophrenia: Selective association to affect decoding SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Cognitive deficits; Social cognition; Facial information processing; Compensatory mechanisms ID FUSIFORM FACE AREA; AFFECT RECOGNITION; EMOTION; FMRI; PERCEPTION; EXPRESSIONS; INFORMATION; CORTEX; ROBUST; OPTIMIZATION AB Schizophrenia patients exhibit impaired facial affect perception, yet the exact nature of this impairment remains unclear. We investigated neural activity related to processing facial emotional and non-emotional information and complex images in 12 schizophrenia patients and 15 healthy controls using functional magnetic resonance imaging. All subjects performed a facial information processing task with three conditions: matching facial emotion, matching facial identity, and matching complex visual patterns. Patients and controls showed comparable behavioral performance in all task conditions. The neural activation patterns in schizophrenia patients and healthy controls were distinctly different while processing affect-related facial information but not other non-emotional facial features. During emotion matching, orbital frontal cortex and left amydala activations were found in controls but not in patients. When comparing emotion versus identity matching, controls activated the fusiform and middle temporal gyri, left superior temporal gyrus, and right inferior and middle frontal gyrus, whereas schizophrenia patients only activated the middle and inferior frontal gyri, the frontal operculi and the right insular cortex. Our findings suggest that schizophrenia patients and healthy controls may utilize different neural networks when processing facial emotional information. Published by Elsevier Ireland Ltd. C1 [Quintana, Javier] Univ Calif Los Angeles, Dept Psychiat, Greater Los Angeles VA Healthcare Syst, Mental Illness Res Educ & Clin Ctr MIRECC VSN22, Los Angeles, CA 90073 USA. [Quintana, Javier; Lee, Junghee; Marcus, Michael; Kee, Kimmy; Wong, Tiffany; Yerevanian, Armen] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Kee, Kimmy] Calif State Univ Channel Isl, Dept Psychol, Camarillo, CA 93012 USA. RP Quintana, J (reprint author), Univ Calif Los Angeles, Dept Psychiat, Greater Los Angeles VA Healthcare Syst, Mental Illness Res Educ & Clin Ctr MIRECC VSN22, 11301 Wilshire Blvd,Bldg 210A MIRECC,Room 128, Los Angeles, CA 90073 USA. EM xquintan@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 FU Veterans Administration Medical Research Service; Northstar Fund FX This research was partially supported by a Merit Review Award from the Veterans Administration Medical Research Service to J. Quintana. We would like to thank Jonathan Osowsky and Nicolle Ma for their helpful assistance.; We also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, and Northstar Fund for their generous support of the UCLA Brain Mapping Center. NR 50 TC 9 Z9 9 U1 0 U2 0 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 JAN 30 PY 2011 VL 191 IS 1 BP 44 EP 50 DI 10.1016/j.pscychresns.2010.09.005 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 737TM UT WOS:000288591100007 PM 21145212 ER PT J AU Reyon, D Kirkpatrick, JR Sander, JD Zhang, F Voytas, DF Joung, JK Dobbs, D Coffman, CR AF Reyon, Deepak Kirkpatrick, Jessica R. Sander, Jeffry D. Zhang, Feng Voytas, Daniel F. Joung, J. Keith Dobbs, Drena Coffman, Clark R. TI ZFNGenome: A comprehensive resource for locating zinc finger nuclease target sites in model organisms SO BMC GENOMICS LA English DT Article ID POOL ENGINEERING OPEN; CLEAVAGE DOMAIN; GENE-THERAPY; STEM-CELLS; MUTAGENESIS; PROTEINS; DATABASE; BINDING; DROSOPHILA; INFORMATION AB Background: Zinc Finger Nucleases (ZFNs) have tremendous potential as tools to facilitate genomic modifications, such as precise gene knockouts or gene replacements by homologous recombination. ZFNs can be used to advance both basic research and clinical applications, including gene therapy. Recently, the ability to engineer ZFNs that target any desired genomic DNA sequence with high fidelity has improved significantly with the introduction of rapid, robust, and publicly available techniques for ZFN design such as the Oligomerized Pool ENgineering (OPEN) method. The motivation for this study is to make resources for genome modifications using OPEN-generated ZFNs more accessible to researchers by creating a user-friendly interface that identifies and provides quality scores for all potential ZFN target sites in the complete genomes of several model organisms. Description: ZFNGenome is a GBrowse-based tool for identifying and visualizing potential target sites for OPEN-generated ZFNs. ZFNGenome currently includes a total of more than 11.6 million potential ZFN target sites, mapped within the fully sequenced genomes of seven model organisms; S. cerevisiae, C. reinhardtii, A. thaliana, D. melanogaster, D. rerio, C. elegans, and H. sapiens and can be visualized within the flexible GBrowse environment. Additional model organisms will be included in future updates. ZFNGenome provides information about each potential ZFN target site, including its chromosomal location and position relative to transcription initiation site(s). Users can query ZFNGenome using several different criteria (e.g., gene ID, transcript ID, target site sequence). Tracks in ZFNGenome also provide "uniqueness" and ZiFOpT ((Z) under bar inc (F) under bar inger (O) under bar PEN (T) under bar argeter) "confidence" scores that estimate the likelihood that a chosen ZFN target site will function in vivo. ZFNGenome is dynamically linked to ZiFDB, allowing users access to all available information about zinc finger reagents, such as the effectiveness of a given ZFN in creating double-stranded breaks. Conclusions: ZFNGenome provides a user-friendly interface that allows researchers to access resources and information regarding genomic target sites for engineered ZFNs in seven model organisms. This genome-wide database of potential ZFN target sites should greatly facilitate the utilization of ZFNs in both basic and clinical research. ZFNGenome is freely available at: http://bindr.gdcb.iastate.edu/ZFNGenome or at the Zinc Finger Consortium website: http://www.zincfingers.org/. C1 [Reyon, Deepak; Kirkpatrick, Jessica R.; Dobbs, Drena; Coffman, Clark R.] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. [Sander, Jeffry D.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA 02129 USA. [Sander, Jeffry D.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Sander, Jeffry D.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zhang, Feng; Voytas, Daniel F.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Zhang, Feng; Voytas, Daniel F.] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Zhang, Feng] Cellectis Plant Sci, St Paul, MN 55114 USA. [Reyon, Deepak; Dobbs, Drena] Iowa State Univ, Bioinformat & Computat Biol Grad Program, Ames, IA 50011 USA. RP Reyon, D (reprint author), Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. EM dreyon@iastate.edu FU NSF [DBI 0923827]; NIH [R01 GM069906, R01 GM088040, T32 CA009216]; The Roy J. Carver Charitable Trust [083185]; Center for Integrated Animal Genomics at Iowa State University FX We thank members of our research groups for helpful discussions and Chris Campbell for assistance with 64 bit conversion. We also thank Jo Anne Powell-Coffman, Jeff Essner, David Wright, Ben Lewis and Rasna Walia for critical comments on the ZFNGenome server and the manuscript. This work was supported by NSF DBI 0923827 to DFV, DD, and JKJ, NIH grants R01 GM069906 and R01 GM088040 to JKJ, The Roy J. Carver Charitable Trust 083185 to CRC, and the Center for Integrated Animal Genomics at Iowa State University to DD. JDS was supported by the NIH T32 CA009216. NR 51 TC 15 Z9 18 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 28 PY 2011 VL 12 AR 83 DI 10.1186/1471-2164-12-83 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 723TR UT WOS:000287530500002 PM 21276248 ER PT J AU Echchgadda, I Chang, TH Sabbah, A Bakri, I Ikeno, Y Hubbard, GB Chatterjee, B Bose, S AF Echchgadda, Ibtissam Chang, Te-Hung Sabbah, Ahmed Bakri, Imad Ikeno, Yuji Hubbard, Gene B. Chatterjee, Bandana Bose, Santanu TI Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense SO BMC CANCER LA English DT Article ID RNA VIRUSES; CANCER; RESISTANT; CELLS; RECEPTOR; REPLICATION; ACTIVATION; INFECTION; DEFECTS AB Background: Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. Methods: The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors Results: We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFN alpha/beta)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells. Conclusions: We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells. C1 [Echchgadda, Ibtissam; Bakri, Imad; Chatterjee, Bandana] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Inst Biotechnol, San Antonio, TX 78245 USA. [Chang, Te-Hung; Sabbah, Ahmed; Bose, Santanu] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Ikeno, Yuji; Hubbard, Gene B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Ikeno, Yuji; Chatterjee, Bandana] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Chatterjee, B (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, Inst Biotechnol, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM chatterjee@uthscsa.edu; bose@uthscsa.edu FU American Lung Association [RG-49629-N]; NIH [AI069062, AI083387, CA129246, AG10486, AG19660]; UTHSCSA-UTSA SALSI; VA Merit Review; UTHSCSA IIMS; NIH NIDCR [DE14318]; Cancer Center Program [CA54174 (NIH-P30)]; Cancer Therapy and Research Center at the University of Texas Health Science Center-San Antonio through the NCI Cancer Center [2 P30 CA054174-17] FX We would like to thank Jesus Segovia for technical assistance. This work was supported in part by the American Lung Association National Biomedical Research grant (RG-49629-N) (S. Bose), NIH grants AI069062 (SB), AI083387 (SB), CA129246 (SB; BC), AG10486 & AG19660 (BC), UTHSCSA-UTSA SALSI Grant (SB; BC), VA Merit Review Grant (BC). The work was also supported by Translational Technology Resources Award (to IE) from UTHSCSA IIMS. AS was supported by NIH NIDCR grant DE14318 for the COSTAR program. BC is a VA Senior Research Career Scientist. FACS at the UTHSCSA Core Facility was supported by the Cancer Center Program grant CA54174 (NIH-P30). Financial assistance was also provided to SB and BC by the Cancer Therapy and Research Center at the University of Texas Health Science Center-San Antonio through the NCI Cancer Center Support Grant (2 P30 CA054174-17). NR 33 TC 8 Z9 9 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 28 PY 2011 VL 11 AR 43 DI 10.1186/1471-2407-11-43 PG 18 WC Oncology SC Oncology GA 720WY UT WOS:000287314600002 PM 21276246 ER PT J AU Vickers, AJ Cronin, AM Begg, CB AF Vickers, Andrew J. Cronin, Angel M. Begg, Colin B. TI One statistical test is sufficient for assessing new predictive markers SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article ID OPERATING CHARACTERISTIC CURVES; RISK PREDICTION; ROC CURVE; MODELS; PROSTATECTOMY; PERFORMANCE; FRAMEWORK; ABILITY; BIOPSY; CANCER AB Background: We have observed that the area under the receiver operating characteristic curve (AUC) is increasingly being used to evaluate whether a novel predictor should be incorporated in a multivariable model to predict risk of disease. Frequently, investigators will approach the issue in two distinct stages: first, by testing whether the new predictor variable is significant in a multivariable regression model; second, by testing differences between the AUC of models with and without the predictor using the same data from which the predictive models were derived. These two steps often lead to discordant conclusions. Discussion: We conducted a simulation study in which two predictors, X and X*, were generated as standard normal variables with varying levels of predictive strength, represented by means that differed depending on the binary outcome Y. The data sets were analyzed using logistic regression, and likelihood ratio and Wald tests for the incremental contribution of X* were performed. The patient-specific predictors for each of the models were then used as data for a test comparing the two AUCs. Under the null, the size of the likelihood ratio and Wald tests were close to nominal, but the area test was extremely conservative, with test sizes less than 0.006 for all configurations studied. Where X* was associated with outcome, the area test had much lower power than the likelihood ratio and Wald tests. Summary: Evaluation of the statistical significance of a new predictor when there are existing clinical predictors is most appropriately accomplished in the context of a regression model. Although comparison of AUCs is a conceptually equivalent approach to the likelihood ratio and Wald test, it has vastly inferior statistical properties. Use of both approaches will frequently lead to inconsistent conclusions. Nonetheless, comparison of receiver operating characteristic curves remains a useful descriptive tool for initial evaluation of whether a new predictor might be of clinical relevance. C1 [Vickers, Andrew J.; Begg, Colin B.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Cronin, Angel M.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Vickers, AJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave,Box 44, New York, NY 10065 USA. EM vickersa@mskcc.org OI Vickers, Andrew/0000-0003-1525-6503 FU Prostate Cancer Foundation; Sidney Kimmel Center for Prostate and Urologic Cancers; National Cancer Institute [P50-CA92629, CA136783] FX Supported in part by funds from David H. Koch provided through the Prostate Cancer Foundation, the Sidney Kimmel Center for Prostate and Urologic Cancers, the P50-CA92629 SPORE grant from the National Cancer Institute to Dr. P. T. Scardino and an NCI grant on predictive modeling (CA136783). The funding body had no role in 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. NR 27 TC 70 Z9 70 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JAN 28 PY 2011 VL 11 AR 13 DI 10.1186/1471-2288-11-13 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 723UC UT WOS:000287531700001 PM 21276237 ER PT J AU Zhong, SP Machida, K Tsukamoto, H Johnson, DL AF Zhong, Shuping Machida, Keigo Tsukamoto, Hide Johnson, Deborah L. TI Alcohol Induces RNA Polymerase III-dependent Transcription through c-Jun by Co-regulating TATA-binding Protein (TBP) and Brf1 Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ONCOGENIC TRANSFORMATION; CELL-PROLIFERATION; INHIBITION; ACTIVATION; STRESS; TFIIIB; ELK-1; JNK1 AB Chronic alcohol consumption is associated with steatohepatitis and cirrhosis, enhancing the risk for hepatocellular carcinoma. RNA polymerase (pol) III transcribes a variety of small, untranslated RNAs, including tRNAs and 5S rRNAs, which determine the biosynthetic capacity of cells. Increased RNA pol III-dependent transcription, observed in transformed cells and human tumors, is required for oncogenic transformation. Given that alcohol consumption increases risk for liver cancer, we examined whether alcohol regulates this class of genes. Ethanol induces RNA pol III-dependent transcription in both HepG2 cells and primary mouse hepatocytes in a manner that requires ethanol metabolism and the activation of JNK1. This regulatory event is mediated, at least in part, through the ability of ethanol to induce expression of the TFIIIB components, Brf1, and the TATA-binding protein (TBP). Induction of TBP, Brf1, and RNA pol III-dependent gene expression is driven by enhanced c-Jun expression. Ethanol promotes a marked increase in the direct recruitment of c-Jun to TBP, Brf1, and tRNA gene promoters. Chronic alcohol administration in mice leads to enhanced expression of TBP, Brf1, tRNA, and 5S rRNA gene transcription in the liver. These alcohol-dependent increases are more pronounced in transgenic animals that express the HCV NS5A protein that display increased incidence of liver tumors. Together, these results identify a new class of genes that are regulated by alcohol through the co-regulation of TFIIIB components and define a central role for c-Jun in this process. C1 [Tsukamoto, Hide] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Tsukamoto, Hide] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Machida, Keigo] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Zhong, Shuping; Johnson, Deborah L.] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [Zhong, Shuping; Johnson, Deborah L.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. RP Zhong, SP (reprint author), 2011 Zonal Ave,HMR 605 MC 9097, Los Angeles, CA 90033 USA. EM szhong@usc.edu FU National Institutes of Health through the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis [P50 AA011999]; National Institutes of Health [AA017288, CA108614] FX This work was supported, in whole or in part, by National Institutes of Health Grant P50 AA011999 (to S.Z.) through the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and National Institutes of Health Grants AA017288 (to S.Z.) and CA108614 (to D.L.J.). NR 27 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2011 VL 286 IS 4 BP 2393 EP 2401 DI 10.1074/jbc.M110.192955 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709TM UT WOS:000286464300003 PM 21106530 ER PT J AU Lin, WY Wu, GY Li, SY Weinberg, EM Kumthip, K Peng, LF Mendez-Navarro, J Chen, WC Jilg, N Zhao, H Goto, K Zhang, LL Brockman, MA Schuppan, D Chung, RT AF Lin, Wenyu Wu, Guoyang Li, Shaoyong Weinberg, Ethan M. Kumthip, Kattareeya Peng, Lee F. Mendez-Navarro, Jorge Chen, Wen-Chi Jilg, Nikolaus Zhao, Hong Goto, Kaku Zhang, Leiliang Brockman, Mark A. Schuppan, Detlef Chung, Raymond T. TI HIV and HCV Cooperatively Promote Hepatic Fibrogenesis via Induction of Reactive Oxygen Species and NF kappa B SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VIRUS CORE PROTEIN; INDUCED LIVER FIBROSIS; C VIRUS; STELLATE CELLS; MITOCHONDRIAL INJURY; OXIDATIVE STRESS; GENE-EXPRESSION; RAT-LIVER; ACTIVATION; REPLICATION AB HIV/HCV coinfection leads to accelerated hepatic fibrosis progression, with higher rates of cirrhosis, liver failure, and liver death than does HCV mono-infection. However, the pro-fibrogenic role of HIV on hepatocytes and hepatic stellate cells (HSC) has not been fully clarified. We hypothesized that HIV, HCV induce liver fibrosis through altered regulation of the production of extracellular matrix and matrix metalloproteinases. We examined the fibrogenesis- and fibrolysis-related gene activity in LX2 HSC and Huh7.5.1 cells in the presence of inactivated CXCR4 and CCR5 HIV, as well as HCV JFH1 virus. The role of reactive oxygen species (ROS) upon fibrosis gene expression was assessed using the ROS inhibitor. Fibrosis-related transcripts including procollagen alpha 1(I) (CoL1A), TIMP1, and MMP3 mRNA were measured by qPCR. TIMP1 and MMP3 protein expression were assessed by ELISA. We found that inactivated CXCR4 HIV and CCR5 HIV increased CoL1A, and TIMP1 expression in both HSC and Huh7.5.1 cells; the addition of JFH1 HCV further increased CoL1A and TIMP1 expression. CXCR4 HIV and CCR5 HIV induced ROS production in HSC and Huh7.5.1 cells which was further enhanced by JFH1 HCV. The ROS inhibitor DPI abrogated HIV -and HCV-induced CoL1A and TIMP1 expression. HIV and HCV-induced CoL1A and TIMP1 expression were also blocked by NF kappa B siRNA. Our data provide further evidence that HIV and HCV independently regulate hepatic fibrosis progression through the generation of ROS; this regulation occurs in an NF kappa B-dependent fashion. Strategies to limit the viral induction of oxidative stress are warranted to inhibit fibrogenesis. C1 [Mendez-Navarro, Jorge; Chen, Wen-Chi; Jilg, Nikolaus; Zhao, Hong; Goto, Kaku; Zhang, Leiliang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02114 USA. [Wu, Guoyang] Xiamen Univ, Hepatobiliary Surg Dept, Zhongshan Hosp, Xiamen, Fujian, Peoples R China. [Li, Shaoyong; Schuppan, Detlef] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Brockman, Mark A.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. RP Chung, RT (reprint author), MA Gen Hosp, Gastrointestinal Unit, Warren 1007, Boston, MA 02114 USA. EM rtchung@partners.org RI LI, Shaoyong/D-1052-2013 FU National Institutes of Health-MGH Center For Human Immunology Pilot/Feasibility Study; National Institutes of Health [AI069939, AI082630, AI066313U19] FX This work was supported, in whole or in part, by National Institutes of Health-MGH Center For Human Immunology Pilot/Feasibility Study Grant (to W. L.), and National Institutes of Health Grants AI069939 (to R. T. C.), AI082630 (to R. T. C.), and AI066313U19 (to D. S.). NR 46 TC 42 Z9 44 U1 0 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 JAN 28 PY 2011 VL 286 IS 4 BP 2665 EP 2674 DI 10.1074/jbc.M110.168286 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709TM UT WOS:000286464300032 PM 21098019 ER PT J AU Zou, CB Butler, PL Coon, TA Smith, RM Hammen, G Zhao, YT Chen, BB Mallampalli, RK AF Zou, Chunbin Butler, Phillip L. Coon, Tiffany A. Smith, Rebecca M. Hammen, Gary Zhao, Yutong Chen, Bill B. Mallampalli, Rama K. TI LPS Impairs Phospholipid Synthesis by Triggering beta-Transducin Repeat-containing Protein (beta-TrCP)-mediated Polyubiquitination and Degradation of the Surfactant Enzyme Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (LPCAT1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; GLYCOGEN-SYNTHASE KINASE-3; ADULT-RAT LUNG; LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE; REGULATORY ENZYME; CELLS; PHOSPHORYLATION; EXPRESSION; PHOSPHATIDYLCHOLINE; TRANSCRIPTION AB Acyl-CoA: lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a relatively newly described and yet indispensable enzyme needed for generation of the bioactive surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPtdCho). Here, we show that lipopolysaccharide (LPS) causes LPCAT1 degradation using the Skp1-Cullin-F-box ubiquitin E3 ligase component, beta-transducin repeat-containing protein (beta-TrCP), that polyubiquitinates LPCAT1, thereby targeting the enzyme for proteasomal degradation. LPCAT1 was identified as a phosphoenzyme as Ser(178) within a phosphodegron was identified as a putative molecular recognition site for glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylation that recruits beta-TrCP docking within the enzyme. beta-TrCP ubiquitinates LPCAT1 at an acceptor site (Lys(221)), as substitution of Lys(221) with Arg abrogated LPCAT1 polyubiquitination. LPS profoundly reduced immunoreactive LPCAT1 levels and impaired lung surfactant mechanics, effects that were overcome by siRNA to beta-TrCP and GSK-3 beta or LPCAT1 gene transfer, respectively. Thus, LPS appears to destabilize the LPCAT1 protein by GSK-3 beta-mediated phosphorylation within a canonical phosphodegron for beta-TrCP docking and site-specific ubiquitination. LPCAT1 is the first lipogenic substrate for beta-TrCP, and the results suggest that modulation of the GSK-3 beta-SCF beta(TrCP) E3 ligase effector pathway might be a unique strategy to optimize dipalmitoylphosphatidylcholine levels in sepsis. C1 [Mallampalli, Rama K.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15260 USA. [Hammen, Gary] Washington Univ, Dept Anat & Neurobiol, St Louis, MO 63110 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Med, Acute Lung Injury Ctr Excellence, 628 NW Montefiore,3459 5th Ave, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU NHLBI NIH HHS [R01 HL098174, HL098174, R01 HL091916-02, R01 HL097376, R01 HL091916, HL096376, R01 HL096376, HL097376] NR 26 TC 26 Z9 26 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 28 PY 2011 VL 286 IS 4 BP 2719 EP 2727 DI 10.1074/jbc.M110.192377 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 709TM UT WOS:000286464300038 PM 21068446 ER PT J AU Smits, M Mir, SE Nilsson, RJA van der Stoop, PM Niers, JM Marquez, VE Cloos, J Breakefield, XO Krichevsky, AM Noske, DP Tannous, BA Wurdinger, T AF Smits, Michiel Mir, Shahryar E. Nilsson, R. Jonas A. van der Stoop, Petra M. Niers, Johanna M. Marquez, Victor E. Cloos, Jacqueline Breakefield, Xandra O. Krichevsky, Anna M. Noske, David P. Tannous, Bakhos A. Wuerdinger, Thomas TI Down-Regulation of miR-101 in Endothelial Cells Promotes Blood Vessel Formation through Reduced Repression of EZH2 SO PLOS ONE LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; H3 LYSINE-27 METHYLATION; GROUP PROTEIN EZH2; GENE-EXPRESSION; TUMOR-GROWTH; ANGIOGENESIS; CANCER; MICRORNAS; COMPLEX; OVEREXPRESSION AB Angiogenesis is a balanced process controlled by pro-and anti-angiogenic molecules of which the regulation is not fully understood. Besides classical gene regulation, miRNAs have emerged as post-transcriptional regulators of angiogenesis. Furthermore, epigenetic changes caused by histone-modifying enzymes were shown to modulate angiogenesis as well. However, a possible interplay between miRNAs and histone-modulating enzymes during angiogenesis has not been described. Here we show that VEGF-mediated down-regulation of miR-101 caused pro-angiogenic effects. We found that the pro-angiogenic effects are partly mediated through reduced repression by miR-101 of the histone-methyltransferase EZH2, a member of the Polycomb group family, thereby increasing methylation of histone H3 at lysine 27 and transcriptome alterations. In vitro, the sprouting and migratory properties of primary endothelial cell cultures were reduced by inhibiting EZH2 through up-regulation of miR-101, siRNA-mediated knockdown of EZH2, or treatment with 3-Deazaneplanocin-A (DZNep), a small molecule inhibitor of EZH2 methyltransferase activity. In addition, we found that systemic DZNep administration reduced the number of blood vessels in a subcutaneous glioblastoma mouse model, without showing adverse toxicities. Altogether, by identifying a pro-angiogenic VEGF/miR-101/EZH2 axis in endothelial cells we provide evidence for a functional link between growth factor-mediated signaling, post-transcriptional silencing, and histone-methylation in the angiogenesis process. Inhibition of EZH2 may prove therapeutic in diseases in which aberrant vascularization plays a role. C1 [Smits, Michiel; Mir, Shahryar E.; Nilsson, R. Jonas A.; van der Stoop, Petra M.; Niers, Johanna M.; Cloos, Jacqueline; Noske, David P.; Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Neurosurg, Amsterdam, Netherlands. [Smits, Michiel; Mir, Shahryar E.; Nilsson, R. Jonas A.; van der Stoop, Petra M.; Niers, Johanna M.; Cloos, Jacqueline; Noske, David P.; Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Pediat Oncol Hematol, Amsterdam, Netherlands. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurogenet Unit, Boston, MA USA. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Mol Neurogenet Unit, Boston, MA USA. [Niers, Johanna M.; Breakefield, Xandra O.; Tannous, Bakhos A.; Wuerdinger, Thomas] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Marquez, Victor E.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Krichevsky, Anna M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Smits, M (reprint author), Vrije Univ Amsterdam, Med Ctr, Canc Ctr Amsterdam, Neurooncol Res Grp,Dept Neurosurg, Amsterdam, Netherlands. EM t.wurdinger@vumc.nl FU Dutch Cancer Society/KWF; Lions Cancer Research Foundation; Umea University, Sweden; Stichting Translational Research CCA/VU University Medical Center; Swedish Research Counsil; National Cancer Institute (NCI) [CA069246, CA86355]; American Brain Tumor Association FX This work was supported by the Dutch Cancer Society/KWF (S. E. M.), Lions Cancer Research Foundation, Umea University, Sweden; Stichting Translational Research CCA/VU University Medical Center; Swedish Research Counsil (R.J.A.N.), National Cancer Institute (NCI) CA069246 and CA86355 (X.O.B.), and the American Brain Tumor Association (T. W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 42 Z9 45 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 JAN 28 PY 2011 VL 6 IS 1 AR e16282 DI 10.1371/journal.pone.0016282 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712JX UT WOS:000286664100018 PM 21297974 ER PT J AU Parsons, DW Li, M Zhang, XS Jones, S Leary, RJ Lin, JCH Boca, SM Carter, H Samayoa, J Bettegowda, C Gallia, GL Jallo, GI Binder, ZA Nikolsky, Y Hartigan, J Smith, DR Gerhard, DS Fults, DW VandenBerg, S Berger, MS Marie, SKN Shinjo, SMO Clara, C Phillips, PC Minturn, JE Biegel, JA Judkins, AR Resnick, AC Storm, PB Curran, T He, YP Rasheed, BA Friedman, HS Keir, ST McLendon, R Northcott, PA Taylor, MD Burger, PC Riggins, GJ Karchin, R Parmigiani, G Bigner, DD Yan, H Papadopoulos, N Vogelstein, B Kinzler, KW Velculescu, VE AF Parsons, D. Williams Li, Meng Zhang, Xiaosong Jones, Sian Leary, Rebecca J. Lin, Jimmy Cheng-Ho Boca, Simina M. Carter, Hannah Samayoa, Josue Bettegowda, Chetan Gallia, Gary L. Jallo, George I. Binder, Zev A. Nikolsky, Yuri Hartigan, James Smith, Doug R. Gerhard, Daniela S. Fults, Daniel W. VandenBerg, Scott Berger, Mitchel S. Marie, Suely Kazue Nagahashi Shinjo, Sueli Mieko Oba Clara, Carlos Phillips, Peter C. Minturn, Jane E. Biegel, Jaclyn A. Judkins, Alexander R. Resnick, Adam C. Storm, Phillip B. Curran, Tom He, Yiping Rasheed, B. Ahmed Friedman, Henry S. Keir, Stephen T. McLendon, Roger Northcott, Paul A. Taylor, Michael D. Burger, Peter C. Riggins, Gregory J. Karchin, Rachel Parmigiani, Giovanni Bigner, Darell D. Yan, Hai Papadopoulos, Nick Vogelstein, Bert Kinzler, Kenneth W. Velculescu, Victor E. TI The Genetic Landscape of the Childhood Cancer Medulloblastoma SO SCIENCE LA English DT Article ID MYELOID-LEUKEMIA GENOME; SOMATIC MUTATIONS; COLORECTAL CANCERS; HUMAN BREAST; AMPLIFICATION; METHYLATION; PROGRESSION; CARCINOMA; SEQUENCES; COMPLEX AB Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis. C1 [Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Sian; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Bettegowda, Chetan; Riggins, Gregory J.; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.] Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. [Parsons, D. Williams; Li, Meng; Zhang, Xiaosong; Jones, Sian; Leary, Rebecca J.; Lin, Jimmy Cheng-Ho; Bettegowda, Chetan; Riggins, Gregory J.; Papadopoulos, Nick; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD 21231 USA. [Parsons, D. Williams] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Parsons, D. Williams] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Parsons, D. Williams] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Boca, Simina M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Carter, Hannah; Samayoa, Josue; Karchin, Rachel] Johns Hopkins Med Inst, Dept Biomed Engn, Inst Computat Med, Baltimore, MD 21218 USA. [Bettegowda, Chetan; Gallia, Gary L.; Jallo, George I.; Binder, Zev A.; Riggins, Gregory J.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA. [Nikolsky, Yuri] GeneGo Inc, St Joseph, MI 49085 USA. [Hartigan, James; Smith, Doug R.] Beckman Coulter Genom Inc, Danvers, MA 01923 USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fults, Daniel W.] Univ Utah, Sch Med, Dept Neurosurg, Salt Lake City, UT 84132 USA. [VandenBerg, Scott] Univ Calif San Diego, Dept Pathol, Div Neuropathol, San Diego, CA 92103 USA. [Berger, Mitchel S.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, Brazil. [Clara, Carlos] Barretos Canc Hosp, Pio XII Fdn, Sao Paulo, Brazil. [Phillips, Peter C.; Minturn, Jane E.; Biegel, Jaclyn A.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Resnick, Adam C.; Storm, Phillip B.] Childrens Hosp Philadelphia, Div Neurosurg, Philadelphia, PA 19104 USA. [Judkins, Alexander R.; Curran, Tom] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Bigner, Darell D.; Yan, Hai] Duke Univ, Med Ctr, Pediat Brain Tumor Fdn Inst, Preston Robert Tisch Brain Tumor Ctr,Dept Pathol, Durham, NC 27710 USA. [He, Yiping; Rasheed, B. Ahmed; Friedman, Henry S.; Keir, Stephen T.; McLendon, Roger; Bigner, Darell D.; Yan, Hai] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Northcott, Paul A.; Taylor, Michael D.] Univ Toronto, Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1L7, Canada. [Burger, Peter C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Vogelstein, B (reprint author), Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD 21231 USA. EM vogelbe@gmail.com; kinzlke@jhmi.edu; velculescu@jhmi.edu RI Karchin, Rachel/A-3385-2010; Jones, Sian/A-5050-2012; Oba-Shinjo, Sueli /C-4017-2012; Marie, Suely/D-1870-2012; Papadopoulos, Nickolas/K-7272-2012; Curran, Tom/C-1164-2008; Curran, Tom/D-7515-2011 OI Curran, Tom/0000-0003-1444-7551; FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Virginia and D. K. Ludwig Fund for Cancer Research; Alex's Lemonade Stand Foundation; American Brain Tumor Association; Brain Tumor Research Fund at Johns Hopkins; Hoglund Foundation; Ready or Not Foundation; Children's Brain Tumor Foundation; Pediatric Brain Tumor Foundation Institute; David and Barbara B. Hirschhorn Foundation; American Association for Cancer Research; Johns Hopkins Sommer Scholar Program; NIH [CA121113, CA096832, CA057345, CA118822, CA135877, GM074906-01A1/B7BSCW]; NSF [DBI 0845275]; DOD NDSEG [32 CFR 168a] FX We thank J. Ptak, N. Silliman, L. Dobbyn, and M. Whalen for technical assistance with sequencing analyses, and M. Ehinger, D. Satterfield, E. Lipp, D. Lister, and M. J. Dougherty for help with sample preparation and data collection. This project has been funded in part by the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. This work was supported by the Virginia and D. K. Ludwig Fund for Cancer Research, Alex's Lemonade Stand Foundation, the American Brain Tumor Association, the Brain Tumor Research Fund at Johns Hopkins, the Hoglund Foundation, the Ready or Not Foundation, the Children's Brain Tumor Foundation, the Pediatric Brain Tumor Foundation Institute, the David and Barbara B. Hirschhorn Foundation, American Association for Cancer Research Stand Up To Cancer Dream Team Translational Cancer Research Grant, Johns Hopkins Sommer Scholar Program, NIH grants CA121113, CA096832, CA057345, CA118822, CA135877, and GM074906-01A1/B7BSCW, NSF grant DBI 0845275, and DOD NDSEG Fellowship 32 CFR 168a. D. W. P. is a Graham Cancer Research Scholar at Texas Children's Cancer Center. Under licensing agreements between the Johns Hopkins University and Beckman Coulter, B.V., K.W.K., and V.E.V. are entitled to a share of royalties received by the university on sales of products related to research described in this paper. N.P., B.V., K.W.K., and V.E.V are cofounders of Inostics and Personal Genome Diagnostics and are members of their Scientific Advisory Boards. N.P., B.V., K.W.K., and V.E.V. own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under university policy. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies. NR 43 TC 378 Z9 383 U1 3 U2 47 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 28 PY 2011 VL 331 IS 6016 BP 435 EP 439 DI 10.1126/science.1198056 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 712BB UT WOS:000286635900045 PM 21163964 ER PT J AU Huang, RC Fishman, JA AF Huang, Robert C. Fishman, Jay A. TI Screening of Deceased Organ Donors: No Easy Answers SO TRANSPLANTATION LA English DT Article DE Donor-derived infection; Organ donation; Infection; Microbiologic screening; Human T-cell lymphotropic virus ID CELL LYMPHOTROPIC VIRUS; I-ASSOCIATED MYELOPATHY; TRANSPLANT RECIPIENTS; HTLV-I; LIVER-TRANSPLANTATION; RENAL-TRANSPLANTATION; HIGH-RISK; TRANSMISSION; TRANSFUSION; LEUKEMIA AB Transmission of infection to recipients of solid organs is uncommon but well documented. Improved technologies for the diagnosis of infectious diseases suggest possible changes to paradigms used in the screening of organ donors to prevent disease transmission with transplantation. Available microbiologic assays, including molecular tests, are generally designed for use as diagnostic tools in individuals believed to have a specific infection based on clinical or epidemiological criteria. By contrast, these assays often lack the performance characteristics required for screening of deceased organ donors. This challenge is apparent with the analysis of assays for human T-cell lymphotropic virus-I and -II in low-risk populations. Changing epidemiologic patterns associated with the spread of novel pathogens or altered patterns of immigration will necessitate flexibility in the "list" of potential pathogens. Individual benefits from transplantation generally outweigh the risk of transmission of infection. However, this favorable experience will not obviate the need to continuously improve screening practices. C1 [Fishman, Jay A.] Harvard Univ, Sch Med, Transplant Infect Dis & Compromised Host Program, Massachusetts Gen Hosp,Infect Dis Div, Boston, MA 02114 USA. [Huang, Robert C.] Univ Calif San Diego, Med Ctr, Div Infect Dis, San Diego, CA 92103 USA. RP Fishman, JA (reprint author), Harvard Univ, Sch Med, Transplant Infect Dis & Compromised Host Program, Massachusetts Gen Hosp,Infect Dis Div, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jfishman@partners.org NR 28 TC 6 Z9 6 U1 2 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 JAN 27 PY 2011 VL 91 IS 2 BP 146 EP 149 DI 10.1097/TP.0b013e3181ffb9bb PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 706BM UT WOS:000286190100008 PM 21063244 ER PT J AU Jani, A Zimmerman, M Martin, J Lu, L Turkmen, K Ravichandran, K Pacic, A Ljubanovic, D Edelstein, CL AF Jani, Alkesh Zimmerman, Michael Martin, Jessica Lu, Li Turkmen, Kultigin Ravichandran, Kameswaran Pacic, Arijana Ljubanovic, Danica Edelstein, Charles L. TI Perfusion Storage Reduces Apoptosis in a Porcine Kidney Model of Donation After Cardiac Death SO TRANSPLANTATION LA English DT Article DE Deceased cardiac donation; Perfusion storage; Apoptosis ID ACUTE TUBULAR-NECROSIS; ACUTE-RENAL-FAILURE; EXPANDED CRITERIA DONORS; COLD-STORAGE; MACHINE-PERFUSION; PULSATILE PERFUSION; CASPASE-1-DEFICIENT MICE; ORGAN PROCUREMENT; PROSPECTIVE TRIAL; UNITED-STATES AB Background. Donation after cardiac death (DCD) kidneys suffer a high incidence of delayed graft function attributable to warm ischemia and cold ischemia (CI). Neither the mechanism of injury nor type of cell death has been described. Clinical studies suggest that perfusion storage (PS) of DCD kidneys may reduce injury although the mechanism of protection is unknown. In a porcine model of DCD, we hypothesized that DCD kidneys have increased caspase-1 due to warm ischemia (WI) and increased caspase-3 and apoptosis due to CI. Methods. Male Yorkshire pigs subjected to cardiac death were perfused with cold University of Wisconsin solution. The perfused kidneys were removed and stored in cold University of Wisconsin solution for 24 hr. Kidney biopsies were obtained before cardiac death and at 0 and 24 hr of CI. Results. There was an increase in caspase-1 activity due to WI before cold preservation. CI was associated with a massive increase in apoptosis, caspase-3/7 activity, and caspase-3 protein expression. Next, we hypothesized that PS would protect against apoptosis. We compared DCD kidneys subjected to static versus PS for 24 hr. PS significantly reduced proximal tubular apoptosis and was associated with increased B-cell lymphoma-extra large, and hypoxia-inducible transcription factor-1 alpha. Conclusions. These findings suggest that in DCD kidneys, WI preferentially activates caspase-1, whereas CI activates caspase-3 and causes apoptosis. PS may protect DCD kidneys through activation of antiapoptotic pathways involving B-cell lymphoma-extra large and hypoxia-inducible transcription factor-1 alpha. C1 [Jani, Alkesh; Lu, Li] Denver Vet Affairs Med Ctr, Renal Sect, Denver, CO USA. [Zimmerman, Michael; Martin, Jessica; Turkmen, Kultigin; Ravichandran, Kameswaran; Edelstein, Charles L.] Univ Colorado, Div Renal Dis & Hypertens, Denver, CO 80202 USA. [Pacic, Arijana; Ljubanovic, Danica] Univ Zagreb SOM, Zagreb Univ Hosp Dubrava, Zagreb, Croatia. RP Jani, A (reprint author), Univ Colorado Denver, Div Renal Dis & Hypertens, 12700 E 19th Ave,C281, Aurora, CO 80045 USA. EM Alkesh.jani@ucdenver.edu FU NIH [K08DK69512, RO1-DK-056851, RO1-DK-074835] FX This work was supported by NIH grant K08DK69512 (A.J.) and NIH grants RO1-DK-056851 and RO1-DK-074835 (C.L.E.). NR 42 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2011 VL 91 IS 2 BP 169 EP 175 DI 10.1097/TP.0b013e3182013753 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 706BM UT WOS:000286190100013 PM 21200363 ER PT J AU Falini, B Martelli, MP Bolli, N Sportoletti, P Liso, A Tiacci, E Haferlach, T AF Falini, Brunangelo Martelli, Maria Paola Bolli, Niccolo Sportoletti, Paolo Liso, Arcangelo Tiacci, Enrico Haferlach, Torsten TI Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? SO BLOOD LA English DT Article ID INTERNAL TANDEM DUPLICATION; MINIMAL RESIDUAL DISEASE; FAVORABLE PROGNOSTIC IMPACT; ACUTE MYELOGENOUS LEUKEMIA; GENE-EXPRESSION PROFILE; SINGLE CEBPA MUTATIONS; ARF TUMOR-SUPPRESSOR; CYTOPLASMIC NUCLEOPHOSMIN; NORMAL KARYOTYPE; ADULT PATIENTS AB After the discovery of NPM1-mutated acute myeloid leukemia (AML) in 2005 and its subsequent inclusion as a provisional entity in the 2008 World Health Organization classification of myeloid neoplasms, several controversial issues remained to be clarified. It was unclear whether the NPM1 mutation was a primary genetic lesion and whether additional chromosomal aberrations and multilineage dysplasia had any impact on the biologic and prognostic features of NPM1-mutated AML. Moreover, it was uncertain how to classify AML patients who were double-mutated for NPM1 and CEBPA. Recent studies have shown that: (1) the NPM1 mutant perturbs hemopoiesis in experimental models; (2) leukemic stem cells from NPM1-mutated AML patients carry the mutation; and (3) the NPM1 mutation is usually mutually exclusive of biallelic CEPBA mutations. Moreover, the biologic and clinical features of NPM1-mutated AML do not seem to be significantly influenced by concomitant chromosomal aberrations or multilineage dysplasia. Altogether, these pieces of evidence point to NPM1-mutated AML as a founder genetic event that defines a distinct leukemia entity accounting for approximately one-third of all AML. (Blood. 2011;117(4):1109-1120) C1 [Falini, Brunangelo; Martelli, Maria Paola; Sportoletti, Paolo; Tiacci, Enrico] Univ Perugia, Inst Hematol, I-06132 Perugia, Italy. [Bolli, Niccolo] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Liso, Arcangelo] Univ Foggia, Inst Hematol, Foggia, Italy. [Haferlach, Torsten] MLL Munich Leukemia Lab, Munich, Germany. RP Falini, B (reprint author), Univ Perugia, Inst Hematol, Osped S Maria Misericordia, I-06132 Perugia, Italy. EM faliniem@unipg.it RI Martelli, Maria Paola/I-5618-2012; Bolli, Niccolo/D-4057-2011; OI Bolli, Niccolo/0000-0002-1018-5139; SPORTOLETTI, PAOLO/0000-0002-5630-9862 FU Associazione Italiana per la Ricerca sul Cancro; Fondazione Cassa di Risparmio di Perugia; Fondazione Cassa di Risparmio di Spoleto FX This work was supported by the Associazione Italiana per la Ricerca sul Cancro, Fondazione Cassa di Risparmio di Perugia, and Fondazione Cassa di Risparmio di Spoleto. NR 102 TC 100 Z9 107 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 JAN 27 PY 2011 VL 117 IS 4 BP 1109 EP 1120 DI 10.1182/blood-2010-08-299990 PG 12 WC Hematology SC Hematology GA 711WZ UT WOS:000286623400008 PM 21030560 ER PT J AU Brill, A Fuchs, TA Chauhan, AK Yang, JJ De Meyer, SF Kollnberger, M Wakefield, TW Lammle, B Massberg, S Wagner, DD AF Brill, Alexander Fuchs, Tobias A. Chauhan, Anil K. Yang, Janie J. De Meyer, Simon F. Koellnberger, Maria Wakefield, Thomas W. Laemmle, Bernhard Massberg, Steffen Wagner, Denisa D. TI von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models SO BLOOD LA English DT Article ID ACTIVATED PROTEIN-C; VENOUS THROMBOSIS; P-SELECTIN; GLYCOPROTEIN-IB; TISSUE FACTOR; FACTOR-VIII; VONWILLEBRAND DISEASE; DEFICIENT MICE; MURINE MODEL; IN-VIVO AB Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF-/- mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF-/- mice. Infusion of GPG-290, a mutant glycoprotein Ib alpha-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF-/- IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis. (Blood. 2011; 117(4): 1400-1407) C1 [Brill, Alexander; Fuchs, Tobias A.; Chauhan, Anil K.; Yang, Janie J.; De Meyer, Simon F.; Laemmle, Bernhard; Wagner, Denisa D.] Immune Dis Inst, Boston, MA USA. [Brill, Alexander; Fuchs, Tobias A.; Chauhan, Anil K.; Yang, Janie J.; De Meyer, Simon F.; Laemmle, Bernhard; Wagner, Denisa D.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Brill, Alexander; Fuchs, Tobias A.; Chauhan, Anil K.; De Meyer, Simon F.; Laemmle, Bernhard; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Koellnberger, Maria; Massberg, Steffen] Tech Univ Munich, Deutsch Herzzentrum, Munich, Germany. [Wakefield, Thomas W.] Univ Michigan, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Laemmle, Bernhard] Univ Hosp Bern, Dept Haematol, CH-3010 Bern, Switzerland. [Laemmle, Bernhard] Univ Bern, Bern, Switzerland. RP Wagner, DD (reprint author), 3 Blackfan Cir,3rd Fl, Boston, MA 02115 USA. EM wagner@idi.harvard.edu RI Fuchs, Tobias/F-1189-2013 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [R01 HL095091, R01 HL041002]; Deutsche Forschungsgemeinschaft [FU 742/1-1] FX This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grants R01 HL095091 (D.D.W and T.W.W) and R01 HL041002 (D.D.W). T.A.F was supported by a fellowship of the Deutsche Forschungsgemeinschaft (FU 742/1-1). S.F.D.M is a postdoctoral fellow of the Flemish Fonds voorWetenschappelijk Onderzoek (FWO; Brussels, Belgium). NR 47 TC 126 Z9 134 U1 2 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 27 PY 2011 VL 117 IS 4 BP 1400 EP 1407 DI 10.1182/blood-2010-05-287623 PG 8 WC Hematology SC Hematology GA 711WZ UT WOS:000286623400040 PM 20959603 ER PT J AU Cusack, JC Clark, JW Curley, SA Sahani, DV Zukerberg, LR AF Cusack, James C., Jr. Clark, Jeffrey W. Curley, Steven A. Sahani, Dushyant V. Zukerberg, Lawrence R. TI A Woman with a Mass in the Liver Poorly differentiated neuroendocrine carcinoma arising in a tubulovillous adenoma of the cecum, with metastasis to the liver SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SMALL-CELL CARCINOMA; UNKNOWN PRIMARY; TUMORS; RECTUM; MANAGEMENT; SURGERY; COLON C1 [Cusack, James C., Jr.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Boston, MA 02114 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Curley, Steven A.] MD Anderson Hosp, Dept Surg Oncol, Houston, TX USA. [Curley, Steven A.] Univ Texas Med Sch, Dept Surg, Houston, TX USA. [Cusack, James C., Jr.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Clark, Jeffrey W.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sahani, Dushyant V.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cusack, JC (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. FU Department of Continuing Education, Harvard Medical School FX This case was presented at the postgraduate course Advances in Cancer Management for the Surgeon, 2009, sponsored by the Department of Continuing Education, Harvard Medical School. NR 19 TC 0 Z9 0 U1 0 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 JAN 27 PY 2011 VL 364 IS 4 BP 362 EP 370 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 711LH UT WOS:000286592600013 PM 21268729 ER PT J AU Dubin, R Cushman, M Folsom, AR Fried, LF Palmas, W Peralta, CA Wassel, C Shlipak, MG AF Dubin, Ruth Cushman, Mary Folsom, Aaron R. Fried, Linda F. Palmas, Walter Peralta, Carmen A. Wassel, Christina Shlipak, Michael G. TI Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis SO BMC NEPHROLOGY LA English DT Article ID CORONARY-HEART-DISEASE; FACTOR PATHWAY INHIBITOR; VON-WILLEBRAND-FACTOR; CARDIOVASCULAR-DISEASE; CYSTATIN-C; TISSUE FACTOR; ELDERLY PERSONS; INFLAMMATORY BIOMARKERS; SOLUBLE THROMBOMODULIN; VENOUS THROMBOEMBOLISM AB Background: Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis. Methods: We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities. Results: In comparison to persons with eGFRcys >90 ml/min/1.73 m(2), subjects with eGFRcys < 60 ml/min/1.73 m(2) had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m(2) had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr. Conclusions: Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk. C1 [Dubin, Ruth; Peralta, Carmen A.; Shlipak, Michael G.] Univ Calif San Francisco, Div Nephrol, Dept Med, San Francisco, CA 94143 USA. [Cushman, Mary] Fletcher Allen Hlth Care, Thrombosis & Hemostasis Program, Hematol Oncol Clin, Burlington, VT 05401 USA. [Folsom, Aaron R.] Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Fried, Linda F.] 7E121 VA Pittsburgh Healthcare Syst, Div Nephrol, Univ Dr Ctr, Pittsburgh, PA 15240 USA. [Palmas, Walter] Columbia Univ, Presbyterian Hosp, Dept Internal Med, New York, NY 10032 USA. [Wassel, Christina] UCSD Sch Med, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Peralta, Carmen A.; Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. RP Dubin, R (reprint author), Univ Calif San Francisco, Div Nephrol, Dept Med, 521 Parnassus Ave,Room C443, San Francisco, CA 94143 USA. EM ruth.dubin@ucsf.edu FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 44 TC 25 Z9 31 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JAN 26 PY 2011 VL 12 AR 3 DI 10.1186/1471-2369-12-3 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 946MI UT WOS:000304355400001 PM 21269477 ER PT J AU Hashimoto, JG Forquer, MR Tanchuck, MA Finn, DA Wiren, KM AF Hashimoto, J. G. Forquer, M. R. Tanchuck, M. A. Finn, D. A. Wiren, K. M. TI IMPORTANCE OF GENETIC BACKGROUND FOR RISK OF RELAPSE SHOWN IN ALTERED PREFRONTAL CORTEX GENE EXPRESSION DURING ABSTINENCE FOLLOWING CHRONIC ALCOHOL INTOXICATION SO NEUROSCIENCE LA English DT Article DE alcoholism; chronic ethanol; abstinence; relapse; microarray; gene expression ID CORTICOTROPIN-RELEASING-FACTOR; ETHANOL WITHDRAWAL; C57BL/6J MICE; CELL-PROLIFERATION; GENDER-DIFFERENCES; NUCLEUS-ACCUMBENS; SEX-DIFFERENCES; FAMILY-HISTORY; FRONTAL-CORTEX; USE DISORDERS AB Alcoholism is a relapsing disorder associated with excessive consumption after periods of abstinence. Neuro-adaptations in brain structure, plasticity and gene expression occur with chronic intoxication but are poorly characterized. Here we report identification of pathways altered during abstinence in prefrontal cortex, a brain region associated with cognitive dysfunction and damage in alcoholics. To determine the influence of genetic differences, an animal model was employed with widely divergent responses to alcohol withdrawal, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines. Mice were chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days. Transcriptional profiling by microarray analyses identified a total of 562 genes as significantly altered during abstinence. Hierarchical cluster analysis revealed that the transcriptional response correlated with genotype/withdrawal phenotype rather than sex. Gene Ontology category overrepresentation analysis identified thyroid hormone metabolism, glutathione metabolism, axon guidance and DNA damage response as targeted classes of genes in low response WSR mice, with acetylation and histone deacetylase complex as highly dimorphic between WSR and WSP mice. Confirmation studies in WSR mice revealed both increased neurotoxicity by histopathologic examination and elevated triidothyronine (T3) levels. Most importantly, relapse drinking was reduced by inhibition of thyroid hormone synthesis in dependent WSR mice compared to controls. These findings provide in vivo physiological and behavioral validation of the pathways identified. Combined, these results indicate a fundamentally distinct neuroadaptive response during abstinence in mice genetically selected for divergent withdrawal severity. Identification of pathways altered in abstinence may aid development of novel therapeutics for targeted treatment of relapse in abstinent alcoholics. Published by Elsevier Ltd on behalf of IBRO. C1 [Hashimoto, J. G.; Forquer, M. R.; Finn, D. A.; Wiren, K. M.] Portland VA Med Ctr, Res Serv, Portland, OR 97239 USA. [Hashimoto, J. G.; Tanchuck, M. A.; Finn, D. A.; Wiren, K. M.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Wiren, K. M.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA. RP Wiren, KM (reprint author), VA Med Ctr, Res Serv P3R&D 39, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM wirenk@ohsu.edu OI Wiren, Kristine/0000-0002-6159-4450 FU Department of Veterans Affairs; National Institute on Alcohol Abuse and Alcoholism [R01 AA013194, R01 AA012439] FX The authors gratefully acknowledge the support of Drs. John Crabbe and Pamela Metten for providing the WSR and WSP mice and for assistance with chronic alcohol exposure. This work was made possible by grants from the Department of Veterans Affairs Merit Review program (KMW) and the National Institute on Alcohol Abuse and Alcoholism R01 AA013194 (KMW) and R01 AA012439 (DAF). All work was performed in facilities provided by the Department of Veterans Affairs. NR 85 TC 11 Z9 11 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 26 PY 2011 VL 173 BP 57 EP 75 DI 10.1016/j.neuroscience.2010.11.006 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 710BX UT WOS:000286487000005 PM 21081154 ER PT J AU Martin, JA Hu, ZT Fenz, KM Fernandez, J Dittman, JS AF Martin, Jesse A. Hu, Zhitao Fenz, Katherine M. Fernandez, Joel Dittman, Jeremy S. TI Complexin Has Opposite Effects on Two Modes of Synaptic Vesicle Fusion SO CURRENT BIOLOGY LA English DT Article ID ELEGANS NEUROMUSCULAR-JUNCTION; MEMBRANE-FUSION; NEUROTRANSMITTER RELEASE; SNARE COMPLEXES; TRANSMISSION; EXOCYTOSIS; SYNAPSES; PROTEINS; TOMOSYN; BINDING AB Background: Synaptic transmission can occur in a binary or graded fashion, depending on whether transmitter release is triggered by action potentials or by gradual changes in membrane potential. Molecular differences of these two types of fusion events and their differential regulation in a physiological context have yet to be addressed. Complexin is a conserved SNARE-binding protein that has been proposed to regulate both spontaneous and stimulus-evoked synaptic vesicle (SV) fusion. Results: Here we examine complexin function at a graded synapse in C. elegans. Null complexin (cpx-1) mutants are viable, although nervous system function is significantly impaired. Loss of CPX-1 results in a 3-fold increase in the rate of tonic synaptic transmission at the neuromuscular junction, whereas stimulus-evoked SV fusion is decreased 10-fold. A truncated CPX-1 missing its C-terminal domain can rescue stimulus-evoked synaptic vesicle exocytosis but fails to suppress tonic activity, demonstrating that these two modes of exocytosis can be distinguished at the molecular level. A CPX-1 variant with impaired SNARE binding also rescues evoked, but not tonic, neurotransmitter release. Finally, tonic, but not evoked, release can be rescued in a syntaxin point mutant by removing CPX-1. Rescue of either form of exocytosis partially restores locomotory behavior, indicating that both types of synaptic transmission are relevant. Conclusion: These observations suggest a dual role for CPX-1: suppressing SV exocytosis, driven by low levels of endogenous neural activity, while promoting synchronous fusion of SVs driven by a depolarizing stimulus. Thus, patterns of synaptic activity regulate complexin's inhibitory and permissive roles at a graded synapse. C1 [Martin, Jesse A.; Fenz, Katherine M.; Fernandez, Joel; Dittman, Jeremy S.] Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. [Hu, Zhitao] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Dittman, JS (reprint author), Weill Cornell Med Coll, Dept Biochem, 1300 York Ave, New York, NY 10065 USA. EM jed2019@med.cornell.edu RI hu, zhitao/H-5626-2011; OI Dittman, Jeremy S./0000-0002-3850-9078 FU Rita Allen Foundation [188423]; March of Dimes (Basil O'Connor Award) [5-FY09-133]; National Institutes of Health [GM095674] FX We thank the C. elegans Stock Center and S. Mitani for strains. We thank Miriam Goodman's laboratory for use of their worm tracking software; Cori Bargmann, Josh Kaplan, Jihong Bai, Peter Juo, Anant Menon, Erik Jorgensen, Tim Ryan, and members of the Ryan laboratory for advice and for critically reading the manuscript; and Kashyap Rajagopal for assisting in developing the locomotion analysis. This work was supported by awards from the Rita Allen Foundation (188423) and the March of Dimes (Basil O'Connor Award 5-FY09-133) and by National Institutes of Health grant GM095674 (J.S.D.). NR 45 TC 56 Z9 59 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 25 PY 2011 VL 21 IS 2 BP 97 EP 105 DI 10.1016/j.cub.2010.12.014 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 712QH UT WOS:000286680800018 PM 21215634 ER PT J AU Vickrey, BG Koroshetz, WJ AF Vickrey, Barbara G. Koroshetz, Walter J. TI Ensuring that the fruits of clinical trial research translate to equitable care SO NEUROLOGY LA English DT Editorial Material C1 [Vickrey, Barbara G.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Vickrey, Barbara G.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. RP Vickrey, BG (reprint author), Univ Calif Los Angeles, Dept Neurol, C-109 RNRC,Box 951769, Los Angeles, CA 90095 USA. EM bvickrey@ucla.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 25 PY 2011 VL 76 IS 4 BP 314 EP 315 DI 10.1212/WNL.0b013e31820c7509 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 711IA UT WOS:000286581500006 PM 21209371 ER PT J AU Zhang, C Montgomery, TA Gabel, HW Fischer, SEJ Phillips, CM Fahlgren, N Sullivan, CM Carrington, JC Ruvkun, G AF Zhang, Chi Montgomery, Taiowa A. Gabel, Harrison W. Fischer, Sylvia E. J. Phillips, Carolyn M. Fahlgren, Noah Sullivan, Christopher M. Carrington, James C. Ruvkun, Gary TI mut-16 and other mutator class genes modulate 22G and 26G siRNA pathways in Caenorhabditis elegans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SMALL INTERFERING RNAS; DOUBLE-STRANDED-RNA; C-ELEGANS; ENDOGENOUS SIRNAS; CHROMOSOME SEGREGATION; MOUSE OOCYTES; GERM-LINE; MICRORNAS; HELICASE; 21U-RNAS AB Argonaute-associated siRNAs and Piwi-associated piRNAs have overlapping roles in silencing mobile genetic elements in animals. In Caenorhabditis elegans, mutator (mut) class genes mediate siRNA-guided repression of transposons as well as exogenous RNAi, but their roles in endogenous RNA silencing pathways are not well-understood. To characterize the endogenous small RNAs dependent on mut class genes, small RNA populations from a null allele of mut-16 as well as a regulatory mut-16(mg461) allele that disables only somatic RNAi were subjected to deep sequencing. Additionally, each of the mut class genes was tested for a requirement in 26G siRNA pathways. The results indicate that mut-16 is an essential factor in multiple endogenous germline and somatic siRNA pathways involving several distinct Argonautes and RNA-dependent RNA polymerases. The results also reveal essential roles for mut-2 and mut-7 in the ERGO-1 class 26G siRNA pathway and less critical roles for mut-8, mut-14, and mut-15. We show that transposons are hypersusceptible to mut-16-dependent silencing and identify a requirement for the siRNA machinery in piRNA biogenesis from Tc1 transposons. We also show that the somaspecific mut-16(mg461) mutant allele is present in multiple C. elegans laboratory strains. GENETICS INAUGURAL ARTICLE C1 [Zhang, Chi; Montgomery, Taiowa A.; Gabel, Harrison W.; Fischer, Sylvia E. J.; Phillips, Carolyn M.; Ruvkun, Gary] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. [Fahlgren, Noah; Sullivan, Christopher M.; Carrington, James C.] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. RP Ruvkun, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu RI Phillips, Carolyn/E-8305-2011; Carrington, James/A-4656-2012; Fahlgren, Noah/D-4404-2011; OI Phillips, Carolyn/0000-0002-6228-6468; Carrington, James/0000-0003-3572-129X; Fahlgren, Noah/0000-0002-5597-4537; Montgomery, Taiowa/0000-0001-7857-3253 FU National Institutes of Health [GM46419]; Massachusetts General Hospital Executive Committee; Damon Runyon Cancer Research Foundation [DRG-2029-09, DRG1988-08] FX We thank Victor Ambros, Rene Ketting, and John Kim for helpful comments; Darryl Conte and Weifeng Gu in Craig Mello's laboratory for providing protocols for generation of small RNA cDNA libraries for deep sequencing; Allison Billi, Amanda Day, Ting Han, and John Kim for protocols for 26G siRNA Taqman qRT-PCR and sharing preliminary data; Christian Daly and Jiangwen Zhang at Faculty of Arts and Sciences Center for Systems Biology of Harvard University and Kaleena Shirley at Massachusetts General Hospital for Illumina deep sequencing; Mark Borowsky and Brad Chapman at Massachusetts General Hospital for computational assistance; Leah Frater- Rubsam, Phil Anderson, Jennifer Whangbo, Aidan Porter, Craig Hunter, and Andrew Fire for communicating data before publication; and the Caenorhabditis Genetics Center (CGC) and Shohei Mitani of the Japanese National Bioresources Project for stains. This work was supported by National Institutes of Health Grant GM46419 (to G.R.) and Massachusetts General Hospital Executive Committee of Research Fund for Medical Discovery fellowship awards (to C.Z. and S.E.J.F.). Both T.A.M. and C.M.P. are supported by Damon Runyon Cancer Research Foundation Grants DRG-2029-09 and DRG1988-08. T.A.M. is a Damon Runyon Fellow, and C.M.P. is the Marion Abbe Fellow of the Damon Runyon Cancer Research Foundation. NR 48 TC 36 Z9 42 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1201 EP 1208 DI 10.1073/pnas.1018695108 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800005 PM 21245313 ER PT J AU Sankaran, VG Menne, TF Scepanovic, D Vergilio, JA Ji, P Kim, J Thiru, P Orkin, SH Lander, ES Lodish, HF AF Sankaran, Vijay G. Menne, Tobias F. Scepanovic, Danilo Vergilio, Jo-Anne Ji, Peng Kim, Jinkuk Thiru, Prathapan Orkin, Stuart H. Lander, Eric S. Lodish, Harvey F. TI MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE erythropoiesis; globin gene regulation ID C-MYB; GENE-EXPRESSION; ERYTHROPOIESIS; D1; DIFFERENTIATION; HEMATOPOIESIS; LINEAGE; SCREEN; BCL11A; MOUSE AB Many human aneuploidy syndromes have unique phenotypic consequences, but in most instances it is unclear whether these phenotypes are attributable to alterations in the dosage of specific genes. In human trisomy 13, there is delayed switching and persistence of fetal hemoglobin (HbF) and elevation of embryonic hemoglobin in newborns. Using partial trisomy cases, we mapped this trait to chromosomal band 13q14; by examining the genes in this region, two microRNAs, miR-15a and -16-1, appear as top candidates for the elevated HbF levels. Indeed, increased expression of these microRNAs in primary human erythroid progenitor cells results in elevated fetal and embryonic hemoglobin gene expression. Moreover, we show that a direct target of these microRNAs, MYB, plays an important role in silencing the fetal and embryonic hemoglobin genes. Thus we demonstrate how the developmental regulation of a clinically important human trait can be better understood through the genetic and functional study of aneuploidy syndromes and suggest that miR-15a, -16-1, and MYB may be important therapeutic targets to increase HbF levels in patients with sickle cell disease and beta-thalassemia. C1 [Sankaran, Vijay G.; Ji, Peng; Kim, Jinkuk; Thiru, Prathapan; Lander, Eric S.; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Sankaran, Vijay G.; Lander, Eric S.; Lodish, Harvey F.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Sankaran, Vijay G.; Lander, Eric S.; Lodish, Harvey F.] Harvard Univ, Cambridge, MA 02142 USA. [Sankaran, Vijay G.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Menne, Tobias F.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Lander, Eric S.; Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Kim, Jinkuk] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Scepanovic, Danilo; Kim, Jinkuk] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02142 USA. [Menne, Tobias F.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Lodish, HF (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM lodish@wi.mit.edu FU Kay Kendall Leukaemia Fund; Department of Energy [DE-FG02-97ER25308]; National Institutes of Health [R01 DK068348, P01 HL32262] FX We thank D. Nathan and S. Lux for their inspiration and guidance; C. Epstein, D. Bartel, C. Walkley, C. Sieff, J. Menne, J. Hirschhorn, J. Flygare, M. Bousquet, D. Nguyen, B. Wong, Y. Jeong, H. B. Larman, and G. Bell for valuable advice; T. DiCesare for valuable assistance in producing the model illustration; and C. Kitidis-Mitrokostas and N. Cohen for technical assistance. T.F.M. was supported by the Kay Kendall Leukaemia Fund. D.S. was supported by a Department of Energy Computational Science Graduate Fellowship (Grant DE-FG02-97ER25308). This work was supported by National Institutes of Health Grants R01 DK068348 and P01 HL32262 (to H.F.L). NR 39 TC 85 Z9 90 U1 3 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 25 PY 2011 VL 108 IS 4 BP 1519 EP 1524 DI 10.1073/pnas.1018384108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 711MD UT WOS:000286594800059 PM 21205891 ER PT J AU Johansen, KL AF Johansen, Kirsten L. TI Choice of Dialysis Modality in the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID PERITONEAL-DIALYSIS; HEMODIALYSIS; SELECTION; THERAPY C1 [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect 111J, 4150 Clement St, San Francisco, CA 94121 USA. EM Kirsten.johansen@ucsf.edu NR 17 TC 4 Z9 4 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 24 PY 2011 VL 171 IS 2 BP 107 EP 109 DI 10.1001/archinternmed.2010.370 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 710OB UT WOS:000286520000006 PM 20876395 ER PT J AU Novak, N Bar, V Sabanay, H Frechter, S Jaegle, M Snapper, SB Meijer, D Peles, E AF Novak, Nurit Bar, Vered Sabanay, Helena Frechter, Shahar Jaegle, Martine Snapper, Scott B. Meijer, Dies Peles, Elior TI N-WASP is required for membrane wrapping and myelination by Schwann cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PERIPHERAL NERVOUS-SYSTEM; AXON ENSHEATHMENT; RHO-GTPASES; ACTIN CYTOSKELETON; EXCHANGE FACTOR; CLAW-PAW; PROTEIN; BIOLOGY; NERVES; OLIGODENDROCYTES AB During peripheral nerve myelination, Schwann cells sort larger axons, ensheath them, and eventually wrap their membrane to form the myelin sheath. These processes involve extensive changes in cell shape, but the exact mechanisms involved are still unknown. Neural Wiskott Aldrich syndrome protein (N-WASP) integrates various extracellular signals to control actin dynamics and cytoskeletal reorganization through activation of the Arp2/3 complex. By generating mice lacking N-WASP in myelinating Schwann cells, we show that N-WASP is crucial for myelination. In N-WASP-deficient nerves, Schwann cells sort and ensheath axons, but most of them fail to myelinate and arrest at the promyelinating stage. Yet, a limited number of Schwann cells form unusually short internodes, containing thin myelin sheaths, with the occasional appearance of myelin misfoldings. These data suggest that regulation of actin filament nucleation in Schwann cells by N-WASP is crucial for membrane wrapping, longitudinal extension, and myelination. C1 [Novak, Nurit; Bar, Vered; Sabanay, Helena; Frechter, Shahar; Peles, Elior] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Snapper, Scott B.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Jaegle, Martine; Meijer, Dies] Erasmus Univ, Med Ctr, Dept Cell Biol & Genet, NL-3000 CA Rotterdam, Netherlands. RP Peles, E (reprint author), Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. EM peles@weizmann.ac.il RI Meijer, Dies/C-7786-2012 OI Meijer, Dies/0000-0002-8461-6341 FU National Institutes of Health [NS50220, 5P01 HL59561]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Israel Science Foundation; Shapell Family Biomedical Research Foundation at the Weizmann Institute; Moskowitz Center for Imaging; European Community [FP7/2007-2013, HEALTH-F2-2008-201535] FX This work was supported by grants from the National Institutes of Health (NS50220 to E. Peles and 5P01 HL59561 to S.B. Snapper), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Israel Science Foundation, the Shapell Family Biomedical Research Foundation at the Weizmann Institute, the Moskowitz Center for Imaging, and the European Community's Seventh Framework Program (FP7/2007-2013; HEALTH-F2-2008-201535 to E. Peles and D. Meijer). E. Peles is the Incumbent of the Hanna Hertz Professorial Chair for Multiple Sclerosis and Neuroscience. NR 45 TC 33 Z9 33 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JAN 24 PY 2011 VL 192 IS 2 BP 243 EP 250 DI 10.1083/jcb.201010013 PG 8 WC Cell Biology SC Cell Biology GA 727DW UT WOS:000287778800006 PM 21263026 ER PT J AU Deo, RC Wilson, JG Xing, C Lawson, K Kao, WHL Reich, D Tandon, A Akylbekova, E Patterson, N Mosley, TH Boerwinkle, E Taylor, HA AF Deo, Rahul C. Wilson, James G. Xing, Chao Lawson, Kim Kao, W. H. Linda Reich, David Tandon, Arti Akylbekova, Ermeg Patterson, Nick Mosley, Thomas H., Jr. Boerwinkle, Eric Taylor, Herman A., Jr. TI Single-Nucleotide Polymorphisms in LPA Explain Most of the Ancestry-Specific Variation in Lp(a) Levels in African Americans SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; TRANSCRIPTION-FACTOR-BINDING; ATHEROSCLEROSIS RISK; PLASMA LIPOPROTEIN(A); JACKSON HEART; APOLIPOPROTEIN(A) SIZE; CARDIOVASCULAR HEALTH; APO(A) GENE; ASSOCIATION; ISOFORMS AB Lipoprotein(a) (Lp(a)) is an important causal cardiovascular risk factor, with serum Lp(a) levels predicting atherosclerotic heart disease and genetic determinants of Lp(a) levels showing association with myocardial infarction. Lp(a) levels vary widely between populations, with African-derived populations having nearly 2-fold higher Lp(a) levels than European Americans. We investigated the genetic basis of this difference in 4464 African Americans from the Jackson Heart Study (JHS) using a panel of up to 1447 ancestry informative markers, allowing us to accurately estimate the African ancestry proportion of each individual at each position in the genome. In an unbiased genome-wide admixture scan for frequency-differentiated genetic determinants of Lp(a) level, we found a convincing peak (LOD = 13.6) at 6q25.3, which spans the LPA locus. Dense fine-mapping of the LPA locus identified a number of strongly associated, common biallelic SNPs, a subset of which can account for up to 7% of the variation in Lp(a) level, as well as >70% of the African-European population differences in Lp(a) level. We replicated the association of the most strongly associated SNP, rs9457951 (p = 6x10(-22), 27% change in Lp(a) per allele, similar to 5% of Lp(a) variance explained in JHS), in 1,726 African Americans from the Dallas Heart Study and found an even stronger association after adjustment for the kringle(IV) repeat copy number. Despite the strong association with Lp(a) levels, we find no association of any LPA SNP with incident coronary heart disease in 3,225 African Americans from the Atherosclerosis Risk in Communities Study. C1 [Deo, Rahul C.; Reich, David; Tandon, Arti; Patterson, Nick] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02163 USA. [Deo, Rahul C.] Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp, Boston, MA USA. [Deo, Rahul C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Wilson, James G.; Akylbekova, Ermeg; Mosley, Thomas H., Jr.; Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Xing, Chao] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Lawson, Kim; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Lawson, Kim; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Kao, W. H. Linda] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Reich, David; Patterson, Nick] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Akylbekova, Ermeg; Taylor, Herman A., Jr.] Jackson State Univ, Jackson, MS USA. [Taylor, Herman A., Jr.] Tougaloo Coll, Tougaloo, MS USA. RP Deo, RC (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02163 USA. EM rdeo@partners.org FU National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities [R01 HL084107]; NIH [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Institutes of Health [T32 HL007208, K08 HL098361]; Donald W. Reynolds Foundation; NHLBI [HL082896, HL092550]; National Center for Research Resources [UL1RR024982]; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; WHLK [R21DK073482, K01DK067207] FX These studies were supported by the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities through R01 HL084107 to JGW and NIH contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172. RCD was supported by National Institutes of Health grant T32 HL007208 and K08 HL098361. The Dallas Heart Study was supported by the Donald W. Reynolds Foundation and grants HL082896 and HL092550 from NHLBI. CX was supported by a Pilot Award from UL1RR024982 from the National Center for Research Resources. The ARIC Study was carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022 with support for this analysis by R21DK073482 and K01DK067207 (WHLK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 24 Z9 26 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 24 PY 2011 VL 6 IS 1 AR e14581 DI 10.1371/journal.pone.0014581 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710PJ UT WOS:000286523400003 PM 21283670 ER PT J AU Zhang, C Tanzi, RE AF Zhang, Can Tanzi, Rudolph E. TI Response to Mancuso et al.: Curcumin and Alzheimer Disease: This Marriage Is Not to Be Performed SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Letter C1 [Zhang, Can] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Zhang, C (reprint author), Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu NR 1 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 21 PY 2011 VL 286 IS 3 AR le4 DI 10.1074/jbc.N110.133520 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 706BV UT WOS:000286191500005 ER PT J AU Song, MS Carracedo, A Salmena, L Song, SJ Egia, A Malumbres, M Pandolfi, PP AF Song, Min Sup Carracedo, Arkaitz Salmena, Leonardo Song, Su Jung Egia, Ainara Malumbres, Marcos Pandolfi, Pier Paolo TI Nuclear PTEN Regulates the APC-CDH1 Tumor-Suppressive Complex in a Phosphatase-Independent Manner SO CELL LA English DT Article ID SMALL-MOLECULE INHIBITOR; ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; GROWTH IN-VIVO; AURORA KINASES; CELLULAR SENESCENCE; MUTATIONAL SPECTRA; CHROMOSOME-10 PTEN; GENOMIC STABILITY; EXPRESSION; GENE AB PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. C1 [Song, Min Sup; Carracedo, Arkaitz; Salmena, Leonardo; Song, Su Jung; Egia, Ainara; Pandolfi, Pier Paolo] Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Genet Program,Sch Med, Beth Israel Deaconess Canc Ctr,Dept Med & Pathol, Boston, MA 02215 USA. [Malumbres, Marcos] CNIO, Cell Div & Canc Grp, Mol Oncol Programme, Madrid 28029, Spain. RP Pandolfi, PP (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Canc Genet Program,Sch Med, Beth Israel Deaconess Canc Ctr,Dept Med & Pathol, Boston, MA 02215 USA. EM ppandolf@bidmc.harvard.edu RI Malumbres, Marcos/E-8834-2011; Carracedo, Arkaitz/F-7029-2011 OI Malumbres, Marcos/0000-0002-0829-6315; Carracedo, Arkaitz/0000-0001-5957-1260 FU NIH; European Molecular Biology Organization; Canadian Institutes of Health Research FX We are grateful to former and present members of the Pandolfi lab for experimental support, advice, or discussion. We are thankful to Drs. Manuel Serrano, Pumin Zhang, Wenyi Wei, and Hongtao Yu for providing reagents. We thank Dr. John Asara for mass-spectrometric analysis. This work was supported by NIH grants to P.P.P. A.C. is supported by a Long-Term Fellowship Award from the European Molecular Biology Organization, and L.S. is supported by a Fellowship from the Canadian Institutes of Health Research. NR 56 TC 181 Z9 188 U1 0 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 JAN 21 PY 2011 VL 144 IS 2 BP 187 EP 199 DI 10.1016/j.cell.2010.12.020 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 709RU UT WOS:000286459900005 PM 21241890 ER PT J AU Novershtern, N Subramanian, A Lawton, LN Mak, RH Haining, WN McConkey, ME Habib, N Yosef, N Chang, CY Shay, T Frampton, GM Drake, ACB Leskov, I Nilsson, B Preffer, F Dombkowski, D Evans, JW Liefeld, T Smutko, JS Chen, JZ Friedman, N Young, RA Golub, TR Regev, A Ebert, BL AF Novershtern, Noa Subramanian, Aravind Lawton, Lee N. Mak, Raymond H. Haining, W. Nicholas McConkey, Marie E. Habib, Naomi Yosef, Nir Chang, Cindy Y. Shay, Tal Frampton, Garrett M. Drake, Adam C. B. Leskov, Ilya Nilsson, Bjorn Preffer, Fred Dombkowski, David Evans, John W. Liefeld, Ted Smutko, John S. Chen, Jianzhu Friedman, Nir Young, Richard A. Golub, Todd R. Regev, Aviv Ebert, Benjamin L. TI Densely Interconnected Transcriptional Circuits Control Cell States in Human Hematopoiesis SO CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; EMBRYONIC STEM-CELLS; ERYTHROID-DIFFERENTIATION; EXPRESSION PROFILES; MODULE NETWORKS; T-CELLS; GENE; BINDING; LINE; ERYTHROPOIESIS AB Though many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly coexpressed genes, some of which are restricted to a single lineage but most of which are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed. C1 [Novershtern, Noa; Subramanian, Aravind; Mak, Raymond H.; Yosef, Nir; Chang, Cindy Y.; Shay, Tal; Nilsson, Bjorn; Liefeld, Ted; Golub, Todd R.; Regev, Aviv; Ebert, Benjamin L.] Broad Inst, Cambridge, MA 02142 USA. [Novershtern, Noa; Frampton, Garrett M.; Drake, Adam C. B.; Leskov, Ilya; Chen, Jianzhu; Young, Richard A.; Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02140 USA. [Novershtern, Noa; Habib, Naomi; Friedman, Nir] Hebrew Univ Jerusalem, Sch Comp Sci, IL-91904 Jerusalem, Israel. [Lawton, Lee N.; Frampton, Garrett M.; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Haining, W. Nicholas; Evans, John W.; Golub, Todd R.; Ebert, Benjamin L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [McConkey, Marie E.; Chang, Cindy Y.; Nilsson, Bjorn; Ebert, Benjamin L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Drake, Adam C. B.; Leskov, Ilya; Chen, Jianzhu] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Dombkowski, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smutko, John S.] Nugen Technol, San Carlos, CA 94070 USA. [Golub, Todd R.; Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Regev, A (reprint author), Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM aregev@broad.mit.edu; bebert@partners.org RI Young, Richard/F-6495-2012; Friedman, Nir/H-9692-2012; Shay, Tal/J-4028-2016; OI Young, Richard/0000-0001-8855-8647; Friedman, Nir/0000-0002-9678-3550; Shay, Tal/0000-0003-0755-1350; Novershtern, Noa/0000-0002-2244-6877 FU NIH [R01 HL082945, P01 CA108631]; Burroughs-Wellcome Fund; Landon and Lavinia Clay; HHMI FX We thank E. Lander, I. Amit, and I. Gat-Viks for critical review of the manuscript; D. Scadden for helpful discussions; L. Gaffney and S. Hart for assistance with figure generation; and D. Peck, J. Lamb, R. Onofrio, and the Broad Genetic Analysis Platform for assistance with expression arrays. The work was funded by the NIH (grants R01 HL082945 and P01 CA108631 to B.L.E. and the PIONEER award to A.R.), the Burroughs-Wellcome Fund (CAMS to B.L.E. and CASI to A.R.), funds from Landon and Lavinia Clay (R.A.Y.) and HHMI (T.R.G. and A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. J.S.S. is an employee of NuGEN Technologies, Inc. NR 56 TC 325 Z9 325 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JAN 21 PY 2011 VL 144 IS 2 BP 296 EP 309 DI 10.1016/j.cell.2011.01.004 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 709RU UT WOS:000286459900013 PM 21241896 ER PT J AU Truong, QA Bamberg, F Mahabadi, AA Toepker, M Lee, H Rogers, IS Seneviratne, SK Schlett, CL Brady, TJ Nagurney, JT Hoffmann, U AF Truong, Quynh A. Bamberg, Fabian Mahabadi, Amir A. Toepker, Michael Lee, Hang Rogers, Ian S. Seneviratne, Sujith K. Schlett, Christopher L. Brady, Thomas J. Nagurney, John T. Hoffmann, Udo TI Left atrial volume and index by multi-detector computed tomography: Comprehensive analysis from predictors of enlargement to predictive value for acute coronary syndrome (ROMICAT study) SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Left atrium; Left atrial volume; Left atrial volume index; Computed tomography; Acute coronary syndrome ID ACUTE MYOCARDIAL-INFARCTION; ACUTE CHEST-PAIN; STRESS ECHOCARDIOGRAPHY; ISCHEMIC CARDIOMYOPATHY; DIASTOLIC FUNCTION; EJECTION FRACTION; HEART-FAILURE; SIZE; ASSOCIATION; RISK AB Objectives: We aimed to identify the predictors of left atrial (LA) enlargement by multi-detector computed tomography (CT) and determine its association and predictive value for acute coronary syndrome (ACS). Background: LA enlargement is associated with myocardial ischemia and coronary artery disease (CAD) and is a strong predictor for cardiovascular events. These studies were performed primarily with echocardiography. With the rise of cardiac CT, LA volume can be readily measured. Methods: In 377 emergency department patients with chest pain, we performed 64-slice CT for coronary artery assessment. We derived LA volumes (LAV(max), LAV(min)) and indices (LAVI(max), LAVI(min)) using a threshold-based volumetric method. Results: Subjects, with cardiac risk factors or CAD by CT, had larger LA (Delta LAV(max) 9.1 ml, p=0.004; Delta LAV(min) 8.1 ml, p=0.001; Delta LAVI(max) 3.3 ml/m(2), p=0.03; Delta LAVI(min) 3.4 ml/m(2), p=0.006) than controls. Predictors of LA enlargement were related to risk factors for diastolic dysfunction. ACS risk was greater in patients with top quartile LAV(max) (odds ratio [OR] 3.4, p=0.02) and LAV(min) (OR 4.7, p=0.01) than lowest quartile, but not when indexed. Similarly, the predictive values of LA volumes were incrementally better when added to CT finding of indeterminate stenosis (LAV(max): C statistic 0.62 to 0.70, p=0.046; LAV(min): C statistic 0.65 to 0.73, p=0.008), but not when indexed. Conclusions: Risk factors related to diastolic dysfunction are independent predictors of LA enlargement. LA enlargement by volumes are associated with a 3-5 fold increase risk for ACS and have incremental value for predicting ACS when added to the CT finding of indeterminate stenosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Truong, Quynh A.; Bamberg, Fabian; Mahabadi, Amir A.; Toepker, Michael; Rogers, Ian S.; Seneviratne, Sujith K.; Schlett, Christopher L.; Brady, Thomas J.; Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Truong, Quynh A.; Rogers, Ian S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Truong, Quynh A.; Bamberg, Fabian; Brady, Thomas J.; Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lee, Hang] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Nagurney, John T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Truong, QA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NIH [R01 HL080053, T32HL076136, L30HL093896]; Siemens Medical Solutions; General Electrics Healthcare; German National Academic Foundation FX This work was supported by the NIH R01 HL080053, and in part supported by Siemens Medical Solutions and General Electrics Healthcare. Drs. Rogers and Truong received support from NIH grant T32HL076136 and L30HL093896. Amir A. Mahabadi is supported by a grant from the German National Academic Foundation. NR 36 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JAN 21 PY 2011 VL 146 IS 2 BP 171 EP 176 DI 10.1016/j.ijcard.2009.06.029 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 706AQ UT WOS:000286184400014 PM 19615769 ER PT J AU Wang, W Zhu, JQ Springer, TA Luo, BH AF Wang, Wei Zhu, Jieqing Springer, Timothy A. Luo, Bing-Hao TI Tests of Integrin Transmembrane Domain Homo-oligomerization during Integrin Ligand Binding and Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOPLASMIC DOMAINS; STRUCTURAL BASIS; EXTRACELLULAR SEGMENT; CRYSTAL-STRUCTURE; CELL-MEMBRANES; ALPHA-SUBUNIT; OUTSIDE-IN; ACTIVATION; ALPHA-IIB-BETA-3; ALPHA(IIB)BETA(3) AB Integrin transmembrane (TM) and/or cytoplasmic domains play a critical role in integrin bidirectional signaling. Although it has been shown that TM and/or cytoplasmic alpha and beta domains associate in the resting state and separation of these domains is required for both inside-out and outside-in signaling, the role of TM homomeric association remains elusive. Formation of TM homo-oligomers was observed in micelles and bacterial membranes previously, and it has been proposed that homomeric association is important for integrin activation and clustering. This study addresses whether integrin TM domains form homo-oligomers in mammalian cell membranes using cysteine scanning mutagenesis. Our results show that TM homomeric interaction does not occur before or after soluble ligand binding or during inside-out activation. In addition, even though the cysteine mutants and the heterodimeric disulfide-bounded mutant could form clusters after adhering to immobilized ligand, the integrin TM domains do not form homo-oligomers, suggesting that integrin TM homomeric association is not critical for integrin clustering or outside-in signaling. Therefore, integrin TM homo-oligomerization is not required for integrin activation, ligand binding, or signaling. C1 [Luo, Bing-Hao] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Zhu, Jieqing; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. [Zhu, Jieqing; Springer, Timothy A.] Childrens Hosp, Boston, MA 02115 USA. RP Luo, BH (reprint author), Louisiana State Univ, Dept Biol Sci, 202 Life Sci Bldg, Baton Rouge, LA 70803 USA. EM luo@lsu.edu FU American Heart Association [10GRNT3960011]; Louisiana Board of Regents [LEQSF(2009-12)-RD-A07] FX This work was supported by American Heart Association Grant 10GRNT3960011 and Louisiana Board of Regents Grant LEQSF(2009-12)-RD-A07. NR 58 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 21 PY 2011 VL 286 IS 3 BP 1860 EP 1867 DI 10.1074/jbc.M110.193797 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 706BV UT WOS:000286191500026 PM 21081497 ER PT J AU Moskwa, P Buffa, FM Pan, YF Panchakshari, R Gottipati, P Muschel, RJ Beech, J Kulshrestha, R Abdelmohsen, K Weinstock, DM Gorospe, M Harris, AL Helleday, T Chowdhury, D AF Moskwa, Patryk Buffa, Francesca M. Pan, Yunfeng Panchakshari, Rohit Gottipati, Ponnari Muschel, Ruth J. Beech, John Kulshrestha, Ritu Abdelmohsen, Kotb Weinstock, David M. Gorospe, Myriam Harris, Adrian L. Helleday, Thomas Chowdhury, Dipanjan TI miR-182-Mediated Downregulation of BRCA1 Impacts DNA Repair and Sensitivity to PARP Inhibitors SO MOLECULAR CELL LA English DT Article ID CANCER-CELL-LINES; SPORADIC BREAST-CANCER; MICRORNA TARGETS; GENE-EXPRESSION; MESSENGER-RNA; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; PROMOTER-REGION; TUMORS; IDENTIFICATION AB Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by mill 182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-over-expressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy. C1 [Gottipati, Ponnari; Muschel, Ruth J.; Beech, John; Helleday, Thomas] Univ Oxford, Canc Res UK Med Res Council, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. [Moskwa, Patryk; Pan, Yunfeng; Panchakshari, Rohit; Kulshrestha, Ritu; Chowdhury, Dipanjan] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Buffa, Francesca M.; Harris, Adrian L.] Univ Oxford, Canc Res UK Dept Med Oncol, Weatherall Inst Mol Med, John Radcliffe Hosp, Oxford OX3 9DS, England. [Abdelmohsen, Kotb; Gorospe, Myriam] NIA IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Helleday, Thomas] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden. [Helleday, Thomas] Stockholm Univ, Sci Life Lab, SE-17121 Solna, Sweden. RP Helleday, T (reprint author), Univ Oxford, Canc Res UK Med Res Council, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. EM helleday@gmt.su.se; dipanjan_chowdhury@dfci.harvard.edu RI Buffa, Francesca/D-2574-2013; Helleday, Thomas/D-5224-2013; OI Buffa, Francesca/0000-0003-0409-406X; Helleday, Thomas/0000-0002-7384-092X; abdelmohsen, Kotb/0000-0001-6240-5810; Harris, Adrian/0000-0003-1376-8409 FU NCI [R01CA142698]; JCRT; Barr Award; Medical Research Council; NIHR Biomedical Research Centre, Oxford; NIA-IRP, NIH FX This work was supported by R01CA142698 (NCI), JCRT and a Barr Award (D.C.); by the Medical Research Council (T.H.); and by the NIHR Biomedical Research Centre, Oxford (A.L.H.). M.G. and K.A. were supported by the NIA-IRP, NIH. Dr. Mark O'Connor (AstraZeneca) kindly provided olaparib. We thank members of the Harris, Helleday, and Chowdhury laboratories for useful discussions. NR 63 TC 196 Z9 206 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 21 PY 2011 VL 41 IS 2 BP 210 EP 220 DI 10.1016/j.molcel.2010.12.005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 713AV UT WOS:000286708300011 PM 21195000 ER PT J AU Gibert, Y Lattanzi, VJ Zhen, AW Vedder, L Brunet, F Faasse, SA Babitt, JL Lin, HY Hammerschmidt, M Fraenkel, PG AF Gibert, Yann Lattanzi, Victoria J. Zhen, Aileen W. Vedder, Lea Brunet, Frederic Faasse, Sarah A. Babitt, Jodie L. Lin, Herbert Y. Hammerschmidt, Matthias Fraenkel, Paula G. TI BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin SO PLOS ONE LA English DT Article ID IRON OVERLOAD; JUVENILE HEMOCHROMATOSIS; SOLUBLE HEMOJUVELIN; METABOLISM; MEMBRANE; MODEL; GENE; FERROPORTIN1; HOMEOSTASIS; DEFICIENCY AB Hemojuvelin (Hjv), a member of the repulsive-guidance molecule (RGM) family, upregulates transcription of the iron regulatory hormone hepcidin by activating the bone morphogenetic protein (BMP) signaling pathway in mammalian cells. Mammalian models have identified furin, neogenin, and matriptase-2 as modifiers of Hjv's function. Using the zebrafish model, we evaluated the effects of hjv and its interacting proteins on hepcidin expression during embryonic development. We found that hjv is strongly expressed in the notochord and somites of the zebrafish embryo and that morpholino knockdown of hjv impaired the development of these structures. Knockdown of hjv or other hjv-related genes, including zebrafish orthologs of furin or neogenin, however, failed to decrease hepcidin expression relative to liver size. In contrast, overexpression of bmp2b or knockdown of matriptase-2 enhanced the intensity and extent of hepcidin expression in zebrafish embryos, but this occurred in an hjv-independent manner. Furthermore, we demonstrated that zebrafish hjv can activate the human hepcidin promoter and enhance BMP responsive gene expression in vitro, but is expressed at low levels in the zebrafish embryonic liver. Taken together, these data support an alternative mechanism for hepcidin regulation during zebrafish embryonic development, which is independent of hjv. C1 [Gibert, Yann; Lattanzi, Victoria J.; Zhen, Aileen W.; Vedder, Lea; Fraenkel, Paula G.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Gibert, Yann; Lattanzi, Victoria J.; Zhen, Aileen W.; Vedder, Lea; Fraenkel, Paula G.] Harvard Univ, Sch Med, Boston, MA USA. [Brunet, Frederic] Ecole Normale Super, Inst Genom Fonct Lyon, Lyon, France. [Faasse, Sarah A.; Babitt, Jodie L.; Lin, Herbert Y.] Massachusetts Gen Hosp, Div Nephrol, Program Membrane Biol, Boston, MA 02114 USA. [Hammerschmidt, Matthias] Univ Cologne, Inst Dev Biol, Cologne, Germany. RP Gibert, Y (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. EM pfraenke@bidmc.harvard.edu OI Fraenkel, Paula/0000-0001-8894-0117 FU NIH [K08 DK061685, 3P30 DK034854-24S1, K08 DK075846, R01 DK087727, R01 DK071837, R01 DK069533]; Cooley's Anemia Foundation FX This work was supported by NIH K08 DK061685 (P.G.F.), 3P30 DK034854-24S1 (P.G.F.), K08 DK075846 (J.L.B.), R01 DK087727 (J.L.B), R01 DK071837 (H.Y.L.), R01 DK069533 (H.Y.L) and the Cooley's Anemia Foundation (P.G.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 11 Z9 12 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2011 VL 6 IS 1 AR e14553 DI 10.1371/journal.pone.0014553 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710OY UT WOS:000286522300003 PM 21283739 ER PT J AU Gopalan, S Ausubel, FM AF Gopalan, Suresh Ausubel, Frederick M. TI A High Throughput Amenable Arabidopsis-P. aeruginosa System Reveals a Rewired Regulatory Module and the Utility to Identify Potent Anti-Infectives SO PLOS ONE LA English DT Article ID ANTIBIOTIC-RESISTANCE; VIRULENCE FACTORS; PSEUDOMONAS; GACA; PATHOGENICITY; INFLAMMATION; EXPRESSION; MUTUALISM; INTESTINE; DISEASE AB We previously demonstrated that in a metasystem consisting of Arabidopsis seedlings growing in liquid medium (in 96 well plates) even microbes considered to be innocuous such as laboratory strains of E. coli and B. subtilis can cause potent damage to the host. We further posited that such environment-induced adaptations are brought about by 'system status changes' (rewiring of pre-existing cellular signaling networks and components) of the host and the microbe, and that prolongation of such a situation could lead to the emergence of pathogenic states in real-life. Here, using this infection model, we show that the master regulator GacA of the human opportunistic pathogen P. aeruginosa (strain PA14) is dispensable for pathogenesis, as evidenced by three independent read-outs. The gene expression profile of the host after infection with wild type PA14 or the gacA mutant are also identical. GacA normally acts upstream of the quorum sensing regulatory circuit (that includes the regulator LasR) that controls a subset of virulence factors. Double mutants in gacA and lasR behave similar to the lasR mutant, as seen by abrogation of a characteristic cell type specific host cell damage caused by PA14 or the gacA mutant. This indicates that a previously unrecognized regulatory mechanism is operative under these conditions upstream of LasR. In addition, the detrimental effect of PA14 on Arabidopsis seedlings is resistant to high concentrations of the aminoglycoside antibiotic gentamicin. These data suggest that the Arabidopsis seedling infection system could be used to identify anti-infectives with potentially novel modes of action. C1 [Gopalan, Suresh; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Gopalan, Suresh; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Gopalan, S (reprint author), ReSurfX LLC, Lexington, MA USA. EM gopalans@resurfx.com FU NIH [R37 GM48707] FX Funded by grant R37 GM48707 from NIH to F.M.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 21 PY 2011 VL 6 IS 1 AR e16381 DI 10.1371/journal.pone.0016381 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710OY UT WOS:000286522300042 PM 21283656 ER PT J AU Jiang, SX Alberich-Jorda, M Zagozdzon, R Parmar, K Fu, YG Mauch, P Banu, N Makriyannis, A Tenen, DG Avraham, S Groopman, JE Avraham, HK AF Jiang, Shuxian Alberich-Jorda, Meritxell Zagozdzon, Radoslaw Parmar, Kalindi Fu, Yigong Mauch, Peter Banu, Naheed Makriyannis, Alexandros Tenen, Daniel G. Avraham, Shalom Groopman, Jerome E. Avraham, Hava Karsenty TI Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization (Retracted article. See vol. 118, pg. 2027, 2011) SO BLOOD LA English DT Article; Retracted Publication ID COLONY-STIMULATING FACTOR; CB2 RECEPTOR; BONE-MARROW; ENDOCANNABINOID SYSTEM; IMMUNE CELLS; BRAIN-INJURY; MIGRATION; DIFFERENTIATION; EXPRESSION; LIGAND AB Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB(1) and CB(2)) and the enzymes involved in their biosynthesis and degradation. However, their roles in hematopoiesis and hematopoietic stem and progenitor cell (HSPC) functions are not well characterized. Here, we show that bone marrow stromal cells express endocannabinoids (anandamide and 2-arachidonylglycerol), whereas CB(2) receptors are expressed in human and murine HSPCs. On ligand stimulation with CB(2) agonists, CB(2) receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and G alpha i-Rac1 pathways. In vivo, the CB(2) agonist AM1241 induced mobilization of murine HSPCs with shortand long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB(2) antagonists and was impaired in Cnr2(-/-)cannabinoid type 2 receptor knockout mice. Taken together, these results demonstrate that the endocannabinoid system is involved in hematopoiesis and that CB(2)/CB(2) agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB(2) agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation. (Blood.2011; 117(3):827-838) C1 [Avraham, Hava Karsenty] Beth Israel Deaconess Med Ctr, Div Expt Med, Harvard Inst Med, Boston, MA 02215 USA. [Jiang, Shuxian; Alberich-Jorda, Meritxell; Zagozdzon, Radoslaw; Parmar, Kalindi; Fu, Yigong; Mauch, Peter; Banu, Naheed; Tenen, Daniel G.; Avraham, Shalom; Groopman, Jerome E.; Avraham, Hava Karsenty] Harvard Univ, Sch Med, Boston, MA USA. [Alberich-Jorda, Meritxell; Tenen, Daniel G.] Harvard Stem Cell Inst, Boston, MA USA. [Parmar, Kalindi; Mauch, Peter] Dana Farber Canc Inst, Boston, MA 02115 USA. [Makriyannis, Alexandros] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Makriyannis, Alexandros] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Tenen, Daniel G.] Natl Univ Singapore, Canc Sci Inst, Singapore 117548, Singapore. RP Avraham, HK (reprint author), Beth Israel Deaconess Med Ctr, Div Expt Med, Harvard Inst Med, 99 Brookline Ave,3rd Floor, Boston, MA 02215 USA. EM havraham@bidmc.harvard.edu FU National Institutes of Health [CA 096805, CA135226]; National Blood Foundation; European Hematology Association; DOD [BC086398, CA10941, HL56745, CA118316] FX This work was supported by the National Institutes of Health (grants CA 096805 and CA135226, H. K. A.), National Blood Foundation (H. K. A.), and European Hematology Association (EHA research fellowship, M.A.-J.; DOD concept award BC086398, S.J.; CA10941, P. M.; and HL56745 and CA118316, D.G.T.). NR 52 TC 17 Z9 20 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 JAN 20 PY 2011 VL 117 IS 3 BP 827 EP 838 DI 10.1182/blood-2010-01-265082 PG 12 WC Hematology SC Hematology GA 709GM UT WOS:000286426300014 PM 21063029 ER PT J AU Tolar, J Park, IH Xia, L Lees, CJ Peacock, B Webber, B McElmurry, RT Eide, CR Orchard, PJ Kyba, M Osborn, MJ Lund, TC Wagner, JE Daley, GQ Blazar, BR AF Tolar, Jakub Park, In-Hyun Xia, Lily Lees, Chris J. Peacock, Brandon Webber, Beau McElmurry, Ron T. Eide, Cindy R. Orchard, Paul J. Kyba, Michael Osborn, Mark J. Lund, Troy C. Wagner, John E. Daley, George Q. Blazar, Bruce R. TI Hematopoietic differentiation of induced pluripotent stem cells from patients with mucopolysaccharidosis type I (Hurler syndrome) SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CENTRAL-NERVOUS-SYSTEM; ENZYME-REPLACEMENT THERAPY; HUMAN SOMATIC-CELLS; HEPARAN-SULFATE; STORAGE DISEASES; GENERATION; MICROGLIA; MICE; ABNORMALITIES AB Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a congenital deficiency of alpha-L-iduronidase, leading to lysosomal storage of glycosaminoglycans that is ultimately fatal following an insidious onset after birth. Hematopoietic cell transplantation (HCT) is a life-saving measure in MPS IH. However, because a suitable hematopoietic donor is not found for everyone, because HCT is associated with significant morbidity and mortality, and because there is no known benefit of immune reaction between the host and the donor cells in MPS IH, gene-corrected autologous stem cells may be the ideal graft for HCT. Thus, we generated induced pluripotent stem cells from 2 patients with MPS IH (MPS-iPS cells). We found that alpha-L-iduronidase was not required for stem cell renewal, and that MPS-iPS cells showed lysosomal storage characteristic of MPS IH and could be differentiated to both hematopoietic and nonhematopoietic cells. The specific epigenetic profile associated with de-differentiation of MPS IH fibroblasts into MPS-iPS cells was maintained when MPS-iPS cells are gene-corrected with virally delivered alpha-L-iduronidase. These data underscore the potential of MPS-iPS cells to generate autologous hematopoietic grafts devoid of immunologic complications of allogeneic transplantation, as well as generating nonhematopoietic cells with the potential to treat anatomical sites not fully corrected with HCT. (Blood.2011;117(3):839-847) C1 [Tolar, Jakub] Univ Minnesota, Dept Pediat, Div Hematol Oncol, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Park, In-Hyun; Daley, George Q.] Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA USA. [Park, In-Hyun; Daley, George Q.] Dana Farber Canc Inst, Boston, MA USA. [Park, In-Hyun; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA USA. [Park, In-Hyun; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Tolar, J (reprint author), Univ Minnesota, Dept Pediat, Div Hematol Oncol, Blood & Marrow Transplant Program, 420 Delaware St SE,MMC 366, Minneapolis, MN 55455 USA. EM tolar003@umn.edu OI Kyba, Michael/0000-0002-5579-7534; Tolar, Jakub/0000-0002-0957-4380 FU Children's Cancer Research Fund; National Institutes of Health [R21 A1079755, AI081918, P01 CA067493] FX This work was supported by the Children's Cancer Research Fund, MN, and by National Institutes of Health grants R21 A1079755 (J.T.), AI081918 (B.R.B.), and P01 CA067493 (B.R.B.). NR 48 TC 48 Z9 48 U1 1 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 20 PY 2011 VL 117 IS 3 BP 839 EP 847 DI 10.1182/blood-2010-05-287607 PG 9 WC Hematology SC Hematology GA 709GM UT WOS:000286426300015 PM 21037085 ER PT J AU Nakao, S Zandi, S Hata, Y Kawahara, S Arita, R Schering, A Sun, DW Melhorn, MI Ito, Y Lara-Castillo, N Ishibashi, T Hafezi-Moghadam, A AF Nakao, Shintaro Zandi, Souska Hata, Yasuaki Kawahara, Shuhei Arita, Ryoichi Schering, Alexander Sun, Dawei Melhorn, Mark I. Ito, Yasuhiro Lara-Castillo, Nuria Ishibashi, Tatsuro Hafezi-Moghadam, Ali TI Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an endogenous trapping mechanism links lymph- and angiogenesis SO BLOOD LA English DT Article ID GROWTH-FACTOR C; IN-VIVO; BREAST-CANCER; CELLS; NEOVASCULARIZATION; RECRUITMENT; METASTASIS; RECEPTOR-3; LIGAND; INJURY AB Angio- and lymphangiogenesis are inherently related processes. However, how blood and lymphatic vessels regulate each other is unknown. This work introduces a novel mechanism explaining the temporal and spatial relation of blood and lymphatic vessels. Vascular endothelial growth factor-A (VEGF-A) surprisingly reduced VEGF-C in the supernatant of blood vessel endothelial cells, suggesting growth factor (GF) clearance by the growing endothelium. The orientation of lymphatic sprouting toward angiogenic vessels and away from exogenous GFs was VEGF-C dependent. In vivo molecular imaging revealed higher VEGF receptor (R)-2 in angiogenic tips compared with normal vessels. Consistently, lymphatic growth was impeded in the angiogenic front. VEGF-C/R-2 complex in the cytoplasm of VEGF-A-treated endothelium indicated that receptor-mediated internalization causes GF clearance from the extracellular matrix. GF clearance by receptor-mediated internalization is a new paradigm explaining various characteristics of lymphatics. (Blood. 2011; 117(3): 1081-1090) C1 [Nakao, Shintaro; Zandi, Souska; Schering, Alexander; Sun, Dawei; Melhorn, Mark I.; Ito, Yasuhiro; Hafezi-Moghadam, Ali] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol, Boston, MA USA. [Nakao, Shintaro; Hata, Yasuaki; Kawahara, Shuhei; Arita, Ryoichi; Ishibashi, Tatsuro] Kyushu Univ, Dept Ophthalmol, Grad Sch Med Sci, Fukuoka 812, Japan. RP Hafezi-Moghadam, A (reprint author), Brigham & Womens Hosp, Ctr Excellence Funct & Mol Imaging, 221 Longwood Ave,3rd Fl, Boston, MA 02115 USA. EM AHM@BWH.harvard.edu OI Hafezi-Moghadam, Ali/0000-0002-5336-0697 FU National Institutes of Health [AI050775]; Bausch and Lomb; Japan Eye Bank Association; Tear Film and Ocular Surface Society; American Health Assistance Foundation; Malaysian Palm Oil Board; Young Investigator Fellowship FX This work was supported by National Institutes of Health grant AI050775 (AH-M), an overseas Research Fellowship Award from Bausch and Lomb, a Fellowship Award from the Japan Eye Bank Association and Tear Film and Ocular Surface Society and Young Investigator Fellowship, the American Health Assistance Foundation, and the Malaysian Palm Oil Board. NR 29 TC 22 Z9 26 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 20 PY 2011 VL 117 IS 3 BP 1081 EP 1090 DI 10.1182/blood-2010-02-267427 PG 10 WC Hematology SC Hematology GA 709GM UT WOS:000286426300042 PM 20705758 ER PT J AU Driver, JA Logroscino, G Lu, LD Gaziano, JM Kurth, T AF Driver, Jane A. Logroscino, Giancarlo Lu, Linda Gaziano, J. Michael Kurth, Tobias TI Use of non-steroidal anti-inflammatory drugs and risk of Parkinson's disease: nested case-control study SO BRITISH MEDICAL JOURNAL LA English DT Article ID CARDIOVASCULAR-DISEASE; PHYSICIANS HEALTH; BETA-CAROTENE; COMORBIDITY; PROTECT; CANCER; NEUROPROTECTION; SALICYLATE; ADJUSTMENT; MORTALITY AB Objective To evaluate the relation between Parkinson's disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men. Design Case-control analysis nested in the Physicians' Health Study. Participants 22 007 male physicians aged 40-84 years without indications for or contraindications to regular NSAID use and free of Parkinson's disease at baseline. Cases and controls were matched by age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores. Setting United States. Main outcome measures Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson's disease and by their controls in each case-control set. Results Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson's disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson's disease in men who had 12 years of regular non-aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for >= 5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson's disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson's disease tended to disappear when analyses were limited to drug use >= 5 years before the disease diagnosis. Conclusions This case-control study did not find evidence that NSAID use reduces Parkinson's disease risk. The positive associations observed between NSAID use and Parkinson's disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis. C1 [Driver, Jane A.; Lu, Linda; Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, Boston, MA 02120 USA. [Driver, Jane A.; Gaziano, J. Michael] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Driver, Jane A.; Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res Informat Ctr, Boston, MA USA. [Logroscino, Giancarlo] Univ Bari, Dept Neurol & Psychiat Sci, Bari, Italy. [Gaziano, J. Michael; Kurth, Tobias] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02120 USA. [Kurth, Tobias] INSERM, Neuroepidemiol U708, Paris, France. [Kurth, Tobias] Univ Paris 06, Paris, France. RP Driver, JA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, 1620 Tremont St, Boston, MA 02120 USA. EM jdriver@partners.org RI Kurth, Tobias/A-9243-2012; LOGROSCINO, GIANCARLO/K-5148-2016 OI Kurth, Tobias/0000-0001-7169-2620; LOGROSCINO, GIANCARLO/0000-0003-0423-3242 FU Parkinson's Disease Foundation; National Cancer Institute [CA-34944, CA-40360, CA-097193]; National Heart, Lung, and Blood Institute, Bethesda, MD [HL-26490, HL-34595]; Hartford Foundation; Harvard Medical School; Veteran's Administration; Amyotrophic Lateral Sclerosis Association, Italian Ministry of Health; Apulia Region; Italian Ministry of Universities; National Institutes of Health; BASF; DSM Pharmaceuticals; Wyeth Pharmaceuticals; McNeil Consumer Products; Pliva; French National Research Agency; US National Institutes of Health; Merck; Migraine Research Foundation; Parkinson's Research Foundation FX This research is funded by a grant from the Parkinson's Disease Foundation. The Physicians' Health Study is supported by grants CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, MD. The study sponsor had no role in study design; data collection, analysis, or interpretation; writing the article; or the decision to submit it for publication. The researchers are independent from funders and sponsors.; All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: JAD has support from the Parkinson's Disease Foundation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work. We report a full disclosure for the past five years for each of the authors. JAD has a research grant from the Parkinson's Disease Foundation, the Hartford Foundation, Harvard Medical School, and a Career Development Award from the Veteran's Administration. LL has nothing to disclose. GL has received research funding from the Amyotrophic Lateral Sclerosis Association, Italian Ministry of Health, the Apulia Region, and special funding from the Italian Ministry of Universities and has received honorariums from Pfizer, Novartis, Glaxo, and Lilly Pharmaceutical for speaking engagements. JMG has received investigator initiated research funding and support as principal investigator from National Institutes of Health, BASF, DSM Pharmaceuticals, Wyeth Pharmaceuticals, McNeil Consumer Products, and Pliva; received honoraria from Bayer and Pfizer for speaking engagements; and is a consultant for Bayer, McNeil Consumer Products, Wyeth Pharmaceuticals, Merck, Nutraquest, and GlaxoSmithKline. TK has received investigator initiated research funding from the French National Research Agency, the US National Institutes of Health, Merck, the Migraine Research Foundation, and the Parkinson's Research Foundation; is a consultant to i3 Drug Safety and World Health Information Science Consultants, LLC; and has received honoraria from the American Academy of Neurology, Genzyme, Merck, and Pfizer for educational lectures. NR 36 TC 28 Z9 29 U1 2 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 20 PY 2011 VL 342 AR d198 DI 10.1136/bmj.d198 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 711PE UT WOS:000286603100002 PM 21252104 ER PT J AU Lin, NU Winer, EP AF Lin, Nancy U. Winer, Eric P. TI Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Time to Step Out of the Limelight SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PHASE-II TRIAL; 1ST-LINE THERAPY; PLUS VINORELBINE; TRASTUZUMAB; COMBINATION; DOCETAXEL; EFFICACY; P95HER2; SAFETY; HER2 C1 [Lin, Nancy U.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 22 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2011 VL 29 IS 3 BP 251 EP 253 DI 10.1200/JCO.2010.32.5290 PG 3 WC Oncology SC Oncology GA 707VU UT WOS:000286319000012 PM 21149664 ER PT J AU Bains, M Zaegel, V Mize-Berge, J Heidenreich, KA AF Bains, Mona Zaegel, Vincent Mize-Berge, Janna Heidenreich, Kim A. TI IGF-I stimulates Rab7-RILP interaction during neuronal autophagy SO NEUROSCIENCE LETTERS LA English DT Article DE Autophagy; Rab7; IGF-I; Neurons ID LYSOSOMAL PROTEIN; RAB34 INTERACTION; PURKINJE NEURONS; CELL-DEATH; FUSION; RILP; ACTIVATION; RECEPTOR; ACCUMULATION; MICROTUBULES AB Restoration of autophagy represents a potential therapeutic target for neurodegenerative disorders, but factors that regulate autophagic flux are largely unknown. When deprived of trophic factors, cultured Purkinje neurons die by an autophagy associated cell death mechanism. The accumulation of autophagic vesicles and cell death of Purkinje neurons is inhibited by insulin-like growth factor, by a mechanism that enhances autophagic vesicle turnover. In this report, we identify Rab7 as an IGF-I regulated target during neuronal autophagy. Purkinje neurons transfected with EGFP-Rab7-WT and constitutively active EGFP-Rab7-Q67L contained few RFP-LC3 positive autophagosomes and little co-localization with GFP-Rab7 under control conditions. Upon induction of autophagy. RFP-LC3 positive autophagosomes increased and co-localized with GFP-Rab7. Conversely, expression of the dominant negative mutant EGFP-Rab7-T22N increased the accumulation of autophagosomes under control conditions, which accumulated even further during trophic factor withdrawal. There was no vesicular co-localization between Rab7-T22N and RFP-LC3 under control or trophic factor withdrawal conditions. During prolonged trophic factor withdrawal, a condition that leads to the accumulation of autophagic vesicles and cell death, Rab7 activity decreased significantly. IGF-I, added at the time of trophic factor withdrawal, prevented the deactivation of Rab7 and increased the interaction of Rab7 with its interacting protein (RILP), restoring autophagic flux. These results provide a novel mechanism by which IGF-I regulates autophagic flux during neuronal stress. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Bains, Mona; Zaegel, Vincent; Mize-Berge, Janna; Heidenreich, Kim A.] Univ Colorado Denver, Dept Pharmacol, Aurora, CO 80045 USA. [Heidenreich, Kim A.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Bains, M (reprint author), Univ Colorado Denver, Dept Pharmacol, MS 8303,POB 6511, Aurora, CO 80045 USA. EM mona.bains@ucdenver.edu FU Department of Veterans Affairs; NIH [NS045560]; NIH/NINDS [1F32NS062534-01A1]; NIH DERC [P30-DK57516] FX We are grateful to Dr. Bo van Deurs for the Rab7 plasmids, Dr. Aimee Edinger for the GST-RILP plasmid and Dr. Aviva M. Tolkovsky for the adeno-RFP-LC3. This work was supported by Department of Veterans Affairs Merit Award, NIH grant NS045560 and NIH/NINDS grant 1F32NS062534-01A1. Molecular Biology Core Services were supported by the NIH DERC grant P30-DK57516. NR 29 TC 21 Z9 22 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 20 PY 2011 VL 488 IS 2 BP 112 EP 117 DI 10.1016/j.neulet.2010.09.018 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 715CQ UT WOS:000286858400002 PM 20849920 ER PT J AU Caronia, LM Martin, C Welt, CK Sykiotis, GP Quinton, R Thambundit, A Avbelj, M Dhruvakumar, S Plummer, L Hughes, VA Seminara, SB Boepple, PA Sidis, Y Crowley, WF Martin, KA Hall, JE Pitteloud, N AF Caronia, Lisa M. Martin, Cecilia Welt, Corrine K. Sykiotis, Gerasimos P. Quinton, Richard Thambundit, Apisadaporn Avbelj, Magdalena Dhruvakumar, Sadhana Plummer, Lacey Hughes, Virginia A. Seminara, Stephanie B. Boepple, Paul A. Sidis, Yisrael Crowley, William F., Jr. Martin, Kathryn A. Hall, Janet E. Pitteloud, Nelly TI A Genetic Basis for Functional Hypothalamic Amenorrhea. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; EATING-DISORDERS; WOMEN; MUTATIONS; RECEPTOR; DEFICIENCY; WEIGHT AB Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. Methods: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Results: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Conclusions: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.) N Engl J Med 2011;364:215-25. C1 [Sidis, Yisrael; Pitteloud, Nelly] Univ Lausanne, CHU Vaudois, Div Endocrine, CH-1011 Lausanne, Switzerland. [Caronia, Lisa M.; Martin, Cecilia; Welt, Corrine K.; Sykiotis, Gerasimos P.; Thambundit, Apisadaporn; Avbelj, Magdalena; Dhruvakumar, Sadhana; Plummer, Lacey; Hughes, Virginia A.; Seminara, Stephanie B.; Boepple, Paul A.; Sidis, Yisrael; Crowley, William F., Jr.; Martin, Kathryn A.; Hall, Janet E.; Pitteloud, Nelly] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Caronia, Lisa M.; Martin, Cecilia; Welt, Corrine K.; Sykiotis, Gerasimos P.; Thambundit, Apisadaporn; Avbelj, Magdalena; Dhruvakumar, Sadhana; Plummer, Lacey; Hughes, Virginia A.; Seminara, Stephanie B.; Boepple, Paul A.; Sidis, Yisrael; Crowley, William F., Jr.; Martin, Kathryn A.; Hall, Janet E.; Pitteloud, Nelly] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. [Caronia, Lisa M.; Martin, Cecilia; Welt, Corrine K.; Sykiotis, Gerasimos P.; Thambundit, Apisadaporn; Avbelj, Magdalena; Dhruvakumar, Sadhana; Plummer, Lacey; Hughes, Virginia A.; Seminara, Stephanie B.; Boepple, Paul A.; Sidis, Yisrael; Crowley, William F., Jr.; Martin, Kathryn A.; Hall, Janet E.; Pitteloud, Nelly] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Quinton, Richard] Royal Victoria Infirm, Dept Endocrinol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Pitteloud, N (reprint author), Univ Lausanne, CHU Vaudois, Div Endocrine, Rue Bugnon 46, CH-1011 Lausanne, Switzerland. EM nelly.pitteloud@chuv.ch RI PITTELOUD, Nelly/K-2709-2014; OI Welt, Corrine/0000-0002-8219-5504; Avbelj Stefanija, Magdalena/0000-0002-0836-5114; Sykiotis, Gerasimos/0000-0002-9565-4941 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) [5U54HD028138, 1R01HD056264, 5R01HD015788, 5R01HD42708]; National Center for Research Resources [1 UL1 RR025758-01, M01-RR-01066]; Newcastle University Teaching Hospitals Special Trustees; Pew Latin American Fellows Program in the Biomedical Sciences FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) (through cooperative agreement 5U54HD028138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and NICHD-NIH grants 1R01HD056264, 5R01HD015788, and 5R01HD42708), by the National Center for Research Resources (grants 1 UL1 RR025758-01 and M01-RR-01066 to the Harvard Clinical and Translational Science Center), the Newcastle University Teaching Hospitals Special Trustees, and the Pew Latin American Fellows Program in the Biomedical Sciences (grant to Dr. Martin). NR 45 TC 64 Z9 66 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 20 PY 2011 VL 364 IS 3 BP 215 EP 225 DI 10.1056/NEJMoa0911064 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 708SF UT WOS:000286383900006 PM 21247312 ER PT J AU Moellering, RC Abbott, GF Ferraro, MJ AF Moellering, Robert C., Jr. Abbott, Gerald F. Ferraro, Mary Jane TI A Woman with Shock after Treatment of a Furuncle Sepsis due to community-acquired methicillinresistant Staphylococcus aureus, strain USA300-0047, PVL-positive. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIRULENCE; EXPRESSION; PATHOGENESIS; ANTIBIOTICS; INFECTIONS C1 [Moellering, Robert C., Jr.] Beth Israel Deaconess Med Ctr, Dept Med, Div Infect Dis, Boston, MA 02215 USA. [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Moellering, Robert C., Jr.; Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Abbott, Gerald F.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Moellering, RC (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Infect Dis, Boston, MA 02215 USA. NR 12 TC 9 Z9 9 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 20 PY 2011 VL 364 IS 3 BP 266 EP 275 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 708SF UT WOS:000286383900014 PM 21247318 ER PT J AU Robinson, CM Singh, G Henquell, C Walsh, MP Peigue-Lafeuille, H Seto, D Jones, MS Dyer, DW Chodosh, J AF Robinson, Christopher M. Singh, Gurdeep Henquell, Cecile Walsh, Michael P. Peigue-Lafeuille, Helene Seto, Donald Jones, Morris S. Dyer, David W. Chodosh, James TI Computational analysis and identification of an emergent human adenovirus pathogen implicated in a respiratory fatality SO VIROLOGY LA English DT Article DE Adenovirus; Viral genomics; Viral recombination; Viral evolution; Viral bioinformatics ID EPIDEMIC KERATOCONJUNCTIVITIS; SIALIC-ACID; GENITAL INFECTIONS; MAMMARY-TUMORS; FIBER KNOBS; CREF CELLS; PROTEIN; RECEPTOR; DISEASE; BINDING AB Adenoviral infections are typically acute, self-limiting, and not associated with death. However, we present the genomic and bioinformatics analysis of a novel recombinant human adenovirus (HAdV-D56) isolated in France that caused a rare neonatal fatality, and keratoconjunctivitis in three health care workers who cared for the neonate. Whole genome alignments revealed the expected diversity in the penton base, hexon, E3, and fiber coding regions, and provided evidence for extensive recombination. Bootscan analysis confirmed recombination between HAdV-D9, HAdV-D26, HAdV-D15, and HAdV-D29 in the penton base and hexon proteins, centered around hypervariable loops within the putative proteins. Protein structure analysis of the fiber coding region revealed similarity with HAdV-D8, HAdV-D9, and HAdV-D53, possibly accounting for the ocular tropism of the virus. Based on these data, this virus appears to be a new HAdV-D type (HAdV-D56), underscoring the importance of recombination events in human adenovirus evolution and the emergence of new adenovirus pathogens. (C) 2010 Elsevier Inc. All rights reserved. C1 [Robinson, Christopher M.; Singh, Gurdeep; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Henquell, Cecile; Peigue-Lafeuille, Helene] Univ Auvergne, Hop Gabriel Montpied, Virol Lab, CHU Clermont Ferrand, Clermont Ferrand, France. [Walsh, Michael P.; Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA 20110 USA. [Jones, Morris S.] David Grant USAF Med Ctr, Clin Invest Facil, Fairfield, CA 94535 USA. [Robinson, Christopher M.; Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU NIH [EY013124-S1, P30EY014104]; Research to Prevent Blindness, Inc FX Supported by NIH grants EY013124-S1 and P30EY014104, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School from Research to Prevent Blindness, Inc. The views expressed in this material are those of the authors, and do not reflect the official policy or position of the U.S. Government, the Department of Defense, or the Department of the Air Force. The funding sponsors played no role in any aspect of the study. The authors wish to thank Sarah Torres for her technical assistance. The authors wish to note a genomic sequence highly similar to HAdV-D56 was released after submission of this manuscript: GenBank accession no. AB562588. NR 63 TC 73 Z9 80 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2011 VL 409 IS 2 BP 141 EP 147 DI 10.1016/j.virol.2010.10.020 PG 7 WC Virology SC Virology GA 708MV UT WOS:000286366800001 PM 21056888 ER PT J AU Yaffe, K Weston, A Graff-Radford, NR Satterfield, S Simonsick, EM Younkin, SG Younkin, LH Kuller, L Ayonayon, HN Ding, JZ Harris, TB AF Yaffe, Kristine Weston, Andrea Graff-Radford, Neill R. Satterfield, Suzanne Simonsick, Eleanor M. Younkin, Steven G. Younkin, Linda H. Kuller, Lewis Ayonayon, Hilsa N. Ding, Jingzhong Harris, Tamara B. TI Association of Plasma beta-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ALZHEIMERS-DISEASE; CARDIOVASCULAR HEALTH; OLDER PERSONS; RISK; IMPAIRMENT; DEMENTIA; PROTEIN; EDUCATION; LITERACY; MEMORY AB Context Lower plasma beta-amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia. Objective To determine if plasma beta-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve. Design, Setting, and Participants We studied 997 black and white community-dwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n=550) were female; and 54.0% (n=538) were black. Main Outcome Measures Association of near-baseline plasma beta-amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results. Results Low beta-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest beta-amyloid tertile: mean change in 3MS score, -6.59 [95% confidence interval [CI], -5.21 to -7.67] points; middle tertile: -6.16 [95% CI, -4.92 to -7.32] points; and highest tertile: -3.60 [95% CI, -2.27 to -4.73] points; P<.001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking, and apolipoprotein E [APOE] e4 status and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (at least a high school diploma, higher than sixth-grade literacy, or no APOE e4 allele), beta-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with less than a high school diploma, the 3MS score decline was -8.94 (95% CI, -6.94 to -10.94) for the lowest tertile compared with -4.45 (95% CI, -2.31 to -6.59) for the highest tertile, but for those with at least a high school diploma, 3MS score decline was -4.60 (95% CI, -3.07 to -6.13) for the lowest tertile and -2.88 (95% CI, -1.41 to -4.35) for the highest tertile (P=.004 for interaction). Interactions were also observed for literacy (P=.005) and for APOE e4 allele (P=.02). Conclusion Lower plasma beta-amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve. JAMA. 2011; 305(3): 261-266 C1 [Yaffe, Kristine; Weston, Andrea] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Younkin, Steven G.; Younkin, Linda H.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Kuller, Lewis] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ding, Jingzhong] Wake Forest Univ, Med Ctr, Dept Gerontol & Geriatr Med, Winston Salem, NC USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU National Institute on Aging [N01-AG62101, N01-AG62103, N01-AG62106, K24AG031155] FX This study was funded by National Institute on Aging contracts N01-AG62101, N01-AG62103, and N01-AG62106. This research was supported in part by the Intramural Research Program of the National Institute on Aging. Dr Yaffe is supported in part by National Institute on Aging grant K24AG031155 and by an anonymous foundation. NR 33 TC 93 Z9 96 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 19 PY 2011 VL 305 IS 3 BP 261 EP 266 DI 10.1001/jama.2010.1995 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 707YY UT WOS:000286328700021 PM 21245181 ER PT J AU Freeman, EW Guthrie, KA Caan, B Sternfeld, B Cohen, LS Joffe, H Carpenter, JS Anderson, GL Larson, JC Ensrud, KE Reed, SD Newton, KM Sherman, S Sammel, MD LaCroix, AZ AF Freeman, Ellen W. Guthrie, Katherine A. Caan, Bette Sternfeld, Barbara Cohen, Lee S. Joffe, Hadine Carpenter, Janet S. Anderson, Garnet L. Larson, Joseph C. Ensrud, Kristine E. Reed, Susan D. Newton, Katherine M. Sherman, Sheryl Sammel, Mary D. LaCroix, Andrea Z. TI Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PLACEBO-CONTROLLED TRIAL; VASOMOTOR SYMPTOMS; CLINICAL-TRIAL; NEWER ANTIDEPRESSANTS; POSTMENOPAUSAL WOMEN; HORMONE-THERAPY; DOUBLE-BLIND; CITALOPRAM; GABAPENTIN; DEPRESSION AB Context Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes. Objective To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes. Design, Setting, and Patients A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010. Intervention Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. Main Outcome Measures Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency >= 50% decrease from baseline). Results Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P<.001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P=.009) at the 8-week follow-up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to -0.17 for placebo; P<.001). Race did not significantly modify the treatment effect (P=.62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P=.02) more hot flashes per day than women in the placebo group. Conclusion Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. C1 [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Obstet, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Sch Med, Dept Gynecol & Psychiat, Philadelphia, PA 19104 USA. [Sammel, Mary D.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Stat, Philadelphia, PA 19104 USA. [Guthrie, Katherine A.; Anderson, Garnet L.; Larson, Joseph C.; LaCroix, Andrea Z.] Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, Seattle, WA 98104 USA. [Reed, Susan D.] Univ Washington, Sch Med, Seattle, WA USA. [Newton, Katherine M.] Grp Hlth Res Inst, Seattle, WA USA. [Caan, Bette; Sternfeld, Barbara] Kaiser Permanente, Div Res, Oakland, CA USA. [Cohen, Lee S.; Joffe, Hadine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Carpenter, Janet S.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. [Ensrud, Kristine E.] Univ Minnesota, VA Med Ctr, Minneapolis, MN USA. [Sherman, Sheryl] NIA, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Freeman, EW (reprint author), 3701 Market St,Ste 820 Mudd, Philadelphia, PA 19104 USA. EM freemane@mail.med.upenn.edu FU Forest Laboratories, Inc; Wyeth; Pfizer; Xanodyne Pharmaceuticals; National Alliance for Research on Schizophrenia and Depression; Astra-Zeneca Pharmaceuticals; Sepracor, Inc; Bayer HealthCare; Bristol-Myers; Stanley Foundation; Ortho-McNeill Jansen; Pfizer, Inc.; Eli Lilly; GlaxoSmithKline; Sanofi-Events; Wyeth-Ayerst Pharmaceuticals; National Institute of Aging [U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700]; Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD); National Center for Complementary and Alternative Medicine (NCCAM); Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources [UL1 RR025761] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Freeman reported research support from Forest Laboratories, Inc, Wyeth, Pfizer and Xanodyne Pharmaceuticals; honoraria for consulting and presentations from Wyeth, Forest Laboratories, Inc, Pherin Pharmaceuticals and Bayer Health Care. Dr Cohen reported research support from National Alliance for Research on Schizophrenia and Depression; Astra-Zeneca Pharmaceuticals; Sepracor, Inc; Bayer HealthCare; Bristol-Myers; Stanley Foundation; Ortho-McNeill Jansen; Pfizer, Inc. Advisory/Consulting: Eli Lilly; GlaxoSmithKline; JDS/Noven Pharmaceuticals; Wyeth-Ayerst Pharmaceuticals; Honoraria, Eli Lilly, Forest Laboratories, Inc; GlaxosmithKline; Pfizer, Inc, and Wyeth-Ayerst Pharmaceuticals. Dr Joffe reported research support from AstraZeneca Pharmaceuticals, Bayer HealthCare, Eli Lilly, Forest Laboratories, Inc, GlaxoSmithKline, Sanofi-Events (product support only), Sepracor, Inc, and Wyeth-Ayerst Pharmaceuticals; speaking honoraria, Eli Lilly, GlaxoSmithKline; Advisory/Consulting, Abbott Laboratories, Eli Lilly, Forest Laboratories, Inc, JDS-Noven Pharmaceuticals, Sanofi-Events, Sepracor Inc, and Wyeth-Ayerst Pharmaceuticals. No other authors reported having a financial conflict of interest.; The study was supported by a cooperative agreement issued by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Research and Women's Health (ORWH), and grants U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700 from the NIA. At the Indiana University site, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, funded in part by grant UL1 RR025761 from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award. Escitalopram and matching placebo pills were provided by Forest Research Institute. NR 29 TC 87 Z9 91 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 19 PY 2011 VL 305 IS 3 BP 267 EP 274 DI 10.1001/jama.2010.2016 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 707YY UT WOS:000286328700022 PM 21245182 ER PT J AU Liberman, LD Wang, HB Liberman, MC AF Liberman, Leslie D. Wang, Haobing Liberman, M. Charles TI Opposing Gradients of Ribbon Size and AMPA Receptor Expression Underlie Sensitivity Differences among Cochlear-Nerve/Hair-Cell Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AUDITORY-NERVE; CAT COCHLEA; HAIR-CELLS; CHARACTERISTIC FREQUENCY; SYNAPTIC RIBBONS; SERIAL SECTIONS; SPIRAL GANGLION; GUINEA-PIG; FIBERS; INNERVATION AB The auditory system transduces sound-evoked vibrations over a range of input sound pressure levels spanning six orders of magnitude. An important component of the system mediating this impressive dynamic range is established in the cochlear sensory epithelium, where functional subtypes of cochlear nerve fibers differ in threshold sensitivity, and spontaneous discharge rate (SR), by more than a factor of 1000 (Liberman, 1978), even though, regardless of type, each fiber contacts only a single hair cell via a single ribbon synapse. To study the mechanisms underlying this remarkable heterogeneity in threshold sensitivity among the 5-30 primary sensory fibers innervating a single inner hair cell, we quantified the sizes of presynaptic ribbons and postsynaptic AMPA receptor patches in > 1200 synapses, using high-power confocal imaging of mouse cochleas immunostained for CtBP2 (C-terminal binding protein 2, a major ribbon protein) and GluR2/3 (glutamate receptors 2 and 3). We document complementary gradients, most striking in mid-cochlear regions, whereby synapses from the modiolar face and/or basal pole of the inner hair cell have larger ribbons and smaller receptor patches than synapses located in opposite regions of the cell. The AMPA receptor expression gradient likely contributes to the differences in cochlear nerve threshold and SR seen on the two sides of the hair cell in vivo (Liberman, 1982a); the differences in ribbon size may contribute to the heterogeneity of EPSC waveforms seen in vitro (Grant et al., 2010). C1 [Liberman, Leslie D.; Wang, Haobing; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Liberman, M. Charles] Harvard Massachusetts Inst Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02114 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 [RO1 DC0188, P30 DC5029] FX This work was supported by Grants RO1 DC0188 and P30 DC5029 from the National Institute on Deafness and other Communication Disorders. NR 38 TC 74 Z9 76 U1 1 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 19 PY 2011 VL 31 IS 3 BP 801 EP 808 DI 10.1523/JNEUROSCI.3389-10.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 708OS UT WOS:000286373700003 PM 21248103 ER PT J AU Haroush, K Deouell, LY Hochstein, S AF Haroush, Keren Deouell, Leon Y. Hochstein, Shaul TI Hearing While Blinking: Multisensory Attentional Blink Revisited SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EVENT-RELATED POTENTIALS; HUMAN AUDITORY-CORTEX; MISMATCH NEGATIVITY; SELECTIVE ATTENTION; ELECTROPHYSIOLOGICAL EVIDENCE; INATTENTIONAL BLINDNESS; SENSORY MODALITIES; WITHIN-MODALITY; WORKING-MEMORY; PITCH CHANGES AB It is well established that cognitive system overload is reflected in the attentional blink (AB), the failure to report a second target when it closely follows detection of a first target within a rapid series of stimuli. However, there is intense controversy concerning the effect of first-target detection in one modality on subsequent dynamics of attentional resources in other modalities. Mixed results were found using an audiovisual AB paradigm: depletion of resources in one modality either impaired performance in the other modality or had no effect. Here, we circumvent the need for task switching by measuring an event-related potential, the mismatch negativity, which reflects implicit auditory change detection without requiring task engagement and is present even for background sounds that participants ignore. Surprisingly, we find that during the visual AB, auditory processing is enhanced rather than inhibited, as would be expected by system overload. We suggest that multimodal attentional resources may be freed rather than engaged during the visual AB. Suppression of irrelevant input may require active control by a central executive, which is preoccupied during the visual AB, and/or there may be no reason to suppress other-modal input since the visual system will miss its second target anyway. C1 [Haroush, Keren; Hochstein, Shaul] Hebrew Univ Jerusalem, Dept Neurobiol, IL-91904 Jerusalem, Israel. [Deouell, Leon Y.] Hebrew Univ Jerusalem, Dept Psychol, IL-91904 Jerusalem, Israel. [Deouell, Leon Y.; Hochstein, Shaul] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci, IL-91904 Jerusalem, Israel. [Deouell, Leon Y.; Hochstein, Shaul] Hebrew Univ Jerusalem, Interdisciplinary Ctr Neural Computat, IL-91904 Jerusalem, Israel. RP Haroush, K (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM kharoush@gmail.com; leon.deouell@huji.ac.il; shaul@vms.huji.ac.il FU Israel Science Foundation of the Israel Academy of Sciences; U.S.-Israel Binational Science Foundation; National Institute for Psychobiology in Israel [9-2004-5] FX This work was supported by grants from the Israel Science Foundation of the Israel Academy of Sciences and the U.S.-Israel Binational Science Foundation (S.H.) and Grant 9-2004-5 from the National Institute for Psychobiology in Israel founded by the Charles E. Smith family (L.Y.D.). NR 53 TC 2 Z9 2 U1 3 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 19 PY 2011 VL 31 IS 3 BP 922 EP 927 DI 10.1523/JNEUROSCI.0420-10.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 708OS UT WOS:000286373700017 PM 21248117 ER PT J AU Wang, J Ferruzzi, MG Varghese, M Qian, XJ Cheng, A Xie, M Zhao, W Ho, L Pasinetti, GM AF Wang, Jun Ferruzzi, Mario G. Varghese, Merina Qian, Xianjuan Cheng, Alice Xie, Mathew Zhao, Wei Ho, Lap Pasinetti, Giulio M. TI Preclinical study of dimebon on beta-amyloid-mediated neuropathology in Alzheimer's disease SO MOLECULAR NEURODEGENERATION LA English DT Article ID MOUSE MODEL; TRANSGENIC MICE; PROTEIN; OLIGOMERS; COGNITION; MEMORY; BRAIN; LATREPIRDINE; MITOCHONDRIA; INHIBITION AB Background: Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD. Results: The present studies are designed specifically to assess whether dimebon might modulate beta-amyloid (A beta)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total A beta as well as soluble oligomeric A beta in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon. Conclusion: Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type A beta-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function. C1 [Wang, Jun; Varghese, Merina; Qian, Xianjuan; Cheng, Alice; Xie, Mathew; Zhao, Wei; Ho, Lap; Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Wang, Jun; Varghese, Merina; Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Ferruzzi, Mario G.] Purdue Univ, Dept Food Sci & Foods & Nutr, W Lafayette, IN 47907 USA. [Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY 10468 USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu RI Zhao, Wei/B-3220-2010 FU Mount Sinai School of Medicine FX This work was supported by discretionary funds to GMP from Mount Sinai School of Medicine NR 30 TC 21 Z9 21 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JAN 19 PY 2011 VL 6 AR 7 DI 10.1186/1750-1326-6-7 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 718UD UT WOS:000287150900001 PM 21247479 ER PT J AU Huang, YH Snuderl, M Jain, RK AF Huang, Yuhui Snuderl, Matija Jain, Rakesh K. TI Polarization of Tumor-Associated Macrophages: A Novel Strategy for Vascular Normalization and Antitumor Immunity SO CANCER CELL LA English DT Editorial Material ID OXYGENATION; THERAPY AB Vascular normalization is an emerging concept in cancer treatment. In this issue of Cancer Cell, Rolny et al. show that histidine-rich glycoprotein normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis. Placental Growth Factor deletion in macrophages phenocopies many of these effects. C1 [Huang, Yuhui; Snuderl, Matija; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab Tumor Biol, Boston, MA 02114 USA. [Huang, Yuhui; Snuderl, Matija; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab Tumor Biol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu OI Huang, Yuhui/0000-0003-1985-3575; Snuderl, Matija/0000-0003-0752-0917 NR 10 TC 19 Z9 19 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JAN 18 PY 2011 VL 19 IS 1 BP 1 EP 2 DI 10.1016/j.ccr.2011.01.005 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 720OP UT WOS:000287290300001 ER PT J AU Castillo, LS Williams, BA Hooper, SM Sabatino, CP Weithorn, LA Sudore, RL AF Castillo, Lesley S. Williams, Brie A. Hooper, Sarah M. Sabatino, Charles P. Weithorn, Lois A. Sudore, Rebecca L. TI Lost in Translation: The Unintended Consequences of Advance Directive Law on Clinical Care SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID OF-LIFE CARE; SURROGATE DECISION-MAKING; HEALTH LITERACY; END; DEATH; COMMUNICATION; PREFERENCES; BARRIERS; SHE AB Background: Advance directive law may compromise the clinical effectiveness of advance directives. Purpose: To identify unintended legal consequences of advance directive law that may prevent patients from communicating end-of-life preferences. Data Sources: Advance directive legal statutes for all 50 U. S. states and the District of Columbia and English-language searches of LexisNexis, Westlaw, and MEDLINE from 1966 to August 2010. Study Selection: Two independent reviewers selected 51 advance directive statutes and 20 articles. Three independent legal reviewers selected 105 legal proceedings. Data Extraction: Two reviewers independently assessed data sources and used critical content analysis to determine legal barriers to the clinical effectiveness of advance directives. Disagreements were resolved by consensus. Data Synthesis: Legal and content-related barriers included poor readability (that is, laws in all states were written above a 12th-grade reading level), health care agent or surrogate restrictions (for example, 40 states did not include same-sex or domestic partners as default surrogates), and execution requirements needed to make forms legally valid (for example, 35 states did not allow oral advance directives, and 48 states required witness signatures, a notary public, or both). Vulnerable populations most likely to be affected by these barriers included patients with limited literacy, limited English proficiency, or both who cannot read or execute advance directives; same-sex or domestic partners who may be without legally valid and trusted surrogates; and unbefriended, institutionalized, or homeless patients who may be without witnesses and suitable surrogates. Limitation: Only appellate-level legal cases were available, which may have excluded relevant cases. Conclusion: Unintended negative consequences of advance directive legal restrictions may prevent all patients, and particularly vulnerable patients, from making and communicating their end-of-life wishes and having them honored. These restrictions have rendered advance directives less clinically useful. Recommendations include improving readability, allowing oral advance directives, and eliminating witness or notary requirements. Primary Funding Source: U.S. Department of Veterans Affairs and the Pfizer Foundation. Ann Intern Med. 2011;154:121-128. C1 [Sudore, Rebecca L.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Hastings Coll Law, San Francisco, CA 94102 USA. Amer Bar Assoc, Washington, DC 20013 USA. RP Sudore, RL (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St,151R, San Francisco, CA 94121 USA. EM Rebecca.Sudore@ucsf.edu FU Veterans Affairs Career Development Award; Pfizer; University of California, Hastings College of the Law; U.S. Department of Veterans Affairs; Pfizer Foundation; National Institutes of Health; University of California, San Francisco; Hartford Foundation Center of Excellence FX Ms. Castillo and Dr. Sudore are supported by a Veterans Affairs Career Development Award and a Pfizer Fellowship in Clear Health Communication. Ms. Hooper is supported by the University of California, Hastings College of the Law.r U.S. Department of Veterans Affairs and the Pfizer Foundation.r Dr. Williams: Grants received (money to institution): National Institutes of Health and University of California, San Francisco, Hartford Foundation Center of Excellence; Consultancy: Independent Medical Monitor of Michigan and Disability Legal Rights Center of Southern California; Expert testimony: University of Denver Student Law Office, Hunton & Williams LLP, and Holland & Knight LLP. Ms. Hooper: Consulting fee or honorarium (money to institution): Department of Veterans Affairs; Payment for writing or reviewing the manuscript (money to institution): Department of Veterans Affairs. Dr. Sudore: Grants received (money to institution): Pfizer Foundation. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M10-1985. NR 64 TC 36 Z9 36 U1 9 U2 20 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 18 PY 2011 VL 154 IS 2 BP 121 EP + DI 10.7326/0003-4819-154-2-201101180-00012 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 706MW UT WOS:000286223500007 PM 21242368 ER PT J AU Nathan, DM AF Nathan, David M. TI Time for Clinically Relevant Comparative Effectiveness Studies in Type 2 Diabetes SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID BLOOD-GLUCOSE CONTROL; COMPLICATIONS; MELLITUS; EXENATIDE; METFORMIN; THERAPY; DISEASE C1 Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Ctr Diabet, 50 Staniford St, Boston, MA 02114 USA. EM dnathan@partners.org NR 17 TC 5 Z9 5 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 18 PY 2011 VL 154 IS 2 BP 131 EP + DI 10.7326/0003-4819-154-2-201101180-00303 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 706MW UT WOS:000286223500009 PM 21135287 ER PT J AU Erlich, RL Jia, XM Anderson, S Banks, E Gao, XJ Carrington, M Gupta, N DePristo, MA Henn, MR Lennon, NJ de Bakker, PIW AF Erlich, Rachel L. Jia, Xiaoming Anderson, Scott Banks, Eric Gao, Xiaojiang Carrington, Mary Gupta, Namrata DePristo, Mark A. Henn, Matthew R. Lennon, Niall J. de Bakker, Paul I. W. TI Next-generation sequencing for HLA typing of class I loci SO BMC GENOMICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; EXTENDED HUMAN MHC; DISEASE ASSOCIATION; HIGH-RESOLUTION; HIGH-THROUGHPUT; GENE MAP; NOMENCLATURE; SYSTEM; ALIGNMENT; IMGT/HLA AB Background: Comprehensive sequence characterization across the MHC is important for successful organ transplantation and genetic association studies. To this end, we have developed an automated sample preparation, molecular barcoding and multiplexing protocol for the amplification and sequence-determination of class I HLA loci. We have coupled this process to a novel HLA calling algorithm to determine the most likely pair of alleles at each locus. Results: We have benchmarked our protocol with 270 HapMap individuals from four worldwide populations with 96.4% accuracy at 4-digit resolution. A variation of this initial protocol, more suitable for large sample sizes, in which molecular barcodes are added during PCR rather than library construction, was tested on 95 HapMap individuals with 98.6% accuracy at 4-digit resolution. Conclusions: Next-generation sequencing on the 454 FLX Titanium platform is a reliable, efficient, and scalable technology for HLA typing. C1 [Erlich, Rachel L.; Jia, Xiaoming; Anderson, Scott; Banks, Eric; Gupta, Namrata; DePristo, Mark A.; Henn, Matthew R.; Lennon, Niall J.; de Bakker, Paul I. W.] MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Jia, Xiaoming] Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Gao, Xiaojiang; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Gao, Xiaojiang; Carrington, Mary] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [de Bakker, Paul I. W.] Harvard Univ, Div Genet, Dept Med, Brigham & Womens Hosp,Med Sch, Boston, MA 02114 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP de Bakker, PIW (reprint author), MIT & Harvard, Broad Inst, Cambridge, MA 02142 USA. EM pdebakker@rics.bwh.harvard.edu RI Sincan, Murat /A-3794-2010; de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU Bill & Melinda Gates Foundation; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded [in part] through the Collaboration for AIDS Vaccine Discovery with support from the Bill & Melinda Gates Foundation (MRH & PIWDB). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 28 TC 54 Z9 57 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 18 PY 2011 VL 12 AR 42 DI 10.1186/1471-2164-12-42 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 717YA UT WOS:000287083500003 PM 21244689 ER PT J AU Ueno, K Hirata, H Shahryari, V Chen, Y Zaman, MS Singh, K Tabatabai, ZL Hinoda, Y Dahiya, R AF Ueno, K. Hirata, H. Shahryari, V. Chen, Y. Zaman, M. S. Singh, K. Tabatabai, Z. L. Hinoda, Y. Dahiya, R. TI Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE miRNA-584; motility; RCC; ROCK-1 ID RHO-ASSOCIATED-KINASE; PROTEIN-KINASE; KIDNEY CANCER; IDENTIFICATION; PATHWAY; GENOME; GENES; PROGRESSION; MIRNA AB BACKGROUND: The purpose of this study was to identify new tumour suppressor microRNAs (miRs) in clear cell renal cell carcinoma (ccRCC), carry out functional analysis of their suppressive role and identify their specific target genes. METHODS: To explore suppressor miRs in RCC, miR microarray and real-time PCR were performed using HK-2 and A-498 cells. Cell viability, invasion and wound healing assays were carried out for functional analysis after miR transfection. To determine target genes of miR, we used messenger RNA (mRNA) microarray and target scan algorithms to identify target oncogenes. A 3'UTR luciferase assay was also performed. Protein expression of target genes in ccRCC tissues was confirmed by immunohistochemistry and was compared with miR-584 expression in ccRCC tissues. RESULTS: Expression of miR-584 in RCC (A-498 and 769-P) cells was downregulated compared with HK-2 cells. Transfection of miR-584 dramatically decreased cell motility. The ROCK-1 mRNA was inhibited by miR-584 and predicted to be target gene. The miR-584 decreased 3'UTR luciferase activity of ROCK-1 and ROCK-1 protein expression. Low expression of miR-584 in ccRCC tissues was correlated with high expression of ROCK-1 protein. The knockdown of ROCK-1 by siRNA inhibited cell motility. CONCLUSION: miR-584 is a new tumour suppressor miR in ccRCC and inhibits cell motility through downregulation of ROCK-1. British Journal of Cancer (2011) 104, 308-315. doi: 10.1038/sj.bjc.6606028 www.bjcancer.com Published online 30 November 2010 (C) 2011 Cancer Research UK C1 [Ueno, K.; Hirata, H.; Shahryari, V.; Chen, Y.; Zaman, M. S.; Singh, K.; Dahiya, R.] Univ Calif San Francisco, Dept Urol, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Tabatabai, Z. L.] Univ Calif San Francisco, Dept Pathol, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Hinoda, Y.] Yamaguchi Univ, Dept Oncol & Lab Med, Grad Sch Med, Yamaguchi, Japan. RP Dahiya, R (reprint author), Univ Calif San Francisco, Dept Urol, San Francisco Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu RI Chen, Yi /J-4807-2012 FU NIH [R01CA130860, R01CA138642, R01CA111470, R01CA154374, T32DK007790]; VA Research Enhancement Award Program (REAP); Merit Review grants FX We thank Dr Roger Erickson for his support and assistance with the preparation of the manuscript. This study was supported by Grants R01CA130860, R01CA138642, R01CA111470, R01CA154374, T32DK007790 from the NIH, VA Research Enhancement Award Program (REAP), and Merit Review grants. NR 31 TC 43 Z9 48 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 18 PY 2011 VL 104 IS 2 BP 308 EP 315 DI 10.1038/sj.bjc.6606028 PG 8 WC Oncology SC Oncology GA 708NZ UT WOS:000286370900011 PM 21119662 ER PT J AU Viswanath, K Ackerson, LK AF Viswanath, Kasisomayajula Ackerson, Leland K. TI Race, Ethnicity, Language, Social Class, and Health Communication Inequalities: A Nationally-Representative Cross-Sectional Study SO PLOS ONE LA English DT Article ID INFORMATION-SEEKING; TRENDS SURVEY; DECISION-MAKING; DIGITAL DIVIDE; CANCER; INTERNET; DISPARITIES; RESOURCES; PATIENT; SUPPORT AB Background: While mass media communications can be an important source of health information, there are substantial social disparities in health knowledge that may be related to media use. The purpose of this study is to investigate how the use of cancer-related health communications is patterned by race, ethnicity, language, and social class. Methodology/Principal Findings: In a nationally-representative cross-sectional telephone survey, 5,187 U.S. adults provided information about demographic characteristics, cancer information seeking, and attention to and trust in health information from television, radio, newspaper, magazines, and the Internet. Cancer information seeking was lowest among Spanish-speaking Hispanics (odds ratio: 0.42; 95% confidence interval: 0.28-0.63) compared to non-Hispanic whites. Spanish-speaking Hispanics were more likely than non-Hispanic whites to pay attention to (odds ratio: 3.10; 95% confidence interval: 2.07-4.66) and trust (odds ratio: 2.61; 95% confidence interval: 1.53-4.47) health messages from the radio. Non-Hispanic blacks were more likely than non-Hispanic whites to pay attention to (odds ratio: 2.39; 95% confidence interval: 1.88-3.04) and trust (odds ratio: 2.16; 95% confidence interval: 1.61-2.90) health messages on television. Those who were college graduates tended to pay more attention to health information from newspapers (odds ratio: 1.98; 95% confidence interval: 1.42-2.75), magazines (odds ratio: 1.86; 95% confidence interval: 1.32-2.60), and the Internet (odds ratio: 4.74; 95% confidence interval: 2.70-8.31) and had less trust in cancer-related health information from television (odds ratio: 0.44; 95% confidence interval: 0.32-0.62) and radio (odds ratio: 0.54; 95% confidence interval: 0.34-0.86) compared to those who were not high school graduates. Conclusions/Significance: Health media use is patterned by race, ethnicity, language and social class. Providing greater access to and enhancing the quality of health media by taking into account factors associated with social determinants may contribute to addressing social disparities in health. C1 [Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Ackerson, Leland K.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Ackerson, Leland K.] Univ Massachusetts Lowell, Dept Community Hlth & Sustainabil, Lowell, MA USA. RP Viswanath, K (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. EM leland_ackerson@uml.edu FU Dana-Farber/Harvard Cancer Center FX This work was supported by the Dana-Farber/Harvard Cancer Center (http://www.dana-farber.org/res/dana-farber/default.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 49 Z9 49 U1 2 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 18 PY 2011 VL 6 IS 1 AR e14550 DI 10.1371/journal.pone.0014550 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 710NW UT WOS:000286519500018 PM 21267450 ER PT J AU Koria, P Yagi, H Kitagawa, Y Megeed, Z Nahmias, Y Sheridan, R Yarmush, ML AF Koria, Piyush Yagi, Hiroshi Kitagawa, Yuko Megeed, Zaki Nahmias, Yaakov Sheridan, Robert Yarmush, Martin L. TI Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE skin; fusion peptides; regeneration ID PROTEIN-BASED POLYMERS; FACTOR EXPRESSION; COLLAGEN SPONGE; DIABETIC MOUSE; KGF RECEPTOR; POLYPEPTIDE; FIBROBLASTS; INDUCTION; MODEL; DIFFERENTIATION AB Chronic wounds are associated with poor epidermal and dermal remodeling. Previous work has shown the efficacy of keratinocyte growth factor (KGF) in reepithelialization and elastin in dermal wound healing. Here we demonstrate the fabrication of a fusion protein comprising of elastin-like peptides and KGF. This fusion protein retains the performance characteristics of KGF and elastin as evidenced by its enhancement of keratinocyte and fibroblast proliferation. It also preserved the characteristic elastin-like peptides inverse phase transitioning allowing the recombinant protein to be expressed in bacterial hosts (such as Escherichia coli) and purified rapidly and easily using inverse temperature cycling. The fusion protein self-assembled into nanoparticles at physiological temperatures. When applied to full thickness, wounds in Lepr(db) diabetic mice these particles enhanced reepithelialization and granulation, by 2- and 3-fold respectively, when compared to the controls. The data strongly suggests that these self-assembled nanoparticles may be beneficial in the treatment of chronic wounds resulting from diabetes or other underlying circulatory conditions. C1 [Koria, Piyush; Yagi, Hiroshi; Megeed, Zaki; Nahmias, Yaakov; Sheridan, Robert; Yarmush, Martin L.] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02129 USA. [Koria, Piyush; Yagi, Hiroshi; Megeed, Zaki; Nahmias, Yaakov; Sheridan, Robert; Yarmush, Martin L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Koria, Piyush; Yagi, Hiroshi; Megeed, Zaki; Nahmias, Yaakov; Sheridan, Robert; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Koria, Piyush] Univ S Florida, Dept Chem & Biomed Engn, Tampa, FL 33620 USA. [Yagi, Hiroshi; Kitagawa, Yuko] Keio Univ, Sch Med, Dept Surg, Shinjuku Ku, Tokyo 1608582, Japan. [Nahmias, Yaakov] Hebrew Univ Jerusalem, Selim & Rachel Benin Sch Engn, IL-91904 Jerusalem, Israel. [Yarmush, Martin L.] Rutgers State Univ, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02129 USA. EM ireis@sbi.org RI Nahmias, Yaakov/H-4725-2013; OI Nahmias, Yaakov/0000-0002-6051-616X FU US Department of Defense [W81XWH-07-1-0302]; Shriners Hospitals for Children; University of South Florida FX We thank Dr. Vinay Gupta in the Department of Chemical and Biomedical Engineering at University of South Florida for assistance with dynamic light scattering experiments. We also thank Edward Haller of the Microscopy Core Facility in the Department of Integrative Biology at the University of South Florida for assistance with transmission electron microscopy (TEM) imaging and Robert Buzzeo in the CMMB Core Facility at the University of South Florida for cell culture and Western blot experiments. This work was funded by US Department of Defense Grant W81XWH-07-1-0302 (Z.M. and M.L.Y.), a grant from Shriners Hospitals for Children (P.K., Y.N., and M.L.Y.) and startup funds from the University of South Florida (P.K.). NR 37 TC 56 Z9 60 U1 2 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 18 PY 2011 VL 108 IS 3 BP 1034 EP 1039 DI 10.1073/pnas.1009881108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 707TF UT WOS:000286310300030 PM 21193639 ER PT J AU Sethi, DK Schubert, DA Anders, AK Heroux, A Bonsor, DA Thomas, CP Sundberg, EJ Pyrdol, J Wucherpfennig, KW AF Sethi, Dhruv K. Schubert, David A. Anders, Anne-Kathrin Heroux, Annie Bonsor, Daniel A. Thomas, Chantz P. Sundberg, Eric J. Pyrdol, Jason Wucherpfennig, Kai W. TI A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; MYELIN BASIC-PROTEIN; CLASS-II MOLECULE; CRYSTAL-STRUCTURE; TRANSGENIC MICE; AMINO-ACIDS; RECOGNITION; ANTIGEN; SPECIFICITY; AUTOIMMUNITY AB Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-alpha chain with the MHC class II beta chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3 beta loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3 alpha loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand. C1 [Sethi, Dhruv K.; Schubert, David A.; Anders, Anne-Kathrin; Thomas, Chantz P.; Pyrdol, Jason; Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. [Anders, Anne-Kathrin; Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. [Heroux, Annie] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Bonsor, Daniel A.; Sundberg, Eric J.] Boston Biomed Res Inst, Watertown, MA 02472 USA. RP Wucherpfennig, KW (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. EM kai_wucherpfennig@dfci.harvard.edu FU National Institutes of Health [P01 AI045757, R01 AI064177]; National Multiple Sclerosis Society; Cancer Research Institute; Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy; National Center for Research Resources of the National Institutes of Health FX This work was supported by grants from the National Institutes of Health (P01 AI045757 and R01 AI064177 to K.W. Wucherpfennig) and postdoctoral fellowships from the National Multiple Sclerosis Society (to D.K. Sethi) and the Cancer Research Institute (to D. A. Schubert). Data were collected at beamline X29 of the National Synchrotron Light Source. Financial support for the National Synchrotron Light Source comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. NR 62 TC 49 Z9 50 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 17 PY 2011 VL 208 IS 1 BP 91 EP 102 DI 10.1084/jem.20100725 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 707SV UT WOS:000286309300008 PM 21199956 ER PT J AU McCloskey, ML de Lafaille, MAC Carroll, MC Erlebacher, A AF McCloskey, Megan L. de Lafaille, Maria A. Curotto Carroll, Michael C. Erlebacher, Adrian TI Acquisition and presentation of follicular dendritic cell-bound antigen by lymph node-resident dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; IN-VIVO DEPLETION; APOPTOTIC CELLS; T-CELLS; IMMUNE-COMPLEXES; MICE; COMPLEMENT; MEMORY; CLEARANCE; TOLERANCE AB Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node-resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen-antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance. C1 [McCloskey, Megan L.; de Lafaille, Maria A. Curotto; Erlebacher, Adrian] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [de Lafaille, Maria A. Curotto] NYU, Sch Med, Program Mol Pathogenesis, Skirball Inst Biomol Med, New York, NY 10016 USA. [Erlebacher, Adrian] NYU, Sch Med, Inst Canc, New York, NY 10016 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Immune Dis Inst,Childrens Hosp Boston, Boston, MA 02115 USA. RP Erlebacher, A (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. EM adrian.erlebacher@nyumc.org FU Vittorio Defendi Fellowship in Pathobiology; National Institutes of Health [RO1-AI062980]; Leona M. and Harry B. Helmsley Charitable Trust FX This work was supported by the Vittorio Defendi Fellowship in Pathobiology to M.L. McCloskey and grants from the National Institutes of Health (RO1-AI062980) and the Leona M. and Harry B. Helmsley Charitable Trust to A. Erlebacher. NR 58 TC 21 Z9 21 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 17 PY 2011 VL 208 IS 1 BP 135 EP 148 DI 10.1084/jem.20100354 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 707SV UT WOS:000286309300012 PM 21173103 ER PT J AU Wrammert, J Koutsonanos, D Li, GM Edupuganti, S Sui, JH Morrissey, M McCausland, M Skountzou, I Hornig, M Lipkin, WI Mehta, A Razavi, B Del Rio, C Zheng, NY Lee, JH Huang, M Ali, Z Kaur, K Andrews, S Amara, RR Wang, YL Das, SR O'Donnell, CD Yewdell, JW Subbarao, K Marasco, WA Mulligan, MJ Compans, R Ahmed, R Wilson, PC AF Wrammert, Jens Koutsonanos, Dimitrios Li, Gui-Mei Edupuganti, Srilatha Sui, Jianhua Morrissey, Michael McCausland, Megan Skountzou, Ioanna Hornig, Mady Lipkin, W. Ian Mehta, Aneesh Razavi, Behzad Del Rio, Carlos Zheng, Nai-Ying Lee, Jane-Hwei Huang, Min Ali, Zahida Kaur, Kaval Andrews, Sarah Amara, Rama Rao Wang, Youliang Das, Suman Ranjan O'Donnell, Christopher David Yewdell, Jon W. Subbarao, Kanta Marasco, Wayne A. Mulligan, Mark J. Compans, Richard Ahmed, Rafi Wilson, Patrick C. TI Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; A VIRUS; IMMUNE-RESPONSE; VACCINATION; VACCINES; MEMORY; SWINE; MICE; NEUTRALIZATION; GENERATION AB The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates. C1 [Wrammert, Jens; Li, Gui-Mei; McCausland, Megan; Amara, Rama Rao; Wang, Youliang; Compans, Richard; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Wrammert, Jens; Koutsonanos, Dimitrios; Li, Gui-Mei; McCausland, Megan; Skountzou, Ioanna; Amara, Rama Rao; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Mehta, Aneesh; Del Rio, Carlos] Emory Univ, Sch Med, Div Infect Dis, Dept Med, Atlanta, GA 30322 USA. [Edupuganti, Srilatha; Del Rio, Carlos; Mulligan, Mark J.] Emory Vaccine Ctr, Hope Clin, Sch Med, Div Infect Dis, Decatur, GA 30030 USA. [Edupuganti, Srilatha; Razavi, Behzad] Emory Univ, Dept Internal Med, Atlanta, GA 30322 USA. [Sui, Jianhua; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Morrissey, Michael; Zheng, Nai-Ying; Lee, Jane-Hwei; Huang, Min; Ali, Zahida; Kaur, Kaval; Andrews, Sarah; Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Comm Immunol,Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Hornig, Mady; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Del Rio, Carlos] Emory Univ, Sch Med, Hubert Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Del Rio, Carlos] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. [Das, Suman Ranjan; Yewdell, Jon W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [O'Donnell, Christopher David; Subbarao, Kanta] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu; wilsonp@uchicago.edu RI yewdell, jyewdell@nih.gov/A-1702-2012; Mehta, Aneesh/B-8054-2012; Das, Suman/C-8760-2009; Compans, Richard/I-4087-2013; Skountzou, Ioanna/A-4454-2010; del Rio, Carlos/B-3763-2012; Chiang, Vincent, Ming-Hsien/D-4312-2016 OI Mehta, Aneesh/0000-0002-6552-9162; Compans, Richard/0000-0003-2360-335X; Skountzou, Ioanna/0000-0002-6429-244X; del Rio, Carlos/0000-0002-0153-3517; Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863 FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) [U19-AI057266, U19 AI057266-06S2, HHSN266200500026C, 5U19AI062629-05, U01 AI074518]; NIH/NIAID, Center of Excellence for Influenza Research and Surveillance [HHSN266200700006C]; Northeast Biodefense Center [U54-AI057158-Lipkin]; National Foundation for Cancer Research; Center of Excellence for Influenza Research and Surveillance; NIAID; [U01-AI074579] FX This work was funded in parts by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) U19-AI057266 with ARRA supplement funding U19 AI057266-06S2 (R. Ahmed and P.C. Wilson), by NIH/NIAID HHSN266200700006C Center of Excellence for Influenza Research and Surveillance (R. Ahmed, R. Compans, and P.C. Wilson), by the Northeast Biodefense Center U54-AI057158-Lipkin (R. Ahmed, W.I. Lipkin, and P.C. Wilson), by NIH/NIAID HHSN266200500026C (P.C. Wilson), by NIH/NIAID 5U19AI062629-05 (P.C. Wilson), and by NIH/NIAID U01 AI074518 (W.A. Marasco) and the National Foundation for Cancer Research (W.A.M.). J. Wrammert was supported by a training fellowship through the Center of Excellence for Influenza Research and Surveillance and D. Koutsonanos by U01-AI074579 (R. Compans). This research was supported in part by the Intramural Research Program of the NIAID. NR 40 TC 349 Z9 353 U1 2 U2 37 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 17 PY 2011 VL 208 IS 1 BP 181 EP 193 DI 10.1084/jem.20101352 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 707SV UT WOS:000286309300015 PM 21220454 ER PT J AU Kim, KH Park, BH Tu, YP Hasan, T Lee, B Li, JA de Boer, JF AF Kim, Ki Hean Park, B. Hyle Tu, Yupeng Hasan, Tayyaba Lee, Byunghak Li, Jianan de Boer, Johannes F. TI Polarization-sensitive optical frequency domain imaging based on unpolarized light SO OPTICS EXPRESS LA English DT Article ID RESOLVED MUELLER MATRIX; HUMAN VOCAL FOLD; COHERENCE TOMOGRAPHY; IN-VIVO; BIOLOGICAL TISSUE; MACULAR DEGENERATION; MAINTAINING FIBER; HUMAN SKIN; BIREFRINGENCE; MODULATION AB Polarization-sensitive optical coherence tomography (PS-OCT) is an augmented form of OCT, providing 3D images of both tissue structure and polarization properties. We developed a new method of polarization-sensitive optical frequency domain imaging (PS-OFDI), which is based on a wavelength-swept source. In this method the sample was illuminated with unpolarized light, which was composed of two orthogonal polarization states (i.e., separated by 180 in the Poincare sphere) that are uncorrelated to each other. Reflection of these polarization states from within the sample was detected simultaneously and independently using a frequency multiplexing scheme. This simultaneous sample probing with two polarization states enabled determination of the depth-resolved Jones matrices of the sample. Polarization properties of the sample were obtained by analyzing the sample Jones matrices through eigenvector decomposition. The new PS-OFDI system ran at 31K wavelength-scans/s with 3072 pixels per wavelength-scan, and was tested by imaging a polarizer and several birefringent tissues such as chicken muscle and human skin. Lastly the new PS-OFDI was applied to imaging two cancer animal models: a mouse model by injecting cancer cells and a hamster cheek pouch model. These animal model studies demonstrated the significant differences in tissue polarization properties between cancer and normal tissues in vivo. (C) 2011 Optical Society of America C1 [Kim, Ki Hean; Lee, Byunghak] Pohang Univ Sci & Technol, Dept Mech Engn, Pohang 790784, South Korea. [Kim, Ki Hean; Lee, Byunghak] Pohang Univ Sci & Technol, Div Integrat Biosci & Biotechnol, Pohang 790784, South Korea. [Park, B. Hyle] UC Riverside, Dept Bioengn, Riverside, CA 92521 USA. [Tu, Yupeng; Hasan, Tayyaba; de Boer, Johannes F.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Li, Jianan; de Boer, Johannes F.] Vrije Univ Amsterdam, Dept Phys & Astron, Inst Lasers Life & Biophoton Amsterdam, NL-1081 HV Amsterdam, Netherlands. RP Kim, KH (reprint author), Pohang Univ Sci & Technol, Dept Mech Engn, Pohang 790784, South Korea. EM jfdeboer@few.vu.nl RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 FU POSTECH Basic Science Research Institute, Korean Science Foundation [2010-0028014, 2010-0014874]; Ministry of Education, Science and Technology [R31-2008-000-10105-0]; Dutch foundation for fundamental sciences (FOM) [09NIG 03] FX We would like to thank Charles Kerbage and Wang-Yuhl Oh at the Wellman Center for Photomedicine for valuable discussion on PS-OFDI design, and James A Burns and James Kobler at the Center for Laryngeal Surgery and Voice Rehabilitation of Massachusetts General Hospital for providing the hamster cheek pouch model. This research was supported in part by the POSTECH Basic Science Research Institute Grant, Korean Science Foundation Grant 2010-0028014, 2010-0014874, World Class University Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-2008-000-10105-0), and the Dutch foundation for fundamental sciences (FOM) grant 09NIG 03. NR 36 TC 25 Z9 26 U1 1 U2 12 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JAN 17 PY 2011 VL 19 IS 2 BP 552 EP 561 DI 10.1364/OE.19.000552 PG 10 WC Optics SC Optics GA 707US UT WOS:000286314600016 PM 21263595 ER PT J AU Manzano-Fernandez, S Mueller, T Pascual-Figal, D Truong, QA Januzzi, JL AF Manzano-Fernandez, Sergio Mueller, Thomas Pascual-Figal, Domingo Truong, Quynh A. Januzzi, James Louis TI Usefulness of Soluble Concentrations of Interleukin Family Member ST2 as Predictor of Mortality in Patients With Acutely Decompensated Heart Failure Relative to Left Ventricular Ejection Fraction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ASYMPTOMATIC SYSTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; PLASMA-CONCENTRATIONS; NATRIURETIC PEPTIDE; 1-YEAR MORTALITY; ACUTE DYSPNEA; RECEPTOR; DIAGNOSIS; MECHANISMS; METOPROLOL AB The aim of the present study was to determine whether the risk of mortality associated with the concentration of soluble ST2 (sST2) differs in patients with acutely decompensated heart failure with preserved ejection fraction (HFpEF) compared to patients with systolic heart failure. We prospectively enrolled 447 patients with acutely decompensated heart failure. Blood samples were collected at presentation to determine the sST2 concentration. HFpEF was defined as symptoms or signs of acutely decompensated heart failure and left ventricular ejection fraction of >= 50% on the echocardiogram. The patients were followed up for 1 year, and the vital status was obtained for all. The sST2 concentrations were greater in the patients with systolic heart failure (n = 250) than in those with HFpEF (n = 197) at 0.55 versus 0.38 ng/ml (p <0.001). Receiver operating characteristic curve analyses showed different cutoff point values for sST2 for the prediction of 1-year mortality in patients with HFpEF (>0.35 ng/ml) and systolic heart failure (>0.56 mg//ml). These cutoff points had similar prognostic accuracy (area under the curve of 0.69 vs 0.73; p >0.05). In the adjusted analyses that included amino terminal B-type natriuretic peptide concentrations, elevated sST2 concentrations were associated with a greater mortality risk in both populations (HFpEF, per ng/ml, hazard ratio 1.41, 95% confidence interval 1.14 to 1.76, p = 0.002; and systolic heart failure, per ng/ml, hazard ratio 1.20, 95% confidence interval 1.10 to 1.32, p <0.001). The determination of the sST2 concentration improved the clinical risk prediction compared to amino terminal B-type natriuretic peptide, as assessed by both the improved C-statistic and an improvement in the net reclassification index and integrated discrimination improvement analyses. In conclusion, in the present multicenter study, sST2 concentrations were lower in patients with HfpEF; however, sST2 remained an independent predictor of mortality, regardless of the left ventricular ejection fraction. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107: 259-267) C1 [Manzano-Fernandez, Sergio; Pascual-Figal, Domingo] Univ Murcia, Dept Cardiol, Virgen de la Arrixaca Hosp, Sch Med, Murcia, Spain. [Mueller, Thomas] Konventhosp Barmherzige Brueder, Dept Lab Med, Linz, Austria. [Truong, Quynh A.; Januzzi, James Louis] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Manzano-Fernandez, S (reprint author), Univ Murcia, Dept Cardiol, Virgen de la Arrixaca Hosp, Sch Med, Murcia, Spain. EM sergiosmf13@hotmail.com RI Pascual Figal, Domingo /B-3794-2008 OI Pascual Figal, Domingo /0000-0002-4993-9540 FU Roche Diagnostics; Siemens; Critical Diagnostics; NIH [K23HL098370] FX Dr. Januzzi received grant support from Roche Diagnostics, Siemens, and Critical Diagnostics. Dr. Pascual-Figal received grant support from Roche Diagnostics. Dr. Truong received grant support from NIH K23HL098370. NR 27 TC 64 Z9 70 U1 0 U2 6 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2011 VL 107 IS 2 BP 259 EP 267 DI 10.1016/j.amjcard.2010.09.011 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 714EB UT WOS:000286789200019 PM 21211603 ER PT J AU Booher, AM Isselbacher, EM Nienaber, CA Froehlich, JB Trimarchi, S Cooper, JV Demertzis, S Ramanath, VS Januzzi, JL Harris, KM O'Gara, PT Sundt, TM Pyeritz, RE Eagle, KA AF Booher, Anna M. Isselbacher, Eric M. Nienaber, Christoph A. Froehlich, James B. Trimarchi, Santi Cooper, Jeanna V. Demertzis, Stefanos Ramanath, Vijay S. Januzzi, James L. Harris, Kevin M. O'Gara, Patrick T. Sundt, Thoralf M., III Pyeritz, Reed E. Eagle, Kim A. CA Int Registry Acute Aortic Dissecti TI Ascending Thoracic Aorta Dimension and Outcomes in Acute Type B Dissection (from the International Registry of Acute Aortic Dissection [IRAD]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID STENT-GRAFT PLACEMENT; MARFAN-SYNDROME; FOLLOW-UP; VALVE; MANAGEMENT; ROOT; DILATATION; REPAIR; REPLACEMENT; COARCTATION AB It is not well known if the size of the ascending thoracic aorta at presentation predicts features of presentation, management, and outcomes in patients with acute type B aortic dissection. The International Registry of Acute Aortic Dissection (IRAD) database was queried for all patients with acute type B dissection who had documentation of ascending thoracic aortic size at time of presentation. Patients were categorized according to ascending thoracic aortic diameters <= 4.0, 4.1 to 4.5, and >= 4.6 cm. Four hundred eighteen patients met inclusion criteria; 291 patients (69.6%) were men with a mean age of 63.2 +/- 13.5 years. Ascending thoracic aortic diameter <= 4.0 cm was noted in 250 patients (59.8%), 4.1 to 4.5 cm in 105 patients (25.1%), and >= 4.6 cm in 63 patients (15.1%). Patients with an ascending thoracic aortic diameter >= 4.6 cm were more likely to be men (p = 0.01) and have Marfan syndrome (p < 0.001) and known bicuspid aortic valve disease (p = 0.003). In patients with an ascending thoracic aorta cm, there was an increased incidence of surgical intervention (p = 0.013). In those with an ascending thoracic aorta >= 4.6 cm, the root, ascending aorta, arch, and aortic valve were more often involved in surgical repair. Patients with an ascending thoracic aorta <= 4.0 were more likely to have endovascular therapy than those with larger ascending thoracic aortas (p = 0.009). There was no difference in overall mortality or cause of death. In conclusion, ascending thoracic aortic enlargement in patients with acute type B aortic dissection is common. Although its presence does not appear to predict an increased risk of mortality, it is associated with more frequent open surgical intervention that often involves replacement of the proximal aorta. Those with smaller proximal aortas are more likely to receive endovascular therapy. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:315-320) C1 [Booher, Anna M.; Froehlich, James B.; Cooper, Jeanna V.; Eagle, Kim A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Isselbacher, Eric M.; Januzzi, James L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nienaber, Christoph A.] Univ Rostock, Rostock, Germany. [Trimarchi, Santi] IRCCS Policlin San Donato, San Donato Milanese, Italy. [Demertzis, Stefanos] Cardioctr Ticino, Lugano, Switzerland. [Ramanath, Vijay S.] Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. [Harris, Kevin M.] Minneapolis Heart Inst, Minneapolis, MN USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Sundt, Thoralf M., III] Mayo Clin, Rochester, MN USA. [Pyeritz, Reed E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Booher, AM (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. EM amanion@med.umich.edu RI Trimarchi, Santi/J-7361-2016 OI Trimarchi, Santi/0000-0001-5996-3264 FU University of Michigan Health System; Varbedian Fund for Aortic Research, Bloomfield Hills, Michigan; Mardigian Foundation; Gore, Inc., Flagstaff, Arizona; sanofi-aventis; Biosite, San Diego, California FX The International Registry of Acute Aortic Dissection is supported by grants from the University of Michigan Health System, the Varbedian Fund for Aortic Research, Bloomfield Hills, Michigan, the Mardigian Foundation, and Gore, Inc., Flagstaff, Arizona.; Dr. Froehlich has served on the speakers bureaus for Pfizer Pharmaceuticals, New York, New York, Merck, Whitehouse Station, New Jersey, and sanoti-aventis, Bridgewater, New Jersey; and as a consultant for Pfizer and sanofi-aventis. He has provided research support for sanofi-aventis. Dr. Sundt has served as a consultant for St. Jude Medical, St. Paul, Minnesota. Dr. Eagle has been awarded grants from Biosite, San Diego, California and has a consulting agreement with NHLBI, Bethesda, Maryland. NR 27 TC 14 Z9 14 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2011 VL 107 IS 2 BP 315 EP 320 DI 10.1016/j.amjcard.2010.09.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 714EB UT WOS:000286789200028 PM 21211610 ER PT J AU Desai, RV Ahmed, MI Mujib, M Aban, IB Zile, MR Ahmed, A AF Desai, Ravi V. Ahmed, Mustafa I. Mujib, Marjan Aban, Inmaculada B. Zile, Michael R. Ahmed, Ali TI Natural History of Concentric Left Ventricular Geometry in Community-Dwelling Older Adults Without Heart Failure During Seven Years of Follow-Up SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID NORMAL EJECTION FRACTION; CARDIOVASCULAR HEALTH; HYPERTROPHY; PREDICTORS; MORTALITY AB Presence of concentric left ventricular (LV) geometry has important pathophysiologic and prognostic implications. However, little is known about its natural history in older adults. Of the 5,795 community-dwelling adults >= 65 years of age in the Cardiovascular Health Study, 1,871 without baseline heart failure had data on baseline and 7-year echocardiograms. Of these 343 (18%) had baseline concentric LV geometry (concentric remodeling 83%, concentric LV hypertrophy [LVH] 17%) and are the focus of the present study. LV geometry at year 7 was categorized into 4 groups based on LVH (LV mass indexed for height >51 g/m(2.7)) and relative wall thickness (RWT): eccentric hypertrophy (RWT <= 0.42 with LVH), concentric hypertrophy (RWT >0.42 with LVH), concentric remodeling (RWT >0.42 without LVH), and normal (RWT.0.42 without LVH). At year 7, LV geometry normalized in 57%, remained unchanged in 35%, and transitioned to eccentric hypertrophy in 7% of participants. Incident eccentric hypertrophy occurred in 4% and 25% of those with baseline concentric remodeling and concentric hypertrophy, respectively, and was associated with increased LV end-diastolic volume and decreased LV ejection fraction at year 7. Previous myocardial infarction and baseline above-median LV mass (>39 g/m(2.7)) and RWT (>0.46) had significant unadjusted associations with incident eccentric LVH; however, only LV mass >39 g/m(2.7) (odds ratio.17.52, .95% confidence interval 3.91 to 78.47, p <0.001) and previous myocardial infarction (odds ratio 4.73, 95% confidence interval 1.16 to 19.32, p = 0.031) had significant independent associations. In conclusion, in community-dwelling older adults with concentric LV geometry, transition to eccentric hypertrophy was uncommon but structurally maladaptive. Published by Elsevier Inc. (Am J Cardiol 2011;107:321-324) C1 [Desai, Ravi V.; Ahmed, Mustafa I.; Mujib, Marjan; Aban, Inmaculada B.; Ahmed, Ali] Univ Alabama, Birmingham, AL USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Ahmed, Ali] Vet Affairs Med Ctr, Birmingham, AL USA. RP Ahmed, A (reprint author), Univ Alabama, Birmingham, AL USA. EM aahmed@uab.edu RI Mujib, Marjan/J-2709-2013 OI Mujib, Marjan/0000-0002-3261-8599 FU National Heart, Lung, and Blood Institute [R01-HL085561, R01-HL097047]; Research Service of the Department of Veterans Affairs, Washington, DC FX Dr. Ahmed is supported by the National Institutes of Health, Bethesda, Maryland through Grants R01-HL085561 and R01-HL097047 from the National Heart, Lung, and Blood Institute and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama. Dr. Zile is funded by the Research Service of the Department of Veterans Affairs, Washington, DC. NR 13 TC 12 Z9 12 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 15 PY 2011 VL 107 IS 2 BP 321 EP 324 DI 10.1016/j.amjcard.2010.09.019 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 714EB UT WOS:000286789200029 PM 21129719 ER PT J AU Mandal, CC Ganapathy, S Gorin, Y Mahadev, K Block, K Abboud, HE Harris, SE Ghosh-Choudhury, G Ghosh-Choudhury, N AF Mandal, Chandi C. Ganapathy, Suthakar Gorin, Yves Mahadev, Kalyankar Block, Karen Abboud, Hanna E. Harris, Stephen E. Ghosh-Choudhury, Goutam Ghosh-Choudhury, Nandini TI Reactive oxygen species derived form Nox4 mediate BMP2 gene transcription and osteoblast differentiation SO BIOCHEMICAL JOURNAL LA English DT Article DE bone morphogenetic protein-2 (BMP-2); bone morphogenetic protein-2 gene autoregulation; bone morphogenetic protein-2 signalling; osteoblast differentiation; reactive oxygen species ID BONE MORPHOGENETIC PROTEIN-2; KAPPA-B LIGAND; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNAL-TRANSDUCTION; NADPH OXIDASE; NAD(P)H OXIDASE; MESANGIAL CELLS; OSTEOCLAST DIFFERENTIATION; RECEPTOR ACTIVATOR; EXPRESSION AB BMP-2 (bone morphogenetic protein-2) promotes differentiation of osteoblast precursor cells to mature osteoblasts that form healthy bone. In the present study, we demonstrate a novel mechanism of BMP-2-induced osteoblast differentiation. The antioxidant NAC (N-acetyl-L-cysteine) and the flavoprotein enzyme NAD(P)H oxidase inhibitor DPI (diphenyleneiodonium) prevented BMP-2-stimulated alkaline phosphatase expression and mineralized bone nodule formation in mouse 2T3 pre-osteoblasts. BMP-2 elicited a rapid generation of ROS (reactive oxygen species) concomitant with increased activation of NAD(P)H oxidase. NAC and DPI inhibited BMP-2-induced ROS production and NAD(P)H oxidase activity respectively. NAD(P)H oxidases display structurally similar catalytic subunits (Nox1-5) with differential expression in various cells. We demonstrate that 2T3 pre-osteoblasts predominantly express the Nox4 isotype of NAD(P)H oxidase. To extend this finding, we tested the functional effects of Nox4. Adenovirus-mediated expression of dominant-negative Nox4 inhibited BMP-2-induced alkaline phosphatase expression. BMP-2 promotes expression of BMP-2 for maintenance of the osteoblast phenotype. NAC and DPI significantly blocked BMP-2-stimulated expression of BMP2 mRNA and protein due to a decrease in BMP2 gene transcription. Dominant-negative Nox4 also mimicked this effect of NAC and DPI. Our results provide the first evidence for a new signalling pathway linking BMP-2-stimulated Nox4-derived physiological ROS to BMP-2 expression and osteoblast differentiation. C1 [Mandal, Chandi C.; Ganapathy, Suthakar; Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Gorin, Yves; Block, Karen; Abboud, Hanna E.; Ghosh-Choudhury, Goutam] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Mahadev, Kalyankar] Univ Penn, Dept Med, Inst Diabet Obes & Metab, Philadelphia, PA USA. [Harris, Stephen E.] S Texas Vet Hlth Care Syst, VA Res, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Goutam; Ghosh-Choudhury, Nandini] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. EM choudhury@uthscsa.edu RI Ganapathy, Suthakar/C-1266-2013 OI Ganapathy, Suthakar/0000-0003-3828-5382 FU National Institutes of Health [R01 AR52425, R01 DK50190]; VA Research Service Merit Review; Department of Veterans Affairs; Juvenile Diabetes Research Foundation [1-2008-185] FX This work was supported by the National Institutes of Health [grant number R01 AR52425]; and the VA Research Service Merit Review (to N.G.-C.). G.G.-C. is the recipient of a Senior Research Career Scientist Award from the Department of Veterans Affairs. G.G.-C. is supported by the National Institutes of Health [grant number R01 DK50190]; VA Research Service Merit Review; and the Juvenile Diabetes Research Foundation [grant number 1-2008-185]. NR 52 TC 39 Z9 39 U1 0 U2 7 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2011 VL 433 BP 393 EP 402 DI 10.1042/BJ20100357 PN 2 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 757AI UT WOS:000290055800014 PM 21029048 ER PT J AU Zhou, WJ Ercan, D Janne, PA Gray, NS AF Zhou, Wenjun Ercan, Dalia Jaenne, Pasi A. Gray, Nathanael S. TI Discovery of selective irreversible inhibitors for EGFR-T790M SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE EGFR; Kinase inhibitor; T790M; Mutant selective ID KINASE INHIBITORS; ACQUIRED-RESISTANCE; LUNG-CANCER; EGFR; RECEPTOR; GEFITINIB; T790M AB Targeting the epidermal growth factor receptor kinase (EGFR) with ATP-competitive kinase inhibitors results in dramatic but short-lived responses in patients with EGFR mutant non small cell lung cancer. A series of novel covalent EGFR kinase inhibitors with selectivity for the clinically relevant T790M 'gatekeeper' resistance mutation relative to wild-type EGFR were discovered by library screening. A representative compound 3i was obtained through a systematic SAR study guided by mutant EGFR-dependent cellular proliferation assays. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Zhou, Wenjun; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhou, Wenjun; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ercan, Dalia; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Ercan, Dalia; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu FU NCI NIH HHS [R01 CA130876, P01 CA154303, R01 CA130876-01A1, R01 CA130876-04, R01 CA135257, R01 CA130876-03, R01 CA130876-02]; NIGMS NIH HHS [P41 GM079575-03S1, P41 GM079575, P41 GM079575-02, P41 GM079575-01, P41 GM079575-03] NR 11 TC 41 Z9 41 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2011 VL 21 IS 2 BP 638 EP 643 DI 10.1016/j.bmcl.2010.12.036 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 703RC UT WOS:000285998000004 PM 21208802 ER PT J AU Konry, T Dominguez-Villar, M Baecher-Allan, C Hafler, DA Yarmush, ML AF Konry, Tania Dominguez-Villar, Margarita Baecher-Allan, Clare Hafler, David A. Yarmush, Martin L. TI Droplet-based microfluidic platforms for single T cell secretion analysis of IL-10 cytokine SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Microfluidic; Droplets; Single cell; Cell secretion; Microsphere ID ENCAPSULATION; ARRAYS; MICROARRAY; MICROWELLS; PROTEINS AB Here we present a microfluidic method for the analysis of single cell secretions. The method co-encapsulates cells with microspheres conjugated with capture antibodies and detection fluorescence-labeled antibodies. The secreted substance captured on the microsphere surface and detected via detection antibodies generating a localized fluorescent signal on a microsphere surface. Using this method, CD4+CD25+ regulatory T cells were encapsulated and assayed to detect IL-10 secreting cell in population. (c) 2010 Elsevier B.V. All rights reserved. C1 [Konry, Tania; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02115 USA. [Konry, Tania; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA USA. [Dominguez-Villar, Margarita; Baecher-Allan, Clare] Harvard Univ, Brigham & Womens Hosp, Div Mol Immunol, Ctr Neurol Dis,Sch Med, Boston, MA 02115 USA. [Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Konry, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, 51 Blossom St, Boston, MA 02115 USA. EM konry.tania@gmail.com FU NIH [AI063795, EB002503] FX We thank Dr. Jon Edd, Dr. Erkin Seker and Dr. Eric Yang for technical assistance in the device operation. We would like to acknowledged support from NIH grant AI063795 and EB002503. NR 19 TC 42 Z9 42 U1 7 U2 43 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JAN 15 PY 2011 VL 26 IS 5 BP 2707 EP 2710 DI 10.1016/j.bios.2010.09.006 PG 4 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 715RW UT WOS:000286904400151 PM 20888750 ER PT J AU Pieters, R Hunger, SP Boos, J Rizzari, C Silverman, L Baruchel, A Goekbuget, N Schrappe, M Pui, CH AF Pieters, Rob Hunger, Stephen P. Boos, Joachim Rizzari, Carmelo Silverman, Lewis Baruchel, Andre Goekbuget, Nicola Schrappe, Martin Pui, Ching-Hon TI L-Asparaginase Treatment in Acute Lymphoblastic Leukemia SO CANCER LA English DT Review DE acute lymphoblastic leukemia; asparagine depletion; asparaginase; Erwinia asparaginase; Erwinase; ALL ID ESCHERICHIA-COLI-ASPARAGINASE; ACUTE LYMPHOCYTIC-LEUKEMIA; IU/M(2) PEG-ASPARAGINASE; PEDIATRIC-ONCOLOGY-GROUP; DOSE L-ASPARAGINASE; CANCER-STUDY-GROUP; ERWINIA-ASPARAGINASE; INTENSIVE ASPARAGINASE; INTRAMUSCULAR THERAPY; CONSORTIUM PROTOCOLS AB Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second-or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. Cancer 2011; 117: 238-49. (C) 2010 American Cancer Society. C1 [Pieters, Rob] Erasmus MC Sophia Childrens Hosp, Rotterdam, Netherlands. [Hunger, Stephen P.] Univ Colorado, Dept Pediat, Denver Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp, Aurora, CO USA. [Boos, Joachim] Univ Childrens Hosp Munster, Dept Pediat Hematol & Oncol, Munster, Germany. [Rizzari, Carmelo] Univ Milano Bicocca, Hosp S Gerardo, Dept Pediat, Monza, Italy. [Silverman, Lewis] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Baruchel, Andre] Univ Paris Diderot, Hosp St Louis & Robert Debre, AP HP, Paris, France. [Goekbuget, Nicola] JW Goethe Univ Hosp, Dept Internal Med 2, Frankfurt, Germany. [Schrappe, Martin] Univ Med Ctr Schleswig Holstein, Dept Gen Pediat, Kiel, Germany. [Pui, Ching-Hon] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Pui, Ching-Hon] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. RP Pieters, R (reprint author), Erasmus MC Sophia Childrens Hosp, Dr Molewaterpl 60, Rotterdam, Netherlands. EM rob.pieters@erasmusmc.nl; ching-hon.pui@stjude.org FU US National Institutes of Health [CA-21,765]; American Lebanese Syrian Associated Charities; EUSA Pharma FX This work was supported in part by grant CA-21,765 from the US National Institutes of Health, by the American Lebanese Syrian Associated Charities, and by EUSA Pharma. Pieters is involved in scientific collaborations with different companies producing and developing asparaginases. Hunger is the Ergen Family Chair in Pediatric Cancer. Boos served personally as consultant and participated in advisory boards for different asparaginase-selling companies, including EUSA Pharma and former license holders. In addition, Boos is also involved in scientific collaborations with different companies producing and developing asparaginase. Rizzari is involved in scientific researches supported by different companies producing and/or marketing asparaginase products. Silverman served on an advisory board for EUSA Pharma and as a consultant for Enzon Pharmaceuticals. Baruchel received an honorarium from OPI for a lecture. Goekbuget is involved in scientific collaborations with different companies producing and developing asparaginases. Schrappe is involved in scientific collaborations with different companies producing and developing asparaginases. Pui received an honorarium from EUSA Pharma for a lecture. NR 73 TC 130 Z9 140 U1 6 U2 25 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 JAN 15 PY 2011 VL 117 IS 2 BP 238 EP 249 DI 10.1002/cncr.25489 PG 12 WC Oncology SC Oncology GA 703KF UT WOS:000285976100002 PM 20824725 ER PT J AU Nguyen, PL Chen, MH Goldhaber, SZ Martin, NE Beard, CJ Dosoretz, DE Katin, MJ Ross, R Salenius, SA D'Amico, AV AF Nguyen, Paul L. Chen, Ming H. Goldhaber, Samuel Z. Martin, Neil E. Beard, Clair J. Dosoretz, Daniel E. Katin, Michael J. Ross, Rudi Salenius, Sharon A. D'Amico, Anthony V. TI Coronary Revascularization and Mortality in Men With Congestive Heart Failure or Prior Myocardial Infarction Who Receive Androgen Deprivation SO CANCER LA English DT Article DE prostate cancer; hormone therapy; androgen deprivation therapy; cardiovascular; revascularization; death ID LOCALIZED PROSTATE-CANCER; RANDOMIZED CONTROLLED-TRIAL; RADIATION-THERAPY; HORMONAL-THERAPY; BRACHYTHERAPY; RADIOTHERAPY; SURVIVAL; SUPPRESSION; IMPACT; LIFE AB BACKGROUND: A study was undertaken to determine the impact of prior coronary revascularization (angioplasty, stent, or coronary artery bypass graft) on the risk of all-cause mortality after neoadjuvant hormonal therapy (HT) for prostate cancer (PC) in men with a history of coronary artery disease (CAD)-induced congestive heart failure (CHF) or myocardial infarction (MI). METHODS: Among 7839 men who received radiation with or without a median of 4 months of HT for PC from 1991 to 2006, 495 (6.3%) had CAD-induced CHF or MI and formed the study cohort. Of these men, 250 (50.5%) had been revascularized before treatment for PC. Cox regression was used to determine whether HT increased the risk of all-cause mortality, and whether revascularization altered this risk, after adjusting for known PC prognostic factors and a propensity score for revascularization. RESULTS: Median follow-up was 4.1 years. Neoadjuvant HT was associated with an increased risk of all-cause mortality (28.9% vs 15.7% at 5 years; adjusted hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.13-2.64; P = .01). Men who received HT without revascularization had the highest risk of all-cause mortality (33.3%; adjusted HR, 1.48; 95% CI, 1.01-2.18; P = .047), whereas men who were revascularized and did not receive HT had the lowest risk of all-cause mortality (9.4%; adjusted HR, 0.51; 95% CI, 0.28-0.93; P = .028). The reference group had an intermediate risk of all-cause mortality (23.4%) and was comprised of men in whom HT use and revascularization were either both given or both withheld. CONCLUSIONS: In men with a history of CAD-induced CHF or MI, neoadjuvant HT is associated with an excess risk of mortality, which appears to be reduced but not eliminated by prior revascularization. Cancer 2011; 117:406-13. (C) 2010 American Cancer Society. C1 [Nguyen, Paul L.; Martin, Neil E.; Beard, Clair J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.; Goldhaber, Samuel Z.; Martin, Neil E.; Beard, Clair J.; D'Amico, Anthony V.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Ming H.] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Dosoretz, Daniel E.; Katin, Michael J.; Ross, Rudi; Salenius, Sharon A.] 21st Century Oncol, Ft Myers, FL USA. RP Nguyen, PL (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 NR 19 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JAN 15 PY 2011 VL 117 IS 2 BP 406 EP 413 DI 10.1002/cncr.25597 PG 8 WC Oncology SC Oncology GA 703KF UT WOS:000285976100021 PM 21108457 ER PT J AU Frigo, DE Howe, MK Wittmann, BM Brunner, AM Cushman, I Wang, QB Brown, M Means, AR McDonnell, DP AF Frigo, Daniel E. Howe, Matthew K. Wittmann, Bryan M. Brunner, Abigail M. Cushman, Ian Wang, Qianben Brown, Myles Means, Anthony R. McDonnell, Donald P. TI CaM Kinase Kinase beta-Mediated Activation of the Growth Regulatory Kinase AMPK Is Required for Androgen-Dependent Migration of Prostate Cancer Cells SO CANCER RESEARCH LA English DT Article ID MEMBRANE TESTOSTERONE RECEPTORS; PROTEIN-KINASE; GENE-EXPRESSION; ENDOTHELIAL-CELLS; IN-VITRO; RAC1; PROLIFERATION; SUPPRESSION; PROGRESSION; RESISTANCE AB While patients with advanced prostate cancer initially respond favorably to androgen ablation therapy, most experience a relapse of the disease within 1-2 years. Although hormone-refractory disease is unresponsive to androgen-deprivation, androgen receptor (AR)-regulated signaling pathways remain active and are necessary for cancer progression. Thus, both AR itself and the processes downstream of the receptor remain viable targets for therapeutic intervention. Microarray analysis of multiple clinical cohorts showed that the serine/threonine kinase Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKK beta) is both highly expressed in the prostate and further elevated in prostate cancers. Using cellular models of prostate cancer, we have determined that androgens (a) directly increase the expression of a CaMKK beta splice variant and (b) increase functional CaMKK beta protein level