FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Cherukupally, SR Eavey, R AF Cherukupally, SR Eavey, R TI Vaccine-preventable pediatric postmeningitic sensorineural hearing loss in southern India SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT 17th Annual Meeting of the American-Society-for-Pediatric-Otolaryngology CY MAY 13-14, 2002 CL BOCA RATON, FL SP Amer Soc Pediatr Otolarygol ID PNEUMOCOCCAL CONJUGATE VACCINE; BACTERIAL-MENINGITIS; UNITED-STATES; CHILDREN; IMPAIRMENT AB OBJECTIVE. The study goal was to assess vaccine-preventable pediatric postmeningitic sensorineural hearing loss in southern India. STUDY DESIGN AND SETTING: We conducted a prospective pilot study from January through March 2001 in a tertiary pediatric hospital in southern India. RESULTS: Sixty-five patients were studied. Thirty-five (54%) patients had positive cerebrospinal fluid cultures, with the most common organisms being Streptococcus pneumoniae and Hoemophilus influenzae. An additional 10 (15%) patients were diagnosed with tuberculous meningitis. Of 28 patients who could comply with audiometric evaluations, 8 (28%) had sensorineural hearing loss. CONCLUSIONS: The etiologic organisms of bacterial meningitis in this study population are similar to those organisms in the developed world, with the minority exception of tuberculous meningitis. Further, a similar prevalence of postmeningific sensorineural hearing loss occurred. SIGNIFICANCE: An effective vaccination program against S. pneumoniae and H. influenzae type b should reduce the prevalence of sensorineural hearing loss due to bacterial meningitis in developing countries with similar bacterial profiles. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Pediat Otolaryngol Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Cambridge, MA 02138 USA. RP Eavey, R (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Pediat Otolaryngol Serv, 243 Charles St, Boston, MA 02114 USA. EM Roland_Eavey@meei.harvard.edu NR 17 TC 5 Z9 5 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2004 VL 130 IS 3 BP 339 EP 343 DI 10.1016/j.otohns.2003.11.017 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808NE UT WOS:000220575000009 PM 15054376 ER PT J AU Mikulec, AA McKenna, MJ Ramsey, MJ Rosowski, JJ Herrmann, BS Rauch, SD Curtin, HD Merchant, SN AF Mikulec, AA McKenna, MJ Ramsey, MJ Rosowski, JJ Herrmann, BS Rauch, SD Curtin, HD Merchant, SN TI Superior semicircular canal dehiscence presenting as conductive hearing loss without vertigo SO OTOLOGY & NEUROTOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Otological-Society CY MAY 03, 2003 CL Nashville, TN SP Amer Otol Soc DE superior semicircular canal; conductive hearing loss; audiometry; stapedectomy ID PAROXYSMAL POSITIONAL VERTIGO; PRESSURE-INDUCED VERTIGO; BONE DEHISCENCE; STAPEDECTOMY; EXPERIENCE; OCCLUSION AB Objective: The objective of this study was to describe superior semicircular canal dehiscence (SSCD) presenting as otherwise unexplained conductive hearing loss without vestibular symptoms. Study Design: Retrospective. Setting: Tertiary referral center. Patients: The study comprised 8 patients (10 ears), 5 males and 5 females aged 27 to 59 years. All 10 ears had SSCD on high-resolution computed tomography scan of the temporal bone. Diagnostic Tests and Results: All 10 ears had significant conductive hearing loss. The air-bone gaps were largest in the lower frequencies at 250, 500, and 1000 Hz; the mean gaps for these 3 frequencies for the 10 ears were 49, 37, and 35 dB, respectively. Bone-conduction thresholds below 2000 Hz were negative (-5 dB to -15 dB) at one or more frequencies in 8 of the 10 ears. There were no middle ear abnormalities to explain the air-bone gaps in these 10 ears. Computed tomography scan and laboratory testing indicated lack of middle ear pathology; acoustic reflexes were present, vestibular evoked myogenic potentials (VEMPs) were present with abnormally low thresholds, and umbo velocity measured by laser Doppler vibrometry was above mean normal. Middle ear exploration was negative in six ears; of these six, stapedectomy had been performed in three ears and ossiculoplasty in two cars, but the air-bone gap was unchanged postoperatively. The data are consistent with the hypothesis that the SSCD introduced a third mobile window into the inner ear, which in turn produced the conductive hearing loss by 1) shunting air-conducted sound away from the cochlea, thus elevating air-conduction thresholds; and 2) increasing the difference in impedance between the oval and round windows, thus improving thresholds for bone-conducted sound. Conclusion: SSCD can present with a conductive hearing loss that mimics otosclerosis and could explain some cases of persistent conductive hearing loss after uneventful stapedectomy. Audiometric testing with attention to absolute bone-conduction thresholds, acoustic reflex testing, VEMP testing, laser vibrometry of the umbo, and computed tomograph scanning can help to identify patients with SSCD presenting with conductive hearing loss without vertigo. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Merchant, SN (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM snm@epl.meei.harvard.edu FU NIDCD NIH HHS [R01 DC04425, R01 DC04798] NR 24 TC 139 Z9 152 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAR PY 2004 VL 25 IS 2 BP 121 EP 129 DI 10.1097/00129492-200403000-00007 PG 9 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 803XJ UT WOS:000220263500007 PM 15021770 ER PT J AU Lee, JCR Shannon, L Boyle, NG Klitzner, TS Bersohn, MM AF Lee, JCR Shannon, L Boyle, NG Klitzner, TS Bersohn, MM TI Evaluation of safety and efficacy of pacemaker and defibrillator implantation by axillary incision in pediatric patients SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article ID TRANSVENOUS PACING LEADS; SYSTEMS AB We successfully implanted 11 pacemakers, 6 defibrillators, and 1 biventricular pacemaker in 18 Pediatric patients (15 female; 4 to 15 years, average age: 9) using the retropectoral transvenous approach with a hidden axillary incision. The average follow-up period was 24 months (range 49 months). Eight patients had congenital structural heart conditions (d-transposition of great arteries SIP Mustard operation, d-transposition of great arteries SIP arterial switch operation, truncus arteriosus, right ventricular diverticula, ventricular septal defect, hypertrophic cardiomyopathy). Four patients had acquired heart conditions (dilated cardiomyopathy, myocarditis). Excellent sensing and pacing thresholds were achieved in all attempted implantations. There was no pneumothorax. There was one lead dislodgement. One lead fracture distant from the subclavian vein occurred 4 months after implantation. Implantation of pacemakers and defibrillators via axillary incisions can be safe and effective in pediatric patients. This approach avoids skin erosion when implanting large devices such as defibrillotors or biventricular devices in small patients with limited muscle mass while achieving superior aesthetic results. The axillary or extrathoracic venous entry site avoids subclavian crush syndrome. C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Div Pediat Cardiol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Div Cardiol, Los Angeles, CA 90024 USA. RP Lee, JCR (reprint author), Heart Inst Children, Med Corp, POB 24854, Los Angeles, CA 90024 USA. EM lee@stanfordalumni.org NR 8 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL FUTURA PUBLISHING, INC PI MALDEN PA 350 MAIN STREET, MALDEN, MA 01248-5018 USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD MAR PY 2004 VL 27 IS 3 BP 304 EP 307 DI 10.1111/j.1540-8159.2004.00432.x PG 4 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 805JD UT WOS:000220361700005 PM 15009854 ER PT J AU Kulich, RJ Driscoll, S Scrivoni, SJ McAlary, P Mehta, N AF Kulich, RJ Driscoll, S Scrivoni, SJ McAlary, P Mehta, N TI A survey of medico-legal practice patterns among pain specialists SO PAIN MEDICINE LA English DT Article DE medico-legal; forensic; pain; guidelines; ethical AB Objective. Pain clinicians are increasingly asked to provide expert commentary in a variety of medico-legal or forensic contexts. The purpose of this study was to discover the frequency and type of medico-legal activity undertaken by pain specialists, their familiarity with current guidelines, and their opinions with respect to a need for formal ethical or practice guidelines. Design. Members of the New England Pain Association were surveyed with a 20-item questionnaire addressing specific areas of practice including the completion of disability forms, letters/attorney reports, depositions, testimony in court, record reviews, and return-to-work forms. Respondents also were asked to distinguish medico-legal activities for their patients from those that occurred for third parties. Setting/Participants. Participants included pain specialists from a range of disciplines represented by the membership of a regional pain society. The response rate was 67%, with a total of 144 returned surveys. Results. Survey data revealed that 72% of pain specialists had engaged in some form of medico-legal work within the past year. Of those who engaged in this work, 96% completed this work as a treating clinician for their patients. While the majority of respondents engaged in activities such as the completion of disability forms, other high frequency activities included depositions and testimony. Differences between physicians and nonphysicians also were noted. Results revealed that the majority of pain specialists supported the development of guidelines for medico-legal practice. It was suggested that pain societies move to develop ethical and/or clinical practice guidelines to address this issue. C1 Massachusetts Gen Hosp, Pain Ctr, Boston, MA 02114 USA. Tufts Univ, Sch Dent Med, Craniofacial Pain Ctr, Boston, MA 02111 USA. Spaulding Rehabil Hosp, Pain Ctr, Boston, MA USA. RP Kulich, RJ (reprint author), 30 Union St, Charlestown, MA 02129 USA. EM rkulich@partners.org NR 10 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD MAR PY 2004 VL 5 IS 1 BP 98 EP 103 DI 10.1111/j.1526-4637.2004.04012.x PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 774PK UT WOS:000188991600013 PM 14996242 ER PT J AU Borsook, D Edwards, AD AF Borsook, D Edwards, AD TI Antineuropathic effects of the antibiotic derivative spicamycin KRN5500 SO PAIN MEDICINE LA English DT Article DE neuropathic pain; KRN5500; Raynaud's disease; monoclonal gammopathy ID NEUROPATHIC PAIN; MECHANICAL ALLODYNIA; CELL-LINES; MODEL; APOPTOSIS; INJECTION; DECREASES; RATS AB Excellence in neuropathic pain management continues to challenge the ability of health care providers. Current medications are helpful but often create significant side effects or simply fail to provide adequate analgesia. We report here on a serendipitous finding of the successful attenuation of neuropathic pain in a patient with long-standing monoclonal gammopathy, Raynaud's disease, and neuropathic pain who received the trial chemotherapeutic agent KRN5500. This finding led to animal studies that have provided support for the possible use of KRN5500 in the treatment of neuropathic pain in humans as well as some insight into the possible mechanism(s) of action of this drug. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Ctr Funct Pain Neuroimaging & Therapy Res, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia, Boston, MA USA. RP Borsook, D (reprint author), 790 Mem Dr, Cambridge, MA 02139 USA. EM dborsook@dtrx.com NR 20 TC 8 Z9 8 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD MAR PY 2004 VL 5 IS 1 BP 104 EP 108 DI 10.1111/j.1526-4637.2004.04004.x PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 774PK UT WOS:000188991600014 PM 14996243 ER PT J AU Ko, SH Suh, SH Kim, BJ Ahn, YB Song, KH Yoo, SJ Son, HS Cha, BY Lee, KW Son, HY Kang, SK Bonner-Weir, S Weir, GC Yoon, KH Park, CG AF Ko, SH Suh, SH Kim, BJ Ahn, YB Song, KH Yoo, SJ Son, HS Cha, BY Lee, KW Son, HY Kang, SK Bonner-Weir, S Weir, GC Yoon, KH Park, CG TI Expression of the intermediate filament vimentin in proliferating duct cells as a marker of pancreatic precursor cells SO PANCREAS LA English DT Article DE pancreatic duct cell; cytokeratin; vimentin; dedifferentiation; intermediate filament pancreatic precursor cell ID EPITHELIAL-MESENCHYMAL TRANSITION; BETA-CELLS; ENDOCRINE PANCREAS; ISLET GROWTH; RAT PANCREAS; IN-VIVO; DIFFERENTIATION; ADULT; EXOCRINE; CULTURE AB Objectives: The expression of the intermediate filament ( IF) vimentin, usually considered a marker of mesenchymal cells, has been observed in the epithelial cells during embryogenesis, carcinogenesis, and dedifferentiation, suggesting that it might be useful as a marker of proliferating precursor cells in the pancreas. Methods: Rat pancreata at E18 and at different time points after partial pancreatectomy (Px) and human and neonatal pig pancreatic tissue sections and monolayer cultured pancreatic duct cells were observed. All tissues were simultaneously immunostained with pancytokeratin and vimentin antibodies. In costained duct cells, PDX-1 or PCNA expression was also analyzed using confocal microscope images. Results: In the rat embryonic pancreas at E18, all epithelial cells that formed ductlike structures expressed both cytokeratin and vimentin IF, whereas no duct cells costained for IF in the adult rat or neonatal pig pancreas. Such costaining reappeared in the following order: common pancreatic duct, main ducts, foci of regeneration and then disappeared completely at 30 days after Px. In humans, costaining was found in only 1 diabetic patient's pancreatic section, which was accompanied companied by massive duct cell proliferation. In monolayer culture, most of the duct cells of human and neonatal pigs coexpressed both IF proteins. Only a few costained duct cells also expressed PDX-1, and most of those cells were also stained with PCNA in rat embryonic pancreas and regenerating foci after partial Px. Conclusions: Vimentin IF expression might be a useful marker for pancreatic precursor cells and could be used to investigate the concept of the dedifferentiation of fully matured duct cells during the process of the beta-cell neogenesis. C1 Catholic Univ Korea, Div Endocrinol & Metab, Seoul, South Korea. Catholic Inst Med Sci, Seoul, South Korea. Catholic Univ Korea, Dept Physiol, Seoul, South Korea. Joslin Diabet Ctr, Islet Transplantat & Cell Biol Sect, Boston, MA 02215 USA. Seoul Natl Univ, Coll Med, Transplantat Res Inst, Dept Microbiol & Immunol, Seoul 151, South Korea. RP Yoon, KH (reprint author), Kang Nam St Marys Hosp, Dept Internal Med, 505 Banpo Dong, Seoul, South Korea. EM yoonk@catholic.ac.kr RI Park, Chung-Gyu/C-3596-2011; OI Park, Chung-Gyu/0000-0003-4083-8791 NR 39 TC 26 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2004 VL 28 IS 2 BP 121 EP 128 DI 10.1097/00006676-200403000-00002 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 802DL UT WOS:000220144100002 PM 15028943 ER PT J AU Mohit, AA Samii, A Slimp, JC Grady, MS Goodkin, R AF Mohit, AA Samii, A Slimp, JC Grady, MS Goodkin, R TI Mechanical failure of the electrode wire in deep brain stimulation SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE deep brain stimulation.; mechanical failure; wire breakage; tremor; Parkinson's disease AB The feasibility and efficacy of deep brain stimulation (DBS) has offered new possibilities for treatment of movement disorders. Mechanical failure of the DBS system is a potential complication. Here we report five patients who presented with mechanical failure of the DBS system. Radiographs of the skull and cervical spine were analyzed for disruptions. Seven instances of lead breakage near the connection of the DBS electrode with the extension wire were identified. In one patient this was in the paramastoid area over the skull, while in all others were in the supraclavicular location. The patients consisted of three men and two women ranging in age from 24 to 78 (at the time of first operation), one person suffering three breakages. The length of spanned time from implantation to presentation ranged from 8 to 32 months. Palpation of the electrode lead wire in the neck for breakage proved unreliable. Radiography localized the site of breakage in all but one patient who required intraoperative exploration, which revealed that although the lead wire was disrupted, the two ends remained in contact. The fact that all breakages occurred near the connection wire suggests that to-and-fro motion of the DBS electrode with repeated head turning leads to fatigue and eventual disruption. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Washington, Sch Med, Dept Neurol, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98108 USA. Univ Penn, Dept Neurol Surg, Philadelphia, PA 19104 USA. RP Samii, A (reprint author), Univ Washington, Sch Med, Dept Neurol, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,Mailstop 127, Seattle, WA 98108 USA. EM asamii@u.washington.edu NR 5 TC 7 Z9 7 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAR PY 2004 VL 10 IS 3 BP 153 EP 156 DI 10.1016/j.parkreldis.2003.11.001 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 802KX UT WOS:000220163500007 ER PT J AU Gilles, FH Tavare, CJ Leviton, A Hedley-Whyte, ET Sotrel, A Adelman, L Davis, RL Rorke, LB AF Gilles, FH Tavare, CJ Leviton, A Hedley-Whyte, ET Sotrel, A Adelman, L Davis, RL Rorke, LB TI Prognostic limitations of the Daumas-Duport grading scheme in infratentorial neuroglial tumors in children SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article ID CHILDHOOD CEREBELLAR ASTROCYTOMA; QUANTITATIVE HISTOLOGIC FACTORS; GLIOBLASTOMA-MULTIFORME; ANAPLASTIC ASTROCYTOMA; PILOCYTIC ASTROCYTOMA; GLIOMAS; SUPRATENTORIAL; CONFIGURATION; RELIABILITY; DEFINITION AB The Daumas-Duport grading scheme (DDGS) utilizes four histologic features in an additive method (grade 1 if none present, grade 2 if only one is present, etc.). Its efficacy in achieving prognostically homogeneous groups of childhood infratentorial neuroglial tumors and its concordance with World Health Organization (WHO) diagnoses has not been evaluated. We investigated these questions using the Childhood Brain Tumor Consortium (CBTC) database of 1241 neuroglial tumors limited to the infratentorial compartment. We calculated survival function estimates for various DDGS grades as well as the histologic features within each grade. The feature of endothelial prominence improved survival expectation, whereas the remaining three features of nuclear atypia, mitoses, and necrosis were associated with worsened survival. Survival estimates for tumors with DDGS grades 2 and 3 did not differ. Some grades contained feature subsets with significantly different survival distributions. The survival distributions of DDGS grade 1, DDGS grade 2 with only endothelial prominence, and DDGS grade 3 with nuclear atypia and endothelial prominence were not significantly different. DDGS grade within WHO diagnoses had no significant effect on survival expectation. We conclude that grading by summation of only four histologic features, as in the DDGS, is inappropriate for assessment of childhood neuroglial tumors. A classification scheme considering the complete histologic content is more likely to provide clinically useful diagnoses. Such a scheme, based on the CBTC database is available. This scheme uses 26 histologic features identified as reliable in read-reread studies. C1 Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Div Neuropathol, Los Angeles, CA 90027 USA. Univ So Calif, Sch Med, Los Angeles, CA 90027 USA. Childrens Hosp, Dept Neuroepidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Neuropathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Miami Childrens Hosp, Dept Pathol, Miami, FL 33155 USA. Tufts Univ, New England Med Ctr Hosp, Dept Pathol Lab, Boston, MA 02111 USA. Univ Calif San Francisco, Dept Pathol, Sch Med, San Francisco, CA 94143 USA. Childrens Hosp Philadelphia, Dept Neuropathol, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Gilles, FH (reprint author), Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Div Neuropathol, 4650 Sunset Blvd,MS 43, Los Angeles, CA 90027 USA. EM fgilles@usc.edu FU NCI NIH HHS [R01 CA20462, R01 CA49532] NR 46 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD MAR-APR PY 2004 VL 7 IS 2 BP 138 EP 147 DI 10.1007/s10024-003-6972-0 PG 10 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 822FU UT WOS:000221525000004 PM 14994132 ER PT J AU Palmert, MR Alexander, SW Goorin, AM AF Palmert, MR Alexander, SW Goorin, AM TI Ovarian toxicity after chemotherapy: Possible association with ifosfamide administration SO PEDIATRIC BLOOD & CANCER LA English DT Article DE gonadal failure; ifosfamide; osteosarcoma ID LONG-TERM SURVIVORS; GERM-CELL TUMORS; HODGKINS-DISEASE; COMBINATION CHEMOTHERAPY; REPRODUCTIVE FUNCTION; GONADAL DAMAGE; CHILDHOOD; CANCER C1 Childrens Hosp, Div Endocrinol, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. RP Palmert, MR (reprint author), Univ Hosp Cleveland, Div Pediat Endocrinol & Metab, Rainbow Babies & Childrens Hosp, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM rmp13@po.cwru.edu FU NCRR NIH HHS [K23 RR15544] NR 18 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2004 VL 42 IS 3 BP 216 EP 219 DI 10.1002/pbc.10320 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 812WE UT WOS:000220868800003 PM 14752857 ER PT J AU Nimkin, K Gupta, P McCauley, R Gilchrist, BF Lessin, MS AF Nimkin, K Gupta, P McCauley, R Gilchrist, BF Lessin, MS TI The growing teratoma syndrome SO PEDIATRIC RADIOLOGY LA English DT Article DE growing teratoma syndrome; immature teratoma ovary; pediatric ovarian tumor; CT ID GERM-CELL TUMOR; IMMATURE TERATOMA; OVARY; CHEMOTHERAPY AB Growing teratoma syndrome is defined as enlarging masses of mature teratoma following chemotherapy for malignant nonseminomatous germ-cell tumors. Typically, there is associated normalization of initially elevated serum tumor markers. We describe clinical and imaging findings in a case of growing teratoma syndrome originating from immature teratoma of the ovary in a 12-year-old girl. Familiarity with this unusual entity is important to avoid confusion with advancing malignancy. C1 Floating Hosp Children, Dept Pediat Surg, Boston, MA USA. Floating Hosp Children, Dept Radiol, Boston, MA USA. RP Nimkin, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Pediat Radiol, 55 Fruit St,White 246, Boston, MA 02114 USA. EM knimkin@partners.org NR 11 TC 16 Z9 17 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD MAR PY 2004 VL 34 IS 3 BP 259 EP 262 DI 10.1007/s00247-003-1045-z PG 4 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 801IQ UT WOS:000220090000014 PM 14551755 ER PT J AU Moore, MM Rifas-Shiman, SL Rich-Edwards, JW Kleinman, KP Camargo, CA Gold, DR Weiss, ST Gillman, MW AF Moore, MM Rifas-Shiman, SL Rich-Edwards, JW Kleinman, KP Camargo, CA Gold, DR Weiss, ST Gillman, MW TI Perinatal predictors of atopic dermatitis occurring in the first six months of life SO PEDIATRICS LA English DT Article DE atopic dermatitis; eczema; perinatal; infancy; gestational age; race/ethnicity; gender ID BIRTH-WEIGHT INFANTS; MATERNAL INHERITANCE; FOLLOW-UP; ECZEMA; ASTHMA; PREVALENCE; CHILDREN; AGE; CHILDHOOD; RISK AB Objective. Previous studies of predictors of atopic dermatitis have had limited sample size, small numbers of variables, or retrospective data collection. The purpose of this prospective study was to investigate several perinatal predictors of atopic dermatitis occurring in the first 6 months of life. Design. We report findings from 1005 mothers and their infants participating in Project Viva, a US cohort study of pregnant women and their offspring. The main outcome measure was maternal report of a provider's diagnosis of eczema or atopic dermatitis in the first 6 months of life. We used multiple logistic regression models to assess the associations between several simultaneous predictors and incidence of atopic dermatitis. Results. Cumulative incidence of atopic dermatitis in the first 6 months of life was 17.1%. Compared with infants born to white mothers, the adjusted odds ratio ( OR) for risk of atopic dermatitis among infants born to black mothers was 2.41 (95% confidence interval [CI]: 1.47, 3.94) and was 2.58 among infants born to Asian mothers ( 95% CI: 1.27, 5.24). Male infants had an OR of 1.76 ( 95% CI: 1.24, 2.51). Increased gestational age at birth was a predictor ( OR: 1.14; 95% CI: 1.02, 1.27, for each 1-week increment), but birth weight for gestational age was not. Infants born to mothers with a history of eczema had an OR of 2.67 ( 95% CI: 1.74, 4.10); paternal history of eczema also was predictive, although maternal atopic history was more predictive than paternal history. Several other perinatal, social, feeding, and environmental variables were not related to risk of atopic dermatitis. Conclusions. Black and Asian race/ ethnicity, male gender, higher gestational age at birth, and family history of atopy, particularly maternal history of eczema, were associated with increased risk of atopic dermatitis in the first 6 months of life. These findings suggest that genetic and pre- and perinatal influences are important in the early presentation of this condition. C1 Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. Harvard Pilgrim Hlth Care, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Environm Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Gillman, MW (reprint author), Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. EM matthew_gillman@hms.harvard.edu FU NHLBI NIH HHS [K24 HL068041, HL 68041, HL 64925, R01 HL064925]; NICHD NIH HHS [R37 HD034568, R01 HD034568, HD 34568] NR 47 TC 78 Z9 84 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR 1 PY 2004 VL 113 IS 3 BP 468 EP 474 DI 10.1542/peds.113.3.468 PG 7 WC Pediatrics SC Pediatrics GA 779ZT UT WOS:000189344400006 PM 14993536 ER PT J AU Kuhlthau, K Nyman, RM Ferris, TG Beal, AC Perrin, JM AF Kuhlthau, K Nyman, RM Ferris, TG Beal, AC Perrin, JM TI Correlates of use of specialty care SO PEDIATRICS LA English DT Article DE Medicaid; specialist; insurance; pediatric; child; disability; chronic condition ID MEDICAID MANAGED CARE; HEALTH-CARE; ETHNIC-DIFFERENCES; ENROLLED CHILDREN; CHRONIC ILLNESS; ADOLESCENTS; ACCESS; PARTICIPATION; GENERALISTS; PREVALENCE AB Objective. This study examines patterns of specialist use among children and adolescents by presence of a chronic condition or disability, insurance, and sociodemographic characteristics. Design. Cross-sectional analysis of national survey data, describing rates of specialist use, with logistic regressions to examine associations with having a chronic condition or disability, insurance status, and sociodemographic variables. Setting. The 1999 National Health Interview Survey, a nationally representative household survey. Participants. Children and adolescents 2 to 17 years old. Outcome. Parental/respondent reports of specialist visits based on reports of the child having seen or talked to a medical doctor who specializes in a particular medical disease or problem about the child's health during the last 12 months. Results. Thirteen percent of US children were reported as seeing a specialist in the past year. Specialist-visit rates were twice as high for children with a chronic condition or disability (26% vs 10.2%). The specialist utilization rates for children without insurance were much lower than those for insured children, but among the children who have coverage (private, Medicaid, or other), specialist-utilization rates were similar (no statistically significant difference). Results of multivariate analyses predicting the use of specialists confirm the above-mentioned findings. Additionally, they show that use of specialist care was lower among children in the middle age group, minorities, children in families between 100% and 200% of the federal poverty level, and lower parental educational levels. We found no difference in specialist-visit rates between rural- and urban-dwelling children, by family status, or by gender. Differences in specialist use by gatekeeping status are found only among subgroups. Conclusions. The results showed that, overall, 13% of children used a specialist in a year. Among the insured, a slightly greater percentage of children used such care (15%). These numbers were slightly lower than the 18% to 28% of pediatric patients referred per year in 5 US health plans, although the sources of data and definitions of specialist use differ. Our results showed that 26% of children with a chronic condition or disability who were insured by Medicaid use a specialist. Although the data are not directly comparable, this is within the range of previous findings showing annual rates by condition of use between 24% and 59%. These findings are consistent also with greater use of many different types of health care by children with special health care needs. Medicaid-utilization rates presented here were similar also to the rates found among privately insured children and children with "other" insurance. In our earlier work examining use of specialists by children insured by Medicaid, we speculated that Medicaid-insured children might face particular difficulty with access (eg, due to transportation or language barriers). The findings presented here suggest that children insured by Medicaid had no different use of specialists than other insured children. We do not know, however, whether similar rates are appropriate. As predicted, sociodemographic differences were pronounced and followed patterns typically found for use of health services. Lower rates of specialist use by non-Hispanic blacks and Hispanics remains even, controlling for chronic condition/disability, status, insurance, and socioeconomic status. This is an important issue that not only needs to be addressed in using specialist care but also in many areas in health care. It is the near poor who seem to have difficulty accessing care (as is evidenced by lower use of specialists). In a study of access to care, similar results were found, with those between 125% and 200% of the federal poverty level being less likely to have a usual source of care. This is roughly the population targeted by the State Children's Health Insurance Programs. These findings cannot determine whether rates of use are too high or too low. Additional work on outcomes for children who do and do not use specialist care would further inform the work presented here. Extending that work to examine patterns of care including but not limited to specialists and generalists would be even better. C1 Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat,Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Hlth Policy,Dept Med,Div Gen Med, Boston, MA USA. Commonwealth Fund, Qual Care Underserved Populat, New York, NY USA. RP Kuhlthau, K (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat,Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Ste 901, Boston, MA 02114 USA. EM kkuhlthau@partners.org NR 32 TC 49 Z9 49 U1 2 U2 5 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 MAR 1 PY 2004 VL 113 IS 3 BP E249 EP E255 DI 10.1542/peds.113.3.e249 PG 7 WC Pediatrics SC Pediatrics GA 779ZT UT WOS:000189344400059 PM 14993584 ER PT J AU Swanson, JM Wigal, SB Wigal, T Sonuga-Barke, EJS Greenhill, LL Biederman, J Kollins, S Nguyen, AS DeCory, HH Dirksen, SJH Hatch, SJ AF Swanson, JM Wigal, SB Wigal, T Sonuga-Barke, EJS Greenhill, LL Biederman, J Kollins, S Nguyen, AS DeCory, HH Dirksen, SJH Hatch, SJ CA COMACS Study Grp TI A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (The COMACS study) SO PEDIATRICS LA English DT Article DE ADHD; methylphenidate; pharmacodynamic effects; children; laboratory classroom; SKAMP; Metadate CD; Concerta ID DEFICIT HYPERACTIVITY DISORDER; A-DAY; ADHD; MTA AB Objective. The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended- release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended- release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration. Methods. This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs. Results. The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day: 1) PLA > MCD similar to CON ( PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD similar to CON > PLA during the afternoon ( PD equivalence of MCD and CON); and 4) CON > MCD similar to PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose x treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period. 2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels. The correlation (r) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures (r similar to .9), indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation. For the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs were large and indistinguishable (eg, deportment ES similar to 0.75 for both). Conclusions. Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration. C1 Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Massachusetts Gen Hosp, Cambridge, MA USA. Duke Univ, Med Ctr, Duke Child & Family Study Ctr, Durham, NC USA. Celltech Amer Inc, Rochester, NY USA. RP Swanson, JM (reprint author), Univ Calif Irvine, Child Dev Ctr, 19722 MacArthur Centerpointe, Irvine, CA 92612 USA. EM jmswanso@uci.edu RI Sonuga-Barke, Edmund/D-9137-2011; Kollins, Scott/G-2965-2012 NR 31 TC 120 Z9 126 U1 0 U2 13 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR 1 PY 2004 VL 113 IS 3 BP E206 EP E216 DI 10.1542/peds.113.3.e206 PG 11 WC Pediatrics SC Pediatrics GA 779ZT UT WOS:000189344400053 PM 14993578 ER PT J AU Murray, MD Harris, LE Overhage, JM Zhou, XH Eckert, GJ Smith, FE Buchanan, NN Wolinsky, FD McDonald, CJ Tierney, WM AF Murray, MD Harris, LE Overhage, JM Zhou, XH Eckert, GJ Smith, FE Buchanan, NN Wolinsky, FD McDonald, CJ Tierney, WM TI Failure of computerized treatment suggestions to improve health outcomes of outpatients with uncomplicated hypertension: Results of a randomized controlled trial SO PHARMACOTHERAPY LA English DT Article DE computers; practice guidelines; hypertension; randomized controlled trials ID CLINICAL-PRACTICE GUIDELINES; PREVENTIVE CARE GUIDELINES; JOINT NATIONAL COMMITTEE; HIGH BLOOD-PRESSURE; MEDICAL OUTCOMES; WORK PATTERNS; JNC-V; PHYSICIANS; REMINDERS; QUALITY AB Study Objective. To assess the effects of evidence-based treatment suggestions for hypertension made to physicians and pharmacists using a comprehensive electronic medical record system. Design. Randomized controlled trial with a 2 x 2 factorial design of physician and pharmacist interventions, which resulted in four groups of patients: physician intervention only, pharmacist intervention only, intervention by physician and pharmacist, and intervention by neither physician nor pharmacist (control). Setting. Academic primary care internal medicine practice. Subjects. Seven hundred twelve patients with uncomplicated hypertension. Measurements and Main Results. Suggestions were displayed to physicians on computer workstations used to write outpatient orders and to pharmacists when filling prescriptions. The primary end point was generic health-related quality of life. Secondary end points were symptom profile and side effects from antihypertensive drugs, number of emergency department visits and hospitalizations, blood pressure measurements, patient satisfaction with physicians and pharmacists, drug therapy compliance, and health care charges. In the control group, implementation of care changes in accordance with treatment suggestions was observed in 26% of patients. In the intervention groups, compliance with suggestions was poor, with treatment suggestions implemented in 25% of patients for whom suggestions were displayed only to pharmacists, 29% of those for whom suggestions were displayed only to physicians, and 35% of the group for whom both physicians and pharmacists received suggestions (p=0.13). Intergroup differences were neither statistically significant nor clinically relevant for generic health-related quality of life, symptom and side-effect profiles, number of emergency department visits and hospitalizations, blood pressure measurements, charges, or drug therapy compliance. Conclusion. Computer-based intervention using a sophisticated electronic physician order-entry system failed to improve compliance with treatment suggestions or outcomes of patients with uncomplicated hypertension. C1 St Louis Univ, Sch Publ Hlth, St Louis, MO 63103 USA. Univ Washington, VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Dept Biostat, Tacoma, WA USA. Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. Purdue Univ, Sch Pharm, Dept Pharm Practice, W Lafayette, IN 47907 USA. Purdue Univ, Sch Pharm, Regenstrief Inst, W Lafayette, IN 47907 USA. Indiana Univ, Sch Med, Dept Med, Bloomington, IN USA. RP Murray, MD (reprint author), Regenstrief Inst Hlth Care, Regenstrief Inst, 6th Floor,1050 Wishard Blvd, Indianapolis, IN 46202 USA. EM mmurray@regenstrief.org RI Wolinsky, Fredric/F-9231-2011; OI Wolinsky, Fredric/0000-0002-0916-4955; Overhage, Joseph/0000-0003-0223-0195 FU AHRQ HHS [R01 HS07763] NR 59 TC 72 Z9 73 U1 2 U2 3 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD MAR PY 2004 VL 24 IS 3 BP 324 EP 337 DI 10.1592/phco.24.4.324.33173 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 779QY UT WOS:000189312800003 PM 15040645 ER PT J AU Vacanti, FX AF Vacanti, FX TI PHEMA as a fibrous capsule-resistant breast prosthesis SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID SMOOTH SILICONE; FOLLOW-UP; RECONSTRUCTION; IMPLANTS; QUALITY AB The presence of a silicone (poly-dimethyl siloxane) breast prosthesis in a breast reconstruction patient typically leads to fibrous tissue encapsulation of the prosthesis. Fibrous capsular contracture forces the prosthesis into a hardened sphere. The initially satisfactory cosmetic result can thus be changed into a deformed mass of inappropriate compliance. It is the author's hope with the present study to identify a material for implantation with a diminished tendency to form fibrous encapsulation, to improve the long-term results of prosthetic implants. The purpose of this investigation was to compare the early capsule production quality of poly-2-hydroxyethyl methacrylate (PHEMA) and poly-dimethyl siloxane (silicone). Each of five rats subcutaneously underwent implantation with both a disk of poly-dimethyl siloxane (control) and a similar disk of PHEMA. In this study, the extent of fibrous encapsulation was assessed at 6 weeks after implantation of the two disk types. The five disks of poly-dimethyl siloxane were embedded in fibrous tissue, whereas there was no apparent fibrous tissue surrounding the implants of PHEMA. The author concludes that the results for PHEMA were superior to those for silicone at 6 weeks with regard to fibrous encapsulation (p = 0.0312). C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Vacanti, FX (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM fvacanti@partners.org NR 12 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD MAR PY 2004 VL 113 IS 3 BP 949 EP 952 DI 10.1097/01.PRS.0000105643.90120.A4 PG 4 WC Surgery SC Surgery GA 800YL UT WOS:000220063500022 PM 15108887 ER PT J AU Netscher, DT AF Netscher, DT TI Aesthetic outcome of breast implant removal in 85 consecutive patients SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID EXPLANTATION C1 Baylor Coll Med, Div Plast Surg, Houston, TX 77030 USA. Dept Vet Affairs Med Ctr, Plast Surg Serv, Houston, TX USA. RP Netscher, DT (reprint author), 6624 Fannin,Suite 2730, Houston, TX 77030 USA. EM netscher@bcm.tmc.edu NR 7 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD MAR PY 2004 VL 113 IS 3 BP 1057 EP 1059 DI 10.1097/01.PRS.0000105686.02437.74 PG 3 WC Surgery SC Surgery GA 800YL UT WOS:000220063500046 PM 15108906 ER PT J AU Planz, B Tabatabaei, S Kirley, SD Aretz, HT Wang, QF Lin, CW McDougal, WS Marberger, M AF Planz, B Tabatabaei, S Kirley, SD Aretz, HT Wang, QF Lin, CW McDougal, WS Marberger, M TI Studies on the differentiation pathway and growth characteristics of epithelial culture cells of the human prostate SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE culture; epithelium ID NEOPLASTIC HUMAN-PROSTATE; ANDROGEN-RECEPTOR GENE; RAT PROSTATE; EXPLANT CULTURE; STROMAL CELLS; CARCINOMA CELLS; CANCER CELLS; SERUM-FREE; IN-VITRO; MODEL AB We established explant primary cultures in order to study the growth and hormone responsiveness, and the differentiation process of prostatic epithelial cells. Cell outgrowth was achieved from explant tissue by using a new DU145-cell-conditioned medium and special plastic coverslips. To define the present model, proliferation assays were tested by [H-3]thymidine assay and planimetric analysis. Cells were analyzed using immunocytochemistry, light, phase contrast and electron microscopy, polymerase chain reaction, telomerase ELISA and immunoassay (PSA). Morphology and electron microscopy revealed typical epithelial differentiation. Immunocytochemistry showed the content of basal and secretory epithelial cells, endocrine paracrine cells and a high level of proliferation. With increasing culture time, mature epithelial differentiation (PSA) increases and the initial increase of alpha-smooth muscle actin (alpha-SMA) decreases again. After further passaging, alpha-SMA expression is no longer detected and PSA expression decreases. Furthermore, epithelial cells showed both androgen responsiveness and androgen receptor expression. These findings show the presence of epithelial cells in a process of differentiation with endocrine paracrine cells and a high level of proliferation. This model may maintain the cellular and functional properties more closely related to the human prostate and may provide a valuable tool for studying stem cells and differentiation characteristics. C1 Univ Vienna, Dept Urol, Vienna, Austria. Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Reprod Endocrinol, Boston, MA 02114 USA. RP Planz, B (reprint author), Dept Urol, Friedrich Laustr 11, D-40472 Dusseldorf, Germany. EM bplanz@hotmail.com FU NICHD NIH HHS [HD29164] NR 55 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAR PY 2004 VL 7 IS 1 BP 73 EP 83 DI 10.1038/sj.pcan.4500704 PG 11 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 810GL UT WOS:000220692700013 PM 14999242 ER PT J AU Flashman, LA Green, MF AF Flashman, LA Green, MF TI Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID FIRST-EPISODE SCHIZOPHRENIA; TREATMENT-RESISTANT SCHIZOPHRENIA; NEUROLEPTIC-NAIVE PATIENTS; PLACEBO-CONTROLLED TRIAL; CAUDATE NUCLEI VOLUMES; MAGNETIC-RESONANCE; FOLLOW-UP; 1ST-EPISODE SCHIZOPHRENIA; ANTIPSYCHOTIC-DRUGS; PSYCHOTIC-PATIENTS AB Schizophrenia is a serious, chronic mental illness that presents with neurocognitive and neuroanatomic abnormalities. This article briefly reviews the literature on the neurocognitive and neuroanatomic profiles of individuals with schizophrenia and addresses the issue of whether these performance deficits and structural abnormalities are stable across the course of the illness. Finally, the article discusses the effects of psychopharmacology on the neurocognitive deficits seen in patients with schizophrenia, examining the effects of conventional and atypical antipsychotics. C1 Dartmouth Coll Sch Med, Dept Psychiat, Dartmouth Hitchcock Med Ctr, Lebanon, NH 03756 USA. New Hampshire Hosp, Concord, NH 03301 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Flashman, LA (reprint author), Dartmouth Coll Sch Med, Dept Psychiat, Dartmouth Hitchcock Med Ctr, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM flashman@dartmouth.edu NR 128 TC 60 Z9 63 U1 4 U2 12 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD MAR PY 2004 VL 27 IS 1 BP 1 EP + DI 10.1016/S0193-983X(03)00105-9 PG 28 WC Psychiatry SC Psychiatry GA 810OC UT WOS:000220712600002 PM 15062627 ER PT J AU Wynn, JK Dawson, ME Schell, AM AF Wynn, JK Dawson, ME Schell, AM TI The functional relationship between visual backward masking and prepulse inhibition SO PSYCHOPHYSIOLOGY LA English DT Article DE visual backward masking; visual prepulse inhibition; auditory prepulse inhibition; information processing ID WEAK PRE-STIMULATION; STARTLE REFLEX; P50 SUPPRESSION; SCHIZOPHRENIA; DISCRETE; EYEBLINK; ATTENTION; CHANNELS; ONSET; BLINK AB This, experiment demonstrated a relationship between prepulse inhibition (PPI) of the startle eyeblink and visual backward masking in college students. It was hypothesized that recovery from backward masking effects is due in part to sensory gating, as assessed by auditory and visual PPI. Visual presentations of letters served as targets or visual prepulses in an intermixed session of backward masking and PPI. Backward masking and PPI (both auditory and visual) were assessed at stimulus onset asynchronies of 30, 45, 60, 120, and 150 ms. A repeated-measures regression revealed that there was a relationship between backward masking and PPI for both visual and auditory PPI, with higher levels of PPI being associated with greater recovery from backward masking. The data are consistent with the hypothesis that recovery from backward masking effects is affected by sensory gating acting in part to gate out the interruptive effects of the mask. C1 Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. Occidental Coll, Dept Psychol, Los Angeles, CA 90041 USA. RP Wynn, JK (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,MIRECC 210A, Los Angeles, CA 90073 USA. EM jkwynn@ucla.edu RI Wynn, Jonathan/H-3749-2014 OI Wynn, Jonathan/0000-0002-1763-8540 FU NIMH NIH HHS [MH01086, MH46433, MH 14584] NR 28 TC 8 Z9 11 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2004 VL 41 IS 2 BP 306 EP 312 DI 10.1111/j.1469-8986.2004.00153.x PG 7 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 804QI UT WOS:000220312800015 PM 15032996 ER PT J AU Wright, EF Thompson, RL Paunovich, ED AF Wright, EF Thompson, RL Paunovich, ED TI Post-traumatic stress disorder: Considerations for dentistry SO QUINTESSENCE INTERNATIONAL LA English DT Article DE bruxism; occlusal appliance; periodontal ligament inflammation; post-traumatic stress disorder; pulpitis; temporomandibular disorder; temporomandibular joint ID MOTOR-VEHICLE ACCIDENTS; VIETNAM VETERANS; TRAUMATIC EVENTS; PAIN; COMORBIDITY; IMPAIRMENT; PREVALENCE; MANAGEMENT; COMMUNITY; PATTERNS AB A dental patient with post-traumatic stress disorder (PTSD) may present with greater dental and behavioral challenges than most dental patients. The background review of PTSD's initiating factors, diagnostic criteria, and medical management should help practitioners better understand and manage these challenges. Many of the challenges the clinician may encounter and managing recommendations are described. A case report of a PTSD patient complaining of constant bilateral tooth pain of the maxillary and mandibular bicuspids and molars is presented. Recommended techniques for identifying the tooth pain source and contributing factors are provided. The primary contributing factor for the patient's tooth pain was determined to be his severe tooth clenching activity. A maxillary acrylic appliance provided some pain reduction and a subsequent mandibular soft occlusal appliance worn opposing the maxillary appliance provided additional relief. C1 S Texas Vet Hlth Care Syst, Dept Restorat Dent, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, GRECC, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Clin Oral Hlth Program Geriatr & Extended Care, San Antonio, TX 78229 USA. RP Wright, EF (reprint author), S Texas Vet Hlth Care Syst, Dept Restorat Dent, Mail Code 7890,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM wrighte@uthscsa.edu NR 47 TC 8 Z9 8 U1 1 U2 4 PU QUINTESSENCE PUBL CO INC PI CAROL STREAM PA 551 NORTH KIMBERLY DR, CAROL STREAM, IL 60188-1881 USA SN 0033-6572 J9 QUINTESSENCE INT JI Quintessence Int. PD MAR PY 2004 VL 35 IS 3 BP 206 EP 210 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 813CM UT WOS:000220885200007 PM 15119679 ER PT J AU Sharma, A Fidias, P Hayman, LA Loomis, SL Taber, KH Aquino, SL AF Sharma, A Fidias, P Hayman, LA Loomis, SL Taber, KH Aquino, SL TI Patterns of lymphadenopathy in thoracic malignancies SO RADIOGRAPHICS LA English DT Article; Proceedings Paper CT 88th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY DEC 01-06, 2002 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE breast neoplasms, metastases; esophagus, neoplasms; lung neoplasms, metastases; lymphatic system, CT; lymphatic system, neoplasms; lymphoma, staging; mesothelioma; thorax, neoplasms ID CELL LUNG-CANCER; INITIAL STAGING EVALUATION; SENTINEL NODE BIOPSY; BREAST-CANCER; LYMPHATIC DRAINAGE; PLEURAL MESOTHELIOMA; COMPUTED-TOMOGRAPHY; CHEST CT; CARCINOMA; LYMPHOMA AB There are different lymphatic drainage pathways in the thorax that are relevant in the staging of lung cancer, breast cancer, lymphoma, esophageal cancer, and malignant mesothelioma. To properly search for metastatic spread, it is important to carefully evaluate the specific nodal stations that drain the thoracic structures from which a primary tumor originates. Because size criteria have limitations in the prediction of nodal status, pathologic confirmation is essential for accurate staging. Computed tomography (CT) is useful in helping the surgeon or interventional radiologist determine the most appropriate approach for nodal sampling. Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has an increasing role in detection of diseased lymph nodes that appear normal at CT alone, particularly when FDG PET images are fused with CT images. However, the role of radiologic imaging extends beyond initial staging and the guidance of interventions to include posttreatment assessment and the detection of recurrent disease. Therefore, at all levels of cancer imaging, it is essential to identify the relevant lymph node regions and their relations to the primary tumor. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. Baylor Coll Med, Herbert J Frensley Ctr Imaging Res, Houston, TX 77030 USA. RP Sharma, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St,Founders 202, Boston, MA 02114 USA. EM asharma2@partners.org NR 46 TC 57 Z9 69 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAR-APR PY 2004 VL 24 IS 2 BP 419 EP 434 DI 10.1148/rg.242035075 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 802UB UT WOS:000220187300007 PM 15026591 ER PT J AU Harisinghani, MG Blake, MA Saksena, M Hahn, PF Gervais, D Zalis, M Fernandes, LDD Mueller, PR AF Harisinghani, MG Blake, MA Saksena, M Hahn, PF Gervais, D Zalis, M Fernandes, LDD Mueller, PR TI Importance and effects of altered workplace ergonomics in modern radiology suites SO RADIOGRAPHICS LA English DT Article; Proceedings Paper CT 88th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY DEC 01-06, 2002 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE radiology and radiologists, design of radiological facilities; workstation ID ROOM AB The transition from a film-based to a filmless soft-copy picture archiving and communication system (PACS)-based environment has resulted in improved work flow as well as increased productivity, diagnostic accuracy, and job satisfaction. Adapting to this filmless environment in an efficient manner requires seamless integration of various components such as PACS workstations, the Internet and hospital intranet, speech recognition software, paperless electronic hospital medical records, e-mail, office software, and telecommunications. However, the importance of optimizing workplace ergonomics has received little attention. Factors such as the position of the work chair, workstation table., keyboard, mouse, and monitors, along with monitor refresh rates and ambient room lighting, have become secondary considerations. Paying close attention to the basics of workplace ergonomics can go a long way in increasing productivity and reducing fatigue, thus allowing full realization of the potential benefits of a PACS. Optimization of workplace ergonomics should be considered in the basic design of any modern radiology suite. C1 Massachusetts Gen Hosp, Dept Radiol, Div Adominal Imaging & Intervent, Boston, MA 02114 USA. RP Harisinghani, MG (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Adominal Imaging & Intervent, 55 fruit St,White 289, Boston, MA 02114 USA. EM mharisinghani@partners.org NR 6 TC 23 Z9 24 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD MAR-APR PY 2004 VL 24 IS 2 BP 615 EP 627 DI 10.1148/rg.242035089 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 802UB UT WOS:000220187300022 PM 15026606 ER PT J AU Kalra, MK Maher, MM Toth, TL Hamberg, LM Blake, MA Shephard, JA Saini, S AF Kalra, MK Maher, MM Toth, TL Hamberg, LM Blake, MA Shephard, JA Saini, S TI Strategies for CT radiation dose optimization SO RADIOLOGY LA English DT Review DE computed tomography (CT), image quality; computed tomography (CT), multidetector row; computed tomography (CT), radiation exposure; radiations, exposure to patients and personnel; review ID NOISE-REDUCTION FILTERS; SPIRAL COMPUTED-TOMOGRAPHY; TUBE CURRENT MODULATION; HIGH-RESOLUTION CT; IMAGE QUALITY; HELICAL CT; CHEST CT; PEDIATRIC-PATIENTS; ONLINE MODULATION; PARANASAL SINUSES AB Recent technologic advances have markedly enhanced the clinical applications of computed tomography (CT). While the benefits of CT exceed the harmful effects of radiation exposure in patients, increasing radiation doses to the population have raised a compelling case for reduction of radiation exposure from CT. Strategies for radiation dose reduction are difficult to devise, however, because of a lack of guidelines regarding CT examination and scanning techniques. Various methods and strategies based on individual patient attributes and CT technology have been explored for dose optimization. It is the purpose of this review article to outline basic principles of CT radiation exposure and emphasize the need for CT radiation dose optimization based on modification of scanning parameters and application of recent technologic innovations. (C) RSNA, 2004. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Gen Elect Med Syst, Milwaukee, WI USA. RP Saini, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, White 270-E,55 Fruit St, Boston, MA 02114 USA. EM ssaini@partners.org NR 76 TC 469 Z9 529 U1 7 U2 36 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 MAR PY 2004 VL 230 IS 3 BP 619 EP 628 DI 10.1148/radiol.2303021726 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 777PJ UT WOS:000189186500006 PM 14739312 ER PT J AU Stone, ME AF Stone, ME TI Contemporary gay American poets and playwrights: An A-to-Z guide. SO REFERENCE & USER SERVICES QUARTERLY LA English DT Book Review C1 Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp, Treadwell Lib, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER LIBRARY ASSOC PI CHICAGO PA 50 E HURON ST, CHICAGO, IL 60611 USA SN 1094-9054 J9 REF USER SERV Q JI Ref. User Serv. Q. PD SPR PY 2004 VL 43 IS 3 BP 263 EP 264 PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 839TZ UT WOS:000222809100017 ER PT J AU Jafari, B Ouyang, B Li, LF Hales, CA Quinn, DA AF Jafari, B Ouyang, B Li, LF Hales, CA Quinn, DA TI Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like cells SO RESPIROLOGY LA English DT Article DE antioxidants; buthionine sulfoximine; N-acetylcysteine ID RESPIRATORY-DISTRESS-SYNDROME; FACTOR-KAPPA-B; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; HUMAN LUNG-CARCINOMA; SMOOTH-MUSCLE-CELLS; N-ACETYLCYSTEINE; EPITHELIAL-CELLS; INTERLEUKIN-8 PRODUCTION; ENDOTHELIAL-CELLS; KINASE ACTIVATION AB Objective: Ventilator-induced lung injury (VILI) is characterized by release of inflammatory cytokines, but the mechanisms are not well understood. We hypothesized that stretch-induced cytokine production is dependent on oxidant release and is regulated by intracellular glutathione (GSH) inhibition of nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) binding. Methodology: Type 2-like alveolar epithelial cells (A549) were exposed to cyclic stretch at 15% strain for 4 h at 20 cycles/min with or without N-acetylcysteine (NAC) or glutathione monoethylester (GSH-e) to increase intracellular GSH, or buthionine sulfoximine (BSO), to deplete intracellular GSH. Results: Cyclic stretch initially caused a decline in intracellular GSH and a rise in the levels of isoprostane, a marker of oxidant injury. This was followed by a significant increase in intracellular GSH and a decrease in isoprostane. Stretch-induced IL-8 and IL-6 production were significantly inhibited when intracellular GSH was further increased by NAC or GSH-e (P < 0.0001). Stretch-induced IL-8 and IL-6 production were augmented when intracellular GSH was depleted by BSO (P < 0.0001). NAC blocked stretch-induced NF-kappaB and AP-1 binding and inhibited IL-8 mRNA expression. Conclusions: We conclude that oxidant release may play a role in lung cell stretch-induced cytokine release, and antioxidants, which increase intracellular GSH, may protect lung cells against stretch-induced injury. C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Quinn, DA (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM dquinn1@partners.org FU NHLBI NIH HHS [HL 03920, HL 39150] NR 70 TC 49 Z9 59 U1 0 U2 3 PU BLACKWELL PUBLISHING ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 1323-7799 J9 RESPIROLOGY JI Respirology PD MAR PY 2004 VL 9 IS 1 BP 43 EP 53 DI 10.1111/j.1440-1843.2003.00527.x PG 11 WC Respiratory System SC Respiratory System GA 819UX UT WOS:000221342500007 PM 14982601 ER PT J AU Abdolmaleky, HM Faraone, SV Glatt, SJ Tsuang, MT AF Abdolmaleky, HM Faraone, SV Glatt, SJ Tsuang, MT TI Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE meta-analysis; T102C polymorphism; 5HT2a receptor ID FAMILY-BASED ASSOCIATION; 5-HT2A RECEPTOR; 2A RECEPTOR; 102T/C POLYMORPHISM; DNA METHYLATION; NO ASSOCIATION; TARDIVE-DYSKINESIA; SUICIDAL-BEHAVIOR; MSPI POLYMORPHISM; VARIANT 102T/C AB A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI = 0.9-1.8, z = 1.47, p = 0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed. (C) 2003 Published by Elsevier B.V. C1 Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA 02115 USA. Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. Iran Univ Med Sci, Dept Psychiat, Tehran Inst Psychiat, Tehran, Iran. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. Brockton W Roxbury Vet Affairs Med Ctr, Psychiat Serv, Brockton, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Tsuang, MT (reprint author), Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, 74 Fenwood Rd, Boston, MA 02115 USA. EM ming_tsuang@hms.harvard.edu OI Glatt, Stephen/0000-0002-0360-7567; Faraone, Stephen/0000-0002-9217-3982 NR 67 TC 124 Z9 136 U1 4 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2004 VL 67 IS 1 BP 53 EP 62 DI 10.1016/S0920-9964(03)00183-X PG 10 WC Psychiatry SC Psychiatry GA 770PH UT WOS:000188738800006 PM 14741324 ER PT J AU Kee, KS Horan, WP Mintz, J Green, MF AF Kee, KS Horan, WP Mintz, J Green, MF TI Do the siblings of schizophrenia patients demonstrate affect perception deficits? SO SCHIZOPHRENIA RESEARCH LA English DT Article; Proceedings Paper CT 8th International Congress on Schizophrenia Research CY APR 28-MAY 02, 2001 CL WHISTLER, CANADA DE siblings; schizophrenia patients; affect perception deficits ID GENERALIZED POOR PERFORMANCE; FACIAL-AFFECT RECOGNITION; EMOTION RECOGNITION; SOCIAL COGNITION; BEHAVIOR; EXPRESSIONS; COMPETENCE; RISK AB Affect perception deficits have been extensively documented in schizophrenia and are associated with the social dysfunction that is characteristic of this disorder. The two previous studies examined facial affect perception in genetically at-risk samples and yielded mixed results. The current study was designed to provide a rigorous test of affect perception abilities among schizophrenia patients (n=58), their biological siblings without psychosis (n=51), and nonpsychiatric controls (n=49). Participants completed three measures of affect perception, including facial, vocal, and combined modality. Schizophrenia patients performed significantly worse than controls on two of the three affect perception tests as well as a composite index based on all three tests. The performance of the sibling group fell between the patient and control groups on each of the affect perception tests. However, group differences achieved statistical significance only for the composite index with the siblings performing significantly worse than controls and significantly better than the schizophrenia group. These findings demonstrate that subtle deficits in affect perception are detectable in the unaffected siblings of schizophrenia patients when multiple measures of different types of affect perception abilities are used in combination. (C) 2003 Elsevier B.V. All rights reserved. C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA USA. RP Kee, KS (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,MIRECC 210A,Bldg 210,VISN22, Los Angeles, CA 90073 USA. EM kee@ucla.edu FU NIMH NIH HHS [MH43292] NR 44 TC 83 Z9 85 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2004 VL 67 IS 1 BP 87 EP 94 DI 10.1016/S0920-9964(03)00217-2 PG 8 WC Psychiatry SC Psychiatry GA 770PH UT WOS:000188738800010 PM 14741328 ER PT J AU Overdeck, KH Palmer, WE AF Overdeck, KH Palmer, WE TI Imaging of hip and groin injuries in athletes SO SEMINARS IN MUSCULOSKELETAL RADIOLOGY LA English DT Article DE hip; athlete; injuries ID ACETABULAR LABRAL TEARS; MR ARTHROGRAPHY; TROCHANTERIC BURSITIS; LESSER TROCHANTER; SPORTSMANS HERNIA; SKELETAL-MUSCLE; PAIN; FRACTURES; DIAGNOSIS; AVULSION AB Proper function of the hip joint is imperative for athletes who participate in sporting activities that rely on utilization of the lower extremity; these primarily include kicking, running, and jumping activities. Sports-related injuries of the hip and groin are not frequent sources of disability in athletes; however, they may present a significant diagnostic dilemma, both from a clinical and radiological standpoint. Delay in diagnosis and treatment may result in undesired complications, such as premature degenerative disease, as well as time lost from athletic activities. Magnetic resonance (MR) imaging of the hip, particularly following the intra-articular administration of gadolinium, has proven to be extremely valuable in the diagnosis of radiographically occult osseous abnormalities as well as soft-tissue injuries, such as pubalgia, musculotendinous abnormalities, and bursitis. This article will review several pathological conditions of the hip and groin in both recreational and professional athletes, with an emphasis on MR imaging as the modality of choice in the diagnosis of these injuries. C1 Massachusetts Gen Hosp, Dept Bone & Joint Radiol, Boston, MA 02114 USA. RP Overdeck, KH (reprint author), Massachusetts Gen Hosp, Dept Bone & Joint Radiol, 15 Parkman St,WACC 515, Boston, MA 02114 USA. NR 52 TC 20 Z9 20 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1089-7860 J9 SEMIN MUSCULOSKEL R JI Semin. Musculoskelet. Radiol. PD MAR PY 2004 VL 8 IS 1 BP 41 EP 55 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 914QF UT WOS:000228241900006 PM 15085477 ER PT J AU Kesler, KA Wright, CD Loehrer, PJ AF Kesler, KA Wright, CD Loehrer, PJ TI Thymoma: Current medical and surgical management SO SEMINARS IN NEUROLOGY LA English DT Article DE thymoma; myasthenia gravis; surgery; chemotherapy ID MYASTHENIA-GRAVIS; INVASIVE THYMOMA; COMPLETE RESECTION; MALIGNANT THYMOMA; RADIATION-THERAPY; INTERGROUP TRIAL; ADJUVANT RADIATION; THYMIC CARCINOMA; TITIN ANTIBODIES; CLINICAL STAGES AB Thymoma is a rare neoplasm usually with an indolent growth pattern; however, local invasion and/or dissemination may occur. Surgery has been the standard of care for early stage disease with good to excellent cure rates anticipated. This neoplasm has been found to be relatively sensitive to cisplatinum-based chemotherapy as compared with most other epithelial tumors. Aggressive multimodality therapy therefore can result in long-term disease-free survival for patients presenting with locally advanced or even disseminated disease. This chapter outlines the current medical and surgical treatment options for thymoma. C1 Indiana Univ, Sch Med, Thorac Div, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Div Hematol Oncol, Indianapolis, IN 46202 USA. Massachusetts Gen Hosp, Thorac Div, Boston, MA 02114 USA. RP Kesler, KA (reprint author), Indiana Univ, Sch Med, Thorac Div, 545 Barnhill Dr,EH 212, Indianapolis, IN 46202 USA. FU NCI NIH HHS [R 10 CA 28171-04, P 30 CA 82709-04, CA 23318, 2 R 35 CA 39844-08, U 10 CA 21115] NR 64 TC 9 Z9 11 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD MAR PY 2004 VL 24 IS 1 BP 63 EP 73 DI 10.1055/s-2004-829588 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 833AV UT WOS:000222309700009 PM 15229793 ER PT J AU Bruno, A McConnell, JP Cohen, SN Tietjen, GE Wallis, RA Gorelick, PB Bang, NU AF Bruno, A McConnell, JP Cohen, SN Tietjen, GE Wallis, RA Gorelick, PB Bang, NU TI Serial urinary 11-dehydrothromboxane B2, aspirin dose, and vascular events in blacks after recent cerebral infarction SO STROKE LA English DT Article DE aspirin; cerebral infarction; platelets ID ACUTE ISCHEMIC STROKE; DISEASE; B-2; RESISTANCE; TRIAL AB Background and Purpose-Incomplete platelet inhibition by aspirin ( aspirin resistance) may be a reason for stroke recurrence in some patients. 11-Dehydrothromboxane B2 (11-DTB2) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation. This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance. Methods-All subjects were screened for the African American Antiplatelet Stroke Prevention Study (AAASPS) 7 to 90 days after noncardioembolic cerebral infarction. Of 83 subjects with at least 1 urine sample, 52 were enrolled in AAASPS (randomized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d), and 31 were enrolled in an open-label antiplatelet therapy cohort. Subjects were followed up for 2 years, with 11-DTB2 measurements scheduled at baseline and 6, 12, and 24 months. Vascular events were cerebral infarction, myocardial infarction, or vascular death. Results-Despite considerable individual up or down fluctuations, the median 11-DTB2 change did not significantly differ from zero in any of the subgroups. However, in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d, the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine (P=0.06). Vascular events occurred in 7 of 61 aspirin-treated subjects, and 11-DTB2 levels did not correlate with the events. Conclusions-Fluctuations in urinary 11-DTB2 after cerebral infarction in blacks do not correlate with changes in aspirin doses, except perhaps when the dose changes by a factor of 4 or more. A larger study is needed to look further for aspirin resistance. C1 Indiana Univ, Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. Mayo Clin, Rochester, MN USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Med Coll Ohio, Toledo, OH 43699 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Bruno, A (reprint author), Indiana Univ, Sch Med, Dept Neurol, 541 Clin Dr,Room 290C, Indianapolis, IN 46202 USA. EM abruno@iupui.edu NR 12 TC 20 Z9 23 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2004 VL 35 IS 3 BP 727 EP 730 DI 10.1161/01.STR.0000117097.76953.A6 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 778LQ UT WOS:000189243400022 PM 14963281 ER PT J AU Fox, CS Larson, MG Corey, D Feng, DL Lindpaintner, K Polak, JF Wolf, PA D'Agostino, RB Tofler, GH O'Donnell, CJ AF Fox, CS Larson, MG Corey, D Feng, DL Lindpaintner, K Polak, JF Wolf, PA D'Agostino, RB Tofler, GH O'Donnell, CJ TI Absence of association between polymorphisms in the hemostatic factor pathway genes and carotid intimal medial thickness - The Framingham Heart Study SO STROKE LA English DT Article DE coagulation; epidemiology; genetics; risk factors ID DISEASE AB Background and Purpose-Fibrinogen, plasminogen activator inhibitor-1, and other key proteins in the coagulation cascade have been implicated in the origin of cardiovascular disease. Polymorphisms in genes encoding these proteins have been associated with variability in plasma levels of these proteins. Carotid intimal medial thickness (IMT) is a heritable, quantitative measure of atherosclerosis that is predictive of subsequent myocardial infarction and stroke. We sought to test whether carotid IMT is associated with polymorphisms in several well-characterized genes in the hemostatic factor pathways. Methods-Here, 867 men and 911 women (mean age, 57 years) in the Framingham offspring cohort underwent B-mode carotid ultrasonography to determine the mean internal (ICA) and common carotid artery (CCA) IMT. Age-, sex-, and multivariable-adjusted linear regression was used to estimate the association of the following variants with log-transformed CCA and ICA IMT: factor V Leiden, factor VII Arg/Gln, fibrinogen HindIII beta-148, plasminogen activator inhibitor-1 4G/5G, and the glycoprotein IIIa Pl(A2) polymorphism. Results-Mean ICA IMT was 0.58 mm; mean CCA IMT was 0.60 mm. There were no differences in ICA or CCA IMT by genotype for any of the candidate genes in unadjusted, age- or sex-adjusted, and multivariable-adjusted models. Conclusions-There is no evidence for an association between well-studied polymorphisms in the hemostatic factor genes and carotid IMT. Whether other common genetic variants in hemostatic factor genes are associated with subclinical atherosclerosis remains to be determined. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Med Sch, Dept Internal Med, Boston, MA USA. Roche Genet, Basel, Switzerland. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP O'Donnell, CJ (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM chris@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254 NR 15 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2004 VL 35 IS 3 DI 10.1161/01.STR.0000117095.96234.A6 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 778LQ UT WOS:000189243400044 ER PT J AU Livingston, EH Ko, CY AF Livingston, EH Ko, CY TI Socioeconomic characteristics of the population eligible for obesity surgery SO SURGERY LA English DT Article ID BODY-MASS INDEX; CORONARY HEART-DISEASE; SELF-REPORTED HEIGHT; HEALTH-CARE COSTS; UNITED-STATES; ECONOMIC CONSEQUENCES; LIFETIME HEALTH; RELATIVE WEIGHT; US ADULTS; MORTALITY AB Background. Obesity is increasing in the American population in epidemic proportions. Weight reduction surgery results in sustained weight loss for morbidly obese individuals-a group of patients refractory to nonsurgical obesity treatment. Surgical indications were outlined in a National Institutes Of Health (NIH) consensus, conference published in 1991. Using the NIH criteria, we compared the socioeconomic characteristics of the population eligible for these operations to those receiving them. Methods. The 2000 National Health Interview Survey database was examined to identify how many individuals in the American population were eligible for obesity operations. Socioeconomic characteristics for those individuals were then assessed. The Healthcare Cost and Utility Project and National Hospital Discharge Survey databases were queried to determine how many gastric bypass operations were performed and what the patient's socioeconomic characteristics were. Results. There are 5,324,123 people, or 2.8% of the American population, who are eligible for obesity surgery. Of these, a disproportionate number were black, poorly educated, or impoverished, and 38% rely on Medicare or Medicaid for their health insurance. Of the 28,590 gastric bypass operations performed in 2000, only 13% of patients used Medicare or Medicaid to pay for the operation. Fewer than expected operations were performed on blacks. Regional differences were observed with disproportionately more operations performed in the Northeast and fewer in the Midwest than would be predicted from the surgery-eligible population living in these regions. Conclusions. A significant fraction of the American population could potentially benefit from obesity surgery. However, many of those individuals are black, poorly educated, and impoverished. Public assistance programs need to account for these patients. Centers performing bariatric operations need to accommodate the educational and financial constraints these patients have when planning long-term postoperative care. C1 Univ Texas, SW Med Ctr, Div Gastrointestinal & Endocrine Surg, Dallas, TX USA. VA N Texas Hlth Care Syst, Dallas, TX USA. VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Livingston, EH (reprint author), Univ Texas, SW Med Ctr, Div Gastrointestinal & Endocrine Surg, 5323 Harry Hines Blvd,Room E7-126, Dallas, TX USA. NR 45 TC 69 Z9 69 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAR PY 2004 VL 135 IS 3 BP 288 EP 296 DI 10.1016/j.surg.2003.07.008 PG 9 WC Surgery SC Surgery GA 779QE UT WOS:000189310900008 PM 14976479 ER PT J AU Tsao, D Tootell, R AF Tsao, D Tootell, R TI Response to Tyler: Representation of stereoscopic structure in human and monkey cortex SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material ID VISUAL-CORTEX; SELECTIVITY; MECHANISMS; AREAS; 3D C1 Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, NMR Ctr, Athinoula A Martinos Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Tsao, D (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. EM doris@nmr.mgh.harvard.edu NR 10 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD MAR PY 2004 VL 27 IS 3 BP 118 EP 120 DI 10.1016/j.tins.2003.12.010 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 804VR UT WOS:000220326700004 ER PT J AU Freedland, SJ Presti, JC Kane, CJ Aronson, WJ Terris, MK Dorey, F Amling, CL AF Freedland, SJ Presti, JC Kane, CJ Aronson, WJ Terris, MK Dorey, F Amling, CL CA Search Database Study Grp TI Do younger men have better biochemical outcomes after radical prostatectomy? SO UROLOGY LA English DT Article ID EXTERNAL-BEAM RADIATION; OF-DEFENSE CENTER; SEXTANT BIOPSIES; CANCER INCIDENCE; DISEASE RESEARCH; SEARCH DATABASE; FREE SURVIVAL; ANTIGEN; RECURRENCE; TRENDS AB Objectives. To examine the relationship between age and biochemical failure after radical prostatectomy (RP), controlling for the year of surgery. Prior studies have suggested that younger men have lower prostate-specific antigen recurrence rates after RP, although none of the prior studies had controlled for the year of surgery. Methods. We examined the data from 1753 men treated with RP between 1988 and 2002 at five equal access medical centers. We compared age, as a categorical variable according to decade of life (50 years old or younger, 51 to 60, 61 to 70, and older than 70 years), with the clinical and pathologic variables at RP, as well as the time to biochemical recurrence, using a multivariate Cox proportional hazards model. Results. Age was significantly related to the year of surgery, with the more recently treated patients being younger than less recently treated patients (P <0.001). After controlling for the year of surgery, the younger men had smaller prostates, fewer high-grade tumors on biopsy, and less lymph node metastasis, but a greater percentage of cores with cancer. On multivariate analysis, men 50 years old or younger had significantly lower recurrence rates than did the older men. Moreover, men older than 70 years had significantly greater prostate-specific antigen failure rates than men aged 51 to 70 years or men aged 50 years or younger. Conclusions. The average age of men undergoing RP has decreased with time. Independent of this, young men have more favorable outcomes after RP than older men. Continued screening to detect prostate cancer among younger men when it is most curable appears warranted. C1 Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21287 USA. Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA 94304 USA. Vet Affairs Med Ctr, Dept Surg, Urol Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Sch Med, Dept Urol, San Francisco, CA 94143 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Biostat, Los Angeles, CA USA. Med Coll Georgia, Div Urol, Augusta, GA 30912 USA. San Diego Naval Hosp, Dept Urol, San Diego, CA USA. RP Freedland, SJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Urol, 600 N Wolfe St, Baltimore, MD 21287 USA. OI Terris, Martha/0000-0002-3843-7270 NR 26 TC 39 Z9 45 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD MAR PY 2004 VL 63 IS 3 BP 518 EP 522 DI 10.1016/j.urology.2003.10.045 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 803HZ UT WOS:000220223500020 PM 15028449 ER PT J AU Dodel, RC Haacke, C Zamzow, K Pawelzik, S Spottke, A Rethfeldt, M Siebert, U Oertel, WH Schoffski, O Back, T AF Dodel, RC Haacke, C Zamzow, K Pawelzik, S Spottke, A Rethfeldt, M Siebert, U Oertel, WH Schoffski, O Back, T TI Resource utilization and costs of stroke unit care in Germany SO VALUE IN HEALTH LA English DT Article DE cost; health-care utilization; stroke; stroke unit; TIA ID TRANSIENT ISCHEMIC ATTACKS; QUALITY-OF-LIFE; GOTEBORG 70+ STROKE; CEREBROVASCULAR EVENTS; ELDERLY PATIENTS; INPATIENT COSTS; DATA-BANK; 1ST YEAR; PERSPECTIVE; CONTINUUM AB Objectives: Stroke imposes a considerable economic burden on the individual and society. Recently, the concept of an integrated stroke unit has been established in several countries to improve the outcome of patients. This study evaluates the costs of acute care of the different cerebrovascular insults in a stroke unit. Methods: The study population included 340 patients who were consecutively admitted to the Department of Neurology, Philipps University Marburg, with the diagnosis of stroke or transient ischemic attack (TIA) between January 1 and June 30, 2000. Clinical status and course were evaluated by using the Barthel index and the modified Rankin scale. Employing a "bottom-up" approach, we calculated the costs from the perspective of the hospital and the third-party payer using data from provider departments and other published sources. Results: Inpatient costs were 3020 (US$3290) for TIA, 3480 (US$3790) for ischemic stroke (IS), and 5080 (US-$5540) for intracerebral hemorrhage (ICH) and differed significantly among these subgroups (P < .05). Patient subgroups ranked in the same order for average length of stay at 9.4 days for TIA, 10.2 days for IS, and 11.9 days for ICH (P > .05). Approximately 30% of the hospital costs are due to physician charges and care. Imaging amounted to 10% and lab investigations to 14% of total costs, independent of the diagnosis. Postacute treatment, including inpatient rehabilitation, cost 9880 per patient. Across all diagnostic groups, a mean clinical improvement was observed at time of discharge. Conclusions: Care of patients with cerebrovascular events in a stroke unit causes a high demand of resources and has a considerable impact on health-care expenditure. Therefore, investigations comparing the stroke unit concept with other strategies in stroke care are necessary to evaluate the stroke unit concept for a rational use of available resources in patients with cerebrovascular events. C1 Univ Bonn, Dept Neurol, D-53105 Bonn, Germany. Univ Marburg, Dept Neurol, Marburg, Germany. Univ Marburg, Inst Med Biometry & Epidemiol, Marburg, Germany. Harvard Univ, Sch Publ Hlth, Ctr Risk Anal, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. Univ Erlangen Nurnberg, Chair Hlth Management, Erlangen, Germany. RP Dodel, RC (reprint author), Univ Bonn, Dept Neurol, Sigmund Freud Str 25, D-53105 Bonn, Germany. EM richard.dodel@ukb.uni-bonn.de NR 38 TC 40 Z9 40 U1 4 U2 8 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD MAR-APR PY 2004 VL 7 IS 2 BP 144 EP 152 DI 10.1111/j.1524-4733.2004.72314.x PG 9 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 802PB UT WOS:000220174300005 PM 15164804 ER PT J AU Kuwaki, K Knosalla, C Moran, K Alt, A Katopodis, AG Duthaler, RO Schuurman, HJ Awwad, M Cooper, DKC AF Kuwaki, K Knosalla, C Moran, K Alt, A Katopodis, AG Duthaler, RO Schuurman, HJ Awwad, M Cooper, DKC TI Reduction of anti-Gal alpha 1,3Gal antibodies by infusion of types 2 and 6 gal trisaccharides conjugated to poly-L-lysine SO XENOTRANSPLANTATION LA English DT Article DE anti-Gal antibodies; baboons; Gal alpha 1,3Gal; poly-L-lysine; soluble Gal-conjugates ID IMMUNOAFFINITY COLUMN; INTRAVENOUS-INFUSION; HYPERACUTE REJECTION; NATURAL ANTIBODIES; SERUM CYTOTOXICITY; NONHUMAN PRIMATE; IN-VIVO; BABOONS; OLIGOSACCHARIDES; IMMUNOADSORPTION AB To investigate the specificity of anti-Galalpha1,3Gal (Gal) antibodies (Abs) with respect to Gal oligosaccharides of types 2 and 6, eight baboons received an intravenous infusion of either a poly-L-lysine conjugate of Gal type 2 (n = 5) or type 6 (n = 3), followed 48 h later by the alternative Gal type 6 or 2 conjugate, respectively. IgM Abs reactive to Gal type 2 were depleted by 80 to 89% by either Gal conjugate. IgM reactive to Gal type 6 was less efficiently depleted by the Gal type 2 conjugate (57% depletion) than the Gal type 6 (82% depletion). Gal-reactive IgG was depleted more slowly and less efficiently by either glycoconjugate (initially by only 28 to 54%). Our results indicate that the Gal type 6 conjugate depletes most anti-Gal IgM, but the Gal type 2 conjugate is less efficient in depleting anti-Gal IgM reactive with type 6. There remain small fractions of antibody that are unadsorbed, particularly of IgG, probably due to their low affinity and distribution in both the intra- and extra-vascular compartments. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Immerge BioTherapeut Inc, Cambridge, MA USA. Novartis Pharma AG, Basel, Switzerland. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.cooper@tbrc.mgh.harvard.edu FU NIAID NIH HHS [1P01 AI45897] NR 19 TC 15 Z9 16 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD MAR PY 2004 VL 11 IS 2 BP 210 EP 215 DI 10.1046/j.1399-3089.2003.00096.x PG 6 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 774PR UT WOS:000188992300012 PM 14962283 ER PT J AU Lui, KJ Zhou, XH AF Lui, KJ Zhou, XH TI Testing non-inferiority (and equivalence) between two diagnostic procedures in paired-sample ordinal data SO STATISTICS IN MEDICINE LA English DT Article DE non-inferiority; equivalence; ordinal scale; sensitivity; specificity; paired-sample data ID SIZE DETERMINATION; MATCHED-PAIRS; NONINFERIORITY; BIOEQUIVALENCE AB Before adopting a new diagnostic procedure, which is more convenient and less expensive than the standard existing procedure, it is essentially important to assess whether the diagnostic accuracy of the new procedure is non-inferior (or equivalent) to that of the standard procedure. In this paper, we consider the situation where test responses are on an ordinal scale with more than two categories. We give two definitions of non-inferiority, one in terms of the probability of correctly identifying the case for a randomly selected pair of a case and a non-case over all possible cut-off points, and the other in terms of both the sensitivity and specificity directly. On the basis of large sample theory, we develop two simple test procedures for detecting non-inferiority. We further conduct Monte Carlo simulation to evaluate the finite sample performance of these test procedures. We note that the two asymptotic test procedures proposed here can actually perform reasonably well in a variety of situations even when the numbers of studied subjects from the diseased and non-diseased populations are not large. To illustrate the use of the proposed test procedures, we include an example of determining whether the diagnostic accuracy of using a digitized film is non-inferior to that of using a plain film for screening breast cancer. Finally, we note that the extension of these results to accommodate the case of detecting (two-sided) equivalence is simply straightforward. Copyright (C) 2004 John Wiley Sons, Ltd. C1 San Diego State Univ, Coll Sci, Dept Math & Stat, San Diego, CA 92182 USA. Univ Washington, Hlth Serv Res & Dev Ctr Excellence, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Biostat, Seattle, WA 98108 USA. RP Lui, KJ (reprint author), San Diego State Univ, Coll Sci, Dept Math & Stat, San Diego, CA 92182 USA. EM kjl@rohan.sdsu.edu NR 23 TC 7 Z9 7 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2004 VL 23 IS 4 BP 545 EP 559 DI 10.1002/dim.1607 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 770NY UT WOS:000188737900002 PM 14755388 ER PT J AU Mehle, A Strack, B Ancuta, P Zhang, CS McPike, M Gabuzda, D AF Mehle, A Strack, B Ancuta, P Zhang, CS McPike, M Gabuzda, D TI Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 VIF; REVERSE TRANSCRIPTION; ENZYME APOBEC3G; SOR GENE; PROTEIN; DNA; HYPERMUTATION; STABILITY; COMPLEX AB Viruses must overcome diverse intracellular defense mechanisms to establish infection. The Vif (virion infectivity factor) protein of human immunodeficiency virus 1 (HIV-1) acts by overcoming the antiviral activity of APOBEC3G (CEM15), a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. In the absence of Vif, APOBEC3G incorporation into virions renders HIV-1 non-infectious. We report here that Vif counteracts the antiviral activity of APOBEC3G by targeting it for destruction by the ubiquitin-proteasome pathway. Vif forms a complex with APOBEC3G and enhances APOBEC3G ubiquitination, resulting in reduced steady-state APOBEC3G levels and a decrease in protein half-life. Furthermore, Vif-dependent degradation of APOBEC3G is blocked by proteasome inhibitors or ubiquitin mutant K48R. A mutation of highly conserved cysteines or the deletion of a conserved SLQ(Y/F)LA motif in Vif results in mutants that fail to induce APOBEC3G degradation and produce non-infectious HIV-1; however, mutations of conserved phosphorylation sites in Vif that impair viral replication do not affect APOBEC3G degradation, suggesting that Vif is important for other functions in addition to inducing proteasomal degradation of APOBEC3G. Vif is mon-oubiquitinated in the absence of APOBEC3G but is poly-ubiquitinated and rapidly degraded when APOBEC3G is coexpressed, suggesting that coexpression accelerates the degradation of both proteins. These results suggest that Vif functions by targeting APOBEC3G for degradation via the ubiquitin-proteasome pathway and implicate the proteasome as a site of dynamic interplay between microbial and cellular defenses. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, JF816,44 Binney St, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu FU NIAID NIH HHS [AI28691, AI36186] NR 39 TC 315 Z9 331 U1 0 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 27 PY 2004 VL 279 IS 9 BP 7792 EP 7798 DI 10.1074/jbc.M313093200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776EG UT WOS:000189103300053 PM 14672928 ER PT J AU Hewison, M Zehnder, D Chakraverty, R Adams, JS AF Hewison, M Zehnder, D Chakraverty, R Adams, JS TI Vitamin D and barrier function: a novel role for extra-renal 1 alpha-hydroxylase SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 4th Workshop on Molecular Steroidogenesis CY APR 24-27, 2003 CL Bath, ENGLAND SP Serono Fdn Advancement Med Sci DE vitamin D; 1 alpha-hydroxylase; extra-renal; macrophage; dendritic cell; epithelial cell ID TOLL-LIKE RECEPTORS; PROTEIN-KINASE-C; 25-HYDROXYVITAMIN D-3-1-ALPHA-HYDROXYLASE; 1,25-DIHYDROXYVITAMIN D-3; ALVEOLAR MACROPHAGES; ABNORMAL REGULATION; PROSTATE-CANCER; GENE-EXPRESSION; BREAST-CANCER; D METABOLITES AB Much recent attention has focused on the positive health benefits of vitamin D beyond its established role in calcium homeostasis. Epidetmology has highlighted the link between vitamin D deficiency and prevalent diseases such as common cancers and autoimmune disease. Furthermore, studies in vitro have shown that the active form of vitamin D, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is a potent antiproliferative and itnmunosuppressive agent. The net effect of this has been the generation and analysis of synthetic analogues of vitamin D for potential use in the treatment of cancers and other disorders including psoriasis. However, there is increasing interest in the impact that vitamin D may have on normal physiology above and beyond its classical effects on calcium homeostasis and bone metabolism. We have postulated that these `non-calcetnic' effects of vitamin D are dependent on extra-renal synthesis of 1,25(OH)2D3 via the enzyme la-hydroxylase at barrier sites throughout the body. Here we present a review of the mechanisms associated with extra-renal 1 a-hydroxylase, and we also speculate on how this `new' physiological role for vitamin D may actually reflect an ancient function for this pluripotent secosteroid. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Univ Birmingham, Queen Elizabeth Hosp, Inst Clin Res, Div Med Sci, Birmingham B15 2TH, W Midlands, England. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Biol Res Ctr,Bone Marrow Transplantat, Boston, MA 02129 USA. Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. RP Hewison, M (reprint author), Univ Birmingham, Queen Elizabeth Hosp, Inst Clin Res, Div Med Sci, Birmingham B15 2TH, W Midlands, England. EM m.hewison@bham.ac.uk RI Zehnder, Daniel/B-2519-2010; Adams, John/I-3365-2013 OI Adams, John/0000-0001-9607-5020 NR 68 TC 119 Z9 123 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 27 PY 2004 VL 215 IS 1-2 BP 31 EP 38 DI 10.1016/j.mce.2003.11.017 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 806FF UT WOS:000220419100005 PM 15026172 ER PT J AU Tewari, M Hu, PJ Ahn, JS Ayivi-Guedehoussou, N Vidalain, PO Li, SM Milstein, S Armstrong, CM Boxem, M Butler, MD Busiguina, S Rual, JF Ibarrola, N Chaklos, ST Bertin, N Vaglio, P Edgley, ML King, KV Albert, PS Vandenhaute, J Pandey, A Riddle, DL Ruvkun, G Vidal, M AF Tewari, M Hu, PJ Ahn, JS Ayivi-Guedehoussou, N Vidalain, PO Li, SM Milstein, S Armstrong, CM Boxem, M Butler, MD Busiguina, S Rual, JF Ibarrola, N Chaklos, ST Bertin, N Vaglio, P Edgley, ML King, KV Albert, PS Vandenhaute, J Pandey, A Riddle, DL Ruvkun, G Vidal, M TI Systematic interactome mapping and genetic perturbation analysis of a C-elegans TGF-beta signaling network SO MOLECULAR CELL LA English DT Article ID FUNCTIONAL GENOMIC ANALYSIS; DAUER LARVA DEVELOPMENT; CAENORHABDITIS-ELEGANS; TETRATRICOPEPTIDE REPEAT; CHEMOSENSORY NEURONS; PROTEIN-KINASE; SMAD PROTEINS; SKI; RECEPTOR; ENCODES AB To initiate a system-level analysis of C. elegans DAF-7/TGF-beta signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-beta pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-beta pathway mutant animals, identified nine DAF-7/TGF-beta signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-beta signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-beta signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules. C1 Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. CSIC, Inst Cajal, Neuroendocrinol Lab, E-28002 Madrid, Spain. Fac Notre Dame Paix, Unite Rech & Biol Mol, B-5000 Namur, Belgium. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. Univ Missouri, Program Mol Biol, Columbia, MO 65211 USA. Midwest Res Inst, Kansas City, MO 64110 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Bertin, Nicolas/C-3025-2008; Pandey, Akhilesh/B-4127-2009; Boxem, Mike/B-8857-2011 OI Bertin, Nicolas/0000-0002-9835-9606; Pandey, Akhilesh/0000-0001-9943-6127; Boxem, Mike/0000-0003-3966-4173 FU NCI NIH HHS [7R33CA]; NHGRI NIH HHS [5R01HG01715-02]; NIA NIH HHS [K08-AG21613]; NIDDK NIH HHS [K08-DK62884]; NIGMS NIH HHS [GM60151] NR 69 TC 81 Z9 109 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 27 PY 2004 VL 13 IS 4 BP 469 EP 482 DI 10.1016/S1097-2765(04)00033-4 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800AG UT WOS:000220000700006 PM 14992718 ER PT J AU Hughes, CM Rozenblatt-Rosen, O Milne, TA Copeland, TD Levine, SS Lee, JC Hayes, DN Shanmugam, KS Bhattacharjee, A Biondi, CA Kay, GF Hayward, NK Hess, JL Meyerson, M AF Hughes, CM Rozenblatt-Rosen, O Milne, TA Copeland, TD Levine, SS Lee, JC Hayes, DN Shanmugam, KS Bhattacharjee, A Biondi, CA Kay, GF Hayward, NK Hess, JL Meyerson, M TI Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus SO MOLECULAR CELL LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-1; JUND-ACTIVATED TRANSCRIPTION; ELEGANS DOSAGE COMPENSATION; H3 LYSINE-4 METHYLATION; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-TRITHORAX; NUCLEAR-PROTEIN; ACUTE LEUKEMIAS; GENE AB The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. NCI, Basic Res Labs, Frederick, MD 21702 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. Queensland Inst Med Res, Herston, Qld 4006, Australia. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu RI Kay, Graham/A-4130-2011; Meyerson, Matthew/E-7123-2012; hayward, nicholas/C-1367-2015; Milne, Tom/E-1872-2016; OI hayward, nicholas/0000-0003-4760-1033; Milne, Tom/0000-0002-0413-4271; Hayes, D. Neil/0000-0001-6203-7771 FU NCI NIH HHS [CA92251, CA78815] NR 62 TC 371 Z9 387 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 27 PY 2004 VL 13 IS 4 BP 587 EP 597 DI 10.1016/S1097-2765(04)00081-4 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 800AG UT WOS:000220000700015 PM 14992727 ER PT J AU Kulkarni, RN Kahn, CR AF Kulkarni, RN Kahn, CR TI Molecular biology - HNFs - Linking the liver and pancreatic islets in diabetes SO SCIENCE LA English DT Editorial Material ID INSULIN-RECEPTOR SUBSTRATE-1; BETA-CELL GROWTH; PHOSPHATIDYLINOSITOL 3-KINASE; TRANSCRIPTION; HEPATOCYTES; MECHANISMS; SURVIVAL; DELETION; STORES; LEADS C1 Joslin Diabet Ctr, Dept Cell & Mol Physiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Kulkarni, RN (reprint author), Joslin Diabet Ctr, Dept Cell & Mol Physiol, Boston, MA 02215 USA. EM rohit.kulkarni@joslin.harvard.edu NR 27 TC 22 Z9 24 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 27 PY 2004 VL 303 IS 5662 BP 1311 EP 1312 DI 10.1126/science.1095486 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778JN UT WOS:000189238600030 PM 14988544 ER PT J AU Hettiaratchy, S Melendy, E Randolph, MA Coburn, RC Neville, DM Sachs, DH Huang, CA Lee, WPA AF Hettiaratchy, S Melendy, E Randolph, MA Coburn, RC Neville, DM Sachs, DH Huang, CA Lee, WPA TI Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine SO TRANSPLANTATION LA English DT Article ID LARGE-ANIMAL-MODEL; TRANSPLANTATION TOLERANCE; MIXED CHIMERISM; INDUCTION; SKIN; REGIMEN AB Background. Tolerance to composite tissue allografts might allow the widespread clinical use of reconstructive allotransplantation if protocols to achieve this could be rendered sufficiently nontoxic. The authors investigated whether tolerance could be generated in miniature swine to composite tissue allografts across a major histocompatibility (MHC) barrier. A clinically relevant tolerance protocol involving hematopoietic cell transplantation without the need for irradiation or myelosuppressive drugs was tested. Methods. Seven recipient animals were transiently T-cell depleted and a short course of cyclosporine was initiated. Twenty-four hours later, a donor hematopoietic cell transplant consisting of cytokine-mobilized peripheral blood mononuclear cells or bone marrow cells and a heterotopic limb transplant were performed. In vitro anti-donor responsiveness was assessed by mixed-lymphocyte reaction and cell-mediated lympholysis assays. Acceptance of the limb allografts was determined by gross and histologic appearance. Chimerism in the peripheral blood and lymphohematopoietic organs was assessed by flow cytometry. Results. All seven experimental animals accepted the musculoskeletal elements but rejected the skin of the allografts. All but one of the animals displayed donor-specific unresponsiveness in vitro. The animals that received cytokine mobilized-peripheral blood mononuclear cells showed chimerism but had clinical evidence of graft-versus-host disease (GVHD). None of the animals that received bone marrow cells showed stable chimerism and none developed GVHD. Conclusions. This protocol can achieve tolerance to the musculoskeletal elements of composite tissue allografts across an MHC barrier in miniature swine. Stable chimerism does not appear to be necessary for tolerance and may not be desirable because of the risk of GVHD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hettiaratchy, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, WACC-453,Fruit St, Boston, MA 02114 USA. EM shehan_h@hotmail.com NR 21 TC 75 Z9 79 U1 0 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 FEB 27 PY 2004 VL 77 IS 4 BP 514 EP 521 DI 10.1097/01.TP.0000113806.52063.42 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 779QL UT WOS:000189311600008 PM 15084927 ER PT J AU Houser, SL Benjamin, LC Wain, JC Madsen, JC Allan, JS AF Houser, SL Benjamin, LC Wain, JC Madsen, JC Allan, JS TI Constitutive expression of major histocompatibility complex class II antigens in pulmonary epithelium and endothelium varies among different species SO TRANSPLANTATION LA English DT Article ID ALLOGRAFT-REJECTION; MINIATURE SWINE AB We have observed high constitutive levels of class II antigen expression on porcine and human coronary endothelium, but not on the endothelium of rats and mice. This study examines whether a similar interspecies difference exists in the expression of class II molecules on pulmonary epithelium and endothelium. Lung tissues from naive human, porcine, and rodent sources were stained with the monoclonal antibody ISCR3 and examined by light microscopy. Immunoperoxidase staining of class II molecules was observed on human and porcine pulmonary epithelium and endothelium, but was absent in rats and mice. By using an antibody with cross-species reactivity, we demonstrated that naive swine pulmonary epithelium and endothelium, unlike those of rodent species, express basal levels of class II antigens in a manner similar to that observed in human lung tissue. These interspecies differences may explain experimental differences observed between murine and large-animal constructs. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Cardiac Surg, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Allan, JS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM jallan@partners.org FU NHLBI NIH HHS [R01 HL67110] NR 11 TC 10 Z9 12 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 FEB 27 PY 2004 VL 77 IS 4 BP 605 EP 607 DI 10.1097/01.TP.0000114285.63313.E7 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 779QL UT WOS:000189311600025 PM 15084944 ER PT J AU Stein, CJ Colditz, GA AF Stein, CJ Colditz, GA TI Modifiable risk factors for cancer SO BRITISH JOURNAL OF CANCER LA English DT Review DE prevention; tobacco; physical activity; obesity; diet; screening ID PHYSICAL-ACTIVITY; COLON-CANCER; BREAST-CANCER; LUNG-CANCER; US ADULTS; CONTROLLED TRIAL; BETA-CAROTENE; FOLATE INTAKE; MORTALITY; PREVENTION AB Over 6 million people around the world die from cancer each year. Modifiable risk factors have been linked to a wide range of malignancies, including cancer's of the oropharynx, oesophagus, larynx, lung, kidney, bladder, pancreas, skin, stomach, ovary, breast, cervix, uterus, prostate, and colon. Research indicates that over half of all cancers in developed countries could be prevented if we implemented population-wide measures to promote the following behaviours: reduce tobacco use, increase physical activity, control weight, improve diet, limit alcohol, utilise safer sex practices, get routine cancer screening tests, and avoid excess sun exposure. C1 Harvard Ctr Canc Prevent, Boston, MA 02115 USA. Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Stein, CJ (reprint author), Harvard Ctr Canc Prevent, 181 Longwood Ave, Boston, MA 02115 USA. EM cynthia.stein@post.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 NR 41 TC 82 Z9 83 U1 1 U2 7 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 FEB 26 PY 2004 VL 90 IS 2 BP 299 EP 303 DI 10.1038/sj.bjc.6601509 PG 5 WC Oncology SC Oncology GA 774XA UT WOS:000189010600004 PM 14735167 ER PT J AU Stremlau, M Owens, CM Perron, MJ Kiessling, M Autissier, P Sodroski, J AF Stremlau, M Owens, CM Perron, MJ Kiessling, M Autissier, P Sodroski, J TI The cytoplasmic body component TRIM5 alpha restricts HIV-1 infection in Old World monkeys SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROMYELOCYTIC LEUKEMIA PROTEIN; SIMIAN CELLS; REVERSE TRANSCRIPTION; VIRAL REPLICATION; MOTIF PROTEIN; RING FINGER; ENTRY; RECRUITMENT; COMPLEXES AB Host cell barriers to the early phase of immunodeficiency virus replication explain the current distribution of these viruses among human and non-human primate species(1-4). Human immunodeficiency virus type 1 (HIV-1), the cause of acquired immunodeficiency syndrome ( AIDS) in humans, efficiently enters the cells of Old World monkeys but encounters a block before reverse transcription(2-4). This species-specific restriction acts on the incoming HIV-1 capsid(5-7) and is mediated by a dominant repressive factor(7-9). Here we identify TRIM5alpha, a component of cytoplasmic bodies, as the blocking factor. HIV-1 infection is restricted more efficiently by rhesus monkey TRIM5alpha than by human TRIM5alpha. The simian immunodeficiency virus, which naturally infects Old World monkeys(10), is less susceptible to the TRIM5alpha-mediated block than is HIV-1, and this difference in susceptibility is due to the viral capsid. The early block to HIV-1 infection in monkey cells is relieved by interference with TRIM5alpha expression. Our studies identify TRIM5alpha as a species-specific mediator of innate cellular resistance to HIV-1 and reveal host cell components that modulate the uncoating of a retroviral capsid. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dept Pathol, Div Aids, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Div Aids, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dept Pathol, Div Aids, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu NR 30 TC 1121 Z9 1171 U1 0 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 26 PY 2004 VL 427 IS 6977 BP 848 EP 853 DI 10.1038/nature02343 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777WU UT WOS:000189207500042 PM 14985764 ER PT J AU Sands, BE Anderson, FH Bernstein, CN Chey, WY Feagan, BG Fedorak, RN Kamm, MA Korzenik, JR Lashner, BA Onken, JE Rachmilewitz, D Rutgeerts, P Wild, G Wolf, DC Marsters, PA Travers, SB Blank, MA van Deventer, SJ AF Sands, BE Anderson, FH Bernstein, CN Chey, WY Feagan, BG Fedorak, RN Kamm, MA Korzenik, JR Lashner, BA Onken, JE Rachmilewitz, D Rutgeerts, P Wild, G Wolf, DC Marsters, PA Travers, SB Blank, MA van Deventer, SJ TI Infliximab maintenance therapy for fistulizing Crohn's disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LONG-TERM; FISTULAS; 6-MERCAPTOPURINE; METRONIDAZOLE; LYMPHOMA; EFFICACY; TRIAL AB BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Vancouver Hosp, Dept Med, Vancouver, BC, Canada. Univ Manitoba, Hlth Sci Ctr, Gastroenterol Sect, Winnipeg, MB, Canada. Rochester Inst Digest Dis & Sci, Rochester, NY USA. Univ Western Ontario, Robarts Res Inst, London, ON, Canada. Univ Alberta, Div Gastroenterol, Edmonton, AB, Canada. St Marks Hosp, Physiol Unit, London EC1V 2PS, England. Washington Univ, Sch Med, Div Gastroenterol, St Louis, MO USA. Cleveland Clin Fdn, Dept Gastroenterol, Ctr Inflammatory Bowel Dis, Cleveland, OH 44195 USA. Duke Univ, Med Ctr, Dept Gastroenterol, Durham, NC USA. Tel Aviv Sourasky Med Ctr, Div Med, Tel Aviv, Israel. Univ Hosp Leuven, Div Gastroenterol, Louvain, Belgium. Montreal Gen Hosp, Div Gastroenterol, Montreal, PQ H3G 1A4, Canada. Altanta Gastroenterol Associates, Atlanta, GA USA. Centocor Inc, Malvern, PA 19355 USA. Univ Amsterdam, Acad Med Ctr, Afdeling Gastroenterol, NL-1105 AZ Amsterdam, Netherlands. RP Sands, BE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ 7, Boston, MA 02114 USA. RI Feagan, Brian/M-4283-2015; OI Fedorak, Richard/0000-0002-7382-0080 FU NIDDK NIH HHS [K23 DK002850] NR 22 TC 1008 Z9 1074 U1 2 U2 21 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 26 PY 2004 VL 350 IS 9 BP 876 EP 885 DI 10.1056/NEJMoa030815 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 777UM UT WOS:000189197300006 PM 14985485 ER PT J AU Swartz, MN AF Swartz, MN TI Cellulitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SOFT-TISSUE INFECTIONS; RESISTANT STAPHYLOCOCCUS-AUREUS; SKIN-STRUCTURE INFECTIONS; THREATENING FOOT INFECTIONS; STREPTOCOCCAL CELLULITIS; NECROTIZING FASCIITIS; CUTANEOUS CELLULITIS; COST-EFFECTIVENESS; NEEDLE ASPIRATION; DIABETIC-PATIENTS C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Jackson Firm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Swartz, MN (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM mswartz@partners.org NR 50 TC 147 Z9 152 U1 1 U2 13 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 26 PY 2004 VL 350 IS 9 BP 904 EP 912 DI 10.1056/NEJMcp031807 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 777UM UT WOS:000189197300009 PM 14985488 ER PT J AU Tsao, H Sober, AJ Niendorf, KB Zembowicz, A AF Tsao, H Sober, AJ Niendorf, KB Zembowicz, A TI Case 6-2004: A 48-year-old woman with multiple pigmented lesions and a personal and family history of melanoma - Hereditary melanoma with a deleterious CDKN2A mutation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MELANOCORTIN-1 RECEPTOR MC1R; CUTANEOUS MELANOMA; XERODERMA-PIGMENTOSUM; MALIGNANT-MELANOMA; DYSPLASTIC NEVI; RISK; GENETICS; MARKERS; DISEASE C1 Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Pigmented Les Clin, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc Risk Anal, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dermatopathol Unit, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. NR 31 TC 8 Z9 8 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 26 PY 2004 VL 350 IS 9 BP 924 EP 932 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 777UM UT WOS:000189197300013 PM 14985491 ER PT J AU Holroyd-Leduc, JM Straus, SE AF Holroyd-Leduc, JM Straus, SE TI Management of urinary incontinence in women - Scientific review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; MIDDLE-AGED WOMEN; DOUBLE-BLIND; RISK-FACTORS; OVERACTIVE BLADDER; STRESS-INCONTINENCE; ELECTRICAL-STIMULATION; DETRUSOR INSTABILITY; URGE INCONTINENCE; POSTMENOPAUSAL WOMEN AB Context Urinary incontinence is a common health problem among women that negatively impacts quality of life. Therefore, it is important that primary care physicians have an understanding of how to manage urinary incontinence effectively. Objective To review the most recent, high-quality evidence regarding the etiology and management of urinary incontinence in women. Data Sources and Study Selection Searches of MEDLINE, EMBASE, The Cochrane Library, and the ACP Journal Club were performed to identify English-language articles published between 1998-2003 that focused on the etiology or treatment of urinary incontinence in adult women. The references of each retrieved article were reviewed and an expert in the field was contacted to identify additional relevant articles. Data Extraction Using a combination of more than 80 search terms, we included articles of etiology that were cohort studies, case-control studies, cross-sectional studies, or systematic reviews of cohort, case-control, and/or cross-sectional studies. Studies of treatment had to be randomized controlled trials or systematic reviews of randomized controlled trials. The quality of each article was assessed independently by each author and inclusion (n = 66) was determined by consensus. Data Synthesis Multiple factors have been found to be associated with urinary incontinence, some of which are amenable to modification. Factors associated with incontinence include age, white race, higher educational attainment, pregnancy-related factors, gynecological factors, urological and gastrointestinal tract factors, comorbid diseases, higher body mass index, medications, smoking, caffeine, and functional impairment. There are several effective non pharmacological treatments including pelvic floor muscle training, electrical stimulation, bladder training, and prompted voiding. Anticholinergic drugs are effective in the treatment of urge urinary incontinence. Several surgical interventions are effective in the management of stress incontinence, including open retropubic colposuspension and suburethral sling procedure. Conclusion Urinary incontinence in women is an important public health concern, and effective treatment options exist. C1 San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. Univ Toronto, Univ Hlth Network, Div Gen Internal Med, Toronto, ON, Canada. RP Holroyd-Leduc, JM (reprint author), SFVAMC 181G, 4150 Clement St,Bldg 1, San Francisco, CA 94121 USA. EM Jayna.Holroyd-Leduc@med.va.gov; sstraus@mtsinai.on.ca NR 76 TC 106 Z9 110 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 25 PY 2004 VL 291 IS 8 BP 986 EP 995 DI 10.1001/jama.291.8.986 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 777MK UT WOS:000189182000027 PM 14982915 ER PT J AU Holroyd-Leduc, JM Straus, SE AF Holroyd-Leduc, JM Straus, SE TI Management of urinary incontinence in women - Clinical applications SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CONTROLLED TRIAL; HEALTH-CARE-SEEKING; OVERACTIVE BLADDER; HELP-SEEKING; TOLTERODINE; OXYBUTYNIN; SYMPTOMS; EFFICACY; OLDER; TOLERABILITY AB Urinary incontinence, defined as involuntary loss of urine, is a common health problem among women. The prevalence rate is between 12% and 55% for having ever experienced urinary incontinence. It is associated with poor self-rated health, impaired quality of life, social isolation, and depressive symptoms. However, physicians are usually not the ones to initiate discussion about incontinence with their patients. We present clinical cases to illustrate common scenarios in which a physician may be able to help a female patient manage her urinary incontinence by specifically addressing associated factors and offering treatments to improve or possibly even cure her symptoms. Several evidence-based effective nonpharmacological, pharmacological, and surgical treatment options are outlined. C1 San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. Univ Toronto, Univ Hlth Network, Div Gen Internal Med, Toronto, ON, Canada. RP Holroyd-Leduc, JM (reprint author), SFVAMC 181G, 4150 Clement St,Bldg 1, San Francisco, CA 94121 USA. EM Jayna.Holroyd-Leduc@med.va.gov; sstraus@mtsinai.on.ca NR 19 TC 26 Z9 27 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 25 PY 2004 VL 291 IS 8 BP 996 EP 999 DI 10.1001/jama.291.8.996 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 777MK UT WOS:000189182000028 PM 14982916 ER PT J AU Grande, LA Kinney, GA Miracle, GL Spain, WJ AF Grande, LA Kinney, GA Miracle, GL Spain, WJ TI Dynamic influences on coincidence detection in neocortical pyramidal neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE coincidence detection; synchrony; phase delay; neocortex; pyramidal neuron; synaptic inhibition; jitter; dynamic clamp ID NUCLEUS LAMINARIS; VISUAL-CORTEX; SYNAPTIC DEPRESSION; BRAIN-STEM; INTEGRATIVE PROPERTIES; SENSORIMOTOR CORTEX; CORTICAL-NEURONS; SPIKING NEURONS; MOTOR CORTEX; FIRING RATE AB The firing rate of neocortical pyramidal neurons is believed to represent primarily the average arrival rate of synaptic inputs; however, it has also been found to vary somewhat depending on the degree of synchrony among synaptic inputs. We investigated the ability of pyramidal neurons to perform coincidence detection, that is, to represent input timing in their firing rate, and explored some factors that influence that representation. We injected computer-generated simulated synaptic inputs into pyramidal neurons during whole-cell recordings, systematically altering the phase delay between two groups of periodic simulated input events. We explored how input intensity, the synaptic time course, inhibitory synaptic conductance, and input jitter influenced the firing rate representation of input timing. In agreement with computer modeling studies, we found that input synchronization increases firing rate when intensity is low but reduces firing rate when intensity is high. At high intensity, the effect of synchrony on firing rate could be switched from reducing to increasing firing rate by shortening the simulated excitatory synaptic time course, adding inhibition ( using the dynamic clamp technique), or introducing a small input jitter. These opposite effects of synchrony may serve different computational functions: as a means of increasing firing rate it may be useful for efficient recruitment or for computing a continuous parameter, whereas as a means of decreasing firing rate it may provide gain control, which would allow redundant or excessive input to be ignored. Modulation of dynamic input properties may allow neurons to perform different operations depending on the task at hand. C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Physiol & Biophys, Seattle, WA 98105 USA. Univ Washington, Dept Neurol, Seattle, WA 98105 USA. Univ Washington, Dept Rehabil Med, Seattle, WA 98105 USA. RP Spain, WJ (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM spain@u.washington.edu FU BLRD VA [I01 BX000386] NR 66 TC 26 Z9 26 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 25 PY 2004 VL 24 IS 8 BP 1839 EP 1851 DI 10.1523/JNEUROSCI.3500-03.2004 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 777XZ UT WOS:000189210300006 PM 14985424 ER PT J AU Samad, TA Srinivasan, A Karchewski, LA Jeong, SJ Campagna, JA Ji, RR Fabrizio, DA Zhang, Y Lin, HY Bell, E Woolf, CJ AF Samad, TA Srinivasan, A Karchewski, LA Jeong, SJ Campagna, JA Ji, RR Fabrizio, DA Zhang, Y Lin, HY Bell, E Woolf, CJ TI DRAGON: A member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties SO JOURNAL OF NEUROSCIENCE LA English DT Article DE development; GPI anchor; neuron; spinal cord; brain; muscle ID DORSAL SPINAL-CORD; SENSORY NEURONS; MOTOR-NEURONS; NEURAL CREST; GENE; SPECIFICATION; INTERNEURONS; DIFFERENTIATION; IDENTIFICATION; EMBRYOS AB DRG11, a transcription factor expressed in embryonic dorsal root ganglion (DRG) and dorsal horn neurons, has a role in the development of sensory circuits. We have used a genomic binding strategy to screen for the promoter region of genes regulated by DRG11. One gene with a promoter region binding to the DNA binding domain of DRG11 encodes a novel membrane-associated [glycosyl-phosphatidylinositol (GPI)-anchored] protein that we call DRAGON. DRAGON expression is transcriptionally regulated by DRG11, and it is coexpressed with DRG11 in embryonic DRG and spinal cord. DRAGON expression in these areas is reduced in DRG11 null mutants. DRAGON is expressed, however, in the neural tube before DRG11, and unlike DRG11 it is expressed in the brain and therefore must be regulated by other transcriptional regulatory elements. DRAGON shares high sequence homology with two other GPI-anchored membrane proteins: the mouse ortholog of chick repulsive guidance molecule (mRGM), which is expressed in the mouse nervous system in areas complementary to DRAGON, and DRAGON-like muscle (DL-M), the expression of which is restricted to skeletal and cardiac muscle. A comparative genomic analysis indicates that the family of RGM-related genes-mRGM, DRAGON, and DL-M-are highly conserved among mammals, zebrafish, chick, and Caenorhabditis elegans but not Drosophila. DRAGON, RGM, and DL-M mRNA expression in the zebrafish embryo is similar to that in the mouse. Neuronal cell adhesion assays indicate that DRAGON promotes and mRGM reduces adhesion of mouse DRG neurons. We show that DRAGON interacts with itself homophilically. The dynamic expression, ordered spatial localization, and adhesive properties of the RGM-related family of membrane-associated proteins are compatible with specific roles in development. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02129 USA. Massachusetts Gen Hosp, Program Membrane Biol, Dept Med, Boston, MA 02129 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02129 USA. Rockefeller Univ, Lab Vertebrate Embryol, New York, NY 10021 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 149 13th St, Boston, MA 02129 USA. EM woolf.clifford@mgh.harvard.edu RI Bell, Esther/C-5329-2009; OI Ji, Ru-Rong/0000-0002-9355-3688 FU NICHD NIH HHS [HD38533]; NINDS NIH HHS [NS38253, R01 NS040698] NR 34 TC 78 Z9 84 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 25 PY 2004 VL 24 IS 8 BP 2027 EP 2036 DI 10.1523/JNEUROSCI.4115-03.2004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 777XZ UT WOS:000189210300027 PM 14985445 ER PT J AU Biorn, AC Cocklin, S Madani, N Si, ZH Ivanovic, T Samanen, J Van Ryk, DI Pantophlet, R Burton, DR Freire, E Sodroski, J Chaiken, IM AF Biorn, AC Cocklin, S Madani, N Si, ZH Ivanovic, T Samanen, J Van Ryk, DI Pantophlet, R Burton, DR Freire, E Sodroski, J Chaiken, IM TI Mode of action for linear peptide inhibitors of HIV-1 gp120 interactions SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; CD4 BINDING-SITE; ENVELOPE GLYCOPROTEIN; TYPE-1 GP120; NEUTRALIZATION; EPITOPE; 2G12; MINIPROTEIN; SEQUENCES AB The linear peptide 12p1 (RINNIPWSEAMM) was previously isolated from a phage display library and was found to inhibit interaction of HIV-1 gp120 with both CD4 and a CCR5 surrogate, mAb 17b [Ferrer, M., and Harrison, S. (1999) J. Virol. 73, 5795-5802]. In this work, we investigated the mechanism that leads to this dual inhibition of gp120 binding. We found that there is a direct interaction of 12p1 with gp120, which occurs with a binding stoichiometry of 1:1. The peptide inhibits binding of monomeric YU2 gp120 to both sCD4 and 17b at IC50 values of 1. 1 and 1.6 muM, respectively. The 12p1 peptide also inhibited the binding of these ligands to trimeric envelope glycoproteins, blocked the binding of gp120 to the native coreceptor CCR5, and specifically inhibited HIV-1 infection of target cells in vitro. Analyses of sCD4 saturation of monomeric gp120 in the presence or absence of a fixed concentration of peptide suggest that 12p1 suppression of CD4 binding to gp120 is due to allosteric inhibitory effects rather than competitive inhibition of CD4 binding. Using a panel of gp120 mutants that exhibit weakened inhibition by 12p1, the putative binding site of the peptide was mapped to a region immediately adjacent to, but distinguishable from, the CD4 binding footprint. In the case of the peptide, the effects of single-12p1 residue substitutions and various peptide truncations indicate that the side chain of Trp7 and other structural elements of 12p1 are critical for gp120 binding or efficient inhibition of binding of a ligand to gp120. Finally, 12p1 was unable to inhibit binding of sCD4 to a gp120 mutant that is believed to resemble the CD4-induced conformation of gp120. These results suggest that 12p1 preferentially binds gp120 prior to engagement of CD4; binding of the peptide to gp120 limits the interaction with ligands (CD4 and CCR5) that are generally crucial for viral entry. More importantly, these results indicate that 12p1 binds to a unique site that may prove to be a prototypic target for novel CD4-gp120 inhibitors. C1 Drexel Univ, Coll Med, Dept Biochem, Philadelphia, PA 19102 USA. Harvard Univ, Sch Med, Dept Pathol, Dana Farber Canc Inst,Div Human Retrovirol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Canc Biol, Boston, MA 02115 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. GlaxoSmithKline, King Of Prussia, PA 19406 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Biol Mol, La Jolla, CA 92037 USA. RP Chaiken, IM (reprint author), Drexel Univ, Coll Med, Dept Biochem, 11102 New Coll Bldg,MS 497,245 N 15th St, Philadelphia, PA 19102 USA. EM imc23@drexel.edu FU NIGMS NIH HHS [P01 GM-56550] NR 24 TC 35 Z9 38 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 24 PY 2004 VL 43 IS 7 BP 1928 EP 1938 DI 10.1021/bi035088i PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774TJ UT WOS:000189000700017 PM 14967033 ER PT J AU Chroni, A Liu, T Fitzgerald, ML Freeman, MW Zannis, VI AF Chroni, A Liu, T Fitzgerald, ML Freeman, MW Zannis, VI TI Cross-linking and lipid efflux properties of ApoA-I mutants suggest direct association between ApoA-I helices and ABCA1 SO BIOCHEMISTRY LA English DT Article ID APOLIPOPROTEIN-A-I; HIGH-DENSITY-LIPOPROTEIN; REVERSE CHOLESTEROL TRANSPORT; CENTRAL-NERVOUS-SYSTEM; ONE-STEP PURIFICATION; NI-NTA RESIN; B TYPE-I; RECEPTOR-BINDING; TANGIER-DISEASE; RECOMBINANT PROTEINS AB To explore the functional interactions between apoA-I and ABCA1, we correlated the cross-linking properties of several apoA-I mutants with their ability to promote cholesterol efflux. In a competitive cross-linking assay, amino-terminal deletion and double amino- and carboxy-terminal deletion mutants of apoA-I competed effectively the cross-linking of WT I-125-apoA-I to ABCA1, while the carboxy-terminal deletion mutant apoA-I[Delta(220-243)] competed poorly. Direct cross-linking of WT apoA-I, amino-terminal, and double deletion mutants of apoA-I to ABCA1 showed similar apparent K-d values (49-74 nM), whereas the apparent K-d values of the carboxy-terminal deletion mutants apoA-I[Delta(185-243)] and apoA-I[Delta(220-243)] were increased 3-fold. Analysis of several internal deletions and point mutants of apoA-I showed that apoA-I[Delta(61-78)], apoA-I[Delta(89-99)], apoA-I[Delta(136-143)], apoA-I[Delta(144-165)], apoA-I[D102A/D103A], apoA-I[E125K/E128K/K133E/E139K], apoA-I[L141R], apoA-I[R160V/H162A], and WT apoA-I had similar ABCA1-mediated lipid efflux, and all competed efficiently the cross-linking of WT I-125-apoA-I to ABCA1. WT apoA-I and ABCA1 could be cross-linked with a 3 A cross-linker. The WT apoA-I, amino, carboxy and double deletion mutants of apoA-I showed differences in the cross-linking to WT ABCA1 and the mutant ABCA1[W590S]. The findings are consistent with a direct association of different combinations of apoA-I helices with a complementary ABCA1 domain. Mutations that alter ABCA1/apoA-I association affect cholesterol efflux and inhibit biogenesis of HDL. C1 Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Biochem, Boston, MA 02118 USA. Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Zannis, VI (reprint author), Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Med, 715 Albany St W509, Boston, MA 02118 USA. EM vzannis@bu.edu FU NHLBI NIH HHS [HL-48739, HL-68988] NR 57 TC 72 Z9 78 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 24 PY 2004 VL 43 IS 7 BP 2126 EP 2139 DI 10.1021/bi035813p PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774TJ UT WOS:000189000700036 PM 14967052 ER PT J AU Hsu, LF Jais, P Keane, D Wharton, JM Deisenhofer, I Hocini, M Shah, DC Sanders, P Scavee, C Weerasooriya, R Clementy, J Haissaguerre, M AF Hsu, LF Jais, P Keane, D Wharton, JM Deisenhofer, I Hocini, M Shah, DC Sanders, P Scavee, C Weerasooriya, R Clementy, J Haissaguerre, M TI Atrial fibrillation originating from persistent left superior vena cava SO CIRCULATION LA English DT Article DE catheter ablation; fibrillation; mapping ID THORACIC VEINS; MARSHALL; LIGAMENT; POTENTIALS; ABLATION AB Background - The left superior vena cava (LSVC) is the embryological precursor of the ligament of Marshall, which has been implicated in the initiation and maintenance of atrial fibrillation (AF). Rarely, the LSVC may persist and has been associated with some organized arrhythmias, though not with AF. We report 5 patients in whom the LSVC was a source of ectopy, initiating AF. Methods and Results - In 5 patients ( 4 men; age, 46 +/- 11 years) with symptomatic drug-refractory AF, ectopy from the LSVC resulting in AF was observed after pulmonary vein isolation. The ectopics were spontaneous in 2 and induced by isoproterenol in the others and preceded P-wave onset by 67 +/- 13 ms. During multielectrode or electroanatomic mapping, venous potentials were recorded circumferentially at the proximal LSVC near its junction with the coronary sinus ( CS), but at the mid-LSVC level, they were recorded only on part of the circumference. The LSVC was electrically connected to the lateral left atrium ( LA) and through the CS to the right atrium, with 4.1 +/- 2.3 CS-LSVC and 1.6 +/- 0.5 LA-LSVC connections per patient. Catheter ablation in the LSVC targeting these connections resulted in electrical isolation in 4 of the 5 patients without complications. After 15 +/- 10 months, the 4 patients with successful isolation, including 1 who had successful reablation for LA flutter, remained in sinus rhythm without drugs. Conclusions - The LSVC can be the arrhythmogenic source of AF with connections to the CS and LA. Ablation of these connections resulted in electrical isolation. C1 Hop Cardiol Haut Leveque, F-33604 Bordeaux, France. Massachusetts Gen Hosp, Boston, MA 02114 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Hsu, LF (reprint author), Hop Cardiol Haut Leveque, Ave Magellan, F-33604 Bordeaux, France. EM hsulifern@yahoo.com.sg RI Sanders, Prashanthan/D-7641-2013 OI Sanders, Prashanthan/0000-0003-3803-8429 NR 11 TC 62 Z9 71 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 BP 828 EP 832 DI 10.1161/01.CIR.0000116753.56467.BC PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800006 PM 14757689 ER PT J AU Sabatine, MS Morrow, DA Giugliano, RP Murphy, SA Demopoulos, LA DiBattiste, PM Weintraub, WS McCabe, CH Antman, EM Cannon, CP Braunwald, E AF Sabatine, MS Morrow, DA Giugliano, RP Murphy, SA Demopoulos, LA DiBattiste, PM Weintraub, WS McCabe, CH Antman, EM Cannon, CP Braunwald, E TI Implications of upstream glycoprotein IIb/IIIa inhibition and coronary artery stenting in the invasive management of unstable angina/non-ST-elevation myocardial infarction - A Comparison of the Thrombolysis in Myocardial Infarction (TIMI) IIIB Trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS)-TIMI 18 Trial SO CIRCULATION LA English DT Article DE angiography; inhibitors; risk factors; angina ID TIMI RISK SCORE; BALLOON ANGIOPLASTY; SEGMENT ELEVATION; RANDOMIZED TRIAL; DISEASE; TIROFIBAN AB Background - TIMI IIIB and TACTICS-TIMI 18 were 2 trials of an early invasive strategy in unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI) that were conducted nearly a decade apart but with virtually identical enrollment criteria and designs, except that upstream glycoprotein IIb/IIIa inhibition was mandated and coronary artery stenting was routinely used in TACTICS-TIMI 18. We sought to examine the effect of these advances on clinical outcomes and the benefits of an early invasive strategy in UA/NSTEMI. Methods and Results - Patients were stratified on the basis of their TIMI risk score into low-, intermediate-, and high-risk categories. Within each risk category, the rates of clinical outcomes and the benefit of an early invasive strategy were compared. Compared with patients in TIMI IIIB and adjusting for baseline risk, patients in TACTICS-TIMI 18 had lower rates of death, MI, or rehospitalization for acute coronary syndromes ( OR, 0.62; P < 0.0001). Across both trials, the benefit of an early invasive strategy was significantly greater with increasing baseline risk: OR, 1.39 in low- risk, 0.80 in intermediate- risk, and 0.57 in high-risk patients ( P &LE; 0.004 for interactions). After adjustment for baseline risk, an early invasive strategy tended toward a more favorable result in TACTICS-TIMI 18 than in TIMI IIIB ( OR, 0.79; 95% CI, 0.56 to 1.11). Conclusions - Advances in the care of patients with UA/NSTEMI, including glycoprotein IIb/IIIa inhibition and stenting, were associated with lower rates of death, MI, and rehospitalization for acute coronary syndromes and a trend toward a greater benefit of an early invasive strategy. C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Merck & Co Inc, W Point, PA USA. Emory Univ, Atlanta, GA 30322 USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU NHLBI NIH HHS [F32-HL68455-01] NR 17 TC 37 Z9 40 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 BP 874 EP 880 DI 10.1161/01.CIR.0000112604.74713.35 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800014 PM 14757697 ER PT J AU Yun, JJ Whiting, D Fischbein, MP Banerji, A Irie, Y Stein, D Fishbein, MC Proudfoot, AEI Laks, H Berliner, JA Ardehali, A AF Yun, JJ Whiting, D Fischbein, MP Banerji, A Irie, Y Stein, D Fishbein, MC Proudfoot, AEI Laks, H Berliner, JA Ardehali, A TI Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection SO CIRCULATION LA English DT Article DE transplantation; lymphocytes; rejection; chemokine ID CARDIAC ALLOGRAFT VASCULOPATHY; SMOOTH-MUSCLE-CELLS; RANTES PRODUCTION; MONOCYTE ARREST; IN-VITRO; ACTIVATION; ATHEROSCLEROSIS; RECRUITMENT; LYMPHOCYTES; HEARTS AB Background - Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model. Methods and Results - B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice ( myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2(+) monocytes/ macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts. Conclusions - Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets. C1 Univ Calif Los Angeles, Med Ctr, Div Cardiothorac Surg, Dept Surg, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA. Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. Serono Pharmaceut Res Inst, Geneva, Switzerland. RP Ardehali, A (reprint author), Univ Calif Los Angeles, Med Ctr, Div Cardiothorac Surg, Dept Surg, CHS 62-182,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM aardehali@mednet.ucla.edu FU NHLBI NIH HHS [P01 HL30568]; NIAID NIH HHS [AI07126-23] NR 27 TC 66 Z9 74 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 BP 932 EP 937 DI 10.1161/01.CIR.0000112595.65972.8A PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800023 PM 14757698 ER PT J AU Fang, MC Chang, Y Go, AS Hylek, EM Singer, DE AF Fang, MC Chang, Y Go, AS Hylek, EM Singer, DE TI Anticoagulant intensity and risk of intracranial hemorrhage: Impact of case-control vs. case-crossover methods, the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Kaiser Permanente No Calif, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P113 BP E103 EP E103 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800168 ER PT J AU Fox, CS Larson, MG Leip, EP Meigs, JB Wilson, PW Levy, D AF Fox, CS Larson, MG Leip, EP Meigs, JB Wilson, PW Levy, D TI Glycemic status and development of kidney disease over 8-years: the Framingham Heart Study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P199 BP E120 EP E120 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800252 ER PT J AU Go, AS Hylek, EM Udaltsova, N Chang, YC Jensvold, NG Henault, LE Singer, DE AF Go, AS Hylek, EM Udaltsova, N Chang, YC Jensvold, NG Henault, LE Singer, DE TI Improving risk stratification in atrial fibrillation: Renal dysfunction and risk of thromboembolism and death in nonvalvular atrial fibrillation. The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Kaiser Permanente No Calif, Oakland, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P59 BP E92 EP E92 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800117 ER PT J AU Kathiresan, S Larson, MG Corey, D Benjamin, EJ Fox, CS Wilson, P AF Kathiresan, S Larson, MG Corey, D Benjamin, EJ Fox, CS Wilson, P TI Clinical correlates of serum aldosterone in the community. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston Univ, Sch Med, NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P180 BP E116 EP E116 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800233 ER PT J AU Lopez-Garcia, E Schulze, MB Manson, JAE Meigs, JB Rifai, N Willett, WC Hu, FB AF Lopez-Garcia, E Schulze, MB Manson, JAE Meigs, JB Rifai, N Willett, WC Hu, FB TI Consumption of omega 3 fatty acids and plasma concentrations of inflammatory and endothelial dysfunction markers. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P127 BP E106 EP E106 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800181 ER PT J AU Pereira, MA Swain, J Rifai, N Goldfine, A Ludwig, DS AF Pereira, MA Swain, J Rifai, N Goldfine, A Ludwig, DS TI Effects of dietary glycemic load on cardiovascular disease risk factors during weight loss. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 Univ Minnesota, Minneapolis, MN USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P130 BP E106 EP E107 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800184 ER PT J AU Ruo, B Rumsfeld, JS Pipkin, S Browner, WS Whooley, MA AF Ruo, B Rumsfeld, JS Pipkin, S Browner, WS Whooley, MA TI Depressive symptoms and treadmill exercise capacity: Findings from the heart and soul study. SO CIRCULATION LA English DT Meeting Abstract CT 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention CY MAR 03-06, 2004 CL San Francisco, CA SP Amer Heart Assoc C1 UCSF VA, San Francisco, CA USA. Denver Vet Affairs Med Ctr, Denver, CO USA. Calif Pacific Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 24 PY 2004 VL 109 IS 7 MA P107 BP E102 EP E102 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 777FR UT WOS:000189165800162 ER PT J AU Yang, W Shimaoka, M Chen, JF Springer, TA AF Yang, W Shimaoka, M Chen, JF Springer, TA TI Activation of integrin beta-subunit I-like domains by one-turn C-terminal alpha-helix deletions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; A-DOMAIN; CONFORMATIONAL-CHANGES; EXTRACELLULAR SEGMENT; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; DISULFIDE BOND; BINDING; LIGAND; INHIBITION AB Integrins contain two structurally homologous but distantly related domains: an I-like domain that is present in all beta-subunits and an I domain that is present in some alpha-subunits. Atomic resolution and mutagenesis studies of a I domains demonstrate a C-terminal, axial displacement of the alpha7-helix that allosterically regulates the shape and affinity of the ligand-binding site. Atomic resolution studies of beta I-like domains have thus far demonstrated no similar a7-helix displacement; however, other studies are consistent with the idea that alpha I and beta I-like domains undergo structurally analogous rearrangements. To test the hypothesis that C-terminal, axial displacement of the alpha7-helix, coupled with beta6-alpha7 loop reshaping, activates beta I-like domains, we have mimicked the effect of a7-helix displacement on the beta6-alpha7 loop by shortening the a7-helix by two independent, four-residue deletions of about one turn of a-helix. In the case of integrin alpha(L)beta(2), each mutant exhibits constitutively high affinity for the physiological ligand intercellular adhesion molecule 1 and full exposure of a beta I-like domain activation-dependent antibody epitope. In the case of analogous mutants in integrin alpha(4)beta(7), each mutant shows the activated phenotype of firm adhesion, rather than rolling adhesion, in shear flow. The results show that integrins that contain or lack alpha I domains share a common pathway of beta I-like domain activation, and they suggest that beta I-like and alpha I domain activation involves structurally analogous alpha7-helix axial displacements. C1 Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, 200 Longwood Ave, Boston, MA 02115 USA. EM springeroffice@cbr.med.harvard.edu FU NCI NIH HHS [CA31798, R01 CA031798, R37 CA031798] NR 42 TC 51 Z9 51 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2333 EP 2338 DI 10.1073/pnas.0307291101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400021 PM 14983010 ER PT J AU Yang, FJ DeBeaumont, R Zhou, S Naar, AM AF Yang, FJ DeBeaumont, R Zhou, S Naar, AM TI The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HERPES-SIMPLEX-VIRUS; HISTONE ACETYLTRANSFERASE COMPLEXES; RNA-POLYMERASE-II; DEPENDENT TRANSCRIPTION; NUCLEAR RECEPTORS; IN-VITRO; PROTEIN; DOMAIN; MEDIATOR; BINDING AB The human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator, was recently identified based on functional association with the activation domains of multiple cellular and viral transcriptional activators, including the herpes simplex viral activator VP16, sterol regulatory element binding protein, and NF-kappaB. Here we describe the biochemical purification and cloning of the 92-kDa ARC/Mediator subunit, ARC92, that is specifically targeted by the activation domain of the VP16 transactivator. Affinity chromatography using the VP16 activation domain followed by peptide microsequencing led to the identification of ARC92 as a specific cellular interaction partner of the VP16 activation domain. ARC92 associates with the VP16 activation domain in vitro and in vivo, and the VP16 binding domain of ARC92 is a strong competitive inhibitor of Gal4-VP16 in vivo. Moreover, small interfering RNA-mediated knockdown of ARC92 in human cells results in selective inhibition of Gal4-VP16 gene activation. Taken together, our results suggest that ARC92 is a direct and specific target of the VP16 transactivator that serves in the context of the ARC/Mediator coactivator as an important transducer of transcription activating signals from the VP16 activation domain to the RNA polymerase II transcriptional machinery. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Canc Ctr, Dept Cell Biol, Charlestown, MA 02129 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Naar, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Canc Ctr, Dept Cell Biol, Bldg 149,13th St, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu NR 39 TC 87 Z9 92 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2339 EP 2344 DI 10.1073/pnas.0308676100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400022 PM 14983011 ER PT J AU Hur, JY Chesnes, J Coser, KR Lee, RS Geck, P Isselbacher, KJ Shioda, T AF Hur, JY Chesnes, J Coser, KR Lee, RS Geck, P Isselbacher, KJ Shioda, T TI The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BCL-2 FAMILY; MCF-7 CELLS; LINE MCF-7; DNA FRAGMENTATION; DRUG-RESISTANCE; GENE-EXPRESSION; DOWN-REGULATION; MESSENGER-RNA; INDUCTION; TAMOXIFEN AB Evidence has been accumulating that some estrogen-dependent human breast cancers require estrogen for not only proliferation but also survival. To obtain insights into the molecular mechanisms of apoptosis of breast cancer cells subjected to estrogen starvation or exposed to antiestrogens, we characterized changes in the gene expression profile of MCF-7/BUS human breast cancer cells and revealed a strong induction of Bilk, a member of the BH3-only proapoptotic proteins. The Bilk mRNA transcript and protein were strongly induced by estrogen starvation or exposure to fulvestrant, a pure antiestrogen that competes with the natural estrogens for binding to the estrogen receptors. This Bik induction preceded apoptotic cell death, which was blocked by zVAD-fmk, a pan-caspase inhibitor. Amounts of the Bcl-2-related proteins, such as Bcl-2, Bcl-X-L, or Bax, showed only marginal changes in the presence or absence of estrogens or antiestrogens. Suppression of Bilk expression by using the small interfering RNA effectively blocked the fulvestrant-induced breast cancer cell apoptosis. These results indicate that Bik is induced in MCF-7/BUS cells in the absence of estrogen signaling and plays a critical role in the antiestrogen-provoked breast cancer cell apoptosis. C1 Massachusetts Gen Hosp, Ctr Canc, Dept Tumor Biol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Canc, DNA Microrray Core Facil, Charlestown, MA 02129 USA. Tufts Univ, Sch Med, Dept Anat & Cell Biol, Boston, MA 02111 USA. RP Shioda, T (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Tumor Biol, Bldg 149,7th Floor,13th St, Charlestown, MA 02129 USA. EM tshioda@partners.org FU NCI NIH HHS [R01 CA082230, R01 CA82230] NR 47 TC 62 Z9 62 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2351 EP 2356 DI 10.1073/pnas.0307337101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400024 PM 14983013 ER PT J AU Cantor, S Drapkin, R Zhang, F Lin, YF Han, JL Pamidi, S Livingston, DM AF Cantor, S Drapkin, R Zhang, F Lin, YF Han, JL Pamidi, S Livingston, DM TI The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID XERODERMA-PIGMENTOSUM; ESCHERICHIA-COLI; WERNER-SYNDROME; ATPASE ACTIVITY; RECQ HELICASES; REPAIR; TRANSCRIPTION; BINDING; FAMILY; DAMAGE AB BACH1 is a nuclear protein that directly interacts with the highly conserved, C-terminal BRCT repeats of the tumor suppressor, BRCA1. Mutations within the BRCT repeats disrupt the interaction between BRCA1 and BACH1, lead to defects in DNA repair, and result in breast and ovarian cancer. BACH1 is necessary for efficient double-strand break repair in a manner that depends on its association with BRCA1. Moreover, some women with early-onset breast cancer and no abnormalities in either BRCA1 or BRCA2 carry germline BACH1 coding sequence changes, suggesting that abnormal BACH1 function contributes to tumor induction. Here, we show that BACH1 is both a DNA-dependent ATPase and a 5'-to-3' DNA helicase. In two patients with early-onset breast cancer who carry distinct germline BACH1 coding sequence changes, the resulting proteins are defective in helicase activity, indicating that these sequence changes disrupt protein function. These results reinforce the notion that mutant BACH1 participates in breast cancer development. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM david_livingston@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 43 TC 148 Z9 156 U1 2 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 FEB 24 PY 2004 VL 101 IS 8 BP 2357 EP 2362 DI 10.1073/pnas.0308717101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400025 PM 14983014 ER PT J AU Lopez-Rodriguez, C Antos, CL Shelton, JM Richardson, JA Lin, FM Novobrantseva, TI Bronson, RT Igarashi, P Rao, A Olson, EN AF Lopez-Rodriguez, C Antos, CL Shelton, JM Richardson, JA Lin, FM Novobrantseva, TI Bronson, RT Igarashi, P Rao, A Olson, EN TI Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ENHANCER-BINDING PROTEIN; ALDOSE REDUCTASE GENE; TRANSCRIPTION FACTORS; HYPERTONICITY; TRANSPORTERS; HYDRATION; DEFECT; RAT AB The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl--coupled betaine/gamma-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Inst Biomed Res, Ctr Blood Res, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Dept Biol Mol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Internal Med Nephrol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX 75390 USA. Tufts Univ, Sch Vet Med, Dept Pathol, North Grafton, MA 01536 USA. RP Rao, A (reprint author), Max Planck Inst Entwicklungsbiol, Spermannstr 35-111, D-72026 Tubingen, Germany. EM arao@cbr.med.harvard.edu; eolson@hamon.swmed.edu RI Antos, Christopher/E-8171-2010; Lopez-Rodriguez, C/G-4482-2014; OI Lopez-Rodriguez, C/0000-0002-2311-2406; Igarashi, Peter/0000-0001-8698-1185 NR 24 TC 146 Z9 149 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2392 EP 2397 DI 10.1073/pnas.0308703100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400031 PM 14983020 ER PT J AU Rooney, S Sekiguchi, J Whitlow, S Eckersdorff, M Manis, JP Lee, C Ferguson, DO Alt, FW AF Rooney, S Sekiguchi, J Whitlow, S Eckersdorff, M Manis, JP Lee, C Ferguson, DO Alt, FW TI Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; V(D)J RECOMBINATION; DNA-REPAIR; C-MYC; GENOMIC INSTABILITY; EMBRYONIC LETHALITY; GENE AMPLIFICATION; MURINE DEVELOPMENT; MICE; LYMPHOMA AB The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes. C1 Harvard Univ, Sch Med, Dept Genet, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med,Div Cytogenet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu OI Sekiguchi, JoAnn/0000-0002-7178-4258 FU NCI NIH HHS [P01 CA092625, CA92625]; NHLBI NIH HHS [K08 HL67580-02, K08 HL067580]; NIAID NIH HHS [P01 AI035714, AI35714] NR 44 TC 79 Z9 80 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2410 EP 2415 DI 10.1073/pnas.0308757101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400034 PM 14983023 ER PT J AU Skulina, C Schmidt, S Dornmair, K Babbe, H Roers, A Rajewsky, K Wekerle, H Hohlfeld, R Goebels, N AF Skulina, C Schmidt, S Dornmair, K Babbe, H Roers, A Rajewsky, K Wekerle, H Hohlfeld, R Goebels, N TI Multiple sclerosis: Brain-infiltrating CD8(+) T cells persist as clonal expansions in the cerebrospinal fluid and blood SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; V-BETA REPERTOIRE; RECEPTOR; DISEASE; MODEL; PATHOGENESIS; LYMPHOCYTES; LESIONS; OLIGOCLONALITY; IMMUNOTHERAPY AB We surveyed the T cell receptor repertoire in three separate compartments (brain, cerebrospinal fluid, and blood) of two multiple sclerosis patients who initially had diagnostic brain biopsies to clarify their unusual clinical presentation but were subsequently confirmed to have typical multiple sclerosis. One of the brain biopsy specimens had been previously investigated by microdissection and single-cell PCR to determine the clonal composition of brain-infiltrating T cells at the single-cell level. Using complementarity-determining region 3 spectratyping, we identified several identical, expanded CD8(+) (but not CD4(+)) T cell clones in all three compartments. Some of the expanded CD8(+) T cells also occurred in sorted CD38(+) blood cells, suggesting that they were activated. Strikingly, some of the brain-infiltrating CD8(+) T cell clones persisted for >5 years in the cerebrospinal fluid and/or blood and may thus contribute to the progression of the disease. C1 Univ Munich, Inst Clin Neuroimmunol, D-81377 Munich, Germany. Max Planck Inst Neurobiol, D-82152 Martinsried, Germany. Univ Bonn, Dept Neurol, D-53127 Bonn, Germany. Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Univ Cologne, Dept Dermatol, D-50931 Cologne, Germany. RP Goebels, N (reprint author), Univ Zurich Hosp, Dept Neurol, Frauenklin Str 26, CH-8091 Zurich, Switzerland. EM norbert.goebels@usz.ch NR 40 TC 196 Z9 198 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2428 EP 2433 DI 10.1073/pnas.0308689100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400037 PM 14983026 ER PT J AU Gennuso, F Fernetti, C Tirolo, C Testa, N L'Episcopo, F Caniglia, S Morale, MC Ostrow, JD Pascolo, L Tiribelli, C Marchetti, B AF Gennuso, F Fernetti, C Tirolo, C Testa, N L'Episcopo, F Caniglia, S Morale, MC Ostrow, JD Pascolo, L Tiribelli, C Marchetti, B TI Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; BLOOD-BRAIN-BARRIER; P-GLYCOPROTEIN EXPRESSION; UNCONJUGATED BILIRUBIN; OXIDATIVE STRESS; CHOROID-PLEXUS; ENDOTHELIAL-CELLS; MICROGLIAL CELLS; GOLGI-APPARATUS; RAT ASTROCYTES AB Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (B-f) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bf above aqueous saturation produced a similar but aborted response. Exposure to this higher Bf for 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltrans-ferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, B-f = 40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation. C1 OASI Inst Res & Care Mental Retardat & Brain Agin, Neuropharmacol Sect, I-94010 Troina, Italy. Univ Trieste, Dept Biochem, I-34127 Trieste, Italy. Univ Trieste, Liver Res Ctr, I-34127 Trieste, Italy. Univ Washington, Sch Med, Dept Med, Div Gastroenterol Hepatol, Seattle, WA 98108 USA. Vet Affairs Puget Sound Hlth Care Syst, Res Serv 151L, Seattle, WA 98108 USA. Univ Sassari, Fac Med, Dept Pharmacol, I-07100 Sassari, Italy. RP Marchetti, B (reprint author), OASI Inst Res & Care Mental Retardat & Brain Agin, Neuropharmacol Sect, I-94010 Troina, Italy. EM bianca.marchetti@oasi.en.it RI Tirolo, Cataldo/C-9929-2017; Caniglia, Salvatore/D-1001-2017; Morale, Maria Concetta/D-5847-2017; Nunzio, Testa/D-8023-2017; OI Tirolo, Cataldo/0000-0003-1747-8134; Caniglia, Salvatore/0000-0003-1238-6193; Morale, Maria Concetta/0000-0003-0624-7234; Nunzio, Testa/0000-0002-4024-2325; Marchetti, Bianca/0000-0002-9287-8448; L'Episcopo, Francesca/0000-0003-3292-9677 NR 47 TC 92 Z9 94 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 FEB 24 PY 2004 VL 101 IS 8 BP 2470 EP 2475 DI 10.1073/pnas.0308452100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400044 PM 14983033 ER PT J AU He, JX Baldini, RL Deziel, E Saucier, M Zhang, QH Liberati, NT Lee, D Urbach, J Goodman, HM Rahme, LG AF He, JX Baldini, RL Deziel, E Saucier, M Zhang, QH Liberati, NT Lee, D Urbach, J Goodman, HM Rahme, LG TI The broad host range pathogen Pseudomonas aeruginosa strain PA14 carries two pathogenicity islands harboring plant and animal virulence genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMPLETE GENOME SEQUENCE; ESCHERICHIA-COLI; BIOFILM FORMATION; IDENTIFICATION; RESISTANCE; INFECTION; DETERMINANTS; EVOLUTION; PATHWAYS; SYSTEM AB The ubiquitous bacterium Pseudomonas aeruginosa is the quintessential opportunistic pathogen. Certain isolates infect a broad range of host organisms, from plants to humans. The pathogenic promiscuity of particular variants may reflect an increased virulence gene repertoire beyond the core A aeruginosa genome. We have identified and characterized two P. aeruginosa pathogenicity islands (PAPI-1 and PAPI-2) in the genome of PA14, a highly virulent clinical isolate. The 108-kb PAPI-1 and 11-kb PAPI-2, which are absent from the less virulent reference strain PAO1, exhibit highly modular structures, revealing their complex derivations from a wide array of bacterial species and mobile elements. Most of the genes within these islands that are homologous to known genes occur in other human and plant bacterial pathogens. For example, PAPI-1 carries a complete gene cluster predicted to encode a type IV group B pilus, a well known adhesin absent from strain PAO1. However, >80% of the PAPI-1 DNA sequence is unique, and 75 of its 115 predicted ORF products are unrelated to any known proteins or functional domains. Significantly, many PAPI-1 ORFs also occur in several A aeruginosa cystic fibrosis isolates. Twenty-three PAPI ORFs were mutated, and 19 were found to be necessary for full plant or animal virulence, with 11 required for both. The large set of "extra" virulence functions encoded by both PAPIs may contribute to the increased promiscuity of highly virulent A aeruginosa strains, by directing additional pathogenic functions. C1 Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biol Mol, Boston, MA 02114 USA. RP Rahme, LG (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu RI Baldini, Regina/C-4035-2012; Deziel, Eric/A-7678-2008 OI Baldini, Regina/0000-0003-4349-6352; Deziel, Eric/0000-0002-4609-0115 FU NHLBI NIH HHS [U01 HL066678, U01 HL66678] NR 42 TC 190 Z9 200 U1 3 U2 14 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 24 PY 2004 VL 101 IS 8 BP 2530 EP 2535 DI 10.1073/pnas.0304622101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400054 PM 14983043 ER PT J AU Sui, JH Li, WH Murakami, A Tamin, A Matthews, LJ Wong, SK Moore, MJ Tallarico, ASC Olurinde, M Choe, H Anderson, LJ Bellini, WJ Farzan, M Marasco, WA AF Sui, JH Li, WH Murakami, A Tamin, A Matthews, LJ Wong, SK Moore, MJ Tallarico, ASC Olurinde, M Choe, H Anderson, LJ Bellini, WJ Farzan, M Marasco, WA TI Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INFECTIOUS-BRONCHITIS VIRUS; IN-VIVO; PROTECTIVE IMMUNITY; MURINE CORONAVIRUS; HEPATITIS-VIRUS; AMINO-ACIDS; ANTIBODIES; GLYCOPROTEIN; IDENTIFICATION; PREVENTION AB Effective prophylaxis and antiviral therapies are urgently needed in the event of reemergence of the highly contagious and often fatal severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) infection. We have identified eight recombinant human single-chain variable region fragments (scFvs) against the S1 domain of spike (S) protein of the SARS-CoV from two nonimmune human antibody libraries. One scFv 80R efficiently neutralized SARS-CoV and inhibited syncytia formation between cells expressing the S protein and those expressing the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2). Mapping of the 80R epitope showed it is located within the N-terminal 261-672 amino acids of S protein and is not glycosylation-dependent. 80R scFv competed with soluble ACE2 for association with the S1 domain and bound S1 with high affinity (equilibrium dissociation constant, K-d = 32.3 nM). A human IgG1 form of 80R bound S1 with a 20-fold higher affinity of 1.59 nM comparable to that of ACE2 (K-d = 1.70 nM), and neutralized virus 20-fold more efficiently than the 80R scFv. These data suggest that the 80R human monoclonal antibody may be a useful viral entry inhibitor for the emergency prophylaxis and treatment of SARS, and that the ACE2-binding site of S1 could be an attractive target for subunit vaccine and drug development. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat, Div Pulm, Ina Sue Perlmutter Lab, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Dept Microbiol & Mol Genet,Partners AIDS, Boston, MA 02115 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. RP Marasco, WA (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM wayne.marasco@dfci.harvard.edu OI Li, Wenhui/0000-0003-1305-7404; SUI, JIANHUA/0000-0002-1272-9662 FU NIAID NIH HHS [AI053822, AI28691, AI28785, AI48436, P30 AI028691, R01 AI048436, R21 AI053822] NR 27 TC 248 Z9 282 U1 3 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 24 PY 2004 VL 101 IS 8 BP 2536 EP 2541 DI 10.1073/pnas.0307140101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802CA UT WOS:000220140400055 PM 14983044 ER PT J AU Barr, RG Wentowski, CC Grodstein, F Somers, SC Stampfer, MJ Schwartz, J Speizer, FE Camargo, CA AF Barr, RG Wentowski, CC Grodstein, F Somers, SC Stampfer, MJ Schwartz, J Speizer, FE Camargo, CA TI Prospective study of postmenopausal hormone use and newly diagnosed asthma and chronic obstructive pulmonary disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; FOOD FREQUENCY QUESTIONNAIRE; NITRIC-OXIDE SYNTHASE; C-REACTIVE PROTEIN; ADULT-ONSET ASTHMA; BODY-MASS INDEX; MENSTRUAL-CYCLE; GENDER-DIFFERENCES; LUNG-FUNCTION; AIRWAY RESPONSIVENESS AB Background: Female reproductive hormones appear to influence asthma, although data are conflicting, and may modulate development of chronic obstructive pulmonary disease (COPD). Therefore, in a prospective cohort study, we evaluated whether postmenopausal hormone use was associated with an increased rate of newly diagnosed asthma and, separately, newly diagnosed COPD. Methods: Postmenopausal hormone use was assessed by questionnaire biennially from 1976 onward. New physician diagnoses of asthma or COPD were reported on questionnaires from 1988 to 1996 and confirmed in 1998 using supplementary questionnaires. Grades of diagnostic certainty were established from reports of medication use and pulmonary function using validated definitions. Results: During 546 259 person-years of follow-up, current use of estrogen alone was associated with an increased rate of asthma (multivariate rate ratio, 2.29; 95% confidence interval [CI], 1.59-3.29) compared with those who never used hormones. Current users of estrogen plus progestin had a similarly increased rate of newly diagnosed asthma. Rate ratios increased with certainty of diagnosis of asthma. In contrast, rates of newly diagnosed COPD were the same among hormone users and non-users (multivariate rate ratio, 1.05; 95% Cl, 0.80-1.37). Conclusions: Postmenopausal hormone use was associated with an increased rate of newly diagnosed asthma but not newly diagnosed COPD. Female reproductive hormones may contribute to the onset of asthma among adult women, but do not appear to hasten the development of COPD. C1 Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gen Med, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Columbia Univ, Coll Phys & Surg, Div Gen Med, Dept Med, New York, NY USA. RP Barr, RG (reprint author), Columbia Presbyterian Med Ctr, Div Gen Med, PH-9E 105,622 W 168th St, New York, NY 10032 USA. EM rgb9@columbia.edu FU BHP HRSA HHS [PE-11001]; NCI NIH HHS [CA-87969]; NHLBI NIH HHS [HL-07427, HL-63841]; NIAID NIH HHS [AI52338] NR 72 TC 88 Z9 89 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2004 VL 164 IS 4 BP 379 EP 386 DI 10.1001/archinte.164.4.379 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 776ZE UT WOS:000189148600004 PM 14980988 ER PT J AU Dobie, DJ Kivlahan, DR Maynard, C Bush, KR Davis, TM Bradley, KA AF Dobie, DJ Kivlahan, DR Maynard, C Bush, KR Davis, TM Bradley, KA TI Posttraumatic stress disorder in female veterans - Association with self-reported health problems and functional impairment SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID QUALITY-OF-LIFE; MALE VIETNAM VETERANS; PTSD CHECKLIST; PRIMARY-CARE; SCREENING INSTRUMENT; SEXUAL VICTIMIZATION; TRAUMATIC EVENTS; AFFAIRS PATIENTS; BREAST-CANCER; DESERT-STORM AB Background: The purpose of this report is to identify self-reported health problems and functional impairment associated with screening positive for posttraumatic stress disorder (PTSD) in women seen for care at a Department of Veterans Affairs (VA) medical center. Methods: A survey was mailed to all women (N = 1935) who received care at the VA Puget Sound Health Care System between October 1996 and January 1998. The survey inquired about health history and habits. It included the PTSD Checklist-Civilian Version (PCL-C) and validated screening measures for other psychiatric disorders. The veteran's version of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36-V) was included to assess health-related quality of life. Results: Of the 1259 eligible women who completed the survey, 266 women (21%) screened positive for current PTSD (PCL-C score greater than or equal to50). In age-adjusted bivariate analyses, women who screened positive for PTSD reported more psychiatric problems, substance abuse, and lifetime exposure to domestic violence. They were significantly more likely to endorse physical health problems including obesity, smoking, irritable bowel syndrome, fibromyalgia, chronic pelvic pain, polycystic ovary disease, asthma, cervical cancer, and stroke. In fully adjusted multivariate models, a PCL-C score of 50 or greater was independently associated with scoring in the lowest quartile on SF-36-V subscales and composite scales. Conclusions: Symptoms of PTSD are common in women treated at VA facilities. In addition, PTSD is associated with self-reported mental and physical health problems and poor health-related quality of life in these patients. These findings have implications for the design of VA primary care services for the growing population of female veterans. C1 Univ Washington, Sch Med, Dept Psychiat, Seattle, WA USA. Univ Washington, Sch Med, Dept Behav Sci, Seattle, WA USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. Hlth Serv Res & Dev, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Dobie, DJ (reprint author), S-116 VA PSHCS,1660 S Columbian Way, Seattle, WA 98108 USA. EM djdobie@u.washington.edu RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 NR 60 TC 182 Z9 187 U1 3 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2004 VL 164 IS 4 BP 394 EP 400 DI 10.1001/archinte.164.4.394 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 776ZE UT WOS:000189148600006 PM 14980990 ER PT J AU Redline, S Kirchner, L Quan, SF Gottlieb, DJ Kapur, V Newman, A AF Redline, S Kirchner, L Quan, SF Gottlieb, DJ Kapur, V Newman, A TI The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SLOW-WAVE SLEEP; POSITIVE AIRWAY PRESSURE; GENDER DIFFERENCES; CORTISOL-LEVELS; GROWTH-HORMONE; NORMAL HUMANS; REM-SLEEP; APNEA; DEPRIVATION; ADULTS AB Background: Polysomnography is used to assess sleep quality and to gauge the functional effect of sleep disorders. Few population-based data are available to estimate the variation in sleep architecture across the population and the extent to which sleep-disordered breathing (SDB), a common health condition, contributes to poor sleep independent of other factors. The objective of this study was to describe the population variability in sleep quality and to quantify the independent associations with SDB. Methods: Cross-sectional analyses were performed on data from 2685 participants, aged 37 to 92 years, in a community-based multicenter cohort study. Dependent measures included the percentage time in each sleep stage, the arousal index, and sleep efficiency. Independent measures were age, sex, ethnicity, comorbidity status, and the respiratory disturbance index. Results: Lighter sleep was found in men relative to women and in American Indians and blacks relative to other ethnic groups. Increasing age was associated with impaired sleep in men, with less consistent associations in women. Notably, women had, on average, 106% more slow wave sleep. Sleep-disordered breathing was associated with poorer sleeps however, these associations were generally smaller than associations with sex, ethnicity, and age. Current smokers had lighter sleep than ex-smokers or never smokers. Obesity had little effect on sleep. Conclusions: Sleep architecture varies with sex, age, ethnicity, and SDB. Individual assessment of the effect of SDB on sleep quality needs to account for other host characteristics. Men, but not women, show evidence of poorer sleep with aging, suggesting important sex differences in sleep physiology. C1 Case Western Reserve Univ, Dept Pediat, Div Clin Epidemiol, Rainbow Babies & Childrens Hosp, Cleveland, OH 44106 USA. Univ Arizona, Coll Med, Resp Sci & Sleep Disorders Ctr, Tucson, AZ USA. Boston Univ, Dept Med, Boston, MA 02215 USA. VA Boston Healthcare, Boston, MA USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA USA. RP Redline, S (reprint author), Rainbow Babies & Childrens Hosp, Dept Pediat, Div Clin Epidemiol, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM sxr15@po.cwru.edu RI Newman, Anne/C-6408-2013; Kapur, Vishesh/K-1054-2014 OI Newman, Anne/0000-0002-0106-1150; Kapur, Vishesh/0000-0002-5417-1097 FU NHLBI NIH HHS [U01 HL053938, U01 HL53931, U01 HL53934, U01 HL53937, U01 HL53938, U01 HL53940, U01 HL63463, U01HL53941] NR 48 TC 232 Z9 235 U1 4 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 23 PY 2004 VL 164 IS 4 BP 406 EP 418 DI 10.1001/archinte.164.4.406 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 776ZE UT WOS:000189148600008 PM 14980992 ER PT J AU Mukherjee, S AF Mukherjee, S TI The anatomy of hope - How people prevail in the face of illness SO NEW YORK TIMES BOOK REVIEW LA English DT Book Review C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA. RP Mukherjee, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU NEW YORK TIMES PI NEW YORK PA 229 W 43RD ST, NEW YORK, NY 10036-3959 USA SN 0028-7806 J9 NY TIMES BK REV JI N. Y. Times Book Rev. PD FEB 22 PY 2004 BP 22 EP 22 PG 1 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 774FD UT WOS:000188968300032 ER PT J AU Driscoll, SD Meininger, GE Lareau, MT Dolan, SE Killilea, KM Hadigan, CM Lloyd-Jones, DM Klibanski, A Frontera, WR Grinspoon, SK AF Driscoll, SD Meininger, GE Lareau, MT Dolan, SE Killilea, KM Hadigan, CM Lloyd-Jones, DM Klibanski, A Frontera, WR Grinspoon, SK TI Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients SO AIDS LA English DT Article DE lipodystrophy; HIV; exercise; metformin; body composition; cardiovascular ID HUMAN-IMMUNODEFICIENCY-VIRUS; CORONARY-HEART-DISEASE; PROTEASE INHIBITOR THERAPY; ANTIRETROVIRAL THERAPY; INSULIN SENSITIVITY; GLUCOSE-TOLERANCE; FAT DISTRIBUTION; RISK-FACTORS; METABOLIC ABNORMALITIES; COMPUTED-TOMOGRAPHY AB Objective: To determine whether exercise training in combination with metformin improves cardiovascular risk indices and insulin in comparison to metformin alone among HIV-infected patients. Methods and design: We conducted a prospective, randomized, 3-month study of HIV patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution. Subjects received metformin alone or metformin and exercise training consisting of 1 h of aerobic and resistance training three times a week. Cardiovascular parameters, including blood pressure and endurance during sub-maximal stress testing, body composition, strength, insulin and other biochemical parameters were determined. Results: Thirty-seven patients were randomized and 25 subjects completed the study. Subjects receiving exercise training and metformin demonstrated significant decreases in median waist-to-hip ratio [-0.02 (-0.06, -0.01) (median (interquartile range) versus -0.01 (0.03, 0.02), P = 0.026], resting systolic [-12 (-20, -4) versus 0 (-11, 11), P = 0.012] and diastolic blood pressures [-10 (-14, -8) versus 0 (-7, 8), P = 0.001], increased thigh muscle cross-sectional area [3 (-3, 12) versus -7 (-11, 0), P = 0.015], and improved exercise time [3 (0,4) versus 0 (-1, 1), P = 0.045] compared with subjects receiving metformin alone. Fasting insulin and insulin area under the curve decreased significantly more in the exercise and metformin group (P < 0.05). Lipids and resting lactate did not change significantly between treatment groups. Conclusions: These data demonstrate that exercise training in combination with metformin significantly improves cardiovascular and biochemical parameters more than metformin alone in HIV-infected patients with fat redistribution and hyperinsulinemia. Combined treatment was safe, well tolerated and may be a useful strategy to decrease cardiovascular risk in this population. (C) 2004 Lippincott Williams Wilkins. C1 Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Grinspoon, SK (reprint author), Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02144 USA. EM sgrinspoon@partners.org RI Lloyd-Jones, Donald/C-5899-2009 FU NCRR NIH HHS [RR01066, RR00088]; NIDDK NIH HHS [DK49302] NR 45 TC 68 Z9 71 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 20 PY 2004 VL 18 IS 3 BP 465 EP 473 DI 10.1097/00002030-200402200-00013 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 803LQ UT WOS:000220233000013 PM 15090799 ER PT J AU Dolan, SE Huang, JS Killilea, KM Sullivan, MP Aliabadi, N Grinspoon, S AF Dolan, SE Huang, JS Killilea, KM Sullivan, MP Aliabadi, N Grinspoon, S TI Reduced bone density in HIV-infected women SO AIDS LA English DT Article DE HIV; women; bone density; osteoporosis; osteopenia ID HUMAN-IMMUNODEFICIENCY-VIRUS; X-RAY ABSORPTIOMETRY; BODY-MASS INDEX; ANTIRETROVIRAL THERAPY; POSTMENOPAUSAL WOMEN; ANOREXIA-NERVOSA; MINERAL DENSITY; OSTEOPENIA; WEIGHT; TURNOVER AB Objectives: Although bone density has been previously investigated in HIV-infected men, little is known regarding bone density in HIV-infected women. Methods and design: Bone density was measured by dual-energy X-ray absorptiometry in 84 ambulatory, HIV-infected females and 63 healthy female control subjects similar in age (41 +/- 1 versus 41 +/- 1 years, P = 0.83), body mass index (26.0 +/- 0.6 versus 27.0 +/- 0.5 kg/m(2), P = 0.44) and racial background (% non-Caucasian, 61 versus 51 %; P = 0.24, HIV-infected versus control). Results: Lumbar spine (1.02 +/- 0.02 versus 1.07 +/- 0.02 g/cm(2), P = 0.03) and total hip (0.93 +/- 0.01 versus 0.99 +/- 0.01 g/cm(2), P = 0.004) bone density were reduced in HIV-infected compared with control subjects. Osteopenia was demonstrated in 54 versus 30% (P = 0.004) of HIV-infected versus control subjects and was 2.5 times more likely in a multivariate model accounting for age, race, menstrual function and body mass index. Urinary N-telopeptides of type 1 collagen (NTx) (39.6 +/- 3.5 versus 29.9 +/- 2.0 nM/mM urine creatinine, P = 0.03) and osteoprotegerin (4.76 +/- 0.23 versus 3.39 +/- 0.17 pmol/l, P less than or equal to 0.0001) were increased in HIV-infected compared with control subjects. Among the HIV-infected women, bone density correlated with weight (r = 0.41, P < 0.001) and inversely with urinary NTx (r = -0.28, P = 0.01). Bone density did not differ by current or past protease inhibitor, nucleoside reverse trancriptase inhibitor, or non-nucleoside reverse transcriptase inhibitor exposure. Conclusions: HIV-infected women demonstrate reduced bone density. Altered nutritional status, hormonal function and body composition may contribute to lower bone density in HIV-infected women. Consideration should be given to testing bone density in HIV-infected women with risk factors for osteopenia. (C) 2004 Lippincott Williams Wilkins. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. Univ Calif San Diego, Program Pediat Gastroenterol & Nutr, San Diego, CA 92103 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [3-M01-RR 01066-25S1]; NIAID NIH HHS [AI51947, K23 AI051947, K23 AI051947-03]; NIDDK NIH HHS [DK 59535] NR 28 TC 88 Z9 91 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 20 PY 2004 VL 18 IS 3 BP 475 EP 483 DI 10.1097/00002030-200402200-00014 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 803LQ UT WOS:000220233000014 PM 15090800 ER PT J AU Goo, YH Na, SY Zhang, H Xu, JM Hong, SH Cheong, JH Lee, SK Lee, JW AF Goo, YH Na, SY Zhang, H Xu, JM Hong, SH Cheong, JH Lee, SK Lee, JW TI Interactions between activating signal cointegrator-2 and the tumor suppressor retinoblastoma in androgen receptor transactivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREB-BINDING PROTEIN; NUCLEAR-RECEPTOR; DEPENDENT TRANSACTIVATION; HORMONE-RECEPTORS; COACTIVATOR; CANCER; MICE; TRANSCRIPTION; MOTIF; COREGULATORS AB Activating signal cointegrator-2 (ASC-2), a cancer-amplified transcription coactivator of nuclear receptors and numerous other transcription factors, was previously shown to contain two LXXLL motifs, each of which interacts with a distinct set of nuclear receptors. In this work, we showed that ASC-2 has an indirect, separate binding site for androgen receptor (AR). Interestingly, this region overlapped with the direct interaction interfaces with the tumor suppressor retinoblastoma (Rb). Although ASC-2 alone stimulated AR transactivation in cotransfections of HeLa cells, ectopic expression of Rb effected ASC-2 to act as a transcription coactivator of AR in Rb-null Saos2 cells. These results, along with the previous report in which AR was shown to directly interact with Rb (Yeh, S., Miyamoto, H., Nishimura, K., Kang, H., Ludlow, J., Hsiao, P., Wang, C., Su, C., and Chang C. (1998) Biochem. Biophys. Res. Commun. 248, 361-367), suggest that the AR-ASC-2 interactions in vivo may involve Rb. Thus, ASC-2 appears to contain at least three distinct nuclear receptor interaction domains. C1 Baylor Coll Med, Dept Med, Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Pusan Natl Univ, Dept Mol Biol, Pusan 609735, South Korea. Salk Inst Biol Studies, Gene Express Lab, San Diego, CA 92185 USA. RP Lee, JW (reprint author), Baylor Coll Med, Dept Med, Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. EM jwlee@bcm.tmc.edu NR 27 TC 11 Z9 12 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 20 PY 2004 VL 279 IS 8 BP 7131 EP 7135 DI 10.1074/jbc.M312563200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 774FM UT WOS:000188969200112 PM 14645241 ER PT J AU Padera, TP Stoll, BR Tooredman, JB Capen, D di Tomaso, E Jain, RK AF Padera, TP Stoll, BR Tooredman, JB Capen, D di Tomaso, E Jain, RK TI Cancer cells compress intratumour vessels SO NATURE LA English DT Editorial Material ID SOLID TUMORS; PRESSURE C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. RP Padera, TP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu NR 10 TC 354 Z9 364 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 19 PY 2004 VL 427 IS 6976 BP 695 EP 695 DI 10.1038/427695a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775DT UT WOS:000189026000028 PM 14973470 ER PT J AU Niquet, J Allen, SG Baldwin, RA Wasterlain, CG AF Niquet, J Allen, SG Baldwin, RA Wasterlain, CG TI Evidence of caspase-3 activation in hyposmotic stress-induced necrosis SO NEUROSCIENCE LETTERS LA English DT Article DE dentate gyrus culture; electron microscopy; immunocytochemistry ID TRANSIENT CEREBRAL-ISCHEMIA; CELL-DEATH; APOPTOTIC NEURODEGENERATION; BRAIN; HIPPOCAMPUS; NEURONS AB Primary culture of dentate gyrus was submitted to a hyposmotic stress that induces a rapid cell death that is necrosis morphologically. Surprisingly, we observed a rapid and dramatic upregulation of the active form of caspase-3 (caspase-3(a)) in both neurons and glial cells. Caspase-3(a) immunoreactivity appears as early as 1 min after hyposmotic treatment, when some neurons are still alive, suggesting that caspase-3a may contribute to further necrotic cell death. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. RP Niquet, J (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jniquet@ucla.edu FU NINDS NIH HHS [NS13515] NR 12 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 19 PY 2004 VL 356 IS 3 BP 225 EP 227 DI 10.1016/j.neulet.2003.11.063 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 774DX UT WOS:000188965400018 PM 15036635 ER PT J AU Kales, SN Christiani, DC AF Kales, SN Christiani, DC TI Current concepts - Acute chemical emergencies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SUBWAY SARIN ATTACK; EAR VESICANT MODEL; HYDROGEN-SULFIDE; SULFUR MUSTARD; HYDROFLUORIC-ACID; HYPERBARIC-OXYGEN; TOKYO SUBWAY; SODIUM-NITRITE; WARFARE AGENTS; UNITED-STATES C1 Harvard Univ, Sch Med, Cambridge Hlth Alliance, Dept Med Occupat & Environm Hlth, Cambridge, MA 02139 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Occupat Hlth Program, Boston, MA 02115 USA. Massachusetts Gen Hosp, Pulm Crit Care Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NE Specialty & Rehabil Hosp, Ctr Occupat & Environm Med, Braintree, MA USA. RP Kales, SN (reprint author), Harvard Univ, Sch Med, Cambridge Hlth Alliance, Dept Med Occupat & Environm Hlth, 1493 Cambridge St, Cambridge, MA 02139 USA. EM skales@challiance.org FU NIEHS NIH HHS [ES00002] NR 77 TC 58 Z9 58 U1 1 U2 6 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 19 PY 2004 VL 350 IS 8 BP 800 EP 808 DI 10.1056/NEJMra030370 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 774VM UT WOS:000189006400008 PM 14973213 ER PT J AU Sheridan, RL Schulz, JT McGinnis, PJ Ryan, CM Harris, NL AF Sheridan, RL Schulz, JT McGinnis, PJ Ryan, CM Harris, NL TI Case 6-2004: A 35-year-old woman with extensive, deep burns from a nightclub fire SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HYPERBARIC-OXYGEN; MANAGEMENT; RESUSCITATION; CHILDREN C1 Massachusetts Gen Hosp, Burn Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Trauma Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Sheridan, RL (reprint author), Massachusetts Gen Hosp, Burn Serv, Boston, MA 02114 USA. NR 30 TC 4 Z9 4 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 19 PY 2004 VL 350 IS 8 BP 810 EP 821 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 774VM UT WOS:000189006400011 PM 14973211 ER PT J AU Luoh, SW Venkatesan, N Tripathi, R AF Luoh, SW Venkatesan, N Tripathi, R TI Overexpression of the amplified Pip4k2 beta gene from 17q11-12 in breast cancer cells confers proliferation advantage SO ONCOGENE LA English DT Article DE tumor biology; breast cancer; gene amplification; gene expression; HER-2/Neu ID IN-SITU HYBRIDIZATION; PHOSPHATIDYLINOSITOL PHOSPHATE KINASES; GROWTH-FACTOR RECEPTOR; HER-2/NEU GENE; N-MYC; INOSITIDE PHOSPHORYLATION; AMPLIFICATION STATUS; 11Q13 AMPLIFICATION; PUTATIVE ONCOGENE; PROGNOSTIC-FACTOR AB Gene amplification is common in solid tumors and is associated with adverse prognosis, disease progression, and development of drug resistance. A small segment from chromosome 17q11-12 containing the HER-2/Neu gene is amplified in about 25% of breast cancer. HER-2/Neu amplification is associated with adverse prognosis and may predict response to chemotherapy and hormonal manipulation. Moreover, HER-2/Neu amplification may select patients for anti-HER-2/Neu-based therapy with Herceptin. We and others recently described a common sequence element from the HER-2/Neu region that was amplified in breast cancer cells. In addition, most, if not all, of the amplified genes from this region display overexpression. This raises the intriguing possibility that genes immediately adjacent to HER-2/Neu may influence the biological behavior of breast cancer carrying HER-2/ Neu amplification and serve as rational targets for therapy. By extracting sequence information from public databases, we have constructed a contig in bacterial artificial chromosomes (BACs) that extends from HER-2/ Neu to a phosphotidylinositol phosphate kinase (PIPK), Pip4k2beta from 17q11 - 12. Although a role of PI-3-kinase and AKT in cancer biology has been previously described, PIPK has not been previously implicated. We show that Pip4k2b, initially known as Pip5k2beta, is amplified in a subset of breast cancer cell lines and primary breast cancer samples that carry HER-2/ Neu amplification. Out of eight breast cancer cell lines with HER-2/ Neu amplification, three have concomitant amplification of the Pip4k2beta gene - UACC-812, BT-474 and ZR-75-30. Similarly, two out of four primary breast tumors with HER-2/ Neu amplification carry Pip4k2b gene amplification. Intriguingly, one tumor displays an increase in the gene copy number of Pip4k2b that is significantly more than that of HER-2/ Neu. Moreover, dual color FISH reveals that amplified Pip4k2b gene may exist in a distinct structure from that of HER-2/ Neu in ZR-75-30 cell line. These studies suggest that Pip4k2b may reside on an amplification maximum distinct from that of HER-2/Neu and serve as an independent target for amplification and selective retention. Pip4k2beta amplification is associated with overexpression at the RNA and protein level in breast cancer cell lines. Stable expression of Pip4k2b in breast cancer cell lines with and without HER-2/Neu amplification increases cell proliferation and anchorage-independent growth. The above observations implicate Pip4k2b in the development and/or progression of breast cancer. Our study suggests that Pip4k2b may be a distinct target for gene amplification and selective retention from 17q11-12. C1 Univ Calif Los Angeles, Med Ctr, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. Cincinnati Vet Affairs Med Ctr, Cincinnati, OH 45220 USA. Univ Cincinnati, Coll Med, Dept Med, Div Hematol & Oncol, Cincinnati, OH 45267 USA. RP Luoh, SW (reprint author), Oregon Hlth Sci Univ, Portland VA Med Ctr, RAD 47,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. NR 67 TC 29 Z9 29 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 19 PY 2004 VL 23 IS 7 BP 1354 EP 1363 DI 10.1038/sj.onc.1207251 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 775HZ UT WOS:000189035800003 PM 14691457 ER PT J AU Tegeder, I Niederberger, E Schmidt, R Kunz, S Guhring, H Ritzeler, O Michaelis, M Geisslinger, G AF Tegeder, I Niederberger, E Schmidt, R Kunz, S Guhring, H Ritzeler, O Michaelis, M Geisslinger, G TI Specific inhibition of I kappa B kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats SO JOURNAL OF NEUROSCIENCE LA English DT Article DE behavior; dorsal horn; hyperalgesia; neuropathy; protein kinase; transcription ID SPINAL-CORD; TRANSCRIPTION FACTORS; SODIUM-SALICYLATE; GLIAL ACTIVATION; BREAST-CANCER; NERVE INJURY; P65 SUBUNIT; IKK-BETA; ALPHA; EXPRESSION AB Phosphorylation of IkappaB through IkappaB kinase (IKK) is the first step in nuclear factor kappaB (NF-kappaB) activation and upregulation of NF-kappaB-responsive genes. Hence, inhibition of IKK activity may be expected to prevent injury-, infection-, or stress-induced upregulation of various proinflammatory genes and may thereby reduce hyperalgesia and inflammation. In the present study, we tested this hypothesis using a specific and potent IKK inhibitor (S1627). In an IKK assay, S1627 inhibited IKK activity with an IC50 value of 10.0 +/- 1.2 nM. In cell culture experiments, S1627 inhibited interleukin (IL)-1beta-stimulated nuclear translocation and DNA-binding of NF-kappaB. Plasma concentration time courses after intraperitoneal injection revealed a short half-life of 2.8 hr in rats. Repeated intraperitoneal injections were, therefore, chosen as the dosing regimen. S1627 reversed thermal and mechanical hyperalgesia at 3 X 30 mg/kg in the zymosan-induced paw inflammation model and reduced the inflammatory paw edema at 3 X 40 mg/kg. S1627 also significantly reduced tactile and cold allodynia in the chronic constriction injury model of neuropathic pain at 30 mg/kg once daily. The drug had no effect on acute inflammatory nociception in the formalin test and did not affect responses to heat and tactile stimuli in naive animals. As hypothesized, S1627 prevented the zymosan-induced nuclear translocation of NF-kappaB in the spinal cord and the upregulation of NF-kappaB-responsive genes including cyclooxygenase-2, tumor necrosis factor-alpha, and IL-1beta. Our data indicate that IKK may prove an interesting novel drug target in the treatment of pathological pain and inflammation. C1 Univ Frankfurt Klinikum, Inst Klin Pharmakol, Pharmazentrum Frankfurt, D-60590 Frankfurt, Germany. Aventis Pharma Deutschland, D-65929 Frankfurt, Germany. RP Tegeder, I (reprint author), Massachusetts Gen Hosp, Dept Anesthesia, Neural Plast Res Grp, Room 4309,149 13th St, Charlestown, MA 02129 USA. EM itegeder@partners.org OI Tegeder, Irmgard/0000-0001-7524-8025 NR 53 TC 103 Z9 117 U1 0 U2 3 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 FEB 18 PY 2004 VL 24 IS 7 BP 1637 EP 1645 DI 10.1523/JNEUROSCI.3118-03.2004 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 775HU UT WOS:000189035300013 PM 14973242 ER PT J AU Roe, MT Green, CL Giugliano, RP Gibson, CM Baran, K Greenberg, M Palmeri, ST Crater, S Trollinger, K Hannan, K Harrington, RA Krucoff, MW AF Roe, MT Green, CL Giugliano, RP Gibson, CM Baran, K Greenberg, M Palmeri, ST Crater, S Trollinger, K Hannan, K Harrington, RA Krucoff, MW CA INTEGRITI Investigators TI Improved speed and stability of ST-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute ST-segment elevation myocardial infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID GLYCOPROTEIN IIB/IIIA INHIBITION; TISSUE-PLASMINOGEN ACTIVATOR; LEFT-VENTRICULAR FUNCTION; ACUTE CORONARY SYNDROMES; TIMI 14 TRIAL; REPERFUSION THERAPY; THROMBOLYTIC THERAPY; PRIMARY ANGIOPLASTY; COMBINATION THERAPY; PATENCY ASSESSMENT AB OBJECTIVES This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results. BACKGROUND Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics. METHODS We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 mug/kg) plus high-dose eptifibatide (2 boluses of 180 mug/kg separated by 10 min, 2.0 mug/kg/min infusion) was compared with full-dose tenecteplase (0.53 mug/kg). RESULTS The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min. CONCLUSIONS Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes. (C) 2004 by the American College of Cardiology Foundation. C1 Duke Clin Res Inst, Durham, NC 27715 USA. Duke Med Ctr, Div Cardiol, Durham, NC USA. Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. John Nasseff Heart Hosp, St Paul, MN USA. Montefiore Med Ctr, New York, NY USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. RP Roe, MT (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM roe00001@mc.duke.edu NR 36 TC 18 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 18 PY 2004 VL 43 IS 4 BP 549 EP 556 DI 10.1016/j.jacc.2003.09.039 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 773VJ UT WOS:000188944600008 PM 14975462 ER PT J AU Januzzi, JL Isselbacher, EM Fattori, R Cooper, JV Smith, DE Fang, JM Eagle, KA Mehta, RH Nienaber, CA Pape, LA AF Januzzi, JL Isselbacher, EM Fattori, R Cooper, JV Smith, DE Fang, JM Eagle, KA Mehta, RH Nienaber, CA Pape, LA TI Characterizing the young patient with aortic dissection: Results from the international registry of aortic dissection (IRAD) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID VALVE; MALFORMATION; PREDICTORS; ANEURYSM; AGE AB OBJECTIVES The goal of this study was to better characterize the young patient with aortic dissection (AoD). BACKGROUND Aortic dissection is unusual in young patients, and frequently associated with unusual presentations. METHODS Data were collected on 951 patients diagnosed with AoD between January 1996 and November 2001. Two categories of patients, <40 years and 40 years, were compared using chi-square cross tabulations for categorical and Student t test for continuous data. RESULTS Sixty-eight patients (7%) with AoD were <40 years of age. Compared with patients greater than or equal to40 years, younger patients were less likely to have a prior history of hypertension (p < 0.05); however, younger patients were more likely to have Marfan syndrome, bicuspid aortic valve, and prior aortic surgery (all, p < 0.05). Clinical presentations in the two age groups were similar; however, younger patients were less likely to be hypertensive (25% vs. 45%, p = 0.003). The proximal aortas of young AoD patients were larger (all, p < 0.05) compared with older patients. These differences in aortic size between age groups were not entirely related to Marfan syndrome. Mortality among young patients was similar to patients greater than or equal to40 years of age (22% vs. 24%, p = NS), irrespective of the site of dissection. CONCLUSIONS Compared with older patients with AoD, young patients have unique risk factors for dissection: Marfan syndrome, bicuspid aortic valves, and larger aortic dimensions. Surprisingly, the mortality risk for young AoD patients is not lower than older AoD patients. (C) 2004 by the American College of Cardiology Foundation. C1 Univ Massachusetts, Sch Med, Div Cardiol, Worcester, MA 01655 USA. Massachusetts Gen Hosp, Thorac Aorta Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Univ Bologna, Hosp S Orsola, Bologna, Italy. Univ Michigan, Med Ctr, Div Cardiol, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Coordinating Ctr IRAD Invest, Ann Arbor, MI 48109 USA. Univ Rostock, Div Cardiol, Rostock, Germany. RP Pape, LA (reprint author), Univ Massachusetts, Sch Med, Div Cardiol, 55 Lake Ave N,S3-850, Worcester, MA 01655 USA. EM Linda.pape@umassmed.edu NR 14 TC 157 Z9 165 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD FEB 18 PY 2004 VL 43 IS 4 BP 665 EP 669 DI 10.1016/j.jacc.2003.08.054 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 773VJ UT WOS:000188944600026 PM 14975480 ER PT J AU Umar, A Boland, CR Terdiman, JP Syngal, S de la Chapelle, A Ruschoff, J Fishel, R Lindor, NM Burgart, LJ Hamelin, R Hamilton, SR Hiatt, RA Jass, J Lindblom, A Lynch, HT Peltomaki, P Ramsey, SD Rodriguez-Bigas, MA Vasen, HFA Hawk, ET Barrett, JC Freedman, AN Srivastava, S AF Umar, A Boland, CR Terdiman, JP Syngal, S de la Chapelle, A Ruschoff, J Fishel, R Lindor, NM Burgart, LJ Hamelin, R Hamilton, SR Hiatt, RA Jass, J Lindblom, A Lynch, HT Peltomaki, P Ramsey, SD Rodriguez-Bigas, MA Vasen, HFA Hawk, ET Barrett, JC Freedman, AN Srivastava, S TI Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID MISMATCH REPAIR; COLON-CANCER; CELL-LINES; POPULATION; HNPCC; MUTATIONS; TUMORS; CARCINOMAS; EXPRESSION; FAMILIES AB Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with NISI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for NISI testing. C1 NCI, Div Canc Prevent, NIH, US Dept HHS, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, US Dept HHS, Bethesda, MD 20892 USA. Baylor Univ, Med Ctr, Div Gastroenterol, Dallas, TX USA. Univ Calif San Francisco, Dept Med, Ctr Comprehens Canc, San Francisco, CA 94143 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Klinikum Kassel, Inst Pathol, Kassel, Germany. Thomas Jefferson Univ, Genet & Mol Biol Program, Dept Microbiol & Immunol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Ctr Etud Polymorphisme Humain, INSERM, U434, F-75010 Paris, France. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. McGill Univ, Dept Pathol, Montreal, PQ, Canada. Karolinska Inst, Dept Mol Med, Clin Genet Unit, Stockholm, Sweden. Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA. Univ Helsinki, Dept Med Genet, Helsinki, Finland. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Fdn Detect Hereditary Tumours, Leiden, Netherlands. RP Umar, A (reprint author), NCI, Div Canc Prevent, NIH, US Dept HHS, 6130 Execut Blvd,EPN 2141, Bethesda, MD 20892 USA. EM asad.umar@nih.gov OI Peltomaki, Paivi/0000-0001-8819-2980 FU NCI NIH HHS [U01 CA074800-05, R01 CA067007, U01 CA074800] NR 60 TC 1380 Z9 1421 U1 4 U2 59 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 18 PY 2004 VL 96 IS 4 BP 261 EP 268 DI 10.1093/jnci/djh034 PG 8 WC Oncology SC Oncology GA 773YW UT WOS:000188953800008 PM 14970275 ER PT J AU Hur, C Nishioka, NS Gazelle, GS AF Hur, C Nishioka, NS Gazelle, GS TI Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NONVALVULAR ATRIAL-FIBRILLATION; PREVENT COLORECTAL ADENOMAS; HIGH-GRADE DYSPLASIA; GASTROESOPHAGEAL-REFLUX; CARDIOVASCULAR EVENTS; RANDOMIZED-TRIAL; UNITED-STATES; CANCER-RISK; TASK-FORCE; SURVEILLANCE AB Background: Recent data suggest that nonsteroidal anti-inflammatory drugs, including aspirin, may prevent the progression of Barrett's esophagus to adenocarcinoma. However, use of aspirin is associated with numerous potential complications, including gastrointestinal bleeding and hemorrhagic strokes. We used a modeling approach to determine and compare the effectiveness and cost-effectiveness of aspirin with and without endoscopic surveillance to prevent esophageal adenocarcinoma. Methods: A Markov Monte Carlo decision model was constructed to compare four strategies for management of Barrett's esophagus: aspirin therapy, endoscopic surveillance with biopsies, both, or neither. Patients who took a daily enteric-coated aspirin were modeled to have a 50% reduction in the incidence of esophageal adenocarcinoma but could have complications related to therapy, at which point the aspirin was discontinued. Potential cardiac benefits of aspirin and its role in the chemoprevention of other cancers were not included in the analysis. The analysis was from a societal perspective from age 55 years until death. Sensitivity analyses were performed to investigate the effects of changes in model parameters on estimated costs and effectiveness outcomes across a wide range of assumptions. Results: Aspirin therapy was more effective and less costly than no therapy, resulting in 0.19 more quality-adjusted life years (QALYs). The combination of aspirin and endoscopic surveillance produced 0.27 more QALYs than no therapy at a cost of U.S.$13 400 more, for an associated incremental cost-effectiveness ratio of U.S.$49 600/QALY. Aspirin use in combination with endoscopic surveillance dominated endoscopic surveillance alone, resulting in 0.06 more QALYs and U.S.$11 400 less cost. The model's results were sensitive to increasing age and to decreased benefit or delay in aspirin's chemopreventive efficacy. Conclusion: Using published values of parameters, regardless of whether a patient undergoes endoscopic surveillance, aspirin use in the management of Barrett's esophagus appears to be a cost-effective strategy to prevent esophageal adenocarcinoma. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Hur, C (reprint author), 101 Merrimac St,10th Fl, Boston, MA 02114 USA. EM chur@partners.org OI Hur, Chin/0000-0002-2819-7576 NR 52 TC 36 Z9 38 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 18 PY 2004 VL 96 IS 4 BP 316 EP 325 DI 10.1093/jnci/djh039 PG 10 WC Oncology SC Oncology GA 773YW UT WOS:000188953800013 PM 14970280 ER PT J AU Chen, GC Gajowniczek, P Settleman, J AF Chen, GC Gajowniczek, P Settleman, J TI Rho-LIM kinase signaling regulates ecdysone-induced gene expression and morphogenesis during Drosophila metamorphosis SO CURRENT BIOLOGY LA English DT Article ID STUBBLE-STUBBLOID LOCUS; SERUM RESPONSE FACTOR; BROAD-COMPLEX; ACTIN CYTOSKELETON; DYNAMICS; ACTIVATION; POLARITY; ENCODES AB The steroid hormone 20-hydroxyecdysone (ecdysone) is the key regulator of postembryonic developmental transitions in insects and controls metamorphosis by triggering the morphogenesis of adult tissues from larvae. The Rho GTPase, which mediates cell shape change and migration, is also an essential regulator of tissue morphogenesis during development. Rho activity can modulate gene expression, in part, by activating LIM kinase (LIMK) and consequently affecting actin-induced SRF transcriptional activity. We have established a link between Rho-LIMK-SRF signaling and the ecdysone-induced transcriptional response during Drosophila development. Specifically, we determined that the Rho GTPase, via LIMK, regulates the expression of several ecdysone-responsive genes, including those encoding the ecdysone receptor itself, a downstream transcription factor (Br-C), and Stubble, a transmembrane protease required for proper leg formation. Stubble and Br-C mutants exhibit strong genetic interactions with several Rho pathway components in the formation of adult structures, but not with Rac or Cdc42. In cultured SL2 cells, inhibition of Rho, F-actin assembly, or SRF blocks the transcriptional response to ecdysone. Together, these findings indicate a link between Rho-LIMK-SRF signaling and steroid hormone-induced gene expression in the context of metamorphosis and thereby establish a novel role for the Rho GTPase in development. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu FU NIGMS NIH HHS [R01 GM60466] NR 19 TC 17 Z9 18 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 17 PY 2004 VL 14 IS 4 BP 309 EP 313 DI 10.1016/j.cub.2004.01.056 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 776UK UT WOS:000189136600020 PM 14972681 ER PT J AU Scacheri, PC Rozenblatt-Rosen, O Caplen, NJ Wolfsberg, TG Umayam, L Lee, JC Hughes, CM Shanmugam, KS Bhattacharjee, A Meyerson, M Collins, FS AF Scacheri, PC Rozenblatt-Rosen, O Caplen, NJ Wolfsberg, TG Umayam, L Lee, JC Hughes, CM Shanmugam, KS Bhattacharjee, A Meyerson, M Collins, FS TI Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR; MENIN INTERACTS; CAENORHABDITIS-ELEGANS/; GENE-EXPRESSION; MICRORNAS; PRODUCT; IDENTIFICATION; MECHANISMS; SIRNAS; MOUSE AB RNA interference (RNAi) mediated by short interfering RNAs (siRNAs) is a widely used method to analyze gene function. To use RNAi knockdown accurately to infer gene function, it is essential to determine the specificity of siRNA-mediated RNAi. We have assessed the specificity of 10 different siRNAs corresponding to the MEN1 gene by examining the expression of two additional genes, TP53 (p53) and CDKN1A (p21), which are considered functionally unrelated to menin but are sensitive markers of cell state. MEN1 RNA and corresponding protein levels were all reduced after siRNA transfection of HeLa cells, although the degree of inhibition mediated by individual siRNAs varied. Unexpectedly, we observed dramatic and significant changes in protein levels of p53 and p21 that were unrelated to silencing of the target gene. The modulations in p53 and p21 levels were not abolished on titration of the siRNAs, and similar results were obtained in three other cell lines; in none of the cell lines tested did we see an effect on the protein levels of actin. These data suggest that siRNAs can induce nonspecific effects on protein levels that are siRNA sequence dependent but that these effects may be difficult to detect until genes central to a pivotal cellular response, such as p53 and p21, are studied. We find no evidence that activation of the double-stranded RNA- triggered IFN-associated antiviral pathways accounts for these effects, but we speculate that partial complementary sequence matches to off-target genes may result in a micro-RNA-like inhibition of translation. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Agilent Technol, Andover, MA 01810 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bldg 31,Room 4809,31 Ctr Dr, Bethesda, MD 20892 USA. EM fc23a@nih.gov RI Meyerson, Matthew/E-7123-2012; Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 NR 29 TC 392 Z9 415 U1 2 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2004 VL 101 IS 7 BP 1892 EP 1897 DI 10.1073/pnas.0308698100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600020 PM 14769924 ER PT J AU Pai, SY Truitt, ML Ho, IC AF Pai, SY Truitt, ML Ho, IC TI GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR GATA-3; CYTOKINE GENE-EXPRESSION; IL-4 GENE; COORDINATE REGULATOR; LINEAGE COMMITMENT; IN-VIVO; DIFFERENTIATION; ACTIVATION; TH1; MICE AB T helper type 2 (Th2) cells secrete IL-4, IL-5, IL-10, and IL-13 and mediate allergic and asthmatic disease. GATA-3 is a Th2-specific transcription factor that appears in overexpression studies and transgenic systems to function as a Th2 lineage determinant. Because GATA-3 is also crucial for development of the T lineage and throughout thymic development, direct demonstration that GATA-3 is required for Th2 development by targeted deletion has been lacking. Using a conditional knockout approach, we found that GATA-3 is required for optimal Th2 cytokine production in vitro and in vivo. Our data also show that GATA-3 expression must be sustained to maintain the Th2 phenotype. C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Rheumatol Immunol & Allergy, Boston, MA 02115 USA. RP Ho, IC (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM iho@hsph.harvard.edu FU NIAID NIH HHS [AI50601, K08 AI050601, R01 AI029673, R01 AI29673, R37 AI029673] NR 38 TC 216 Z9 226 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 17 PY 2004 VL 101 IS 7 BP 1993 EP 1998 DI 10.1073/pnas.0308697100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775GP UT WOS:000189032600037 PM 14769923 ER PT J AU Walsh, CR Larson, MG Kupka, MJ Levy, D Vasan, RS Benjamin, EJ Manning, WJ Clouse, ME O'Donnell, CJ AF Walsh, CR Larson, MG Kupka, MJ Levy, D Vasan, RS Benjamin, EJ Manning, WJ Clouse, ME O'Donnell, CJ TI Association of aortic valve calcium detected by electron beam computed tomography with echocardiographic aortic valve disease and with calcium deposits in the coronary arteries and thoracic aorta SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CALCIFICATION; STENOSIS; PREVALENCE; ATHEROSCLEROSIS; QUANTIFICATION; SPECIFICITY; SENSITIVITY; PROGRESSION; WOMEN; MEN AB We conducted electron beam computed tomographic (EBCT) testing in a representative sample of 327 Framingham Heart Study subjects without clinical cardiovascular disease. EBCT was compared with 2-dimensional echocardiography for the detection of degenerative aortic valve (AV) disease. We determined the association between EBCT measures of AV calcium and calcium deposits in the coronary arteries and thoracic aorta. Of 327 subjects (mean age 60 9 years; 51% men), 14% had EBCT AV calcium (median Agatston score 0, range 0 to 1,592). The prevalence of AV calcium increased predictably across decades of age. Compared with echocardiography, the sensitivity and specificity of EBCT for the detection of degenerative AV disease were 24% and 94%, respectively. In unadjusted logistic regression models, the prevalence of EBCT AV calcium increased across tertiles of coronary artery calcium (for trend across tertiles, odds ratio [OR] 2.2, 95% confidence interval [CI] 1.4 to 3.5) and thoracic aorta calcium (for trend OR 2.8, 95% CI 1.7 to 4.4). After adjustment for age and gender, the associations of AV calcium with coronary calcium and thoracic aorta calcium were attenuated and no longer statistically significant. Thus, compared with echocardiography, EBCT was specific but insensitive for the detection of degenerative AV disease. EBCT AV calcium was associated with calcium deposits in the coronary arteries and the thoracic aorta, but these associations were confounded by age and risk factors. (C) 2004 by Excerpta Medica, Inc. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Cardiovasc Div, Boston, MA USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM chris@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24 HL 04334-01A1, N01-HC-38038]; NINDS NIH HHS [R01-NS-17950] NR 30 TC 18 Z9 18 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2004 VL 93 IS 4 BP 421 EP 425 DI 10.1016/j.amjcard.2003.10.035 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 774FJ UT WOS:000188968800007 PM 14969614 ER PT J AU Fihn, SD McDonell, MB Diehr, P Anderson, SM Bradley, KA Au, DH Spertus, JA Burman, M Reiber, GE Kiefe, CI Cody, M Sanders, KM Whooley, MA Rosenfeld, K Baczek, LA Sauvigne, A AF Fihn, SD McDonell, MB Diehr, P Anderson, SM Bradley, KA Au, DH Spertus, JA Burman, M Reiber, GE Kiefe, CI Cody, M Sanders, KM Whooley, MA Rosenfeld, K Baczek, LA Sauvigne, A TI Effects of sustained audit/feedback on self-reported health status of primary care patients SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CONTINUING MEDICAL-EDUCATION; CORONARY-ARTERY DISEASE; QUALITY-OF-LIFE; PHYSICIAN PERFORMANCE; PRACTICE GUIDELINES; PROBLEM DRINKING; QUESTIONNAIRE; DATABASES; FEEDBACK AB PURPOSE: Because limited audit/feedback of health status information has yielded mixed results, we evaluated the effects of a sustained program of audit/feedback on patient health and satisfaction. METHODS: We conducted a group-randomized effectiveness trial in which firms within Veterans Administration general internal medicine clinics served as units of randomization, intervention, and analysis. Respondents to a baseline health inventory were regularly mailed the 36-Item Short Form (SF-36) and, as relevant, questionnaires about six chronic conditions (ischemic heart disease, diabetes, chronic obstructive pulmonary disease, depression, alcohol use, and hypertension) and satisfaction with care. Data were reported to primary providers at individual patient visits and in aggregate during a 2-year period. RESULTS: Baseline forms were mailed to 34,050 patients; of the 22,413 respondents, 15,346 completed and returned follow-up surveys. Over the 2-year study, the difference between intervention and control groups (as measured by difference in average slope) was -0.26 (95% confidence interval [CI]: -0.79 to 0.27; P = 0.28) for the SF-36 Physical Component Summary score and -0.53 (95% CI: -1.09 to 0.03; P = 0.06) for the SF-36 Mental Component Summary score. No significant differences emerged after adjusting for deaths. There were no significant differences in condition -specific measures or satisfaction between groups after adjustment for provider type, panel size, and number of intervention visits, or after analysis of patients who completed all forms. CONCLUSION: An elaborate, sustained audit/feedback program of general and condition-specific measures of health/satisfaction did not improve outcomes. To be effective, such data probably should be incorporated into a comprehensive chronic disease management program. (C) 2004 by Excerpta Medica Inc. C1 NW Hlth Serv Res & Dev Ctr Excellence, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Missouri, Sch Med, Kansas City, MO 64110 USA. Dept Vet Affairs Med Ctr, Birmingham, AL USA. Dept Vet Affairs Med Ctr, Little Rock, AR USA. Dept Vet Affairs Med Ctr, Richmond, VA USA. Dept Vet Affairs Med Ctr, San Francisco, CA USA. Dept Vet Affairs Med Ctr, Los Angeles, CA USA. Dept Vet Affairs Med Ctr, White River Jct, VT USA. RP Fihn, SD (reprint author), NW Hlth Serv Res & Dev Ctr Excellence, VA Puget Sound Hlth Care Syst, 152,1660 S Columbian Way, Seattle, WA 98108 USA. EM sfihn@u.washington.edu NR 44 TC 56 Z9 57 U1 5 U2 6 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD FEB 15 PY 2004 VL 116 IS 4 BP 241 EP 248 DI 10.1016/j.amjmed.2003.10.026 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 774UH UT WOS:000189003300005 PM 14969652 ER PT J AU Li, LF Yu, LY Quinn, DA AF Li, LF Yu, LY Quinn, DA TI Ventilation-induced neutrophil infiltration depends on c-Jun N-terminal kinase SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chemokine; mitogen-activated protein kinase; lung stretch ID INDUCED LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; FACTOR-KAPPA-B; SIGNAL-TRANSDUCTION; INDUCED ACTIVATION; TIDAL VOLUMES; RAT LUNGS; PROTEIN; EXPRESSION; CYTOKINE AB Positive pressure ventilation with large VTS has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human interleukin-8. The mechanisms regulating ventilation-induced cytokine production are unclear. Based on our previous in vitro model of lung cell stretch, we hypothesized that high VT ventilation-induced MIP-2 production is dependent on the activation of the c-Jun N-terminal kinase (JNK). We exposed C57BL/6 mice to high VT (30 ml/kg) or low VT (6 ml/kg) mechanical ventilation for 5 hours. High VT ventilation-induced neutrophil migration into the lung, MIP-2 protein production, MIP-2 messenger RNA expression, and JNK activation. Large VT ventilation of JNK knockout mice and pharmacologic JNK inhibition with SP600125 attenuated neutrophil sequestration and blocked MIP-2 messenger RNA expression and MIP-2 production. We conclude that lung cell stretch in vivo results in increased lung neutrophil sequestration and increased MIP-2 production, which was, at least in part, dependent upon the JNK pathway. C1 Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Chang Gung Univ, Grad Inst Clin Med Sci, Taoyuan, Taiwan. RP Quinn, DA (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Dept Med, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM dquinn1@partners.org FU NHLBI NIH HHS [HL039020, HL61688, HL67371] NR 44 TC 74 Z9 81 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2004 VL 169 IS 4 BP 518 EP 524 DI 10.1164/rccm.200305-660OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 771JK UT WOS:000188781700020 PM 14644930 ER PT J AU Shen, YF Jacobs, JM Camp, DG Fang, RH Moore, RJ Smith, RD Xiao, WZ Davis, RW Tompkins, RG AF Shen, YF Jacobs, JM Camp, DG Fang, RH Moore, RJ Smith, RD Xiao, WZ Davis, RW Tompkins, RG TI Ultra-high-efficiency strong cation exchange LC/RPLC/MS/MS for high dynamic range characterization of the human plasma proteome SO ANALYTICAL CHEMISTRY LA English DT Article ID RESONANCE MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; IDENTIFICATION TECHNOLOGY; YEAST PROTEOME; GROWTH-FACTOR; HUMAN BLOOD; PURIFICATION; PEPTIDES; ONLINE; PSEUDOTRYPSIN AB High-efficiency nanoseale reversed-phase liquid chromatography (chromatographic peak capacities of similar to1000: Shen, Y.; Zhao, R.; Berger, S. J.; Anderson, G. A.; Rodriguez, N.; Smith, R. D. Anal. Chem. 2002, 74, 4235. Shen, Y.; Moore, R. J.; Zhao, R.; Blonder, J.; Auberry, D. L.; Masselon, C.; Pasa-Tolic, L.; Hixson, K K; Auberry, K J.; Smith, R. D. Anal. Chem. 2003, 75, 3596.) and strong cation exchange LC was used to obtain ultra-high-efficiency separations (combined chromatographic peak capacities of > 10(4)) in conjunction with tandem mass spectrometry (MS/MS) for characterization of the human plasma proteome. Using conservative SEQUEST peptide identification criteria (i.e., without considering chymotryptic or elastic peptides) and peptide LC normalized elution time constraints, the separation quality enabled the identification of proteins over a dynamic range of greater than 8 orders of magnitude in relative abundance using ion trap MS/MS instrumentation. Between 800 and 1682 human proteins were identified, depending on the criteria used for identification, from a total of 365 mug of human plasma. The analyses identified relatively low-level (similar topg/mL) proteins (e.g., cytokines) coexisting with high-abundance proteins (e.g., mg/mL-level serum albumin). C1 Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. Stanford Univ, Sch Med, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Shriners Burn Ctr, Dept Surg, Boston, MA 02114 USA. RP Smith, RD (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; xiao, wenzhong/0000-0003-4944-6380 FU NCRR NIH HHS [RR 018522]; NIGMS NIH HHS [U54 GM 62119-02, U54 GM062119] NR 35 TC 240 Z9 250 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 15 PY 2004 VL 76 IS 4 BP 1134 EP 1144 DI 10.1021/ac034869m PG 11 WC Chemistry, Analytical SC Chemistry GA 776QC UT WOS:000189127100035 PM 14961748 ER PT J AU Stone, JR AF Stone, JR TI An assessment of proposed mechanisms for sensing hydrogen peroxide in mammalian systems SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE tyrosine phosphatase; peroxiredoxin; peroxidase; OxyR; reactive oxygen species; oxidative stress; thiolate; sulfenic acid; hydrogen peroxide; redox ID PROTEIN-TYROSINE-PHOSPHATASE; ENTEROCOCCAL NADH PEROXIDASE; OXYR TRANSCRIPTION FACTOR; NUCLEAR RIBONUCLEOPROTEIN C1/C2; CYTOCHROME-C PEROXIDASE; CYSTEINE-SULFENIC ACID; OXIDATIVE STRESS; REDOX REGULATION; ACTIVE-SITE; COMPOUND-I AB Despite much recent interest in the biochemistry of reactive oxygen species, the mechanisms by which hydrogen peroxide (H2O2) functions in mammalian cells remain poorly defined. Proposed mechanisms for sensing H2O2 in mammalian cells include inactivation of protein tyrosine phosphatases and dual specificity phosphatases as well as inactivation of peroxiredoxins. In this critical review, proteins proposed to serve as sensors for H2O2 in mammals will be compared to peroxidases, catalases, and the bacterial H2O2 sensor OxyR for their ability to react with H2O2, in the context of our current knowledge concerning the concentrations of H2O2 present in cells. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Stone, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Warren 501B,55 Fruit St, Boston, MA 02114 USA. EM jrstone@partners.org FU NHLBI NIH HHS [R01 HL074324] NR 62 TC 111 Z9 118 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 2004 VL 422 IS 2 BP 119 EP 124 DI 10.1016/j.abb.2003.12.029 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 771NE UT WOS:000188791600001 PM 14759598 ER PT J AU Chen, XL Liang, HY Van Remmen, H Vijg, J Richardson, A AF Chen, XL Liang, HY Van Remmen, H Vijg, J Richardson, A TI Catalase transgenic mice: characterization and sensitivity to oxidative stress SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE catalase; transgenic mice; oxidative stress; antioxidant enzymes ID ZINC-SUPEROXIDE-DISMUTASE; NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; HYDROGEN-PEROXIDE; GLUTATHIONE-PEROXIDASE; ACATALASEMIC MICE; INDUCED APOPTOSIS; SMALL-INTESTINE; MOUSE-LIVER; CELLS AB The role of catalase in the antioxidant defense system was studied using transgenic mice [Tg(CAT)] harboring a human genomic clone containing the entire human CAT gene. Catalase activity was 2-fold higher in the tissues of hemizygous [Tg(CAT)(+/o)] mice and 3- to 4-fold higher in the tissues of homozygous [Tg(CAT)(+/+)] mice compared to wild type mice. The human CAT transgene was expressed in a tissue-specific pattern that was similar to the endogenous catalase gene. The levels of other major antioxidant enzymes were not altered in the tissues of the transgenic mice. Hepatocytes and fibroblasts from the Tg(CA T)(+/+) mice were more resistant to hydrogen peroxide-induced cell death but were more sensitive to paraquat and TNFalpha toxicity. Fibroblasts from the Tg(CA T)(+/+) mice showed reduced growth rate in culture without treatment and reduced colony-forming capability after gamma-irradiation compared to fibroblasts from wild type mice. In addition, the Tg(CAT)(+/+) animals were more sensitive to gamma-irradiation. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Barshop Ctr Longev & Aging Studies, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX 78284 USA. RP Richardson, A (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM richardsona@uthscsa.edu RI Liang, Hanyu/A-1066-2010 FU NIA NIH HHS [P01 AG14674, P01 AG020591, P03 AG13319] NR 73 TC 47 Z9 52 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 2004 VL 422 IS 2 BP 197 EP 210 DI 10.1016/j.abb.2003.12.023 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 771NE UT WOS:000188791600011 PM 14759608 ER PT J AU Tuxworth, WJ Saghir, AN Spruill, LS Menick, DR McDermott, PJ AF Tuxworth, WJ Saghir, AN Spruill, LS Menick, DR McDermott, PJ TI Regulation of protein synthesis by eIF4E phosphorylation in adult cardiocytes: the consequence of secondary structure in the 5 '-untranslated region of mRNA SO BIOCHEMICAL JOURNAL LA English DT Article DE cardiocyte; eIF4E (eukaryotic initiation factor 4E); hypertrophy; Mnk1 (MAP kinase signal-integrating kinase 1); protein synthesis; translation ID INITIATION-FACTOR 4E; CAP-BINDING PROTEIN; NA+-CA2+ EXCHANGER GENE; TRANSLATION INITIATION; CARDIAC-HYPERTROPHY; FELINE CARDIOCYTES; SYNTHESIS RATES; FACTOR EIF-4E; KINASE MNK1; FACTOR 4G AB In adult cardiocytes. eIF4E (eukaryotic initiation factor 4E) activity and protein synthesis are increased concomitantly in response to stimuli that induce hypertrophic growth. We tested the hypothesis that increases in eIF4E activity selectively improve the translational efficiency of mRNAs that have an excessive amount of secondary structure in the 5'-UTR (5'-untranslated region). The activity of eIF4E was modified in primary cultures of adult cardiocytes using adenoviral gene transfer to increase either the amount of eIF4E or the extent of endogenous eIF4E phosphorylation. Subsequently, the effects of eIF4E on translational efficiency were assayed following adenoviral-mediated expression of luciferase reporter mRNAs that were either 'stronger' (less structure in the 5'-UTR) or 'weaker' (more structure in the 5'-UTR) with respect to translational efficiency. The insertion of G + C-rich repeats into the 5'-UTR doubled the predicted amount of secondary structure and was sufficient to reduce translational efficiency of the reporter mRNA by 48 +/- 13 %. Translational efficiency of the weaker reporter mRNA was not significantly improved by overexpression of wild-type eIF4E when compared with the stronger reporter mRNA. In contrast, overexpression of the eIF4E kinase Mnk1 [MAP (mitogen-activated protein) kinase signal-integrating kinase 1] was sufficient to increase the translational efficiency of either reporter mRNA, independent of the amount of secondary structure in their respective 5'-UTRs. The increases in translational efficiency produced by Mnk1 occurred in association with corresponding decreases in mRNA levels. These findings indicate that the positive effect of eIF4E phosphorylation on translational efficiency in adult cardiocytes is coupled with the stability of mRNA. C1 Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Charleston, SC 29403 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29403 USA. RP McDermott, PJ (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Strom Thurmond Biomed Res Bldg,Room 303,114 Dough, Charleston, SC 29403 USA. EM mcdermp@musc.edu FU NHLBI NIH HHS [P01 HL-48788] NR 50 TC 25 Z9 26 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2004 VL 378 BP 73 EP 82 DI 10.1042/BJ20031027 PN 1 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 779JB UT WOS:000189290600009 PM 14629199 ER PT J AU Lacerda, ALT Keshavan, MS Hardan, AY Yorbik, O Brambilla, P Sassi, RB Nicoletti, M Mallinger, AG Frank, E Kupfer, DJ Soares, JC AF Lacerda, ALT Keshavan, MS Hardan, AY Yorbik, O Brambilla, P Sassi, RB Nicoletti, M Mallinger, AG Frank, E Kupfer, DJ Soares, JC TI Anatomic evaluation of the orbitofrontal cortex in major depressive disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE neuroimaging; magnetic resonance imaging; unipolar depression; prefrontal cortex; orbital frontal cortex; OFC ID SUBGENUAL PREFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; MOOD DISORDERS; GENDER DIFFERENCES; FRONTAL-LOBE; FUNCTIONAL NEUROANATOMY; UNIPOLAR DEPRESSION; PARKINSONS-DISEASE; ONSET DEPRESSION AB Background: The orbitofrontal cortex (OFC) plays a major role in neuropsychologic functioning including exteroceptive and interoceptive information coding, reward-guided behavior, impulse control, and mood regulation, This study examined the OFC and its subdivisions in patients with MDD and matched healthy control subjects. Methods. Magnetic resonance imaging (MRI) was performed on 31 unmedicated MDD and 34 control subjects matched for age, gender, and race. Gray matter volumes of the OFC and its lateral and medial subdivisions were measured blindly. Results: The MDD patients had smaller gray matter volumes in tight medial [two-way analysis of covariance F(1, 60) = 4.285; p = .043] and left lateral OFC [F (1, 60) = 4.252; p = .044]. Left lateral OFC volume correlated negatively with age in patients but not in control subjects. Male, but not female patients exhibited smaller left and right medial OFC volumes compared with healthy control subjects of the same gender. Conclusions: These findings suggest that patients with MDD have reduced OFC gray matter volumes. Although this reduction might be important in understanding the pathophysiology of MDD, its functional and psychopathologic consequences are as yet unclear. Future studies examining the relationship between specific symptomatic dimensions of MDD and OFC volumes could be especially informative. C1 Univ Texas, Hlth Sci Ctr, Div Mood & Anxiety Disorders, Dept Psychiat, San Antonio, TX 78229 USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Sch Med, Pittsburgh, PA 15260 USA. State Univ Campinas, Sch Med Sci, Dept Med Psychol & Psychiat, Campinas, Brazil. GATA, Child & Adolescent Psychiat Dept, Ankara, Turkey. Univ Pavia, Sch Med, Dept Psychiat, I-27100 Pavia, Italy. Univ Sao Paulo, Sch Med, Inst Psychiat, Dept Psychiat, BR-05508 Sao Paulo, Brazil. Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15260 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Soares, JC (reprint author), Univ Texas, Hlth Sci Ctr, Div Mood & Anxiety Disorders, Dept Psychiat, MC 7792,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RI Lacerda, Acioly/A-7052-2010; brambilla, paolo/B-4184-2010 OI Lacerda, Acioly/0000-0002-9370-0449; brambilla, paolo/0000-0002-4021-8456 FU NCRR NIH HHS [M01 RRR 00056]; NIMH NIH HHS [MH 01180, MH 01736, MH 30915, MH 45156, MH 45203, MH 64027] NR 73 TC 120 Z9 127 U1 8 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2004 VL 55 IS 4 BP 353 EP 358 DI 10.1016/j.biopsych.2003.08.021 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 774DP UT WOS:000188964700004 PM 14960287 ER PT J AU Hahn, WC AF Hahn, WC TI Targeting cancer with telomerase SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID SUICIDE GENE-THERAPY; EXPRESSING BACTERIAL NITROREDUCTASE; HUMAN-CELLS; PROMOTER; HTERT; INHIBITION C1 Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Hahn, WC (reprint author), Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM William_Hahn@dfci.harvard.edu FU NCI NIH HHS [CA94223] NR 25 TC 2 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2004 VL 10 IS 4 BP 1203 EP 1205 DI 10.1158/1078-0432.CCR-04-0060 PG 3 WC Oncology SC Oncology GA 776JE UT WOS:000189112200001 PM 14977815 ER PT J AU Beer, TM Garzotto, M Lowe, BA Ellis, WJ Montalto, MA Lange, PH Higano, CS AF Beer, TM Garzotto, M Lowe, BA Ellis, WJ Montalto, MA Lange, PH Higano, CS TI Phase I study of weekly mitoxantrone and docetaxel before prostatectomy in patients with high-risk localized prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID NEOADJUVANT HORMONAL-THERAPY; RADICAL PROSTATECTOMY; PELVIC LYMPHADENECTOMY; CONSECUTIVE PATIENTS; BREAST-CANCER; CHEMOTHERAPY; TRIAL; ESTRAMUSTINE; RECURRENCE; ANTIGEN AB Purpose: The purpose is to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of mitoxantrone and docetaxel administered weekly before prostatectomy in men with localized prostate cancer at high risk for recurrence. Experimental Design: Twenty-two patients were treated with four cycles of docetaxel 35 mg/m(2) and increasing doses of mitoxantrone starting at 2 mg/m(2) repeated weekly for 3 weeks of a 4-week cycle before prostatectomy. The MTD was defined as that dose at which fewer than one-third of patients experienced a DLT (greater than or equal tograde 4 hematological or greater than or equal tograde 3 nonhematological toxicity). Changes in serum prostate-specific antigen and serum testosterone, and pathological outcome with surgery were secondary endpoints. Results: The MTD for mitoxantrone in combination with this dose of docetaxel was 4 mg/m(2). Neutropenia was the DLT for the combination. Ten of 12 patients treated at the MTD completed the planned 16 weeks of chemotherapy, whereas 2 discontinued therapy early because of toxicity. The median reduction in PSA was 41% (range, 4-88%). Serum testosterone levels remained constant postchemotherapy. Conclusions: In this patient population, the planned Phase II regimen is 4 mg/m(2) mitoxantrone and 35 mg/m(2) docetaxel weekly for 3 of every 4 weeks. Delivery of this regimen before prostatectomy is feasible with acceptable toxicity. Additional studies are needed to determine whether this combined modality approach will reduce cancer recurrence rates in this high-risk population. Because extent of disease and exposure to prior therapy may impact treatment tolerance these safety data may not be applicable to patients with advanced prostate cancer. C1 Oregon Hlth Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Div Urol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. Univ Washington, Div Urol, Seattle, WA 98195 USA. Univ Washington, Div Oncol, Seattle, WA 98195 USA. RP Beer, TM (reprint author), Oregon Hlth & Sci Univ, Dept Med, Mail Code L586,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM beert@ohsu.edu FU NCRR NIH HHS [3M01RR00334-33S2] NR 26 TC 28 Z9 28 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2004 VL 10 IS 4 BP 1306 EP 1311 DI 10.1158/1078-0432.CCR-1021-03 PG 6 WC Oncology SC Oncology GA 776JE UT WOS:000189112200015 PM 14977829 ER PT J AU Kang, YH Berthiaume, F Nath, BD Yarmush, ML AF Kang, YH Berthiaume, F Nath, BD Yarmush, ML TI Growth factors and nonparenchymal cell conditioned media induce mitogenic responses in stable long-term adult rat hepatocyte cultures SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE hepatocyte; cell cycle; nonparenchymal cells; liver regeneration; growth factors; cytokines ID EXTRACELLULAR-MATRIX; LIVER-REGENERATION; KUPFFER CELLS; SANDWICH CONFIGURATION; PARTIAL-HEPATECTOMY; ENDOTHELIAL-CELLS; PROLIFERATION; DIFFERENTIATION; STIMULATION; INVITRO AB Most prior studies have characterized hepatocyte proliferative responses in culture systems that do not express a stable differentiated phenotype. We investigated the DNA synthetic response of long-term stable hepatocyte cultures to growth factor stimulation as well as conditioning with nonparenchymal cells (NPCs). Primary rat hepatocytes were cultured on a single layer of collagen (h/C) or Matrigel (h/M), or in a collagen sandwich (C/h/C) or collagen-Matrigel sandwich (M/h/C). Hepatocytes were cultured for 7 days to allow phenotypic stabilization before growth factor addition, except for h/C cultures, which are unstable, where growth factors were added 1 day after seeding. Culture medium was supplemented with a mixture of hepatocyte, epidermal, and vascular endothelial growth factors and interleukin-6, either directly or after conditioning with NPCs for 24 h. Growth factors alone induced hepatocyte DNA synthesis, as measured via [H-3]thymidine uptake, in the h/C, C/h/C, and M/h/C configurations. h/M exhibited very low levels of DNA synthesis. In the C/h/C and M/h/C configurations, the greatest stimulation was obtained using NPC-conditioned growth factors. This response was sustained for several days and without decreasing albumin or urea synthesis. These results suggest that hepatocyte mitogens and NPC-derived factors can stimulate DNA synthesis in stable and differentiated hepatocyte cultures. (C) 2003 Elsevier Inc. All rights reserved. C1 Shriners Hosp Children, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org FU NIDDK NIH HHS [DK 043371] NR 32 TC 18 Z9 18 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2004 VL 293 IS 2 BP 239 EP 247 DI 10.1016/j.yexer.2003.10.011 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 767QB UT WOS:000188462700006 PM 14729461 ER PT J AU Slaugenhaupt, SA Mull, J Leyne, M Cuajungco, MP Gill, SP Hims, MM Quintero, F Axelrod, FB Gusella, JF AF Slaugenhaupt, SA Mull, J Leyne, M Cuajungco, MP Gill, SP Hims, MM Quintero, F Axelrod, FB Gusella, JF TI Rescue of a human mRNA splicing defect by the plant cytokinin kinetin SO HUMAN MOLECULAR GENETICS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; VALPROIC ACID INCREASES; FAMILIAL DYSAUTONOMIA; POTENTIAL THERAPY; SMN LEVELS; IN-VIVO; GENE; DISEASE; MUTATIONS; PROTEIN AB The defective splicing of pre-mRNA is a major cause of human disease. Exon skipping is a common result of splice mutations and has been reported in a wide variety of genetic disorders, yet the underlying mechanism is poorly understood. Often, such mutations are incompletely penetrant, and low levels of normal transcript and protein are maintained. Familial dysautonomia (FD) is caused by mutations in IKBKAP, and all cases described to date involve an intron 20 mutation that results in a unique pattern of tissue-specific exon skipping. Accurate splicing of the mutant IKBKAP allele is particularly inefficient in the nervous system. Here we show that treatment with the plant cytokinin kinetin alters splicing of IKBKAP. Kinetin significantly increases inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene. By contrast the drug does not enhance inclusion of alternatively spliced exon 31 in MYO5A. Benzyladenine, the most closely related cytokinin, showed a similar but less dramatic effect. Our findings reveal a remarkable impact on splicing fidelity by these small molecules, which therefore provide new tools for the dissection of mechanisms controlling tissue-specific pre-mRNA splicing. Further, kinetin should be explored as a treatment for increasing the level of normal IKAP in FD, and for other splicing disorders that may share a similar mechanism. C1 Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Harvard Inst Human Genet, Boston, MA 02115 USA. NYU, Sch Med, Dept Pediat, New York, NY 10021 USA. RP Slaugenhaupt, SA (reprint author), NRB Bldg,Room 160C,4 Blackfan Circle, Boston, MA 02115 USA. EM susan_slaugenhaupt@hms.harvard.edu RI Cuajungco, Math/B-2647-2008 OI Cuajungco, Math/0000-0003-0749-9564 NR 37 TC 83 Z9 84 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2004 VL 13 IS 4 BP 429 EP 436 DI 10.1093/hmg/ddh046 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 771PM UT WOS:000188795300007 PM 14709595 ER PT J AU Rubin, MA Kantoff, PW AF Rubin, MA Kantoff, PW TI Effect of finasteride on risk of prostate cancer: How little we really know SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE prostate cancer; finasteride; chemoprevention; Gleason grading ID BENIGN; THERAPY; MEN; TESTOSTERONE; PROGRESSION; HYPERPLASIA; TISSUE AB The Prostate Cancer Prevention Trial (PCPT) reported conclusively that finasteride prevents or delays the detection of prostate cancer. One perplexing finding was that more high-grade tumors were detected in the finasteride treated group. It is hard to put this into perspective because of the limited published data on the effects of finasteride on prostate cancer. The strong possibility exists that the increase in high-grade tumors may be due to a treatment effect, which causes intermediate grade cancers to appear to be high-grade or aggressive tumors. Confirmation of a spurious tumor grade "inflation" will make the conclusions of this study clearer and define the benefits of finasteride chemoprevention in a more favorable light. (C) 2004 Wiley-Liss, Inc. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Rubin, MA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Amory 3-195,75 Francis St, Boston, MA 02115 USA. EM marubin@partners.org OI Rubin, Mark/0000-0002-8321-9950 FU NCI NIH HHS [P50CA69568, P50CA90381]; NIA NIH HHS [R01AG21404] NR 15 TC 9 Z9 9 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD FEB 15 PY 2004 VL 91 IS 3 BP 478 EP 482 DI 10.1002/jcb.10787 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 771NC UT WOS:000188791400005 PM 14755678 ER PT J AU Taplin, ME Balk, SP AF Taplin, ME Balk, SP TI Androgen receptor: A key molecule in the progression of prostate cancer to hormone independence SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE androgen receptor; prostate cancer; androgen-independent; hormone refractory; steroid hormone receptor ID N-TERMINAL DOMAIN; GENE-MUTATIONS; DEPRIVATION THERAPY; LIGAND SPECIFICITY; STEROID BINDING; CAG REPEAT; AMPLIFICATION; EXPRESSION; ACTIVATION; INTERLEUKIN-6 AB Despite earlier detection and recent advances in surgery and radiation, prostate cancer is second only to lung cancer in male cancer deaths in the United States. Hormone therapy in the. form of medical or surgical castration remains the mainstay of, systemic treatment in prostate cancer. Over the last 15 years with the clinical use of prostate specific antigen (PSA), there has been a shift to using hormone therapy earlier in the disease course and for longer duration. Despite initial favorable response to hormone therapy, over a period of time these tumors will develop androgen-independence that results in death. The androgen receptor (AR) is central to the initiation and growth of prostate cancer and to its response to hormone therapy. Analyses have shown that AR continues to be expressed in androgen-independent tumors and AIR signaling remains intact as demonstrated by the expression of the AIR regulated gene, PSA. Androgen-independent prostate cancers have demonstrated a variety of AIR alterations that are either not found in hormone naive tumors or found at lower frequency. These changes include AIR amplification, AIR point mutation, and changes in expression of AR co-regulatory proteins. These AR changes result in a "super AR" that can respond to lower concentrations of androgens or to a wider variety of agonistic ligands. There is also mounting evidence that AIR can be activated in a ligand independent fashion by compounds such as growth factors or cytokines working independently or in combination. These growth factors working through receptor tyrosine kinase pathways may promote AIR activation and growth in low androgen environments. The clinical significance of these AIR alterations in the development and progression of androgen-independent prostate cancer remains to be determined. Understanding the changes in AIR signaling in the evolution of androgen-independent prostate cancer will be key to the development of more effective hormone therapy (C) 2003 Wiley-Liss, Inc. C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Beth Israel Med Ctr, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Taplin, ME (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 44 Binney St, Boston, MA 02115 USA. EM mtaplin@partners.org NR 57 TC 269 Z9 281 U1 1 U2 18 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD FEB 15 PY 2004 VL 91 IS 3 BP 483 EP 490 DI 10.1002/jcb.10653 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 771NC UT WOS:000188791400006 PM 14755679 ER PT J AU Senzer, N Mani, S Rosemurgy, A Nemunaitis, J Cunningham, C Guha, C Bayol, N Gillen, M Chu, K Rasmussen, C Rasmussen, H Kufe, D Weichselbaum, R Hanna, N AF Senzer, N Mani, S Rosemurgy, A Nemunaitis, J Cunningham, C Guha, C Bayol, N Gillen, M Chu, K Rasmussen, C Rasmussen, H Kufe, D Weichselbaum, R Hanna, N TI TNFerade biologic, an adenovector with a radiation-inducible, promoter, carrying the human tumor necrosis factor alpha gene: A phase I study in patients with solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TNF-ALPHA; IONIZING-RADIATION; CANCER-PATIENTS; SOFT-TISSUE; INTRAVENOUS-INFUSION; ADENOVIRUS ONYX-015; INTERFERON-GAMMA; THERAPY; TRIAL; SARCOMA AB Purpose TNFerade is a replication deficient adenovector that expresses human tumor necrosis factor alpha under control of the radiation-inducible Egr-1 promoter. The goals of this study were to determine the safety and toxicity of TNFerade in combination with radiation therapy. Patients and Methods TNFerade,was administered by intratumoral administration, weekly for 6 weeks with concomitant radiation (30 to 70 Gy). Seven dose levels were studied (4 X 10(7) particle units [pu] to 4 X 10(11) pu) in patients with solid tumors being treated with radiation. Results Thirty-six patients were assessable for toxicity and 30 for tumor response. Most frequent TNFerade-related toxicities were fever (22%), injection site pain (19%), and chills (19%). No dose-limiting toxicities were observed. Overall, 21 of 30 patients (70%) demonstrated objective tumor response (five complete responses, nine partial responses, and seven minimal responses). In four of five patients with synchronous lesions, a differential response between lesions treated with TNFerade + radiation compared with radiation only was observed. Conclusion This is the first human study with TNFerade and radiation. The integrated treatment was well tolerated in patients with predominantly prior treatment-refractory solid tumors. Controlled prospective clinical trials have been initiated to more fully define the therapeutic contribution of TNFerade. (C) 2004 by American Society of Clinical Oncology. C1 Univ Kentucky, Med Ctr, Dept Gen Surg, Lexington, KY USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. GenVec Inc, Gaithersburg, MD USA. Univ S Florida, Tampa, FL 33612 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. US Oncol, Dallas, TX USA. RP Hanna, N (reprint author), Univ Kentucky, Med Ctr, Dept Gen Surg, Lexington, KY USA. EM nhanna1@pop.uky.edu NR 46 TC 133 Z9 141 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2004 VL 22 IS 4 BP 592 EP 601 DI 10.1200/JCO.2004.01.227 PG 10 WC Oncology SC Oncology GA 775AP UT WOS:000189018800006 PM 14726502 ER PT J AU Meyerhardt, JA Tepper, JE Niedzwiecki, D Hollis, DR McCollum, AD Brady, D O'Connell, MJ Mayer, RJ Cummings, B Willett, C Macdonald, JS Benson, AB Fuchs, CS AF Meyerhardt, JA Tepper, JE Niedzwiecki, D Hollis, DR McCollum, AD Brady, D O'Connell, MJ Mayer, RJ Cummings, B Willett, C Macdonald, JS Benson, AB Fuchs, CS TI Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: Findings from intergroup trial 0114 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IGF-BINDING PROTEIN-3; GROWTH-FACTOR-I; COLORECTAL-CANCER; COLON-CANCER; PHYSICAL-ACTIVITY; RISK-FACTORS; ANASTOMOTIC LEAKAGE; ADJUVANT THERAPY; ADIPOSE-TISSUE; FACTOR (IGF)-I AB Purpose To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer. Patients and Methods We evaluated a nested cohort of 1,688. patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy. Results Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% Cl, 1 27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P < .0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% Cl, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% Cl, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals. Conclusion Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified. (C) 2004 by American Society of Clinical Oncology. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Univ N Carolina, Sch Med, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. Canc & Leukemia Grp B Stat Ctr, Durham, NC USA. Baylor Sammons Canc Ctr, Dallas, TX USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. St Vincents Clin Canc Ctr, New York, NY USA. Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM jmeyerhardt@partners.org FU NCI NIH HHS [1K07CA097992-01A1, CA31946] NR 57 TC 142 Z9 143 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 15 PY 2004 VL 22 IS 4 BP 648 EP 657 DI 10.1200/JCO.2004.07.121 PG 10 WC Oncology SC Oncology GA 775AP UT WOS:000189018800013 PM 14966087 ER PT J AU Taylor, JA Havari, E McInerney, MF Bronson, R Wucherpfennig, KW Lipes, MA AF Taylor, JA Havari, E McInerney, MF Bronson, R Wucherpfennig, KW Lipes, MA TI A spontaneous model for autoimmune myrocarditis using the human MHC molecule HLA-DQ8 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; NONOBESE DIABETIC MICE; COLLAGEN-INDUCED ARTHRITIS; II-DEFICIENT MICE; T-CELL-RECEPTOR; DILATED CARDIOMYOPATHY; TRANSGENIC MICE; CELIAC-DISEASE; IMMUNOSUPPRESSIVE THERAPY; HUMAN CD4 AB Genome-wide analyses have shown that the MHC class II region is the principal locus that confers susceptibility to a number of human autoimmune diseases. Due to the high degree of linkage disequilibrium across the MHC, it has been difficult to dissect the contribution of individual genes to disease susceptibility. As a result, intensive efforts have been made to generate mice transgenic for human class II molecules as models of autoimmune disease. However, in every case, additional manipulations-such as immunization with Ag in adjuvant, expression of immunostimulants on target tissues, or coexpression of TCR transgenes-have been required to induce disease. In this study, we show that expression of the human HLA-DQ8 (DQA1*0301/DQB1*0302) molecule alone in three lines of transgenic nonobese diabetic murine class II-deficient (mII(-/-)) mice results in the spontaneous development of autoimmune myocarditis. The disease shares key features of human myocarditis and was characterized by lymphocytic infiltrates in the myocardium and cardiac myocyte destruction, circulating IgG autoantibodies against cardiac myosin heavy chain, and premature death due to heart failure. We demonstrate that myocarditis could be transferred into healthy HLA-DQ8(+)RAG-1(-/-)mII(-/-) nonobese diabetic recipients with lymphocytes, but not sera. It has been widely thought that autoimmune myocarditis is of infectious etiology, with the immune responses arising secondary to cardiac damage from pathogens. These studies provide direct experimental evidence that spontaneous autoimmune myocarditis can occur in the absence of infection and that expression of HLA-DQ8 confers susceptibility to this organ-specific autoimmune disease. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, Joslin Diabet Ctr, Dept Med, Sect Immunol & Immunogenet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Lipes, MA (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM myra.lipes@joslin.harvard.edu FU NIAID NIH HHS [P01AI39619]; NIDDK NIH HHS [P30 DK36836] NR 55 TC 34 Z9 34 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2004 VL 172 IS 4 BP 2651 EP 2658 PG 8 WC Immunology SC Immunology GA 771LZ UT WOS:000188788600081 PM 14764740 ER PT J AU Fischer, TH Connolly, R Thatte, HS Schwaitzberg, SS AF Fischer, TH Connolly, R Thatte, HS Schwaitzberg, SS TI Comparison of structural and hemostatic properties of the poly-N-acetyl glucosamine Syvek Patch with products containing chitosan SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE hemostasis; N-acetyl glucosamine; hemostatic patches ID BETA-CHITIN; OLIGOSACCHARIDES; MORTALITY; INJURY; AGENT AB Polysaccharides are becoming increasingly developed as therapeutics and medical products, as the new field of Glycomics expands. Glycosaminoglycans that contain N-acetyl glucosamine constituents have been the focus of research leading to medical devices. A new hemostatic bandage, the Syvek Patch, has been introduced in the recent past for the control of bleeding at vascular access sites in interventional cardiology and radiology procedures. This product consists of poly-N-acetyl glucosamine (pGlcNAc) isolated in a unique fiber crystalline structural form from the large-scale culture and processing of a marine diatom. The Syvek pGlcNAc fiber material has chemical, physical, and biological properties that result in its favorable performance as a hemostat. Two new products, the Clo-Sur PAD and ChitoSeal, have recently become available also as patch hemostats. These two products both use chitosan, another N-acetyl glucosamine containing glycosaminoglycan, as their active ingredient. Structural, chemical, and biological comparisons of Syvek pGlcNAc and chitosan reveal a number of important differences. Syvek pGlcNAc fibers contain similar to50 fully acetylated, high molecular weight pGlcNAc molecules in a crystalline, three-dimensional beta structure array, and are insoluble. Chitosan is a low molecular weight mixed amorphous cationic polymer with no regular structure as a solid, and is water-soluble taking on a random coil configuration when in solution. These structural dissimilarities result in differences in the hemostatic properties of the two materials. Syvek pGlcNAc is able to significantly reduce the in vitro fibrin clot formation time of platelet-rich plasma samples and has the ability to cause aggregation of red blood cells in vitro. Chitosan is no better than gauze or other controls in these in vitro assays. The Syvek Patch is able to control the bleeding and cause hemostasis in a coagulopathic swine spleen-bleeding animal model 100% of the time, whereas Clo-Sur PAD was completely unsuccessful (0%) and ChitoSeal (25%) was worse than a gauze pad control (50%) in the same model. Syvek pGlcNAc fibers have structural and chemical properties that provide a unique basis for their ability to interact with blood components to cause hemostasis. Chitosan does not have the same properties and capabilities. C1 Univ N Carolina, Dept Patholbiol & Lab Med, Chapel Hill, NC 27516 USA. Tufts Univ New England Med Ctr, Dept Surg, Boston, MA 02111 USA. Harvard Univ, Sch Med, Dept Surg, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Fischer, TH (reprint author), Frances Owen Blood Res Lab, 350 S Old Fayetteville Rad, Chapel Hill, NC 27516 USA. EM tfischer@med.unc.edu NR 24 TC 39 Z9 42 U1 0 U2 15 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD FEB 15 PY 2004 VL 63 IS 3 BP 168 EP 174 DI 10.1002/jemt.20017 PG 7 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 769QQ UT WOS:000188661600006 PM 14755604 ER PT J AU Torbeyns, A Marder, SR Carson, W Jody, D Kaplita, S Saba, A Stock, E AF Torbeyns, A Marder, SR Carson, W Jody, D Kaplita, S Saba, A Stock, E TI Glycemic control and plasma lipids in long-term treatment with aripiprazole SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 12th Biennial Winter Workshop on Schizophrenia CY FEB 07-13, 2004 CL DAVOS, SWITZERLAND C1 Bristol Myers Squibb Co, Waterloo, Belgium. Bristol Myers Squibb Co, Princeton, NJ 08543 USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. W Los Angeles VA, Dept Psychiat, Los Angeles, CA USA. Otsuka Amer Pharmaceut Inc, Princeton, NJ USA. Otsuka Maryland Res Inst, Rockville, MD USA. EM anne.torbeyns@bms.com NR 0 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 15 PY 2004 VL 67 IS 1 SU S BP 192 EP 193 PG 2 WC Psychiatry SC Psychiatry GA 771LW UT WOS:000188788100461 ER PT J AU Baden, LR Rubin, RH AF Baden, LR Rubin, RH TI The sentinel chicken revisited: The impact of West Nile virus infection on transplant patients. SO TRANSPLANTATION LA English DT Editorial Material ID MANIFESTATIONS; ENCEPHALITIS C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Baden, LR (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 15 PY 2004 VL 77 IS 3 BP 356 EP 357 DI 10.1097/01.TP.0000101436.76588.D4 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 774UC UT WOS:000189002700006 PM 14983876 ER PT J AU Koyama, I Kawai, T Andrews, D Boskovic, S Nadazdin, O Wee, SL Sogawa, H Wu, DL Smith, RN Colvin, RB Sachs, DH Cosimi, AB AF Koyama, I Kawai, T Andrews, D Boskovic, S Nadazdin, O Wee, SL Sogawa, H Wu, DL Smith, RN Colvin, RB Sachs, DH Cosimi, AB TI Thrombophilia associated with anti-CD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates SO TRANSPLANTATION LA English DT Article ID RENAL-ALLOGRAFT TOLERANCE; CD40 LIGAND; PLATELETS; CHIMERISM; MONKEYS; CELLS AB Background. The authors previously reported thromboembolic complications associated with anti-CD154 monoclonal antibody (mAb) treatment in non-human primates. The underlying mechanisms of this complication and its management have not been established. Methods. Eighty cynomolgus monkey renal allograft recipients treated with anti-CD154 mAb were studied for the incidence of thrombosis and its prophylaxis. Results. Without anticoagulation prophylaxis, thromboembolic complications were seen in 5 of 11 recipients. With addition of perioperative heparin, the incidence was decreased to 2 of 10. No further improvement was observed by adding intraoperative prostaglandin (PG) E, However, addition of ketorolac tromethamine to PGE(1), and heparin decreased the incidence of thrombosis (one of eight). Most recently, the authors have found that ketorolac administration alone resulted in no thrombosis in 25 consecutive recipients. Conclusions. Ketorolac is remarkably effective in preventing thromboembolism associated with anti-CD154 mAb treatment, suggesting the mechanism underlying this complication may be related to platelet activation leading to enhanced aggregation. C1 Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Harvard Med Sch, Dept Pathol, Boston, MA 02114 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Surg, Transplantat Unit, White 510,55 Fruit St, Boston, MA 02114 USA. EM tatsuo.kawai@tbrc.mgh.harvard.edu FU NHLBI NIH HHS [P01-HL18646]; NIAID NIH HHS [R01 AI037692, R01 AI037692-09, R01 AI037692-10, R01 AI37692-05, R21 AI037692, R21 AI037692-06] NR 13 TC 66 Z9 67 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 15 PY 2004 VL 77 IS 3 BP 460 EP 462 DI 10.1097/01.TP.0000110291.29370.C0 PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 774UC UT WOS:000189002700027 PM 14966427 ER PT J AU Quayle, AJ Fidel, P Rosenberg, ES AF Quayle, AJ Fidel, P Rosenberg, ES TI Sex, allolmmunisation, and susceptibility to HIV infection SO LANCET LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; SEMINAL PLASMA; TRANSMISSION; INDUCTION; ALLOIMMUNIZATION; PREECLAMPSIA; CHEMOKINES; PREGNANCY; MACAQUES; PARTNERS C1 Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Quayle, AJ (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USA. EM AQuayl@LSUHSC.EDU NR 24 TC 4 Z9 4 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 14 PY 2004 VL 363 IS 9408 BP 503 EP 504 DI 10.1016/S0140-6736(04)15575-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 774TA UT WOS:000188999900003 PM 14975608 ER PT J AU Ferrando, AA Neuberg, DS Dodge, RK Paietta, E Larson, RA Wiernik, PH Rowe, JM Caligiuri, MA Bloomfield, CD Look, AT AF Ferrando, AA Neuberg, DS Dodge, RK Paietta, E Larson, RA Wiernik, PH Rowe, JM Caligiuri, MA Bloomfield, CD Look, AT TI Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia SO LANCET LA English DT Article AB The activation of oncogenic transcription factors defines distinct molecular subsets of T-cell acute lymphoblastic leukaemia and has prognostic. relevance in children. We investigated the prognostic effect of the expression levels of eight oncogenic transcription factors-TLX1 (HOX11), TLX3 (HOX11L2), TAL1, TAL2, LYL1, OLIG2 (BHLHB1), LMO1, and LMO2-in 52 adults with T-cell acute lymphoblastic leukaemia. The leukaemia-specific survival rate for the 16 TLX1-positive patients was 88% (90% CI 73-100%), compared with 56% (42-70%) for all other cases (p=0.019). Only the TLX1 oncogene expression subgroup showed difference in leukaemia-specific survival. Our results suggest that overexpression of TLX1 confers a good outlook for adults with T-cell acute lymphoblastic leukaemia. Furthermore, our findings lead to questions about whether stem-cell transplantation in first remission is necessary for effective treatment of patients in the low-risk subgroup of patients with TLX1 oncogene expression. C1 Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Our Lady Mercy Med Ctr, Eastern Cooperat Oncol Grp, Bronx, NY USA. Duke Univ, Med Ctr, Canc & Leukemia Grp B, Durham, NC 27706 USA. Univ Chicago, Chicago, IL 60637 USA. Rambam Med Ctr, Dept Hematol & BMT, Haifa, Israel. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Look, AT (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St,Mayer 630, Boston, MA 02115 USA. EM thomas_look@dfci.harvard.edu OI Larson, Richard/0000-0001-9168-3203 FU NCI NIH HHS [CA21115, CA101140, CA23318, CA31946, CA16058, CA77658] NR 5 TC 93 Z9 97 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 14 PY 2004 VL 363 IS 9408 BP 535 EP 536 DI 10.1016/S0140-6736(04)15542-6 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 774TA UT WOS:000188999900013 PM 14975618 ER PT J AU Ligeti, E Dagher, MC Hernandez, SE Koleske, AJ Settleman, J AF Ligeti, E Dagher, MC Hernandez, SE Koleske, AJ Settleman, J TI Phospholipids can switch the GTPase substrate preference of a GTPase-activating protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RHO; RAS; PHOSPHORYLATION; IDENTIFICATION; ASSOCIATION; INHIBITION; DOMAIN; LIPIDS; FAMILY; ARF AB The major cellular inhibitors of the small GTPases of the Ras superfamily are the GTPase-activating proteins ( GAPs), which stimulate the intrinsic GTP hydrolyzing activity of GTPases, thereby inactivating them. The catalytic activity of several GAPs is reportedly inhibited or stimulated by various phospholipids and fatty acids in vitro, indicating a likely physiological role for lipids in regulating small GTPases. We find that the p190 RhoGAP, a potent GAP for the Rho and Rac GTPases, is similarly sensitive to phospholipids. Interestingly, however, several of the tested phospholipids were found to effectively inhibit the RhoGAP activity of p190 but stimulate its RacGAP activity. Thus, phospholipids have the ability to "switch" the GTPase substrate preference of a GAP, thereby providing a novel regulatory mechanism for the small GTPases. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Semmelweis Univ, Dept Physiol, H-1444 Budapest, Hungary. CEA Grenoble, Biochim Lab, F-38054 Grenoble, France. Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM Settleman@helix.mgh.harvard.edu FU NINDS NIH HHS [R01 NS039475] NR 17 TC 43 Z9 43 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 13 PY 2004 VL 279 IS 7 BP 5055 EP 5058 DI 10.1074/jbc.C300547200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500003 PM 14699145 ER PT J AU Sundararaj, KP Wood, RE Ponnusamy, S Salas, AM Szulc, Z Bielawska, A Obeid, LM Hannun, YA Ogretmen, B AF Sundararaj, KP Wood, RE Ponnusamy, S Salas, AM Szulc, Z Bielawska, A Obeid, LM Hannun, YA Ogretmen, B TI Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUNTINGTONS-DISEASE FIBROBLASTS; LUNG ADENOCARCINOMA CELLS; CANCER CELLS; PROTEIN; END; RNA; SEQUENCE; POT1; GENE; EXPRESSION AB Ceramide has been demonstrated as one of the upstream regulators of telomerase activity. However, the role for ceramide in the control of telomere length remains unknown. It is shown here that treatment of the A549 human lung adenocarcinoma cells with C-6-ceramide results in rapid shortening of telomere length. During the examination of ceramide-regulated telomere-binding proteins, nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified to associate with both single- and double-stranded telomeric DNA with high specificity in vitro. The association of nuclear GAPDH with telomeres in interphase nuclei was also demonstrated by co-fluorescence in situ hybridization and chromatin immunoprecipitation analysis. Further data demonstrated that the nuclear localization of GAPDH is regulated by ceramide in a cell cycle-dependent manner parallel with the inhibition of its telomere binding activity in response to ceramide. In addition, the results revealed that nuclear GAPDH is distinct from its cytoplasmic isoform and that telomere binding function of nuclear GAPDH is strikingly higher than the cytoplasmic isoform. More importantly, the functional role for nuclear GAPDH in the maintenance and/or protection of telomeric DNA was identified by partial inhibition of the expression of GAPDH using small interfering RNA, which resulted in rapid shortening of telomeres. In contrast, overexpression of nuclear GAPDH resulted in the protection of telomeric DNA in response to exogenous ceramide as well as in response to anticancer drugs, which have been shown to induce endogenous ceramide levels. Therefore, these results demonstrate a novel function for nuclear GAPDH in the maintenance and/or protection of telomeres and also show that mechanisms of the rapid degradation of telomeres in response to ceramide involve the inhibition of the telomere binding activity of nuclear GAPDH. C1 Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Ogretmen, B (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 173 Ashley Ave,BSB-518E, Charleston, SC 29425 USA. EM ogretmen@musc.edu OI obeid, lina/0000-0002-0734-0847 FU NCI NIH HHS [CA88932, P01 CA097132]; NIA NIH HHS [AG16583] NR 49 TC 78 Z9 86 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 FEB 13 PY 2004 VL 279 IS 7 BP 6152 EP 6162 DI 10.1074/jbc.M310549200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500131 PM 14630908 ER PT J AU Ben-Zeev, O Doolittle, MH AF Ben-Zeev, O Doolittle, MH TI Maturation of hepatic lipase - Formation of functional enzyme in the endoplasmic reticulum is the rate-limiting step in its secretion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PANCREATIC TRIGLYCERIDE LIPASE; LIPOPROTEIN-LIPASE; QUALITY-CONTROL; GENE FAMILY; MISFOLDED GLYCOPROTEINS; LINKED GLYCOSYLATION; CHAPERONE CALNEXIN; CATALYTIC-ACTIVITY; GOLGI COMPARTMENT; INSECT CELLS AB Among three lipases in the lipase gene family, hepatic lipase (HL), lipoprotein lipase, and pancreatic lipase, HL exhibits the lowest intracellular specific activity (i.e. minimal amounts of catalytic activity accompanied by massive amounts of inactive lipase mass in the endoplasmic reticulum ( ER)). In addition, HL has a distinctive sedimentation profile, where the inactive mass overlaps the region containing active dimeric HL and trails into progressively larger molecular forms. Eventually, at least half of the HL inactive mass in the ER reaches an active, dimeric conformation (t(1/2) = 2 h) and is rapidly secreted. The remaining inactive mass is degraded. HL maturation occurs in the ER and is strongly dependent on binding to calnexin in the early co-/post-translational stages. Later stages of HL maturation occur without calnexin assistance, although inactive HL at all stages appears to be associated in distinct complexes with other ER proteins. Thus, unlike other lipases in the gene family, HL maturation is the rate-limiting step in its secretion as a functional enzyme. C1 Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. RP Doolittle, MH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 113,Rm 312, Los Angeles, CA 90073 USA. EM markdool@ucla.edu FU NHLBI NIH HHS [HL28481] NR 57 TC 16 Z9 16 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 13 PY 2004 VL 279 IS 7 BP 6171 EP 6181 DI 10.1074/jbc.M310051200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 771GD UT WOS:000188776500133 PM 14630921 ER PT J AU Lavigne, M Francis, NJ King, IFG Kingston, RE AF Lavigne, M Francis, NJ King, IFG Kingston, RE TI Propagation of silencing: Recruitment and repression of naive chromatin - In trans by polycomb repressed chromatin SO MOLECULAR CELL LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; CONVEYS EPIGENETIC INHERITANCE; RESPONSE ELEMENT; GROUP-COMPLEXES; GAGA FACTOR; TRANSCRIPTION FACTOR; BITHORAX COMPLEX; CELLULAR MEMORY; GENE-EXPRESSION; IN-VITRO AB The Polycomb group (PcG) proteins maintain stable and heritable repression of homeotic genes. Typically, Polycomb response elements (PRE) that direct PcG repression are located at great distances (10s of kb) from the promoters of PcG-repressed genes, and it is not known how these PREs can communicate with promoters over such distances. Using Class II mouse PRC core complexes (mPCCs) assembled from recombinant subunits, we investigated how PcG complexes might bridge distant chromosomal regions. Like native and recombinant Drosophila Class II complexes, mPCC represses chromatin remodeling and transcription. Interestingly, mPCC bound to one polynucleosome template can recruit a second template from solution and renders it refractory to transcription and chromatin remodeling. A Drosophila PRC core complex (dPCC) also is able to recruit a second template. Posterior sex combs (PSC), a subunit of dPCC, inhibits chromatin remodeling and transcription efficiently but requires assembly with dRING1 to recruit chromatin. Thus, repression and template bridging require different subunits of PcG complexes, suggesting that long-range effects may be mechanistically distinct from repression. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, 50 Blossom St, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu NR 53 TC 65 Z9 72 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 13 PY 2004 VL 13 IS 3 BP 415 EP 425 DI 10.1016/S1097-2765(04)00006-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 774BC UT WOS:000188959000013 PM 14967148 ER PT J AU Kennedy, S Wang, D Ruvkun, G AF Kennedy, S Wang, D Ruvkun, G TI A conserved siRNA-degrading RNase negatively regulates RNA interference in C-elegans SO NATURE LA English DT Article ID CAENORHABDITIS-ELEGANS; MESSENGER-RNA; GENETIC INTERFERENCE; ESCHERICHIA-COLI; PROTEIN; INDUCTION; INTERACTS; PATHWAY; DOMAIN; RDE-1 AB In many organisms, introducing double-stranded RNA (dsRNA) causes the degradation of messenger RNA that is homologous to the trigger dsRNA-a process known as RNA interference. The dsRNA is cleaved into short interfering RNAs (siRNAs), which hybridize to homologous mRNAs and induce their degradation(1). dsRNAs vary in their ability to trigger RNA interference: many mRNA-targeting dsRNAs show weak phenotypes, and nearly all mRNAs of the Caenorhabditis elegans nervous system are refractory to RNA interference(2-4). C. elegans eri-1 was identified in a genetic screen for mutants with enhanced sensitivity to dsRNAs. Here we show that eri-1 encodes an evolutionarily conserved protein with domains homologous to nucleic-acid-binding and exonuclease proteins. After exposure to dsRNA or siRNAs, animals with eri-1 mutations accumulate more siRNAs than do wild-type animals. C. elegans ERI-1 and its human orthologue degrade siRNAs in vitro. In the nematode worm, ERI-1 is predominantly cytoplasmic and is expressed most highly in the gonad and a subset of neurons, suggesting that ERI-1 siRNase activity suppresses RNA interference more intensely in these tissues. Thus, ERI-1 is a negative regulator that may normally function to limit the duration, cell-type specificity or endogenous functions of RNA interference. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Ruvkun, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu NR 21 TC 369 Z9 401 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 12 PY 2004 VL 427 IS 6975 BP 645 EP 649 DI 10.1038/nature02302 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773AJ UT WOS:000188875300044 PM 14961122 ER PT J AU Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Omland, T Wolf, PA Vasan, RS AF Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Omland, T Wolf, PA Vasan, RS TI Plasma natriuretic peptide levels and the risk of cardiovascular events and death SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGESTIVE-HEART-FAILURE; VENTRICULAR SYSTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; ATRIAL-FIBRILLATION; DIASTOLIC DYSFUNCTION; PROGNOSTIC VALUE; MORTALITY; DISEASE; STROKE; HYPERTROPHY AB Background: The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established. Methods: We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. Results: During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro-atrial natriuretic peptide. Conclusions: In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Med Ctr, Cardiol Sect, Boston, MA USA. Boston Med Ctr, Dept Neurol, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Akershus Hosp, Dept Med, Oslo, Norway. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,2, Framingham, MA 01702 USA. EM vasan@fram.nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23-HL074077-01, K24-HL-04334, N01-HC-25195] NR 45 TC 800 Z9 839 U1 1 U2 17 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 12 PY 2004 VL 350 IS 7 BP 655 EP 663 DI 10.1056/NEJMoa031994 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500006 PM 14960742 ER PT J AU Levine, RJ Maynard, SE Qian, C Lim, KH England, LJ Yu, KF Schisterman, EF Thadhani, R Sachs, BP Epstein, FH Sibai, BM Sukhatme, VP Karumanchi, SA AF Levine, RJ Maynard, SE Qian, C Lim, KH England, LJ Yu, KF Schisterman, EF Thadhani, R Sachs, BP Epstein, FH Sibai, BM Sukhatme, VP Karumanchi, SA TI Circulating angiogenic factors and the risk of preeclampsia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED-TRIAL; FACTOR RECEPTOR; SERUM LEVELS; 2ND-TRIMESTER; BEVACIZUMAB; EXPRESSION; CALCIUM; CANCER AB Background: The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. Methods: We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. Results: During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Conclusions: Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Allied Technol Grp, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Obstet, Boston, MA 02114 USA. Univ Cincinnati, Coll Med, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. RP Levine, RJ (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. EM levinerj@mail.nih.gov; sananth@bidmc.harvard.edu OI Schisterman, Enrique/0000-0003-3757-641X NR 25 TC 1597 Z9 1679 U1 6 U2 49 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 12 PY 2004 VL 350 IS 7 BP 672 EP 683 DI 10.1056/NEJMoa031884 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500008 PM 14764923 ER PT J AU Carter, BS Rabinov, JD Pfannl, R Schwamm, LH Black-Schaffer, RM Chapman, P AF Carter, BS Rabinov, JD Pfannl, R Schwamm, LH Black-Schaffer, RM Chapman, P TI A man with slurred speech and left hemiparesis - Stroke involving the right middle cerebral artery, with the malignant middle-cerebral-artery edema syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TISSUE-PLASMINOGEN-ACTIVATOR; INTERNAL CAROTID-ARTERY; ACUTE ISCHEMIC-STROKE; RT-PA STROKE; INTRAARTERIAL THROMBOLYSIS; HEMISPHERIC INFARCTION; DECOMPRESSIVE SURGERY; CT ANGIOGRAPHY; PROACT II; HEMICRANIECTOMY C1 Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Div Neuropathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurosurg, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02138 USA. RP Carter, BS (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. NR 30 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 12 PY 2004 VL 350 IS 7 BP 707 EP 716 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 772YB UT WOS:000188869500013 PM 14960747 ER PT J AU Koh, EY Chen, T Daley, GQ AF Koh, EY Chen, T Daley, GQ TI Genetic complementation of cytokine signaling identifies central role of kinases in hematopoietic cell proliferation SO ONCOGENE LA English DT Article DE expression cloning; cytokine signaling; tyrosine kinase; myeloproliferative disease ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; COLONY-STIMULATING FACTOR; HOMEOBOX GENE; PROTEIN-KINASE; MYELODYSPLASTIC SYNDROMES; DIFFERENTIAL EXPRESSION; TRANSCRIPTION FACTORS; TRANSFORMING GENE; MYELOID-LEUKEMIA AB Molecular evidence suggests a multistep process in the development of acute leukemia. Since inappropriate activation of cytokine signaling cascades is a recurring theme in human leukemia, we performed expression screens to identify genes that transform cytokine-dependent cells. Using retroviral cDNA libraries derived from peripheral blood mononuclear cells of patients with myeloproliferative disorders, we isolated numerous genes that genetically complement cytokine requirements for proliferation of BaF/3 and TF-1 cells. The majority of recovered genes represent members of the kinase family, including several previously linked to leukemogenesis. Our unbiased screen highlights the central role of kinase activation in hematopoietic cell proliferation and identifies a number of potential leukemic oncoproteins. C1 Whitehead Inst, Cambridge Ctr 9, Cambridge, MA 02142 USA. Harvard Univ, Sch Med,Childrens Hosp, Dept Biol Chem & Mol Pharmacol, Div Pediat Hematol Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Whitehead Inst, Cambridge Ctr 9, Cambridge, MA 02142 USA. EM daley@wi.mit.edu FU NCI NIH HHS [CA76418, CA09541, CA86991]; NIGMS NIH HHS [T32 GM007753, GM07753-22] NR 61 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 12 PY 2004 VL 23 IS 6 BP 1214 EP 1220 DI 10.1038/sj.onc.1207209 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 773HH UT WOS:000188892200005 PM 14647454 ER PT J AU Itoh, F Itoh, S Goumans, MJ Valdimarsdottir, G Iso, T Dotto, GP Hamamori, Y Kedes, L Kato, M ten Dijke, P AF Itoh, F Itoh, S Goumans, MJ Valdimarsdottir, G Iso, T Dotto, GP Hamamori, Y Kedes, L Kato, M ten Dijke, P TI Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells SO EMBO JOURNAL LA English DT Article DE angiogenesis; BMP; Notch; signal transduction; Hairy-related proteins ID BONE MORPHOGENETIC PROTEIN; TGF-BETA RECEPTOR; GROWTH-FACTOR; FUNCTIONAL-CHARACTERIZATION; INTRACELLULAR DOMAIN; PRIMARY TARGET; RBP-J; DIFFERENTIATION; ACTIVATION; ANGIOGENESIS AB Notch and bone morphogenetic protein signaling pathways are important for cellular differentiation, and both have been implicated in vascular development. In many cases the two pathways act similarly, but antagonistic effects have also been reported. The underlying mechanisms and whether this is caused by an interplay between Notch and BMP signaling is unknown. Here we report that expression of the Notch target gene, Herp2, is synergistically induced upon activation of Notch and BMP receptor signaling pathways in endothelial cells. The synergy is mediated via RBP-Jkappa/CBF-1 and GC-rich palindromic sites in the Herp2 promoter, as well as via interactions between the Notch intracellular domain and Smad that are stabilized by p/CAF. Activated Notch and its downstream effector Herp2 were found to inhibit endothelial cell (EC) migration. In contrast, BMP via upregulation of Id1 expression has been reported to promote EC migration. Interestingly, Herp2 was found to antagonize BMP receptor/ Id1-induced migration by inhibiting Id1 expression. Our results support the notion that Herp2 functions as a critical switch downstream of Notch and BMP receptor signaling pathways in ECs. C1 Netherlands Canc Inst, Div Cellular Biochem, NL-1066 CX Amsterdam, Netherlands. Gunma Univ, Sch Med, Dept Internal Med 2, Gunma, Japan. Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Baylor Coll Med, Ctr Cardiovasc Dev, Dept Med & Mol & Cellular Biol, Houston, TX 77030 USA. Univ So Calif, Keck Sch Med, Inst Med Genet, Dept Med, Los Angeles, CA USA. Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA USA. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. RP ten Dijke, P (reprint author), Netherlands Canc Inst, Div Cellular Biochem, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM p.t.dijke@nki.nl NR 42 TC 151 Z9 154 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 11 PY 2004 VL 23 IS 3 BP 541 EP 551 DI 10.1038/sj.emboj.7600065 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 773KA UT WOS:000188921900007 PM 14739937 ER PT J AU Seddon, JM Gensler, G Milton, RC Klein, ML Rifai, N AF Seddon, JM Gensler, G Milton, RC Klein, ML Rifai, N TI Association between C-reactive protein and age-related macular degeneration SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RISK-FACTORS; DIETARY-FAT; EYE DISEASE; VITAMIN-C; INFLAMMATION; PROGRESSION; MODEL; AREDS AB Context C-reactive protein (CRP) is a systemic inflammatory marker associated with risk for cardiovascular disease (CVD). Some risk factors for CVD are associated with age-related macular degeneration (AMD), but the association between CRP and AMD is unknown. Objective To test the hypothesis that elevated CRP levels are associated with an increased risk for AMD. Design, Setting, and Participants A total of 930 (91%) of 1026 participants at 2 centers in the Age-Related Eye Disease Study (AREDS), a multicenter randomized trial of antioxidant vitamins and minerals, were enrolled in this case-control study. There were 183 individuals without any maculopathy, 200 with mild maculopathy, 325 with intermediate disease, and 222 with advanced AMD (geographic atrophy or neovascular AMD). The AMD status was assessed by standardized grading of fundus photographs, and stored fasting blood specimens drawn between January 1996 and April 1997 were analyzed for high-sensitivity CRP levels. Main Outcome Measure Association between CRP and AMD. Results The CRP levels were significantly higher among participants with advanced AMD (case patients) than among those with no AMD (controls; median values, 3.4 vs 2.7 mg/L; P=.02). After adjustment for age, sex, and other variables, including smoking and body mass index, CRP levels were significantly associated with the presence of intermediate and advanced stages of AMD. The odds ratio (OR) for the highest vs the lowest quartile of CRP was 1.65 (95% confidence interval [0], 1.07-2.55; P for trend =.02). The OR for CRP values at or above the 90th percentile (10.6 mg/L) was 1.92 (95% Cl, 1.20-3.06), and the OR for CRP values at or above the mean plus 2 SDs (16.8 mg/L) was 2.03 (95% Cl, 1.03-4.00). A trend for an increased risk for intermediate and advanced AMD with higher levels of CRP was seen for smokers (OR, 2.16; 95% Cl, 1.33-3.49) and those who never smoked (OR, 2.03; 95% Cl, 1.19-3.46) with the highest level of CRP. Conclusion Our results suggest that elevated CRP level is an independent risk factor for AMD and may implicate the role of inflammation in the pathogenesis of AMD. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Epidemiol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EMMES Corp, Rockville, MD USA. Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Lab Med, Boston, MA USA. RP Seddon, JM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Epidemiol Unit, 243 Charles St, Boston, MA 02114 USA. EM Johanna_Seddon@meei.harvard.edu FU NEI NIH HHS [N01EY02126, N01EY02117, R01EY13982] NR 21 TC 255 Z9 268 U1 0 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 11 PY 2004 VL 291 IS 6 BP 704 EP 710 DI 10.1001/jama.291.6.704 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 772AY UT WOS:000188819200023 PM 14871913 ER PT J AU Jiang, R Manson, JE Meigs, JB Ma, J Rifai, N Hu, FB AF Jiang, R Manson, JE Meigs, JB Ma, J Rifai, N Hu, FB TI Body iron stores in relation to risk of type 2 diabetes in apparently healthy women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; SERUM FERRITIN; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; FREE-RADICALS; MELLITUS; HYPERINSULINEMIA; HEMOCHROMATOSIS; REPRODUCIBILITY; CLASSIFICATION AB Context Type 2 diabetes is a common manifestation of hemochromatosis, a disease of iron overload. However, it is not clear whether higher iron stores predict the development of type 2 diabetes in a healthy population. Objective To examine plasma ferritin concentration and the ratio of the concentrations of transferrin receptors to ferritin in relation to risk of type 2 diabetes. Design, Setting, and Participants Prospective nested case-control study within the Nurses' Health Study cohort. Of the 32826 women who provided blood samples during 1989-1990 and were free of diagnosed diabetes, cardiovascular disease, and cancer, 698 developed diabetes during 10 years of follow-up. The controls (n=716) were matched to cases on age, race, and fasting status; and on body mass index (BMI) for cases in the top BMI decile. Main Outcome Measure Incident cases of type 2 diabetes. Results Among cases, the mean (SD) concentration of ferritin was significantly higher (109 [1051 vs 71.5 [68.7] ng/mL for controls; P<.001 for difference) and the mean (SD) ratio of transferrin receptors to ferritin was significantly lower (102 [205] vs 141 [340], respectively; P=.01). In conditional logistic regression stratified on the matching factors and controlled for BMI and other diabetes risk factors, the multivariate relative risks [RRs] of incident type 2 diabetes across increasing quintiles of ferritin were 1.00, 1.09 (95% confidence interval [CI], 0.70-1.70),1.26 (95% Cl, 0.82-1.95),1.30 (95% Cl, 0.83-2.04), and 2.68 (95% Cl, 1.75-4.11) (P<.001 for trend). The RRs across increasing quintiles of transferrin receptors to ferritin ratio were 2.44 (95% Cl, 1.61-3.71), 1.00 (95% Cl, 0.64-1.56),1.13 (95% Cl, 0.73-1.74), 0.99 (95% Cl, 0.64-1.53), and 1.00 (P=.01 for trend). Further adjustment for an inflammatory marker (C-reactive protein) did not change the results appreciably. The associations persisted within strata defined by levels of BMI, menopausal status, alcohol consumption, and C-reactive protein. Conclusion Higher iron stores (reflected by an elevated ferritin concentration and a lower ratio of transferrin receptors to ferritin) are associated with an increased risk of type 2 diabetes in healthy women independent of known diabetes risk factors. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Prevent Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. Channing Labs, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Childrens Hosp, Med Ctr, Boston, MA 02115 USA. RP Jiang, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM rjiang@hsph.harvard.edu FU NCI NIH HHS [CA87969, CA78293]; NIDDK NIH HHS [DK58845] NR 31 TC 294 Z9 307 U1 5 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 11 PY 2004 VL 291 IS 6 BP 711 EP 717 DI 10.1001/jama.291.6.711 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 772AY UT WOS:000188819200024 PM 14871914 ER PT J AU Kang, HJ Choi, YS Hong, SB Kim, KW Woo, RS Won, SJ Kim, EJ Jeon, HK Jo, SY Kim, TK Bachoo, R Reynolds, IJ Gwag, BJ Lee, HW AF Kang, HJ Choi, YS Hong, SB Kim, KW Woo, RS Won, SJ Kim, EJ Jeon, HK Jo, SY Kim, TK Bachoo, R Reynolds, IJ Gwag, BJ Lee, HW TI Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity SO JOURNAL OF NEUROSCIENCE LA English DT Article DE catalytic subunit of telomerase; ischemia; excitotoxicity; NMDA; calcium; mitochondria ID REVERSE-TRANSCRIPTASE; INDUCED APOPTOSIS; CORTICAL-NEURONS; CALCIUM-UPTAKE; CELL-CULTURE; TUMOR-CELLS; LIFE-SPAN; C-MYC; PROLIFERATION; MITOCHONDRIA AB The catalytic subunit of telomerase reverse transcriptase ( TERT) protects dividing cells from replicative senescence in vitro. Here, we show that expression of TERT mRNA is induced in the ipsilateral cortical neurons after occlusion of the middle cerebral artery in adult mice. Transgenic mice that overexpress TERT showed significant resistance to ischemic brain injury. Among excitotoxicity, oxidative stress, and apoptosis comprising of routes of ischemic neuronal death, NMDAreceptor-mediated excitotoxicity was reduced in forebrain cell cultures overexpressing TERT. NMDA-induced accumulation of cytosolic free Ca2+ ([Ca2+](c)) was reduced in forebrain neurons from TERT transgenic mice, which was attributable to the rapid flow of [Ca2+](c) into the mitochondria from the cytosol without change in Ca2+ influx and efflux through the plasma membrane. The present study provides evidence that TERT is inducible in postmitotic neurons after ischemic brain injury and prevents NMDA neurotoxicity through shift of the cytosolic free Ca2+ into the mitochondria, and thus plays a protective role in ameliorating ischemic neuronal cell death. C1 Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Dept Mol Cell Biol, Suwon 440746, South Korea. Ajou Univ, Sch Med, Dept Neurosci, Suwon 442749, South Korea. Ajou Univ, Sch Med, Dept Pharmacol, Suwon 442749, South Korea. Chonbuk Univ Med Sch, Dept Pharmacol, Chonju 561180, South Korea. Chonbuk Univ Med Sch, Inst Med Sci, Chonju 561180, South Korea. Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. RP Gwag, BJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Dept Mol Cell Biol, Suwon 440746, South Korea. EM bjgwag@madang.ajou.ac.kr; hwl@skku.ac.kr RI Reynolds, Ian/C-4358-2008 NR 46 TC 89 Z9 102 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 11 PY 2004 VL 24 IS 6 BP 1280 EP 1287 DI 10.1523/JNEUROSCI.4082-03.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 773JF UT WOS:000188896100003 PM 14960598 ER PT J AU Wiviott, SD Cannon, CP Morrow, DA Murphy, SA Gibson, CM McCabe, CH Sabatine, MS Rifai, N Giugliano, RP DiBattiste, PM Demopoulos, LA Antman, EM Braunwald, E AF Wiviott, SD Cannon, CP Morrow, DA Murphy, SA Gibson, CM McCabe, CH Sabatine, MS Rifai, N Giugliano, RP DiBattiste, PM Demopoulos, LA Antman, EM Braunwald, E TI Differential expression of cardiac biomarkers by gender in patients with unstable angina/non-ST-elevation myocardial infarction - A TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18) Substudy SO CIRCULATION LA English DT Article DE cardiovascular diseases; natriuretic peptides; creatine kinase; inflammation; women ID ACUTE CORONARY SYNDROMES; C-REACTIVE PROTEIN; TROPONIN-T LEVELS; NATRIURETIC PEPTIDE; ARTERY-DISEASE; RISK STRATIFICATION; PROGNOSTIC VALUE; CARDIOVASCULAR-DISEASE; TIMI 11A; WOMEN AB Background-Diagnosis of coronary artery disease in women is more difficult because of lower specificity of symptoms and diagnostic accuracy of noninvasive testing. We sought to examine the relationship between gender and cardiac biomarkers in patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI). Methods and Results-In the TACTICS-TIMI 18, OPUS-TIMI 16, and TIMI 11 studies, baseline samples were analyzed in the Thrombolysis In Myocardial Infarction ( TIMI) biomarker core laboratory. We examined the relationship between gender and elevated biomarkers. Of 1865 patients from TACTICS-TIMI 18, 34% were women. Fewer women had elevated creatine kinase-MB or troponins, whereas more had elevated high-sensitivity C-reactive protein or brain natriuretic peptide. Presence of ST-segment deviation and TIMI risk scores were not significantly different. This pattern was confirmed in TIMI 11 and OPUS-TIMI 16. The prognostic value of the markers in TACTICS-TIMI 18 was similar in women and men. When a multimarker approach was examined, a greater proportion of high-risk women were identified. Marker-positive patients of both genders had improved outcome with an invasive strategy; however, marker-negative women appeared to have improved outcomes with a conservative strategy. Conclusions-In patients with UA/NSTEMI, there was a different pattern of presenting biomarkers. Men were more likely to have elevated creatine kinase-MB and troponins, whereas women were more likely to have elevated C-reactive protein and brain natriuretic peptide. This suggests that a multimarker approach may aid the initial risk assessment of UA/NSTEMI, especially in women. Further research is necessary to elucidate whether gender-related pathophysiological differences exist in presentation with acute coronary syndromes. C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Childrens Hosp, Boston, MA 02115 USA. Merck Inc, W Point, PA USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM swiviott@partners.org NR 35 TC 97 Z9 108 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 10 PY 2004 VL 109 IS 5 BP 580 EP 586 DI 10.1161/01.CIR.0000109491.66226.26 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772HM UT WOS:000188836600007 PM 14769678 ER PT J AU Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Wilson, PWF Vasan, RS AF Wang, TJ Larson, MG Levy, D Benjamin, EJ Leip, EP Wilson, PWF Vasan, RS TI Impact of obesity on plasma natriuretic peptide levels SO CIRCULATION LA English DT Article DE natriuretic peptides; obesity; epidemiology ID BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; RECEPTOR EXPRESSION; ADIPOSE-TISSUE; HEART; BRAIN; DISEASE; GENE AB Background-The mechanisms linking obesity to hypertension have not been established, but sodium retention and excessive sympathetic tone are key contributors. The natriuretic peptides are important regulators of sodium homeostasis and neurohormonal activation, raising the possibility that obese individuals have an impaired natriuretic peptide response. Methods and Results-We examined the relations of plasma B-type natriuretic peptide (BNP) and N-terminal proatrial natriuretic peptide (N-ANP) to body mass index in 3389 Framingham Study participants (1803 women) without heart failure. Multivariable regression analyses were performed, adjusting for clinical and echocardiographic covariates. BNP levels below the assay detection limit and N-ANP levels in the lowest sex-specific quartile were categorized as low. Multivariable-adjusted mean plasma BNP levels in lean (<25 kg/m(2)), overweight (25 to 29.9 kg/m(2)), and obese (&GE;30 kg/m(2)) men were 21.4, 15.5, and 12.7 pg/mL, respectively (trend P<0.0001). Corresponding values in women were 21.1, 16.3, and 13.1 pg/mL (trend P<0.001). A similar pattern was noted for plasma N-ANP. Obese individuals had higher odds of having low plasma BNP (multivariable-adjusted odds ratios: men, 2.51; 95% CI, 1.71 to 3.68; women, 1.84; 95% CI, 1.32 to 2.58) and low plasma N-ANP (odds ratios: men, 4.81; 95% CI, 2.98 to 7.76; women, 2.85; 95% CI, 2.01 to 4.04) compared with lean individuals. Diabetes also was associated with low plasma natriuretic peptide levels, and the negative effects of obesity and diabetes on natriuretic peptide levels were additive. Conclusions-Obese individuals have low circulating natriuretic peptide levels, which may contribute to their susceptibility to hypertension and hypertension-related disorders. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston Med Ctr, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston Med Ctr, Sect Prevent Med, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,2, Framingham, MA 01702 USA. EM vasan@fram.nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23 HL074077-01, K24-HL-04334, N01-HC-25195] NR 32 TC 465 Z9 491 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 10 PY 2004 VL 109 IS 5 BP 594 EP 600 DI 10.1161/01.CIR.0000112582.16683.EA PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 772HM UT WOS:000188836600009 PM 14769680 ER PT J AU Kabakci, K Hedrich, K Leung, JC Mitterer, M Vieregge, P Lencer, R Hagenah, J Garrels, J Witt, K Klostermann, F Svetel, M Friedman, J Kostic, V Bressman, SB Breakefield, XO Ozelius, LJ Pramstaller, PP Klein, C AF Kabakci, K Hedrich, K Leung, JC Mitterer, M Vieregge, P Lencer, R Hagenah, J Garrels, J Witt, K Klostermann, F Svetel, M Friedman, J Kostic, V Bressman, SB Breakefield, XO Ozelius, LJ Pramstaller, PP Klein, C TI Mutations in DYT1 - Extension of the phenotypic and mutational spectrum SO NEUROLOGY LA English DT Article ID PRIMARY TORSION DYSTONIA; AUTOSOMAL DOMINANT INHERITANCE; ASHKENAZI JEWS; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; MUTANT TORSINA; GAG DELETION; LEWY BODIES; HUMAN BRAIN; GENE DYT1 AB Background: Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three-base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD). Objective: To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls. Methods: The authors screened 197 patients with dystonia (generalized: n=5; focal/segmental: n=126; myoclonus-dystonia: n=34; neuroleptic-induced: n=32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases. Results: The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1. Conclusions: In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD. C1 Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. Univ Lubeck, Dept Human Genet, D-23538 Lubeck, Germany. Univ Lubeck, Dept Psychiat & Psychotherapy, D-23538 Lubeck, Germany. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Hosp Merano, Dept Transfus Med, Merano, Italy. Hosp Lippe Lemgo, Dept Neurol, Lemgo, Germany. Univ Kiel, Dept Neurol, D-24098 Kiel, Germany. Free Univ Berlin, Dept Neurol, D-1000 Berlin, Germany. Univ Belgrade, Dept Neurol, YU-11001 Belgrade, Yugoslavia. Beth Israel Med Ctr, Dept Neurol, New York, NY 10003 USA. Albert Einstein Coll Med, Dept Mol Genet, New York, NY USA. Reg Gen Hosp Bolzano, Dept Neurol, Bolzano, Italy. RP Klein, C (reprint author), Univ Lubeck, Dept Neurol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM klein_ch@neuro.mu-luebeck.de RI Pramstaller, Peter/C-2357-2008; Lencer, Rebekka/A-4994-2009 OI Lencer, Rebekka/0000-0003-4032-7297 FU NINDS NIH HHS [NS28384] NR 45 TC 44 Z9 45 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 10 PY 2004 VL 62 IS 3 BP 395 EP 400 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 778JQ UT WOS:000189238800011 PM 14872019 ER PT J AU Fabian, TJ Amico, JA Kroboth, PD Mulsant, BH Corey, SE Begley, AE Bensasi, SG Weber, E Dew, MA Reynolds, CF Pollock, BG AF Fabian, TJ Amico, JA Kroboth, PD Mulsant, BH Corey, SE Begley, AE Bensasi, SG Weber, E Dew, MA Reynolds, CF Pollock, BG TI Paroxetine-induced hyponatremia in older adults - A 12-week prospective study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the New-Clinical-Drug-Evaluation-Unit CY JUN 10-13, 2002 CL BOCA RATON, FLORIDA SP NIMH ID SEROTONIN-REUPTAKE INHIBITORS; ANTIDIURETIC-HORMONE SECRETION; ARGININE VASOPRESSIN; IDIOPATHIC HYPONATREMIA; ELDERLY-PEOPLE; RATING-SCALE; RISK-FACTORS; DEPRESSION; PLASMA; FLUOXETINE AB Background: Older depressed patients are at high risk for development of hyponatremia after initiation of the selective serotonin reuptake inhibitor paroxetine, despite clinical monitoring and preventive management. The purposes of this study were to determine the incidence and etiology of paroxetine-induced hyponatremia in older patients and to identify patient characteristics that may account for variability in susceptibility to this adverse event. Methods: This prospective, longitudinal study was conducted in a university-based ambulatory psychiatric research clinic from August 1999 through September 2001. Patients included 75 men and women aged 63 through 90 years (mean +/- SD age, 75.3 +/- 6.0 years) who received a diagnosis of a current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive episode and were prescribed paroxetine. We monitored plasma sodium levels before initiating paroxetine therapy and after 1, 2, 4, 6, and 12 weeks of treatment. In a subset of individuals, we measured levels of antidiuretic hormone, glucose, serum urea nitrogen, and creatinine. Hyponatremia was defined as a plasma sodium level of less than 135 mEq/L after initiation of paroxetine therapy. Results: Hyponatremia developed in 9 (12%) of the 75 patients after initiation of paroxetine treatment. Mean SD time to development of hyponatremia was 9.3 +/- 4.7 days (median, 9 days; range, 1-14 days; n=8). In the multivariate regression, lower body mass index and lower baseline plasma sodium level (<138 mEq/L) were significant risk factors for the development of hyponatremia in these patients. Conclusions: Hyponatremia is an underrecognized and potentially serious complication of paroxetine treatment in older patients. Our results provide a foundation for understanding the etiology and risk factors associated with paroxetine-induced hyponatremia. C1 Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Intervent Res Ctr Late Life Mood Disorders, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. Vet Affairs Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Fabian, TJ (reprint author), Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Intervent Res Ctr Late Life Mood Disorders, 806 Salk Hall, Pittsburgh, PA 15261 USA. EM fabiant@msx.upmc.edu RI chen, xuanlan/H-4158-2011 FU NIA NIH HHS [AG05133]; NIMH NIH HHS [MH52247, MH01613, MH0295, MH19986, MH37869, MH43832, MH55756, MH65416] NR 38 TC 61 Z9 63 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 9 PY 2004 VL 164 IS 3 BP 327 EP 332 DI 10.1001/archinte.164.3.327 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 771JQ UT WOS:000188782200016 PM 14769630 ER PT J AU Michaelson, MD Shipley, WU Heney, NM Zietman, AL Kaufman, DS AF Michaelson, MD Shipley, WU Heney, NM Zietman, AL Kaufman, DS TI Selective bladder preservation for muscle-invasive transitional cell carcinoma of the urinary bladder SO BRITISH JOURNAL OF CANCER LA English DT Review DE bladder cancer; radiation therapy; chemotherapy; radical cystectomy; cisplatin ID COMBINED-MODALITY PROGRAM; ORGAN-SPARING TREATMENT; QUALITY-OF-LIFE; PHASE-III TRIAL; RADIATION-THERAPY; NEOADJUVANT CHEMOTHERAPY; TRANSURETHRAL SURGERY; RADICAL CYSTECTOMY; PLUS CYSTECTOMY; CANCER AB Invasive transitional cell carcinoma (TCC) of the urinary bladder is traditionally treated with radical cystectomy. This approach results in great morbidity and lifestyle changes, and approximately half of the patients treated in this way will experience recurrent TCC despite surgery. An alternative approach using selective bladder-preservation techniques incorporates transurethral resection of bladder tumours, radiation therapy, and chemotherapy. Over the past 20 years, international experience has demonstrated that this approach is feasible, safe, and well tolerated. Furthermore, the long-term outcomes of overall survival and disease-free survival compare favourably with the outcomes from radical cystectomy. The most important predictor of response is stage, with significantly higher long-term survival in patients with T2 disease. Another important positive predictor of complete response to therapy is the ability of the urologic oncologist to remove all visible tumour through a transurethral approach prior to initiation of radiation therapy. A negative predictive factor is the presence of hydronephrosis, and age and gender do not affect disease-free survival. The majority of patients who enjoy long-term survival do so with an intact native bladder. Quality of life studies have demonstrated that the retained bladder functions well in nearly all of these patients. Selective bladder preservation will not entirely take the place of radical cystectomy, but should be offered as an important alternative to patients newly diagnosed with muscle-invasive TCC. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Hematol Oncol,Canc Ctr, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol & Urol,Canc Ctr, Boston, MA USA. RP Michaelson, MD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Hematol Oncol,Canc Ctr, Boston, MA 02114 USA. EM dmichaelson1@partners.org OI Michaelson, Dror/0000-0001-9249-6338 NR 24 TC 23 Z9 24 U1 0 U2 1 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 FEB 9 PY 2004 VL 90 IS 3 BP 578 EP 581 DI 10.1038/sj.bjc.6601580 PG 4 WC Oncology SC Oncology GA 780PW UT WOS:000189391400004 PM 14760367 ER PT J AU Fischer, H Sandblom, J Herlitz, A Fransson, P Wright, CI Backman, L AF Fischer, H Sandblom, J Herlitz, A Fransson, P Wright, CI Backman, L TI Sex-differential brain activation during exposure to female and male faces SO NEUROREPORT LA English DT Article DE amygdala; anterior temporal cortex; fMRI; functional imaging; human; person perception; sex differences ID GENDER-DIFFERENCES; MENSTRUAL-CYCLE; HUMAN AMYGDALA; RECOGNITION; PREFERENCES; MEMORY; WOMEN AB Sex-discriminating facial features are examples of visual information involved in guiding social behavior. We used functional magnetic resonance imaging (fMRI) to assess brain responses in face-relevant brain areas in men and women during exposure to neutral male and female faces. An increased fMRI signal was found in the left amygdala and adjacent anterior temporal regions in men, but not in women, during exposure to faces of the opposite versus the same sex. These data indicate that the relationship between the sex of the subject and the sex of the face affects activity in the inferior temporal lobe. The sex-differential nature of this activation pattern may reflect sex differences in cognitive style and attentional processes when confronting faces of the opposite sex. C1 Karolinska Inst, NEUROTEC, Div Geriatr Epidemiol, Aging Res Ctr, S-11382 Stockholm, Sweden. Karolinska Hosp, Dept Clin Neurosci, Clin Neurophysiol Sect, Stockholm, Sweden. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat Neuroimaging Res Grp, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Nucl Magnet Resonance Ctr, Boston, MA 02129 USA. Brigham & Womens Hosp, Dept Neurol, Brigham Behav Neurol Grp, Boston, MA 02115 USA. RP Fischer, H (reprint author), Karolinska Inst, NEUROTEC, Div Geriatr Epidemiol, Aging Res Ctr, Box 6401, S-11382 Stockholm, Sweden. EM hakan.fischer@neurotec.ki.se RI Fransson, Peter/M-5679-2014; OI Fransson, Peter/0000-0002-1305-9875; Herlitz, Agneta/0000-0002-9313-4192 NR 25 TC 32 Z9 33 U1 8 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 9 PY 2004 VL 15 IS 2 BP 235 EP 238 DI 10.1097/00001756-200402090-00004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 871NH UT WOS:000225139900004 PM 15076743 ER PT J AU Hadjikhani, N Chabris, CF Joseph, RM Clark, J McGrath, L Aharon, I Feczko, E Tager-Flusberg, H Harris, GJ AF Hadjikhani, N Chabris, CF Joseph, RM Clark, J McGrath, L Aharon, I Feczko, E Tager-Flusberg, H Harris, GJ TI Early visual cortex organization in autism: an fMRI study SO NEUROREPORT LA English DT Article DE Asperger syndrome; autism; brain imaging; retinotopy; visual processing ID CHILDREN; ABILITY; AREAS; INDIVIDUALS; ATTENTION; ILLUSIONS; TASK AB Autism is a neurodevelopmental disorder characterized by preserved visual abilities as well as a special profile for visual cognition. We examined the visual cortex of high-ability individuals with autism in order to assess whether the presence of abnormalities at the primary sensory level in autism could be the basis of their unusual pattern of visual cognitive abilities. We found that the early sensory visual areas are normally organized in individuals with autism, with a normal ratio between central versus peripheral visual field representation. We conclude that the differences observed in the visual capacities of individuals with autism are likely to arise from higher-level cognitive areas and functions, and are the result of top-down processes. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Radiol Comp Aided Diagnost Lab, Boston, MA 02114 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Hadjikhani, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Bldg 36,1st St,Room 417, Charlestown, MA 02129 USA. EM nouchine@nmr.mgh.harvard.edu RI Hadjikhani, Nouchine/C-2018-2008; Tager-Flusberg, Helen/D-5265-2009 OI Hadjikhani, Nouchine/0000-0003-4075-3106; FU NIDCD NIH HHS [DC03610]; NINDS NIH HHS [R01 NS44824-01] NR 25 TC 29 Z9 29 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 9 PY 2004 VL 15 IS 2 BP 267 EP 270 DI 10.1097/01.wnr.0000107523.38715.fa PG 4 WC Neurosciences SC Neurosciences & Neurology GA 871NH UT WOS:000225139900011 PM 15076750 ER PT J AU Nassif, NA Cense, B Park, BH Pierce, MC Yun, SH Bouma, BE Tearney, GJ Chen, TC de Boer, JF AF Nassif, NA Cense, B Park, BH Pierce, MC Yun, SH Bouma, BE Tearney, GJ Chen, TC de Boer, JF TI In vivo high-resolution video-rate spectral-domain optical coherence tomography of the human retina and optic nerve SO OPTICS EXPRESS LA English DT Article ID BLOOD-FLOW; INTERFEROMETRY AB An ultra-high- speed spectral-domain optical coherence tomography system (SD-OCT) was developed for imaging the human retina and optic nerve in vivo at a sustained depth profile (A-line) acquisition speed of 29 kHz. The axial resolution was 6 mum in tissue and the system had shot-noise-limited performance with a maximum sensitivity of 98.4 dB. 3-dimensional data sets were collected in 11 and 13 seconds for the macula and optic nerve head respectively and are presented to demonstrate the potential clinical applications of SD-OCT in ophthalmology. Additionally, a 3-D volume of the optic nerve head was constructed from the acquired data and the retinal vascular network was visualized. C1 Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Nassif, NA (reprint author), Harvard Univ, Sch Med, 50 Blossom St,BAR 724, Boston, MA 02114 USA. EM deboer@helix.mgh.harvard.edu RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 NR 19 TC 366 Z9 375 U1 6 U2 44 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 FEB 9 PY 2004 VL 12 IS 3 BP 367 EP 376 DI 10.1364/OPEX.12.000367 PG 10 WC Optics SC Optics GA 772FK UT WOS:000188830500003 PM 19474832 ER PT J AU Que, W Kung, J Dai, J AF Que, W Kung, J Dai, J TI 'Tongue-and-groove' effect in intensity modulated radiotherapy with static multileaf collimator fields SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID DELIVERY; DISTRIBUTIONS; SYSTEM AB The 'tongue-and-groove problem' in step-and-shoot delivery of intensity modulated radiotherapy is investigated. A 'tongue-and-groove' index (TGI) is introduced to quantify the 'tongue-and-groove' effect in step-and-shoot delivery. Four different types of leaf sequencing methods are compared. The sliding window method and the reducing level method use the same number of field segments to deliver the same intensity map, but the TGI is much less for the reducing. level method. The leaf synchronization method of Van Santvoort and Heijmen fails in step-and-shoot delivery, but a new method inspired by the method of Van Santvoort and Heijmen is shown to eliminate 'tongue-and-groove' underdosage completely. C1 Ryerson Univ, MPCS, Toronto, ON M5B 2K3, Canada. Toronto Sunnybrook Reg Canc Ctr, Dept Med Phys, Toronto, ON, Canada. Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Canc Inst Hosp, Chinese Acad Med Sci, Dept Radiat Oncol, Beijing, Peoples R China. RP Que, W (reprint author), Ryerson Univ, MPCS, 350 Victoria St, Toronto, ON M5B 2K3, Canada. NR 18 TC 19 Z9 20 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 7 PY 2004 VL 49 IS 3 BP 399 EP 405 AR PII S0031-9155(04)63725-0 DI 10.1088/0031-9155/49/3/004 PG 7 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 778PX UT WOS:000189250900005 PM 15012009 ER PT J AU Sharp, GC Jiang, SB Shimizu, S Shirato, H AF Sharp, GC Jiang, SB Shimizu, S Shirato, H TI Prediction of respiratory tumour motion for real-time image-guided radiotherapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID INSPIRATION BREATH-HOLD; EXTERNAL-BEAM RADIOTHERAPY; CELL LUNG-CANCER; DEEP INSPIRATION; TRACKING RADIOTHERAPY; GATED RADIOTHERAPY; RADIATION-THERAPY; CONTROL ABC; FEASIBILITY; IRRADIATION AB Image guidance in radiotherapy and extracranial radiosurgery offers the potential for precise radiation dose delivery to a moving tumour. Recent work has demonstrated how to locate and track the position of a tumour in real-time using diagnostic x-ray imaging to find implanted radio-opaque markers. However, the delivery of a treatment plan through gating or beam tracking requires adequate consideration of treatment system latencies, including image acquisition, image processing, communication delays, control system processing, inductance within the motor, mechanical damping, etc. Furthermore, the imaging dose given over long radiosurgery procedures or multiple radiotherapy fractions may not be insignificant, which means that we must reduce the sampling rate of the imaging system. This study evaluates various predictive models for reducing tumour localization errors when a real-time tumour-tracking system targets a moving tumour at a slow imaging rate and with large system latencies. We consider 14 lung tumour cases where the peak-to-peak motion is greater than 8 mm, and compare the localization error using linear prediction, neural network prediction and Kalman filtering, against a system which uses no prediction. To evaluate prediction accuracy for use in beam tracking, we compute the root mean squared error between predicted and actual 3D motion. We found that by using prediction, root mean squared error is improved for all latencies and all imaging rates evaluated. To evaluate prediction accuracy for use in gated treatment, we present a new metric that compares a gating control signal based on predicted motion against the best possible gating control signal. We found that using prediction improves gated treatment accuracy for systems that have latencies of 200 ms or greater, and for systems that have imaging rates of 10 Hz or slower. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Hokkaido Univ, Sch Med, Dept Radiat Med, Sapporo, Hokkaido 060, Japan. RP Sharp, GC (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM gcsharp@partners.org RI Shimizu, Shinichi/G-4477-2010; Shirato, Hiroki/A-7068-2010 OI Shimizu, Shinichi/0000-0003-3143-0479; NR 45 TC 221 Z9 231 U1 4 U2 22 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 7 PY 2004 VL 49 IS 3 BP 425 EP 440 AR PII S0031-9155(04)69607-2 DI 10.1088/0031-9155/49/3/006 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 778PX UT WOS:000189250900007 PM 15012011 ER PT J AU Kelleher, RJ Govindarajan, A Jung, HY Kang, HJ Tonegawa, S AF Kelleher, RJ Govindarajan, A Jung, HY Kang, HJ Tonegawa, S TI Translational control by MAPK signaling in long-term synaptic plasticity and memory SO CELL LA English DT Article ID LOCAL PROTEIN-SYNTHESIS; LATE-PHASE; NEURONAL PLASTICITY; KINASE PATHWAYS; CA1 REGION; HIPPOCAMPUS; POTENTIATION; CONSOLIDATION; SYNAPSES; FEAR AB Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP. In hippocampal neurons, ERK inhibition blocked neuronal activity-induced translation as well as phosphorylation of the translation factors elF4E, 4EBP1, and ribosomal protein S6. Correspondingly, protein synthesis and translation factor phosphorylation induced in control hippocampal slices by L-LTP-generating tetanization were significantly reduced in mutant slices. Translation factor phosphorylation induced in the control hippocampus by memory formation was similarly diminished in the mutant hippocampus. These results suggest a crucial role for translational control by MAPK signaling in long-lasting forms of synaptic plasticity and memory. C1 MIT, RIKEN,Dept Biol, Neurosci Res Ctr,Howard Hughes Med Inst, Picower Ctr Learning & Memory, Cambridge, MA 02139 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Memory Disorders Unit, Boston, MA 02114 USA. RP Tonegawa, S (reprint author), MIT, RIKEN,Dept Biol, Neurosci Res Ctr,Howard Hughes Med Inst, Picower Ctr Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM tonegawa@mit.edu NR 56 TC 492 Z9 508 U1 1 U2 27 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 6 PY 2004 VL 116 IS 3 BP 467 EP 479 DI 10.1016/S0092-8674(04)00115-1 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 772DR UT WOS:000188825800014 PM 15016380 ER PT J AU Xiao, YF Ke, QG Wang, SY Yang, YK Chen, Y Wang, GK Morgan, JP Cox, B Leaf, A AF Xiao, YF Ke, QG Wang, SY Yang, YK Chen, Y Wang, GK Morgan, JP Cox, B Leaf, A TI Electrophysiologic properties of lidocaine, cocaine, and n-3 fatty-acids block of cardiac Na+ channels SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE fish oil; polyunsaturated fatty acid; arrhythmias; adrenoceptor agonists; eicosapentaenoic acid; docosahexaenoic acid ID RAT VENTRICULAR MYOCYTES; BETA-1 SUBUNIT; SODIUM-CHANNEL; MESSENGER-RNA; PREVENTION; FIBRILLATION; ARRHYTHMIAS; DEATH; SUSCEPTIBILITY; EXPRESSION AB Lidocaine and cocaine, two local anesthetics, and n-3 polyunsaturated fatty acids in fish oils, inhibit the voltage-gated Na+ channels of cardiomyocytes. This inhibition by lidocaine and n-3 fish oil is associated with antiarrhythmic effects, whereas with cocaine lethal arrhythmias may occur. These electrophysiologic studies show that at the concentrations tested, the n-3 fish oil fatty acids and lidocaine share three actions on I-Na: a potent inhibition of I-Na; a strong voltage-dependence of this inhibition, and a large shift of the steady-state inactivation to hyperpolarized potentials. By contrast cocaine shares only the potent inhibition of I-Na. The voltage-dependence of the inhibition is much decreased with cocaine, which produces only a very small leftward shift of the voltage-dependence of inactivation. The large leftward shift of the steady-state inactivation seems very important in the prevention of fatal arrhythmias by the n-3 fatty acids. Thus, we suggest that it is lack of this effect by cocaine, which is one factor, that eliminates its ability to prevent fatal cardiac arrhythmias. Further we report that in cultured neonatal rat cardiomyocytes n-3 fish oil fatty acids terminate the tachycardia induced by the alpha(1) adrenergic agonist, phenylephrine, whereas cocaine accelerates the tachycardia and causes bouts of tachyarythmias. (C) 2003 Elsevier B.V. All rights reserved. C1 Massachusetts Gen Hosp East, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Charles A Dana Res Inst, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Harvard Thorndike Lab, Boston, MA 02215 USA. SUNY Albany, Dept Biol, Albany, NY 12222 USA. Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. RP Leaf, A (reprint author), Massachusetts Gen Hosp East, Dept Med, 149 13th St, Charlestown, MA 02129 USA. EM aleaf@partners.org FU NHLBI NIH HHS [HL62284]; NIDA NIH HHS [DA11762]; NIDDK NIH HHS [DK38165]; NIGMS NIH HHS [GM35401] NR 30 TC 18 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 6 PY 2004 VL 485 IS 1-3 BP 31 EP 41 DI 10.1016/j.ejphar.2003.11.042 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 770FL UT WOS:000188712500004 PM 14757121 ER PT J AU Neid, M Datta, K Stephan, S Khanna, I Pal, S Shaw, L White, M Mukhopadhyay, D AF Neid, M Datta, K Stephan, S Khanna, I Pal, S Shaw, L White, M Mukhopadhyay, D TI Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-I RECEPTOR; HUMAN BREAST-CANCER; PHOSPHATIDYLINOSITOL 3-KINASE; THERAPEUTIC IMPLICATIONS; PLECKSTRIN HOMOLOGY; SIGNALING PATHWAYS; PROMOTER ACTIVITY; IRS PROTEINS; IGF-IR; ACTIVATION AB Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), the critical molecule in tumor angiogenesis, is regulated by different stimuli, such as hypoxia and oncogenes, and also by growth factors. Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. Insulin receptor substrate-1 and -2 (IRS-1 and IRS-2), two major downstream molecules of IGF-1R, are known to be important in the genesis of diabetes. In this study, we have defined a new role of IRS in angiogenesis. Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. Protein kinase C-zeta (PKC-zeta) plays a central role in VPF/VEGF expression and acts as a switching element. Furthermore, we have also demonstrated that the phosphatidylinositol 3-kinase pathway, but not the Ras pathway, is a downstream event of IRS proteins for VPF/VEGF expression in AsPC-1 cells. Interestingly, like renal cancer cells, in AsPC-1 cells PKC-zeta leads to direct Sp1-dependent VPF/VEGF transcription; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85. Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1-dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2. Our data also suggest that IRS proteins, which are known to play crucial roles in IGF-1R signaling, are also important mediators for tumor angiogenesis. C1 Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Mayo Clin Canc Ctr, Rochester, MN 55905 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Biol Sci, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Div Nephrol, Boston, MA 02115 USA. RP Mukhopadhyay, D (reprint author), Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Gugg 1401A,200 1st St SW, Rochester, MN 55905 USA. EM mukhopadhyay.debabrata@mayo.edu FU NCI NIH HHS [CA7838]; NHLBI NIH HHS [HL70567] NR 60 TC 38 Z9 40 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 6 PY 2004 VL 279 IS 6 BP 3941 EP 3948 DI 10.1074/jbc.M303975200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300007 PM 14604996 ER PT J AU Cao, Q Mak, KM Ren, CL Lieber, CS AF Cao, Q Mak, KM Ren, CL Lieber, CS TI Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells - Respective roles of the JAK/STAT and JAK-mediated H2O2-dependent MAPK pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; TRANSFORMING GROWTH-FACTOR-BETA-1; EXTRACELLULAR-MATRIX; SIGNAL-TRANSDUCTION; ALCOHOLIC CIRRHOSIS; ENDOTHELIAL-CELLS; GENE-EXPRESSION; LIVER FIBROSIS; MESSENGER-RNA; SERUM LEPTIN AB Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H2O2-dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38alpha and p38beta mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H2O2-dependent p38 and ERK1/2 pathways via activated JAK. C1 Bronx Vet Affairs Med Ctr, Alcohol & Nutr Res Ctr, Bronx, NY 10468 USA. Mt Sinai Sch Med, Bronx, NY 10468 USA. RP Lieber, CS (reprint author), Bronx Vet Affairs Med Ctr, Alcohol & Nutr Res Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM liebercs@aol.com FU NIAAA NIH HHS [AA11115, R01 AA012867] NR 64 TC 112 Z9 128 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 6 PY 2004 VL 279 IS 6 BP 4292 EP 4304 DI 10.1074/jbc.M308351200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300047 PM 14625304 ER PT J AU Lee, DU Avni, O Chen, L Rao, A AF Lee, DU Avni, O Chen, L Rao, A TI A distal enhancer in the interferon-gamma (IFN-gamma) locus revealed by genome sequence comparison SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR; GENE-EXPRESSION; T-BET; LINEAGE COMMITMENT; REGULATORY ELEMENTS; IN-VIVO; COORDINATE REGULATOR; CELL-DIFFERENTIATION; BINDING-SITES; MOUSE GENOME AB Large-scale cross-species DNA sequence comparison has become a powerful tool to identify conserved cis-regulatory modules of genes. However, bioinformatic analysis alone cannot reveal how an evolutionarily conserved region regulates gene expression: whether it functions as an enhancer, silencer, or insulator; whether its function is cell-type restricted; and whether biologically relevant transcription factors bind to the element. Here we combine bioinformatics with wet-lab techniques to illustrate a general and systematic method of identifying functional conserved regulatory regions of genes. We applied this approach to the interferon-gamma (IFN-gamma) gene. Comparison of human and mouse IFN-gamma reveals a highly conserved non-coding sequence located similar to5 kb 5' of the transcription start site. This region coincides with constitutive and inducible DNase I hypersensitivity sites present in IFN-gamma-producing Th1 cells but not in Th2 cells that do not produce IFN-gamma. Histone methylation at the 5' conserved non-coding sequences indicates a more accessible chromatin structure in Th1 cells compared with Th2 cells. This element binds two transcription factors known to be essential for IFN-gamma expression: nuclear factor of activated T cells, an inducible transcription factor, and T-box protein expressed in T cells, a cell lineage-restricted transcription factor. Together, these findings identify a highly conserved distal enhancer in the IFN-gamma cytokine locus and validate our approach as a successful method to detect cis-regulatory elements. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Ctr Blood Res, Inst Biomed Res, Boston, MA 02115 USA. Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Alpert Bldg Rm 152,200 Longwood Ave, Boston, MA 02115 USA. EM arao@cbr.med.harvard.edu RI Chen, Lin/A-3392-2008 FU NHLBI NIH HHS [HL-67664]; NIAID NIH HHS [AI-44432, R21 AI049905]; NIGMS NIH HHS [R01 GM064642] NR 54 TC 103 Z9 105 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 FEB 6 PY 2004 VL 279 IS 6 BP 4802 EP 4810 DI 10.1074/jbc.M307904200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 768UW UT WOS:000188554300105 PM 14607827 ER PT J AU Kang, JX Wang, JD Wu, L Kang, ZB AF Kang, JX Wang, JD Wu, L Kang, ZB TI Transgenic mice - Fat-1 mice convert n-6 to n-3 fatty acids SO NATURE LA English DT Editorial Material ID DESATURASE; EXPRESSION; CELLS C1 Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kang, JX (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM kang.jing@mgh.harvard.edu NR 7 TC 283 Z9 308 U1 7 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 5 PY 2004 VL 427 IS 6974 BP 504 EP 504 DI 10.1038/427504a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 770KM UT WOS:000188721800031 PM 14765186 ER PT J AU Freedman, SD Blanco, PG Zaman, MM Shea, JC Ollero, M Hopper, IK Weed, DA Gelrud, A Regan, MM Laposata, M Alvarez, JG O'Sullivan, BP AF Freedman, SD Blanco, PG Zaman, MM Shea, JC Ollero, M Hopper, IK Weed, DA Gelrud, A Regan, MM Laposata, M Alvarez, JG O'Sullivan, BP TI Association of cystic fibrosis with abnormalities in fatty acid metabolism SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DOCOSAHEXAENOIC ACID; ADIPOSE-TISSUE; CFTR(-/-) MICE; ION-TRANSPORT; GENE; INFLAMMATION; PANCREATITIS; MUTATIONS; DISEASE; CELLS AB Background: Patients with cystic fibrosis have altered levels of plasma fatty acids. We previously demonstrated that arachidonic acid levels are increased and docosahexaenoic acid levels are decreased in affected tissues from cystic fibrosis-knockout mice. In this study we determined whether humans with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have a similar fatty acid defect in tissues expressing CFTR. Methods: Fatty acids from nasal- and rectal-biopsy specimens, nasal epithelial scrapings, and plasma were analyzed from 38 subjects with cystic fibrosis and compared with results in 13 obligate heterozygotes, 24 healthy controls, 11 subjects with inflammatory bowel disease, 9 subjects with upper respiratory tract infection, and 16 subjects with asthma. Results: The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects. In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease in docosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acid was increased in subjects with cystic fibrosis (P<0.001), as compared with healthy controls, with values in obligate heterozygotes intermediate between these two groups (P<0.001). The ratio was not increased in subjects with inflammatory bowel disease. Subjects with asthma and those with upper respiratory tract infection had values intermediate between those in subjects with cystic fibrosis and those in healthy control subjects. Conclusions: These data indicate that alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis. C1 Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Div Lab Med, Boston, MA 02114 USA. Hosp San Rafael, Ctr Infertilidad Masculina Androgen, Inst Infertilidad Masculina, La Coruna, Spain. Univ Massachusetts, Sch Med, UMass Mem Hlth Care, Dept Pediat, Worcester, MA USA. RP Freedman, SD (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Dana 552,330 Brookline Ave, Boston, MA 02215 USA. EM sfreedma@caregroup.harvard.edu FU NCRR NIH HHS [RR 01032] NR 44 TC 213 Z9 220 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 5 PY 2004 VL 350 IS 6 BP 560 EP 569 DI 10.1056/NEJMoa021218 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 770FP UT WOS:000188712800007 PM 14762183 ER PT J AU Hilliard, AA Weinberger, SE Tierney, LM Midthun, DE Saint, S AF Hilliard, AA Weinberger, SE Tierney, LM Midthun, DE Saint, S TI Occam's razor versus Saint's Triad SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Mayo Clin & Mayo Fdn, Dept Med, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Div Pulm & Crit Care Med, Rochester, MN 55905 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. Ann Arbor Vet Affairs Hlth Serv Res & Dev Ctr Exc, Ann Arbor, MI USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Saint, S (reprint author), Box 0429,300 NIB,Room 7E08, Ann Arbor, MI 48109 USA. EM saint@umich.edu FU AHRQ HHS [P20-HS11540] NR 5 TC 38 Z9 41 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 5 PY 2004 VL 350 IS 6 BP 599 EP 603 DI 10.1056/NEJMcps031794 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 770FP UT WOS:000188712800013 PM 14762188 ER PT J AU Christie, MA Dalrymple-Alford, JC AF Christie, MA Dalrymple-Alford, JC TI A new rat model of the human serial reaction time task: Contrasting effects of caudate and hippocampal lesions SO JOURNAL OF NEUROSCIENCE LA English DT Article DE declarative memory; nondeclarative memory; procedural memory; multiple-memory systems; sequence learning; caudate; hippocampus; lesion; rat; serial reaction time task; intracranial self-stimulation ID MULTIPLE MEMORY-SYSTEMS; PARKINSONS-DISEASE; HUNTINGTONS-DISEASE; DOUBLE DISSOCIATION; NUCLEUS LESIONS; MAZE TASKS; IMPLICIT; SEQUENCE; ASSOCIATIONS; PERFORMANCE AB There is often little correspondence between human and animal examples of nondeclarative memory. The serial reaction time task (SRT) is a sequence learning example of human nondeclarative memory that may be suitable for development as an animal model. The SRT is believed to be impaired by basal ganglia, not limbic system damage, but there is uncertainty whether limbic system pathology does in fact leave the SRT unimpaired. We therefore developed a new rat model that closely approximated the human SRT, using intracranial self-stimulation to promote rapid continuous responding to four adjacent nose pokes in a single test session. Intact rats that experienced repeated sequences demonstrated robust interference effects when switched to a random sequence of cued responses (at 4-, 8-, and 12-sequence lengths), unlike intact controls that experienced the random sequences only. The interference effect in the human task is a key measure for nondeclarative sequence learning. Rats with dorsal caudate lesions that experienced massed sequence repetitions showed an interference effect at the four-sequence length only. By contrast, rats with dorsal hippocampal lesions showed an interference effect at all sequence lengths. This new rat SRT model clarifies the basal ganglia-limbic system dichotomy suggested by human work. C1 Massachusetts Gen Hosp, Dept Neurol, Ctr Aging Genet & Neurodegenerat, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Univ Canterbury, Dept Psychol, Christchurch Brain Res Grp, Christchurch 1, New Zealand. RP Christie, MA (reprint author), Ctr Aging Genet & Neurodegenerat, 114 16th St,Charlestown Naval Yards, Charlestown, MA 02129 USA. EM mchristi@helix.mgh.harvard.edu NR 34 TC 27 Z9 27 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 4 PY 2004 VL 24 IS 5 BP 1034 EP 1039 DI 10.1523/JNEUROSCI.3340-03.2004 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 770UZ UT WOS:000188750300004 PM 14762121 ER PT J AU Wallner, P Arthur, D Bartelink, H Connolly, J Edmundson, G Giuliano, A Goldstein, N Hevezi, J Julian, T Kuske, R Lichter, A McCormick, B Orecchia, R Pierce, L Powell, S Solin, L Vicini, F Whelan, T Wong, J Coleman, CN AF Wallner, P Arthur, D Bartelink, H Connolly, J Edmundson, G Giuliano, A Goldstein, N Hevezi, J Julian, T Kuske, R Lichter, A McCormick, B Orecchia, R Pierce, L Powell, S Solin, L Vicini, F Whelan, T Wong, J Coleman, CN TI Workshop on Partial Breast Irradiation: State of the Art and the Science, Bethesda, MD, December 8-10, 2002 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CONFORMAL RADIATION-THERAPY; DETECTED DUCTAL CARCINOMA; CONSERVING SURGERY; CONSERVATIVE SURGERY; LOCAL RECURRENCE; RANDOMIZED TRIAL; TUMOR BED; BRACHYTHERAPY APPLICATOR; SOLE BRACHYTHERAPY; RADICAL-MASTECTOMY AB Breast conserving surgery followed by radiation therapy has been accepted as an alternative to mastectomy in the management of patients with early-stage breast cancer. Over the past decade there has been increasing interest in a variety of radiation techniques designed to treat only the portion of the breast deemed to be at high risk for local recurrence (partial-breast irradiation [PBI]) and to shorten the duration of treatment (accelerated partial-breast irradiation [APBI]). To consider issues regarding the equivalency of the various radiation therapy approaches and to address future needs for research, quality assurance, and training, the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Radiation Research Program, hosted a Workshop on PBI in December 2002. Although 5- to 7-year outcome data on patients treated with PBI and APBI are now becoming available, many issues remain unresolved, including clinical and pathologic selection criteria, radiation dose and fractionation and how they relate to the standard fractionation for whole breast irradiation, appropriate target volume, local control within the untreated ipsilateral breast tissue, and overall survival. This Workshop report defines the issues in relation to PBI and APBI, recommends parameters for consideration in clinical trials and for reporting of results, serves to enhance dialogue among the advocates of the various radiation techniques, and emphasizes the importance of education and training in regard to results of PBI and APBI as they become emerging clinical treatments. C1 NCI, RRP, DCTD, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. William Beaumont Hosp, Dept Radiat Oncol, Royal Oak, MI USA. John Wayne Canc Inst, Santa Monica, CA USA. Canc Therapy & Res Ctr S Texas, San Antonio, TX 78229 USA. Allegheny Gen Hosp, Dept Human Oncol, Pittsburgh, PA 15212 USA. Arizona Oncol Serv, Scottsdale, AZ USA. Univ Michigan, Sch Med, Dept Radiat Oncol, Ann Arbor, MI USA. Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. European Inst Oncol, Dept Radiotherapy, Milan, Italy. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. Hamilton Reg Canc Ctr, Support Canc Care Res Unit, Hamilton, ON L8V 1C3, Canada. RP Coleman, CN (reprint author), NCI, RRP, DCTD, NIH, 6130 Execut Blvd,EPN Room 6015A, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov RI Whelan, Timothy/D-3185-2017 NR 50 TC 59 Z9 61 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 4 PY 2004 VL 96 IS 3 BP 175 EP 184 DI 10.1093/jnci/djh023 PG 10 WC Oncology SC Oncology GA 778JU UT WOS:000189239100007 PM 14759984 ER PT J AU Telford, JJ Saltzman, JR Kuntz, KM Syngal, S AF Telford, JJ Saltzman, JR Kuntz, KM Syngal, S TI Impact of preoperative staging and chemoradiation versus postoperative chemoradiation on outcome in patients with rectal cancer: A decision analysis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID LYMPH-NODE INVOLVEMENT; ABDOMINO-PERINEAL RESECTION; TOTAL MESORECTAL EXCISION; COMBINED-MODALITY THERAPY; SURGICAL ADJUVANT BREAST; LOW ANTERIOR RESECTION; QUALITY-OF-LIFE; LOCAL EXCISION; TRANSRECTAL ULTRASONOGRAPHY; ENDORECTAL ULTRASONOGRAPHY AB Background: Although radical resection and postoperative chemoradiation have been the standard therapy for patients with rectal cancer, preoperative staging by local imaging and chemoradiation are widely used. We used a decision analysis to compare the two strategies for rectal cancer management. Methods: We developed a decision model to compare survival outcomes after postoperative chemoradiation versus preoperative staging and chemoradiation in patients aged 70 years with resectable rectal cancer. In the postoperative chemoradiation strategy, patients undergo radical resection and receive postoperative chemoradiation. In the preoperative staging and chemoradiation strategy, patients with locally advanced cancer receive preoperative chemoradiation and radical resection, whereas those with amenable localized tumors undergo local excision. The cohorts of patients were entered into a Markov model incorporating age-adjusted and disease-specific mortality. Outcomes were evaluated by modeling 5-year disease-specific survival for preoperative chemoradiation as less than, equal to, or greater than that of postoperative chemoradiation. Base-case probabilities were derived from published data; the Surveillance, Epidemiology, and End Results (SEER) Program database; and U.S. Life Tables. One-way and two-way sensitivity analyses were performed. The outcome measures were life expectancy and quality-adjusted life expectancy. Results: Life expectancy and quality-adjusted life expectancy were 9.72 and 8.72 years, respectively, in the postoperative chemoradiation strategy. In the preoperative staging and chemoradiation strategy, life expectancy was 9.36, 9.72, and 10.09 years and quality-adjusted life expectancy was 8.71, 9.04, and 9.37 years when 5-year disease-specific survival was less than, equal to, or greater than that of postoperative chemoradiation, respectively. The decision model was sensitive to differences in the long-term toxicity of pre- and postoperative chemoradiation. When the 5-year disease-specific survival for patients after pre- or postoperative chemoradiation was equal, the decision model was sensitive to surgical mortality and to the probability of residual lymph node disease after local excision. Conclusion: If efficacy and toxicity after preoperative chemoradiation are equal to or better than that after postoperative chemoradiation in patients with locally advanced rectal cancer, then preoperative staging to select patients appropriate for preoperative chemoradiation is beneficial. C1 Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, Div Populat Sci, Smith 209,44 Binney St, Boston, MA 02115 USA. EM ssyngal@partners.org NR 98 TC 9 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 4 PY 2004 VL 96 IS 3 BP 191 EP 201 DI 10.1093/jnci/djh026 PG 11 WC Oncology SC Oncology GA 778JU UT WOS:000189239100009 PM 14759986 ER PT J AU Colditz, GA Rosner, BA Chen, WY Holmes, MD Hankinson, SE AF Colditz, GA Rosner, BA Chen, WY Holmes, MD Hankinson, SE TI Risk factors for breast cancer according to estrogen and progesterone receptor status SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NATIONAL DEATH INDEX; NURSES HEALTH; AGE-INCIDENCE; BODY-SIZE; MODEL; CARCINOGENESIS; EPIDEMIOLOGY; FEMALES; PARITY AB Background: Evaluations of epidemiologic risk factors in relation to breast cancer classified jointly by estrogen receptor (ER) and progesterone receptor (PR) status have been inconsistent. To address this issue, we conducted a prospective evaluation of risk factors for breast cancer classified according to receptor status. Methods: During 1029 414 person-years of follow-up of 66 145 women participating in the Nurses' Health Study from 1980 through 2000, we identified 2096 incident cases of breast cancer for which information on ER/PR status was available: 1281 were ER+/ PR+, 318 were ER+/PR-, 80 were ER-/PR+, and 417 were ER-/PR-. We fit a log-incidence model of breast cancer and used polychotomous logistic regression to compare coefficients for breast cancer risk factors in patients with different ER/PR status. To test for differences in risk factor odds ratios based on marginal ER/PR categories, we evaluated ER status controlling for PR status and vice versa. The predictive ability of our log-incidence model to discriminate between women who would develop ER+/PR+ breast cancer and those who would not (and similarly for ER-/ PR- breast cancer) was evaluated by using receiver operator characteristic curve analysis. All statistical tests were two-sided. Results: We observed statistically significant heterogeneity among the four ER/PR categories for some risk factors (age, menopausal status, body mass index [BMI] after menopause, the one-time adverse effect of first pregnancy, and past use of postmenopausal hormones) but not for others (benign breast disease, family history of breast cancer, alcohol use, and height). The one-time adverse association of first pregnancy with incidence was present for PR- but not for PR+ tumors after controlling for ER status (P =.007). However, the association of BMI after menopause with incidence was present for PR+ but not PR- tumors (P =.005). Statistically significant differences in the incidence of ER+ and ER- tumors were seen with age, both before and after menopause (P =.003), and with past use of postmenopausal hormones (P =.01). Area under the receiver operator characteristic curve, adjusted for age, was 0.64 (95% confidence interval [CI] = 0.63 to 0.66) for ER+/PR+ tumors and 0.61 (95% CI = 0.58 to 0.64) for ER-/PR- tumors. Conclusions: Incidence rates and risk factors for breast cancer differ according to ER and PR status. Thus, to accurately estimate breast cancer risk, breast cancer cases should be divided according to the ER and PR status of the tumor. C1 Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Colditz, GA (reprint author), Brigham & Womens Hosp, Channing Lab, 181 Longwood Ave,3rd Fl, Boston, MA 02115 USA. EM graham.colditz@channing.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA87969] NR 39 TC 289 Z9 299 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 4 PY 2004 VL 96 IS 3 BP 218 EP 228 DI 10.1093/jnci/djh025 PG 11 WC Oncology SC Oncology GA 778JU UT WOS:000189239100012 PM 14759989 ER PT J AU Chan, AT Giovannucci, EL Schernhammer, ES Colditz, GA Hunter, DJ Willett, WC Fuchs, CS AF Chan, AT Giovannucci, EL Schernhammer, ES Colditz, GA Hunter, DJ Willett, WC Fuchs, CS TI A prospective study of aspirin use and the risk for colorectal adenoma SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT Digestive Disease Week Meeting/104th Annual Meeting of the American-Gastroenterological-Association CY MAY 17-22, 2003 CL ORLANDO, FLORIDA SP Amer Gastroenterol Assoc ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; LONG-TERM USE; COLON-CANCER CELLS; NF-KAPPA-B; LARGE-BOWEL; RANDOMIZED-TRIAL; UNITED-STATES; PRIMARY PREVENTION; PHYSICAL-ACTIVITY; REDUCED RISK AB Background: Randomized, double-blind, placebo-controlled trials have established that regular aspirin use reduces the risk for recurrent colorectal adenoma. However, the effect of dose and duration of use, particularly in an average-risk population, is not well understood. Objective: To examine the influence of dose and duration of aspirin use in the primary prevention of colorectal adenoma. Design: Prospective cohort study. Setting: Nurses' Health Study. Participants: 27 077 women, 34 to 77 years of age, without a history of adenoma, cancer, inflammatory bowel disease, or familial polyposis, who underwent lower endoscopy between 1980 and 1998. Measurements: 1368 cases of confirmed distal colorectal adenoma were diagnosed between 1980 and 1998. Self-reported data on aspirin use were collected from biennial questionnaires. Results: After other risk factors for adenoma were adjusted, women who regularly used aspirin (greater than or equal to2 standard aspirin tablets/wk) had a multivariate relative risk for adenoma of 0.75 (95% Cl, 0.66 to 0.84) compared with nonregular users. Compared with women who denied any aspirin use, the multivariate relative risks for adenoma were 0.80 (Cl, 0.70 to 0.93) for women who used 0.5 to 1.5 standard tablets per week, 0.74 (Cl, 0.62 to 0.88) for those who used 2 to 5 tablets per week, 0.72 (Cl, 0.61 to 0.85) for those who used 6 to 14 tablets per week, and 0.49 (Cl, 0.36 to 0.65) for those who used more than 14 tablets per week (P<0.001 for trend). Similar dose-response relationships were found among regular short-term users (less than or equal to5 years; P<0.001) and long-term users (>5 years; P<0.001). In contrast, after adjustments were made for dose, increasing duration of aspirin use did not confer greater risk reduction (P>0.2). Conclusions: Regular, short-term use of aspirin is inversely associated with risk for colorectal adenoma. However, the greatest protective effect is evident at substantially higher doses (>14 tablets/wk) than those recommended for the prevention of cardiovascular disease. Before aspirin can be recommended for chemo-prevention in the general adult population, these results suggest the need for a more thorough evaluation of the risks and benefits of routine aspirin use at doses not previously considered. C1 Harvard Univ, Gastrointestinal Unit, Massachusetts Gen Hosp,Med Sch, Brigham & Womens Hosp,Dana Farber Canc Inst, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Chan, AT (reprint author), Harvard Univ, Gastrointestinal Unit, Massachusetts Gen Hosp,Med Sch, Brigham & Womens Hosp,Dana Farber Canc Inst, 55 Fruit St,GRJ-722, Boston, MA 02114 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA 55075, CA 87969]; NHLBI NIH HHS [HL 34594]; NIDDK NIH HHS [T32DK07191] NR 58 TC 106 Z9 112 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 3 PY 2004 VL 140 IS 3 BP 157 EP 166 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 770BZ UT WOS:000188704500001 PM 14757613 ER PT J AU Haas, JS Kaplan, CP Gerstenberger, EP Kerlikowske, K AF Haas, JS Kaplan, CP Gerstenberger, EP Kerlikowske, K TI Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; CORONARY HEART-DISEASE; MYOCARDIAL-INFARCTION; PLUS PROGESTIN; UNITED-STATES; BREAST-CANCER; WOMEN; PREVENTION AB Background: The recent publication of clinical trial results has led to a dramatic shift in the evidence about postmenopausal hormone therapy. Objective: To examine whether the publication of clinical trial results, specifically the Heart and Estrogen/progestin Replacement Study (HERS) in 1998 and the Women's Health Initiative (WHI) in 2002, has influenced the use of hormone therapy among postmenopausal women. Design: Observational cohort (1997 to 2003). Setting: San Francisco Mammography Registry, San Francisco, California. Participants: Postmenopausal women between the ages of 50 and 74 years without a personal history of breast cancer who underwent mammography (151862 mammograms). Measurements: Self-reported current use of hormone therapy. Results: Among menopausal women who had mammography, it was estimated that 41% were currently using hormone therapy in 1997. Before the publication of HERS, the use of hormone therapy was increasing at a rate of 1% (95% Cl, 0% to 2%) per quarter. After the publication of HERS, use decreased by 1% (Cl, -3% to 0%) per quarter. In contrast, the publication of the WHI in 2002 was associated with a more substantial decline in the use of hormone therapy of 18% (Cl, -21% to -16%) per quarter. Similar associations were observed for most subgroups of women, including women older than 65 years of age; women with a previous hysterectomy; and women who described their race or ethnicity as white, African American, Latina, Chinese, or Filipina. Conclusions: The release of the HERS data was temporally associated with a modest decline in the use of hormone therapy. In contrast, the release of the principal findings from the WHI was associated with a more substantial decline in use by postmenopausal women. The reason for the differences in decline may relate to the fact that the WHI results were widely publicized or were more applicable to most postmenopausal women because the WHI study was performed in healthy women. C1 Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU NCI NIH HHS [U01CA63740] NR 16 TC 211 Z9 211 U1 1 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 3 PY 2004 VL 140 IS 3 BP 184 EP 188 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 770BZ UT WOS:000188704500004 PM 14757616 ER PT J AU Deziel, E Lepine, F Milot, S He, JX Mindrinos, MN Tompkins, RG Rahme, LG AF Deziel, E Lepine, F Milot, S He, JX Mindrinos, MN Tompkins, RG Rahme, LG TI Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID QUINOLONE SIGNAL; FLUORESCENT PSEUDOMONADS; SECONDARY METABOLITES; VIRULENCE FACTORS; BACTERIA; GENES; IDENTIFICATION; EXPRESSION; MODEL; DIHYDROSTREPTOMYCIN AB Bacterial communities use "quorum sensing" (QS) to coordinate their population behavior through the action of extracellular signal molecules, such as the N-acyl-L-homoserine lactones (AHLs). The versatile and ubiquitous opportunistic pathogen Pseudomonas aeruginosa is a well-studied model for AHL-mediated QS. This species also produces an intercellular signal distinct from AHLs, 3,4-dihydroxy-2-heptylquinoline (PQS), which belongs to a family of poorly characterized 4-hydroxy-2-alkylquinolines (HAQs) previously identified for their antimicrobial activity. Here we use liquid chromatography (LC)/MS, genetics, and whole-genome expression to investigate the structure, biosynthesis, regulation, and activity of HAQs. We show that the pqsA-E operon encodes enzymes that catalyze the biosynthesis of five distinct classes of HAQs, and establish the sequence of synthesis of these compounds, which include potent cytochrome inhibitors and antibiotics active against human commensal and pathogenic bacteria. We find that anthranilic acid, the product of the PhnAB synthase, is the primary precursor of HAQs and that the HAQ congener 4-hydroxy-2-heptylquinoline (HHQ) is the direct precursor of the PQS signaling molecule. Significantly, whereas phnAB and pqsA-E are positively regulated by the virulence-associated transcription factor MvfR, which is also required for the expression of several QS-regulated genes, the conversion of HHQ to PQS is instead controlled by LasR. Finally, our results reveal that HHQ is itself both released from, and taken up by, bacterial cells where it is converted into PQS, suggesting that it functions as a messenger molecule in a cell-to-cell communication pathway. HAQ signaling represents a potential target for the pharmacological intervention of P. aeruginosa-mediated infections. C1 Massachusetts Gen Hosp, Shriners Burns Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Inst Armand Frappier, Inst Natl Rech Sci, Laval, PQ H7V 1B7, Canada. Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. RP Rahme, LG (reprint author), Massachusetts Gen Hosp, Shriners Burns Inst, Wellman 340,50 Blossom St, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu RI Deziel, Eric/A-7678-2008 OI Deziel, Eric/0000-0002-4609-0115 NR 45 TC 279 Z9 293 U1 3 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 3 PY 2004 VL 101 IS 5 BP 1339 EP 1344 DI 10.1073/pnas.0307694100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 771QD UT WOS:000188796800044 PM 14739337 ER PT J AU Lee, JM AF Lee, JM TI Screening issues for radiologists - Critical thinking skills symposium SO ACADEMIC RADIOLOGY LA English DT Article ID CANCER ACTION PROJECT; LUNG-CANCER; COMPUTED-TOMOGRAPHY; UNITED-STATES; CARCINOMA; DISEASE; BREAST; TRENDS C1 Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA 02114 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. NR 19 TC 4 Z9 4 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2004 VL 11 IS 2 BP 162 EP 168 DI 10.1016/S1076-6332(03)00653-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768NW UT WOS:000188549900007 PM 14974591 ER PT J AU Swan, JS AF Swan, JS TI A software application for multiattribute utility models SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Association-of-University-Radiologists CY APR 21-24, 2004 CL SAN FRANCISCO, CALIFORNIA SP Assoc Univ Radiologists DE utility; preferences; cost-effectiveness analysis ID HEALTH-CARE DECISIONS; QUALITY-OF-LIFE; DETERMINE WHETHER; HRQOL MEASURE; INDEX; PREFERENCES; VALIDITY; SYSTEM; DOWIE,JACK; SF-36 AB Rationale and Objectives. A software application for the building of preference-weighted quality of life instruments was constructed. The purpose of this application is to make the process of building such instruments with multiattribute utility (MAU) methods more accessible to physician investigators. Our application, "multiattribute outcomes evaluator" or "MOE," could facilitate the use of such methods for constructing disease-specific instruments for assessing the cost-effectiveness of new treatments. MOE could also be useful for building outcomes measures that are intended to aid individual decision making, assessment of patient satisfaction with care, or measuring of multiattribute outcomes that do not need to be scaled for cost-effectiveness analysis. Materials and Methods. MOE was programmed in Visual Basic and runs atop a Microsoft Access data base. Data from groups or individuals can be stored, and valuations of health states can be performed using standard gambles and rating scale methods. Solutions to MAU models with multiplicative or additive utility independence are possible with this application. Results. Initial tests of the program algorithms have been successful. Conclusion. We anticipate The MOE approach to MAU modeling will be a useful tool for health services researchers. C1 Indiana Univ, Dept Radiol, Educ & Res Inst, Indianapolis, IN 46202 USA. RP Swan, JS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. FU NIA NIH HHS [1R03 AG/HS 021766-01] NR 26 TC 4 Z9 4 U1 2 U2 2 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2004 VL 11 IS 2 BP 190 EP 205 DI 10.1016/S1076-6332(03)00718-9 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768NW UT WOS:000188549900010 PM 14974594 ER PT J AU Rosen, MP Jarvik, JG Swan, JS AF Rosen, MP Jarvik, JG Swan, JS TI Expect the unexpected: Thoughts, insights and musing about research in radiology - Special mentoring research roundtable SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Association-of-University-Radiologists CY APR 21-24, 2004 CL SAN FRANCISCO, CALIFORNIA SP Assoc Univ Radiologists ID HIPAA C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Univ Washington, Dept Radiol, Seattle, WA 98195 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA USA. RP Rosen, MP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. EM mrosen2@bidmc.harvard.edu FU AHRQ HHS [HS-09499]; NIAMS NIH HHS [P60 AR48093] NR 7 TC 1 Z9 1 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2004 VL 11 IS 2 BP 206 EP 212 DI 10.1016/S1076-6332(03)00672-X PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768NW UT WOS:000188549900011 PM 14974595 ER PT J AU Doherty, MJ Bird, TD Leverenz, JB AF Doherty, MJ Bird, TD Leverenz, JB TI alpha-Synuclein in motor neuron disease: an immunohistologic study SO ACTA NEUROPATHOLOGICA LA English DT Article DE amyotrophic lateral sclerosis; alpha-Synuclein; Lewy body; immunohistochemistry ID AMYOTROPHIC-LATERAL-SCLEROSIS; SUPEROXIDE-DISMUTASE GENE; BRAIN IRON ACCUMULATION; MULTIPLE SYSTEM ATROPHY; BODY-LIKE INCLUSIONS; PARKINSONS-DISEASE; LEWY BODIES; DEMENTIA; NEURODEGENERATION; IMMUNOREACTIVITY AB alpha-Synuclein (ASN) has been implicated in neurodegenerative disorders characterized by Lewy body inclusions such as Parkinson's disease and dementia with Lewy bodies. Lewy body-like inclusions have also been observed in spinal neurons of patients with amyotrophic lateral sclerosis (ALS) and reports suggest possible ASN abnormalities in ALS patients. We assessed ASN immunoreactivity in spinal and brain tissues of subjects who had died of progressive motor neuron disorders (MND). Clinical records of subjects with MND and a comparison group were reviewed to determine the diagnosis according to El-Escariol Criteria of ALS. Cervical, thoracic and lumbar cord sections were stained with an antibody to ASN. A blinded, semiquantitative review of sections from both groups included examination for evidence of spheroids, neuronal staining, cytoplasmic inclusions, anterior horn granules, white and gray matter glial staining, corticospinal tract axonal fiber and myelin changes. MND cases, including ALS and progressive muscular atrophy, displayed significantly increased ASN staining of spheroids (Pless than or equal to0.001), and glial staining in gray and white matter (Pless than or equal to0.05). Significant abnormal staining of corticospinal axon tract fibers and myelin was also observed (Pless than or equal to0.05 and 0.01). Detection of possible ASN-positive neuronal inclusions did not differ between groups. Significant ASN abnormalities were observed in MND. These findings suggest a possible role for ASN in MND; however, the precise nature of this association is unclear. C1 VA Puget Sound Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. VA Puget Sound Healthcare Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA 98108 USA. VA Puget Sound Healthcare Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Med Genet & Med, Seattle, WA 98195 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. RP Leverenz, JB (reprint author), VA Puget Sound Healthcare Syst, Mental Illness Res Educ & Clin Ctr, 116MIRECC,1660 S Columbian Way, Seattle, WA 98108 USA. EM leverenz@u.washington.edu NR 28 TC 21 Z9 21 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD FEB PY 2004 VL 107 IS 2 BP 169 EP 175 DI 10.1007/s00401-003-0790-2 PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 765UH UT WOS:000188301800011 PM 14648076 ER PT J AU DiFranza, JR Savageau, JA Fletcher, K Ockene, JK Rigotti, NA McNeill, AD Coleman, M Wood, C AF DiFranza, JR Savageau, JA Fletcher, K Ockene, JK Rigotti, NA McNeill, AD Coleman, M Wood, C TI Recollections and repercussions of the first inhaled cigarette SO ADDICTIVE BEHAVIORS LA English DT Article DE tobacco; addiction; adolescents; smoking ID NICOTINE DEPENDENCE; SMOKING-BEHAVIOR; WOMEN SMOKERS; NEVER-SMOKERS; ADOLESCENTS; SYMPTOMS; EXPOSURE; TOBACCO; ONSET AB Context: It has not been determined if a youth's reaction to the first smoking experience is predictive of future nicotine dependence, or whether the impact of the first cigarette can be altered by manipulating levels of tar, nicotine and menthol. Objective: To determine if the recalled response to the first cigarette is predictive of the development of symptoms of nicotine dependence and whether it is influenced by the type of cigarette smoked. Design and Setting: A retrospective/prospective longitudinal study of the natural history of nicotine dependence employing individual interviews conducted three times annually in two urban school systems over 3 years. Subjects were asked to recall their first smoking experience. Participants: A cohort of 237 subjects who had inhaled on a cigarette. Main Outcome Measures: Symptoms associated with smoking; the Hooked on Nicotine Checklist of 10 symptoms of dependence. Results: Reactions to the initial smoking experience were unrelated to gender or cigarette brand, strength or mentholation. Relaxation in response to the first inhalation was the strongest predictor of symptoms of nicotine dependence. Dizziness and nausea were also independent predictors of dependence symptoms. Conclusions: The data suggest that increased sensitivity to nicotine as manifested by relaxation, dizziness, or nausea in response to the first exposure to nicotine represents a risk factor for the development of nicotine dependence. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. Univ London, St Georges Hosp Med Sch, London, England. RP DiFranza, JR (reprint author), Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, 55 Lake Ave, Worcester, MA 01655 USA. EM difranzj@ummhc.org FU NCI NIH HHS [CA77067-03] NR 29 TC 83 Z9 84 U1 5 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD FEB PY 2004 VL 29 IS 2 BP 261 EP 272 DI 10.1016/j.addbeh.2003.08.002 PG 12 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 768YY UT WOS:000188600000004 PM 14732415 ER PT J AU Sureka, A Parada, JP Deloria-Knoll, M Chmiel, JS Phan, L Lyons, TM Ali, S Yarnold, PR Weinstein, RA DeHovitz, JA Jacobson, JM Goetz, MB Campo, RE Berland, D Bennett, CL Uphold, CR AF Sureka, A Parada, JP Deloria-Knoll, M Chmiel, JS Phan, L Lyons, TM Ali, S Yarnold, PR Weinstein, RA DeHovitz, JA Jacobson, JM Goetz, MB Campo, RE Berland, D Bennett, CL Uphold, CR TI HIV-related pneumonia care in older patients hospitalized in the early HAART era SO AIDS PATIENT CARE AND STDS LA English DT Article ID PNEUMOCYSTIS-CARINII-PNEUMONIA; ACTIVE ANTIRETROVIRAL THERAPY; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; STAGE BREAST-CANCER; PULMONARY COMPLICATIONS; BACTERIAL PNEUMONIA; PROGNOSTIC-FACTORS; COLORECTAL-CANCER; INFECTION; AGE AB Age-related variations in care have been identified for HIV-associated Pneumocystis carinii pneumonia (PCP) in both the 1980s and 1990s. We evaluated if age-related variations affected all aspects of HIV-specific and non-HIV-specific care for HIV-infected individuals with PCP or community-acquired pneumonia (CAP), or whether age-related variations were primarily limited to HIV-specific aspects of care. Subjects were HIV-infected persons with PCP (n = 1855) or CAP (n = 1415) hospitalized in 8 cities from 1995 to 1997. Nine percent of our study patients had received protease inhibitors and 39% had received any type of antiretroviral therapy prior to hospitalization. Data were abstracted from medical records and included severity of illness, HIV-specific aspects of care ( initiation of PCP medications), general measures of care [ initiation of CAP medications, intubation, and intensive care units (ICU)], and inpatient mortality. Compared to younger patients, pneumonia patients 50 years of age or older were significantly more likely to: be severely ill (PCP, 20.4% vs. 10.4%; CAP, 27.5% vs. 14.9%; each p = 0.001), receive ICU care (PCP, 22.0% vs. 12.8%, p = 0.002; CAP: 15.1% vs. 9.4%; p = 0.02), and be intubated (PCP, 14.6% vs. 8.4%, p = 0.01; CAP, 9.9% vs. 5.6%, p = 0.03). Compared to younger patients, older patients (greater than or equal to50 years) had similar rates of timely medications for CAP (48.5% vs. 50.8%) but had lower rates of receiving anti-PCP medications (85.8% vs. 92.9%, p = 0.002). Differences by age in timely initiation of PCP medications, ICU use, and intubation were limited to the nonseverely ill patients. Older hospitalized patients were more likely to die (PCP, 18.3% vs. 10.4%; CAP, 13.4% vs. 8.5%; each p< 0.05). After adjustment for disease severity and timeliness of antibiotic use, mortality rates were similar for both age groups. Physicians should develop strategies that increase awareness of the possibility of HIV infection in older individuals. C1 VA Chicago Hlth Care Syst, Lakeside Div, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Buehler Ctr Aging, Chicago, IL USA. Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. Edward Hines Jr Vet Adm Hosp, Midw Ctr Hlth Serv Res & Policy, Hines, IL 60141 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. Cook Cty Hosp, Dept Med, Chicago, IL 60612 USA. Rush Med Coll, Chicago, IL 60612 USA. SUNY Hlth Sci Ctr, Dept Med, Brooklyn, NY 11203 USA. Mt Sinai Med Ctr, AIDS Ctr, New York, NY 10029 USA. VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Miami, Sch Med, Div Infect Dis, Miami, FL USA. Sinai Hlth Syst, Dept Med, Chicago, IL USA. Malcolm Randall VA Med Ctr, Rehabil Outcomes Res Ctr, Gainesville, FL USA. RP Bennett, CL (reprint author), VA Chicago Hlth Care Syst, Lakeside Div, 400 E Ontario St,Suite 205, Chicago, IL 60611 USA. EM cbenne@nwu.edu RI Bennett, Charles/C-2050-2008; Andrade, Hugo/M-6631-2013; OI Andrade, Hugo/0000-0001-6781-6125; Goetz, Matthew/0000-0003-4542-992X FU NIDA NIH HHS [5R01DA10628-02] NR 29 TC 8 Z9 9 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD FEB PY 2004 VL 18 IS 2 BP 99 EP 107 DI 10.1089/108729104322802524 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 777RY UT WOS:000189192400005 PM 15006184 ER PT J AU Samet, JH Phillips, SJ Horton, NJ Traphagen, ET Freedberg, KA AF Samet, JH Phillips, SJ Horton, NJ Traphagen, ET Freedberg, KA TI Detecting alcohol problems in HIV-infected patients: Use of the CAGE questionnaire SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTION-DRUG USERS; PRIMARY-CARE; SUBSTANCE-ABUSE; RISK BEHAVIORS; UNITED-STATES; PREVALENCE; CONSUMPTION; ADHERENCE; DRINKING AB The HIV epidemic has been consistently associated with injection drug use and crack cocaine, but alcohol problems in HIV-infected persons are less well described. Our objectives were 2-fold: (1) to assess the prevalence of alcohol problems in HIV-infected patients initiating medical care; and (2) to determine the positive predictive value of the CAGE questionnaire for alcohol abuse or dependence in HIV-infected patients. Between July 1997 and October 2000, we assessed a consecutive series of patients who were establishing primary care for HIV infection (clinic sample), using an established alcohol screening test, the CAGE questionnaire. In addition, we enrolled other HIV-infected patients, including some of the clinic sample, who had two or more positive responses to the CAGE questionnaire into a longitudinal cohort (cohort sample), performed a diagnostic interview for lifetime history of alcohol abuse and dependence, and determined the positive predictive value of CAGE for alcohol diagnoses. In the clinic sample (n = 664), 42% (276 of 664) had two or more positive responses to the four CAGE questions. In the cohort sample (n = 141)9 95% (134 of 141) met DSM-IV criteria for diagnosis of lifetime alcohol abuse or dependence. For patients initiating HIV primary care, a history of alcohol problems is very common. The CAGE questionnaire identifies a lifetime history of alcohol abuse or dependence in HIV-infected patients. Routine screening for alcohol problems should be performed in all patients entering HIV medical care and the CAGE questions are useful in this setting. C1 Boston Univ, Med Ctr, Sch Med, Dept Med,CARE Unit,Sect Gen Internal Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Social & Behav Sci, CARE Unit,Sect Gent Internal Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Med, CARE Unit,Sect Gen Internal Med, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, CARE Unit,Sect Gen Internal Med, Boston, MA USA. Smith Coll, Dept Math, Northampton, MA 01063 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. RP Samet, JH (reprint author), Boston Univ, Med Ctr, Sch Med, Dept Med,CARE Unit,Sect Gen Internal Med, 91 E Concord St,Suite 200, Boston, MA 02118 USA. EM jsamet@bu.edu RI Horton, Nicholas/A-2493-2008; OI Horton, Nicholas/0000-0003-3332-4311 FU NCRR NIH HHS [M01 RR000533, M01 RR00533]; NIAAA NIH HHS [R01 AA010870, R01 AA011785, R01-AA10870, R01-AA11785, R01-AA13766] NR 45 TC 75 Z9 77 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB PY 2004 VL 20 IS 2 BP 151 EP 155 DI 10.1089/088922204773004860 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 778UR UT WOS:000189260200004 PM 15018702 ER PT J AU Si, ZH Gorry, P Babcock, G Owens, CM Cayabyab, M Phan, N Sodroski, J AF Si, ZH Gorry, P Babcock, G Owens, CM Cayabyab, M Phan, N Sodroski, J TI Envelope glycoprotein determinants of increased entry in a pathogenic simian-human immunodeficiency virus (SHIV-HXBc2P 3.2) passaged in monkeys SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID PIG-TAILED MACAQUES; CHEMOKINE RECEPTORS; RHESUS-MONKEYS; IN-VIVO; GP120 GLYCOPROTEIN; V3 LOOP; NEUTRALIZATION RESISTANCE; PERSISTENT INFECTION; LYMPHOCYTE DEPLETION; GLYCOSYLATION SITES AB Passage of a nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) in monkeys resulted in changes in the viral envelope glycoproteins that are responsible for a dramatic increase in replication and pathogenicity in vivo. Here, we show that the envelope glycoproteins of the pathogenic SHIV-HXBc2P 3.2 mediate virus entry into rhesus monkey peripheral blood mononuclear cells (PBMC) more efficiently than the parental SHIV-HXBc2 envelope glycoproteins, and study the basis for this increase. Both parental and pathogenic SHIVs exclusively use CXCR4 as a coreceptor. The determinants of the increased entry associated with the SHIV-HXBc2P 3.2 envelope glycoproteins are located in both the gp120 and gp41 subunits. Changes in the gp120 V3 variable loop specify a decreased sensitivity to SDF-1, consistent with an increase in the affinity of the HXBc2P 3.2 gp120 glycoprotein for CXCR4. Thus, multiple changes in the gp120 variable loops and the gp41 ectodomain of a pathogenic SHIV cooperate to allow enhanced replicative capacity, which in part results from increased chemokine receptor binding. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Div AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,JFB 824, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU NIAID NIH HHS [AI42848, AI31783, AI39420] NR 63 TC 12 Z9 12 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB PY 2004 VL 20 IS 2 BP 163 EP 173 DI 10.1089/088922204773004888 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 778UR UT WOS:000189260200006 PM 15018704 ER PT J AU Duka, T Gentry, J Malcolm, R Ripley, TL Borlikova, G Stephens, DN Veatch, LM Becker, HC Crews, FT AF Duka, T Gentry, J Malcolm, R Ripley, TL Borlikova, G Stephens, DN Veatch, LM Becker, HC Crews, FT TI Consequences of multiple withdrawals from alcohol SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE binge drinking; executive function; EEG; appetitive conditioning ID NUCLEUS-ACCUMBENS CORE; CORTICOTROPIN-RELEASING-FACTOR; ANTERIOR CINGULATE CORTEX; CHRONIC ETHANOL EXPOSURE; EVENT-RELATED POTENTIALS; BRAIN-DAMAGE; BASOLATERAL AMYGDALA; FACIAL EXPRESSIONS; ANIMAL-MODEL; REPEATED DEPRIVATIONS AB This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL, organized by Theodora Duka and chaired by Dai Stephens. The purpose of the symposium was to examine the effects of multiple experiences of withdrawal from alcohol in animals made dependent on alcohol and in humans who are alcohol dependent. Parallels were drawn to the effects of repeated short-lived high-content alcohol exposures in animals and in humans who are social drinkers but indulge in binge drinking. The presentations were (1) Multiple detoxifications and risk of relapse in abstinent alcoholics, by John Gentry and Robert Malcolm; (2) Emotional and cognitive impairments after long-term use of alcohol: relationship to multiple detoxifications and binge drinking, by Theodora Duka; (3) The effect of repeated withdrawal from ethanol on conditioning to appetitive stimuli, by Tamzin Ripley, Gilyanna Borlikova, and Dai Stephens; (4) Alcohol withdrawal kindling: electrographic measures in a murine model of behavioral seizure sensitization, by Lynn Veatch and Howard Becker; and (5) Binge drinking induced changes in CNS, by Fulton Crews. C1 Univ Sussex, Lab Expt Psychol, Brighton BN1 9QG, E Sussex, England. Univ Sussex, Sch Life Sci, Psychol Dept, Brighton BN1 9QG, E Sussex, England. Med Univ S Carolina, Charleston Alcohol Res Ctr, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Vet Affairs, Charleston, SC USA. Univ N Carolina, Sch Med, Ctr Alcohol Studies, Chapel Hill, NC USA. RP Duka, T (reprint author), Univ Sussex, Lab Expt Psychol, Brighton BN1 9QG, E Sussex, England. EM dorad@biols.susx.ac.uk RI Borlikova, Gilyana/E-8245-2012; Stephens, David/G-2384-2012 NR 127 TC 66 Z9 66 U1 4 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2004 VL 28 IS 2 BP 233 EP 246 DI 10.1097/01.ALC.000113780.41701.81 PG 14 WC Substance Abuse SC Substance Abuse GA 776YR UT WOS:000189147400005 PM 15112931 ER PT J AU Gelfand, EV Cannon, CP AF Gelfand, EV Cannon, CP TI Antibiotics for secondary prevention of coronary artery disease: An ACES hypothesis but we need to PROVE IT SO AMERICAN HEART JOURNAL LA English DT Article ID CHLAMYDIA-PNEUMONIAE INFECTION; CARDIOVASCULAR RISK-FACTORS; ACUTE MYOCARDIAL-INFARCTION; BLOOD MONONUCLEAR-CELLS; NF-KAPPA-B; HEART-DISEASE; HELICOBACTER-PYLORI; ENDOTHELIAL-CELLS; ATHEROSCLEROTIC PLAQUES; SMOOTH-MUSCLE C1 Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM cpcannon@partners.org NR 67 TC 16 Z9 17 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2004 VL 147 IS 2 BP 202 EP 209 DI 10.1016/j.ahj.2003.09.011 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 803TR UT WOS:000220253900007 PM 14760314 ER PT J AU Syed, MA Borzak, S Asfour, A Gunda, M Obeidat, O Murphy, SA Gibbons, RJ Gourlay, SG Barron, HV Weaver, WD Hudson, M AF Syed, MA Borzak, S Asfour, A Gunda, M Obeidat, O Murphy, SA Gibbons, RJ Gourlay, SG Barron, HV Weaver, WD Hudson, M TI Single lead ST-segment recovery: A simple, reliable measure of successful fibrinolysis after acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY PATENCY; ELEVATION RESOLUTION; VENTRICULAR-FUNCTION; RESCUE ANGIOPLASTY; STRONG PREDICTOR; BEDSIDE MARKERS; THROMBOLYSIS; REPERFUSION; EXTENT; TRIAL AB Background Successful reperfusion after acute ST-elevation myocardial infarction improves prognosis. Among the different electrocardiographic markers of reperfusion, sum ST resolution is considered the hallmark of reperfusion, but is cumbersome to use. Methods To assess the usefulness of a single lead ST resolution at 90 minutes after fibrinolysis compared with the sum ST resolution in predicting Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, we used prospectively collected data from the Limitation of Myocardial Injury Following Thrombolysis in Acute Myocardial Infarction (LIMIT-AMI) study. All patients had electrocardiograms recorded at presentation and 90 minutes and a coronary angiogram 90 minutes after fibrinolysis., Results Infarction artery potency was assessed in 238 patients with 4 different ST resolution criteria: single lead ST resolution greater than or equal to50% and greater than or equal to70% and sum ST resolution greater than or equal to50% and greater than or equal to70%. The most sensitive criteria for TIMI grade 3 flow was single lead ST resolution greater than or equal to50% (sensitivity rate, 70%; specificity rate, 54%), whereas sum ST resolution greater than or equal to70% was most the specific criteria (sensitivity rate, 45%; specificity rate, 79%). The proportion of patients with TIMI grade 3 flow was similar in all 4 ST resolution groups (P = .84). Pre-discharge infarction size and ejection fraction were also similar. No single lead or sum lead measure of ST resolution was significantly associated with an increased risk of death, heart failure, or reinfarction. Conclusion We propose that single lead ST-resolution greater than or equal to50% as an optimal electrocardiographic indicator for successful reperfusion 90 minutes after fibrinolysis. This simple electrocardiographic measure should be combined with bedside clinical and hemodynamic assessment to optimize decision making after fibrinolysis. C1 Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. Florida Cardiovasc Res LC, Atlantis, FL USA. Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. Genentech Inc, San Francisco, CA 94080 USA. RP Hudson, M (reprint author), Henry Ford Heart & Vasc Inst, K-14,2799 W Grand Blvd, Detroit, MI 48202 USA. EM mhudson1@hfhs.org NR 23 TC 9 Z9 16 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2004 VL 147 IS 2 BP 275 EP 280 DI 10.1016/j.ahj.2003.08.010 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 803TR UT WOS:000220253900019 PM 14760325 ER PT J AU Butler, J Forman, DE Abraham, WT Gottlieb, SS Loh, E Massie, BM O'Connor, CM Rich, MW Stevenson, LW Wang, YF Young, JB Krumholz, HM AF Butler, J Forman, DE Abraham, WT Gottlieb, SS Loh, E Massie, BM O'Connor, CM Rich, MW Stevenson, LW Wang, YF Young, JB Krumholz, HM TI Relationship between heart failure treatment and development of worsening renal function among hospitalized patients SO AMERICAN HEART JOURNAL LA English DT Article ID SUBCUTANEOUS ERYTHROPOIETIN; INTRAVENOUS IRON; FUROSEMIDE; ANEMIA; PHARMACOKINETICS; INSUFFICIENCY; DYSFUNCTION; PROGRESSION; OUTCOMES; THERAPY AB Background Among patients who are hospitalized with heart failure (HF), worsening renal function (WRF) is associated with worse outcomes. Whether treatment for HF contributes to WRF is unknown. In this study, we sought to assess whether acute treatment for patients who were hospitalized with HF contributes to WRF. Methods Data were collected in a nested case-control study on 382 subjects who were hospitalized with HF (191 patients with WRF, defined as a rise in serum creatinine level >26.5 mumol/L (0.3 mg/dl), and 191 control subjects). The association of medications, fluid intake/output, and weight with WRF was assessed. Results. Calcium channel blocker (CCB) use and loop diuretic doses were higher in patients on the day before WRF (25% vs 10% for CCB; 199 +/- 195 mg vs 143 +/- 119 mg for loop diuretics; both P < .05). There were no significant differences in the fluid intake/output or weight changes in the 2 groups. Angiotensin-converting enzyme (ACE) inhibitor use was not associated with WRF. Other predictors of WRF included elevated creatinine level at admission, uncontrolled hypertension, and history of HF or diabetes mellitus. Higher hematocrit levels were associated with a lower risk. Vasodilator use was higher among patients on the day before WRF (46% vs 35%, P < .05), but was not an independent predictor in the multivariable analysis. Conclusions Several medical strategies, including the use of CCBs and a higher dose of loop diuretics, but not ACE inhibitors, were associated with a higher risk of WRF. Although assessment of inhospital diuresis was limited, WRF could not be explained by greater fluid loss in these patients. Determining whether these interventions are responsible for WRF or are markers of higher risk requires further investigation. C1 Vanderbilt Univ, Med Ctr, Div Cardiol, Nashville, TN 37232 USA. Boston Med Ctr, Boston, MA USA. Univ Kentucky, Lexington, KY USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Penn, Philadelphia, PA 19104 USA. San Francisco VAMC, San Francisco, CA USA. Duke Univ, Durham, NC USA. Barnes Jewish Hosp, St Louis, MO 63110 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Yale Univ, New Haven, CT USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Butler, J (reprint author), Vanderbilt Univ, Med Ctr, Div Cardiol, 383 PRB, Nashville, TN 37232 USA. EM javed.butler@vanderbilt.edu NR 21 TC 261 Z9 282 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2004 VL 147 IS 2 BP 331 EP 338 DI 10.1016/j.ahj.2003.08.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 803TR UT WOS:000220253900029 PM 14760333 ER PT J AU Corvera-Tindel, T Doering, LV Woo, MA Khan, S Dracup, K AF Corvera-Tindel, T Doering, LV Woo, MA Khan, S Dracup, K TI Effects of a home walking exercise program on functional status and symptoms in heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-LIFE; LEFT-VENTRICULAR DYSFUNCTION; CONTROLLED-TRIAL; ACTIVITY RESTRICTION; TEST-PERFORMANCE; CAPACITY; RESISTANCE AB Background Hospital-based exercise programs using a bicycle ergometer or a combination of exercise modalities have shown positive benefits in heart failure, but may not be readily accessible to many patients. Thus, we sought to evaluate the effects of a 12-week home walking exercise program on functional status and symptoms in patients with heart failure. Methods A randomized controlled trial comparing a 12-week progressive home walking exercise program (n = 42) to a "usual activity" control group (n = 37) was conducted in patients with heart failure (78 [99%] male; mean age 62.6 +/- 10.6 years; ejection fraction 27% +/- 8.8%; 63 [80%] New York Heart Association class II; 15[20%] New York Heart Association class III-IV) from a Veterans Affairs medical center and a university-affiliated medical center. Functional status (peak oxygen consumption via cardiopulmonary exercise testing, 6-minute walk test, the Heart Failure Functional Status. Inventory), and symptoms (Dyspnea-Fatigue Index score with a postglobal rating of symptoms) were measured at baseline and 12 weeks. Results No adverse events related to exercise training occurred. Overall mean compliance to training was 74 +/- 37%. Peak oxygen consumption and the Heart Failure Functional Status Inventory were unchanged with training. Compared to the usual activity group, the training group had significantly longer walking distances measured by the 6-minute walk test (1264 +/- 255 vs 1337 +/- 272 feet, P = .00.1), and improved postglobal rating of symptoms (P = .03). Conclusion In patients with heart failure, a progressive home walking exercise program is acceptable, increases walking distance, and decreases global rating of symptoms. C1 Greater Los Angeles Vet Affairs Hlth Care Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Los Angeles, CA 90048 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Corvera-Tindel, T (reprint author), VAGLAHS, Room 6207,Mail Code 118R,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Teresita.Corvera@med.va.gov NR 32 TC 59 Z9 59 U1 0 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2004 VL 147 IS 2 BP 339 EP 346 DI 10.1016/j.ahj.2003.09.007 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 803TR UT WOS:000220253900030 PM 14760334 ER PT J AU Johnson, E Lake, D Herndon, JE Box, JW Lynch, TJ Green, MR AF Johnson, E Lake, D Herndon, JE Box, JW Lynch, TJ Green, MR TI Phase II trial of vinorelbine plus doxorubicin in relapsed small-cell lung cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE vinorelbine; doxorubicin; small-cell lung cancer; phase I trial ID LEUKEMIA GROUP-B; BREAST-CANCER; THERAPY AB Small-cell lung cancer that progresses after initial response may still be sensitive to systemic treatment. This study assessed doxorubicin plus vinorelbine tartrate (Navelbine Injection) in patients who had no prior exposure to these agents. Treatment consisted of vinorelbine at 25 mg/m(2) on days 1 and 8 and doxorubicin at 50 mg/m(2) on day 1 of each 21-day cycle. The trial was stopped early because of excessive toxicity. The partial response rate was 26.7%. Toxicities included grade IV neutropenia in 73%, and febrile neutropenia and/or sepsis in 60%. Three patients died from sepsis during cycle 1. Performance status 2 was significantly associated with febrile neutropenia (p = 0.044). Although this regimen had some activity, the toxicity precluded further evaluation. C1 Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. CALGB Stat Ctr, Durham, NC USA. Dana Farber Canc Care, Boston, MA USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Johnson, E (reprint author), Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. FU NCI NIH HHS [CA37135, CA35421, CA45564, CA60138, CA47642, CA04457, CA32291, CA04326, CA07968, CA08025, CA77651, CA41287, CA45418, CA47555, CA12449, CA60247, CA31983, CA52784, CA77406, CA45389, CA47559, CA03927, CA21060, CA12046, CA33601, CA I 1789] NR 9 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB PY 2004 VL 27 IS 1 BP 19 EP 23 DI 10.1097/01.coc.000004550.98788.ED PG 5 WC Oncology SC Oncology GA 771KF UT WOS:000188783600004 PM 14758128 ER PT J AU Farraye, FA Wong, M Hurwitz, S Puleo, E Emmons, K Wallace, MB Fletcher, RH AF Farraye, FA Wong, M Hurwitz, S Puleo, E Emmons, K Wallace, MB Fletcher, RH TI Barriers to endoscopic colorectal cancer screening: Are women different from men? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID FLEXIBLE SIGMOIDOSCOPY; COST-EFFECTIVENESS; PATIENT PREFERENCES; UNITED-STATES; AVERAGE-RISK; COLONOSCOPY; PREVENTION; GUIDELINES; KNOWLEDGE; PROSTATE AB OBJECTIVES: The goals of this study were to compare women and men's understanding of screening flexible sigmoidoscopy (FS) and to identify predictors of endoscopic colorectal cancer (CRC) screening. METHODS: We mailed a 36-item questionnaire to asymptomatic patients aged 50 years or older who were scheduled for routine health assessments at a large multispecialty health-care group. Data collection included demographics, health behaviors, psychosocial factors, and CRC screening compliance. We followed participants for 1 year and assessed completion of endoscopic CRC screening. Both cross-sectional results examining previous screening and prospective results examining screening I year later were evaluated. RESULTS: 554 (54%) of 998 patients responded to the survey. Responses of 13 patients were excluded in the analyses due to unverifiable screening outcome. The majority of the respondents were white, and their average age was 62 years. Women reported significantly more embarrassment and fear about having FS than men. Women were more willing to consider having a FS if a female endoscopist performed the procedure. Of the 334 participants who were eligible to have endoscopic CRC screening, 53 (16%) had the procedure within a year. The odds of having the endoscopic procedures increased with the length of time the patients were under the care of their primary care providers and how strongly patients believed that one should have an FS even without symptoms. CONCLUSION: Our findings suggest some unique gender-specific attitudes and beliefs that act as potential barriers for CRC screening and further support the important role of primary care providers in facilitating timely completion of screening. C1 Boston Univ, Med Ctr, Gastroenterol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Massachusetts, Amherst, MA 01003 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Med Univ S Carolina, Gastroenterol Sect, Charleston, SC 29425 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. RP Farraye, FA (reprint author), Boston Univ, Med Ctr, Gastroenterol Sect, 88 E Newton St,D408, Boston, MA 02118 USA. OI Farraye, Francis/0000-0001-6371-2441 NR 58 TC 72 Z9 73 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2004 VL 99 IS 2 BP 341 EP 349 DI 10.1111/j.1572-0241.2004.04045.x PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 773KZ UT WOS:000188924100027 PM 15046227 ER PT J AU Fox, CS Cupples, LA Chazaro, I Polak, JF Wolf, PA D'Agostino, RB Ordovas, JM O'Donnell, CJ AF Fox, CS Cupples, LA Chazaro, I Polak, JF Wolf, PA D'Agostino, RB Ordovas, JM O'Donnell, CJ TI Genomewide linkage analysis for internal carotid artery intimal medial thickness: Evidence for linkage to chromosome 12 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CORONARY HEART-DISEASE; DENSITY-LIPOPROTEIN RECEPTOR; SCAVENGER RECEPTOR; SR-BI; MYOCARDIAL-INFARCTION; RISK-FACTORS; GENE LOCUS; DEFICIENT MICE; WIDE SCAN; I GENE AB Carotid intimal medial thickness (IMT) is a heritable quantitative measure of atherosclerosis. A genomewide linkage analysis was conducted to localize a quantitative-trait locus (QTL) influencing carotid IMT. Carotid IMT was measured in 596 men and 629 women from 311 extended families (1,242 sib pairs) in the Framingham Heart Study Offspring cohort. B-mode carotid ultrasonography was used to define mean IMT of the carotid artery segments. Multipoint variance-component linkage analysis was performed. Evidence for significant linkage to internal carotid artery (ICA) IMT (two-point log odds [LOD] score 4.1, multipoint LOD score 3.4) was found 161 cM from the tip of the short arm of chromosome 12; these results were confirmed using the GENEHUNTER package ( multipoint LOD score 4.3). No LOD scores >2.0 were observed for common carotid artery (CCA) IMT. Association analysis of a single-nucleotide-polymorphism variant of SCARB1 (minor allele frequency 0.13), a gene in close proximity to the region of peak linkage, revealed a protective association of the missense variant allele in exon 1 of SCARB1, with decreased ICA IMT compared with subjects homozygous for the common allele. Although the exon 1 variant contributed 2% to overall variation in ICA IMT, there was no significant change in the peak LOD score after adjustment in the linkage analyses. These data provide substantial evidence for a QTL on chromosome 12 influencing ICA IMT and for association of a rare variant of SCARB1, or a nearby locus, with ICA IMT. Because this rare SCARB1 variant does not account for our observed linkage, further investigations are warranted to identify additional candidate-gene variants on chromosome 12 predisposing to atherosclerosis phenotypes and clinical vascular disease. C1 NHLBIs Framingham Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Cambridge, MA 02138 USA. Boston Univ, Sch Med, Dept Neurol & Prevent Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Biostat & Stat, Boston, MA 02215 USA. Boston Univ, Dept Math, Stat & Consulting Unit, Boston, MA 02215 USA. Tufts Univ, USDA, Human Nutr Res Ctr, Medford, MA 02155 USA. NHLBI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM chris@fram.nhlbi.nih.gov OI Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [HL54776, N01-HC-25195, N01HC25195, R01 HL054776]; NINDS NIH HHS [R01 NS017950, R501-NS17950-20] NR 44 TC 60 Z9 61 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2004 VL 74 IS 2 BP 253 EP 261 DI 10.1086/381559 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 772UM UT WOS:000188860000006 PM 14730480 ER PT J AU Lowe, N Kirley, A Hawi, Z Sham, P Wickham, H Kratochvil, CJ Smith, SD Lee, SY Levy, F Kent, L Middle, F Rohde, LA Roman, T Tahir, E Yazgan, Y Asherson, P Mill, J Thapar, A Payton, A Todd, RD Stephens, T Ebstein, RP Manor, I Barr, CL Wigg, KG Sinke, RJ Buitelaar, JK Smalley, SL Nelson, SF Biederman, J Faraone, SV Gill, M AF Lowe, N Kirley, A Hawi, Z Sham, P Wickham, H Kratochvil, CJ Smith, SD Lee, SY Levy, F Kent, L Middle, F Rohde, LA Roman, T Tahir, E Yazgan, Y Asherson, P Mill, J Thapar, A Payton, A Todd, RD Stephens, T Ebstein, RP Manor, I Barr, CL Wigg, KG Sinke, RJ Buitelaar, JK Smalley, SL Nelson, SF Biederman, J Faraone, SV Gill, M TI Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; DOPAMINE TRANSPORTER; DIAGNOSTIC INTERVIEW; POPULATION-SAMPLE; SYSTEM GENES; CHILDREN; ADHD; LINKAGE; METAANALYSIS; ADULTS AB Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes. C1 Trinity Coll Dublin, Dept Genet, Dublin 2, Ireland. Trinity Coll Dublin, Dept Psychiat, Dublin 2, Ireland. Inst Psychiat, Social Genet & Dev Res Ctr, London, England. Univ Nebraska, Med Ctr, Psychopharmacol Res Ctr, Omaha, NE USA. Univ New S Wales, Prince Wales Hosp, Sch Psychiat, Sydney, NSW, Australia. Univ Cambridge, Cambridge CB2 1TN, England. Univ Birmingham, Dept Psychiat, Birmingham, W Midlands, England. Univ Fed Rio Grande Sul, Fed Sch Med Sci Porto Alegre, ADHD Outpatient Program, Porto Alegre, RS, Brazil. Univ Fed Rio Grande Sul, Fed Sch Med Sci Porto Alegre, Dept Genet, Porto Alegre, RS, Brazil. TUBITAK, Res Inst Genet & Biotechnol, Marmara Res Ctr, Kocaeli, Turkey. Univ Wales Coll Med, Dept Psychol Med, Cardiff CF4 4XN, S Glam, Wales. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA. Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. Herzog Hosp, Jerusalem, Israel. Geha Mental Hlth Ctr, Petak Tikvah, Israel. Univ Hlth Network, Toronto Western Res Inst, Div Cell & Mol Biol, Toronto, ON, Canada. Hosp Sick Children, Brain & Behav Programme, Toronto, ON M5G 1X8, Canada. Univ Med Ctr Utrecht, Dept Biomed Genet, Utrecht, Netherlands. Univ Nijmegen, Med Ctr, Dept Psychiat, Nijmegen, Netherlands. Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobehav Genet, Los Angeles, CA USA. Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Lowe, N (reprint author), Trinity Coll Dublin, Dept Genet, Dublin 2, Ireland. EM lowen@tcd.ie RI Rohde, Luis Augusto/A-6426-2008; Sinke, Richard/A-1462-2009; Nelson, Stanley/D-4771-2009; Tahir Turanli, Eda/D-4989-2009; Roman, Tatiana/C-1300-2010; turton, miranda/F-4682-2011; Mill, Jonathan/B-3276-2010; Buitelaar, Jan/E-4584-2012 OI Faraone, Stephen/0000-0002-9217-3982; Hawi, Ziarih/0000-0002-0814-9112; Rohde, Luis Augusto/0000-0002-4552-4188; Gill, Michael/0000-0003-0206-5337; Kent, Lindsey/0000-0002-5315-3399; Barr, Cathy/0000-0003-0361-0106; Mill, Jonathan/0000-0003-1115-3224; Buitelaar, Jan/0000-0001-8288-7757 FU NICHD NIH HHS [R01 HD037694, P50 HD027802, R01 HD036317, R01 HD037999, R01 HD36317, R01 HD37694, R01 HD37999]; NIMH NIH HHS [MH58277, R01 MH050657, R01 MH052813, R01 MH058277, R01 MH52812, R13 MH059126, R13 MH59126]; NINDS NIH HHS [R01 NS043762, R01 NS43762] NR 50 TC 127 Z9 137 U1 2 U2 14 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2004 VL 74 IS 2 BP 348 EP 356 DI 10.1086/381561 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 772UM UT WOS:000188860000015 PM 14732906 ER PT J AU Takahashi, T Koehler, J Swenson, P Duchin, J AF Takahashi, T Koehler, J Swenson, P Duchin, J TI Evaluation of a public health Salmonella surveillance system in King County, Washington SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article AB Objectives: Salmonella infection is the most common cause of foodborne bacterial outbreaks and deaths in the United States. The effectiveness of Salmonella surveillance for detecting outbreaks depends on timeliness of reporting. We evaluated the public health Salmonella surveillance system in King County, Washington, during an outbreak and at baseline. Methods: We assessed the timeliness of the Salmonella surveillance system in King County using the Public Health-Seattle & King County Laboratory (County PHL) database from 1998 to 1999. We determined median days for key steps involved in the Salmonella identification and reporting process and the percentage of suspected Salmonella isolates confirmed. Time intervals for key steps during a Salmonella outbreak were compared to baseline surveillance. Results: Of the 652 suspected Salmonella isolates sent to the County PHL from 22 clinical laboratories, 617 (94.6%) were confirmed as Salmonella. Salmonella confirmation rates improved from 1998 to 1999, and 41% of the submitting laboratories, contributing 32.4% of the isolates, had 100% confirmation rates for both years. The median total identification time during the outbreak did not differ significantly from baseline (13 days vs 17 days). The time interval for serotyping contributed most to the total identification time. Conclusions: King County's Salmonella surveillance system requires more than 2 weeks to confirm and report serotype results for Salmonella isolates. Variation in total identification time depends on serotyping time. A more detailed study of other surveillance systems may identify approaches to decrease total identification time. C1 Publ Hlth Seattle & King Cty, Seattle, WA USA. Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA USA. RP Takahashi, T (reprint author), Vet Adm Med Ctr, 1660 S Columbian Way,S-111-GIMC, Seattle, WA 98108 USA. NR 8 TC 11 Z9 11 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-6553 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD FEB PY 2004 VL 32 IS 1 BP 7 EP 11 DI 10.1016/j.ajic.2003.06.003 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 777AD UT WOS:000189151000003 PM 14755228 ER PT J AU Pogach, L Charns, MP Wrobel, JS Robbins, JM Bonacker, KM Haas, L Reiber, GE AF Pogach, L Charns, MP Wrobel, JS Robbins, JM Bonacker, KM Haas, L Reiber, GE TI Impact of policies and performance measurement on development of organizational coordinating strategies for chronic care delivery SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID SURGICAL SERVICES; DIABETIC-PATIENTS; QUALITY CHASM; MANAGEMENT; OUTCOMES; FOOT; COST AB Objective: To examine the impact of policy directives and performance feedback on the organization (specifically the coordination) of foot care programs for veterans, as mandated by public law within the Department of Veterans Affairs Health Care System (VA). Study Design: Case study of 10 VA medical centers performing diabetes-related amputations. Patients and Methods: Based on expert consensus, we identified 16 recommended foot care delivery coordination strategies. Structured interview protocols developed for primary care, foot care, and surgical providers, as well as administrators, were adapted from a prior study of surgical departments. Results: Although performance measurement results for foot risk screening and referral were high at all study sites over 2 calendar years (average 85%, range 69% to 92%), the number of coordination strategies implemented by any site was relatively low, averaging only 5.4 or 34% (range 1-12 strategies). No facility had systematically collected data to evaluate whether preventive foot care was provided to patients with high-risk foot conditions, or whether these patients had unmet foot care needs. Conclusions: Although foot care policies and data feedback resulted in extremely high rates of adherence to foot-related performance measurement, there remained opportunities for improvement in the development of coordinated, technology-supported, data-driven, patient-centered foot care programs. C1 Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Dept Vet Affairs, VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA USA. Vet Adm Med Ctr, Dept Vet Affairs, Cleveland, OH 44106 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. Dept Vet Affairs, VA Med & Reg Off Ctr, White River Jct, VT USA. Boston Univ, Sch Publ Hlth, Program Hlth Policy & Management, Boston, MA USA. Boston Univ, Sch Publ Hlth, VA Management Decis & Res Ctr, Boston, MA USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. Dept Vet Affairs, Ctr Healthcare Knowledge Management, New Jersey Hlth Care Syst, E Orange, NJ USA. RP Pogach, L (reprint author), E Orange VAMC, VA New Jersey Hlth Care Syst, Hlth Serv Res Ctr Healthcare Knowledge Management, Room 9-160 111,385 Tremont Ave, E Orange, NJ 07018 USA. EM leonard.pogach@med.va.gov NR 34 TC 9 Z9 9 U1 3 U2 6 PU AMER MED PUBLISHING, M W C COMPANY PI JAMESBURG PA 241 FORSGATE DR, STE 102, JAMESBURG, NJ 08831 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD FEB PY 2004 VL 10 IS 2 BP 171 EP 180 PN 2 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 775PD UT WOS:000189049200009 PM 15005510 ER PT J AU Walter, LC de Garmo, P Covinsky, KE AF Walter, LC de Garmo, P Covinsky, KE TI Association of older age and female sex with inadequate reach of screening flexible sigmoidoscopy SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID COLORECTAL-CANCER; ASYMPTOMATIC ADULTS; COLONOSCOPY; DIFFICULT; GENDER; PREDICTORS; RATIONALE; INSERTION; DESIGN; POLYPS AB PURPOSE: Estimates of the sensitivity of screening sigmoidoscopy assume an adequate depth of insertion is reached. However, in clinical practice, the frequency that sigmoidoscopy reaches various lengths of the colon is not known. We assessed the frequency of inadequate reach (depth of <50 cm of the colon) in a large U.S. cohort, according to age and sex. METHODS: We performed a cross-sectional study of 15,406 asymptomatic persons aged 50 years or older who underwent screening flexible sigmoidoscopy between April 1997 and October 2001 at sites participating in the Clinical Outcomes Research Initiative, which examines outcomes of endoscopy in "real life" settings. The maximum depth of insertion of the sigmoidoscope was measured in centimeters from the anus and classified as adequate (greater than or equal to50cm) or inadequate (<50cm). Patient characteristics as well as procedure-related variables were also recorded. RESULTS: Eighteen percent (n=2801) of subjects had an inadequate examination. In men, the percentage of inadequate examinations increased progressively with age, from 10% (343/3338) in those aged 50 to 59 years to 22% (53/248) in those aged 80 years or older (P<0.001). Inadequate examinations were more common in women at all ages, ranging from 19% (733/3798) in those aged 50 to 59 years to 32% (86/267) in those aged 80 years or older (P<0.001). These associations were confirmed in a multivariable analysis. CONCLUSION: Our finding that advancing age and female sex were independently associated with the risk of inadequate reach of screening sigmoidoscopy suggests that the sensitivity of sigmoidoscopy may be lower in these populations. Estimates of the benefits of sigmoidoscopy may need to be tailored to the age and sex of the patient. (C) 2004 by Excerpta Medica Inc. C1 San Francisco Vet Affairs Med Ctr, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Walter, LC (reprint author), San Francisco Vet Affairs Med Ctr, Div Geriatr, 181G,4150 Clement St, San Francisco, CA 94121 USA. EM louisew@itsa.ucsf.edu FU AHRQ HHS [K02HS00006]; NIDDK NIH HHS [DK 57132] NR 41 TC 18 Z9 18 U1 1 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD FEB 1 PY 2004 VL 116 IS 3 BP 174 EP 178 DI 10.1016/j.amjmed.2003.09.030 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 770AX UT WOS:000188701900005 PM 14749161 ER PT J AU Lev, MH Ozsunar, Y Henson, JW Rasheed, AA Barest, GD Harsh, GR Fitzek, MM Chiocca, EA Rabinov, JD Csavoy, AN Rosen, BR Hochberg, FH Schaefer, PW Gonzalez, RG AF Lev, MH Ozsunar, Y Henson, JW Rasheed, AA Barest, GD Harsh, GR Fitzek, MM Chiocca, EA Rabinov, JD Csavoy, AN Rosen, BR Hochberg, FH Schaefer, PW Gonzalez, RG TI Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: Confounding effect of elevated rCBV of oligodendroglimoas SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID CEREBRAL BLOOD-VOLUME; BRAIN-TUMORS; MAGNETIC-SUSCEPTIBILITY; MICROVESSEL DENSITY; GLIOMAS; NEOPLASMS; MAPS; PET; UTILITY AB Background and Purpose: The MR imaging characteristics of oligodendrogliomas and astrocytomas on spin-echo (SE), echo-planar relative cerebral blood volume (rCBV) maps, to our knowledge, have not previously been emphasized. We compared the specificity of SE rCBV mapping with that of conventional, contrast material-enhanced MR imaging in differentiating high-from low-grade glial tumors and in predicting survival of patients with these lesions. Methods: Thirty consecutive adult patients with suspected gliomas underwent conventional and rCBV MR imaging. Representative maximal rCBV regions of interest were chosen from each lesion. Resultant values were normalized to those of corresponding, contralateral, uninvolved regions. These normalized CBV (nCBV) values were correlated with degree of contrast enhancement, histopathologic tumor grade, and survival. Results: Twenty-two patients had astroctyomas and eight had oligodendrogliomas. With an nCBV cutoff ratio of 1.5, 13 of 13 high-grade astrocytomas were correctly categorized, three of which did not enhance. Seven of nine low-grade astrocytomas were correctly classified by their nCBV values, including one enhancing lesion. Of eight oligodendrogliomas, four of four high-grade and two of four low-grade tumors had elevated nCBV values; two low-grade oligodendrogliomas enhanced, one with nCBV greater than 1.5 and one with nCBV less than 1.5. In 19 patients with astrocytoma for whom survival data were available, correlation with survival was better for nCBV (mean survival 91+/-14 months for nCBV <1.5 versus 24&PLUSMN;27 months for nCBV>1.5, P<.0001) than for enhancement (mean survival 61&PLUSMN;35 months without enhancement versus 22&RANGBRAC;29 months with enhancement, P=.03). Conclusion. Elevated SE rCBV was a sensitive, but not specific, marker for high-grade histopathology: all high-grade tumors had nCBV foci values greater than 1.5. No tumor with nCBV region of interest less than 1.5 was high grade (100% predictive value for excluding high grade). Degree of nCBV elevation was a stronger predictor of both tumor grade and survival than was degree of enhancement. A significant proportion of low-grade glial neoplasms, most notably oligodendrogliomas, may display high rCBV foci not reflective of high-grade histopathology. C1 Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Adnan Menderes Univ, Sch Med, Dept Radiol, Aydin, Turkey. Stanford Univ, Sch Med, Dept Neurosurg, Palo Alto, CA 94304 USA. Univ Essen Gesamthsch, Essen, Germany. Radion Inc, Burlington, MA USA. RP Lev, MH (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, 32 Fruit St, Boston, MA 02114 USA. FU NCI NIH HHS [CA83159] NR 28 TC 269 Z9 281 U1 1 U2 6 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2004 VL 25 IS 2 BP 214 EP 221 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 776FG UT WOS:000189105600011 PM 14970020 ER PT J AU Ecker, JL AF Ecker, JL TI Once a pregnancy, always a cesarean? Rationale and feasibility of a randomized controlled trial SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE elective cesarean delivery; vaginal delivery; randomized controlled trial ID VAGINAL DELIVERY; PLACENTA PREVIA; SECTION; TERM; RISK; MODE; INCONTINENCE; INJURY; CHOICE; WOMEN AB Although vaginal delivery has long been assumed to be the preferred route of delivery in women who have not had a prior cesarean delivery, some have recently advocated that women be offered the option of elective, primary cesarean delivery in all pregnancies. Available outcome data, however, do not permit ready comparison of these alternate plans for delivery. Important maternal outcomes include short-term complications such as death, bleeding, infection, and damage to pelvic organs as well as long-term effects on future pregnancies, fecal and urinary incontinence, and pelvic organ prolapse. Important neonatal outcomes. include asphyxic and traumatic birth injury, infection, respiratory complications, and stillbirth. To weigh the relative merits of elective primary cesarean delivery and a trial of labor, a randomized controlled trial is needed. Such a trial would be both ethical and feasible. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Mem Obstet Serv, Boston, MA 02115 USA. RP Ecker, JL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Mem Obstet Serv, Boston, MA 02115 USA. NR 26 TC 26 Z9 26 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2004 VL 190 IS 2 BP 314 EP 318 DI 10.1016/S0002-9378(03)00869-X PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 778PT UT WOS:000189250500004 PM 14981367 ER PT J AU Kunimoto, DY Tasman, W Rapuano, C Recchia, F Busbee, B Pearlman, R Belmont, J Cohen, E Vander, J Laibson, P Raber, I AF Kunimoto, DY Tasman, W Rapuano, C Recchia, F Busbee, B Pearlman, R Belmont, J Cohen, E Vander, J Laibson, P Raber, I TI Endophthalmitis after penetrating keratoplasty: Microbiologic spectrum and susceptibility of isolates SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 04-09, 2003 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol ID VITRECTOMY AB PURPOSE: To present the microbial spectrum and susceptibilities of isolates in endophthalmitis following penetrating keratoplasty. DESIGN: Interventional case series. METHODS: The 1,074 consecutive cases of endophthalmitis presenting to Wills Eye Hospital between 1989 and 2000 were reviewed. Fourteen patients with endophthalmitis after penetrating keratoplasty were identified, and vitreous biopsy isolates from these patients were examined. RESULTS: Eleven (78.6%) of 14 vitreous samples were culture-positive, and two others (14.3%) had organisms viewed on pathology specimen, for a total of 13 (92.9%) organism,proven cases of endophthalmitis. Isolates included 10 (76.9%) gram,positive cocci (six Streptococcus sp., three Staphylococcus sp., one identified on pathology specimen only) and three (23.1%) gram,negative organs isms (Proteus mirabilis, Serratia marcescens, one identified on pathology specimen only). Susceptibilities to organism-appropriate antibiotic testing are reported, including cefazolin (six of eight, 75.0%), ciprofloxacin (four of seven, 57.1%), nafcillin (four of six, 66.7%), and vancomycin (seven of seven, 100.0%). CONCLUSION: This is the largest series on microbial susceptibilities in postpenetrating keratoplasty endophthalmitis. We report a high percentage of culture-positivity, and a high incidence of gram-positive species, and in particular Streptococcus species, with all tested gram. positive organisms susceptible to vancomycin. (C) 2004 by Elsevier Inc. All rights reserved. C1 Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Hosp, Retina Serv, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Wills Eye Hosp, Cornea Serv, Philadelphia, PA 19107 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Tufts Univ, Sch Med, New England Eye Ctr, Retina Serv, Boston, MA 02111 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Retina Serv, Chicago, IL 60611 USA. RP Kunimoto, DY (reprint author), Med Educ, Wills Eye Hosp, 840 Walnut St, Philadelphia, PA 19107 USA. EM derek_kunimoto@yahoo.com NR 5 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD FEB PY 2004 VL 137 IS 2 BP 343 EP 345 DI 10.1016/S0002-9394(03)00874-2 PG 3 WC Ophthalmology SC Ophthalmology GA 776ZB UT WOS:000189148300019 PM 14962427 ER PT J AU Yu, HY Fujii, N Hirshman, MF Pomerleau, JM Goodyear, LJ AF Yu, HY Fujii, N Hirshman, MF Pomerleau, JM Goodyear, LJ TI Cloning and characterization of mouse 5 '-AMP-activated protein kinase gamma 3 subunit SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE adenosine 5 '-monophosphate-activated protein kinase; AMPK gamma 3 short form; AMPK gamma 3 long form; cystathionine beta-synthase domain ID ACETYL-COA CARBOXYLASE; RAT SKELETAL-MUSCLE; GLYCOGEN-SYNTHASE ACTIVITY; FATTY-ACID OXIDATION; HYPERTROPHIC CARDIOMYOPATHY; GLUCOSE-TRANSPORT; BETA-SUBUNIT; EXERCISE; PHOSPHORYLATION; IDENTIFICATION AB Naturally occurring mutations in the regulatory gamma-subunit of 5'-AMP-activated protein kinase ( AMPK) can result in pronounced pathological changes that may stem from increases in muscle glycogen levels, making it critical to understand the role(s) of the gamma-subunit in AMPK function. In this study we cloned the mouse AMPKgamma3 subunit and revealed that there are two transcription start sites, which result in a long form, gamma3L (AF525500) and a short form, gamma3S (AF525501). AMPKgamma3L is the predominant form in mouse and is specifically expressed in mouse skeletal muscle at the protein level. In skeletal muscle, AMPKgamma3 shows higher levels of expression in fast-twitch white glycolytic muscle (type IIb) compared with fast-twitch red oxidative glycolytic muscle (type IIa), whereas gamma3 is undetectable in soleus muscle, a slow-twitch oxidative muscle with predominantly type I fibers. AMPKgamma3 can coimmunoprecipititate with both alpha and beta AMPK subunits. Overexpression of gamma3S and gamma3L in mouse tibialis anterior muscle in vivo has no effect on alpha1 and alpha2 subunit expression and does not alter AMPKalpha2 catalytic activity. However, gamma3S and gamma3L overexpression significantly increases AMPKalpha1 phosphorylation and activity by similar to50%. The increase in AMPKalpha1 activity is not associated with alterations in glycogen accumulation or glycogen synthase expression. In conclusion, the gamma3 subunit of AMPK is highly expressed in fast-twitch glycolytic skeletal muscle, and wild-type gamma3 functions in the regulation of alpha1 catalytic activity, but it is not associated with changes in muscle glycogen concentrations. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Fujii, Nobuharu/J-2724-2014 OI Fujii, Nobuharu/0000-0002-0974-3033 FU NIAMS NIH HHS [AR-42338, AR-45670] NR 51 TC 39 Z9 42 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD FEB 1 PY 2004 VL 286 IS 2 BP C283 EP C292 DI 10.1152/ajpcell.00319.2003 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 760BR UT WOS:000187791200011 PM 14512293 ER PT J AU Koutkia, P Meininger, G Canavan, B Breu, J Grinspoon, S AF Koutkia, P Meininger, G Canavan, B Breu, J Grinspoon, S TI Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE growth hormone-releasing hormone; human immunodeficiency virus ID GH-RELEASING HORMONE; NORMAL SHORT CHILDREN; VIRUS-INFECTED MEN; CIRCULATING GHRELIN; SECRETION; ARGININE; OBESITY; INSULIN; DISEASE; REDISTRIBUTION AB Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1+/-0.6, 4.7+/-0.8, and 4.5+/-0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P>0.05) but markedly reduced GH secretion pulse area (1.14+/-0.27 vs. 4.67+/-1.24 ng.ml(-1).min, P<0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14&PLUSMN;0.27 vs. 3.18&PLUSMN;0.92 ng.ml(-1).min, P<0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418+/-46 vs. 514+/-37 pg/ml, P<0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418&PLUSMN;46 vs. 546&PLUSMN;45 pg/ml, P<0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Nutr Metab, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendocrine Unit, Boston, MA 02114 USA. MIT, Gen Clin Res Ctr, Cambridge, MA 02139 USA. RP Grinspoon, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Nutr Metab, LON 207,55 Fruit St, Boston, MA 02114 USA. FU NCRR NIH HHS [M01 RR-01066]; NIDDK NIH HHS [R01 DK-063639] NR 36 TC 54 Z9 56 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB 1 PY 2004 VL 286 IS 2 BP E296 EP E303 DI 10.1152/ajpendo.00335.2003 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 758UB UT WOS:000187667600018 PM 14559725 ER PT J AU Adelson, DW Million, M Kanamoto, K Palanca, T Tache, Y AF Adelson, DW Million, M Kanamoto, K Palanca, T Tache, Y TI Coordinated gastric and sphincter motility evoked by intravenous CCK-8 as monitored by ultrasonomicrometry in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE lower esophageal sphincter; pylorus; gastric intraluminal pressure; antrum; devazepide ID LOWER ESOPHAGEAL SPHINCTER; CHOLECYSTOKININ-OCTAPEPTIDE; PROXIMAL STOMACH; RELAXATION; PYLORUS; HUMANS; ANTAGONIST; RECEPTORS; PRESSURE; PATHWAY AB Gastric and sphincter motility evoked by intravenous injection of CCK-8 were investigated in urethane-anesthetized rats. Digital ultrasonomicrometry was used to monitor pyloric (PYL), antral ( ANT), corpus ( COR), and lower esophageal sphincter (LES) movements while simultaneously measuring intragastric pressure (IGP) and, in some experiments, subdiaphragmatic intraesophageal pressure (sIEP). Intracrystal distances (ICD) were measured continuously between pairs of piezoelectric crystals affixed to the serosa of PYL, ANT, COR ( circular and longitudinal), and LES. Consecutive intravenous injections of CCK-8 (0.3, 1, and 3 mug/kg) at 30-min intervals caused dose-dependent simultaneous tonic contractions of PYL and ANT, LES opening, and drops in IGP with peak changes at 3 mug/kg of - 17.9 +/- 2.1, - 7.7 +/- 2.5, 6.5 +/- 1.4, and - 29.2 +/- 3.8%, respectively, whereas intravenous saline had no effect. Rhythmic contractile activity was inhibited by CCK-8. COR responses were not significantly different from vehicle controls for most metrics, and the direction of response for circular COR varied between preparations, although not for repeated trials in a single preparation. During the LES response to CCK-8, sIEP rose in parallel with drops in IGP, indicating formation of a common cavity. Recovery of LES ICD after intravenous CCK occurred more rapidly than recovery of PYL ICD, suggesting the importance of preventing simultaneous patency of gastroesophageal and gastroduodenal passages. The CCKA receptor antagonist devazepide ( 500 mug/kg intravenous) inhibited motion responses evoked by intravenous CCK-8. These data revealed CCK-8-induced gastric and sphincter activity consistent with retropulsion of gastric content. C1 Univ Calif Los Angeles, Ctr Ulcer Res & Educ, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Ctr Neurovisceral Sci & Womens Hlth, Div Digest Dis, David Geffen Sch Med, Los Angeles, CA 90073 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Adelson, DW (reprint author), VAGLAHS W LA VAMC, CURE Digest Dis Res Ctr, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM dadelson@ucla.edu FU NIDDK NIH HHS [DK-41301, DK-57238-01A1S1] NR 28 TC 19 Z9 19 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2004 VL 286 IS 2 BP G321 EP G332 DI 10.1152/ajpgi.00057.2003 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 762VH UT WOS:000188002500017 PM 14715522 ER PT J AU Gukovskaya, AS Hosseini, S Satoh, A Cheng, JH Nam, KJ Gukovsky, I Pandol, SJ AF Gukovskaya, AS Hosseini, S Satoh, A Cheng, JH Nam, KJ Gukovsky, I Pandol, SJ TI Ethanol differentially regulates NF-kappa B activation in pancreatic acinar cells through calcium and protein kinase C pathways SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE alcoholic pancreatitis; inflammatory response; cholecystokinin; calcineurin ID INFLAMMATORY RESPONSE; INTRACELLULAR CA2+; GENE-EXPRESSION; CHOLECYSTOKININ; ALCOHOL; RATS; INJURY; SECRETION; ISOFORMS; CCK AB Mechanisms of alcoholic pancreatitis remain unknown. Previously, we showed that ethanol feeding sensitizes rats to pancreatitis caused by CCK-8, at least in part, by augmenting activation of the proinflammatory transcription factor NF-kappaB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca2+- and PKC-mediated pathways of CCK-induced NF-kappaB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-kappaB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-kappaB activation caused by thapsigargin, an agent that mobilizes intracellular Ca2+ bypassing the receptor. Pharmacological analysis showed that NF-kappaB activation by thapsigargin but not by CCK-8 is mediated through the calcineurin pathway and that the inhibitory effect of ethanol on the thapsigargin-induced NF-kappaB activation could be through inhibiting this pathway. Ethanol augmented NF-kappaB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca2+-independent ( novel and/or atypical) PKC isoforms are involved in NF-kappaB activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca2+/calcineurin- and PKC-mediated pathways of NF-kappaB activation in pancreatic acinar cells. These effects may play a role in the ability of ethanol to sensitize pancreas to the inflammatory response and pancreatitis. C1 Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles Ctr, Res Ctr Alcohol Liver & Pancreat Injury, Los Angeles, CA 90073 USA. RP Gukovskaya, AS (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles Ctr, Res Ctr Alcohol Liver & Pancreat Injury, 11301 Wilshire Blvd,Bldg 258,Rm 340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu FU NIAAA NIH HHS [P50-AA11999, T32-AA07578]; NIDDK NIH HHS [DK-59508] NR 53 TC 57 Z9 59 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2004 VL 286 IS 2 BP G204 EP G213 DI 10.1152/ajpgi.00088.2003 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 762VH UT WOS:000188002500004 PM 12958018 ER PT J AU Panoskaltsis-Mortari, A Hermanson, JR Taras, E Wangensteen, OD Charo, IF Rollins, BJ Blazar, BR AF Panoskaltsis-Mortari, A Hermanson, JR Taras, E Wangensteen, OD Charo, IF Rollins, BJ Blazar, BR TI Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE chemokines; mouse models; monocytes; idiopathic pneumonia syndrome; bone marrow transplant ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; IDIOPATHIC PNEUMONIA SYNDROME; BONE-MARROW-TRANSPLANTATION; CHEMOTACTIC PROTEIN-1; CHEMOKINE RECEPTOR-2; T-CELLS; MICE; DISEASE; INFLAMMATION AB Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality post-bone marrow transplant (BMT) in humans. In our murine model, lethal pre-BMT conditioning and allogeneic T cells result in the recruitment of host antigen-presenting cells (APC) and donor T cells into the lung post-BMT concomitant with development of severe lung dysfunction. CCL2 induction is found in bronchoalveolar lavage fluid (BALF) before host monocyte influx. The major receptor for CCL2 is CCR2 present on monocytes; this interaction can play a crucial role in monocyte recruitment in inflammation. To determine whether blockade of the CCL2/CCR2 pathway could hinder host monocyte influx, lethally conditioned wild-type (WT), CCL2(-/-), or CCR2(-/-) mice were transplanted with allogeneic marrow and spleen cells. WT and (-/-) recipients exhibited equivalent lung dysfunction post-BMT. The frequencies of host macrophages as well as donor CD4(+) and CD 8(+) T cells in lungs post-BMT did not differ between WT and (-/-) recipients. However, the T cell dependency of the host CD11b(+) major histocompatibility complex class II+ cell influx was lost in CCR2(-/-) recipients. In CCR2(-/-) mice, this influx was accompanied by elevated levels of CCL20. Post-BMT BALF and sera of (-/-) mice did not reveal any decrease in cytokines or chemokines compared with WT mice. CCL2(-/-) mice had a deficiency of CCL2 in their BALF and sera post-BMT, confirming our hypothesis that CCL2 is predominantly host derived. Therefore, IPS can occur independently of host expression of CCL2 or CCR2, and compensatory mechanisms exist for regulating APC recruitment into the lung during the early post-BMT period. C1 Univ Minnesota, Dept Pediat, Heme Oncol Bone & Marrow Transplant Div, Minneapolis, MN 55455 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Physiol, Minneapolis, MN 55455 USA. Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94141 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Panoskaltsis-Mortari, A (reprint author), Univ Minnesota, Dept Pediat, Div Hematol Oncol, Blood & Marrow Transplant Program, Mayo Mail Code 366,420 Delaware St SE, Minneapolis, MN 55455 USA. FU NCRR NIH HHS [1-S10-RR-16851]; NHLBI NIH HHS [R01-HL-55209, R01-HL-66308] NR 39 TC 10 Z9 10 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD FEB 1 PY 2004 VL 286 IS 2 BP L284 EP L292 DI 10.1152/ajplung.00154.2003 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 761ER UT WOS:000187888200008 PM 14527928 ER PT J AU Ho, RC Alcazar, O Fujii, N Hirshman, MF Goodyear, LJ AF Ho, RC Alcazar, O Fujii, N Hirshman, MF Goodyear, LJ TI p38 gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE mitogen-activated protein kinase; exercise; GLUT1; GLUT4 ID ACTIVATED PROTEIN-KINASE; INSULIN-RECEPTOR SUBSTRATE-1; JUN NH2-TERMINAL KINASE; 3T3-L1 ADIPOCYTES; SIGNAL-TRANSDUCTION; GLUT4 TRANSLOCATION; CELLULAR STRESSES; POTENTIAL ROLE; PDZ DOMAIN; P38 GROUP AB Skeletal muscle expresses at least three p38 MAPKs (alpha, beta, gamma). However, no studies have examined the potential regulation of glucose uptake by p38gamma, the isoform predominantly expressed in skeletal muscle and highly regulated by exercise. L6 myotubes were transfected with empty vector (pCAGGS), activating MKK6 (MKK6CA), or p38gamma-specific siRNA. MKK6CA-transfected cells had higher rates of basal 2-deoxy-D-[H-3] glucose (2-DG) uptake (P < 0.05) but lower rates of 2,4-dinitrophenol (DNP)-stimulated glucose uptake, an uncoupler of oxidative phosphorylation that operates through an insulin-independent mechanism ( P < 0.05). These effects were reversed when MKK6CA cells were cotransfected with p38gamma-specific siRNA. To determine whether the p38gamma isoform is involved in the regulation of contraction-stimulated glucose uptake in adult skeletal muscle, the tibialis anterior muscles of mice were injected with pCAGGS or wild-type p38gamma (p38gammaWT) followed by intramuscular electroporation. Basal and contraction-stimulated 2-DG uptake in vivo was determined 14 days later. Overexpression of p38gammaWT resulted in higher basal rates of glucose uptake compared with pCAGGS ( P < 0.05). Muscles overexpressing p38γWT showed a trend for lower in situ contraction-mediated glucose uptake ( P = 0.08) and significantly lower total GLUT4 levels ( P < 0.05). These data suggest that p38gamma increases basal glucose uptake and decreases DNP- and contraction-stimulated glucose uptake, partially by affecting levels of glucose transporter expression in skeletal muscle. These findings are consistent with the hypothesis that activation of stress kinases such as p38 are negative regulators of stimulated glucose uptake in peripheral tissues. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Fujii, Nobuharu/J-2724-2014 OI Fujii, Nobuharu/0000-0002-0974-3033 FU NIAMS NIH HHS [R01-AR-42238, F32-AR-049662, R01-AR-45670] NR 51 TC 53 Z9 58 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD FEB 1 PY 2004 VL 286 IS 2 BP R342 EP R349 DI 10.1152/ajpregu.00563.2003 PG 8 WC Physiology SC Physiology GA 760BU UT WOS:000187791500015 PM 14592936 ER PT J AU McGuire, M Zhang, Y White, DP Ling, LM AF McGuire, M Zhang, Y White, DP Ling, LM TI Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE respiratory control; plasticity; 5-HT antagonists ID PHRENIC MOTOR OUTPUT; GENOMIC CONSEQUENCES; PROLONGED STIMULATION; NERVE-STIMULATION; RESPIRATION; PLASTICITY; ACTIVATION; PHARMACOLOGY; INDUCTION; MECHANISM AB Respiratory long-term facilitation (LTF), a serotonin-dependent, persistent augmentation of respiratory activity after episodic hypoxia, is enhanced by pretreatment of chronic intermittent hypoxia (CIH; 5 min 11 - 12% O-2-5 min air, 12 h/night for 7 nights). The present study examined the effects of methysergide (serotonin 5-HT1,2,5,6,7 receptor antagonist), ketanserin (5-HT2 antagonist), or clozapine (5-HT2,6,7 antagonist) on both ventilatory LTF and the CIH effect on ventilatory LTF in conscious male adult rats to determine which specific receptor subtype(s) is involved. In untreated rats (i.e., animals not exposed to CIH), LTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O-2) separated by 5-min normoxic intervals, was measured twice by plethysmography. Thus the measurement was conducted 1 - 2 days before (as control) and similar to1 h after systemic injection of methysergide (1 mg/kg ip), ketanserin (1 mg/kg), or clozapine (1.5 mg/kg). Resting ventilation, metabolic rate, and hypoxic ventilatory response (HVR) were unchanged, but LTF (similar to18% above baseline) was eliminated by each drug. In CIH-treated rats, LTF was also measured twice, before and similar to8 h after CIH. Vehicle, methysergide, ketanserin, or clozapine was injected similar to1 h before the second measurement. Neither resting ventilation nor metabolic rate was changed after CIH and/or any drug. HVR was unchanged after methysergide and ketanserin but reduced in four of seven clozapine rats. The CIH-enhanced LTF (similar to28%) was abolished by methysergide and clozapine but only attenuated by ketanserin ( to similar to10%). Collectively, these data suggest that ventilatory LTF requires 5-HT2 receptors and that the CIH effect on LTF requires non-5-HT2 serotonin receptors, probably 5-HT6 and/or 5-HT7 subtype(s). C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, BIDMC,Div Sleep Med, Boston, MA 02115 USA. RP Ling, LM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, BIDMC,Div Sleep Med, 75 Francis St, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-64912] NR 34 TC 67 Z9 70 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD FEB 1 PY 2004 VL 286 IS 2 BP R334 EP R341 DI 10.1152/ajpregu.00463.2003 PG 8 WC Physiology SC Physiology GA 760BU UT WOS:000187791500014 PM 14551171 ER PT J AU Lu, H Sun, TX Bouley, R Blackburn, K McLaughlin, M Brown, D AF Lu, H Sun, TX Bouley, R Blackburn, K McLaughlin, M Brown, D TI Inhibition of endocytosis causes phosphorylation (S256)-independent plasma membrane accumulation of AQP2 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE inner medullary collecting duct; aquaporin-2; methyl-beta-cyclodextrin ID AQUAPORIN-2 WATER CHANNEL; RENAL COLLECTING DUCT; COATED PITS; SUBCELLULAR TRAFFICKING; EPITHELIAL-CELLS; PRINCIPAL CELLS; RAT ADIPOCYTES; GLUT4; VASOPRESSIN; INSULIN AB Inhibition of clathrin-mediated endocytosis by expression of a GTPase-deficient dynamin mutant (dynamin-2/K44A) for 16 h results in an accumulation of plasma membrane aquaporin-2 (AQP2) in epithelial cells stably transfected with wild-type AQP2. We now show a similar effect of K44A dynamin in LLC-PK(1) cells transfected with an S256 phosphorylation-deficient AQP2 mutant, AQP2(S256A), and in AQP2-transfected inner medullary collecting duct (IMCD) cells. More acute blockade of endocytosis in these cells with the cholesterol-depleting agent methyl-beta-cyclodextrin (mbetaCD; 10 mM) resulted in a rapid and extensive cell-surface accumulation of both wild-type AQP2 and AQP2 (S256A) within 15 min after treatment. This effect was similar to that induced by treatment of the cells with vasopressin. Blockade of endocytosis by mbetaCD was confirmed using quantitative analysis of FITC-dextran uptake and AQP2 membrane insertion was verified by cell-surface biotinylation. These data indicate that AQP2 recycles constitutively and rapidly between intracellular stores and the cell surface in LLC-PK1 and IMCD cells. The constitutive trafficking process is not dependent on phosphorylation of the serine-256 residue of AQP2, which is, however, an essential step for regulated vasopressin/ cAMP-mediated translocation of AQP2. Our data show that rapid and extensive plasma membrane accumulation of AQP2 can occur in a vasopressin receptor (V2R)- and phosphorylation-independent manner, pointing to a potential means of bypassing the mutated V2R in X-linked nephrogenic diabetes insipidus to achieve cell surface expression of AQP2. C1 Massachusetts Gen Hosp, Dept Med, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Brown, D (reprint author), Massachusetts Gen Hosp E, Program Membrane Biol, Renal Unit, 149 13th St, Charlestown, MA 02129 USA. EM brown@receptor.mgh.harvard.edu FU NIDDK NIH HHS [DK-57521, DK-65417-01, DK-007540-18, DK-38452, DK-43351] NR 46 TC 75 Z9 78 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB 1 PY 2004 VL 286 IS 2 BP F233 EP F243 DI 10.1152/ajprenal.00179.2003 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 760BT UT WOS:000187791300005 PM 14519593 ER PT J AU Asghar-Ali, AA Taber, KH Hurley, RA Hayman, LA AF Asghar-Ali, AA Taber, KH Hurley, RA Hayman, LA TI Pure neuropsychiatric presentation of multiple sclerosis SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID LATE-LIFE DEPRESSION; EXECUTIVE DYSFUNCTION SYNDROME; MATTER; WHITE; HYPERINTENSITIES; DISORDER; CIRCUITS; MS C1 Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Baylor Coll Med, Herbert J Frensley Ctr Imaging Res, Dept Radiol, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Mental Hlth Care Line, Houston, TX USA. RP Asghar-Ali, AA (reprint author), Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, 1 Baylor Plaza, Houston, TX 77030 USA. EM aasghara@hotmail.com NR 30 TC 30 Z9 31 U1 1 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2004 VL 161 IS 2 BP 226 EP 231 DI 10.1176/appi.ajp.161.2.226 PG 6 WC Psychiatry SC Psychiatry GA 818WT UT WOS:000221275900006 PM 14754769 ER PT J AU Sorensen, G Barbeau, E Hunt, MK Emmons, K AF Sorensen, G Barbeau, E Hunt, MK Emmons, K TI Reducing social disparities in tobacco use: A social-contextual model for reducing tobacco use among blue-collar workers SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Review ID WORKSITE HEALTH PROMOTION; COMMUNITY INTERVENTION TRIALS; WORKING WELL TRIAL; CANCER PREVENTION; UNITED-STATES; CIGARETTE-SMOKING; INTEGRATIVE PERSPECTIVE; WELLWORKS PROJECT; QUITTING SMOKING; BEHAVIOR-CHANGE AB In the United States in 1997, the smoking prevalence among blue-collar workers was nearly double that among white-collar workers, underscoring the need for new approaches to reduce social disparities in tobacco use. These inequalities reflect larger structural forces that shape the social context of workers' lives. Drawing from a range of social and behavioral theories and lessons from social epidemiology, we articulate a social-contextual model for understanding ways in which socioeconomic position, particularly occupation, influences smoking patterns. We present applications of this model to worksite-based smoking cessation interventions among blue-collar workers and provide empirical support for this model. We also propose avenues for future research guided by this model. C1 Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St,Room SM258, Boston, MA 02115 USA. EM glorian_sorensen@dfci.harvard.edu FU NCI NIH HHS [5 P01 CA75308, 5 R01 CA68087, P01 CA075308, R01 CA068087] NR 127 TC 173 Z9 174 U1 0 U2 13 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2004 VL 94 IS 2 BP 230 EP 239 DI 10.2105/AJPH.94.2.230 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 770BP UT WOS:000188703600016 PM 14759932 ER PT J AU Barbeau, EM Krieger, N Soobader, MJ AF Barbeau, EM Krieger, N Soobader, MJ TI Working class matters: Socioeconomic disadvantage, race/ethnicity, gender, and smoking in NHIS 2000 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID WORKSITE CANCER PREVENTION; CIGARETTE-SMOKING; UNITED-STATES; SOCIAL-CLASS; HEALTH PROTECTION; BEHAVIOR-CHANGE; PUBLIC-HEALTH; OCCUPATION; INTERVENTION; ORGANIZATION AB Objectives. We sought to describe the burden of smoking on the US population, using diverse socioeconomic measures. Methods. We analyzed data from the 2000 National Health Interview Survey. Results. Overall, the prevalence of current smoking was greatest among persons in-and independently associated with-working class jobs, low educational level, and low income. Attempts to quit showed no socioeconomic gradient, while success in quitting was greatest among those with the most socioeconomic resources. These patterns held in most but not all race/ethnicity-gender groups. Finer resolution of smoking patterns was obtained using a relational UK occupational measure, compared to the skill-based measure commonly used in US studies. Conclusions. Reducing social disparities in smoking requires attention to the complexities of class along with race/ethnicity and gender. C1 Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Barbeau, EM (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM elizabeth_barbeau@dfci.harvard.edu NR 56 TC 391 Z9 393 U1 3 U2 35 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2004 VL 94 IS 2 BP 269 EP 278 DI 10.2105/AJPH.94.2.269 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 770BP UT WOS:000188703600026 PM 14759942 ER PT J AU Siegel, M Albers, AB Cheng, DM Biener, L Rigotti, NA AF Siegel, M Albers, AB Cheng, DM Biener, L Rigotti, NA TI Effect of local restaurant smoking regulations on environmental tobacco smoke exposure among youths SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID HEALTH; WORKERS; IMPACT; RESTRICTIONS AB Objectives. We examined the effect of local restaurant smoking regulations on restaurant environmental tobacco smoke exposure among youths. Methods. We interviewed 3863 Massachusetts youths aged 12-17 years and ascertained how often they saw smokers in restaurants in their town. We assessed the effect of local restaurant smoking regulation strength on nonexposure to environmental tobacco smoke (seeing smokers never or only rarely). Results. Compared with youths from towns with weak regulations, youths from towns with medium-strength regulations had 1.4 times the odds (odds ratio = 1.36; 95% confidence interval = 1.12, 1.65) and youths from towns with strong regulations had twice the odds (odds ratio = 2.03; 95% confidence interval = 1.64, 2.52) of reporting nonexposure. Conclusions. Strong local restaurant smoking regulations are associated with reduced environmental tobacco smoke exposure among youths. C1 Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Siegel, M (reprint author), Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, 715 Albany St,TW2, Boston, MA 02118 USA. EM mbsiegel@bu.edu OI Biener, Lois/0000-0002-4130-8138 FU NCI NIH HHS [R01 CA086257, 5 R01 CA86257-03] NR 29 TC 24 Z9 24 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2004 VL 94 IS 2 BP 321 EP 325 DI 10.2105/AJPH.94.2.321 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 770BP UT WOS:000188703600033 PM 14759949 ER PT J AU Jaramillo, D Villegas-Medina, OL Doty, DK Rivas, R Strife, K Dwek, JR Mulkern, RV Shapiro, F AF Jaramillo, D Villegas-Medina, OL Doty, DK Rivas, R Strife, K Dwek, JR Mulkern, RV Shapiro, F TI Age-related vascular changes in the epiphysis, physis, and metaphysis: Normal findings on gadolinium-enhanced MRI of piglets SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID CARTILAGE CANALS; ARTICULAR-CARTILAGE; FEMORAL-HEAD; ISCHEMIA; RABBIT; HIP AB OBJECTIVE. We sought to study the normal enhancement patterns seen on MRIs of the epiphysis, physis, and metaphysis and age-related vascular changes in piglets using gadoteridol, a nonionic gadolinium chelate. MATERIALS AND METHODS. We quantitatively and qualitatively analyzed the normal changes on sequential T1-weighted images after the IV administration of gadoteridol. In an investigation approved by the research animal care committee at our hospital, we studied the proximal and distal femurs of 26 piglets 1-6 weeks old and correlated the enhanced images with findings on intermediate-weighted, T2-weighted, and gradient-recalled echo images and at histologic examination. RESULTS. We observed early enhancement of the epiphyseal vascular canals, the main physis, the physis of the secondary ossification center, and a metaphyseal band adjacent to the physis. Enhancement of the epiphyseal and metaphyseal marrow and of the epiphyseal cartilage was slower. In the epiphyseal cartilage, we saw three phases of enhancement: vascular, canalicular, and cartilaginous. As the piglets matured, enhancement of the epiphyseal cartilage decreased, and the epiphyseal vascular canals were less conspicuous. Physeal enhancement was greatest during the first week of life, declined at 3 weeks, and subsequently increased again as the physis came to lie adjacent to a larger segment of the epiphyseal ossification center. CONCLUSION. Gadoteridol-enhanced MRIs showed multiple cartilaginous and vascular structures of the growing skeleton. With maturity and progressive epiphyseal ossification, epiphyseal cartilage enhancement decreased, and epiphyseal cartilage enhancement increased. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Childrens Hosp Boston, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Orthopaed Surg & Orthopaed, Res Lab, Boston, MA 02115 USA. RP Jaramillo, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. FU NIAMS NIH HHS [AR42396-06] NR 17 TC 34 Z9 37 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 353 EP 360 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800023 PM 14736661 ER PT J AU Yamamoto, M Curtin, HD Suwansa-ard, P Sakai, O Sano, T Okano, T AF Yamamoto, M Curtin, HD Suwansa-ard, P Sakai, O Sano, T Okano, T TI Identification of juxtaforaminal fat pads of the second division of the trigeminal pathway on MRI and CT SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article; Proceedings Paper CT 87th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 25-30, 2001 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer ID PERINEURAL TUMOR EXTENSION; CARCINOMA; SPREAD; NERVE C1 Showa Univ, Sch Dent, Dept Radiol, Ohta Ku, Tokyo 1458515, Japan. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Radiol, Boston Med Ctr, Boston, MA 02118 USA. RP Yamamoto, M (reprint author), Showa Univ, Sch Dent, Dept Radiol, Ohta Ku, 2-1-1 Kita Senzoku, Tokyo 1458515, Japan. NR 9 TC 4 Z9 5 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 385 EP 392 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800029 PM 14736668 ER PT J AU Gervais, DA Ho, CH O'Neill, MJ Arellano, RS Hahn, PF Mueller, PR AF Gervais, DA Ho, CH O'Neill, MJ Arellano, RS Hahn, PF Mueller, PR TI Recurrent abdominal and pelvic abscesses: Incidence, results of repeated percutaneous drainage, and underlying causes in 956 drainages SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID ACUTE-PANCREATITIS; CATHETER DRAINAGE; FLUID COLLECTIONS; INTERVENTION AB OBJECTIVE. We undertook this study to determine the incidence and results of repeated (secondary) percutaneous abscess drainage performed on recurrent abscesses after successful initial (primary) percutaneous abscess drainage. MATERIALS AND METHODS. Imaging studies from patients who underwent multiple drainages were reviewed to define a cohort of patients who underwent secondary percutaneous abscess R drainage after successful initial percutaneous abscess drainage of the same abscess. Medical records of. these patients were then reviewed to assess the results of secondary percutaneous abscess drainage. RESULTS. Forty-five abscesses in 43 patients required secondary percutaneous abscess drainage. Twenty-four of the 43 patients avoided surgery. Secondary percutaneous abscess drainage was successful in evacuating the abscess cavity in 39 (91%) of 43 patients. Duration of drainage and time until recurrence were not significant predictors for avoiding surgery. Mean duration of secondary percutaneous abscess drainage was significantly longer than mean duration of primary percutaneous abscess drainage, but duration of secondary percutaneous abscess drainage (25 vs 14 days, respectively; p = 0.007) did not differ significantly between patients who ultimately required surgery and those who did not (17 vs 11 days, respectively; p = 0.10). Time to recurrence ranged from 2 days to I year (mean, 51 days). CONCLUSION. After successful primary percutaneous abscess drainage, secondary percutaneous abscess drainage of recurrent abscesses succeeded in evacuating the abscess cavity in most patients, and surgery was avoided by slightly more than half. Patients with postoperative abscesses were significantly more likely to avoid surgery (p = 0.008), whereas patients with pancreatic abscesses were significantly more likely to require it (p = 0.03). C1 Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Gervais, DA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. NR 13 TC 31 Z9 32 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 463 EP 466 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800042 PM 14736682 ER PT J AU Lee, JM Orel, SG Czerniecki, BJ Solin, LJ Schnall, MD AF Lee, JM Orel, SG Czerniecki, BJ Solin, LJ Schnall, MD TI MRI before reexcision surgery in patients with breast cancer SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID 20-YEAR FOLLOW-UP; CONSERVING SURGERY; MARGIN STATUS; RADIATION-THERAPY; POSITIVE MARGINS; CONSERVATIVE SURGERY; INTERPRETATION MODEL; EXCISIONAL BIOPSY; RE-EXCISION; CARCINOMA AB OBJECTIVE. The aims of this study were to assess the diagnostic accuracy of MRI in evaluating patients for residual cancer, identify the prevalence of multicentric or multifocal disease, and evaluate the impact of MRI on surgical treatment planning. SUBJECTS AND METHODS. Of 101 potentially eligible patients, 80 candidates for breast conservation therapy who had primary breast cancer in 82 breasts diagnosed by excisional biopsy with close or positive margins were included in the study group. All patients underwent contrast-enhanced MRI before further surgery and subsequently underwent either reexcision lumpectomy or mastectomy with histopathologic correlation. RESULTS. Residual carcinoma, either invasive or in situ, was present in 59.8% of the breasts. The sensitivity and specificity of MRI for detecting residual disease were 61.2% and 69.7%, respectively. Twenty-three additional lesions distant from the biopsy site were identified in 19 breasts, and 18 suspicious lesions underwent biopsy. Histology results indicated that six lesions were malignant, so the overall prevalence was 7.3%. The positive predictive value of identifying an additional suspicious lesion was 33.3%. In 24 breasts, MRI changed which procedure would be performed next from reexcision lumpectomy to mastectomy (n = 9), biopsy of an additional lesion in the ipsilateral (n = 12) or contralateral (n = 2) breast, or neoadjuvant chemotherapy (n = 1). Approximately 25% of the breasts underwent mastectomy as definitive surgical treatment. CONCLUSION. Overlap in the appearances of benign and malignant lesions limits MRI evaluation for residual disease. MRI can show additional suspicious lesions that are likely to be multicentric or multifocal disease. These findings changed the original treatment plan for approximately 30% of breasts. C1 Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA 02214 USA. Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, 101 Merrimac St,10th Fl, Boston, MA 02214 USA. EM jlee45@partners.org FU NCI NIH HHS [R01-CA81047] NR 35 TC 48 Z9 48 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 473 EP 480 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800045 PM 14736685 ER PT J AU Kopans, DB AF Kopans, DB TI Sonography screening until its should not be used for breast cancer efficacy has been proven scientifically SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Editorial Material ID MAMMOGRAPHY; WOMEN; ULTRASOUND; CONTROVERSY; LESSONS; WORK C1 Avon Fdn, Comprehens Breast Evaluat Ctr, Wang Ambulatory Care Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Kopans, DB (reprint author), Avon Fdn, Comprehens Breast Evaluat Ctr, Wang Ambulatory Care Ctr, 15 Parkman St,Ste 240, Boston, MA 02114 USA. NR 20 TC 19 Z9 20 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 489 EP 491 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800047 PM 14736687 ER PT J AU Lim, R Wittram, C Ferry, JA Shepard, JAO AF Lim, R Wittram, C Ferry, JA Shepard, JAO TI FDG PET of Rosai-Dorfman disease of the thymus SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID MASSIVE LYMPHADENOPATHY ROSAI; SINUS HISTIOCYTOSIS C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Lim, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. NR 4 TC 19 Z9 19 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2004 VL 182 IS 2 BP 514 EP 514 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 768TP UT WOS:000188590800052 PM 14736692 ER PT J AU Scadden, DT AF Scadden, DT TI The malignant side of successful transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID NON-HODGKINS-LYMPHOMA; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; ANTIBODY RITUXIMAB; IDEC-C2B8; THERAPY; DISEASE C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. RP Scadden, DT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. EM scadden.david@mgh.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2004 VL 4 IS 2 BP 153 EP 154 DI 10.1046/j.1600-6143.2003.00366.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 769HG UT WOS:000188644100001 PM 14974933 ER PT J AU Auchincloss, H Winn, HJ AF Auchincloss, H Winn, HJ TI Clarence Cook Little (1888-1971): The genetic basis of transplant immunology SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Biographical-Item C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Auchincloss, H (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM hauchincloss@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2004 VL 4 IS 2 BP 155 EP 159 DI 10.1046/j.1600-6143.2003.00324.x PG 5 WC Surgery; Transplantation SC Surgery; Transplantation GA 769HG UT WOS:000188644100002 PM 14974934 ER PT J AU Kahn, JP Delmonico, FL AF Kahn, JP Delmonico, FL TI The consequences of public policy to buy and sell organs for transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID PROCUREMENT; INCENTIVES; KIDNEY C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Minnesota, Ctr Bioeth, Minneapolis, MN USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Delmonico, FL (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM francis_delmonico@neob.com NR 15 TC 20 Z9 22 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2004 VL 4 IS 2 BP 178 EP 180 DI 10.1046/j.1600-6143.2003.00370.x PG 3 WC Surgery; Transplantation SC Surgery; Transplantation GA 769HG UT WOS:000188644100005 PM 14974937 ER PT J AU Littooy, FN Gagovic, V Sandu, C Mansour, A Kang, S Greisler, HP AF Littooy, FN Gagovic, V Sandu, C Mansour, A Kang, S Greisler, HP TI Comparison of standard carotid endarterectomy with Dacron patch angioplasty versus eversion carotid endarterectomy during a 4-year period SO AMERICAN SURGEON LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the Midwest-Surgical-Association CY AUG 10-13, 2003 CL Galena, IL SP Midwest Surgical Assoc AB Currently, the two primary approaches to carotid endarterectomy for extracranial carotid stenosis are carotid endarterectomy with patch angioplasty and eversion carotid endarterectomy. In a retrospective study over a 4-year period from 1998 to 2002, we had an opportunity to compare the two approaches as two surgeons utilized carotid endarterectomy with Dacron patch angioplasty and two other surgeons utilized eversion carotid endarterectomy. During the 4-year period, 189 carotid endarterectomies were performed, 125 with Dacron patch angioplasty (CE-P) and 64 with eversion (EE) endarterectomy. There were no significant differences in age of the patients, operative indication, or associated risk factors between the two groups. Perioperative outcome measurement in the CE-P versus EE included stroke or transient ischemic attack, 1.6 per cent versus 1.56 per cent, cranial nerve injury, 2.4 per cent versus 3.13 per cent; death, 0.8 per cent versus 0 per cent; need for operative conversion or revision, 2.4 per cent versus 7.81 per cent, respectively. Only the need for operative conversion or revision reached significant difference (P < 0.05), although the need decreased to 4 per cent for the last 50 EE cases. Recurrent stenosis of 50 per cent to 79 per cent was 4.88 per cent versus 3.13 per cent and >80 per cent was 0.81 per cent versus 0 per cent in the CE-P versus EE group over a follow up of 16.3 months and 17.0 months, respectively. We conclude that both CE-P and EE are equally efficacious operative approaches to extracranial carotid occlusive disease. C1 US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. RP Littooy, FN (reprint author), Edward Hines Vet Adm Med Ctr, Dept Surg, 112, Hines, IL 60141 USA. NR 10 TC 15 Z9 19 U1 1 U2 1 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD FEB PY 2004 VL 70 IS 2 BP 181 EP 185 PG 5 WC Surgery SC Surgery GA 779AZ UT WOS:000189274600030 PM 15011924 ER PT J AU Maiden, MFJ Pham, C Kashket, S AF Maiden, MFJ Pham, C Kashket, S TI Glucose toxicity effect and accumulation of methylglyoxal by the periodontal anaerobe Bacteroides forsythus SO ANAEROBE LA English DT Article; Proceedings Paper CT 6th Biennial Congress of the Anaerobe-Society-of-the-Americas CY JUN 29-JUL 02, 2002 CL PARK CITY, UT SP Anarobe Soc Americas DE autoinhibition; Bacteroides forsythus; glucose toxicity; methylglyoxal; cysteine; periodontal microbiology ID ESCHERICHIA-COLI; CELL DIVISION; BACTERIA; RUMINICOLA; SERUM AB Growth of the periodontal pathogen Bacteroides forsythus in broth cultures showed inhibition in the presence of 10 mM glucose added to the medium. Glucose inhibition in a number of rumen bacteria has been attributed to the accumulation of methylglyoxal (MG), a highly reactive electrophile known to exhibit cytotoxic effects. HPLC analysis revealed elevated concentrations of MG in cultures of seven strains of B. forsythus. MG rose during growth to a maximum at the time of growth inhibition. Maximum MG concentrations for strain ATCC 43037 were 60.6+/-8.2 muM without added glucose, and 185.5+/-21.5 muM (P<0.014) with 10 mM added glucose. Other strains gave values ranging from 24-91 μM and 100-326 μM MG, respectively. Both free and reversibly bound MG were detected in the bacterial cells and in the cell-free culture fluid. Disk sensitivity tests indicated that three B. forsythus strains exhibited different sensitivities to growth inhibition by added MG. Altogether, the results demonstrated the production and accumulation by B. forsythus of high levels of MG in vitro. MG accumulation appears to be related to the marked auto-inhibitory glucose-toxicity effect observed with R forsythus strains, an effect that must be considered in the design of optimal media for the culture of this fastidious species. In the diseased periodontal pocket, production of the highly reactive, cytotoxic MG by R forsythus may contribute significantly to disease pathogenesis. (C) 2003 Elsevier Ltd. All rights reserved. C1 Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. RP Maiden, MFJ (reprint author), Forsyth Inst, Dept Mol Genet, 140 Fenway, Boston, MA 02115 USA. EM mmaiden@forsyth.org NR 30 TC 17 Z9 17 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD FEB PY 2004 VL 10 IS 1 BP 27 EP 32 DI 10.1016/j.anaerobe.2003.12.001 PG 6 WC Microbiology SC Microbiology GA 812GO UT WOS:000220828200005 PM 16701497 ER PT J AU Maiden, MFJ Pham, C Kashket, S AF Maiden, MFJ Pham, C Kashket, S TI Glucose toxicity effect and accumulation of methylglyoxal by the periodontal anaerobe Bacteroides forsythus (vol 10, pg 27, 2004) SO ANAEROBE LA English DT Correction C1 Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. RP Maiden, MFJ (reprint author), Forsyth Inst, Dept Mol Genet, 140 Fenway, Boston, MA 02115 USA. EM mmaiden@forsyth.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD FEB PY 2004 VL 10 IS 1 BP 51 EP 51 DI 10.1016/j.anaerobe.2004.02.001 PG 1 WC Microbiology SC Microbiology GA 812GO UT WOS:000220828200009 ER PT J AU Musch, G Harris, RS Melo, MFV O'Neill, KR Layfield, JDH Winkler, T Venegas, JG AF Musch, G Harris, RS Melo, MFV O'Neill, KR Layfield, JDH Winkler, T Venegas, JG TI Mechanism by which a sustained inflation can worsen oxygenation in acute lung injury SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT 97th International Conference of the American-Thoracic-Society CY MAY 18-23, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Thorac Soc ID RESPIRATORY-DISTRESS-SYNDROME; END-EXPIRATORY PRESSURE; PULMONARY BLOOD-FLOW; LOWER INFLECTION POINT; RECRUITMENT MANEUVERS; GAS-EXCHANGE; GENERAL-ANESTHESIA; TIDAL VOLUME; PROTECTIVE VENTILATION; REGIONAL VENTILATION AB Background: Sustained lung inflations (recruitment maneuvers [RMs]) are occasionally used during mechanical ventilation of patients with acute lung injury to restore aeration to atelectatic alveoli. However, RMs do not improve, and may even worsen, gas exchange in a fraction of these patients. In this study, the authors sought to determine the mechanism by which an RM can impair gas exchange in acute lung injury. Methods: The authors selected a model of acute lung injury that was unlikely to exhibit sustained recruitment in response to a lung inflation. in five sheep, lung injury was induced by lavage with 0.2% polysorbate 80 in saline. Positron emission tomography and [N-13]nitrogen were used to assess regional lung function in dependent, middle, and nondependent lung regions. Physiologic data and positron emission scans were collected before and 5 min after a sustained inflation (continuous positive airway pressure of 50 cm H2O for 30 s). Results: All animals showed greater loss of aeration and higher perfusion and shunting blood flow in the dependent region. After the RM, Pao(2) decreased in all animals by 35 +/- 22 mmHg (P < 0.05). This decrease in Pao(2) was associated with redistribution of pulmonary blood flow from the middle, more aerated region to the dependent, less aerated region (P < 0.05) and with an increase in the fraction of pulmonary blood flow that was shunted in the dependent region (P < 0.05). Neither respiratory compliance nor aeration of the dependent region improved after the RM. Conclusions: When a sustained inflation does not restore aeration to atelectatic regions, it can worsen oxygenation by increasing the fraction of pulmonary blood How that is shunted in nonaerated regions. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Musch, G (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, CLN 309,55 Fruit St, Boston, MA 02114 USA. EM gmusch@partners.org RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 FU NHLBI NIH HHS [HL-56879, HL-68011]; NIGMS NIH HHS [GM-07592] NR 44 TC 55 Z9 58 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD FEB PY 2004 VL 100 IS 2 BP 323 EP 330 DI 10.1097/00000542-200402000-00022 PG 8 WC Anesthesiology SC Anesthesiology GA 767KJ UT WOS:000188438500020 PM 14739807 ER PT J AU Mashour, GA AF Mashour, GA TI Consciousness unbound - Toward a paradigm of general anesthesia SO ANESTHESIOLOGY LA English DT Article ID CORTICAL AREA MT; SEVOFLURANE ANESTHESIA; TEMPORAL BINDING; BRAIN ACTIVITY; SYNCHRONIZATION; MECHANISMS; PROPOFOL; INFORMATION; INTEGRATION; RECOGNITION C1 Harvard Univ, Dept Anesthesia & Crit Care, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mashour, GA (reprint author), Harvard Univ, Dept Anesthesia & Crit Care, Sch Med, Massachusetts Gen Hosp, 55 Fruit St,Clin 309, Boston, MA 02114 USA. EM gmashour@partners.org NR 43 TC 84 Z9 85 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD FEB PY 2004 VL 100 IS 2 BP 428 EP 433 DI 10.1097/00000542-200402000-00035 PG 6 WC Anesthesiology SC Anesthesiology GA 767KJ UT WOS:000188438500033 PM 14739820 ER PT J AU Eng, JA Frosch, MP Choi, KC Rebeck, GW Greenberg, SM AF Eng, JA Frosch, MP Choi, KC Rebeck, GW Greenberg, SM TI Clinical manifestations of cerebral amyloid angiopathy-related inflammation SO ANNALS OF NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; APOLIPOPROTEIN-E GENOTYPE; ALZHEIMERS-DISEASE; GRANULOMATOUS-ANGIITIS; BETA-PEPTIDE; LOBAR HEMORRHAGE; MOUSE MODEL; PROTEIN; BRAIN; RISK AB To explore the clinical effects of inflammation associated with vascular deposits of the amyloid beta peptide (Abeta), we analyzed 42 consecutive patients with pathologically diagnosed cerebral amyloid angiopathy (CAA) for evidence of an inflammatory response. Inflammation with giant-cell reaction surrounding amyloid-laden vessels was identified in 7 of the 42 cases. The clinical symptoms in each of the seven were subacute cognitive decline or seizure rather than hemorrhagic stroke, the primary clinical presentation in 33 of 35 patients with noninflammatory CAA (p<0.001). Inflammatory CAA also was associated with radiographic white matter abnormalities, significantly younger age at presentation, and a marked overrepresentation of the apolipoprotein E ε4/ε4 genotype (71% vs 4%, p<0.001). Of the six inflammatory CAA patients with available follow-up information, five demonstrated clinical and radiographic improvement after immunosuppressive treatment. The syndrome of CAA-related perivascular inflammation appears to represent a subset of CAA with clinically distinct symptoms that may respond to immunosuppressive treatment. These data add to evidence that inflammation against Abeta can cause vascular dysfunction, a potential mechanism for the toxic response recently observed in clinical trials of Abeta immunization. C1 Massachusetts Gen Hosp, Dept Neurol, Wang ACC 836, Boston, MA 02114 USA. Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Wang ACC 836, Boston, MA 02114 USA. EM sgreenberg@partners.org FU NIA NIH HHS [P50 AG05134, R01 AG021084] NR 43 TC 156 Z9 164 U1 1 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2004 VL 55 IS 2 BP 250 EP 256 DI 10.1002/ana.10810 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 768YH UT WOS:000188598300015 PM 14755729 ER PT J AU Moskowitz, MA Bolay, H Dalkara, T AF Moskowitz, MA Bolay, H Dalkara, T TI Deciphering migraine mechanisms: Clues from familial hemiplegic migraine genotypes SO ANNALS OF NEUROLOGY LA English DT Article ID SPREADING DEPRESSION; NEUROTRANSMITTER RELEASE; CALCIUM-CHANNEL; FUNCTIONAL MRI; MUTATIONS; GENE; SUBUNIT; NEURONS; TYPE-2; BRAIN C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol & Neurol,Neurosci Ctr, Charlestown, MA 02129 USA. Gazi Univ Hosp, Dept Neurol, Ankara, Turkey. Univ Hacettepe, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey. RP Moskowitz, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol & Neurol,Neurosci Ctr, 149 13th St,Room 6403, Charlestown, MA 02129 USA. EM moskowitz@helix.mgh.harvard.edu RI Moskowitz, Michael/D-9916-2011 FU NINDS NIH HHS [NS-35611] NR 20 TC 130 Z9 131 U1 1 U2 10 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2004 VL 55 IS 2 BP 276 EP 280 DI 10.1002/ana.20035 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 768YH UT WOS:000188598300018 PM 14755732 ER PT J AU Ng, AK Li, S Neuberg, D Silver, B Weeks, J Mauch, P AF Ng, AK Li, S Neuberg, D Silver, B Weeks, J Mauch, P TI Factors influencing treatment recommendations in early-stage Hodgkin's disease: a survey of physicians SO ANNALS OF ONCOLOGY LA English DT Article DE Hodgkin's disease; physician survey; treatment decision ID BREAST-CANCER; ELDERLY PATIENTS; MANAGEMENT; CHEMOTHERAPY; RADIOTHERAPY; IRRADIATION; CONTROVERSIES; DOXORUBICIN; THERAPY; TRIAL AB Background: The aim of this study was to explore variation in practice patterns and identify factors associated with physicians' treatment decisions for early-stage Hodgkin's disease. Methods: We conducted a one-time mail survey of oncologists randomly selected from directories of national oncology societies (n = 207) and Hodgkin's disease experts (n = 147). The survey included questions on (i) physician factors, (ii) preferred treatment choices for six case scenarios of early-stage Hodgkin's disease that varied by patient factors, and (iii) thresholds for changing treatment recommendations. Results: The response rate was 50%. For non-bulky Hodgkin's disease, 69% of respondents chose combined modality therapy (CMT). On multivariate analysis, physician factors that independently predicted for choice of CMT included a high Hodgkin's disease case load (P = 0.02) and a high percentage of patients enrolled in clinical trials (P = 0.05). Radiation oncologists had a lower threshold for adding radiation therapy (P = 0.02). More experience with second malignancy cases and longer time in practice were associated with a higher threshold for adding radiation therapy (P = 0.04 and P = 0.008, respectively). In stratified analyses, treatment decisions of non-experts were significantly influenced by physician factors, but not by patient factors. Conversely, choices of Hodgkin's disease experts were insensitive to all physician factors, but experts were significantly more likely to select chemotherapy alone in young women and CMT in older patients. Conclusions: Our results indicate that physician factors including practice type and experience may in part explain variation in practice pattern for Hodgkin's disease therapy. Hodgkin's disease experts are more likely to tailor therapy according to individual patient factors. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Ng, AK (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM ang@lroc.harvard.edu NR 33 TC 6 Z9 8 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD FEB PY 2004 VL 15 IS 2 BP 261 EP 269 DI 10.1093/annonc/mdh044 PG 9 WC Oncology SC Oncology GA 774HJ UT WOS:000188973500016 PM 14760120 ER PT J AU Ng, AK Li, S Neuberg, D Silver, B Stevenson, MA Fisher, DC Mauch, PM AF Ng, AK Li, S Neuberg, D Silver, B Stevenson, MA Fisher, DC Mauch, PM TI Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease SO ANNALS OF ONCOLOGY LA English DT Article DE chemotherapy; Hodgkin's disease; radiation therapy; relapse; salvage therapy ID CLINICAL STAGE-I; ELDERLY-PATIENTS; MEDIASTINAL INVOLVEMENT; PROGNOSTIC FACTORS; RANDOMIZED TRIALS; COMBINED-MODALITY; GONADAL TOXICITY; CHEMOTHERAPY; RADIOTHERAPY; DOXORUBICIN AB Background: The aim of this study was to determine salvage outcome in patients with Hodgkin's disease who relapse after radiation therapy, and to compare the efficacy of mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) versus Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) as salvage treatment. Patients and methods: One hundred patients with Hodgkin's disease (97 with stage I-II disease at presentation) who relapsed after radiation therapy alone were salvaged with either MOPP or ABVD. Freedom from second relapse (FFSR) and overall survival (OS) were determined, and prognostic factors for salvage outcome were evaluated. Results: The median follow-up time since salvage therapy was 12 years. The 10-year FFSR and OS rates were 70% and 89%, respectively. Forty-one patients were salvaged with MOPP and 59 received ABVD. The type of salvage chemotherapy did not significantly influence FFSR or OS. Age >50 years at initial diagnosis was the only significant predictor for an inferior FFSR and OS on both univariate and multivari ate analyses. Conclusions: The two salvage regimens of MOPP and ABVD had similar efficacy in this group of patients with predominantly early-stage disease at initial radiation therapy. The inferior salvage outcome in patients aged >50 years is a contributing factor to the overall poor prognosis of patients presenting with Hodgkin's disease at an older age. C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Ng, AK (reprint author), 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM ang@lroc.harvard.edu NR 29 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD FEB PY 2004 VL 15 IS 2 BP 270 EP 275 DI 10.1093/annonc/mdh067 PG 6 WC Oncology SC Oncology GA 774HJ UT WOS:000188973500017 PM 14760121 ER PT J AU Kieff, DA Busaba, NY AF Kieff, DA Busaba, NY TI Same-day discharge for selected patients undergoing combined nasal and palatal surgery for obstructive sleep apnea SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE observation status; obstructive sleep apnea; same-day discharge; septoplasty; uvulopalatal pharyngoplasty ID RESISTANCE AB To determine the safety of same-day discharge for patients who undergo combined nasal and palatal surgery for obstructive sleep apnea syndrome, we undertook a retrospective review and analysis of 2 groups of patients (total, 86 patients) who underwent such surgery. The patients with obstructive sleep apnea syndrome who underwent combined nasal and palatal surgery were considered for same-day discharge if they fulfilled the following postoperative criteria: sustained O2 saturation of 94% or greater on room air while asleep, no history of cardiopulmonary disease or diabetes mellitus, adequate oral analgesia and oral intake, hemostasis, and normal vital signs. Twenty-three patients met these criteria and were assigned to group 1. The remaining 63 patients were admitted overnight for monitoring and were assigned to group 2. The data collected included patient demographics, respiratory disturbance index, lowest O2 saturation, body mass index, and postoperative complications. The mean age, respiratory disturbance index, lowest 02 saturation, and body mass index for group 1 were 45.9 years, 36 events per hour, 84.9%, and 28.7 kg/m(2), respectively. For group 2, the results were 48 years, 36.5 events per hour, 82%, and 32.5 kg/m(2). There were no postoperative complications in group 1, and 3 in group 2. There were no incidents of airway compromise or cardiopulmonary events in the immediate postoperative period in either group. There were no readmissions for either group. We conclude that same-day discharge for patients who have undergone combined nasal and palatal surgery for obstructive sleep apnea syndrome is relatively safe in selected cases in which significant comorbid diseases are not present. These selected cases would have constituted a minority of the patients studied. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Kieff, DA (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 13 TC 14 Z9 15 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD FEB PY 2004 VL 113 IS 2 BP 128 EP 131 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA 774FP UT WOS:000188969400009 PM 14994768 ER PT J AU Maggard, MA Lane, KE O'Connell, JB Ko, CY AF Maggard, MA Lane, KE O'Connell, JB Ko, CY TI Beyond the clinical trials: How prevalent are sentinel lymph node biopsies performed for breast cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 57th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 18-21, 2004 CL NEW YORK, NEW YORK SP Soc Surg Oncol C1 Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. Univ Calif San Francisco, Div Surg Oncol, San Francisco, CA 94143 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2004 VL 11 IS 2 SU S BP S57 EP S57 DI 10.1007/BF02523989 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 771LD UT WOS:000188786100026 ER PT J AU O'Connell, JB Maggard, MA Ko, CY AF O'Connell, JB Maggard, MA Ko, CY TI Variations in the use of curative surgery: How do regions in the US compare SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 57th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 18-21, 2004 CL NEW YORK, NEW YORK SP Soc Surg Oncol C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Greater Los Angeles VA Hlth Care Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2004 VL 11 IS 2 SU S BP S124 EP S124 DI 10.1007/BF02524207 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 771LD UT WOS:000188786100244 ER PT J AU O'Connell, JB Maggard, MA Ko, CY AF O'Connell, JB Maggard, MA Ko, CY TI Cancer-directed surgery for localized disease: Underuse in the elderly SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 57th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 18-21, 2004 CL NEW YORK, NEW YORK SP Soc Surg Oncol C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Greater Los Angeles VA Hlth Care Syst, Los Angeles, CA 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 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2004 VL 11 IS 2 SU S BP S67 EP S68 DI 10.1007/BF02524023 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 771LD UT WOS:000188786100060 ER PT J AU O'Connell, JB Maggard, MA Ko, CY AF O'Connell, JB Maggard, MA Ko, CY TI The new AJCC 6 staging system for colon cancer - Does it prognosticate correctly SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 57th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 18-21, 2004 CL NEW YORK, NEW YORK SP Soc Surg Oncol C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Greater Los Angeles VA Med Ctr, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2004 VL 11 IS 2 SU S BP S68 EP S68 DI 10.1007/BF02524024 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 771LD UT WOS:000188786100061 ER PT J AU Ho, PM Arciniegas, DB Grigsby, J McCarthy, M McDonald, GO Moritz, TE Shroyer, AL Sethi, GK Henderson, WG London, MJ VillaNueva, CB Grover, FL Hammermeister, KE AF Ho, PM Arciniegas, DB Grigsby, J McCarthy, M McDonald, GO Moritz, TE Shroyer, AL Sethi, GK Henderson, WG London, MJ VillaNueva, CB Grover, FL Hammermeister, KE TI Predictors of cognitive decline following coronary artery bypass graft surgery SO ANNALS OF THORACIC SURGERY LA English DT Article ID NEUROPSYCHOLOGICAL DYSFUNCTION; CARDIOPULMONARY BYPASS; LONGITUDINAL ASSESSMENT; CARDIAC OPERATIONS; OUTCOMES; DEMENTIA AB Background. A significant number of patients develop cognitive impairment that persists for months following coronary artery bypass grafting (CABG) surgery. Our objectives were to identify patient-related risk factors, processes of care, and the occurrence of any perioperative complications associated with cognitive decline. Methods. Nine hundred thirty-nine patients enrolled in the Processes, Structures, and Outcomes of Care in Cardiac Surgery study undergoing CABG-only surgery at 14 Veterans Administration medical centers between 1992 and 1996 completed a short battery of cognitive tests at baseline and 6-months post-CABG. The composite cognitive score was based on the sum of errors for each individual item in the battery. Multiple linear regression analyses were used to identify independent predictors of the 6-month composite cognitive score. Results. In multivariable analyses, patient characteristics associated with cognitive decline included cerebrovascular disease (p = 0.009), peripheral vascular disease (p = 0.007), history of chronic disabling neurologic illness (p = 0.016), and living alone (p = 0.049), while the number of years of education (p = 0.001) was inversely related to cognitive decline. After adjustment for baseline patient risk factors, the presence of any postoperative complication(s) (p = 0.001) was also associated with cognitive decline while cardiopulmonary bypass time (p = 0.008) was inversely related to cognitive decline. Conclusions. Patients with noncoronary manifestations of atherosclerosis, chronic disabling neurologic illness, or limited social support are at risk for cognitive decline after CABG surgery. In contrast, more years of education were associated with less cognitive decline. Preoperative assessment of risk factors identified in this study may be useful when counseling patients about the risk for cognitive decline following CABG surgery. (C) 2004 by The Society of Thoracic Surgeons. C1 Denver Vet Affairs Med Ctr, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Surg, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Neuropsychiat, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Biometr, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Colorado Hlth Outcomes Program, Denver, CO 80202 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Dept Vet Affairs, Cent Off, Washington, DC USA. Hines VAMC, Vet Affairs Cooperat Studies Program, Coordinating Ctr, Hines, IL USA. Univ Arizona, Dept Surg, Tucson VAMC, Tucson, AZ 85721 USA. Univ Calif San Francisco, Anesthesia Serv, San Francisco VAMC, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. RP Ho, PM (reprint author), 1055 Clermont St,111B, Denver, CO 80220 USA. EM michael.ho@uchsc.edu RI Arciniegas, David/A-3792-2009; Shroyer, Annie Laurie/B-8836-2016 OI Shroyer, Annie Laurie/0000-0001-6461-0623 FU NHLBI NIH HHS [1 F32 HL69596-01] NR 28 TC 70 Z9 71 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD FEB PY 2004 VL 77 IS 2 BP 597 EP 603 DI 10.1016/S0003-4975(03)01358-4 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 769LQ UT WOS:000188651900050 PM 14759444 ER PT J AU Corzillius, M Muhlberger, N Sroczynski, G Jaeger, H Wasem, J Siebert, U AF Corzillius, M Muhlberger, N Sroczynski, G Jaeger, H Wasem, J Siebert, U TI Cost effectiveness analysis of routine use of genotypic antiretroviral resistance testing after failure of antiretroviral treatment for HIV SO ANTIVIRAL THERAPY LA English DT Article ID DRUG-RESISTANCE; LABORATORY GUIDELINES; PROTEASE INHIBITORS; INFECTED PATIENTS; VIRAL LOAD; THERAPY; TRIAL; RECOMMENDATIONS; HEALTH; MANAGEMENT AB Objectives: Single use of genotypic antiretroviral resistance testing (GART) after first failure of highly active antiretroviral therapy (HAART) was reported to be cost effective; its use prior HAART initiation is unknown. Guidelines recommend GART after each treatment failure. We assessed the cost effectiveness of GART used routinely after first and subsequent treatment failures. Furthermore, we determined the minimum effectiveness required for GART prior to the first HAART to be as cost effective as after treatment failure. Design and methods: We developed a decision-analytic Markov model to estimate lifetime clinical and economic outcomes in a cohort of HIV patients starting HAART. Rates of treatment failure, estimates of GART effectiveness and data on disease progression were derived from published trials and observational studies. A cost effectiveness analysis was performed from the perspective of the healthcare system using cost data from a Central European healthcare setting. Deterministic and probabilistic sensitivity analyses using Monte Carlo technique were performed. Results: GART after treatment failures increased life expectancy by 9 months and undiscounted life-time costs per case by 16406 EURO. The discounted incremental cost effectiveness ratio was 22510EURO per life-year gained (EURO/LY). Best- and worst-case scenarios yielded 16512 EURO/LY and 42900 EURO/LY, respectively. GART prior to the initiation of HAART would be equally cost effective if it could reduce the probability of first HAART failure by at least 36%. Conclusion: Routine use of GART after treatment failures is cost effective. GART prior to the first HAART would be equally cost effective if it could lower the probability of first HAART failure by approximatelly a third. C1 Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Harvard Ctr Risk Anal, Boston, MA 02115 USA. Univ Kiel, Dept Internal Med 2, D-2300 Kiel, Germany. Univ Munich, Dept Infect Dis & Trop Med, Neuherberg, Germany. Natl Res Ctr Environm & Hlth, GSF, Neuherberg, Germany. Univ Munich, Bavarian Publ Hlth Res & Coordinating Ctr, Inst Med Informat Biometry & Epidemiol, Munich, Germany. KIS, Curatorium Immunodeficiency, Munich, Germany. Univ Duisberg Essen, Essen, Germany. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. RP Siebert, U (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Harvard Ctr Risk Anal, Boston, MA 02115 USA. EM uwe@mgh-ita.org OI Wasem, Juergen/0000-0001-9653-168X NR 37 TC 15 Z9 15 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD FEB PY 2004 VL 9 IS 1 BP 27 EP 36 PG 10 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960SY UT WOS:000231614700005 PM 15040534 ER PT J AU Shores, MM Sloan, KL Matsumoto, AM Moceri, VM Felker, B Kivlahan, DR AF Shores, MM Sloan, KL Matsumoto, AM Moceri, VM Felker, B Kivlahan, DR TI Increased incidence of diagnosed depressive illness in hypogonadal older men SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TESTOSTERONE REPLACEMENT THERAPY; PLACEBO-CONTROLLED TRIAL; REFRACTORY DEPRESSION; AFRICAN-AMERICAN; MAJOR DEPRESSION; MOOD; AGE; DISORDER; SYMPTOMS; ESTROGEN AB Context: Age-associated hypogonadism (testosterone deficit) occurs in 30% of men after the age of 55; it is associated with decreased muscle mass, bone mineral density, and libido, and with anorexia, fatigue, and irritability. Although some of these symptoms overlap with those of depression, the association between the 2 disorders is unclear. Objective: To determine if hypogonadal men have an increased incidence of depressive illness compared with eugonadal men. Design: Historical cohort study using computerized medical records, followed by a manual medical record review. Setting: Veterans Affairs Puget Sound Health Care System. Results: The 2-year incidence of diagnosed depressive illness was 21.7% in hypogonadal men vs 7.1% in others (x (2)(1) = 6.0, P = .01). A Kaplan-Meier survival analysis showed a significant difference between hypogonadal and eugonadal men in time to diagnosed depression (log-rank test 2 x (1)(2) = 6.9, P = .008). We used Cox proportional hazards regression models to examine the association of hypogonadism and time to depression diagnosis, adjusting for age, race, number of clinic visits, alcohol use disorders, prostate cancer, and overall medical comorbidity. The unadjusted hazard ratio for depression with hypogonadism was 3.5 (95% confidence interval, 1.3-9.4) (P = .01). Controlling for all covariates, hypogonadism remained significantly associated with depression (adjusted hazard ratio, 4.2; 95% confidence interval, 1.5-12.0) (P = .008). Participants: Two hundred seventy-eight men 45 years and older, without prior diagnosed depressive illness and with consistently normal or low testosterone levels (total testosterone level less than or equal to200 ng/dL [less than or equal to6.94 nmol/L]; or free testosterone level less than or equal to0.9 ng/dL [less than or equal to0.03 nmol/L]) at baseline and during a 2-year follow-up period. Main Outcome Measures: incidence of, and time to, a depression diagnosis. Conclusions: Hypogonadal men showed an increased incidence of depressive illness and a shorter time to diagnosis of depression. Further prospective studies are needed to confirm these preliminary findings and to clarify the role of testosterone in the treatment of depressive illness in older men. C1 Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Shores, MM (reprint author), Vet Affairs Puget Sound Hlth Care Syst, GRECC, 1660 S Columbian Way,S-182, Seattle, WA 98108 USA. EM molly.shores@med.va.gov NR 45 TC 117 Z9 118 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2004 VL 61 IS 2 BP 162 EP 167 DI 10.1001/archpsyc.61.2.162 PG 6 WC Psychiatry SC Psychiatry GA 769MA UT WOS:000188652800006 PM 14757592 ER PT J AU Shin, LM Orr, SP Carson, MA Rauch, SL Macklin, ML Lasko, NB Peters, PM Metzger, LJ Dougherty, DD Cannistraro, PA Alpert, NM Fischman, AJ Pitman, RK AF Shin, LM Orr, SP Carson, MA Rauch, SL Macklin, ML Lasko, NB Peters, PM Metzger, LJ Dougherty, DD Cannistraro, PA Alpert, NM Fischman, AJ Pitman, RK TI Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; CHILDHOOD SEXUAL-ABUSE; SCRIPT-DRIVEN IMAGERY; PSYCHOPHYSIOLOGICAL ASSESSMENT; SYMPTOM PROVOCATION; NURSE VETERANS; ANTERIOR CINGULATE; ANXIETY DISORDERS; CONDITIONED FEAR AB Context: Theoretical neuroanatomic models of posttraumatic stress disorder (PTSD) and the results of previous neuroimaging studies of PTSD highlight the potential importance of the amygdala and medial prefrontal regions in this disorder. However, the functional relationship between these brain regions in PTSD has not been directly examined. Objective: To examine the relationship between the amygdala and medial prefrontal regions during symptom provocation in male combat veterans (MCVs) and female nurse veterans (FNVs) with PTSD. Design: Case-control study. Setting: Academic medical center. events. Psychophysiologic and emotional self-report data also were obtained to confirm the intended effects of script-driven imagery. Participants: Volunteer sample of 17 (7 men and 10 women) Vietnam veterans with PTSD (PTSD group) and 19 (9 men and 10 women) Vietnam veterans without PTSD (control group). Main Outcome Measures: We used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the recollection of personal traumatic and neutral Results: The PTSD group exhibited rCBF decreases in medial frontal gyrus in the traumatic vs neutral comparison. When this comparison was conducted separately by subgroup, MCVs and FNVs with PTSD exhibited these medial frontal gyrus decreases. Only MCVs exhibited rCBF increases in the left amygdala. However, for both subgroups with PTSD, rCBF changes in medial frontal gyrus were inversely correlated with rCBF changes in the left amygdala and the right amygdala/periamygdaloid. cortex. Furthermore, in the traumatic condition, for both subgroups with PTSD, symptom severity was positively related to rCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus. Conclusions: These results suggest a reciprocal relationship between medial prefrontal cortex and amygdala function in PTSD and opposing associations between activity in these regions and symptom severity consistent with current functional neuroanatomic models of this disorder. C1 Tufts Univ, Dept Psychol, Medford, MA 02155 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. VA Res Serv, Manchester, NH USA. St Anselm Coll, Manchester, NH 03102 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Dana Farber Canc Ctr, Boston, MA USA. RP Shin, LM (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM lisa.shin@tufts.edu FU NIMH NIH HHS [MH-60219] NR 41 TC 399 Z9 410 U1 1 U2 44 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2004 VL 61 IS 2 BP 168 EP 176 DI 10.1001/archpsyc.61.2.168 PG 9 WC Psychiatry SC Psychiatry GA 769MA UT WOS:000188652800007 PM 14757593 ER PT J AU Siboo, IR Sieder, F Kumar, K Howe, MM DuBow, MS AF Siboo, IR Sieder, F Kumar, K Howe, MM DuBow, MS TI Characterization of P-lys-proximal morphogenetic genes of transposable bacteriophage Mu SO ARCHIVES OF VIROLOGY LA English DT Article ID COMPLETE GENOME SEQUENCE; LAMBDA TERMINASE ENZYME; DNA PACKAGING ENZYME; FUNCTIONAL DOMAINS; SMALL-SUBUNIT; PHAGE-LAMBDA; INVITRO MATURATION; POSITIVE REGULATOR; PROHEAD BINDING; PORTAL PROTEIN AB Late during the bacteriophage Mu lytic cycle, Mu DNA must be matured and packaged from its dispersed integration sites in the host DNA in order to produce progeny virions. Whereas control of late gene transcription in Mu is becoming well understood, less is known about the phage morphogenetic process. To investigate the latter, we cloned and sequenced a similar to4.3-kb region of the phage DNA beginning just upstream of the leftmost late promoter P-lys. Previous mapping of amber mutations had located the lysis (lys) and proposed DNA maturation genes D and E in this region. When the DNA sequence was analyzed, seven potential open reading frames were found. DNA sequence analysis of amber mutations in genes D and E identified the sixth and seventh open reading frames as D and E, respectively. Cloning and expression of this region enabled production of cell-free protein extracts that specifically recognize the phage-encoded packaging sequence (pac), a characteristic exhibited by phage maturation enzymes. In addition, the E protein was found to share homology with the large subunit of many phage DNA maturation enzymes. These results support the hypothesis that D and E encode subunits of the Mu DNA maturation enzyme. C1 McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA. RP Siboo, IR (reprint author), San Francisco VAMC, 4150 Clemet St 111W2, San Francisco, CA 94121 USA. EM irsiboo@itsa.ucsf.edu OI Siboo, Ian/0000-0002-0055-7058 NR 62 TC 1 Z9 3 U1 0 U2 1 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD FEB PY 2004 VL 149 IS 2 BP 241 EP 259 DI 10.1007/s00705-003-0216-4 PG 19 WC Virology SC Virology GA 767EW UT WOS:000188428100003 PM 14745593 ER PT J AU Abid, R Guo, SD Minami, T Spokes, KC Ueki, K Skurk, C Walsh, K Aird, WC AF Abid, R Guo, SD Minami, T Spokes, KC Ueki, K Skurk, C Walsh, K Aird, WC TI Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE vascular endothelial growth factor; forkhead; endothelial cells; PI3K ID FORKHEAD TRANSCRIPTION FACTOR; SMOOTH-MUSCLE-CELLS; CAENORHABDITIS-ELEGANS; GENE-EXPRESSION; DOWN-REGULATION; KINASE-B; PROMOTER ACTIVITY; FACTOR RECEPTORS; AKT; ANGIOGENESIS AB Objective-Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that promotes endothelial cell (EC) survival, migration, and permeability. The forkhead transcription factors FKHR, FKHRL1, and AFX are mammalian orthologues of DAF-16, a forkhead protein that controls longevity in Caenorhabditis elegans. In this study, we examined whether VEGF is coupled to phosphatidyl inositol 3-kinase (PI3K)/Akt/forkhead in ECs. Methods and Results-We demonstrate that human ECs express members of the forkhead family (FKHR, FKHRL1, and AFX) and that VEGF modulates the phosphorylation, subcellular localization, and transcriptional activity of one or more of these isoforms by a PI3K/Akt signaling pathway. VEGF inhibited EC apoptosis, promoted DNA synthesis and the G(1)-to-S transition, and reduced expression of the cyclin-dependent kinase inhibitor p27(kip1). Each of these effects was blocked by the PI3K inhibitor LY294002 or by a phosphorylation-resistant mutant of FKHRL1, but not by wild-type FKHRL1. Conclusions-These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. RP Aird, WC (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, RW-663, Boston, MA 02215 USA. EM waird@bidmc.harvard.edu NR 40 TC 9 Z9 9 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2004 VL 24 IS 2 BP 294 EP 300 DI 10.1161/01.ATV.0000110502.10593.06 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 771GN UT WOS:000188777400013 ER PT J AU Lehtinen, JT Tingart, MJ Apreleva, M Ticker, JB Warner, JJP AF Lehtinen, JT Tingart, MJ Apreleva, M Ticker, JB Warner, JJP TI Variations in glenoid rim anatomy: Implications regarding anchor insertion SO ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY LA English DT Article DE shoulder; arthroscopy; glenoid; rim; angle ID FOLLOW-UP; ANTERIOR; STABILIZATION; SCAPULA; JOINT AB Purpose: The purpose of this study was to investigate normal bony anatomy of the glenoid rim and to define the angles for successful anchor placement for anterior and posterior labral repairs. Type of Study: An anatomic study using cadaveric shoulder specimens. Methods: Soft tissue was dissected from 20 cadaveric shoulders, and the glenoids were isolated. The glenoid specimens were scanned to obtain cross-sectional images using peripheral quantitative computed tomography (pQCT) in 4 different planes. Glenoid rim angles were measured from the cross-sectional pQCT images of the glenoids at 5 positions: the 3-o'clock, 4:30-, 6-, 7:30-, and 9-o'clock positions. Glenoid morphology was noted for each position. Results: The glenoid rim angles from the 3-o'clock to the 9-o'clock positions were 53degrees +/- 5degrees, 45degrees +/- 7degrees, 80degrees +/- 10degrees, 61degrees +/- 10degrees, 49degrees +/- 4degrees, respectively. Asymmetric morphology of the glenoid was noted with an almost straight line extending medially from the rim at the 3-o'clock position, whereas a concave morphology was noted at the 9-o'clock position. Similarly at the 4:30-o'clock position, the scapular bony surface did not curve toward the base as markedly as it did at the corresponding posterior 7:30-o'clock position. Conclusions: The available bone mass for the anchor insertion was found to vary depending on the position of the glenoid rim. Both rim angle and glenoid morphology for each position must be considered when selecting the ideal anchor insertion angle for labral repair. C1 Isl Orthopaed & Sports Med, Massapequa, NY USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Orthopaed Biomech Lab, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed,Harvard Shoulder Serv, Boston, MA USA. RP Lehtinen, JT (reprint author), Kanta Hame Cent Hosp, Dept Surg, Hameenlinna 13530, Finland. EM janne.lehtinen@khshp.fi NR 15 TC 12 Z9 13 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0749-8063 J9 ARTHROSCOPY JI Arthroscopy PD FEB PY 2004 VL 20 IS 2 BP 175 EP 178 DI 10.1016/j.arthro.2003.11.029 PG 4 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 801IW UT WOS:000220090600010 PM 14760351 ER PT J AU Atri, A Sherman, S Norman, KA Kirchhoff, BA Nicolas, MM Greicius, MD Cramer, SC Breiter, HC Hasselmo, ME Stern, CE AF Atri, A Sherman, S Norman, KA Kirchhoff, BA Nicolas, MM Greicius, MD Cramer, SC Breiter, HC Hasselmo, ME Stern, CE TI Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; MEDIAL SEPTAL-LESIONS; CHOLINESTERASE-INHIBITORS; RECOGNITION MEMORY; PIRIFORM CORTEX; HIPPOCAMPAL TRANSMISSION; ALTERNATION PERFORMANCE; SYNAPTIC PLASTICITY; DELAYED ALTERNATION; SENSORY MODULATION AB Experimental data and computational models suggest that blockade of muscarinic cholinergic receptors impairs paired-associate learning and increases proactive interference (E. DeRosa & M. E. Hasselmo, 2000; M. E. Hasselmo & J. M. Bower, 1993). The results presented here provide evidence in humans supporting these hypotheses. Young healthy subjects first learned baseline word pairs (A-B) and, after a delay, learned additional overlapping (A-C) and nonoverlapping (D-E) word pairs. As predicted, when compared with subjects who received the active placebo glycopyrrolate (4 mug/kg) and subjects who were not injected, those who received scopolamine (8 mug/kg) showed (a) overall impairment in new word paired-associate learning, but no impairment in cued recall of previously learned associates; and (b) greater impairment in learning overlapping (A-C) compared with nonoverlapping (D-E) paired associates. C1 Boston Univ, Ctr Memory & Brain, Boston, MA 02215 USA. Boston Univ, Dept Psychol, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychol, Cambridge, MA 02138 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Memory & Brain, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. Washington Univ, Dept Psychol, St Louis, MO 63130 USA. Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. RP Stern, CE (reprint author), Boston Univ, Ctr Memory & Brain, 2 Cummington St, Boston, MA 02215 USA. EM chantal@bu.edu OI Atri, Alireza/0000-0003-4405-6973; Hasselmo, Michael/0000-0002-9925-6377 FU NIMH NIH HHS [MH60013, MH61492]; NINDS NIH HHS [R01 NS41636-02] NR 98 TC 63 Z9 65 U1 2 U2 15 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD FEB PY 2004 VL 118 IS 1 BP 223 EP 236 DI 10.1037/0735-7044.118.1.223 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 774LR UT WOS:000188981400023 PM 14979800 ER PT J AU Sims, KJ Spassieva, SD Voit, EO Obeid, LM AF Sims, KJ Spassieva, SD Voit, EO Obeid, LM TI Yeast sphingolipid metabolism: clues and connections SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Review DE yeast; sphingolipid metabolism; subcellular localization; protein-protein interactions; stress response; aging ID LONG-CHAIN BASES; INOSITOL PHOSPHORYLCERAMIDE SYNTHASE; PHOSPHOSPHINGOLIPID PHOSPHOLIPASE-C; SACCHAROMYCES-CEREVISIAE CELLS; PROTEIN-PROTEIN INTERACTIONS; BIOCHEMICAL SYSTEMS ANALYSIS; FATTY-ACID ELONGATION; SERINE PALMITOYLTRANSFERASE; CERAMIDE SYNTHESIS; MULTIDRUG-RESISTANCE AB This review of sphingolipid metabolism in the budding yeast Saccharomyces cerevisiae contains information on the enzymes and the genes that encode them, as well as connections to other metabolic pathways. Particular attention is given to yeast homologs, domains, and motifs in the sequence, cellular localization of enzymes, and possible protein-protein interactions. Also included are genetic interactions of special interest that provide clues to the cellular biological roles of particular sphingolipid metabolic pathways and specific sphingolipids. C1 Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Adm, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Adm, Charleston, SC 29425 USA. EM obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847 FU NIA NIH HHS [AG16583]; NIGMS NIH HHS [GM062887]; NLM NIH HHS [T15LM07438] NR 109 TC 44 Z9 45 U1 2 U2 6 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD FEB PY 2004 VL 82 IS 1 BP 45 EP 61 DI 10.1139/003-086 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 809VS UT WOS:000220664800005 PM 15052327 ER PT J AU Benmansour, S Altamirano, AV Jones, DJ Sanchez, TA Gould, GG Pardon, MC Morilak, DA Frazer, A AF Benmansour, S Altamirano, AV Jones, DJ Sanchez, TA Gould, GG Pardon, MC Morilak, DA Frazer, A TI Regulation of the norepinephrine transporter by chronic administration, of antidepressants SO BIOLOGICAL PSYCHIATRY LA English DT Article DE antidepressant; norepinephrine transporter; desipramine; paroxetine; norepinephrine uptake; nisoxetine binding ID SEROTONIN TRANSPORTER; DOWN-REGULATION; H-3 NISOXETINE; MESSENGER-RNA; UPTAKE SITES; RAT-BRAIN; IN-VIVO; DESIPRAMINE; EXPRESSION; OLIGOMERIZATION AB Background. Downregulation of serotonin transporter was observed previously after chronic treatment with selective serotonin reuptake inhibitors (SSRIs) but not selective norepinephrine reuptake inhibitors (NRIs). This study investigated if chronic treatment of rats with selective NRIs or SSRIs also affected the norepinephrine transporter (NET). Methods: Rats were treated for 3 to 6 weeks by osmotic minipumps with either the selective NRIs, desipramine, or the SSRI paroxetine. Results. [H-3]nisoxetine binding sites as well as [H-3]norepinephrine uptake were decreased in hippocampus and cortex after treatment with desipramine. By contrast, paroxetine-treated rats showed no alteration in either [H-3]nisoxetine binding or [H-3]norepinephrine uptake. NET messenger RNA levels in the locus coeruleus were unchanged by desipramine treatment. Conclusions. These results demonstrate that the marked decrease in NET density 1) is not a consequence of a decrease in gene expression; 2) was caused only by a selective NRI; and 3) was associated with a parallel decrease in norepinephrine uptake. C1 Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Anesthesiol, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Benmansour, S (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. OI Pardon, Marie-Christine/0000-0003-4737-9479; Gould, Georgianna/0000-0002-5470-8763 FU NIMH NIH HHS [MH 53851, MH 57001] NR 23 TC 47 Z9 49 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2004 VL 55 IS 3 BP 313 EP 316 DI 10.1016/S0006-3223(03)00676-0 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 767HK UT WOS:000188434000016 PM 14744474 ER PT J AU Ho, VT Hochberg, E Zahrieh, D Cutler, C Steckel, S Lee, SJ Alyea, EP Ritz, J Soiffer, RJ Antin, JH AF Ho, VT Hochberg, E Zahrieh, D Cutler, C Steckel, S Lee, SJ Alyea, EP Ritz, J Soiffer, RJ Antin, JH TI Denileukin diftitox (ONTAK) as targeted therapy against steroid refractory graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Ligand Pharmaceut Inc, San Diego, CA USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 5 BP 7 EP 7 DI 10.1016/j.bbmt.2003.12.015 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500007 ER PT J AU Cutler, C Kim, HT Ho, V Alyea, E Lee, SJ Fisher, DC Hochberg, E Miklos, D Sonis, S Soiffer, RJ Antin, JH AF Cutler, C Kim, HT Ho, V Alyea, E Lee, SJ Fisher, DC Hochberg, E Miklos, D Sonis, S Soiffer, RJ Antin, JH TI Sirolimus and tacrolimus without methotrexate as graft-vs.-host disease prophylaxis after matched, related peripheral blood stem cell transplantation: Low transplant related morbidity and excellent GVHD control SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 7 BP 9 EP 9 DI 10.1016/j.bbmt.2003.12.019 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500009 ER PT J AU Miklos, DB Kim, HT Miller, KH Guo, L Zorn, E Hochberg, EP Lee, SJ Soiffer, RJ Antin, JH Ritz, J AF Miklos, DB Kim, HT Miller, KH Guo, L Zorn, E Hochberg, EP Lee, SJ Soiffer, RJ Antin, JH Ritz, J TI Antibody response to H-Y minor histocompatibility antigens correlates with chronic graft versus host disease and disease remission SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 32 BP 18 EP 19 DI 10.1016/j.bbmt.2003.12.067 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500034 ER PT J AU Zorn, E Floyd, B Lee, SJ Soiffer, RJ Antin, JH Ritz, J AF Zorn, E Floyd, B Lee, SJ Soiffer, RJ Antin, JH Ritz, J TI Defective populations of regulatory T cells correlate with the occurrence of chronic graft versus host disease after allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 36 BP 20 EP 20 DI 10.1016/j.bbmt.2003.12.074 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500038 ER PT J AU Wu, CJ Rogers, SA Kutok, J Krishnamurti, L Hochberg, EP Biernacki, M Antin, JH Ritz, J AF Wu, CJ Rogers, SA Kutok, J Krishnamurti, L Hochberg, EP Biernacki, M Antin, JH Ritz, J TI Ineffective erythropoiesis in recipient precursor cells following non-myeloablative stem cell transplantation in patients with severe sickle cell anemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 94 BP 41 EP 41 DI 10.1016/j.bbmt.2003.12.191 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500096 ER PT J AU Yanik, GA Uberti, JP Ferrara, JLM Levine, JE Hutchinson, RJ Ho, VT Cooke, KR AF Yanik, GA Uberti, JP Ferrara, JLM Levine, JE Hutchinson, RJ Ho, VT Cooke, KR TI Soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of Idiopathic Pneumonia Syndrome following allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT 2004 Meeting CY FEB 13-17, 2004 CL ORLANDO, FLORIDA SP Amer Soc Blood & Marrow Transplantat, Int Bone Marrow Transplant Registry, Autologous Blood & Marrow Transplant Registry C1 Univ Michigan, Med Ctr, Ann Arbor, MI 48109 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2004 VL 10 IS 2 SU 1 MA 244 BP 89 EP 89 DI 10.1016/j.bbmt.2003.12.187 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 773BH UT WOS:000188877500242 ER PT J AU Pek, YS Spector, M Yannas, IV Gibson, LJ AF Pek, YS Spector, M Yannas, IV Gibson, LJ TI Degradation of a collagen-chondroltin-6-sulfate matrix by collagenase and by chondroitinase SO BIOMATERIALS LA English DT Article DE degradation; collagen; glycosaminoglycan; scaffold; enzyme ID CROSS-LINKING AGENTS; ARTIFICIAL SKIN; COLLAGEN/CHONDROITIN-6-SULFATE GELS; EXTRACELLULAR-MATRIX; NERVE REGENERATION; CONTRACTION; DIPHENYLPHOSPHORYLAZIDE; FIBROBLASTS; DIAMINES; FIBERS AB Highly porous, type I collagen-chondroitin-6-sulfate (collagen-GAG) scaffolds, produced by freeze-drying techniques, have proven to be of value as implants to facilitate the regeneration of certain tissues. The objective of this project was to evaluate changes in the microstructure and mechanical properties of selected collagen-GAG scaffolds as they degrade in an in vitro model system. Environmental scanning electron microscopy and video imaging demonstrated that collagenase degradation caused strut erosion through the creation of 1-3 mum diameter micropits within a 2-h period, leading to eventual removal of strut material and strut breakage. Loss of microstructural topography may have been due to gelatinization when collagen was cleaved by collagenase. Chondroitinase degradation of GAG resulted in swelling of the struts, causing the pores to become smaller and rounder. The compressive modulus of the collagen-GAG matrix decreased when degraded by collagenase, but remained unchanged when degraded by chondroitinase. Carbodiimide-cross-linked matrices were found to have a higher cross-link density, a higher compressive stiffness and a greater resistance to collagenase and chondroitinase, compared to non-cross-linked controls and matrices that were cross-linked by the dehydrothermal process. This investigation provides information that can be used to design collagen-GAG scaffolds with desired compressive stiffness and degradation rate to collagenase and chondroitinase. (C) 2003 Elsevier Ltd. All rights reserved. C1 MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed, Boston, MA 02115 USA. VA Boston Healthcare Syst, Boston, MA 02130 USA. MIT, Dept Mech Engn, Cambridge, MA 02139 USA. MIT, Div Biol Engn, Cambridge, MA 02139 USA. RP Gibson, LJ (reprint author), MIT, Dept Mat Sci & Engn, 8-135,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ljgibson@mit.edu RI Gibson, Lorna/K-4738-2012 FU NIBIB NIH HHS [8 R01 EB 000235] NR 31 TC 64 Z9 67 U1 4 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD FEB PY 2004 VL 25 IS 3 BP 473 EP 482 DI 10.1016/S0142-9612(03)00541-6 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 746CA UT WOS:000186727900012 PM 14585696 ER PT J AU Davis, HE Rosinski, M Morgan, JR Yarmush, ML AF Davis, HE Rosinski, M Morgan, JR Yarmush, ML TI Charged polymers modulate retrovirus transduction via membrane charge neutralization and virus aggregation SO BIOPHYSICAL JOURNAL LA English DT Article ID GENE-TRANSFER EFFICIENCY; CELL; INFECTION; KINETICS; BINDING; PROTEOGLYCANS; ADSORPTION AB The specific mechanisms of charged polymer modulation of retrovirus transduction were analyzed by characterizing their effects on virus transport and adsorption. From a standard colloidal perspective two mechanisms, charge shielding and virus aggregation, can potentially account for the experimentally observed changes in adsorption behavior and biophysical parameters due to charged polymers. Experimental testing revealed that both mechanisms could be at work depending on the characteristics of the cationic polymer. All cationic polymers enhanced adsorption and transduction via charge shielding; however, only polymers greater than 15 kDa in size were capable of enhancing these processes via the virus aggregation mechanism, explaining the higher efficiency enhancement of the high molecular weight molecules. The role of anionic polymers was also characterized and they were found to inhibit transduction via sequestration of cationic polymers, thereby preventing charge shielding and virus aggregation. Taken together, these findings suggest the basis for a revised physical model of virus transport that incorporates electrostatic interactions through both virus-cell repulsive and attractive interactions, as well as the aggregation state of the virus. C1 Shriners Hosp Children, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med,Surg Serv, Boston, MA 02114 USA. MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org OI Morgan, Jeffrey/0000-0002-7546-3443 FU NICHD NIH HHS [P01HD 28528-07] NR 29 TC 78 Z9 86 U1 0 U2 5 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2004 VL 86 IS 2 BP 1234 EP 1242 PG 9 WC Biophysics SC Biophysics GA 767JV UT WOS:000188437200052 PM 14747357 ER PT J AU Rowe, PSN Kumagai, Y Gutierrez, G Garrett, IR Blacher, R Rosen, D Cundy, J Navvab, S Chen, D Drezner, MK Quarles, LD Mundy, GR AF Rowe, PSN Kumagai, Y Gutierrez, G Garrett, IR Blacher, R Rosen, D Cundy, J Navvab, S Chen, D Drezner, MK Quarles, LD Mundy, GR TI MEPE has the properties of an osteoblastic phosphatonin and minhibin SO BONE LA English DT Review DE MEPE; renal phosphate excretion; mineralization ID LINKED HYPOPHOSPHATEMIC MICE; MOUSE BONE-CELLS; TUMOR-INDUCED OSTEOMALACIA; OPOSSUM KIDNEY-CELLS; HYP MOUSE; ONCOGENIC OSTEOMALACIA; PARATHYROID-HORMONE; PHEX GENE; PHOSPHONOFORMIC ACID; TRANSPLANTED CELLS AB Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, (PO4)-P-33 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 mug kg(-1) 31 h(-1)), similar to mice given the phosphaturic hormone PTH (80 mug kg(-1) 31 h(-1)). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited (PO4)-P-33 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V-max 53.4% inhibition; K-m 27.4 ng/ml, and V-max 9.1% inhibition; K-m 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serine-aspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Periodont, UTHSCSA, San Antonio, TX 78229 USA. Acologix Inc, Emeryville, CA 94608 USA. Osteoscreen, San Antonio, TX 78229 USA. Univ Wisconsin, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53792 USA. Duke Univ, Dept Med, Ctr Bone Mineral Disorders, Durham, NC 27710 USA. Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. RP Rowe, PSN (reprint author), Univ Texas, Hlth Sci Ctr, Dept Periodont, UTHSCSA, 7703 Floyd Curl Dr,Room 3-579U, San Antonio, TX 78229 USA. EM rowep@uthscsa.edu FU NCI NIH HHS [P01 CA40035, P01 CA040035]; NIAMS NIH HHS [R01 AR051598]; NIDCR NIH HHS [R03 DE015900] NR 106 TC 164 Z9 171 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD FEB PY 2004 VL 34 IS 2 BP 303 EP 319 DI 10.1016/j.bone.2003.10.005 PG 17 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 800FJ UT WOS:000220014000008 PM 14962809 ER PT J AU Wetzler, M Dodge, RK Mrozek, K Stewart, CC Carroll, AJ Tantravahi, R Vardiman, JW Larson, RA Bloomfield, CD AF Wetzler, M Dodge, RK Mrozek, K Stewart, CC Carroll, AJ Tantravahi, R Vardiman, JW Larson, RA Bloomfield, CD TI Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a study of the Cancer and Leukaemia Group B SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE BCR/ABL; Philadelphia chromosome; acute lymphoblastic leukaemia; karyotype; additional aberrations; imatinib ID ACUTE LYMPHOCYTIC-LEUKEMIA; BONE-MARROW TRANSPLANTATION; IN-SITU HYBRIDIZATION; PEDIATRIC-ONCOLOGY-GROUP; CHRONIC MYELOID-LEUKEMIA; TUMOR-SUPPRESSOR GENE; CLINICAL-SIGNIFICANCE; HEMATOLOGIC MALIGNANCIES; FOLLOW-UP; CUMULATIVE INCIDENCE AB We analysed the nature and prognostic significance of secondary cytogenetic changes in 111 newly diagnosed adults with acute lymphoblastic leukaemia (ALL) and t(9;22)(q34;q11.2) or its variants. Secondary aberrations were seen in 75 (68%) patients. They included, in order of descending frequency: +der(22)t(9;22), +21, abnormalities of 9p, high hyperdiploidy (>50 chromosomes), +8, -7, +X and abnormalities resulting in loss of material from 8p, gain of 8q, gain of 1q and loss of 7p. Eighty patients (72%) had greater than or equal to1 normal metaphase in their karyotype. There were four balanced and 12 unbalanced translocations previously unreported in ALL with t(9;22). The t(2;7)(p11;p13) and der(18)t(8;18)(q11.2;p11.2) were seen in two cases each, and have never before been reported in haematological malignancy. All but four patients were treated on front-line Cancer and Leukaemia Group B clinical protocols. The presence of -7 as a sole secondary abnormality was associated with a lower complete remission (CR) rate (P = 0.004), while the presence of greater than or equal to3 aberrations was associated with a higher CR rate (P = 0.009) and +der(22)t(9;22) with a higher cumulative incidence of relapse (P = 0.02). It will be of interest to see if newly diagnosed t(9;22)-positive adult ALL patients with these and other secondary aberrations respond differently to treatment regimens that include imatinib mesylate. C1 Roswell Pk Canc Inst, Dept Med, Leukemia Sect, Buffalo, NY 14263 USA. Duke Univ, Med Ctr, Durham, NC USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Univ Alabama, Birmingham, AL USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Chicago, IL 60637 USA. RP Wetzler, M (reprint author), Roswell Pk Canc Inst, Dept Med, Leukemia Sect, Elm & Carlton St, Buffalo, NY 14263 USA. EM meir.wetzler@roswellpark.org RI Mrozek, Krzysztof/A-3142-2008; OI Larson, Richard/0000-0001-9168-3203 FU NCI NIH HHS [CA 11028, CA 02599, CA 03927, CA 04326, CA 04457, CA 07968, CA 101140, CA 11789, CA 12046, CA 12449, CA 16058, CA 16450, CA 21060, CA 26806, CA 31809, CA 31946, CA 32291, CA 33601, CA 35279, CA 35406, CA 37135, CA 41287, CA 45418, CA 47545, CA 47555, CA 47559, CA 47577, CA 47642, CA 77440, CA 77658] NR 93 TC 36 Z9 38 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD FEB PY 2004 VL 124 IS 3 BP 275 EP 288 DI 10.1046/j.1365-2141.2003.04736.x PG 14 WC Hematology SC Hematology GA 762EL UT WOS:000187958300003 PM 14717774 ER PT J AU Friedman, E AF Friedman, E TI Update of the vascular model of AMD SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID AGE-RELATED MACULOPATHY; MACULAR DEGENERATION; BLOOD-FLOW; STATIN USE; PATHOGENESIS; RISK; ROTTERDAM; DRUSEN; GENE C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Friedman, E (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM ephraimfriedman@mac.com NR 29 TC 36 Z9 46 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD FEB 1 PY 2004 VL 88 IS 2 BP 161 EP 163 DI 10.1136/bjo.2003.036277 PG 3 WC Ophthalmology SC Ophthalmology GA 765UT UT WOS:000188302800003 PM 14736760 ER PT J AU Liu, C Flamoe, E Chen, HJ Carter, D Reed, SG Campos-Neto, A AF Liu, C Flamoe, E Chen, HJ Carter, D Reed, SG Campos-Neto, A TI Expression and purification of immunologically reactive DPPD, a recombinant Mycobacterium tuberculosis skin test antigen, using Mycobacterium smegmatis and Escherichia coli host cells SO CANADIAN JOURNAL OF MICROBIOLOGY LA English DT Article DE Mycobacterium tuberculosis; Mycobacterium smegmatis skin test; DTH; DPPD ID DELAYED-TYPE HYPERSENSITIVITY; BOVIS BCG; PROTEIN; DIAGNOSIS; COMPLEX; ESAT-6; MORTALITY; REAGENTS; CLONING; CFP-10 AB DPPD is a Mycobacterium tuberculosis recombinant antigen that elicits specific delayed type hypersensitivity reactions similar in size and morphological aspects to that elicited by purified protein derivative, in both guinea pigs and humans infected with M. tuberculosis. In addition, earlier clinical studies with DPPD suggested that this molecule could improve the specificity of the tuberculin skin test, which is used as an important aid for the diagnosis of tuberculosis. However, these studies could only be performed with DPPD engineered as a fusion molecule with another Mycobacterium spp. protein because no expression of DPPD could be achieved as a single molecule or as a conventional fusion protein in any commercial system. Although recombinant fusion proteins are in general suitable for several biological studies, they are by definition not ideal for studies involving highly purified and defined polypeptide sequences. Here, we report two alternative approaches for the expression of immunologically reactive recombinant genuine DPPD. The first approach used the rapidly growing, nonpathogenic Mycobacterium smegmatis as host cells transformed with the pSMT3 plasmid vector containing the full-length DPPD gene. The second approach used Escherichia coli transformed with the pET-17b plasmid vector containing the DPPD gene engineered in a three-copy fusion manner in tandem with itself. Though at low levels, expression and purification of immunologically reactive DPPD in M smegmatis could be achieved. More abundant expression and purification of DPPD as a homo-trimer molecule was achieved in E. coli ( greater than or equal to2 mg/L of bacterial broth cultures). Interestingly, expression could only be achieved in host cells transformed with the DPPD gene containing its leader peptide. However, the expressed proteins lacked the leader sequence, which indicates that processing of the M. tuberculosis DPPD gene was accurately achieved and necessary in both M. smegmatis and E. coli. More importantly, the delayed type hypersensitivity reactions elicited by purified molecules in guinea pigs infected with M. tuberculosis were indistinguishable from that elicited by purified protein derivative. Because the DPPD gene is present only in the tuberculosis-complex organisms of the Mycobacterium genus, these highly purified molecules should be helpful in identifying individuals sensitized with tubercle bacilli. C1 Infect Dis Res Inst, Seattle, WA 98104 USA. Corixa Corp, Seattle, WA 98104 USA. Corixa Corp, Seattle, WA 98104 USA. RP Campos-Neto, A (reprint author), Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. EM acampos@forsyth.org OI Carter, Darrick/0000-0001-5901-3402 FU NIAID NIH HHS [AI 44373, AI 43528] NR 29 TC 3 Z9 3 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0008-4166 J9 CAN J MICROBIOL JI Can. J. Microbiol. PD FEB PY 2004 VL 50 IS 2 BP 97 EP 105 DI 10.1139/W03-109 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology; Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology; Microbiology GA 811QA UT WOS:000220785200004 PM 15052311 ER PT J AU Yeazel, MW Oeffinger, KC Gurney, JG Mertens, AC Hudson, MM Emmons, KM Chen, HG Robison, LL AF Yeazel, MW Oeffinger, KC Gurney, JG Mertens, AC Hudson, MM Emmons, KM Chen, HG Robison, LL TI The cancer screening practices of adult survivors of childhood cancer - A report from the childhood cancer survivor study SO CANCER LA English DT Article DE breast self-examination (BSE); mammography; mass screening; neoplasms; survivors; testicular self-examination (TSE); vaginal smears ID LONG-TERM SURVIVORS; BREAST SELF-EXAMINATION; HODGKINS-DISEASE; LYMPHOBLASTIC-LEUKEMIA; 5-YEAR SURVIVORS; HEALTH-STATUS; WOMEN; CARCINOMA; DIAGNOSIS; ABNORMALITIES AB BACKGROUND. The current study characterized the self-reported cancer screening practices of adult survivors of childhood cancer. METHODS. A cohort of 9434 long-term survivors of childhood cancer and a comparison group of 2667 siblings completed a 289-item survey that included items regarding cancer-screening practices. RESULTS. Overall, 27.3% of female respondents reported performing breast self-examination (BSE) regularly, 78.2% reported undergoing a Papanicolaou smear within the previous 3 years, 62.4% underwent a clinical breast examination (CBE) within the last year, and 20.9% had gotten a mammogram at least once in their lifetime. Approximately 17.4% of male respondents reported performing regular testicular self-examination (TSE). Women age greater than or equal to 30 years who had been exposed to chest or mantle radiation therapy were more likely to report undergoing CBE (odds ratio [OR], 1.59; 95% confidence interval [95% Cl], 1.32-1.92) and mammography (OR, 1.92; 95% Cl, 1.47-2.56). Compared with the sibling comparison group, survivors demonstrated an increased likelihood of performing TSE (OR, 1.52; 95% Cl, 1.22-1.85) or BSE (OR, 1.30; 95% Cl, 1.10-1.52), of having undergone a CBE within the last year (OR, 1.18; 95% C1, 1.02-1.35), and of ever having undergone a mammogram (OR, 1.82; 95% Cl, 1.52-2.17). CONCLUSIONS. The results of the current study demonstrate that the cancer screening practices among survivors of childhood cancer are below optimal levels. Primary care physicians who include childhood cancer survivors among their patients could benefit these individuals by informing them about future cancer risks and recommending appropriate evidence-based screening. C1 Univ Minnesota, Sch Med, Dept Family Practice & Community Hlth, Minneapolis, MN 55455 USA. Univ Texas, SW Med Ctr, Dept Family Practice & Community Med, Dallas, TX USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. Univ Tennessee, Coll Med, Memphis, TN USA. Dana Farber Canc Inst, Div Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Maryland, Sch Med, Dept Biostat & Bioinformat, Baltimore, MD 21201 USA. RP Yeazel, MW (reprint author), Univ Minnesota, Sch Med, Dept Family Practice & Community Hlth, Mayo Med Code 381,420 Delaware St SE, Minneapolis, MN 55455 USA. EM yeazel@umn.edu FU NCI NIH HHS [CA 55727] NR 41 TC 62 Z9 62 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 1 PY 2004 VL 100 IS 3 BP 631 EP 640 DI 10.1002/cncr.20008 PG 10 WC Oncology SC Oncology GA 769DP UT WOS:000188611400025 PM 14745882 ER PT J AU Tanabe, KK Curley, SA Dodd, GD Siperstein, AE Goldberg, SN AF Tanabe, KK Curley, SA Dodd, GD Siperstein, AE Goldberg, SN TI Radiofrequency ablation - The experts weigh in SO CANCER LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. Harvard Med Sch, Dept Surg, Boston, MA USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Dept Radiol, San Antonio, TX USA. Cleveland Clin Fdn, Endocrine Surg Sect, Cleveland, OH USA. Beth Israel Med Ctr, Boston, MA USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Cox Bldg,Room 626, Boston, MA 02114 USA. EM ktanabe@partners.org NR 0 TC 44 Z9 45 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2004 VL 100 IS 3 BP 641 EP 650 DI 10.1002/cncr.11919 PG 10 WC Oncology SC Oncology GA 769DP UT WOS:000188611400026 PM 14745883 ER PT J AU Frazier, AL Li, L Cho, EY Willett, WC Colditz, GA AF Frazier, AL Li, L Cho, EY Willett, WC Colditz, GA TI Adolescent diet and risk of breast cancer SO CANCER CAUSES & CONTROL LA English DT Article DE adolescence; breast cancer; diet ID GLYCEMIC INDEX; AMERICAN WOMEN; LOAD; MICRONUTRIENTS; RESTRICTION; PATTERNS; PUBERTY; EVENTS; LIFE AB Objectives: To investigate the components of adolescent diet that may influence risk of breast cancer as an adult. Methods: Retrospective cohort study among 47,355 participants in the Nurses Health Study II who answered a 131-item food frequency questionnaire about diet during high school. Cox proportional hazards regression was used to estimate relative risks and 95% confidence intervals among incident cases of breast cancer between 1989 (inception of the study) and 1998 (when high school diet was assessed). Results: Intakes of fat and fiber were not significantly related to risk of breast cancer in multivariate analysis, but increased intake of vegetable fat (Q(5) versus Q(1) multivariate RR = 0.58, 95% CI (0.38-0.86); test for trend p = 0.005) and vitamin E (Q(5) versus Q(1) multivariate RR = 0.61, 95% CI (0.42-0.89); test for trend p = 0.003) were associated with a lower risk. A higher dietary glycemic index (Q(5) versus Q(1) multivariate RR = 1.47, 95% CI (1.04-2.08); test for trend p = 0.01) was associated with increased risk of breast cancer. Conclusions: The apparent protective effects of vegetable fat and vitamin E and adverse effect of high glycemic foods on risk of breast cancer need confirmation in prospective analyses. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. RP Frazier, AL (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. EM lindsay.frazier@chan-ning.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA50385] NR 43 TC 83 Z9 86 U1 1 U2 7 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2004 VL 15 IS 1 BP 73 EP 82 DI 10.1023/B:CACO.0000016617.57120.df PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 774YY UT WOS:000189015000009 PM 14970737 ER PT J AU Chen, W Possemato, R Campbell, KT Plattner, CA Pallas, DC Hahn, WC AF Chen, W Possemato, R Campbell, KT Plattner, CA Pallas, DC Hahn, WC TI Identification of specific PP2A complexes involved in human cell transformation SO CANCER CELL LA English DT Article ID PROTEIN PHOSPHATASE 2A; SMALL-T-ANTIGEN; SMALL TUMOR-ANTIGEN; REGULATORY SUBUNIT; OKADAIC ACID; CYCLIN-G; EPITHELIAL-CELLS; B56 SUBUNIT; B-SUBUNITS; MIDDLE-T AB The SV40 small t antigen (ST) interacts with the serine-threonine protein phosphatase 2A (PP2A). To investigate the role of this interaction in transformation, we suppressed the expression of the PP2A B56gamma subunit in human embryonic kidney (HEK) epithelial cells expressing SV40 large T antigen, hTERT, and H-RAS. Suppression of PP2A B56gamma expression inhibited PP2A-specific phosphatase activity similar to that achieved by ST and conferred the ability to grow in an anchorage-independent fashion and to form tumors. Overexpression of PP2A B56gamma3 in tumorigenic HEK cells expressing ST or human lung cancer cell lines partially reversed the tumorigenicity of these cells. These observations identify specific PP2A complexes involved in human cell transformation. C1 Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. RP Hahn, WC (reprint author), Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu FU NCI NIH HHS [K01 CA94223, P01 CA50661, R01 CA057327, R01 CA57327] NR 55 TC 196 Z9 214 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB PY 2004 VL 5 IS 2 BP 127 EP 136 DI 10.1016/S1535-6108(04)00026-1 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 779GG UT WOS:000189286500008 PM 14998489 ER PT J AU Ren, J Agata, N Chen, DS Li, YQ Yu, WH Huang, L Raina, D Chen, W Kharbanda, S Kufe, D AF Ren, J Agata, N Chen, DS Li, YQ Yu, WH Huang, L Raina, D Chen, W Kharbanda, S Kufe, D TI Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents SO CANCER CELL LA English DT Article ID MITOCHONDRIAL OUTER-MEMBRANE; GROWTH-FACTOR RECEPTOR; PROSTATE-CANCER CELLS; ABL TYROSINE KINASE; CYTOCHROME-C; BETA-CATENIN; IONIZING-RADIATION; CASPASE ACTIVATION; OXIDATIVE STRESS; APOPTOSIS AB The MUC1 transforming protein is overexpressed by most human carcinomas. The present studies demonstrate that the MUC1C-terminal subunit (MUC1 C-ter) localizes to mitochondria in HCT116/MUC1 colon carcinoma cells and that heregulin stimulates mitochondrial targeting of MUC1 C-ter. We also show that MUC1 attenuates cisplatin-induced (1) release of mitochondrial apoptogenic factors, (2) activation of caspase-3, and (3) induction of apoptosis. Moreover, knockdown of MUC1 expression in A549 lung and ZR-75-1 breast carcinoma cells by MUC1 siRNA was associated with increased sensitivity to genotoxic drugs in vitro and in vivo. These findings indicate that MUC1 attenuates the apoptotic response to DNA damage and that this oncoprotein confers resistance to genotoxic anticancer agents. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. ILEX Prod Inc, Boston, MA 02215 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu OI Yu, Wei-Hsuan/0000-0002-1782-3738 FU NCI NIH HHS [CA29431, CA97098, R01 CA029431, R01 CA097098] NR 52 TC 219 Z9 226 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD FEB PY 2004 VL 5 IS 2 BP 163 EP 175 DI 10.1016/S1535-6108(04)00020-0 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 779GG UT WOS:000189286500011 PM 14998492 ER PT J AU Han, S Santos, TM Puga, A Roy, J Thiele, EA McCollin, M Stemmer-Rachamimov, A Ramesh, V AF Han, S Santos, TM Puga, A Roy, J Thiele, EA McCollin, M Stemmer-Rachamimov, A Ramesh, V TI Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR PROTEINS; MAMMALIAN TARGET; GENE-PRODUCT; 3-KINASE/AKT PATHWAY; IN-VIVO; TSC2; KINASE; IDENTIFICATION; ACTIVATION; RAPAMYCIN AB Tuberous sclerosis complex is caused by mutations in tumor suppressor genes TSC1 or TSC2 and is characterized by the presence of hamartomas in many organs. Although tuberous sclerosis complex is a tumor suppressor gene syndrome with classic "second hits" detectable in renal tumors, conventional genetic analysis has not revealed somatic inactivation of the second allele in the majority of human brain lesions. We demonstrate a novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation, which is specific to tuberous sclerosis complex-associated brain lesions. Additional analysis shows that tissue specificity is due to abnormal activation of the Akt and mitogen-activated protein kinase pathways in brain but not in renal tumors. These results have widespread implications for understanding the tissue specificity of tumor suppressor gene phenotypes. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Stemmer-Rachamimov, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. EM astemmer-rachamimov@partners.org; ramesh@helix.mgh.harvard.edu FU NINDS NIH HHS [NS24279, NS41917] NR 36 TC 59 Z9 59 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2004 VL 64 IS 3 BP 812 EP 816 DI 10.1158/0008-5472.CAN-03-3277 PG 5 WC Oncology SC Oncology GA 771VF UT WOS:000188806200006 PM 14871804 ER PT J AU Hofer, MD Kuefer, R Varambally, S Li, HJ Ma, J Shapiro, GI Gschwend, JE Hautmann, RE Sanda, MG Giehl, K Menke, A Chinnaiyan, AM Rubin, MA AF Hofer, MD Kuefer, R Varambally, S Li, HJ Ma, J Shapiro, GI Gschwend, JE Hautmann, RE Sanda, MG Giehl, K Menke, A Chinnaiyan, AM Rubin, MA TI The role of metastasis-associated protein 1 in prostate cancer progression SO CANCER RESEARCH LA English DT Article ID MTA1 MESSENGER-RNA; PROLIFERATIVE INFLAMMATORY ATROPHY; HISTONE DEACETYLASE; MAMMARY ADENOCARCINOMA; CELL-LINES; GENE; EXPRESSION; DIFFERENTIATION; OVEREXPRESSION; CARCINOMAS AB Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, as current therapy requires over treating men with prostate cancer to prevent the progression of a few cases. Expression of the metastasis-associated protein 1 (MTA1) has previously been found to be associated with progression to the metastatic state in various cancers. Analyzing DNA microarray data, we found MTA1 to be selectively overexpressed in metastatic prostate cancer compared with clinically localized prostate cancer and benign prostate tissue. These results were validated by demonstrating overexpression of MTA1 in metastatic prostate cancer by immunoblot analysis. MTA1 protein expression was evaluated by immunohistochemistry in a broad spectrum of prostate tumors with tissue microarrays containing 1940 tissue cores from 300 cases. Metastatic prostate cancer demonstrated significantly higher mean MTA1 protein expression intensity (score = 3.4/4) and percentage of tissue cores staining positive for MTA1 (83%) compared with clinically localized prostate cancer (score = 2.8/4, 63% positive cores) or benign prostate tissue (score = 1.5/4, 25% positive cores) with a mean difference of 0.54 and 1.84, respectively (P < 0.00001 for both). Paradoxically, for localized disease, higher MTA1 protein expression was associated with lower rates of prostate specific antigen recurrence after radical prostatectomy for localized disease. In summary, this study identified an association of MTA1 expression and prostate cancer progression. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Univ Hosp Ulm, Dept Urol, Ulm, Germany. Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA. Univ Ulm, Dept Pharmacol & Toxicol, Ulm, Germany. Univ Hosp Ulm, Dept Internal Med 1, Ulm, Germany. RP Rubin, MA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Amory 3-195,75 Francis St, Boston, MA 02115 USA. EM marubin@partners.org RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; OI Rubin, Mark/0000-0002-8321-9950 FU NCI NIH HHS [CA58684, CA42182, CA90598, CA97063, P50CA69568] NR 24 TC 96 Z9 122 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2004 VL 64 IS 3 BP 825 EP 829 DI 10.1158/0008-5472.CAN-03-2755 PG 5 WC Oncology SC Oncology GA 771VF UT WOS:000188806200009 PM 14871807 ER PT J AU Yu, JH Nakajima, A Nakajima, H Diller, LR Bloch, KD Bloch, DB AF Yu, JH Nakajima, A Nakajima, H Diller, LR Bloch, KD Bloch, DB TI Restoration of promyelocytic leukemia protein-nuclear bodies in neuroblastoma cells enhances retinoic acid responsiveness SO CANCER RESEARCH LA English DT Article ID INTERFERON-GAMMA; RAR-ALPHA; PML; GROWTH; DIFFERENTIATION; EXPRESSION; TRANSCRIPTION; INHIBITION; BODY; DAXX AB Neuroblastoma is the most common solid tumor of infancy and is believed to result from impaired differentiation of neuronal crest embryonal cells. The promyelocytic leukemia protein (PML)-nuclear body is a cellular structure that is disrupted during the pathogenesis of acute promyelocytic leukemia, a disease characterized by impaired myeloid cell differentiation. During the course or studies to examine the composition and function of PML-nuclear bodies, we observed that the human neuroblastoma cell line SH-SY5Y lacked these structures and that the absence of PML-nuclear bodies was a feature of N- and I-type, but not S-type, neuroblastoma cell lines. Induction of neuroblastoma cell differentiation with 5-bromo-2'deoxyuridine, all-trans-retinoic acid, or IFN-gamma induced PML-nuclear body formation. PML-nuclear bodies were not detected in tissue sections prepared from undifferentiated neuroblastomas but were present in neuroblasts in differentiating tumors. Expression of PML in neuroblastoma cells restored PML-nuclear bodies, enhanced responsiveness to all-trans-retinoic acid, and induced cellular differentiation. Pharmacological therapies that increase PML expression may prove to be important components of combined modalities for the treatment of neuroblastoma. C1 Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Gen Med Serv, Charlestown, MA 02129 USA. Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Bloch, DB (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, E CNY 149 13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [HL-57172]; NIDDK NIH HHS [DK-051179, DK-40561] NR 29 TC 7 Z9 7 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2004 VL 64 IS 3 BP 928 EP 933 DI 10.1158/0008-5472.CAN-03-1199 PG 6 WC Oncology SC Oncology GA 771VF UT WOS:000188806200024 PM 14871822 ER PT J AU Ren, CZ Li, LK Yang, GA Timme, TL Goltsov, A Ren, CH Ji, XR Addai, J Luo, HB Ittmann, MM Thompson, TC AF Ren, CZ Li, LK Yang, GA Timme, TL Goltsov, A Ren, CH Ji, XR Addai, J Luo, HB Ittmann, MM Thompson, TC TI RTVP-1, a tumor suppressor inactivated by methylation in prostate cancer SO CANCER RESEARCH LA English DT Article ID PATHOGENESIS-RELATED PROTEIN; CPG ISLAND; GENE; EXPRESSION; CELLS; P53; HYPERMETHYLATION; CAVEOLIN; MRTVP-1; ORIGIN AB We previously identified and characterized a novel p53-regulated gene in mouse prostate cancer cells that was homologous to a human gene that had been identified in brain cancers and termed RTVP-1 or GLIPR. In this report, we document that the human RTVP-1 gene is also regulated by p53 and induces apoptosis in human prostate cancer cell lines. We show that the expression of the human RTVP-1 gene is down-regulated in human prostate cancer specimens compared with normal human prostate tissue at the mRNA and protein levels. We further document epigenetic changes consistent with RTVP-1 being a tumor suppressor in human prostate cancer. C1 Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Houston, TX USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. RP Thompson, TC (reprint author), 6560 Fannin,Suite 2100, Houston, TX 77030 USA. EM timothyt@www.urol.bcm.tmc.edu FU PHS HHS [P50-58204, R01-50588] NR 24 TC 40 Z9 43 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2004 VL 64 IS 3 BP 969 EP 976 DI 10.1158/0008-5472.CAN-03-2592 PG 8 WC Oncology SC Oncology GA 771VF UT WOS:000188806200029 PM 14871827 ER PT J AU Fang, MC Singer, DE AF Fang, MC Singer, DE TI Anticoagulation for atrial fibrillation SO CARDIOLOGY CLINICS LA English DT Article ID HIGH-RISK PATIENTS; RANDOMIZED CONTROLLED-TRIAL; FIXED MINIDOSE WARFARIN; ADJUSTED-DOSE WARFARIN; STROKE PREVENTION; ANTITHROMBOTIC THERAPY; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; SECONDARY PREVENTION; ORAL ANTICOAGULATION; COST-EFFECTIVENESS AB Atrial fibrillation (AF) is a powerful risk factor for thromboembolism, raising the risk of ischemic stroke fivefold. AF is common among older people, who are at higher stroke risk. As the US population ages, prevention of stroke caused by AF will become an even more important public health concern. Research conducted over the past 15 years has demonstrated that oral anticoagulants are highly effective and reasonably safe in reducing the risk of stroke in AF. This article reviews the efficacy and risks of using oral anticoagulants for nonvalvular AF. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fang, MC (reprint author), Univ Calif San Francisco, 533 Parnassus Ave,Box 0131, San Francisco, CA 94143 USA. EM mfang@medicine.ucsf.edu NR 88 TC 7 Z9 7 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0733-8651 J9 CARDIOL CLIN JI Cardiol. Clin. PD FEB PY 2004 VL 22 IS 1 BP 47 EP + DI 10.1016/S0733-8651(03)00115-2 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 863OH UT WOS:000224570800007 PM 14994847 ER PT J AU Goldberg, SL Makkar, R Duckwiler, G AF Goldberg, SL Makkar, R Duckwiler, G TI New strategies in the percutaneous management of coronary artery fistulae: A case report SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE coronary artery fistula; embolization; congenital heart disease; case report ID INTERNAL CAROTID-ARTERY; TRANSCATHETER EMBOLIZATION; ARTERIOVENOUS-FISTULAS; MYOCARDIAL-INFARCTION; ENDOVASCULAR APPROACH; SACCULAR ANEURYSMS; ELECTROTHROMBOSIS; CHILDREN; CLOSURE; ADULTS AB Coronary artery fistulae are rare anomalies often treated percutaneously. New techniques aiding in the percutaneous closure of a giant coronary artery, not previously described, are presented in a case report. These techniques include the use of intravascular ultrasound imaging and the use of electrolytically detachable platinum coils. (C) 2004 Wiley-Liss, Inc. C1 W Los Angeles Vet Adm, Ctr Med, Div Cardiol, Los Angeles, CA USA. Univ Calif Los Angeles, Ctr Med, Dept Radiol, Los Angeles, CA USA. RP Goldberg, SL (reprint author), Univ Washington, Sch Med, Div Cardiol, Box 356115,1959 NE Pacific St, Seattle, WA 98195 USA. EM stevgold@u.washington.edu NR 28 TC 6 Z9 6 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD FEB PY 2004 VL 61 IS 2 BP 227 EP 232 DI 10.1002/ccd.10758 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 771VU UT WOS:000188807400015 PM 14755818 ER PT J AU Bassing, CH Alt, FW AF Bassing, CH Alt, FW TI H2AX may function as an anchor to hold broken chromosomal DNA ends in close proximity SO CELL CYCLE LA English DT Article DE histone H2AX; double-strand breaks; translocations; chromatin structure; genomic instability ID DOUBLE-STRAND BREAKS; HISTONE H2AX; GENOMIC INSTABILITY; CELL-CYCLE; ATAXIA-TELANGIECTASIA; GENE AMPLIFICATION; DEPENDENT MANNER; PATHOGENIC ROLE; FOCUS FORMATION; REPAIR FACTORS AB The histone H2A variant, H2AX, is a core component of chromatin that is phosphorylated in chromatin flanking DNA double strand breaks (DSBs). Here, we summarize H2AX functions and outline a specific "anchoring" model, that can explain the translocation prone phenotype of H2AX-deficient and H2AX/p53-deficient mice. We also discuss how this model of H2AX function could account for some aspects of the genomic instability and cancer prone human phenotypes associated with Ataxia Telangiectasia ( AT), Nijmegen Breakage Syndrome (NBS), Ataxia Telangiectasia Like Disorder (ATLD), and Bloom's Syndrome (BS). C1 Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Inst Biomed Res, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst,Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu NR 47 TC 149 Z9 154 U1 1 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB PY 2004 VL 3 IS 2 BP 149 EP 153 PG 5 WC Cell Biology SC Cell Biology GA 833TD UT WOS:000222361200017 PM 14712078 ER PT J AU Kim, S Emerman, CL Cydulka, RK Rowe, BH Clark, S Camargo, CA AF Kim, S Emerman, CL Cydulka, RK Rowe, BH Clark, S Camargo, CA CA MARC Investigators TI Prospective multicenter study of relapse following emergency department treatment of COPD exacerbation SO CHEST LA English DT Article DE acute exacerbation; COPD; emergency medicine; relapse ID OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; ACUTE ASTHMA; CHRONIC-BRONCHITIS; LUNG-DISEASE; INFLAMMATORY MARKERS; IPRATROPIUM BROMIDE; PRIMARY-CARE; FREQUENCY; VISITS AB Study objectives: To determine the incidence and risk factors of relapse after an emergency department (ED) visit for COPD exacerbation. Design: Prospective cohort study as part of the Multicenter Airway Research Collaboration. Setting: Twenty-nine North American EDs. Patients: ED patients with COPD exacerbations, age greater than or equal to 55 years. For the present analysis of post-ED relapse, the cohort was restricted to COPD patients who had been discharged from the ED directly to home. Measurements and results: Eligible patients underwent a structured interview to assess their demographic characteristics, COPD history, and details of the current COPD exacerbation. Data on ED medical management and disposition were obtained by chart review. Patients were contacted by telephone 2 weeks later regarding incident relapse events (ie, urgent clinic or ED visit for worsening COPD). The cohort consisted of 140 COPD patients. Over the next 2 weeks, patients demonstrated a consistent daily relapse rate that summed to 21% (95% confidence interval, 15 to 28%) at day 14. In a multivariate model, the significant risk factors for relapse were the number of urgent clinic or ED visits for COPD exacerbation in the past year (odds ratio [OR], 1.49 [per five visits]), self-reported activity limitation during the past 24 h (OR, 2.93 [per unit on scale of 1 [none] to 4 [severe]), and respiratory rate at ED presentation (OR, 1.76 [per 5 breaths/min]). Conclusions: Among patients discharged to home after ED treatment of a COPD exacerbation, one in five patients will experience an urgent/emergent relapse event during the next 2 weeks. Both chronic factors (ie, a history of urgent clinic or ED visits) and acute factors (ie, activity limitations and initial respiratory rate) are associated with increased risk. Further research should focus on ways to decrease the relapse rate among these high-risk patients. The clinicians may wish to consider these historical factors when making ED decisions. C1 Massachusetts Gen Hosp, EMNet Coordinating Ctr, Dept Emergency Med, Boston, MA 02114 USA. Metrohlth Med Ctr, Dept Emergency Med, Cleveland, OH USA. Univ Alberta, Dept Emergency Med, Edmonton, AB T6G 2M7, Canada. RP Kim, S (reprint author), Massachusetts Gen Hosp, EMNet Coordinating Ctr, Dept Emergency Med, 55 Fruit St,Clin Bldg 397, Boston, MA 02114 USA. FU NHLBI NIH HHS [K30 HL 04095, R01 HL 63841]; NIEHS NIH HHS [T32 ES 07069] NR 50 TC 31 Z9 31 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2004 VL 125 IS 2 BP 473 EP 481 DI 10.1378/chest.125.2.473 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 774KJ UT WOS:000188978400021 PM 14769727 ER PT J AU Vonderheide, RH Domchek, SM Schultze, JL George, DJ Hoar, KM Chen, DY Stephans, KF Masutomi, K Loda, M Xia, ZN Anderson, KS Hahn, WC Nadler, LM AF Vonderheide, RH Domchek, SM Schultze, JL George, DJ Hoar, KM Chen, DY Stephans, KF Masutomi, K Loda, M Xia, ZN Anderson, KS Hahn, WC Nadler, LM TI Vaccination of cancer patients against telomerase induces functional antitumor CD8+T lymphocytes SO CLINICAL CANCER RESEARCH LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; TUMOR-ASSOCIATED ANTIGEN; PULSED DENDRITIC CELLS; REVERSE-TRANSCRIPTASE; MELANOMA PATIENTS; IMMUNOLOGICAL IGNORANCE; INTRANODAL INJECTION; CATALYTIC SUBUNIT; PEPTIDE; IMMUNOTHERAPY AB Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in > 85 % of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth. Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT 1540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells. Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes. Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis. C1 Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. Harvard Univ Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Vonderheide, RH (reprint author), Univ Penn, Abramson Family Canc Res Inst, 551 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM rhv@mail.med.upenn.edu RI Schultze, Joachim/D-7794-2011 OI Schultze, Joachim/0000-0003-2812-9853 FU NCI NIH HHS [K08 CA 88444, P30 CA 06516] NR 47 TC 177 Z9 202 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2004 VL 10 IS 3 BP 828 EP 839 DI 10.1158/1078-0432.CCR-0620-3 PG 12 WC Oncology SC Oncology GA 774MF UT WOS:000188982700004 PM 14871958 ER PT J AU Liu, G Gandara, DR Lara, PN Raghavan, D Doroshow, JH Twardowski, P Kantoff, P Oh, W Kim, KM Wilding, G AF Liu, G Gandara, DR Lara, PN Raghavan, D Doroshow, JH Twardowski, P Kantoff, P Oh, W Kim, KM Wilding, G TI A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DEPENDENT KINASE INHIBITOR; CONTINUOUS-INFUSION FLAVOPIRIDOL; ADVANCED COLORECTAL-CANCER; BREAST-CARCINOMA CELLS; GROWTH-INHIBITION; L86-8275; APOPTOSIS; INDUCTION; LYMPHOMA; FLAVONE AB Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase 11 trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer. Experimental Design: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m(2)/day. Dose escalation up to 60 mg/m(2)/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent. Results: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident. Conclusions: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules. C1 Med Oncol Sect, Dept Med, Madison, WI 53792 USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. Univ Calif Davis Canc Ctr, Calif Canc Consortium, Sacramento, CA USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. City Hope Med Ctr, Duarte, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wilding, G (reprint author), Med Oncol Sect, Dept Med, 600 Highland Ave, Madison, WI 53792 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 30 TC 44 Z9 49 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2004 VL 10 IS 3 BP 924 EP 928 DI 10.1158/1078-0432.CCR-03-0050 PG 5 WC Oncology SC Oncology GA 774MF UT WOS:000188982700014 PM 14871968 ER PT J AU Glisson, B Colevas, AD Haddad, R Krane, J El-Naggar, A Kies, M Costello, R Summey, C Arquette, M Langer, C Amrein, PC Posner, M AF Glisson, B Colevas, AD Haddad, R Krane, J El-Naggar, A Kies, M Costello, R Summey, C Arquette, M Langer, C Amrein, PC Posner, M TI HER2 expression in salivary gland carcinomas: Dependence on histological subtype SO CLINICAL CANCER RESEARCH LA English DT Article ID ADENOID CYSTIC CARCINOMA; BREAST-CANCER; PHASE-II; ONCOGENE; CHEMOTHERAPY; HER-2/NEU; CISPLATIN; CYCLOPHOSPHAMIDE; AMPLIFICATION; MALIGNANCIES AB Purpose: Previous evaluation of HER2 overexpression in salivary gland cancers indicated an incidence varying between 7 and 56%, with no clear difference among three histologically different subtypes. As part of a Phase 11 trial of trastuzumab for treatment of incurable salivary gland cancer, we screened 137 tumors for HER2 expression. Experimental Design: Unstained sections of paraffin-embedded tumor samples were stained with p185/HER2 receptor antibody. Tumors with moderate (2+) to strong (3+) complete membrane staining in at least 10% of the tumor cells were scored as positive for overexpression. Results: The overall frequency of overexpression for HER2 was 17% (23 of 137), whereas it was only 8% in the three most common histological subtypes screened. Overexpression was distinctly rare in the most common subtype screened, adenoid cystic carcinoma (4%, 3 of 70). Overexpression was very common in salivary duct cancers; 10 (83%) of 12 were positive for HER2. This observation is consistent with the typical high-grade histological features and aggressive behavior of this subtype as well as with its histogenetic similarity to breast cancer. Analysis based on histogenesis (intercalated duct versus excretory duct) indicated a higher frequency. Conclusions: Our overall results suggest that trastu-zumab will not have a major role in treatment of salivary gland cancers of intercalated duct origin. Further systematic evaluation of trastuzumab in subtypes of excretory duct origin could be supported. C1 Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck, Houston, TX 77030 USA. Washington Univ, St Louis, MO USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Glisson, B (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck, 1515 Holcombe Blvd,Box 432, Houston, TX 77030 USA. EM bglisson@mdanderson.org NR 18 TC 99 Z9 100 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2004 VL 10 IS 3 BP 944 EP 946 DI 10.1158/1078-0432.CCR-03-0253 PG 3 WC Oncology SC Oncology GA 774MF UT WOS:000188982700017 PM 14871971 ER PT J AU Zusman, R AF Zusman, R TI Patients with uncontrolled hypertension or concomitant hypertension and benign prostatic hyperplasia SO CLINICAL CARDIOLOGY LA English DT Review DE hypertension; doxazosin; benign prostatic hyperplasia ID LIPID-LOWERING TREATMENT; ATTACK TRIAL ALLHAT; HIGH BLOOD-PRESSURE; TREATMENT REGIMEN; DOUBLE-BLIND; DOXAZOSIN; COMBINATION; MULTICENTER; EFFICACY; CHLORTHALIDONE AB At optimal doses, individual antihypertensive agents lower blood pressure (BP) by an average of 10 mmHg. Many patients with hypertension, including those with stage 3 hypertension, target organ damage, or those at high risk for cardiovascular events and/or adverse effects of high-dose monotherapy, are likely to require combination antihypertensive drug treatment to achieve the recommended systolic/diastolic BP (< 140/90 mmHg). Two studies, a placebo-controlled, double-blind trial (n = 70) and a community-based, open-label trial (n = 491) investigated the antihypertensive efficacy of doxazosin, a long-acting selective alpha(1)-adrenoceptor blocker, as add-on therapy for uncontrolled hypertension with other antihypertensive medications and in patients with concomitant benign prostatic hyperplasia (BPH) and treated but inadequately controlled hypertension, respectively. The addition of doxazosin to baseline antihypertensive medication(s) significantly lowered BP and had a significantly positive effect on the serum lipid profile. In patients with concomitant BPH, doxazosin significantly improved all BPH symptom scores. regardless of initial symptom severity. Add-on doxazosin sufficiently reduced systolic/diastolic BP such that many patients whose hypertension was previously uncontrolled by other anti hypertensive medications were able to reach goal BP (< 140/90 mmHg). Doxazosin as add-on therapy was well tolerated. In conclusion, doxazosin as add-on therapy improves BP control in hypertensive patients not at goal BP and improves lower urinary tract symptoms in patients with concomitant BPH. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zusman, R (reprint author), Massachusetts Gen Hosp, 15 Parkman St 482, Boston, MA 02114 USA. EM Zusman.randall@MGH.harvard.edu NR 37 TC 4 Z9 5 U1 0 U2 0 PU CLINICAL CARDIOLOGY PUBL CO PI MAHWAH PA PO BOX 832, MAHWAH, NJ 07430-0832 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD FEB PY 2004 VL 27 IS 2 BP 63 EP 69 DI 10.1002/clc.4960270203 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 768NP UT WOS:000188549300002 PM 14979621 ER PT J AU Offner, H Zamora, A Subramanian, S Polanczyk, M Krogstad, A Auci, DL Morgan, EE Reading, CL AF Offner, H Zamora, A Subramanian, S Polanczyk, M Krogstad, A Auci, DL Morgan, EE Reading, CL TI A synthetic androstene analogue inhibits collagen-induced arthritis in the mouse SO CLINICAL IMMUNOLOGY LA English DT Article DE CIA; arthritis; androstene; DHEA; cytokines ID PROLIFERATOR-ACTIVATED RECEPTORS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; IN-VITRO; T-CELLS; DEHYDROEPIANDROSTERONE; MICE; INFLAMMATION; ALPHA AB Dehydroepiandrosterone (DHEA), a precursor of immune-regulating hormones (IRH) including the androstenes, has attracted much interest over the last several decades because of its many antiaging, metabolic, and immune modulating effects. 5-Androstene-16alpha fluoro-17-one (fluasterone, also known as HE2500) is a synthetic androstene analogue that retains anti-inflammatory, antiproliferative, and immuneregulating activities of the parent molecule, but is nontoxic and practically devoid of androgenic or estrogenic side effects. In the present studies, we tested the ability of fluasterone to limit disease in the DBA mouse model of collagen-induced arthritis (CIA). We found that mice receiving injections of fluasterone displayed significant delay in onset, decrease in CIA peak score, and significant decrease of the daily mean clinical score. Benefit was associated with significant decreases in (1) bovine type II collagen (bCII)-specific IgG(1) and IgG(2). antibody levels in serum; (2) production of TNF-alpha, IL-6, IFN-gamma, but not IL-10; (3) lymphocyte proliferative response to bCII protein; and (4) joint inflammation, erosion, and synovial proliferation as judged by histological analysis. This is the first study to report that an IRH can ameliorate ongoing disease in a CIA mouse model with relevance to RA and to correlate that finding with decreases in pro-inflammatory cytokines. (C) 2004 Elsevier Inc. All rights reserved. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97239 USA. Vet Affairs Med Ctr, Portland, OR 97239 USA. Univ Missouri, Dept Vet Pathobiol, Columbia, MO 65211 USA. Hollis Eden Pharmaceut Inc, San Diego, CA 92121 USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D 31, 3710 SW US,Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIAID NIH HHS [AI42376]; NINDS NIH HHS [NS23444] NR 59 TC 9 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2004 VL 110 IS 2 BP 181 EP 190 DI 10.1016/j.clim.2003.11.003 PG 10 WC Immunology SC Immunology GA 803KF UT WOS:000220229300009 PM 15003815 ER PT J AU Stone, VE AF Stone, VE TI Optimizing the care of minority patients with HIV/AIDS SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ADHERENCE; AIDS; PARTICIPATION; PREDICTORS; COMMUNITY; SAMPLE; ACCESS AB Persons belonging to racial/ethnic minorities are disproportionately affected by human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome ( AIDS) in the United States, with higher numbers of infected individuals and higher HIV/AIDS - related death rates. Despite its substantial medical toll among minorities, HIV/AIDS has had a complex sociocultural legacy in many minority communities in the United States, especially in the African American community, which can present a challenge for patients and medical care providers. Many studies have found that minorities receiving care for HIV/AIDS are less likely to be satisfied with their HIV care and less likely to receive highly active antiretroviral therapy ( HAART) than are other patients. The root causes of these disparities in care have not yet been well delineated. However, clinicians can optimize the care they provide for minority patients by using a cultural competence framework, enhancing patient-provider communication, diversifying their clinical staff, proactively enhancing receipt of HAART, and being attentive to issues related to adherence to HAART. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Stone, VE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Bulfinch 130,55 Fruit St, Boston, MA 02114 USA. EM tone@partners.org NR 36 TC 32 Z9 32 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2004 VL 38 IS 3 BP 400 EP 404 DI 10.1086/380969 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 764LD UT WOS:000188207600014 PM 14727211 ER PT J AU Deshmukh, R Mankin, HJ Singer, S AF Deshmukh, R Mankin, HJ Singer, S TI Synovial sarcoma: The importance of size and location for survival SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PROGNOSIS; FEATURES; TUMORS AB A retrospective analysis was done on 135 consecutive patients with extremity and truncal synovial sarcomas seen at our institutions between 1961 and 1996. Ninety-nine patients (73%) presented with a newly diagnosed localized primary sarcoma, nine patients (7%) presented with a locally recurrent sarcoma previously treated at another institution, and 27 patients (20%) presented with metastatic disease. The median followup for surviving patients was 78 months (range, 20-420 months). The overall survival for patients with localized primary and locally recurrent synovial sarcoma was 51% at 10 years. Patients with localized synovial sarcomas less than 5 cm in longest diameter had a survival at 10 years of 88% compared with a 10-year survival of 38% and 8% for patients with sarcomas 5 to 10 cm and greater than 10 cm in longest diameter, respectively. Distal location (hands and feet) and histologic grade also were statistically significant predictors of patient survival for localized synovial sarcoma on univariate analysis. On multivariate analysis size greater than 10 cm and size 5 to 10 cm were associated with an 18-fold and a 3.1-fold increased risk of death compared with tumors smaller than 5 cm. Grade and location were not found to be independent predictors of survival on multivariate analysis. Primary tumor size and initial status at presentation were prognostic for survival and patients with synovial sarcomas larger than 5 cm or locally recurrent at presentation should be considered for more aggressive surgical and adjunctive radiotherapy or chemotherapy. C1 Massachusetts Gen Hosp, Orthopaed Oncol Serv, Boston, MA 02114 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mankin, HJ (reprint author), Massachusetts Gen Hosp, Orthopaed Oncol Serv, Gray 6 Orthopaed, Boston, MA 02114 USA. EM hmankin@partners.org NR 21 TC 26 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2004 IS 419 BP 155 EP 161 DI 10.1097/01.blo.0000111887.82016.b0 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 779VT UT WOS:000189322900025 PM 15021147 ER PT J AU Swarztrauber, K AF Swarztrauber, K TI Barriers to the management of patients with surgically remediable intractable epilepsy SO CNS SPECTRUMS LA English DT Review ID HEALTH-CARE; TEMPORAL-LOBE; UNITED-STATES; ADOLESCENTS; PHYSICIANS; CHILDREN; ACCESS; COMMUNICATION; PREFERENCES; PERCEPTIONS AB It is estimated that only a small proportion of patients with surgically remediable intractable epilepsy receive surgical treatment. There are multiple reasons why this is the case. Patients with intractable epilepsy are sometimes severely disabled and disability can create barriers to getting recommended care. Patients with epilepsy are not well informed about their condition and the available treatments. The incidence of epilepsy is similar in minority populations, and surgically remediable epilepsy frequently presents in adolescence. Nevertheless, these vulnerable populations have specific barriers to receiving epilepsy care, which are often not addressed. In addition, despite scientific evidence for the benefits of the surgical treatment of epilepsy, many healthcare providers do not recommend or adequately discuss surgery with patients. Solutions to these barriers will require interventions that result in informed and capable patients who actively participate in their care and healthcare providers who practice culturally sensitive, recommended care. C1 Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Portland Vet Affairs Med Ctr, Hlth Serv Res, Parkinsons Dis Res Educ & Clin Ctr, Portland, OR USA. RP Swarztrauber, K (reprint author), Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. EM swarztra@ohsu.edu FU NINDS NIH HHS [U01-NS42372] NR 54 TC 9 Z9 9 U1 7 U2 8 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD FEB PY 2004 VL 9 IS 2 BP 146 EP 152 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 895VA UT WOS:000226890700017 PM 14999170 ER PT J AU Caplan, D AF Caplan, D TI The neuro in cognitive neuropsychology SO COGNITIVE NEUROPSYCHOLOGY LA English DT Article C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dcaplan@partners.org NR 0 TC 1 Z9 1 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0264-3294 J9 COGN NEUROPSYCHOL JI Cogn. Neuropsychol. PD FEB PY 2004 VL 21 IS 1 BP 17 EP 20 DI 10.1080/02643290342000140 PG 4 WC Psychology; Psychology, Experimental SC Psychology GA 763YH UT WOS:000188127700002 PM 21038183 ER PT J AU Kalish, LA Buczynski, B Connell, P Gemmel, A Goertz, C Macklin, EA Pian-Smith, M Stevens, S Thompson, J Valaskatgis, P Wayne, PM Zusman, RM AF Kalish, LA Buczynski, B Connell, P Gemmel, A Goertz, C Macklin, EA Pian-Smith, M Stevens, S Thompson, J Valaskatgis, P Wayne, PM Zusman, RM TI Stop Hypertension with the Acupuncture Research Program (SHARP): clinical trial design and screening results SO CONTROLLED CLINICAL TRIALS LA English DT Article DE acupuncture; blood pressure; hypertension; randomized clinical trial; traditional Chinese medicine ID QUALITY-OF-LIFE; BLOOD-PRESSURE; RISK-FACTORS; ARTERIAL-HYPERTENSION; ALTERNATIVE MEDICINE; HEALTH; PLACEBO; POPULATION; THERAPY; EFFICACY AB Hypertension is a major public health problem with serious medical and financial consequences. Barriers to successful conventional pharmacological treatment include side effects, out-of-pocket expenses, patient noncompliance and insufficient dosages. Acupuncture has been studied as an alternative therapy for controlling blood pressure (BP) but previous studies have serious methodological limitations. This paper describes the design of the Stop Hypertension with the Acupuncture Research Program (SHARP) trial, a pilot randomized clinical trial designed to gather preliminary data regarding the efficacy of traditional Chinese medicine (TCM)based acupuncture for control of essential hypertension. The design of the SHARP trial balanced rigorous clinical trial methodology with principles of TCM. Eligible participants had systolic BP (SBP) 140-179 mm Hg and diastolic BP (DBP) 90-109 mm Hg in the absence of antihypertensive therapy. Following screening, participants were randomized to one of three groups: individualized, standardized or control acupuncture. Treatments were designed according to principles of TCM; nonspecific effects associated with the interventions were standardized across the randomized groups. For individualized acupuncture, points were tailored to each participant. Standardized acupuncture used a prespecified set of points. The invasive sham control acupuncture regimen was designed to be non-active. Each participant received a "prescription" for individualized acupuncture from an acupuncturist who was masked to treatment assignment, and was subsequently treated by an independent acupuncturist. Patients and those assessing BP were masked to treatment group. Acupuncture was delivered twice a week for 6 weeks. Follow-up visits were every 2 weeks to week 10 and then at months 4, 6, 9 and 12. The primary endpoint will be change in SBP from baseline to 10 weeks. DBP, BP trajectories over the 12-month follow-up and antihypertensive medication requirements will also be examined. Initial contact was documented for 1442 prospective participants from March 2001 to April 2002; 424 provided informed consent and 192 were ultimately randomized. (C) 2004 Elsevier Inc. All rights reserved. C1 New England Res Inst, Watertown, MA 02472 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Med Serv, Dept Med,Div Hypertens & Vasc Med,Cardiac Unit, Boston, MA USA. Natl Ctr Complementary & Alternat Med, NIH, Bethesda, MD USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. Marblehead Holist Hlth Consultants, Marblehead, MA USA. New England Sch Acupuncture, Watertown, MA USA. RP Kalish, LA (reprint author), Childrens Hosp, Clin Res Program, 300 Longwood Ave, Boston, MA 02115 USA. EM leslie.kalish@childrens.har-vard.edu; emacklin@neri.org RI Macklin, Eric/E-2955-2013; OI Macklin, Eric/0000-0003-1618-3502; Goertz, Christine/0000-0002-4700-3669 FU NCCIH NIH HHS [U01 AT00210] NR 84 TC 27 Z9 28 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 2004 VL 25 IS 1 BP 76 EP 103 DI 10.1016/j.cct.2003.08.006 PG 28 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 809KR UT WOS:000220636100010 PM 14980754 ER PT J AU Rush, AJ Fava, M Wisniewski, SR Lavori, PW Trivedi, MH Sackeim, HA Thase, ME Nierenberg, AA Quitkin, FM Kashner, TM Kupfer, DJ Rosenbaum, JF Alpert, J Stewart, JW McGrath, PJ Biggs, MM Shores-Wilson, K Lebowitz, BD Ritz, L Niederehe, G AF Rush, AJ Fava, M Wisniewski, SR Lavori, PW Trivedi, MH Sackeim, HA Thase, ME Nierenberg, AA Quitkin, FM Kashner, TM Kupfer, DJ Rosenbaum, JF Alpert, J Stewart, JW McGrath, PJ Biggs, MM Shores-Wilson, K Lebowitz, BD Ritz, L Niederehe, G CA STAR D Investigators Grp TI Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design SO CONTROLLED CLINICAL TRIALS LA English DT Article DE major depressive disorder; antidepressants; cognitive therapy; randomized clinical trial; multistep multicenter clinical trial; utilization and costs ID MEDICATION ALGORITHM PROJECT; INTERACTIVE VOICE RESPONSE; MAJOR DEPRESSION; RECURRENT DEPRESSION; SYMPTOMATOLOGY IDS; COGNITIVE THERAPY; ECONOMIC BURDEN; RATING SCALE; HEALTH-CARE; DISORDERS AB STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants without sufficient improvement are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Dept Vet Affairs, Cooperat Studies Program, Palo Alto, CA USA. Stanford Univ, Palo Alto, CA 94304 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Univ Texas, SW Med Ctr, Dept Vet Affairs, Hlth Serv Res & Dev Serv, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. NIMH, Bethesda, MD 20892 USA. RP Rush, AJ (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM john.rush@utsouthwestern.edu RI Biggs, Dr. Melanie/C-1468-2010; McGrath, Patrick/I-6410-2013; OI McGrath, Patrick/0000-0001-7217-7321; Wisniewski, Stephen/0000-0002-3877-9860; Alpert, Jonathan/0000-0002-4332-908X; Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [MH-30915, N01-MH-90003] NR 70 TC 480 Z9 488 U1 4 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD FEB PY 2004 VL 25 IS 1 BP 119 EP 142 DI 10.1016/S0197-2456(03)00112-0 PG 24 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 809KR UT WOS:000220636100012 PM 15061154 ER PT J AU Fink, H Yasuhara, S Blobner, M Martyn, JAJ AF Fink, H Yasuhara, S Blobner, M Martyn, JAJ TI Up-regulation of acetylcholine receptors during subchronic infusion of pancuronium is caused by a posttranscriptional mechanism related to disuse SO CRITICAL CARE MEDICINE LA English DT Article ID CRITICALLY ILL PATIENTS; D-TUBOCURARINE; NEUROMUSCULAR-JUNCTIONS; ELECTRICAL-ACTIVITY; GENE-EXPRESSION; IN-VIVO; MUSCLE; RAT; NUMBER; DEGRADATION AB Objective: Contrasting with the classic theory that competitive block of the acetylcholine receptor induces up-regulation of the receptor, recent studies show that irreversible block of acetylcholine receptors with alpha-bungarotoxin decreases acetylcholine receptor number within hours. This study investigated the early effects of competitive acetylcholine receptor block with the reversible, competitive muscle relaxant, pancuronium. Design: Prospective, randomized, placebo-controlled experimental study. Subjects: Healthy adult Sprague-Dawley rats. Setting: Animal laboratory in a university hospital. Interventions: After internal review board approval, Sprague-Dawley rats were anesthetized and received pancuronium at a rate to completely suppress neuromuscular twitch. The control group received saline. Infusion times were 0, 3, 6, or 12 hrs (n = 8 per group). One sciatic nerve was stimulated to induce muscle twitch, and the other nerve remained unstimulated. Total acetylcholine receptor expression, as well as expression of messenger RNA of the five subunits, was assayed. Measurements and Main Results: There were no differences in acetylcholine receptor number between groups at time points 0, 3, and 6 hrs. At 12 hrs, acetylcholine receptor numbers in both the stimulated (35.2 +/- 4.8 fmol acetylcholine receptor/mg protein) and nonstimulated (38.3 +/- 4.8) pancuronium group, as well as the nonstimulated control saline group (37.5 +/- 4.6), were significantly increased compared with stimulated controls (27.6 +/- 4.0). Pancuronium did not potentiate the acetylcholine receptor up-regulation of the nonstimulated control group at 12 hrs. There were no changes in messenger RNA expression between groups. Conclusions: Infusion of the reversible competitive inhibitor pancuronium up to 12 hrs does not reduce acetylcholine receptor number and therefore contrasts with the irreversible acetylcholine receptor blocker alpha-bungarotoxin. This study documents that 12 hrs of disuse per se leads to an increased expression of the acetylcholine receptor number by a posttranscriptional mechanism that can be prevented by nerve-evoked muscle contraction. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Tech Univ Munich, Klinikum Rechts Isar, Anasthesiol Klin, D-8000 Munich, Germany. RP Fink, H (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM 55082-6, GM 61411-4, R01 GM 31569-19] NR 25 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2004 VL 32 IS 2 BP 509 EP 513 DI 10.1097/01.CCM.0000109445.38396.F5 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 774ME UT WOS:000188982600028 PM 14758171 ER PT J AU Minneci, PC Deans, KJ Banks, SM Eichacker, PQ Natanson, C AF Minneci, PC Deans, KJ Banks, SM Eichacker, PQ Natanson, C TI Should we continue to target the platelet-activating factor pathway in septic patients? SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID TUMOR-NECROSIS-FACTOR; PLACEBO-CONTROLLED TRIAL; INTERLEUKIN-1 RECEPTOR ANTAGONIST; INFLAMMATORY RESPONSE SYNDROME; CONTROLLED MULTICENTER TRIAL; FACTOR ANTIBODY-FRAGMENT; PHASE-II TRIAL; DOUBLE-BLIND; SEVERE SEPSIS; MONOCLONAL-ANTIBODY C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Surg, Cambridge, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Minneci, PC (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 38 TC 12 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2004 VL 32 IS 2 BP 585 EP 588 DI 10.1097/01.CCM.0000110730.38696.9C PG 4 WC Critical Care Medicine SC General & Internal Medicine GA 774ME UT WOS:000188982600041 PM 14758184 ER PT J AU Rual, JF Hill, DE Vidal, M AF Rual, JF Hill, DE Vidal, M TI ORFeome projects: gateway between genomics and omics SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID CAENORHABDITIS-ELEGANS; EXPERIMENTAL-VERIFICATION; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL ANNOTATION; SYSTEMS BIOLOGY; DNA CLONING; HUMAN GENES; YEAST; MOUSE; TRANSCRIPTOME AB The availability of entire genome sequences is expected to revolutionize the way in which biology and medicine are conducted for years to come. However, achieving this promise still requires significant effort in the areas of gene annotation, cloning and expression of thousands of known and heretofore unknown protein-encoding genes. Traditional technologies of manipulating genes are too cumbersome and inefficient when one is dealing with more than a few genes at a time. Entire libraries composed of all protein-encoding open reading frames (ORFs) cloned in highly flexible vectors will be needed to take full advantage of the information found in any genome sequence. The creation of such ORFeome resources using novel technologies for cloning and expressing entire proteomes constitutes an effective gateway from whole genome sequencing efforts to downstream 'omics' applications. C1 Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Ctr Canc Syst Biol, 44 binney St, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Hill, David/B-6617-2011; OI Rual, Jean-Francois/0000-0003-4465-8819 FU NCI NIH HHS [7R33CA81568-02]; NHGRI NIH HHS [5R01HG01715-02] NR 44 TC 48 Z9 49 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD FEB PY 2004 VL 8 IS 1 BP 20 EP 25 DI 10.1016/j.cbpa.2003.12.002 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 780EH UT WOS:000189359000005 PM 15036152 ER PT J AU Pearlberg, J LaBaer, J AF Pearlberg, J LaBaer, J TI Protein expression clone repositories for functional proteomics SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID GENOME SEQUENCE VARIATION; RECOMBINATIONAL CLONING; CAENORHABDITIS-ELEGANS; FLEXGENE REPOSITORY; MEDICINE; BIOLOGY; RESOURCE; PROJECT; LAMBDA; GENES AB The information generated from the sequence of the human genome has inspired efforts to systematically develop organized collections of human cDNA clones for use in expression screens in mammalian cells. These high-throughput cloning initiatives offer significant advantages over the cDNA libraries that have been used in the past, including greater experimental flexibility, immediate identification of hits, information regarding all tested proteins (even for those giving no response) and eventually more comprehensive coverage. Some of the lessons learned and the considerations that underlie the creation of genome-wide cDNA repositories are discussed here. Although still inchoate, these resources are already impacting the manner in which high-throughput functional screens are performed. C1 Harvard Inst Proteom, Cambridge, MA 02141 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. RP Pearlberg, J (reprint author), Harvard Inst Proteom, 320 Charles St, Cambridge, MA 02141 USA. EM josh@hms.harvard.edu NR 38 TC 9 Z9 10 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD FEB PY 2004 VL 8 IS 1 BP 98 EP 102 DI 10.1016/j.cbpa.2003.12.010 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 780EH UT WOS:000189359000016 PM 15036163 ER PT J AU Whitney, JB Ruprecht, RM AF Whitney, JB Ruprecht, RM TI Live attenuated HIV vaccines: pitfalls and prospects SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE live attenuated SIV; live attenuated HIV; immunity; nef; SHIV; correlates of protection ID SIMIAN-IMMUNODEFICIENCY-VIRUS; LONG-TERM SURVIVOR; RHESUS MACAQUES; IN-VIVO; SOOTY MANGABEYS; NEF GENE; INTRACYTOPLASMIC DOMAIN; REPLICATIVE CAPACITY; DELETION MUTANT; IMMUNE-RESPONSE AB Purpose of review When simian immunodeficiency virus (SIV) deleted in the nef gene caused no disease in macaques and provided protection against wild-type SIV challenge, hopes were high that the removal of nef would convert a pathogenic immunodeficiency virus into a live attenuated vaccine. We seek to highlight recent studies focused on several major issues regarding live attenuated AIDS viruses as vaccine candidates: (1) safety, (2) efficacy, (3) the correlates of immune protection, and (4) the molecular determinants for lentiviral virulence or attenuation. Recent findings Nef-deletion mutants have retained virulence; compared with wild-type SIV, disease progression was slowed but not abrogated. After long-term observation, all adult macaques given SIVmac239Delta3 exhibited immune dysfunction; over 50% had T-cell depletion, and 18% developed AIDS. Vaccine efficacy has been disappointing, with limited or no cross-protection and no protection against homologous virus challenge years after initial vaccination. To date, the correlates of protective immunity have defied precise definition; no dominant mechanism has yet emerged. Data from passive serum transfer and CD8+ T-cell depletion studies have raised the possibility that alternate mechanism of protection may be operative. Due to relentless viral replication and continuous selective pressure, initially benign viruses can generate virulent progeny with unpredictable genotypes. Summary Neither safety nor efficacy of the current live attenuated primate immunodeficiency virus vaccines has withstood the test of time. However, such viruses are invaluable tools to address two key questions: (1) what are the correlates of protection, and (2) what are the molecular determinants of viral immunopathogenesis? C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, JFB-809,44 Binney St, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu NR 81 TC 70 Z9 74 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD FEB PY 2004 VL 17 IS 1 BP 17 EP 26 DI 10.1097/01.qco.0000113644.29255.92 PG 10 WC Infectious Diseases SC Infectious Diseases GA 803RN UT WOS:000220248300003 PM 15090885 ER PT J AU Dickson, B Walsh, CA AF Dickson, B Walsh, CA TI Development - Editorial overview SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Editorial Material C1 Austrian Acad Sci, IMBA, A-1030 Vienna, Austria. Harvard Univ, Sch Med, Howard Hughes Med Inst, BIDMC, Boston, MA 02115 USA. RP Dickson, B (reprint author), Austrian Acad Sci, IMBA, Dr Bohr Gasse 7, A-1030 Vienna, Austria. EM dickson@imba.oeaw.ac.at; cwalsh@bidmc.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 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 2004 VL 14 IS 1 BP 1 EP 5 DI 10.1016/j.conb.2004.01.016 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 803HI UT WOS:000220221800001 PM 15018931 ER PT J AU Omer, A Duvivier-Kali, VF Aschenbach, W Tchipashvili, V Goodyear, LJ Weir, GC AF Omer, A Duvivier-Kali, VF Aschenbach, W Tchipashvili, V Goodyear, LJ Weir, GC TI Exercise induces hypoglycemia in rats with islet transplantation SO DIABETES LA English DT Article ID GLUCAGON-SECRETION; PANCREATIC-ISLETS; PLASMA-GLUCOSE; CELL RESPONSES; ALPHA-CELL; INSULIN; LANGERHANS; HUMANS; TERM; MICE AB Recently, islet transplantation in patients with type I diabetes has had greater success than in the past, but the important question of whether the kinetics of islet secretion are able to accommodate the metabolic demands of special conditions such as exercise remains unanswered. Syngeneic rat islets (4,000 islet equivalents/rat) were transplanted into the liver, kidney, and peritoneal cavity (encapsulated or nonencapsulated) of rats with streptozocin-induced diabetes. Normoglycemic transplanted rats and age-matched controls were subjected to 30 min of moderate exercise on a treadmill 5 weeks after transplantation. Although control rats maintained near normoglycemia during and after exercise, the rats with islet transplants had significantly lower blood glucose levels. For the rats with islets in the liver, increased C-peptide levels were found at 30 min (790 +/- 125 and 1,450 +/- 250 pmol/l at 0 and 30 min, respectively; P < 0.01), whereas a decrease was found in controls and in rats with islets transplanted into the peritoneal cavity or under the kidney capsule. Moreover, increased glucagon levels were found after exercise in the rats with islets transplanted into the liver (62 +/- 6, 165 +/- 29, 155 +/- 27, and 97 +/- 13 pg/ml at 0, 30, 60, and 90 min, respectively; P < 0.05), whereas no changes in glucagon levels were observed in controls. In conclusion, moderate exercise caused hypoglycemia in rats with islet transplants in different sites including liver, kidney, and peritoneal cavity. C-peptide and glucagon responses to exercise were very different in rats with transplanted islets compared with controls. This islet dysfunction led to exercise-induced hypoglycemia. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. Joslin Diabet Ctr, Metab Sect, Boston, MA 02215 USA. RP Omer, A (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM abdulkadir.omer@joslin.harvard.edu FU NIAMS NIH HHS [R01-AR-42238]; NIDDK NIH HHS [DK-36836, DK-59769, R01-DK-50657] NR 24 TC 17 Z9 18 U1 0 U2 2 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 2004 VL 53 IS 2 BP 360 EP 365 DI 10.2337/diabetes.53.2.360 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770PQ UT WOS:000188739600012 PM 14747286 ER PT J AU Nikolic, B Takeuchi, Y Leykin, I Fudaba, Y Smith, RN Sykes, M AF Nikolic, B Takeuchi, Y Leykin, I Fudaba, Y Smith, RN Sykes, M TI Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity SO DIABETES LA English DT Article ID BONE-MARROW-TRANSPLANTATION; DONOR-SPECIFIC TOLERANCE; CLASS-II MOLECULES; LARGE-ANIMAL MODEL; T-CELL TOLERANCE; NOD MICE; COSTIMULATORY BLOCKADE; RECURRENT AUTOIMMUNITY; ISLET TRANSPLANTATION; LYMPHOHEMATOPOIETIC CHIMERISM AB Bone marrow transplantation from diabetes-resistant strains with complete replacement of the recipient immune system by the allogeneic donor has led to tolerance to donor islets and cure of diabetes in a mouse model of type 1 diabetes. However, the ability to tolerize host T-cells of diabetic NOD mice is unknown. We demonstrate that nonmyeloablative conditioning achieves mixed hematopoietic chimerism across major histocompatibility complex (MHC) barriers in spontaneously diabetic NOD mice. This conditioning preserves alloreactive and autoreactive diabetogenic host NOD T-cells, but when mixed chimerism was established, diabetic NOD mice accepted donor-type allogeneic islet grafts and were cured of diabetes, despite a significant recipient T-cell contribution. Furthermore, induction of mixed chimerism permitted acceptance of NOD islet grafts, demonstrating reversal of autoimmunity. Allogeneic bone marrow transplantation was critical for tolerization of diabetogenic and alloreactive host T-cells. Thus, mixed hematopoietic chimerism induces tolerance to donor islets and reverses established autoimmunity in diabetic NOD mice. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, MGH East,Bldg 149-5102,13th St, Boston, MA 02129 USA. EM megan.sykes@tbre.mgh.harvard.edu FU NIDDK NIH HHS [1K08DK59919] NR 45 TC 62 Z9 66 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2004 VL 53 IS 2 BP 376 EP 383 DI 10.2337/diabetes.53.2.376 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770PQ UT WOS:000188739600014 PM 14747288 ER PT J AU Pezzolesi, MG Nam, M Nagase, T Klupa, T Dunn, JS Mlynarski, WM Rich, SS Warram, JH Krolewski, AS AF Pezzolesi, MG Nam, M Nagase, T Klupa, T Dunn, JS Mlynarski, WM Rich, SS Warram, JH Krolewski, AS TI Examination of candidate chromosomal regions for type 2 diabetes reveals a susceptibility locus on human chromosome 8p23.1 SO DIABETES LA English DT Article ID GENOME-WIDE SEARCH; MELLITUS GENETICS FUSION; INDEPENDENT REPLICATION; MEXICAN-AMERICANS; FINNISH FAMILIES; LINKAGE ANALYSIS; PIMA-INDIANS; SIB PAIRS; GENES; SCAN AB In a panel of large Caucasian pedigrees, we genotyped markers in eight chromosomal regions previously reported as supporting linkage with type 2 diabetes. We previously reported significant linkage on chromosome 20q (maximum logarithm of odds score [MLS] = 2.79) in this panel. In the present analysis, candidate regions on 1q, 2q, 3q, 5q, 9q, and 10q yielded little evidence for linkage; a region on 2p (MLS = 1.64, P = 0.01 at position 9.0 cM) gave suggestive evidence of linkage; and a region on 8p (MLS = 3.67, P = 2.8 X 10(-5), at position 7.6 cM) gave significant evidence of linkage. Conditional analyses were performed for both 2p and 8p regions and the region reported on 20q. The MLS for 2p increased from 1.64 to 1.79 (empirical P = 0.142) when conditioned for heterogeneity on 20q. The case was similar for 8p, where the MLS increased from 3.67 to 4.51 (empirical P = 0.023) when conditioned on families without evidence of linkage at 20q. In conclusion, our data support a type 2 diabetes susceptibility locus on chromosome 8p that appears to be independent from other susceptibility loci. Although we were able to replicate linkage in our pedigrees on chromosome 2p, we did not find evidence of linkage for regions on 1q, 2q, 3q, 5q, 9q, or 10q. Diabetes 53:486-491, 2004. C1 Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Wake Forest Univ, Dept Publ Hlth Sci, Sch Med, Winston Salem, NC 27109 USA. Inha Univ, Dept Internal Med, Coll Med, Inchon, South Korea. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU NIDDK NIH HHS [DK-36836, DK-47475] NR 41 TC 19 Z9 21 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2004 VL 53 IS 2 BP 486 EP 491 DI 10.2337/diabetes.53.2.486 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770PQ UT WOS:000188739600028 PM 14747302 ER PT J AU McKeown, NM Meigs, JB Liu, S Saltzman, E Wilson, PWF Jacques, PF AF McKeown, NM Meigs, JB Liu, S Saltzman, E Wilson, PWF Jacques, PF TI Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort SO DIABETES CARE LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; DENSITY-LIPOPROTEIN CHOLESTEROL; CARDIOVASCULAR-DISEASE RISK; CORONARY-HEART-DISEASE; DIETARY GLYCEMIC LOAD; POSTMENOPAUSAL WOMEN; FIBER INTAKE; HEALTH-PROFESSIONALS; DIABETES-MELLITUS; PHYSICAL-ACTIVITY AB OBJECTIVE - The aim of this study was to examine the relation between carbohydrate-related dietary factors, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort. RESEARCH DESIGN AND METHODS - We examined cross-sectional associations between carbohydrate-related dietary factors, insulin resistance, and the prevalence of the metabolic syndrome in 2,834 subjects at the fifth examination (1991-1995) of the Framingham Offspring Study. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the following formula (fasting plasma insulin X plasma glucose)/22.5. The metabolic syndrome was defined using the National Cholesterol Education Program criteria. RESULTS - After adjustment for potential confounding variables, intakes of total dietary fiber, cereal fiber, fruit fiber, and whole grains were inversely associated, whereas glycemic index and glycemic load were positively associated with HOMA-IR. The prevalence of the metabolic syndrome was significantly lower among those in the highest quintile of cereal fiber (odds ratio [OR] 0.62; 95% CI 0.45-0.86) and whole-grain (0.67; 0.48-0.91) intakes relative to those in the lowest quintile category after adjustment for confounding lifestyle and dietary factors. Conversely, the prevalence of the metabolic syndrome was significantly higher among individuals in the highest relative to the lowest quintile category of glycemic index (1.41; 1.04-1.91). Total carbohydrate, dietary fiber, fruit fiber, vegetable fiber, legume fiber, glycemic load, and refined grain intakes were not associated with prevalence of the metabolic syndrome. CONCLUSIONS - Whole-grain intake, largely attributed to the cereal fiber, is inversely associated with HOMA-IR and a lower prevalence of the metabolic syndrome. Dietary glycemic index is positively associated with HOMA-IR and prevalence of the metabolic syndrome. Given that both a high cereal fiber content and lower glycemic index are attributes of whole-grain foods recommendation to increase whole-grain intake may reduce the risk of developing the metabolic, syndrome. C1 Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Program Epidemiol, Boston, MA 02111 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Med Univ S Carolina, Dept Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Jacques, PF (reprint author), Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Program Epidemiol, Boston, MA 02111 USA. EM paul.jacques@tufts.edu RI Liu, Simin/I-3689-2014 OI Liu, Simin/0000-0003-2098-3844 FU NHLBI NIH HHS [N01-HC-25195] NR 62 TC 364 Z9 385 U1 0 U2 20 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 2004 VL 27 IS 2 BP 538 EP 546 DI 10.2337/diacare.27.2.538 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 770PU UT WOS:000188739900039 PM 14747241 ER PT J AU Grant, RW Cagliero, E Dubey, AK Gildesgame, C Chueh, HC Barry, MJ Singer, DE Nathan, DM Meigs, JB AF Grant, RW Cagliero, E Dubey, AK Gildesgame, C Chueh, HC Barry, MJ Singer, DE Nathan, DM Meigs, JB TI Clinical inertia in the management of Type 2 diabetes metabolic risk factors SO DIABETIC MEDICINE LA English DT Article DE cardiovascular disease; diabetes mellitus; hyperlipidaemia; hypertension; physician practice patterns; practice guidelines ID DENSITY LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; RANDOMIZED-TRIAL; MELLITUS; CARE; COMPLICATIONS; HYPERTENSION; EFFICACY; PLASMA AB Aims Delays in the initiation and intensification of medical therapy may be one reason patients with diabetes do not reach evidence-based goals for metabolic control. We assessed intensification of medical therapy over time, comparing the management of hyperglycaemia, hypertension, and hyperlipidaemia. Methods Prospective cohort study of 598 adults with Type 2 diabetes receiving primary care in an academic medical centre from May 1997 to April 1999. We assessed whether patients failing to achieve standard treatment goals for haemoglobin A(1c) (HbA(1c)), systolic blood pressure (SBP), or low density lipoprotein (LDL) cholesterol when last measured during 12 months (Year 1, 5/97-4/98) had increases in their corresponding medical regimen during the following 12 months (Year 2, 5/98-4/99). Results Among untreated patients in Year 1, seven of 12 (58%) of those above goal for HbA(1c) were initiated on medical therapy in Year 2, compared with 16 of 48 (34%) above SBP goal (P = 0.02) and 26 of 115 (23%) above LDL cholesterol goal (P = 0.02). Among patients on therapy and above goal, 124 of 244 (51%) patients with elevated HbA(1c) had their regimen increased in Year 2, compared with 85 of 282 (30%) with elevated SBP (P < 0.001) and 22 of 79 (30%) with elevated LDL cholesterol (P < 0.001). From Year 1 to Year 2 there was a decline in the overall proportion of patients above goal for LDL cholesterol (from 58% to 45%, P = 0.002) but not for HbA(1c) or blood pressure. Conclusions Greater initiation and intensification of pharmaceutical therapy, particularly for elevated blood pressure or cholesterol, may represent a specific opportunity to improve metabolic control in Type 2 diabetes. C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Comp Sci Lab, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin Res Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Grant, RW (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM rgrant@partners.org OI Grant, Richard/0000-0002-6164-8025 FU NCRR NIH HHS [RR01066]; PHS HHS [2-T3211001-14] NR 25 TC 96 Z9 97 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD FEB PY 2004 VL 21 IS 2 BP 150 EP 155 DI 10.1111/j.1464-5491.2004.01095.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 773RU UT WOS:000188937200007 PM 14984450 ER PT J AU Heine, RJ Balkau, B Ceriello, A Del Prato, S Horton, ES Taskinen, MR AF Heine, RJ Balkau, B Ceriello, A Del Prato, S Horton, ES Taskinen, MR TI What does postprandial hyperglycaemia mean? SO DIABETIC MEDICINE LA English DT Article DE Type 2 diabetes; postprandial glucose; insulin resistance; postprandial lipids; cardiovascular disease; triglycerides ID CARDIOVASCULAR-DISEASE; DIABETES-MELLITUS; BLOOD-GLUCOSE; PLASMA-GLUCOSE; MICROVASCULAR COMPLICATIONS; INSULIN THERAPY; RISK; ASSOCIATION; MORTALITY; TOLERANCE AB Aims The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well-established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes. Results Post-prandial hyperglycaemia is a risk indicator for micro- and macrovascular complications, not only in patients with Type 2 diabetes but also in those with impaired glucose tolerance. In addition, the metabolic syndrome confers an increased risk of CVD morbidity and mortality. The debate focused on the relative contributions of postprandial hyperglycaemia, the metabolic syndrome and, in particular, raised triglyceride levels in the postprandial state, to the development of cardiovascular complications of diabetes. Conclusions The panel recommended that in the prevention and management of microvascular complications of Type 2 diabetes, targeting both chronic and acute glucose fluctuations is necessary. Lowering the macrovascular risk also requires control of (postprandial) triglyceride levels and other components of the metabolic syndrome. C1 Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, Ctr Diabet, NL-1007 MB Amsterdam, Netherlands. INSERM, U258, Villejuif, France. Univ Udine, Dept Pathol & Med Expt & Clin, Chair Internal Med, I-33100 Udine, Italy. Univ Pisa, Sect Diabet, Pisa, Italy. Joslin Diabet Ctr, Boston, MA 02215 USA. Helsinki Univ Hosp, Dept Med, Helsinki, Finland. RP Heine, RJ (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, Ctr Diabet, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM rj.heine@vumc.nl RI Del Prato, Stefano/K-3405-2016 OI Del Prato, Stefano/0000-0002-5388-0270 NR 31 TC 83 Z9 86 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD FEB PY 2004 VL 21 IS 3 BP 208 EP 213 DI 10.1111/j.1464-5491.2004.01149.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 775QM UT WOS:000189053100002 PM 15008828 ER PT J AU Szyfelbein, WM Baker, PM Bell, DA AF Szyfelbein, WM Baker, PM Bell, DA TI Superficial endometriosis of the cervix: A source of abnormal glandular cells on cervicovaginal smears SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article DE cervicovaginal smear; atypical glandular cells of undetermined; significance; superficial endometriosis of the cervix ID ADENOCARCINOMA IN-SITU; BETHESDA SYSTEM; UTERINE CERVIX; FEATURES AB Superficial endometriosis of the cervix, a benign process which may be associated with atypical glandular cells of undetermined significance (AGUS) on cervicovaginal (CV) smears, is becoming increasingly recognized on colposcopic examination. This study details the clinical, cytologic, and histology features of six cases of superficial cervical endometriosis. All CV smears featured atypical endocervical-like columnar cells in sheets and strips as well as cells with endometrial characteristics including solid cohesive, crowded, overlapping glandular groups, loss of cellular polarity, and a frequent ragged 'feathered" edge appearance with protruding nuclei, occasional rosette formations, and endometrial stroma. Recognition of endometrial stroma in continuity with groups of cells with these features on CV smears may suggest the diagnosis of this benign condition. However, the cytologic features of endometriosis show sufficient overlap with those of precancerous and cancerous glandular lesions that many of these cases will continue to be diagnosed as "atypical glandular cells." (C) 2004 Wiley-Liss, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Hlth Sci Ctr, Dept Pathol, Winnipeg, MB, Canada. RP Bell, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Pathol, James Homer Wright Pathol Labs, Warren 105,32 Fruit St, Boston, MA 02114 USA. EM dbell@partners.org NR 11 TC 7 Z9 7 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD FEB PY 2004 VL 30 IS 2 BP 88 EP 91 DI 10.1002/dc.10418 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 770PK UT WOS:000188739000004 PM 14755757 ER PT J AU Parker, EM Foti, JA Wilbur, DC AF Parker, EM Foti, JA Wilbur, DC TI FocalPoint slide classification algorithms show robust performance in classification of high-grade lesions on SurePath liquid-based cervical cytology slides SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-of-Cytopathology CY NOV 05-09, 2002 CL SALT LAKE CITY, UTAH SP Amer Soc Cytopathol DE cervical cytology; automation; FocalPoint; AutoPap ID PRIMARY SCREENING SYSTEM; QC SYSTEM; SENSITIVITY; SMEARS; CANCER; TRIAL AB The FocalPoint Primary Screening System (FPPS) operates by assigning scores to each slide relative to the probability that an abnormality is present. This information ranks each slide within five "quintiles" (1 = highest risk, 5 = lowest risk) of the "review" population, allowing examining cytologists to understand the risk inherent in each slide. Such information helps to make the primary and quality control rescreening processes most efficient. This study examines the efficiency of AutoPap scoring and, thus, stratification of high-grade cases within a clinical trial setting. A total of 1,275 SurePath (Tri-Path, Burlington, NC) slides were screened on the FPPS. There were 124 high-grade cases in the set (32 HSIL, 5 AIS, and 87 cancers) as determined by cytologic truth adjudication. The efficiency of FPPS ranking was determined by analysis of the numbers of high-grade cases ranked into quintiles 1 (top 20%) and 1+2 (top 40%). FPPS places cases scored as "unsatisfactory" (HSIL, 3; Cancer, 18) into quintile 5 to ensure a manual review. These cases were excluded from the analysis. Overall, 58% of high-grade slides were classified as Q1 and 83% were classified as Q1 + Q2. For HSIL, 66% were classified as Q1 and 90% as Q1 + Q2. For Cancer, 59% were classified as Q1 and 84% as Q1 + Q2. No high-grade slides were ranked in the lower "no review" population (slides that would receive no manual examination). The results confirm the robust performance of the FPPS classification algorithm. Far more high-grade slides are classified into the top two quintiles than would be expected by random chance alone (20% and 40%, respectively). These results validate the safety and effectiveness of this device on SurePath liquid-based slides. (C) 2004 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. ViaHlth, Cytopathol Unit, Rochester, NY USA. RP Wilbur, DC (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. NR 12 TC 13 Z9 13 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD FEB PY 2004 VL 30 IS 2 BP 107 EP 110 DI 10.1002/dc.10358 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 770PK UT WOS:000188739000009 PM 14755762 ER PT J AU Pavlova, MK Shea, SA Bromfield, EB AF Pavlova, MK Shea, SA Bromfield, EB TI Day/night patterns of focal seizures SO EPILEPSY & BEHAVIOR LA English DT Article DE circadian; seizures; temporal lobe epilepsy; time of day ID ENDOGENOUS CIRCADIAN-RHYTHM; MITOCHONDRIA DNA-DAMAGE; LIPID-PEROXIDATION; SLEEP STAGE; MELATONIN; ADENOSINE; EPILEPSY; RATS; MODEL; BRAIN AB Purpose. In many patients with epilepsy seizures occur with a day/night pattern. Our aims were to compare day/night patterns in seizure frequency among patients with different epileptogenic regions. Methods. We analyzed video-EEG recordings in 15 patients with temporal lobe (TLE) and 11 with extratemporal lobe epilepsy (XTLE). Each seizure was classified according to subject group (TLE vs XTLE), sleep/wake state, and time of day of seizure occurrence (grouped into 6 x 4-hour "bins"). Results. Of 90 seizures, 41 occurred in TLE and 49 in XTLE patients. There were day/night patterns of seizure occurrence in each group, with differences in the patterns between groups. In TLE, 50% of seizures occurred between the hours of 15:00 and 19:00 (17% would be expected by chance in each 4-hour "bin": F = 3.59, P < 0.006). In XTLE, there was a peak between 19:00 and 23:00 (47%: F = 4.72, P < 0.0018). The effect of time on seizures was least pronounced in the XTLE patients who had more than one epileptogenic region. The proportion of seizures occurring from sleep was significantly less in TLE (19%) than in XTLE patients (41%) [P < 0.04, Fisher's exact test]. Conclusions. There are clear day/night patterns of seizure occurrence in epilepsy, with differences in the patterns between TLE and XTLE. There is an additional interaction with sleep/wake state, with relatively few seizures occurring from sleep in TLE compared with XTLE. Thus, it appears that both sleep/wake state and day/night or circadian rhythms may affect seizure proclivity, with different effects depending on the location of the epileptogenic region. (C) 2003 Published by Elsevier Inc. C1 Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. Brigham & Womens Hosp, Sleep Disorders Res Program, BIDMC, Boston, MA 02115 USA. RP Pavlova, MK (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM mpavlova1@partners.org OI Shea, Steven/0000-0003-1949-0954 FU NHLBI NIH HHS [T32HL0790] NR 29 TC 52 Z9 52 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD FEB PY 2004 VL 5 IS 1 BP 44 EP 49 DI 10.1016/j.yebeh.2003.10.013 PG 6 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 771ZA UT WOS:000188814900008 PM 14751206 ER PT J AU Drezner, MK AF Drezner, MK TI Treatment of anticonvulsant drug-induced bone disease SO EPILEPSY & BEHAVIOR LA English DT Article DE anticonvulsant drugs; bone remodeling; osteopenia; osteoporosis; osteomalacia; vitamin D; bisphosphonates ID CONTROLLED THERAPEUTIC TRIAL; VITAMIN-D; CALCIUM-METABOLISM; INDUCED OSTEOMALACIA; ANTIEPILEPTIC DRUGS; PARATHYROID-HORMONE; EPILEPTIC PATIENTS; MINERAL DENSITY; PLASMA 25-HYDROXYVITAMIN-D; CHILDREN AB Although the pathophysiology of bone disease in patients treated with anticonvulsant drugs may vary, most affected patients have increased bone remodeling rather than decreased mineralization. Milder cases may show high bone turnover without significant loss of cortical or trabecular bone. Cases of intermediate severity may exhibit the characteristic features of a high-turnover osteopenia/osteoporosis, but some patients with severe bone disease may manifest the features of an osteomalacic disorder. Prophylactic vitamin D supplementation at doses tip to 2000 IU/day can be recommended for all patients on initiation of anticonvulsant therapy. A calcium intake of 600-1000 mg/day should also be ensured. If an osteopenic/osteoporotic disorder exists, treatment with 2000-4000 IU/day vitamin D is appropriate. Vitamin D doses of 5000-15,000 IU/day may be needed to treat osteomalacia. Conventional treatment with bisphosphonates may be needed when the response to vitamin D is inadequate. However, routine use of bisphosphonates in patients receiving long-term anticonvulsant therapy cannot at present be recommended. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Wisconsin, Sch Med, Dept Med, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Hosp, Ctr Geriatr Res Educ & Clin, Madison, WI 53792 USA. RP Drezner, MK (reprint author), Univ Wisconsin, Sch Med, Dept Med, 600 Highland Ave, Madison, WI 53792 USA. EM mkd@medicine.wisc.edu NR 49 TC 53 Z9 56 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD FEB PY 2004 VL 5 SU 2 BP S41 EP S47 DI 10.1016/j.yebeh.2003.11.028 PG 7 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 805ES UT WOS:000220350200007 PM 15123011 ER PT J AU Mazarati, AM Baldwin, R Klitgaard, H Matagne, A Wasterlain, CG AF Mazarati, AM Baldwin, R Klitgaard, H Matagne, A Wasterlain, CG TI Anticonvulsant effects of levetiracetam and levetiracetam-diazepam combinations in experimental status epilepticus SO EPILEPSY RESEARCH LA English DT Article DE status epilepticus; levetiracetam; diazepam; experimental model ID SUSTAINING STATUS EPILEPTICUS; TEMPORAL-LOBE EPILEPSY; ANTIEPILEPTIC DRUG LEVETIRACETAM; RAT PILOCARPINE MODEL; PARTIAL SEIZURES; DOUBLE-BLIND; EFFICACY; PROFILE; TRIAL; SAFETY AB Status epilepticus (SE) is a neurological emergency, with high mortality and high morbidity among survivors, and novel therapeutic agents are needed to improve this picture. We examined the effects of the antiepileptic drug levetiracetam (LEV) in an experimental model Of Self-sustaining status epilepticus (SSSE), induced in rats by electrical stimulation of the perforant path. LEV's unique spectrum of anticonvulsant activity, very high therapeutic index, and neuroprotective properties, make it a potentially interesting agent in the treatment of SE. Pretreatment with LEV intravenously reduced (30 mg/kg) or prevented (50-1000 mg/kg) the development of self-sustaining seizures. Treatment during the maintenance phase of SSSE diminished (at 200 mg/kg) or aborted seizures (in doses of 500 or 1000 mg/kg). Addition of LEV significantly enhanced the anticonvulsant effects of diazepam (DZP), even when both drugs where given in doses far below their therapeutic level. We conclude that LEV deserves further evaluation in the treatment of status epilepticus. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Calif Los Angeles, Geffen Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. UCB Bioprod SA, Pharma Sector, Preclin CNS Res, Braine LAlleud, Belgium. Univ Calif Los Angeles, Geffen Sch Med, Brain Res Inst, Los Angeles, CA USA. RP Mazarati, AM (reprint author), Univ Calif Los Angeles, Geffen Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. EM mazarati@ucla.edu FU NINDS NIH HHS [NS 13515, NS 43409] NR 30 TC 65 Z9 67 U1 2 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD FEB PY 2004 VL 58 IS 2-3 BP 167 EP 174 DI 10.1016/j.eplepsyres.2004.02.002 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 821ZC UT WOS:000221501000008 PM 15120747 ER PT J AU Givertz, MM Braunwald, E AF Givertz, MM Braunwald, E TI Neurohormones in heart failure: predicting outcomes, optimizing care SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID BRAIN NATRIURETIC PEPTIDE; TRIAL VAL-HEFT; NOREPINEPHRINE; VALSARTAN C1 Harvard Univ, Sch Med, Dept Med, Div Cardiovasc, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Braunwald, E (reprint author), TIMI Study Grp, 350 Longwood Ave 1st Floor, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 8 TC 12 Z9 12 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD FEB PY 2004 VL 25 IS 4 BP 281 EP 282 DI 10.1016/j.ehj.2003.12.013 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 802WR UT WOS:000220194100001 PM 14984914 ER PT J AU Dogan, I Dorgham, K Chang, HC Parizot, C Lemaitre, F Ferradini, L Reinherz, EL Debre, P Gorochov, G AF Dogan, I Dorgham, K Chang, HC Parizot, C Lemaitre, F Ferradini, L Reinherz, EL Debre, P Gorochov, G TI Phage-displayed libraries of peptide/major histocompatibility complexes SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE MHC; TCR; pepticle; phage display ID T-CELL RECEPTOR; CLASS-I COMPLEXES; FILAMENTOUS PHAGE; MHC COMPLEXES; LIGHT-CHAINS; SIDE-CHAINS; ANTIBODY; MOLECULE; BINDING; RECOGNITION AB Characterizing peptide epitopes targeted by major histocompatibility complex (MHC)restricted T cells of unknown specificity would have broad implications. In this article we introduce and validate an original phage-displayed library of noncovalent complexes of peptide and MHC (P/MHC). We show that soluble MHC molecules associate with peptides presented by a phage, thereby resulting in the formation of multivalent P/MHC phages. Complex formation is stabilized by the interaction of the soluble partner (MHC) with two components, peptide and beta2-microglobulin, both of which are covalently linked to the phage. As proof of concept, we have used this strategy to express peptide libraries in the context of H-2K(b). Using monoclonal antibody 25D (specific for ovalbumin/H-2K(b)) as a template to screen the library, we were able to select a variant epitope functionally and structurally related to the wild-type peptide. Interaction studies between monoclonal antibody 25D and cells suggest that the variant peptide has been selected on the basis of a decreased dissociation rate between the peptide/H-2K(b) complex and its ligand. A weak agonist of the N15 TCR (vesicular stomatitis virus/H-2K(b)-specific) was also isolated from another P/MHC library. This strategy opens up new perspectives for antigen discovery and the manipulation of T cell responses. C1 Hop La Pitie Salpetriere, CERVI, INSERM, U543, F-75013 Paris, France. Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Inst Pasteur, INSERM, U277, Unite Biol Mol Gene, F-75724 Paris, France. RP Gorochov, G (reprint author), Hop La Pitie Salpetriere, CERVI, INSERM, U543, 83 Bd Hop, F-75013 Paris, France. EM guy.gorochov@psl.ap-hop-paris.fr OI dorgham, karim/0000-0001-9539-3203 NR 34 TC 6 Z9 6 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2004 VL 34 IS 2 BP 598 EP 607 DI 10.1002/eji.200324721 PG 10 WC Immunology SC Immunology GA 774LF UT WOS:000188980400033 PM 14768065 ER PT J AU Park, S Horak, FB Kuo, AD AF Park, S Horak, FB Kuo, AD TI Postural feedback responses scale with biomechanical constraints in human standing SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE balance; equilibrium; posture; motor control; biomechanics ID PARKINSONIAN SUBJECTS; STEP INITIATION; MOVEMENTS; DYNAMICS; ANKLE; PARAMETERS; BALANCE; MUSCLES; MODEL; SET AB We tested whether human postural responses can be described in terms of feedback control gains, and whether these gains are scaled by the central nervous system to accommodate biomechanical constraints. A feedback control model can describe postural responses for a wide range of perturbations, but biomechanical constraints-such as on the torque that can be exerted on the ground-make a single set of feedback gains inappropriate for all perturbations. To observe how postural responses change with perturbation magnitude, we applied fast, backward perturbations of magnitudes 3-15 cm to 13 healthy young volunteers (4 men, 9 women, aged 20-32 years). We used a 3-segment, sagittal-plane biomechanical model and a linear state feedback controller to reproduce the observed postural responses. Optimization was used to identify the best-fit feedback control gains for each trial. Results showed that trajectories of joint angles and joint torques were scaled with perturbation magnitude. This scaling occurred gradually, rather than abruptly changing at magnitudes where biomechanical constraints became active. Feedback gains were found to fit reasonably well with data (R-2=0.92) and to be multivariate and heterogenic in character, meaning that the torque produced at any joint is generally a function of motions not only at the same joint, but other joints as well. Hip gains increased and ankle gains decreased nearly linearly with perturbation magnitude, in accordance with biomechanical limitations on ground reaction torque. These results indicate that postural adjustments can be described as a single feedback control scheme, with scalable heterogenic gains that are adjusted according to biomechanical constraints. C1 Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. Oregon Hlth Sci Univ, Inst Neurol Sci, Portland, OR 97201 USA. RP Park, S (reprint author), Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Room 421,243 Charles Str, Boston, MA 02114 USA. EM sukyung_park@meei.harvard.edu RI Park, Sukyung/C-1628-2011; Kuo, Arthur/L-3359-2013 OI Kuo, Arthur/0000-0001-5233-9709 FU NIA NIH HHS [R01AG06457]; NIDCD NIH HHS [R29DC0231201A1] NR 34 TC 129 Z9 133 U1 3 U2 22 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD FEB PY 2004 VL 154 IS 4 BP 417 EP 427 DI 10.1007/s00221-003-1674-3 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 769VJ UT WOS:000188670200005 PM 14618285 ER PT J AU Aiello, LP Cahill, MT Cavallerano, JD AF Aiello, LP Cahill, MT Cavallerano, JD TI Growth factors and protein kinase C inhibitors as novel therapies for the medical management diabetic retinopathy SO EYE LA English DT Review DE diabetic retinopathy; protein kinase C; vascular endothelial growth factor; growth factors ID INDUCED RETINAL NEOVASCULARIZATION; VASCULAR-PERMEABILITY FACTOR; PIGMENT EPITHELIAL-CELLS; FACTOR INDUCES EXPRESSION; FACTOR MESSENGER-RNA; HEPATOCYTE GROWTH; ENDOTHELIAL-CELL; IN-VIVO; MICROVASCULAR COMPLICATIONS; MACULAR EDEMA AB Diabetic retinopathy is a leading cause of acquired visual loss. Current treatment modalities are not effective in all cases and may have side effects. Investigation of the biochemical basis of diabetic retinopathy suggests that future treatments may reverse or halt the progression of diabetic retinopathy, or actually prevent the development of diabetic retinopathy. Pharmacological manipulation of protein kinase C and various growth factors may form the basis of future treaments for diabetic retinopathy. C1 Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM LPAiello@joslin.harvard.edu NR 88 TC 9 Z9 12 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD FEB PY 2004 VL 18 IS 2 BP 117 EP 125 DI 10.1038/sj.eye.6700585 PG 9 WC Ophthalmology SC Ophthalmology GA 770UU UT WOS:000188749800002 PM 14762400 ER PT J AU Yamashita, K McDaid, J Ollinger, R Tsui, TY Berberat, PO Usheva, A Csizmadia, E Smith, RN Soares, MP Bach, FH AF Yamashita, K McDaid, J Ollinger, R Tsui, TY Berberat, PO Usheva, A Csizmadia, E Smith, RN Soares, MP Bach, FH TI Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts SO FASEB JOURNAL LA English DT Article DE heme oxygenase-1; heart transplantation; tolerance; T cells ID ALLOREACTIVE T-CELLS; HUMAN-LYMPHOCYTES; OXIDATIVE STRESS; BILIRUBIN; OXYGENASE-1; REJECTION; ACTIVATION; DISEASE; PROTEIN; PROLIFERATION AB Biliverdin, a product of heme oxygenase-1 (HO-1) enzymatic action, is converted into bilirubin, which has been considered a waste product in the past. We now show that administration of biliverdin has a salutary effect in organ transplantation. A brief course of treatment with biliverdin leads to long-term survival of H-2 incompatible heart allografts. Furthermore, those recipients harboring long-surviving (>100 days) allografts were tolerant to donor antigens indicated by the acceptance of second donor strain hearts but not third-party grafts. Treatment with biliverdin decreased intragraft leukocyte infiltration and inhibited T cell proliferation. Likely related to tolerance induction, biliverdin interferes with T cell signaling by inhibiting activation of nuclear factor of activated T cells (NEAT) and nuclear factor kappaB (NF-kappaB), two transcription factors involved in interleukin-2 (IL-2) transcription and T cell proliferation, as well as suppressing Th1 interferon-gamma (IFN-gamma) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg,Immunobiol Res Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Immunobiol Res Ctr, Boston, MA 02215 USA. Univ Hong Kong, Med Ctr, Queen Mary Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. Inst Gulbenkian Ciencias, P-2781901 Oeiras, Portugal. RP Yamashita, K (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg,Immunobiol Res Ctr, 99 Brookline Ave, Boston, MA 02215 USA. EM kyamashi@bidmc.harvard.edu RI Ollinger, Robert/D-1538-2009; OI Soares, Miguel/0000-0002-9314-4833 NR 38 TC 134 Z9 140 U1 2 U2 11 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2004 VL 18 IS 2 BP 765 EP + DI 10.1096/fj.03-0839fje PG 16 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 806HM UT WOS:000220425000018 PM 14977878 ER PT J AU Oddsson, LIE Wall, C McPartland, MD Krebs, DE Tucker, CA AF Oddsson, LIE Wall, C McPartland, MD Krebs, DE Tucker, CA TI Recovery from perturbations during paced walking SO GAIT & POSTURE LA English DT Article DE balance; gait; perturbation; stability; vestibular ID POSTURAL RESPONSES; BALANCE; STANCE; STABILITY AB The aim of the current study was to develop a safe, standardized, stability test and to explore a set of metrics to characterize the recovery of gait stability in healthy individuals following a single mechanical perturbation during steady locomotion. Balance perturbations were mechanically applied to the right foot of 12 healthy subjects during paced walking by translating a platform embedded in a 12 m walkway diagonally (+ 45/-135degrees) relative to the direction of travel approximately 200 ms after heel strike. We examined the medio-lateral (ML) displacement of the sternum before, during and after the platform translation. Measurements of ML position of the right and left shanks in relation to the position of the sternum were used as step-by-step estimates of the moment arm controlling ML motion of the body. We hypothesized that when gait is perturbed in the single stance phase of the step cycle via a translation of the support surface, a series of steps after the perturbation input will be altered reflecting an effort by the CNS to maintain the center of mass (COM) within the base of support and to stabilize the upper body for continued gait. Specifically, if the foot is perturbed laterally during mid-stance a widening of the upcoming step will occur and if the foot is perturbed medially a narrowing of the upcoming step will occur. This behavior was frequent for most subjects. Recovery of non-perturbation behavior was achieved on the third step after the platform translation. An additional strategy was seen for some subjects during lateral perturbation inputs. Instead of widening the upcoming step, these subjects acquired the support to stabilize the body by putting their left foot down very quickly with minimal change in stance width. The recovery profiles of the sternum, though directionally asymmetric, were similar in shape among subjects and roughly proportional to the magnitude of the platform translation. Five to six steps were required for complete recovery in the subjects tested in this study. (C) 2003 Elsevier B.V. All rights reserved. C1 Boston Univ, Neuromuscular Res Ctr, Boston, MA 02215 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol,Jenks Vestibular Diagnost La, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biomot Lab, Dept Orthopaed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biomot Lab, MGH Inst Hlth Profess, Boston, MA 02114 USA. Boston Univ, Sargent Coll Hlth & Rehabil Sci, Boston, MA 02215 USA. RP Oddsson, LIE (reprint author), Boston Univ, Neuromuscular Res Ctr, 19 Deerfield St,4th Floor, Boston, MA 02215 USA. EM loddsson@bu.edu FU NCCIH NIH HHS [R21AT000553]; NIA NIH HHS [R01AG11255] NR 25 TC 37 Z9 37 U1 2 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD FEB PY 2004 VL 19 IS 1 BP 24 EP 34 DI 10.1016/S0966-6362(03)00008-0 PG 11 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 769KG UT WOS:000188648800004 PM 14741301 ER PT J AU El-Serag, HB Tran, T Everhart, JE AF El-Serag, HB Tran, T Everhart, JE TI Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma SO GASTROENTEROLOGY LA English DT Article ID NONALCOHOLIC FATTY LIVER; OF-VETERANS-AFFAIRS; UNITED-STATES; NATURAL-HISTORY; CANCER RISK; INSULIN-RESISTANCE; MELLITUS; STEATOHEPATITIS; CIRRHOSIS; HEPATITIS AB Background & Aims: An association between diabetes and chronic liver disease has been reported. However, the temporal relationship between these conditions remains unknown. Methods: We identified all patients with a hospital discharge diagnosis of diabetes between 1985 and 1990 using the computerized records of the Department of Veterans Affairs. We randomly assigned 3 patients without diabetes for every patient with diabetes. We excluded patients with concomitant liver disease. The remaining cohort was followed through 2000 for the occurrence of chronic nonalcoholic liver disease (CNLD) and hepatocellular carcinoma (HCC). Hazard rate ratios (HRR) were determined in Cox proportional hazard survival analysis. Results: The study cohort comprised 173,643 patients with diabetes and 650,620 patients without diabetes. Most were men (98%). Patients with diabetes were older (62 vs. 54 years) than patients without diabetes. The incidence of chronic nonalcoholic liver disease was significantly higher among patients with diabetes (incidence rate: 18.13 vs. 9.55 per 10,000 person-years, respectively, P < 0.0001). Similar results were obtained for HCC (incidence rate: 2.39 vs. 0.87 per 10,000 person-years, respectively, P < 0.0001). Diabetes was associated with an HRR of 1.98 (95% Cl: 1.88 to 2.09, P < 0.0001) of CNLD and an HRR of 2.16 (1.86 to 2.52, P < 0.0001) of hepatocellular carcinoma. Diabetes carried the highest risk among patients with longer than 10 years of follow-up. Conclusions: Among men with diabetes, the risk of CNLD and HCC is doubled. This increase in risk is independent of alcoholic liver disease, viral hepatitis, or demographic features. C1 Houston Dept Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX USA. Houston Dept Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NIDDK, Bethesda, MD 20892 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu NR 51 TC 551 Z9 569 U1 1 U2 18 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2004 VL 126 IS 2 BP 460 EP 468 DI 10.1053/j.gastro.2003.10.065 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 771XJ UT WOS:000188811100013 PM 14762783 ER PT J AU Gukovsky, I Cheng, JH Nam, KJ Lee, OT Lugea, A Fischer, L Penninger, JM Pandol, SJ Gukovskaya, AS AF Gukovsky, I Cheng, JH Nam, KJ Lee, OT Lugea, A Fischer, L Penninger, JM Pandol, SJ Gukovskaya, AS TI Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells SO GASTROENTEROLOGY LA English DT Article ID NF-KAPPA-B; PHOSPHOINOSITIDE 3-KINASE; TRYPSINOGEN ACTIVATION; INTRACELLULAR TRYPSINOGEN; INFLAMMATORY RESPONSE; CA2+ INFLUX; MAST-CELLS; MAP KINASE; CALCIUM; ENTRY AB Background & Aims: Early events in the pancreatic acinar cell critical for development of pancreatitis include activation of the transcription factor nuclear factor kappaB (NF-kappaB), abnormal Ca2+ responses, and trypsinogen activation. Mechanisms underlying these responses, which can be studied in isolated pancreatic acini stimulated with supraphysiologic doses of cholecystokinin (CCK-8), remain poorly understood. We here report that these responses are regulated by phosphatidylinositide 3-kinase (PI3K) gamma. Methods: To inactivate PI3K, we used mice deficient in the catalytic PI3Kgamma subunit p110gamma as well as the PI3K inhibitors LY294002 and wortmannin. We measured Ca2+ responses by using Fura-2, NF-kappaB-binding activity by electromobility shift assay, IkappaB degradation by Western blotting, and trypsinogen activation by fluorogenic assay. Results: CCK-induced intracellular Ca2+ mobilization, Ca2+ influx, trypsinogen, and NF-kappaB activation were all diminished in pancreatic acini isolated from p110gamma(-/-) mice. Both in mouse and rat acini, these responses were inhibited by the PI3K inhibitors. The Ca2+ signal and trypsinogen activation were similarly reduced in acini isolated from p110gamma(-/-) and p110gamma(+/-) mice compared with wild-type mice. By contrast, NF-kappaB activation was inhibited in p110gamma(-/-) acini but not in p110gamma(+/-) acini. These differences indicate that the mechanism of NF-kappaB regulation by PI3Kgamma differs from those for the Ca2+ and trypsinogen responses. CCK-induced responses in p110gamma(-/-) acini were all further inhibited by LY294002, indicating the involvement of other PI3K isoform(s), in addition to PI3Ky. Conclusions: The results show that key pathologic responses of the pancreatic acinar cell are regulated by PI3Kgamma and suggest an important role for this PI3K isoform in pancreatitis. C1 Univ Calif Los Angeles, W Los Angeles VA Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. Austrian Acad Sci, Inst Mol Biotechnol, Dept Med, A-1010 Vienna, Austria. RP Gukovsky, I (reprint author), Univ Calif Los Angeles, W Los Angeles VA Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Med, Bldg 258,Room 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM igukovsk@ucla.edu RI Penninger, Josef/I-6860-2013 OI Penninger, Josef/0000-0002-8194-3777 FU NIAAA NIH HHS [P50-AA11999]; NIDDK NIH HHS [DK59508] NR 62 TC 52 Z9 57 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2004 VL 126 IS 2 BP 554 EP 566 DI 10.1053/j.gastro.2003.11.017 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 771XJ UT WOS:000188811100022 PM 14762792 ER PT J AU Leung, FW AF Leung, FW TI The venerable nasogastric tube SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material ID UPPER-GASTROINTESTINAL-TRACT; RANDOMIZED CONTROLLED-TRIAL; RIGHT SUBCLAVIAN ARTERY; BLEEDING PEPTIC-ULCER; NATIONAL ASGE SURVEY; COLORECTAL SURGERY; ABDOMINAL-SURGERY; ROUTINE USE; HEMORRHAGE; ENDOSCOPY C1 Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr & Nursing Home, Med Serv, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Sepulveda Ambulatory Care Ctr & Nursing Home, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA USA. RP Leung, FW (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr & Nursing Home, Med Serv, Los Angeles, CA USA. NR 64 TC 6 Z9 6 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD FEB PY 2004 VL 59 IS 2 BP 255 EP 260 AR PII S0016-5107(03)02961-9 DI 10.1016/S0016-5107(03)02691-9 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 772ZA UT WOS:000188872100014 PM 14745400 ER PT J AU Lai, L Poneros, J Santilli, J Brugge, W AF Lai, L Poneros, J Santilli, J Brugge, W TI EUS-guided portal vein catheterization and pressure measurement in an animal model: a pilot study of feasibility SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID FINE-NEEDLE-ASPIRATION; BLOOD-FLOW; HYPERTENSION AB Background: The extrahepatic portal vein is inaccessible to direct catheterization. Methods: Because EUS can readily image the portal vein, the feasibility of EUS-guided portal vein catheterization by using a 22-gauge needle was studied in 7 normal pigs and 14 pigs in which portal hypertension was induced (7/14 anticoagulated). Results: Catheterization was not possible by EUS or transhepatic methods in, respectively, 3 and 5 animals. One anticoagulated animal had a small amount of periduodenal bleeding as a result of EUS catheterization. The mean normal portal vein pressure (1 standard deviation) as determined by EUS and transhepatic methods was, respectively, 20.3 (4) mm Hg and 20.4 (2) mm Hg. Injection of polyvinyl alcohol particles increased the portal vein pressure by 10.2 (11.59) mm Hg. There was a close correlation under all conditions between the mean portal vein pressures obtained by EUS and transhepatic catheterization (r = 0.91). Conclusions: EUS-guided portal vein catheterization appears to be feasible in an animal model and provides accurate pressure measurements. C1 Massachusetts Gen Hosp, Vasc Radiol & GI Unit, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Brugge, W (reprint author), Massachusetts Gen Hosp, GI Endoscopy Unit, Blake 452C, Boston, MA 02114 USA. NR 15 TC 38 Z9 39 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD FEB PY 2004 VL 59 IS 2 BP 280 EP 283 AR PII S0016-5107(03)02544-6 DI 10.1016/S0016-5107(03)02544-6 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 772ZA UT WOS:000188872100022 PM 14745408 ER PT J AU Fan, M Rhee, J St-Pierre, J Handschin, C Puigserver, P Lin, JD Jaeger, S Erdjument-Bromage, H Tempst, P Spiegelman, BM AF Fan, M Rhee, J St-Pierre, J Handschin, C Puigserver, P Lin, JD Jaeger, S Erdjument-Bromage, H Tempst, P Spiegelman, BM TI Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1 alpha: modulation by p38 MAPK SO GENES & DEVELOPMENT LA English DT Article DE PGC-1 alpha; Mybbp1a; mitochondria; repressor; p38 MAPK ID TRANSCRIPTIONAL COACTIVATOR PGC-1; PPAR-GAMMA COACTIVATOR-1; HEPATIC GLUCONEOGENESIS; GENE-EXPRESSION; MUSCLE-CELLS; ACTIVATION; BIOGENESIS; ADIPOCYTES; 1-ALPHA; CLONING AB The transcriptional coactivator PPAR gamma coactivator 1 alpha (PGG1alpha) is a key regulator of metabolic processes such as mitochondrial biogenesis and respiration in muscle and gluconeogenesis in liver. Reduced levels of PGC-1alpha in humans have been associated with type II diabetes. PGC-1alpha contains a negative regulatory domain that attenuates its transcriptional activity. This negative regulation is removed by phosphorylation of PGC-1alpha by p38 MAPK, an important kinase downstream of cytokine signaling in muscle and beta-adrenergic signaling in brown fat. We describe here the identification of p160 myb binding protein (p160(MBP)) as a repressor of PGC-1alpha. The binding and repression of PGC-1alpha by p160(MBP) is disrupted by p38 MAPK phosphorylation of PGC-1alpha. Adenoviral expression of p160(MBP) in myoblasts strongly reduces PGC-1alpha's ability to stimulate mitochondrial respiration and the expression of the genes of the electron transport system. This repression does not require removal of PGC-1alpha from chromatin, suggesting that p160(MBP) is or recruits a direct transcriptional suppressor. Overall, these data indicate that p160(MBP) is a powerful negative regulator of PGC-1alpha0 function and provide a molecular mechanism for the activation of PGC-1alpha by p38 MAPK. The discovery of p160(MBP) as a PGC-1alpha regulator has important implications for the understanding of energy balance and diabetes. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu RI Handschin, Christoph/E-6886-2015 OI Handschin, Christoph/0000-0003-0603-1097 FU NCI NIH HHS [P30 CA008748, P30 CA08748]; NEI NIH HHS [5T32EY07110, T32 EY007110]; NIDDK NIH HHS [DK54477, R01 DK054477, R56 DK054477] NR 30 TC 185 Z9 196 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2004 VL 18 IS 3 BP 278 EP 289 DI 10.1101/gad.1152204 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 774HC UT WOS:000188972900006 PM 14744933 ER PT J AU Schnelle, JF AF Schnelle, JF TI Determining the relationship between staffing and quality SO GERONTOLOGIST LA English DT Editorial Material C1 Univ Calif Los Angeles, Borun Ctr Gerontol Res, JHA, Reseda, CA 91335 USA. Univ Calif Los Angeles, Dept Med, Reseda, CA 91335 USA. VA Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. Jewish Home Aging, Reseda, CA USA. RP Schnelle, JF (reprint author), Univ Calif Los Angeles, Borun Ctr Gerontol Res, JHA, 7150 Tampa Ave, Reseda, CA 91335 USA. EM jschnell@ucla.edu NR 11 TC 16 Z9 16 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD FEB PY 2004 VL 44 IS 1 BP 10 EP 12 PG 3 WC Gerontology SC Geriatrics & Gerontology GA 777EZ UT WOS:000189164000002 PM 14978316 ER PT J AU Dinh, TA Oliva, EA Fuller, AF Lee, H Goodman, A AF Dinh, TA Oliva, EA Fuller, AF Lee, H Goodman, A TI The treatment of uterine leiomyosarcoma. Results from a 10-year experience (1990-1999) at the Massachusetts General Hospital SO GYNECOLOGIC ONCOLOGY LA English DT Article DE leiomyosarcoma; surgery; cytoreduction; survival ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; UTERUS; SARCOMAS; PACLITAXEL; METASTASES AB Objective. Uterine leiomyosarcomas (LMS) are rare tumors with a poor prognosis. The purpose of this study is to review the presentation, therapy and outcome of patients with leiomyosarcoma originating from the uterus treated at the Massachusetts General Hospital from 1990 to 1999. Methods. A retrospective chart review was done to, patients treated for uterine leiomyosarcoma during the study period. One author reviewed all available histologic specimens. Statistical analysis was done to determine whether there is an association between histologic criteria or therapy used and overall survival. Results. Forty-seven charts were reviewed to identify 27 patients with leiomyosarcoma arising from the uterus treated in the decade from 1990 to 1999. Most patients received multimodality therapy with surgery followed by chemotherapy and/or radiotherapy. Patients who had no visible disease at the conclusion of primary surgery had a better overall survival than patients who did not achieve surgical remission (P < 0.0003). There is a trend toward improved survival in patients with lower number of mitotic figures per 10 high-power fields (P = 0.062). Current chemotherapy drugs were minimally effective with 80% of treated patients having progression of disease. Adjuvant therapy after optimal cytoreduction does not decrease the rate of recurrence. Conclusion. Uterine leiomyosarcoma continues to be a deadly disease. Aggressive surgical cytoreduction at the time of initial diagnosis offers the possibility of prolonged survival or cure. (C) 2003 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Vincent Mem Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anat & Clin Pathol, Boston, MA 02114 USA. RP Goodman, A (reprint author), Massachusetts Gen Hosp, Vincent Mem Dept Obstet & Gynecol, Div Gynecol Oncol, 100 Blossom St,Cox 5, Boston, MA 02114 USA. EM agoodman@partners.org NR 19 TC 79 Z9 87 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD FEB PY 2004 VL 92 IS 2 BP 648 EP 652 DI 10.1016/j.ygyno.2003.10.044 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 779DX UT WOS:000189281100022 PM 14766261 ER PT J AU Leffert, RD AF Leffert, RD TI Complications of surgery for thoracic outlet syndrome SO HAND CLINICS LA English DT Article ID RIB RESECTION; 1ST RIB; ANATOMY; NERVE; INJURIES; DUCT AB Complications of thoracic outlet surgery range from mildly annoying to disabling and even life threatening. The global incidence of these complications is impossible to determine, so the author discusses them with close attention to the literature and from his 27-year surgical experience. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Leffert, RD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, POB WACC 248, Boston, MA 02114 USA. EM rleffert@partners.org NR 23 TC 11 Z9 11 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0749-0712 J9 HAND CLIN JI Hand Clin. PD FEB PY 2004 VL 20 IS 1 BP 91 EP + DI 10.1016/S0749-0712(03)00084-2 PG 9 WC Orthopedics SC Orthopedics GA 775KQ UT WOS:000189039800016 PM 15005390 ER PT J AU Pinto, C Smith, AG Larsen, CE Fernandez-Vina, M Husain, Z Clavijo, OP Wang, ZC Nisperos, B Hansen, JA Alper, CA Yunis, E AF Pinto, C Smith, AG Larsen, CE Fernandez-Vina, M Husain, Z Clavijo, OP Wang, ZC Nisperos, B Hansen, JA Alper, CA Yunis, E TI HLA-Cw*0409N is associated with HLA-A*2301 and HLA-B*4403-carrying haplotypes SO HUMAN IMMUNOLOGY LA English DT Article DE allele frequency; HLA null allele; Cw*0409N; major histocompatibility complex; polymorphism (genetics) ID SEQUENCE-SPECIFIC PRIMERS; A NULL ALLELE; HLA-B; STOP CODON; NUCLEOTIDE DELETION; EXTENDED HAPLOTYPES; EXON 3; EXPRESSION; INSERTION; MUTATION AB The associations of HLA-B*4402 and HLA-B*4403 with alleles of HLA-A and HLA-Cw were investigated in panels of HLA-B*4403 and HLA-B*4402 homozygous individuals and in selected individuals carrying HLA-Cw*04 and HLA-B*4403. Some of these individuals were genotyped and also carried (HLA-DRB1*0701, DQB1*02). Among the latter, we studied individuals carrying the conserved extended haplotype (CEH) [HLA-Cw*04, B*4403, FC31, DRB1*0701, DQB1*02]. Four different common (HLA-Cw*, B*44) haplotypes were identified that extended to the HLA-A locus: HLA-A*0201, Cw*0501, B*4402; HLA-A*2902, Cw*1601, B*4403; HLA-A*2301, Cw*0401, B*4403; and HLA-A*2301, Cw*0409N, B*4403. We identified eight unrelated examples of the allele HLA-Cw*0409N. HLA-A*2301 was associated with both HLA-Cw*0401 and HLA-Cw*0409N, suggesting that HLA-Cw*0409N may have arisen from a mutation in a CEH. We estimate that approximately 2 to 5 in 1000 Caucasian individuals carry the allele HLA-Cw*0409N, making it one of the most frequent null HLA alleles known to date. Our findings demonstrate the first example of three different HLA-Cw-determined subtypes of a common or CEH carrying a shared HLA-B allele, in this case HLA-B*4403. C1 CBR Inst Biomed Res, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Georgetown Univ, CW Bill Young Donor Marrow Program, Kinsington, MD USA. RP Larsen, CE (reprint author), CBR Inst Biomed Res, 800 Huntington Ave, Boston, MA 02115 USA. EM larsen@cbr.med.harvard.edu; Edmond_Yunis@dcfi.harvard.edu FU NCI NIH HHS [CA18029]; NHLBI NIH HHS [HL29583, HL59838]; NIAID NIH HHS [AI33484, AI49213] NR 28 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD FEB PY 2004 VL 65 IS 2 BP 181 EP 187 DI 10.1016/j.humimm.2003.11.001 PG 7 WC Immunology SC Immunology GA 777RM UT WOS:000189191400010 PM 14969773 ER PT J AU Zubovits, J Buzney, E Yu, L Duncan, LM AF Zubovits, J Buzney, E Yu, L Duncan, LM TI HMB-45, S-100, NK1/C3, and MART-1 in metastatic melanoma SO HUMAN PATHOLOGY LA English DT Article DE melan-a; MART-1; S-100; HMB-45; NK1/C3; immunohistochemistry; melanoma ID SENTINEL LYMPH-NODES; MALIGNANT-MELANOMA; T-CELLS; MONOCLONAL-ANTIBODY; MELANOCYTIC LESIONS; S100 PROTEIN; IN-VIVO; EXPRESSION; DIAGNOSIS; TYROSINASE AB The diagnosis of melanoma metastatic to lymph node remains a difficult problem given its histological diversity. We examined the staining patterns of S-100, NK1/C3, HMB45, and MART-1 (DC10) in melanoma metastases to lymph nodes. Immunohistochemical stains were performed on tissue sections of 126 formalin-fixed lymph nodes from 126 patients with an established diagnosis of metastatic melanoma. A total of 98% of cases (123 of 126) stained positive for S-100, 93% (117 of 125) stained positive for NK1/C3, 82% (103 of 126) stained positive for MART-1, and 76% (95 of 125) stained positive for HMB45. The distribution and intensity of staining varied among these markers. A diffuse staining pattern, defined as >50% of tumor cells stained, was observed in 83% of MART-1-positive cases but in only 56% of S-100-positive cases, 48% of NK1/C3-positive cases, and 34% of HMB-45-positive cases. A maximally intense signal was almost always observed for MART-1 (83% of positive cases) but was rarely observed for NK1/C3 (20%). S-100 and HMB45 showed maximally intense staining in 50% and 54% of cases, respectively. S-100 aid NK1/C3 stained both histiocytes and melanocytes, whereas MART-1 and HMB45 stained only melanocytes. Seventy-eight cases (63%) stained positive for all 4 markers, 17 cases (14%) stained for A markers except HMB-45, 13 cases (10%) stained for all markers except MART-1, 6 cases (5%) stained only with S-100 and NK1/C3, 4 cases (3%) stained only with S-100 and HMB-45, and 2 cases stained for all markers except S-100. One case each stained for the following: only S-100, only S-100 and HMB-45, and all markers except NK1/C3. One case exhibited absence of staining for any of these markers. We demonstrate that lymph node metastases of melanoma are heterogeneous with regard to tumor marker expression. S-100 and NK1/C3 were the most sensitive stains for detecting metastatic melanoma; however, they both also stain other nontumor cells in lymph nodes. MART-1 did not stain histiocytes and exhibited a more frequently intense and diffuse staining pattern than NK1/C3. HMB45 was less sensitive and demonstrated less diffuse staining than MART-1. C1 Massachusetts Gen Hosp, Dermatopathol Unit WRN 820, Boston, MA 02114 USA. Sunnybrook & Womens Coll Hlth Sci Ctr, Dept Pathol, Toronto, ON, Canada. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Western Australia, Nedlands, WA 6009, Australia. RP Duncan, LM (reprint author), Massachusetts Gen Hosp, Dermatopathol Unit WRN 820, Boston, MA 02114 USA. RI Duncan, Lyn/E-9878-2013 NR 32 TC 50 Z9 52 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2004 VL 35 IS 2 BP 217 EP 223 DI 10.1016/j.humpath.2003.09.019 PG 7 WC Pathology SC Pathology GA 779XP UT WOS:000189327700012 PM 14991540 ER PT J AU Varnholt, H Kradin, R AF Varnholt, H Kradin, R TI Pulmonary capillary hemangiomatosis arising in hereditary hemorrhagic telangiectasia SO HUMAN PATHOLOGY LA English DT Article DE capillary hemangiomatosis; hereditary hemorrhagic telangiectasia; nitric oxide synthase ID HYPERTENSION; GENE AB Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant inherited disease characterized by epistaxis, telangiectases, and visceral arteriovenous malformations that can lead to hemorrhage and other complications. We report the case of a 56-year-old female patient with HHT and pulmonary hypertension who died with intractable pulmonary and gastrointestinal bleeding. Autopsy revealed vascular malformations in the lungs, gastrointestinal tract, liver, spleen, and brain. Capillary proliferations in the pulmonary alveolar walls, characteristic of pulmonary capillary hemangiomatosis, were identified, as was evidence of pulmonary hypertensive arteriopathy. To our knowledge, this is the first report of pulmonary capillary hemangiomatosis arising in HHT. The histopathologic findings of HHT and pulmonary capillary hemangiomatosis are reviewed, and a possible role for diminished capillary expression of endothelial nitric oxide synthase is discussed. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kradin, R (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 5, Boston, MA 02114 USA. NR 15 TC 13 Z9 15 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2004 VL 35 IS 2 BP 266 EP 268 DI 10.1016/j.humpath.2003.10.009 PG 3 WC Pathology SC Pathology GA 779XP UT WOS:000189327700020 PM 14991548 ER PT J AU Goodfriend, TL Ball, DL Egan, BM Campbell, WB Nithipatikom, K AF Goodfriend, TL Ball, DL Egan, BM Campbell, WB Nithipatikom, K TI Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion SO HYPERTENSION LA English DT Article; Proceedings Paper CT 57th Annual Fall Conference and Scientific Sessions of the American-Heart-Association-Council-for-Blood-Pressure-Research CY SEP 23-26, 2003 CL WASHINGTON, D.C. SP Amer Heart Assoc Council High Blood Pressure Res DE fatty acids; oxidative stress; hypertension; aldosterone; obesity; adrenal gland ID RAT ADRENAL-CELLS; FREE FATTY-ACID; OXIDATIVE STRESS; BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; GLOMERULOSA CELLS; OBESITY; ANGIOTENSIN; STEROIDOGENESIS AB Plasma levels of aldosterone are not always predictable from the activity of renin and the concentration of potassium. Among the unexplained are elevated levels of aldosterone in some obese humans. Obesity is characterized by increased plasma fatty acids and oxidative stress. We postulated that oxidized fatty acids stimulate aldosteronogenesis. The most readily oxidized fatty acids are the polyunsaturated, and the most abundant of those is linoleic acid. We tested oxidized derivatives of linoleic acid for effects on rat adrenal cells. One derivative, 12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE), was particularly potent. EKODE stimulated aldosteronogenesis at concentrations from 0.5 to 5 mumol/L, and inhibited aldosteronogenesis at higher doses. EKODE's stimulatory effect was most prominent when angiotensin and potassium effects were submaximal. The lipid's mechanism of action was on the early pathway leading to pregnenolone; its action was inhibited by atrial natriuretic peptide. Plasma EKODE was measured by liquid chromatography/mass spectrometry. All human plasmas tested contained EKODE in concentrations ranging from 10(-9) to 5x10(-7) mol/L. In samples from 24 adults, levels of EKODE correlated directly with aldosterone (r=0.53, P=0.007). In the 12 blacks in that cohort, EKODE also correlated with body mass index and systolic pressure. Those other correlations were not seen in white subjects. The results suggest that oxidized derivatives of polyunsaturated fatty acids other than arachidonic are biologically active. Compounds like EKODE, derived from linoleic acid, may affect adrenal steroid production in humans and mediate some of the deleterious effects of obesity and oxidative stress, especially in blacks. C1 William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. Univ Wisconsin, Dept Med, Madison, WI USA. Univ Wisconsin, Dept Pharmacol, Madison, WI 53706 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. RP Goodfriend, TL (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM theodore.goodfriend@med.va.gov NR 31 TC 120 Z9 120 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2004 VL 43 IS 2 BP 358 EP 363 DI 10.1161/01.HYP.0000113294.06704.64 PN 2 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 769VD UT WOS:000188669700012 PM 14718355 ER PT J AU Goldstein, EA Heaton, JT Kobler, JB Stanley, GB Hillman, RE AF Goldstein, EA Heaton, JT Kobler, JB Stanley, GB Hillman, RE TI Design and implementation of a hands-free electrolarynx device controlled by neck strap muscle electromyographic activity SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE electromyography; prosthesis; voice ID ARM; COMMUNICATION; LARYNGECTOMY; SIGNALS AB The electrolarynx (EL) voice prosthesis is widely used, but suffers from the inconvenience of requiring manual control. Therefore, a hands-free EL triggered by neck muscle electromyographic (EMG) activity was developed (EMG-EL). Signal processing circuitry in a belt-mounted control unit transforms EMG activity into control signals for initiation and termination of voicing. These control signals are then fed to an EL held against the neck by an inconspicuous brace. Performance of the EMG-EL was evaluated by comparison to normal voice, manual EL voice, and tracheo-esophageal (TE) voice in a series of reaction time experiments in seven normal subjects and one laryngectomy patient. The normal subjects produced voice initiation with the EMG-EL that was as fast as both normal voice and the manual EL. The laryngectomy subject produced voice initiation that was slower than with the manual EL, but faster than with TE voice. Voice termination with the EMG-EL was slower than normal voice for the normal subjects, but not significantly different than with the manual EL. The laryngectomy subject produced voice termination with the EMG-EL that was slower than with TE or manual EL. The EMG-EL threshold was set at 10% of the range of vocal-related EMG activity above baseline. Simulations of EMG-EL behavior showed that the 10% threshold was not significantly different from the optimum threshold produced through the process of error minimization. The EMG-EL voice reaction time appears to be adequate for use in a day-to-day conversation. C1 Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02143 USA. Harvard Univ, Div Engn & Appl Sci, Cambridge, MA 02143 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Voice & Speech Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. Harvard Univ, Div Engn & Appl Sci, Cambridge, MA 02138 USA. RP Goldstein, EA (reprint author), Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02143 USA. EM ehab@post.harvard.edu NR 19 TC 31 Z9 31 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD FEB PY 2004 VL 51 IS 2 BP 325 EP 332 DI 10.1109/TBME.2003.820373 PG 8 WC Engineering, Biomedical SC Engineering GA 765QY UT WOS:000188296000013 PM 14765705 ER PT J AU Correia, JA Burnham, CA Kaufman, D Brownell, AL Fischman, AJ AF Correia, JA Burnham, CA Kaufman, D Brownell, AL Fischman, AJ TI Performance evaluation of MMP-II: A second-generation small animal PET SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article DE LSO; PET; small animal imaging ID POSITRON EMISSION TOMOGRAPH; HIGH-RESOLUTION PET; SCANNER; MICROPET; DESIGN AB We have completed construction of a second-generation, single-plane small animal PET instrument based on LSO detectors. The second-generation design addresses some of the limitations in the first-generation. The purpose of the work reported here was to characterize the physical performance of this instrument. Results of the performance measurements include: Spatial resolution = 1.25 mm at field center and 1.5 mm at 2 cm radius; point source sensitivity = 56 cps/uCi,; scatter fractions of 0.019 and 0.056 in 3.8 and 6 cm diameter cylinders respectively; linearity of reconstructed signal within 5% up to 100 uCi/cc and acceptable dead-time performance up to 25 k true cps. Examples of phantom and animal images are also presented. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Correia, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM correia@pet.mgh.harvard.edu NR 12 TC 15 Z9 15 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD FEB PY 2004 VL 51 IS 1 BP 21 EP 26 DI 10.1109/TNS.2003.823058 PN 1 PG 6 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 813BR UT WOS:000220883100004 ER PT J AU Badawi, RD Domigan, P Johnson, O Kemp, B Kudrolli, H Rempel, T Rohatgi, R Romanov, LV Surti, S Worstell, WA Zimmerman, RE AF Badawi, RD Domigan, P Johnson, O Kemp, B Kudrolli, H Rempel, T Rohatgi, R Romanov, LV Surti, S Worstell, WA Zimmerman, RE TI Count-rate dependent event mispositioning and NEC in PET SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article DE count-rate; data quality; NEC; PET; pileup ID DETECTORS AB Most current PET detector designs suffer from event mispositioning at high count rates, as scintillation light from nearby and nearly simultaneous gamma ray conversions becomes mixed. We have used the NEMA NU 2-2001 70 cm test phantom and a Na-22 point source to quantify this effect as a function of activity on two block-detector tomographs (the Siemens/CTI HR+ and the General Electric Discovery LS), and two Anger-type PET tomographs (the Siemens ECAM DUET and the Philips CPET+). After accounting for event losses due to dead time, we find that the number of counts on LORs passing through a cylinder of diameter and height equal to the point-source full width at tenth-maximum measured at low rate surrounding the point source decreases by between 9% (HR+) and 35% (CPET+) at the activity giving rise to peak noise equivalent count (NEC) rate. Mispositioned events act to reduce signal-to-noise ratio, both by reducing apparent activity at the originating location and by increasing the signal background. We have reformulated the conventional expression for NEC rate to account for this phenomenon. The new formulation of NEC, which we call NEC*, results in a lower peak value which in turn occurs at a lower activity concentration than for the conventional formulation. C1 Harvard Univ, Sch Med, Joint Program Nucl Med, Dana Farber Canc Inst,Div Nucl Med, Boston, MA 02115 USA. PhotoDetect Syst, Acton, MA 01720 USA. Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. Siemens Med Solut USA Inc, Hoffman Estates, IL 60195 USA. Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Joint Program Nucl Med,Dept Radiol, Boston, MA 02115 USA. RP Badawi, RD (reprint author), Harvard Univ, Sch Med, Joint Program Nucl Med, Dana Farber Canc Inst,Div Nucl Med, Boston, MA 02115 USA. EM ramsey_badawi@dfci.harvard.edu NR 5 TC 12 Z9 12 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD FEB PY 2004 VL 51 IS 1 BP 41 EP 45 DI 10.1109/TNS.2003.823045 PN 1 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 813BR UT WOS:000220883100007 ER PT J AU Mao, CC Jiang, LY Melo-Jorge, M Puthenveetil, M Zhang, XL Carroll, MC Imanishi-Kari, T AF Mao, CC Jiang, LY Melo-Jorge, M Puthenveetil, M Zhang, XL Carroll, MC Imanishi-Kari, T TI T cell-independent somatic hypermutation in murine B cells with an immature phenotype SO IMMUNITY LA English DT Article ID CYTIDINE DEAMINASE AID; IG GENE HYPERMUTATION; DOUBLE-STRAND BREAKS; IMMUNOGLOBULIN GENES; BONE-MARROW; ANTIBODY DIVERSIFICATION; AFFINITY MATURATION; CHAIN REARRANGEMENT; IMMUNE-RESPONSE; PLASMA-CELLS AB Somatic hypermutation contributes to the generation of antibody diversity and is strongly associated with the maturation of antigen-specific immune responses. We asked whether somatic hypermutation also plays a role in the generation of the murine immunoglobulin repertoire during B cell development. To facilitate identification of somatic mutations, we examined mouse systems in which only antibodies expressing lambda1, lambda2, and lambdax light chains can be generated. Somatic mutations were found in cells, which, by surface markers, RAG expression, and rapid turnover, had the phenotype of immature B cells. In addition, expression of AID was detected in these cells. The mutations were limited to V regions and were localized in known hot-spots. Mutation frequency was not diminished in the absence of T cells. Our results support the idea that somatic hypermutation can occur in murine immature B cells and may represent a mechanism for enlarging the V gene repertoire. C1 Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Program Immunol, Boston, MA 02111 USA. Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. RP Imanishi-Kari, T (reprint author), Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. EM thereza.imanishi-kari@tufts.edu FU NIAID NIH HHS [AI45104]; NICHD NIH HHS [HD38749] NR 68 TC 70 Z9 72 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2004 VL 20 IS 2 BP 133 EP 144 DI 10.1016/S1074-7613(04)00019-6 PG 12 WC Immunology SC Immunology GA 821EI UT WOS:000221442400003 PM 14975236 ER PT J AU Pillai, S Cariappa, A Moran, ST AF Pillai, S Cariappa, A Moran, ST TI Positive selection and lineage commitment during peripheral B-lymphocyte development SO IMMUNOLOGICAL REVIEWS LA English DT Review ID NF-KAPPA-B; BRUTONS TYROSINE KINASE; X-LINKED AGAMMAGLOBULINEMIA; SPLENIC MARGINAL ZONE; C-ASSOCIATED KINASE; CELL-DEVELOPMENT; ANTIGEN-RECEPTOR; PROTEIN-KINASE; SIGNALING PATHWAY; B-1 CELLS AB Although it is appreciated that the antigen receptor on B cells is required for peripheral B-lymphocyte development and survival, it has been unclear whether this receptor interacts with self-antigens during development or if it signals constitutively in an antigen-independent fashion. The analysis of mutant mice in which antigen receptor signaling in B cells is either attenuated or enhanced has revealed the existence of a follicular versus marginal zone B-lymphocyte cell-fate decision. These analyses indicate that weak antigen receptor-derived signals favor marginal zone B-cell generation, and relatively strong signals favor the development of mature follicular B cells. Even stronger signals derived from the antigen receptor favor the generation of B1 B cells. This signal strength model for B-cell development supports the notion that self-antigens of varying affinity may mediate positive selection and lineage commitment. Direct evidence supporting such a view has been obtained from the analysis of antigen receptor knockin mice. Specific antigen receptors guide B cells to develop into specific lineages. Although Notch-2, nuclear factor-kappaBp50, and other genes are essential for marginal zone B-cell development, instructive signals delivered by the antigen receptor represent the primary force driving positive selection and lineage commitment in B lymphocytes. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. RP Pillai, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, 149 13th St,Charlestown Navy Yard, Boston, MA 02129 USA. EM pillai@helix.mgh.harvard.edu FU NCI NIH HHS [CA102793]; NIAID NIH HHS [AI54917, AI 33507] NR 93 TC 85 Z9 88 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD FEB PY 2004 VL 197 BP 206 EP 218 DI 10.1111/j.0105-2896.2003.097.x PG 13 WC Immunology SC Immunology GA 774VY UT WOS:000189007800016 PM 14962197 ER PT J AU Henning, KJ Brennan, PJ Hoegg, C O'Rourke, E Dyer, BD Grace, TL AF Henning, KJ Brennan, PJ Hoegg, C O'Rourke, E Dyer, BD Grace, TL TI Health system preparedness for bioterrorism: Bringing the tabletop to the hospital SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID BIOLOGICAL TERRORISM; MASS DESTRUCTION; PUBLIC-HEALTH; WEAPONS AB OBJECTIVE: To evaluate the acceptance and usefulness of a hospital-based tabletop bioterrorism exercise. DESIGN: A descriptive study of responses to a smallpox scenario delivered as a tabletop exercise in three modules. SETTING: A large, multi-institutional urban health system. PARTICIPANTS: Healthcare workers representing 16 hospital departments. RESULTS: Thirty-nine (78%) of 50 invited employees from 4 hospitals participated. Key responses highlighted the importance of pre-event planning in intra-departmental communication, identification of resources for the dependents of healthcare workers, clarification of the chain of command within the hospital, establishment of a link to key governmental agencies, and advanced identification of negative pressure rooms for cohorting large numbers of patients. Almost one-fourth of the participants described their hospital department as poorly prepared for a bioterrorism event of moderate size. At the conclusion of the tabletop, 79% of the participants stated that the exercise had increased their knowledge of preplanning activities. Seventy-nine percent of all participants, 94% of physicians and nurses, and 95% of participants from non-university hospitals ranked the exercise as extremely or very useful. The exercise was completed in 31/2 hours and its total direct cost (excluding lost time from work) was $225 (U.S.). CONCLUSIONS: Tabletop exercises are a feasible, well-accepted modality for hospital bioterrorism preparedness training. Hospital employees, including physicians and nurses, rank this method as highly useful for guiding preplanning activities. Infection control staff and hospital epidemiologists should play a lead role in hospital preparedness activities. Further assessment of the optimal duration, type, and frequency of tabletop exercises is needed. C1 Univ Penn, Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Infect Control & Hosp Epidemiol, Philadelphia, PA USA. Univ Penn Hlth Syst, Safety Management Program, Philadelphia, PA USA. Hosp Univ Penn, Infect Control Dept, Philadelphia, PA 19104 USA. Penn Hosp, Infect Control Dept, Philadelphia, PA 19107 USA. RP Henning, KJ (reprint author), Div Epidemiol, 125 Worth St,Box 315-CN6, New York, NY 10013 USA. NR 31 TC 15 Z9 15 U1 2 U2 3 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2004 VL 25 IS 2 BP 146 EP 155 DI 10.1086/502366 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 775CC UT WOS:000189022300013 PM 14994941 ER PT J AU de Jong, YP Rietdijk, ST Faubion, WA Abadia-Molina, AC Clarke, K Mizoguchi, E Tian, J Delaney, T Manning, S Gutierrez-Ramos, JC Bhan, AK Coyle, AJ Terhorst, C AF de Jong, YP Rietdijk, ST Faubion, WA Abadia-Molina, AC Clarke, K Mizoguchi, E Tian, J Delaney, T Manning, S Gutierrez-Ramos, JC Bhan, AK Coyle, AJ Terhorst, C TI Blocking inducible co-stimulator in the absence of CD28 impairs T(h)1 and CD25(+) regulatory T cells in murine colitis SO INTERNATIONAL IMMUNOLOGY LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; CD40-CD40 LIGAND INTERACTIONS; INTESTINAL INFLAMMATION; MUCOSAL INFLAMMATION; CD28-DEFICIENT MICE; SCID MICE; IN-VITRO; ICOS; DISEASE; EXPRESSION AB Several autoimmune disease models depend on an imbalance in the activation of aggressor T(h)1 and CD4(+)CD25(+) regulatory T (T-reg) cells. Here we compare the requirement for signals through the co-stimulatory molecules CD28 and inducible co-stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease-causing CD45RB(hi) T cells alone or in combination with CD4(+)CD25(+) T cells from either CD28-deficient or wild-type donors were transferred into T cell-deficient animals, half of which were treated with ICOS-blocking reagents. Blocking ICOS on the surface of CD28-deficient T(h)1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T(h)1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor T(h)1 cells, and that CD28 is required for T-reg cells, which should caution against the use of CD28-blocking reagents in inflammatory bowel disease. C1 Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Immunopathol Unit, Boston, MA 02114 USA. Millennium Pharmaceut Inc, Inflammat Div, Cambridge, MA 02139 USA. RP Terhorst, C (reprint author), Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA 02215 USA. EM terhorst@bidmc.harvard.edu FU NIDDK NIH HHS [DK43351, DK47677, DK52510] NR 51 TC 26 Z9 26 U1 0 U2 1 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 2004 VL 16 IS 2 BP 205 EP 213 DI 10.1093/intimm/dxh019 PG 9 WC Immunology SC Immunology GA 771PT UT WOS:000188795800002 PM 14734605 ER PT J AU Paul, E Lutz, J Erikson, J Carroll, MC AF Paul, E Lutz, J Erikson, J Carroll, MC TI Germinal center checkpoints in B cell tolerance in 3H9 transgenic mice SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE anti-DNA antibody; autoimmunity; somatic mutation ID NON-AUTOIMMUNE MICE; ESCAPE TOLERANCE; DNA; CHAIN; HYPERMUTATION; ANTIBODIES; RECEPTORS; REARRANGEMENTS; MATURATION; ARREST AB Regulation throughout B cell maturation and activation prevents autoreactive B cells from entering germinal center (GC) reactions. This study shows that a subset of autoreactive B cells in V(H)3H9mu IgH transgenic mice escapes these serial checkpoints and proceeds into splenic GC. GC B cells isolated from these mice all express the transgenic V(H)3H9mu heavy chain, some co-express light chains that yield an anti-dsDNA specificity and some have somatic mutations, consistent with their GC origin. Nonetheless, B cell tolerance is ultimately preserved as serum titers of anti-dsDNA antibodies are not elevated. These observations suggest that those autoreactive GC B cells that escaped earlier checkpoints and possibly also those cells that acquire autoreactivity de novo by mutating their antigen receptor are arrested within the splenic GC before differentiating further into antibody-secreting plasma cells. C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Div Nephrol, Boston, MA 02115 USA. Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Paul, E (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. EM elahna.paul@tch.harvard.edu FU NIAID NIH HHS [K08-AI01841]; NICHD NIH HHS [HD38749] NR 36 TC 23 Z9 23 U1 0 U2 2 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 2004 VL 16 IS 2 BP 377 EP 384 DI 10.1093/intimm/dxh035 PG 8 WC Immunology SC Immunology GA 771PT UT WOS:000188795800020 PM 14734623 ER PT J AU Asch, SM Fremont, AM Turner, BJ Gifford, A McCutchan, JA Mathews, WMC Bozzette, SA Shapiro, MF AF Asch, SM Fremont, AM Turner, BJ Gifford, A McCutchan, JA Mathews, WMC Bozzette, SA Shapiro, MF TI Symptom-based framework for assessing quality of HIV care SO INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE LA English DT Article DE HIV; patient-centered care; quality indicators; quality of care; symptoms ID HUMAN-IMMUNODEFICIENCY-VIRUS; OF-LIFE; SERVICES UTILIZATION; UNITED-STATES; UNMET EXPECTATIONS; INFECTED PATIENTS; COST; PREVALENCE; DISEASE; RELIABILITY AB Objective. To evaluate HIV quality of care using a symptom-based, patient-centered framework. Methods. An expert panel developed 13 quality indicators for three common symptoms: cough with fever and/or shortness of breath; severe or persistent diarrhea; and significant weight loss. A nationally representative probability sample of HIV-infected adults was interviewed between 1996 and 1997. Participants were asked about the presence and severity of HIV symptoms during the preceding 6 months, and care received. Variation in adherence to the indicators was assessed by symptom type and patient characteristics. Results. In all, 2864 (71%) patients completed interviews and 920 reported being at least moderately bothered with one of the three symptoms. Of these, 41, 74, and 65% of patients with a symptom of cough, weight loss, or diarrhea, respectively, reported receiving all indicated care. Performance was better for patients with more severe HIV, measured as a CD4 cell count <50 cells/microliter, compared with those with less severe HIV, measured as CD4 cell count >500 cells/microliter (43% versus 60%; P = 0.02). Uninsured patients had worse performance than Medicare patients (45% versus 62%; P = 0.04), but care did not differ by patient's age, gender, ethnicity, HIV risk factor, providers' HIV patient load, or region. Only CD4 count remained significantly associated with performance in the multivariate analyses. Conclusions. Symptom-based quality indicators may provide a useful supplement to conventional measures. Patients with HIV reported substantial underuse of services for common, burdensome symptoms. Although adherence to quality indicators was better for patients with more advanced HIV disease, many still received suboptimal care. Vulnerable patient groups generally did not receive worse quality of care, suggesting that symptom-based measures of quality may measure domains that are distinct from those captured by conventional indicators. C1 VA Greater Los Angeles Hlth Syst, Dept Gen Internal Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA USA. RAND Corp, Hlth, Santa Monica, CA USA. Univ Penn, Div Gen Med, Philadelphia, PA 19104 USA. VA San Diego Healthcare Syst, Hlth Serv Res & Dev Program, San Diego, CA USA. Univ Calif San Diego, Sch Med, Dept Med, Div Infect Dis, La Jolla, CA 92093 USA. Univ Calif Los Angeles, Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. RP Asch, SM (reprint author), VA Greater Los Angeles Hlth Syst, Dept Gen Internal Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM sasch@rand.org FU AHRQ HHS [U01 HS 08578] NR 35 TC 7 Z9 8 U1 3 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1353-4505 J9 INT J QUAL HEALTH C JI Int. J. Qual. Health Care PD FEB PY 2004 VL 16 IS 1 BP 41 EP 50 DI 10.1093/intqhc/mzh004 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 771PX UT WOS:000188796200006 PM 15020559 ER PT J AU Shores, MM Ryan-Dykes, P Williams, RM Mamerto, B Sadak, T Pascualy, M Felker, BL Zweigle, M Nichol, P Peskind, ER AF Shores, MM Ryan-Dykes, P Williams, RM Mamerto, B Sadak, T Pascualy, M Felker, BL Zweigle, M Nichol, P Peskind, ER TI Identifying undiagnosed dementia in residential care veterans: comparing telemedicine to in-person clinical examination SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE telemedicine; telepsychiatry; dementia; screening; 7-Minute Screen; veterans ID CLOCK DRAWING TEST; MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; CONTROLLED TRIAL; PROGRAM; EXTENSION; SYSTEM AB Background Dementia is a common but frequently undiagnosed problem in aging. Barriers to early diagnosis include a lack of routine screening for dementia and a lack of access to specialty consultative services. We conducted a pilot study to see if telemedicine could provide reliable, accurate geriatric consultative services to evaluate patients for dementia who were residing at remote sites. Methods This was a prospective cohort study that compared the diagnostic reliability of telemedicine to an in-person examination for dementia. Eligible subjects were residents of a Washington State Veterans' Home, age 60 years or older, with no prior diagnosis of dementia. Eligible subjects were screened for dementia using the 7-Minute Screen. Veterans who screened positive and consented to participate in the study received an in-person neuropsychiatric evaluation at baseline, and then both telemedicine and in-person examinations for dementia conducted by experienced geriatric psychiatrists. The accuracy of the telemedicine diagnosis was estimated by comparing it to the diagnosis from the clinical examination. Three geriatric psychiatrists who were blinded to the results of the clinical examination conducted the telemedicine and in-person examinations. We also assessed attitudes of the subjects and geriatric psychiatrists towards the telemedicine sessions. Results Eighteen of 85 subjects screened were 'positive' for dementia on the 7 Minute Screen. Of these, 16 consented to participate in the telemedicine study. Twelve of the 16 subjects were subsequently diagnosed with dementia by the telemedicine examination. The telemedicine diagnoses were in 100% agreement with the diagnoses from the in-person clinical examinations. Moreover, the subjects reported a high degree of satisfaction with the telemedicine experience and that they would like to have further care through telemedicine in the future. The geriatric psychiatrists reported technical difficulties with the audio-visual quality of telemedicine in the initial phases of the project that resolved as familiarity with the telemedicine equipment increased. None of these problems had an adverse impact on the diagnostic accuracy of telemedicine. Conclusions We found that telemedicine was as accurate as an in-person clinical examination in establishing the diagnosis of dementia. In addition, subjects reported a high degree of satisfaction with telemedicine and a willingness to participate in telemedicine clinical care in the future. Given the large increase in the aging population and the shortage of geriatric psychiatrists nationally, it appears that telemedicine may be a promising means to expand the availability of geriatric psychiatric consultation to remote areas. Published in 2004 by John Wiley Sons, Ltd. C1 GRECC, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. MIRECC, Seattle, WA USA. Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Washington Vet Homes, Orting, WA USA. RP Shores, MM (reprint author), GRECC, VA Puget Sound Hlth Care Syst, 1660 S Columbia Way,S-182B, Seattle, WA 98108 USA. EM molly.shores@med.va.gov NR 38 TC 32 Z9 32 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD FEB PY 2004 VL 19 IS 2 BP 101 EP 108 DI 10.1002/gps.1029 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 776CE UT WOS:000189096800001 PM 14758575 ER PT J AU Okuda, K Sato, Y Sonoda, Y Griffin, JD AF Okuda, K Sato, Y Sonoda, Y Griffin, JD TI The TEL/ARG leukemia oncogene promotes viability and hyperresponsiveness to hematopoietic growth factors SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE leukemia; chimeric oncogene; TEL/ARG; tyrosine kinase; signal transduction ID CHRONIC MYELOGENOUS LEUKEMIA; ABL TYROSINE KINASE; CHRONIC MYELOMONOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; MYELOID CELL-LINE; BCR-ABL; C-ABL; CHROMOSOMAL TRANSLOCATION; SIGNAL-TRANSDUCTION; BCR/ABL EXPRESSION AB The TEL/ARG oncogene associated with acute myeloid leukemia is formed by the t(1;12)(q25;p13) reciprocal translocation, which fuses part of the TEL gene to the tyrosine kinase, c-ARG. In an effort to determine the biological effects and investigate signaling of the TEL/ARG fusion protein, multiple sublines of Ba/F3 cells were generated in which a TEL/ARG complementary DNA was expressed under the control of a tetracycline-inducible promoter. Treatment of these cells with doxycycline, a tetracycline analogue, rapidly induced expression of the TEL/ARG protein. TEL/ARG was heavily phosphorylated on tyrosine residues and was also found to rapidly induce tyrosine phosphorylation of multiple cellular proteins, including rasGAP, CBL, STAT5, PI3K, SHP2, Dok, and SHC. The Ba/F3-tet-TEL/ARG cells remained interleukin (IL)-3 dependent without doxycycline but with doxycycline displayed a marked reduction in cell death in the absence of IL-3. TEL/ ARG cells also displayed an enhanced proliferative response to IL-3 and to insulin-like growth factor 1. At least in Ba/F3 cells, although the growth rate was much lower compared to that with IL-3, TEL/ARG appeared to induce some cell proliferation as an immediate consequence. Nonetheless, the hyperresponsiveness to growth factors reported here is more likely to contribute to the pathogenesis of leukemia. C1 Kyoto Prefectural Univ Med, Dept Hlth Sci & Prevent Med, Kamigyo Ku, Kyoto 6028566, Japan. Int Med Ctr Japan, Res Inst, Dept Clin Pathol, Div Mol Cytogenet, Tokyo, Japan. Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Okuda, K (reprint author), Kyoto Prefectural Univ Med, Dept Hlth Sci & Prevent Med, Kamigyo Ku, Kawaramachi Hirokoji, Kyoto 6028566, Japan. EM keiko_o@koto.kpu-m.ac.jp NR 48 TC 4 Z9 4 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD FEB PY 2004 VL 79 IS 2 BP 138 EP 146 DI 10.1532/IJH97.03125 PG 9 WC Hematology SC Hematology GA 777QN UT WOS:000189189200007 PM 15005341 ER PT J AU Tong, Q Sankale, JL Hadigan, CM Tan, G Rosenberg, ES Kanki, PJ Grinspoon, SK Hotamisligil, GS AF Tong, Q Sankale, JL Hadigan, CM Tan, G Rosenberg, ES Kanki, PJ Grinspoon, SK Hotamisligil, GS TI Direct regulation of adiponectin by HIV and its link to lipodystrophy SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 9th International Congress on Obesity CY AUG 24-29, 2002 CL SAO PAULO, BRAZIL C1 Harvard Univ, Sch Publ Hlth, Div Biol Sci, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Nutr Metab, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2004 VL 28 IS 2 MA 2 BP 340 EP 340 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 765VH UT WOS:000188304700028 ER PT J AU Usui, T Isbida, S Yamasbiro, K Kaji, Y Poulaki, V Moore, J Shima, DT Adamis, AP AF Usui, T Isbida, S Yamasbiro, K Kaji, Y Poulaki, V Moore, J Shima, DT Adamis, AP TI VEGF(164(165)) as the pathological isoform: Differential leukocyte and endothelial responses through VEGFR1 and VEGFR2 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID PROLIFERATIVE DIABETIC-RETINOPATHY; GROWTH-FACTOR VEGF; ADHESION MOLECULE-1 ICAM-1; CORNEAL NEOVASCULARIZATION; VASCULAR-PERMEABILITY; RECEPTOR FLT-1; NEUROPILIN-I; CELLS; ANGIOGENESIS; EXPRESSION AB PURPOSE. Vascular endothelial growth factor (VEGF) induces angiogenesis and vascular permeability and is thought to be operative in several ocular vascular diseases. The VEGF isoforms are highly conserved among species; however, little is known about their differential biological functions in adult tissue. In the current study, the inflammatory potential of two prevalent VEGF isoform splice variants, WGF(120(121)) and VEGF(164(165)), was studied in the transparent and avascular adult mouse cornea. METHODS. Controlled-release pellets containing equimolar amounts of VEGF(120) and VEGF(164) were implanted in corneas. The mechanisms underlying this differential response of VEGF isoforms were explored. The response of VEGF in cultured endothelial cells was determined by Western blot analysis. The response of VEGF isoforms in leukocytes was also investigated. RESULTS. VEGF(164) was found to be significantly more potent at inducing inflammation. In vivo blockade of VEGF receptor (VEGFR)-1 significantly suppressed VEGF(164)-induced corneal inflammation. In vitro, VEGF(165) more potently stimulated intracellular adhesion molecule (ICAM)-1expression on endothelial cells, an effect that was mediated by VEGFR2. VEGF(164) was also more potent at inducing the chemotaxis of monocytes, an effect that was mediated by VEGFR1. In an immortalized human leukocyte cell line, VEGF(165) was found to induce tyrosine phosphorylation of VEGFR1 more efficiently. CONCLUSIONS. Taken together, these data identify VEGF(164(165)) as a proinflammatory isoform. and identify multiple mechanisms underlying its proinflammatory biology. C1 Eyetech Res Ctr, Woburn, MA 01801 USA. Imperial Canc Res, London, England. Univ Tokyo, Fac Med, Dept Ophthalmol, Tokyo 113, Japan. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Adamis, AP (reprint author), Eyetech Res Ctr, 42 Cummings Pk, Woburn, MA 01801 USA. EM tony.adamis@eyetk.com OI Moore, Tara/0000-0002-7659-9326; Moore, Johnny/0000-0001-8451-9421 FU NEI NIH HHS [EY12611] NR 46 TC 91 Z9 105 U1 1 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2004 VL 45 IS 2 BP 368 EP 374 DI 10.1167/iovs.03-0106 PG 7 WC Ophthalmology SC Ophthalmology GA 771CX UT WOS:000188769000003 PM 14744874 ER PT J AU Yang, L Bula, D Arroyo, JG Chen, DF AF Yang, L Bula, D Arroyo, JG Chen, DF TI Preventing retinal detachment-associated photoreceptor cell loss in bax-deficient mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OXYGEN SUPPLEMENTATION; NERVOUS-SYSTEM; NEURONAL DEATH; RAT RETINA; APOPTOSIS; BCL-2; DISEASE; DEGENERATION; ELIMINATION; PROTEIN AB PURPOSE. To characterize photoreceptor cell apoptosis and cell loss in a mouse model of experimental retinal detachment (RD), and to use the technology of mouse genetics to study the molecular mechanisms underlying RD-associated photoreceptor degeneration. METHODS. Retinal detachments were created in adult wild-type and Bax-deficient mice by subretinal injection of 1.4% sodium hyaluronate. At 1, 3, 7, and 28 days after injection, animals were killed, eyes enucleated, and retinal sections studied by histochemistry, immunofluorescence labeling, and confocal microscopy. Rods and cones were labeled, and apoptotic cells were identified with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Photoreceptor cell apoptosis and cell loss were assessed quantitatively by counting both surviving and TUNEL-positive rods and cones. RESULTS. TUNEL-positive cells were found within the outer nuclear layer (ONL) of the detached portions of the retina. They were detected in the detached retina on day 1, peaked on day 3, and dropped precipitously after day 7 after RD. Photoreceptor cell loss of both rods and cones followed a similar time course after RD. Moreover, deletion of the proapoptotic gene Bax in a knockout mouse model abolished the RD-associated photoreceptor cell degeneration. CONCLUSIONS. Apoptosis is a major mechanism leading to photoreceptor cell death after RD. Blockage of the activity of the proapoptotic molecule Bax in a knockout mouse model prevents photoreceptor cell apoptosis and cell loss. These data suggest that the Bax-mediated apoptotic signaling pathway plays a critical role in RD-associated photoreceptor cell death. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retinal Serv,Dept Ophthalmol, Boston, MA 02115 USA. RP Chen, DF (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM dfchen@vision.eri.harvard.edu FU NEI NIH HHS [EY012983] NR 40 TC 56 Z9 68 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2004 VL 45 IS 2 BP 648 EP 654 DI 10.1167/iovs.03-0827 PG 7 WC Ophthalmology SC Ophthalmology GA 771CX UT WOS:000188769000039 PM 14744910 ER PT J AU Safrit, JT Ruprecht, R Ferrantelli, F Xu, WD Kitabwalla, M Van Rompay, K Marthas, M Haigwood, N Mascola, JR Luzuriaga, K Jones, SA Mathieson, BJ Newell, ML AF Safrit, JT Ruprecht, R Ferrantelli, F Xu, WD Kitabwalla, M Van Rompay, K Marthas, M Haigwood, N Mascola, JR Luzuriaga, K Jones, SA Mathieson, BJ Newell, ML CA Ghent IAS Working Grp HIV Women TI Immunoprophylaxis to prevent mother-to-child transmission of HIV-1 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE immunoprophylaxis; prevention mother-to-child transmission; neonates; vaccines ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; BROADLY NEUTRALIZING ANTIBODIES; NEWBORN RHESUS MACAQUES; VERTICAL TRANSMISSION; NEONATAL MACAQUES; PASSIVE-IMMUNIZATION; PHASE-I; ENVELOPE GLYCOPROTEIN; MATERNAL ANTIBODIES AB Antiretroviral therapy can profoundly reduce the risk of mother-to-child transmission (MTCT) of HIV, but the drugs have a relatively short half-life and should thus be administered throughout breast-feeding to optimally prevent postnatal infection of the infant. The potential toxicities and the development of resistance may limit the long-term efficacy of antiretroviral prophylaxis, and a safe and effective active/passive immunoprophylaxis regimen, begun at birth, and potentially overlapping with interpartum or neonatal chemoprophylaxis, would pose an attractive alternative. This review draws on data presented at the Ghent Workshop on prevention of breast milk transmission and on selected issues from a workshop specifically relating to immunoprophylaxis held in Seattle in October 2002. This purpose of this review is to address the scientific rationale for the development of passive (antibody) and active (vaccine) immunization strategies for prevention of MTCT. Data regarding currently or imminently available passive and active immunoprophylaxis products are reviewed for their potential use in neonatal trials within the coming 1-2 years. C1 UCL, Ctr Paediat Epidemiol & Biostat, Inst Child Hlth, London, England. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. NIAID, Vaccine Res Ctr, Bethesda, MD USA. Univ Massachusetts, Sch Med, Worcester, MA USA. NIAID, Div Aids, Bethesda, MD 20892 USA. US Dept HHS, NIH, Off AIDS Res, Bethesda, MD USA. UCL, Inst Child Hlth, London, England. RP Newell, ML (reprint author), UCL, Ctr Paediat Epidemiol & Biostat, Inst Child Hlth, London, England. EM m.newell@ich.ucl.ac.uk RI Van de Perre, Philippe/B-9692-2008; Ferrantelli, Flavia/J-7794-2016; OI Van de Perre, Philippe/0000-0002-3912-0427; Ferrantelli, Flavia/0000-0002-0768-1078; Newell, Marie-Louise/0000-0002-1074-7699 NR 47 TC 43 Z9 43 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 2004 VL 35 IS 2 BP 169 EP 177 DI 10.1097/00126334-200402010-00012 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 804VU UT WOS:000220327000012 PM 14722451 ER PT J AU Yildiz, A Pauler, DK Sachs, GS AF Yildiz, A Pauler, DK Sachs, GS TI Rates of study completion with single versus split daily dosing of antidepressants: a meta-analysis SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE antidepressants; single daily dosing; acceptability; compliance ID DOSAGE REGIMENS; DEPRESSED OUTPATIENTS; GENERAL-PRACTICE; NIGHT-TIME; TRAZODONE; MEDICATION; AMITRIPTYLINE; EFFICACY AB Objective: To examine the tolerability of single versus multiple daily dosing (SDD vs. MDD) of antidepressant drugs in clinical practice. Method: Studies comparing single versus multiple daily dosing of antidepressants were reviewed. Since there were no numeric data available on the rates of adverse events for the SDD versus MDD arms, meta-analyses were carried out to compare rates of study completers (or rates of drop-outs) with single versus multiple daily dosing. Results: The review process identified 22 studies meeting our inclusion criteria. This meta-analysis found no difference in the rates of study completers with SDD or MDD regime of antidepressants. Conclusion: Our analysis on rates of completers (or rates of drop-outs) gives us an estimation of the overall acceptability of treatment and of course, but has limited utility when compared to the rates of adverse events. Yet, the present analyses suggest that adverse events which are significant enough to result in drop-outs, are not more frequent with SDD than MDD. MDD strategy of antidepressants does not seem to be more advantageous for the acceptability of treatment and obviously is disadvantageous for compliance. Thus, a simplified treatment regimen may be practical to increase treatment success rates in depression. (C) 2004 Elsevier B.V. All rights reserved. C1 Dokuz Eylul Med Sch, Dept Psychiat, Izmir, Turkey. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bipolar Program, Boston, MA 02115 USA. RP Yildiz, A (reprint author), 170 Sok Guller Apt 8-8 Pk, TR-35360 Izmir, Turkey. EM agul_yildiz@hotmail.com NR 30 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2004 VL 78 IS 2 BP 157 EP 162 DI 10.1016/S0165-0327(02)00300-2 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 767XX UT WOS:000188500100009 PM 14706727 ER PT J AU Clark, S Bock, SA Gaeta, TJ Brenner, BE Cydulka, RK Camargo, CA AF Clark, S Bock, SA Gaeta, TJ Brenner, BE Cydulka, RK Camargo, CA TI Multicenter study of emergency department visits for food allergies SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE food allergy; emergency department; epinephrine ID ANAPHYLACTIC REACTIONS; EPIDEMIOLOGY; ROOM AB Background: Relatively little is known about the characteristics of patients who visit the emergency department (ED) for an acute allergic reaction. Although anaphylaxis guidelines suggest treatment with epinephrine, teaching about self-injectable epinephrine, and referral to an allergist, current ED management remains uncertain. Objective: The objective of this study was to describe the management of food-related acute allergic reactions. Methods: The Multicenter Airway Research Collaboration performed a chart review study in 21 North American EDs. Investigators reviewed a random sample of 678 charts of patients who presented with food allergy (International Classification of Diseases-ninth revision codes 693.1, 995.0, 995.3, and 995.60-995.69). Results: Patients had an average age of 29 years; the cohort was 57% female and 40% white. A variety of foods provoked the allergic reaction, including nuts (21%), crustaceans (19%), fruit (12%), and fish (10%). Although exposure to these foods can be life threatening, only 18% of patients came to the ED by ambulance. In the ED, 72% of patients received antihistamines, 48% received systemic corticosteroids, and 16% received epinephrine; 33% received respiratory treatments such as inhaled albuterol. Among patients with severe reactions (55% of total), 24% received epinephrine. Overall, 97% of patients were discharged to home. At ED discharge, 16% of patients were prescribed self-injectable epinephrine, and 12% were referred to an allergist. Conclusions: Although guidelines suggest specific approaches for the management of acute allergic reactions, ED concordance for food allergy appears low. These findings support a new collaboration between professional organizations in allergy and emergency medicine and the development of educational programs and materials for ED patients and staff. C1 Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Natl Jewish Med & Res Ctr, Denver, CO USA. New York Methodist Hosp, Dept Emergency Med, Brooklyn, NY USA. Univ Arkansas Med Sci, Dept Emergency Med, Little Rock, AR 72204 USA. Metrohlth Med Ctr, Dept Emergency Med, Cleveland, OH USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA USA. RP Clark, S (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St,Clin Bldg 397, Boston, MA 02114 USA. FU NIEHS NIH HHS [T32 ES07069] NR 18 TC 164 Z9 165 U1 2 U2 13 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2004 VL 113 IS 2 BP 347 EP 352 DI 10.1016/j.jaci.2003.10.053 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 773EX UT WOS:000188885700026 PM 14767453 ER PT J AU Xiao, XS Mukkamala, R Sheynberg, N Grenon, SM Ehrman, MD Mullen, TJ Ramsdell, CD Williams, GH Cohen, RJ AF Xiao, XS Mukkamala, R Sheynberg, N Grenon, SM Ehrman, MD Mullen, TJ Ramsdell, CD Williams, GH Cohen, RJ TI Effects of simulated microgravity on closed-loop cardiovascular regulation and orthostatic intolerance: analysis by means of system identification SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE sympathetic; parasympathetic; syncope; bed rest; autonomic function ID DOWN BED REST; SYMPATHETIC-NERVE ACTIVITY; HEART-RATE-VARIABILITY; VASCULAR-RESISTANCE; CARDIAC ATROPHY; SPACEFLIGHT; BAROREFLEX; PRESSURE; SPACE; HYPOTENSION AB Microgravity-induced orthostatic intolerance (OI) continues to be a primary concern for the human space program. To test the hypothesis that exposure to simulated microgravity significantly alters autonomic nervous control and, thus, contributes to increased incidence of OI, we employed the cardiovascular system identification (CSI) technique to evaluate quantitatively parasympathetic and sympathetic regulation of heart rate (HR). The CSI method analyzes second-to-second fluctuations in noninvasively measured HR, arterial blood pressure, and instantaneous lung volume. The coupling mechanisms between these signals are characterized by using a closed-loop model. Parameters reflecting parasympathetic and sympathetic responsiveness with regard to HR regulation can be extracted from the identified coupling mechanisms. We analyzed data collected from 29 human subjects before and after 16 days of head-down-tilt bed rest ( simulated microgravity). Statistical analyses showed that parasympathetic and sympathetic responsiveness was impaired by bed rest. A lower sympathetic responsiveness and a higher parasympathetic responsiveness measured before bed rest identified individuals at greater risk of OI before and after bed rest. We propose an algorithm to predict OI after bed rest from measures obtained before bed rest. C1 MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02142 USA. Harvard Univ, Brigham & Womens Hosp, Div Endocrine Hypertens,Dept Med, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. McGill Univ, Dept Cardiothorac Surg, Montreal, PQ H3G 1A4, Canada. RP Cohen, RJ (reprint author), MIT, Harvard MIT Div Hlth Sci & Technol, Rm E25-335A,45 Carleton St, Cambridge, MA 02142 USA. FU NCI NIH HHS [CA00206, CA00202]; NCRR NIH HHS [RR-02635] NR 41 TC 15 Z9 15 U1 3 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB 1 PY 2004 VL 96 IS 2 BP 489 EP 497 DI 10.1152/japplphysiol.00602.2003 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 761EU UT WOS:000187888400012 PM 14514703 ER PT J AU Zhao, JL Pergola, PE Roman, LJ Kellogg, DL AF Zhao, JL Pergola, PE Roman, LJ Kellogg, DL TI Bioactive nitric oxide concentration does not increase during reactive hyperemia in human skin SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE skin blood flow; vasodilation; amperometric electrode; laser-Doppler flowmetry ID HUMAN FOREARM; HEAT-STRESS; SUBSTANCE-P; VASODILATATION; SYNTHASE; VESSELS AB This study examined whether nitric oxide ( NO) is involved in the cutaneous response to reactive hyperemia ( RH) in the human forearm. We enrolled seven healthy volunteers. NO concentrations were monitored using a NO selective amperometric electrode (ISO-NOP200, World Precision Instruments) inserted into the skin of the forearm. Laser-Doppler flowmetry ( Moor Instruments) was used for monitoring skin blood flow (SkBF) at the same site. SkBF and NO levels were monitored and recorded continuously throughout the experiment. An intradermal microdialysis probe was inserted adjacent to the NO electrode for drug delivery. Data collection began 140 min after the NO electrodes and microdialysis probes were inserted. RH was achieved by the inflation of a blood pressure cuff to 25 mmHg above systolic pressure for 7 min after which the pressure in the cuff was abruptly released. Acetylcholine (ACh) was given by microdialysis probe at the end of RH study to verify the ability of the electrode system to detect changes in the NO concentration. SkBF and NO data before RH and immediately, 2, 5, 7, and 10 min after cuff deflation were used for analysis. SkBF increased immediately after release of the occlusion ( P < 0.0001) and remained elevated for 2 min. No significant NO changes occurred with the increases in LDF. ACh induced increases in both SkBF and NO ( P < 0.000 and P < 0.037, respectively). We conclude that RH increases SkBF by mechanisms that do not require a measurable increase in NO concentrations. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Geriatr & Gerontol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. Dept Vet Affairs, S Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp Div, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Kellogg, DL (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Geriatr & Gerontol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NHLBI NIH HHS [HL-65599] NR 29 TC 40 Z9 40 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB 1 PY 2004 VL 96 IS 2 BP 628 EP 632 DI 10.1152/japplphysiol.00639.2003 PG 5 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 761EU UT WOS:000187888400029 PM 14715681 ER PT J AU Sinha, RK Kim, SY Rubash, HE AF Sinha, RK Kim, SY Rubash, HE TI Long-stem cemented calcar replacement arthroplasty for proximal femoral bone loss SO JOURNAL OF ARTHROPLASTY LA English DT Article DE calcar; bone loss; revision; hip arthroplasty; long stern ID TOTAL HIP-ARTHROPLASTY; 5-YEAR FOLLOW-UP; REVISION; COMPONENT; 2ND-GENERATION; CLASSIFICATION AB Revision total hip arthroplasty with accompanying bone defects may require calcar replacement prostheses to restore hip stability and function. Twenty-nine hips in 27 patients were followed for a mean of 41 months (range, 24-101 months). The average Harris Hip Score increased from 34 to 82 points. Acceptable cement mantles (A, B, C1) were present in all cases. Three femoral components (10.3%) were re-revised as a result of aseptic loosening. Two others (6.9%) were loose by radiographic criteria. Thus, 24 (82.8%) of the 29 index femoral components were rigidly fixed according to radiographic criteria, whereas 26 (89.7%) still were in place at the time of review. The results of this Study suggest that long-stem cemented calcar-replacement prostheses with modern cementing technique are a reasonable option in femoral revision arthroplasties involving proximal bone loss. (C) 2004 Elsevier Inc. All rights reserved. C1 Desert Orthoped Ctr, Rancho Mirage, CA USA. Kyungpook Univ Hosp, Dept Orthoped Surg, Taegu, South Korea. Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. RP Sinha, RK (reprint author), Desert Orthoped Ctr, Rancho Mirage, CA USA. OI Kim, Shin-Yoon/0000-0002-5445-648X NR 22 TC 4 Z9 7 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2004 VL 19 IS 2 BP 141 EP 150 DI 10.1016/S0883-5403(03)00457-1 PG 10 WC Orthopedics SC Orthopedics GA 776MG UT WOS:000189119300002 PM 14973855 ER PT J AU Bozic, KJ Saleh, KJ Rosenberg, AG Rubash, HE AF Bozic, KJ Saleh, KJ Rosenberg, AG Rubash, HE TI Economic evaluation in total hip arthroplasty - Analysis and review of the literature SO JOURNAL OF ARTHROPLASTY LA English DT Review DE total hip arthroplasty; economic analysis; literature review ID DEEP-VEIN THROMBOSIS; COST-EFFECTIVENESS ANALYSIS; MOLECULAR-WEIGHT HEPARIN; TOTAL JOINT ARTHROPLASTY; POSTOPERATIVE BLOOD SALVAGE; KNEE ARTHROPLASTY; HEALTH-CARE; ORTHOPEDIC-SURGERY; IMPLANT STANDARDIZATION; HOSPITAL COST AB We performed a bibliographic search of MEDLINE databases from January 1966 to July 2002 to identify English language articles that contained either "cost" or "economic" in combination with "total hip arthroplasty" (THA) in the abstract or title. Each study was then critically reviewed for content, technique, and adherence to established healthcare economic principles. Only 81 of the 153 studies retrieved contained actual economic data. Only 6% of studies adhered to established criteria for a comprehensive health care economic analysis. Although the number of publications regarding economic evaluation of THA is on the rise, the methodologic quality of many of these studies remains inadequate. Future studies should employ sound healthcare economic techniques to properly evaluate and assess the true social and economic value of THA. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Calif San Francisco, Med Ctr, Dept Orthopaed Surg, San Francisco, CA 94143 USA. Univ Minnesota, Dept Orthopaed Surg, Minneapolis, MN 55455 USA. Rush Presbyterian St Lukes Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Bozic, KJ (reprint author), Univ Calif San Francisco, Med Ctr, Dept Orthopaed Surg, 500 Parnassus Ave,MU 320W, San Francisco, CA 94143 USA. OI Saleh, Khaled/0000-0002-7734-1933 NR 99 TC 50 Z9 50 U1 2 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2004 VL 19 IS 2 BP 180 EP 189 DI 10.1016/S0883-5403(03)00456-X PG 10 WC Orthopedics SC Orthopedics GA 776MG UT WOS:000189119300008 PM 14973861 ER PT J AU Suggs, JF Li, GA Park, SE Steffensmeier, S Rubash, HE Freiberg, AA AF Suggs, JF Li, GA Park, SE Steffensmeier, S Rubash, HE Freiberg, AA TI Function of the anterior cruciate ligament after unicompartmental knee arthroplasty - An in vitro robotic study SO JOURNAL OF ARTHROPLASTY LA English DT Article DE unicompartmental knee arthroplasty; anterior cruciate ligament; kinematics; knee; biomechanics ID 10-YEAR FOLLOW-UP; OSTEOARTHRITIC KNEES; GRAFT FIXATION; OXFORD KNEE; ARTHRITIS; ACL; REPLACEMENT; KINEMATICS; PROSTHESES; MOVEMENT AB The objective of this study was to investigate the role of the anterior cruciate ligament (ACL) in the anterior-posterior (AP) stability of the knee after unicompartmental knee arthroplasty (UKA). AP tibial loads were applied to human cadaveric knee specimens using a robotic testing system. After UKA, the knee exhibited tibial translations similar to that of the native knee, and the forces in the ACL were also similar to those seen in the native knee. The ACL-deficient knee after UKA exhibited significantly greater anterior tibial translations than the native knee and the knee after UKA with an intact ACL. These data Suggest that medial UKA does not alter the anterior stability of the knee, but a functional ACL is necessary to ensure normal stability after UKA. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Bioengn Lab, Boston, MA 02114 USA. MIT, Dept Mech Engn, Cambridge, MA 02139 USA. Zimmer Inc, Warsaw, Poland. Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Li, GA (reprint author), Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. NR 31 TC 16 Z9 17 U1 0 U2 5 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 J9 J ARTHROPLASTY JI J. Arthroplast. PD FEB PY 2004 VL 19 IS 2 BP 224 EP 229 DI 10.1016/j.arth.2003.08.018 PG 6 WC Orthopedics SC Orthopedics GA 776MG UT WOS:000189119300014 PM 14973867 ER PT J AU Wing, HJ Yan, AW Goldman, SR Goldberg, MB AF Wing, HJ Yan, AW Goldman, SR Goldberg, MB TI Regulation of IcsP, the outer membrane protease of the Shigella actin tail assembly protein IcsA, by virulence plasmid regulators VirF and VirB SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ESCHERICHIA-COLI; TRANSCRIPTIONAL ACTIVATION; INTRACELLULAR MOVEMENT; UNIPOLAR LOCALIZATION; INVASION GENES; SUICIDE VECTOR; CELL INVASION; H-NS; FLEXNERI; EXPRESSION AB The Shigella outer membrane protease IcsP removes the actin assembly protein IcsA from the bacterial surface, and consequently modulates Shigella actin-based motility and cell-to-cell spread. Here, we demonstrate that IcsP expression is undetectable in mutants lacking either of two transcriptional activators, VirF and VirB. In wild-type Shigella spp., virB expression is entirely dependent on VirF; therefore, to circumvent this regulatory cascade, we independently expressed VirF or VirB in Shigella strains lacking both activators and measured both IcsP levels and transcription from the icsP promoter. Our results show that VirB significantly enhanced icsP transcription, even in the absence of VirF. In contrast, when VirF was induced in the absence of VirB, VirF had variable effects. The regulation of icsP is distinctly different from the regulation of the gene encoding its major substrate, icsA, which is activated by VirF and not VirB. We propose that the different pathways regulating icsA and icsP may be critical to the modulation of IcsA-mediated actin-based motility by IcsP. C1 Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. RP Goldberg, MB (reprint author), Univ Pk,65 Landsdowne St, Cambridge, MA 02139 USA. EM mgoldberg1@partners.org FU NIAID NIH HHS [R01 AI035817, AI35817, AI43562] NR 39 TC 22 Z9 24 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2004 VL 186 IS 3 BP 699 EP 705 DI 10.1128/JB.186.3.699-705.2004 PG 7 WC Microbiology SC Microbiology GA 766HU UT WOS:000188371600013 PM 14729695 ER PT J AU Shen, BJ McCreary, CP Myers, HF AF Shen, BJ McCreary, CP Myers, HF TI Independent and mediated contributions of personality, coping, social support, and depressive symptoms to physical functioning outcome among patients in cardiac rehabilitation SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE coronary heart disease (CHD); depression; hostility; optimism; social support ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; HEART-DISEASE; BYPASS-SURGERY; HOSTILITY; HEALTH; METAANALYSIS; PROGNOSIS; RESOURCES; OPTIMISM AB This study examined the direct and mediated contributions of psychosocial variables to posttreatment physical functioning among 142 patients receiving cardiac rehabilitation. Two models were proposed and tested. In the first model, psychosocial factors were correlated and made to predict baseline and 6-week physical functioning. The results showed that after controlling for age, illness severity, baseline physical functioning, and other psychosocial correlates, optimism and social support still significantly predicted better posttreatment physical functioning. In the second model, we explored both the direct and mediational relationships between psychosocial factors and physical health outcomes. Optimism and social support were found to contribute to health outcomes not only directly but also indirectly through the mediation of less engagement in detrimental coping and lower depressive symptoms, whereas hostility and negative coping only predicted outcomes indirectly through mediators. These findings highlighted the importance of addressing psychosocial issues and their interrelationships in cardiac rehabilitation. C1 Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. VA Greater Los Angeles Hlth Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Shen, BJ (reprint author), Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. EM bshen@miami.edu NR 49 TC 55 Z9 58 U1 2 U2 9 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD FEB PY 2004 VL 27 IS 1 BP 39 EP 62 DI 10.1023/B:JOBM.0000013643.36767.22 PG 24 WC Psychology, Clinical SC Psychology GA 768FC UT WOS:000188532100004 PM 15065475 ER PT J AU London, MJ Itani, KMF Perrino, AC Guarino, PD Schwartz, GG Cunningham, F Gottlieb, SS Henderson, WG AF London, MJ Itani, KMF Perrino, AC Guarino, PD Schwartz, GG Cunningham, F Gottlieb, SS Henderson, WG TI Perioperative beta-blockade: A survey of physician attitudes in the department of veterans affairs SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE postoperative complications; perioperative period; beta-adrenergic receptor antagonists; vascular surgery; noncardiac surgery; clinical surveys ID SILENT-MYOCARDIAL-ISCHEMIA; MAJOR VASCULAR-SURGERY; HIGH-RISK PATIENTS; NONCARDIAC SURGERY; CARDIAC EVENTS; CARDIOVASCULAR MORBIDITY; MORTALITY; GUIDELINE; BLOCKERS; ASSOCIATION AB Objective: To delineate clinician opinion on the efficacy, safety, and logistics of perioperative beta-adrenergic blockade for patients undergoing noncardiac surgery. Design: Survey of opinions and clinical practices. Setting: Internet-based survey form. Participants: Members of the Associations of Veterans Affairs Anesthesiologists and Surgeons and chiefs of cardiology in centers with surgical programs. Interventions: None. Measurements and Main Results: One hundred twenty-seven responses from 62 Veterans Affairs Medical Centers in 35 states (57 anesthesiologists, 45 surgeons, 25 cardiologists) were analyzed. Ninety-two percent agreed that it is effective in reducing short-term adverse outcomes, declining to 60% for long-term outcome. There was greater enthusiasm for its use in patients with known coronary artery disease (87%) than in patients with risk factors only (72%). Although 66% considered it efficacious in vascular surgery, only 30% were convinced it was for nonvascular surgery (with a similar distribution for safety in these settings). Preoperative use was favored (94%), with most physicians favoring use within 1 week of surgery (52%). Most favored 1 to 2 weeks of postoperative therapy (43%), with the remainder favoring shorter (19%) or longer (35%) durations. Although 71% of clinicians reported frequent use in their practice, most believed its use was largely informal by their colleagues (83%) and rarely based on a formal clinical pathway (13%). Conclusion: A wide range of opinions by clinicians regarding the efficacy, safety, and logistics of perioperative beta-adrenergic blockade was encountered, suggesting need for additional clinical research and centralized efforts at increasing compliance with existing guidelines. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. Baylor Coll Med, Dept Surg, Houston Vet Affairs Med Ctr, Houston, TX 77030 USA. Yale Univ, Sch Med, Dept Anesthesia, Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 USA. W Haven Cooperat Studies Coordinating Ctr, Dept Vet Affairs, West Haven, CT USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver Vet Affairs Med Ctr, Denver, CO USA. Hines VAMC, Pharm Benefits Management Grp, Hines, IL USA. Univ Maryland, Sch Med, Dept Med, Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. Univ Colorado, Hlth Outcomes Program, Hlth Sci Ctr, Denver, CO 80202 USA. RP London, MJ (reprint author), Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. NR 27 TC 15 Z9 16 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1053-0770 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD FEB PY 2004 VL 18 IS 1 BP 14 EP 24 DI 10.1053/j.jvca.2003.10.004 PG 11 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA 777CZ UT WOS:000189158300003 PM 14973793 ER PT J AU Mann, DP Alston, TA AF Mann, DP Alston, TA TI Bubble trouble SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE air embolus; norepinephrine; prostaglandin E-1 ID NOREPINEPHRINE INFUSION; CARDIOPULMONARY BYPASS; PULMONARY-HYPERTENSION; PROSTAGLANDIN-E1; FAILURE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Cardiac Anesthesia Grp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Alston, TA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Cardiac Anesthesia Grp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM talston@partners.org NR 6 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1053-0770 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD FEB PY 2004 VL 18 IS 1 BP 112 EP 113 DI 10.1053/j.jvca.2003.10.025 PG 2 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA 777CZ UT WOS:000189158300024 PM 14973816 ER PT J AU Barequet, IS Yu, E Vitale, S Cassard, S Azar, DT Stark, WJ AF Barequet, IS Yu, E Vitale, S Cassard, S Azar, DT Stark, WJ TI Astigmatism outcomes of horizontal temporal versus nasal dear corneal incision cataract surgery SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID CLEAR CORNEAL; TUNNEL INCISIONS; FOLLOW-UP; PHACOEMULSIFICATION; SUPERIOR; INFLAMMATION; SUTURE AB Purpose: To compare the short- and long-term astigmatism outcomes after cataract surgery using temporal clear horizontal corneal incisions and nasal horizontal clear corneal incisions. Setting: Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, USA. Methods: This retrospective study included a consecutive series of eyes having phacoemulsification with implantation of a 6.0 mm foldable acrylic intraocular lens through a 3.5 mm horizontal clear corneal incision at 180 degrees (temporal incision in right eyes, nasal incision in left eyes). Astigmatism was measured by keratometry readings before surgery and 6 weeks and 12 months postoperatively. Results: The mean preoperative astigmatism in the 178 eyes (94 right, 84 left) of 161 patients was 0.78 diopter (D); 54.5% of eyes had against-the-rule (ATR) astigmatism, 22.5% had with-the-rule (WTR) astigmatism, and 14.0% were astigmatically neutral. A significant shift toward WTR astigmatism occurred postoperatively. At 6 weeks, 48.3% of eyes had WTR astigmatism and 23.0% had ATR astigmatism. At 12 months, 43.8% had WTR astigmatism and 25.8% had ATR astigmatism. Vector analysis revealed a mean surgically induced astigmatism (SIA) of 1.17 D at 6 weeks and 1.04 D at 12 months. The side of the incision significantly affected SIA. At 6 weeks, temporal incisions yielded a mean SIA of 0.74 D and the nasal incisions, of 1.65 D. This trend in SIA persisted at 12 months: 0.71 D for temporal incisions and 1.41 D for nasal incisions. Conclusions: Cataract surgery using a horizontal clear corneal incision induced WTR astigmatism 6 weeks and 12 months postoperatively. Temporal incisions induced significantly less astigmatism than nasal incisions. C1 Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21287 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. Tel Aviv Univ, Sackler Fac Med, Goldschleger Eye Inst, IL-52621 Tel Hashomer, Israel. RP Stark, WJ (reprint author), Wilmer Eye Inst, Maumenee 327,600 No Wolfe St, Baltimore, MD USA. EM wstark@jhmi.edu NR 24 TC 38 Z9 46 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD FEB PY 2004 VL 30 IS 2 BP 418 EP 423 DI 10.1016/S0886-3350(03)00492-2 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 846CS UT WOS:000223293100025 PM 15030834 ER PT J AU Amory, JK Watts, NB Easley, KA Sutton, PR Anawalt, BD Matsumoto, AM Bremner, WJ Tenover, JL AF Amory, JK Watts, NB Easley, KA Sutton, PR Anawalt, BD Matsumoto, AM Bremner, WJ Tenover, JL TI Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; SEX STEROID-LEVELS; TRANSDERMAL TESTOSTERONE; LONGITUDINAL CHANGES; TURNOVER MARKERS; HYPOGONADAL MEN; HIP FRACTURE; ELDERLY MEN; ESTROGEN; AGE AB Older men, particularly those with low serum testosterone (T) levels, might benefit from T therapy to improve bone mineral density (BMD) and reduce fracture risk. Concerns exist, however, about the impact of T therapy on the prostate in older men. We hypothesized that the combination of T and finasteride (F), a 5alpha-reductase inhibitor, might increase BMD in older men without adverse effects on the prostate. Seventy men aged 65 yr or older, with a serum T less than 12.1 nmol/liter on two occasions, were randomly assigned to receive one of three regimens for 36 months: T enanthate, 200 mg im every 2 wk with placebo pills daily (T-only); T enanthate, 200 mg every 2 wk with 5 mg F daily (T+F); or placebo injections and pills (placebo). Low BMD was not an inclusion criterion. We obtained serial measurements of BMD of the lumbar spine and hip by dual x-ray absorptiometry. Prostate-specific antigen (PSA) and prostate size were measured at baseline and during treatment to assess the impact of therapy on the prostate. Fifty men completed the 36-month protocol. By an intent-to-treat analysis including all men for as long as they contributed data, T therapy for 36 months increased BMD in these men at the lumbar spine [10.2+/-1.4% (mean percentage increase from baseline+/-SEM; T-only) and 9.3+/-1.4% (T+F) vs. 1.3+/-1.4% for placebo (P<0.001)] and in the hip [2.7 +/- 0.7% (T-only) and 2.2 +/- 0.7% (T+F) vs. -0.2 +/- 0.7% for placebo, (P <= 0.02)]. Significant increases in BMD were seen also in the intertrochanteric and trochanteric regions of the hip. After 6 months of therapy, urinary deoxypyridinoline (a bone-resorption marker) decreased significantly compared with baseline in both the T-only and T+F groups (P<0.001) but was not significantly reduced compared with the placebo group. Over 36 months, PSA increased significantly from baseline in the T-only group (P<0.001). Prostate volume increased in all groups during the 36-month treatment period, but this increase was significantly less in the T+F group compared with both the T-only and placebo groups (P=0.02). These results demonstrate that T therapy in older men with low serum T increases vertebral and hip BMD over 36 months, both when administered alone and when combined with F. This finding suggests that dihydrotestosterone is not essential for the beneficial effects of T on BMD in men. In addition, the concomitant administration of F with T appears to attenuate the impact of T therapy on prostate size and PSA and might reduce the chance of benign prostatic hypertrophy or other prostate-related complications in older men on T therapy. These findings have important implications for the prevention and treatment of osteoporosis in older men with low T levels. C1 Emory Univ, Sch Med, Rollins Sch Publ Hlth, Dept Med, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30329 USA. Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH 45267 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Sch Med, Ctr Geriatr Res Educ & Clin, Seattle, WA 98195 USA. RP Tenover, JL (reprint author), Wesley Woods Hlth Ctr, 1841 Clifton Rd NE, Atlanta, GA 30329 USA. RI Easley, Kirk/K-6910-2015 OI Easley, Kirk/0000-0003-4419-2617 FU NIA NIH HHS [AG10975] NR 34 TC 256 Z9 274 U1 0 U2 5 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 1 PY 2004 VL 89 IS 2 BP 503 EP 510 DI 10.1210/jc.2003-031110 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771AT UT WOS:000188763900008 PM 14764753 ER PT J AU Matsumoto, AM Bremner, WJ AF Matsumoto, AM Bremner, WJ TI Editorial: Serum testosterone assays - Accuracy matters SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material ID BINDING GLOBULIN; MEN; TRANSPORT; PLASMA; WOMEN C1 Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. RP Bremner, WJ (reprint author), Univ Washington, Sch Med, Dept Med, 1959 NE Pacific St,Box 356420, Seattle, WA 98195 USA. EM wbremner@u.washington.edu NR 19 TC 123 Z9 128 U1 1 U2 3 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 1 PY 2004 VL 89 IS 2 BP 520 EP 524 DI 10.1210/jc.2003-032175 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771AT UT WOS:000188763900011 PM 14764756 ER PT J AU Miller, KK Rosner, W Lee, H Hier, J Sesmilo, G Schoenfeld, D Neubauer, G Klibanski, A AF Miller, KK Rosner, W Lee, H Hier, J Sesmilo, G Schoenfeld, D Neubauer, G Klibanski, A TI Measurement of free testosterone in normal women and women with androgen deficiency: Comparison of methods SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID COMPETITIVE PROTEIN BINDING; PLASMA TESTOSTERONE; ASSAY; RADIOIMMUNOASSAY; SERUM; REPLACEMENT AB Androgen deficiency in women is increasingly recognized as a new clinical syndrome and has raised our awareness of the importance of accurate and well-validated measurements of serum free testosterone (T) concentrations in women. Therefore, we compared serum free T levels measured by equilibrium dialysis to those measured by a direct RIA (analog method) and to those calculated from the law of mass action (requires the measurement of total T and SHBG). We also calculated the free androgen index, 100 x T/SHBG, as a simple index known to correlate with free T. Subjects were 147 women with variable androgen and estrogen statuses. All were studied three times in 1 month and included women 1) with regular menses (estrogen positive, T positive), 2) more than 50 yr old and not receiving estrogen (estrogen negative, T positive), 3) receiving estrogen (estrogen positive, T negative), and 4) with severe androgen deficiency secondary to hypopituitarism (estrogen negative, T negative). Calculated values for free T using the laws of mass action correlated well with those obtained from equilibrium dialysis (r=0.99; P<0.0001). However, the agreement depended strongly on the specific assays used for total T and SHBG. In contrast, the direct RIA method had unacceptably high systematic bias and random variability and did not correlate as well with equilibrium dialysis values (r=0.81; P<0.0001). In addition, the lower limit of detection was higher for the direct RIA than for equilibrium dialysis or calculated free T. Free androgen index correlates well with free T by equilibrium dialysis (r=0.93; P<0.0001), but is a unitless number without reference to the physical reality of free T. We conclude that the mass action equation and equilibrium dialysis are the preferred methods for use in diagnosing androgen deficiency in women. C1 Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Columbia Univ Coll Phys & Surg, New York, NY 10019 USA. Columbia Univ, St Lukes Roosevelt Hosp Ctr, New York, NY 10019 USA. Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gen Clin Res Ctr, Boston, MA 02114 USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM kkmiller@partners.org RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU NCRR NIH HHS [M01-RR-01066-27S1, M01-RR-01066]; NIDDK NIH HHS [R03-DK-59297] NR 30 TC 170 Z9 177 U1 1 U2 5 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 1 PY 2004 VL 89 IS 2 BP 525 EP 533 DI 10.1210/jc.2003-030680 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771AT UT WOS:000188763900012 PM 14764757 ER PT J AU Economides, PA Caselli, A Tiani, E Khaodhiar, L Horton, ES Veves, A AF Economides, PA Caselli, A Tiani, E Khaodhiar, L Horton, ES Veves, A TI The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID C-REACTIVE PROTEIN; COA-REDUCTASE INHIBITORS; NITRIC-OXIDE SYNTHASE; HIGH-DENSITY-LIPOPROTEIN; DEPENDENT VASODILATION; RANDOMIZED-TRIAL; STATIN THERAPY; MEDIATED VASODILATION; DOUBLE-BLIND; MELLITUS AB We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow-mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNFalpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Microcirculat Lab, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Veves, A (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Microcirculat Lab, Palmer 317,West Campus,1 Deaconess Rd, Boston, MA 02215 USA. EM aveves@bidmc.harvard.edu FU NCRR NIH HHS [RR 01032] NR 43 TC 79 Z9 82 U1 0 U2 0 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 1 PY 2004 VL 89 IS 2 BP 740 EP 747 DI 10.1210/jc.2003-031116 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771AT UT WOS:000188763900046 PM 14764790 ER PT J AU Thadhani, R Mutter, WP Wolf, M Levine, RJ Taylor, RN Sukhatme, VP Ecker, J Karumanchi, SA AF Thadhani, R Mutter, WP Wolf, M Levine, RJ Taylor, RN Sukhatme, VP Ecker, J Karumanchi, SA TI First trimester placental growth factor and soluble Fms-like tyrosine kinase 1 and risk for preeclampsia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LOW-DOSE ASPIRIN; PREGNANCY-INDUCED HYPERTENSION; MATERNAL SERUM LEVELS; INSULIN-RESISTANCE; SUBSEQUENT PREECLAMPSIA; PREVENT PREECLAMPSIA; RANDOMIZED-TRIAL; POTENTIAL ROLE; WOMEN; 2ND-TRIMESTER AB An imbalance of pro- and antiangiogenic factors may lead to preeclampsia (PE). In this prospective nested case-control study, we investigated whether first trimester serum levels of placental growth factor (PlGF), a potent angiogenic factor, and its soluble inhibitor, soluble fms-like tyrosine kinase 1 (sFlt1), distinguished women who developed PE (n = 40) from those who developed gestational hypertension (n = 40), delivered a small for gestational age (SGA) newborn (n = 40), or completed a full term normal pregnancy (n = 80). Compared with controls, serum PlGF levels were lower among women who developed PE (2 +/- 24 pg/ml vs. 63 +/- 145 pg/ml; P < 0.01) or gestational hypertension (27 +/- 19 pg/ml; P = 0.03), or who delivered a SGA newborn (21 +/- 16 pg/ml; P < 0.01). In contrast, serum sFlt1 levels did not markedly differ between the groups: PE, 1048 +/- 657 pg/ml; gestational hypertension, 942 +/- 437 pg/ml; SGA newborns, 1011 +/- 479 pg/ml; and normal controls, 973 +/- 490 pg/ml. Multivariable analysis adjusting for potential confounders and serum sFlt1 levels demonstrated a 3.7-fold (95% confidence interval, 1.2-12.5) increase in risk for PE for every log unit decrease in serum levels of PlGF compared with controls. Analyses for gestational hypertension and SGA were not significant. Examined in tertiles, the risk for PE was increased 28.7-fold (95% confidence interval, 2.3-351.0) in the third (< 12 pg/ml) compared with the first (>39 pg/ml) PlGF tertile. First trimester serum levels of PlGF and sFlt1 may identify women at high risk for PE. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02114 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Obstet & Gynecol, Boston, MA 02215 USA. NICHHD, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. RP Thadhani, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Bullfinch 127,55 Fruit St, Boston, MA 02114 USA. EM thadhani.r@mgh.harvard.edu FU NCRR NIH HHS [RR17376]; NHLBI NIH HHS [HL73469]; NICHD NIH HHS [HD39223]; NIDDK NIH HHS [DK02825, DK64255] NR 55 TC 271 Z9 283 U1 1 U2 10 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 1 PY 2004 VL 89 IS 2 BP 770 EP 775 DI 10.1210/jc.2003-031244 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771AT UT WOS:000188763900051 PM 14764795 ER PT J AU Asilmaz, E Cohen, P Miyazaki, M Dobrzyn, P Ueki, K Fayzikhodjaeva, G Soukas, AA Kahn, CR Ntambi, JM Socci, ND Friedman, JM AF Asilmaz, E Cohen, P Miyazaki, M Dobrzyn, P Ueki, K Fayzikhodjaeva, G Soukas, AA Kahn, CR Ntambi, JM Socci, ND Friedman, JM TI Site and mechanism of leptin action in a rodent form of congenital lipodystrophy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID STEAROYL-COA DESATURASE-1; FATTY-ACID OXIDATION; REVERSES INSULIN-RESISTANCE; ACTIVATED PROTEIN-KINASE; ADIPOSE-TISSUE; MALONYL-COA; GLUCOSE-METABOLISM; DIABETES-MELLITUS; GENE-EXPRESSION; WHITE ADIPOSE AB Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2-associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin's antisteatotic actions. Intracere-broventricular leptin improves glucose homeostasis by improving insulin signal transducrion in liver, but in this case the effect appears to be independent of SCD-1. C1 Rockefeller Univ, Howard Hughes Med Inst, Genet Mol Lab, New York, NY 10021 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. Albert Einstein Coll Med, Seaver Fdn Ctr Bioinformat, Bronx, NY 10467 USA. RP Friedman, JM (reprint author), Rockefeller Univ, Howard Hughes Med Inst, Genet Mol Lab, 1230 York Ave,Box 305, New York, NY 10021 USA. EM friedj@mail.rockefeller.edu RI Dobrzyn, Pawel/R-4076-2016 OI Dobrzyn, Pawel/0000-0002-2433-1897 FU NIDDK NIH HHS [R01 DK041096, R01 DK062388, R01-DK41096, R01-DK62388]; NIGMS NIH HHS [GM07739, T32 GM007739] NR 46 TC 123 Z9 129 U1 0 U2 2 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 2004 VL 113 IS 3 BP 414 EP 424 DI 10.1172/JCI200419511 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 770YQ UT WOS:000188759300014 PM 14755338 ER PT J AU Rohl, M Pasparakis, M Baudler, S Baumgartl, J Gautam, D Huth, M De Lorenzi, R Krone, W Rajewsky, K Bruning, JC AF Rohl, M Pasparakis, M Baudler, S Baumgartl, J Gautam, D Huth, M De Lorenzi, R Krone, W Rajewsky, K Bruning, JC TI Conditional disruption of I kappa B kinase 2 fails to prevent obesity-induced insulin resistance SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NECROSIS-FACTOR-ALPHA; IKK-BETA; RECEPTOR SUBSTRATE-1; MICE LACKING; PHOSPHORYLATION; CELLS; ACTIVATION; DELETION; SUBUNIT; COMPLEX AB The inhibitor of NF-kappaB (IkappaB) kinases (IKK1 [alpha] and IKK2 [beta]), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on serine residues, targeting them for degradation and thus activating the transcription factor NF-kappaB. More recently, IKK2 has been implicated in mediation of insulin resistance caused by obesity, lipid infusion, and TNF-alpha, stimulation, since salicylate and aspirin, known inhibitors of IKK activity, can reverse insulin resistance in obese mouse models. To further genetically elucidate the role of IKK2 in obesity-mediated insulin resistance, we have conditionally inactivated the mouse IKK2 gene in adult myocytes by Cre-loxP-mediated recombination in vivo. We have investigated the development of obesity-induced insulin resistance in muscle-specific IKK2 knockout mice and mice exhibiting a 50% reduction of IKK2 expression in every tissue and have found that, after gold thioglucose treatment, wild-type and mutant mice developed obesity to a similar extent. Surprisingly, no difference in obesity-induced insulin resistance was detectable, either at a physiological or at a molecular level. Moreover, impaired glucose tolerance resulting from a high-fat diet occurred to the same degree in control and IKK2 mutant mice. These data argue against a substantial role for muscular IKK2 in mediating obesity-induced insulin resistance in these models in vivo. C1 Univ Cologne, Dept Mouse Genet & Metab, Inst Genet, D-50931 Cologne, Germany. CMMC, D-50931 Cologne, Germany. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Univ Cologne, KLin 2, Cologne, Germany. Univ Cologne, Poliklin Innere Med, Cologne, Germany. European Mol Biol Lab, Mouse Biol Programme, Monterotondo, Italy. RP Bruning, JC (reprint author), Univ Cologne, Dept Mouse Genet & Metab, Inst Genet, Weyertal 121, D-50931 Cologne, Germany. EM jens.bruening@uni-koeln.de NR 23 TC 73 Z9 76 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 2004 VL 113 IS 3 BP 474 EP 481 DI 10.1172/JCI200418712 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 770YQ UT WOS:000188759300020 PM 14755344 ER PT J AU Chan, IT Kutok, JL Williams, IR Cohen, S Kelly, L Shigematsu, H Johnson, L Akashi, K Tuveson, DA Jacks, T Gilliland, DG AF Chan, IT Kutok, JL Williams, IR Cohen, S Kelly, L Shigematsu, H Johnson, L Akashi, K Tuveson, DA Jacks, T Gilliland, DG TI Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; N-RAS; BONE-MARROW; TRANSGENIC MICE; LYMPHOPROLIFERATIVE DISEASE; ESSENTIAL THROMBOCYTHEMIA; HEMATOLOGIC MALIGNANCIES; INDEPENDENT PATHWAYS; CELL-TRANSFORMATION AB Oncogenic ras alleles are among the most common mutations found in patients with acute myeloid leukemia (AML). Previously, the role of oncogenic ras in cancer was assessed in model systems over-expressing oncogenic ras from heterologous promoters. However, there is increasing evidence that subtle differences in gene dosage and regulation of gene expression from endogenous promoters play critical roles in cancer pathogenesis. We characterized the role of oncogenic K-ras expressed from its endogenous promoter in the hematopoietic system using a conditional allele and IFN-inducible, Cre-mediated recombination. Mice developed a completely penetrant myeloproliferative syndrome characterized by leukocytosis with normal maturation of myeloid lineage cells; myeloid hyperplasia in bone marrow; and extramedullary hematopoiesis in the spleen and liver. Flow cytometry confirmed the myeloproliferative phenotype. Genotypic and Western blot analysis demonstrated Cre-mediated excision and expression, respectively, of the oncogenic K-ras allele. Bone marrow cells formed growth factor-independent colonies in methylcellulose cultures, but the myeloproliferative disease was not transplantable into secondary recipients. Thus, oncogenic K-ras induces a myeloproliferative disorder but not AML, indicating that additional mutations are required for AML development. This model system will be useful for assessing the contribution of cooperating mutations in AML and testing ras inhibitors in vivo. C1 Harvard Univ, Inst Med, Div Hematol, Dept Med,Med Sch, Boston, MA 02115 USA. Harvard Univ, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Exelixis Inc, San Francisco, CA USA. Univ Penn, Sch Med, Dept Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Canc Biol Abramson Family Canc Res Inst, Abramson Canc Ctr, Philadelphia, PA 19104 USA. MIT, Dept Biol, Cambridge, MA USA. MIT, Canc Res Ctr, Cambridge, MA USA. MIT, Ctr Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Gilliland, DG (reprint author), Harvard Univ, Inst Med, Div Hematol, Dept Med,Med Sch, 4 Blackfan Circle,Room 421, Boston, MA 02115 USA. EM gillilan@hihg.med.harvard.edu RI Williams, Ifor/D-3648-2011 OI Williams, Ifor/0000-0002-8810-2911 FU NCI NIH HHS [CA66996, P01 CA066996]; NIDDK NIH HHS [DK51564] NR 73 TC 180 Z9 187 U1 0 U2 2 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 2004 VL 113 IS 4 BP 528 EP 538 DI 10.1172/JCI200420476 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 774WA UT WOS:000189008000008 PM 14966562 ER PT J AU Hamilton, GA Carroll, DL AF Hamilton, GA Carroll, DL TI The effects of age on quality of life in implantable cardioverter defibrillator recipients SO JOURNAL OF CLINICAL NURSING LA English DT Article DE age; comparison with normative data; implantable cardioverter defibrillator; quality of life ID SUDDEN-DEATH; VENTRICULAR-ARRHYTHMIAS; PSYCHOSOCIAL IMPACT; ICD; PREVENTION; ADJUSTMENT; THERAPY AB Background. The implantable cardioverter defibrillator shows superiority over conventional pharmacological therapy. The implantable cardioverter defibrillator has been implanted with increasing frequency in patients who are either at risk for or have experienced a life-threatening dysrhythmia. Implantable cardioverter defibrillator recipients experience a myriad of physical, emotional and social adjustments, with little being known about the impact of age on trajectory. Aims, objectives and design. Therefore the purpose of the study is to examine the effects of age on health status, quality of life, and mood states of implantable cardioverter defibrillator recipients during the first year after implantation using a repeated measures design. Methods. A comparison of implantable cardioverter defibrillator patients' scores with other samples, both ill and well, are discussed to see how the two implantable cardioverter defibrillator age groups compare on the various measures. Human subjects approval was obtained from the institutional review board. Results. Seventy subjects, 51 males and 19 females, were recruited. There were 31 subjects between the ages of 21 and 62 years, mean age of 51 years, that comprised the younger age group, and 39 subjects between the ages of 67 and 84 years, mean age of 74 years, that comprised the older age group. Each subject completed the Medical Outcomes SF-36, the Ferrans and Powers Quality of Life Index, and the Profile of Moods States at time of implantable cardioverter defibrillator implantation, and 6 and 12 months later. Conclusions. The older age group was as expected less physically active, less satisfied with their physical functioning, and had slightly more anxiety at 6 and 12 months than the younger counterparts. The younger implantable cardioverter defibrillator recipients demonstrated some improvements over time in the perception of their physical adjustment and anxiety. Relevance to clinical practice. Comparison of the SF-36 with other populations with or without a medical condition revealed scores below norms in physical health for both groups, and only slightly higher than patients with heart failure for the older group. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hamilton, GA (reprint author), 601 George Hill Rd, Lancaster, MA 01523 USA. EM glenys@mac.com NR 30 TC 37 Z9 37 U1 2 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0962-1067 J9 J CLIN NURS JI J. Clin. Nurs. PD FEB PY 2004 VL 13 IS 2 BP 194 EP 200 DI 10.1046/j.1365-2702.2003.00846.x PG 7 WC Nursing SC Nursing GA 764UH UT WOS:000188224100009 PM 14723671 ER PT J AU Freedland, SJ Aronson, WJ Kane, CJ Presti, JC Amling, CL Elashoff, D Terris, MK AF Freedland, SJ Aronson, WJ Kane, CJ Presti, JC Amling, CL Elashoff, D Terris, MK TI Impact of obesity on biochemical control after radical prostatectomy for clinically localized prostate cancer: A report by the shared equal access regional cancer hospital database study group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; SEXTANT BIOPSIES; SEARCH DATABASE; UNITED-STATES; RISK FACTOR; FOLLOW-UP; RACE; DIET; PREVALENCE; RECURRENCE AB Purpose Given the limited information regarding the impact of obesity on treatment outcomes for prostate cancer, we sought to examine the relationship between body mass index (BMI) and cancer control after radical prostatectomy (RP). Patients and Methods We compared clinicopathologic and biochemical outcome information across BMI groups from 1,106 men treated with BP between 1988 and 2002. Multivariate analysis was used to determine if BMI significantly predicted adverse pathology or biochemical recurrence. Results Obesity was related to year of surgery (P < .001) and race (P < .001), with black men having the highest obesity rates. Obese patients had higher biopsy and pathologic grade tumors (P < .001). On multivariate analysis, BMI greater than or equal to 35 kg/m(2) was associated with a trend for higher rates of positive surgical margins (P = .008). Overweight patients (BMI, 25 to 30 kg/m(2)) had a significantly decreased risk of seminal vesicle invasion (P = .039). After controlling for all preoperative clinical variables including year of surgery, BMI greater than or equal to 35 kg/m(2) significantly predicted biochemical failure after BP (P = .002). After controlling for surgical margin status, BMI greater than or equal to 35 kg/m(2) remained a significant predictor of biochemical failure (P = .012). There was a trend for BMI greater than or equal to 35 kg/m(2) to be associated with higher failure rates than BMI between 30 and 35 kg/m(2) (P = .053). Conclusion The percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI greater than or equal to 35 kg/m(2) was associated with a higher risk of failure than a BMI between 30 and 35 kg/m(2). (C) 2004 by American Society of Clinical Cincology. C1 Johns Hopkins Sch Med, Dept Urol, Baltimore, MD 21287 USA. Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Med, Dept Biostat, Los Angeles, CA 90024 USA. Vet Adm Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. Vet Adm Med Ctr, Urol Sect, Dept Surg, San Francisco, CA 94121 USA. Univ Calif San Francisco, Sch Med, Dept Urol, San Francisco, CA 94143 USA. Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA USA. San Diego Naval Hosp, Dept Urol, San Diego, CA USA. Med Coll Georgia, Urol Sect, Augusta, GA 30912 USA. RP Freedland, SJ (reprint author), Johns Hopkins Sch Med, Dept Urol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM sfreedl1@jhmi.edu NR 41 TC 255 Z9 259 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2004 VL 22 IS 3 BP 446 EP 453 PG 8 WC Oncology SC Oncology GA 770PJ UT WOS:000188738900011 PM 14691122 ER PT J AU Scher, HI Eisenberger, M D'Amico, AV Halabi, S Small, EJ Morris, M Kattan, MW Roach, M Kantoff, P Pienta, KJ Carducci, MA Agus, D Slovin, SF Heller, G Kelly, WK Lange, PH Petrylak, D Berg, W Higano, C Wilding, G Moul, JW Partin, AN Logothetis, C Soule, HR AF Scher, HI Eisenberger, M D'Amico, AV Halabi, S Small, EJ Morris, M Kattan, MW Roach, M Kantoff, P Pienta, KJ Carducci, MA Agus, D Slovin, SF Heller, G Kelly, WK Lange, PH Petrylak, D Berg, W Higano, C Wilding, G Moul, JW Partin, AN Logothetis, C Soule, HR TI Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: Recommendations from the prostate-specific antigen working group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EXTERNAL-BEAM RADIATION; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; POSITRON-EMISSION-TOMOGRAPHY; PREDICT PATHOLOGICAL STAGE; RADICAL PROSTATECTOMY; BIOCHEMICAL FAILURE; HORMONAL-THERAPY; GLEASON SCORE; CANCER; PSA AB Purpose To define methodology to show clinical benefit for patients in the state of a rising prostate-specific antigen (PSA). Results Hypothesis. A clinical states framework was used to address the hypothesis that definitive phase III trials could not be conducted in this patient population. Patient Population. The Group focused on men with systemic (nonlocalized) recurrence and a defined risk of developing clinically detectable metastases. Models to define systemic versus local recurrence, and risk of metastatic progression were discussed. Intervention. Therapies that have shown favorable effects in more advanced clinical states; meaningful biologic surrogates of activity linked with efficacy in other tumor types; and/or effects on a target or pathway known to contribute to prostate cancer progression in this state can be considered for evaluation. Outcomes. An intervention-specific posttherapy PSA-based outcome definition that would justify further testing should be described at the outset. Reporting. Trial reports should include a table showing the number of patients who achieve a specific PSA-based outcome, the number who remain enrolled onto the trial, and the number who came off study at different time points. The term PSA response should be abandoned. Trial Design. The phases of drug development for this state are optimizing dose and schedule, demonstration of a treatment effect, and clinical benefit. To move a drug forward should require a high bar that includes no rise in PSA in a defined proportion of patients for a specified period of time at a minimum. Agents that do not produce this effect can only be tested in combination. The preferred end point of clinical benefit is prostate cancer-specific survival; the time to development of metastatic disease is an alternative. Conclusion Methodology to show that an intervention alters the natural history of prostate cancer is described. At each stage of development, only agents with sufficient activity should be moved forward. (C) 2004 by American Society of Clinical Oncology. C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Uniformed Serv Univ Hlth Sci, Rockville, MD USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. Aventis Pharmaceut, Bridgewater, MA USA. Univ Washington, Seattle, WA 98195 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Duke Univ, Durham, NC USA. Prostate Canc Fdn, CaP CURE, Santa Monica, CA USA. Cedars Sinai Med Ctr, Prostate Canc Ctr, Los Angeles, CA 90048 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM scherh@mskcc.org RI Pienta, Kenneth/E-7679-2015; OI Pienta, Kenneth/0000-0002-4138-2186; Morris, Michael J./0000-0002-9454-0096 FU NCI NIH HHS [CA 05826] NR 85 TC 124 Z9 125 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2004 VL 22 IS 3 BP 537 EP 556 DI 10.1200/JCO.2004.07.099 PG 20 WC Oncology SC Oncology GA 770PJ UT WOS:000188738900022 PM 14752077 ER PT J AU Mack, JW Grier, HE AF Mack, JW Grier, HE TI The day one talk SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BAD-NEWS; TREATMENT PREFERENCES; COMMUNICATION-SKILLS; DIAGNOSIS; BREAKING C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Grier, HE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM holocombe_grier@dfci.harvard.edu NR 20 TC 35 Z9 35 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 1 PY 2004 VL 22 IS 3 BP 563 EP 566 DI 10.1200/JCO.2004.04.078 PG 4 WC Oncology SC Oncology GA 770PJ UT WOS:000188738900026 PM 14752081 ER PT J AU McCluggage, WG Young, RH AF McCluggage, WG Young, RH TI Non-neoplastic granulosa cells within ovarian vascular channels: a rare potential diagnostic pitfall SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article ID GYNECOLOGICAL PATHOLOGY; TUMORS; CALRETININ; INHIBIN AB Aims: To describe six cases seen in consultation in which artefactual vascular involvement within the ovary by benign granulosa cells caused diagnostic confusion. Methods/Results: In five cases, the initial favoured diagnoses of the submitting pathologists were metastatic carcinoma (three cases) and immature neural elements within a teratoma (two cases). In two cases, the ovary contained a benign cystic teratoma (one with struma ovarii), in two cases endometriosis, in one case follicular cysts, and in the other no pathological lesion was present. In all cases, several small ovarian vascular channels contained cohesive groups of cells with mildly atypical nuclei and cytoplasm, which varied from scant to abundant and eosinophilic. In four cases, mitotic figures were identified. The cells were morphologically consistent with benign granulosa cells and were associated in four cases with a nearby follicle lined by similar cells. There was no evidence of a mass lesion, grossly or histologically, to suggest a granulosa cell tumour. The nature of the cells was confirmed using immunohistochemistry for a inhibin and calretinin in one case. Conclusions: This phenomenon is probably an artefact secondary to surgical trauma or sectioning within the laboratory; alternatively, it could be related to ovulation. It is important that this benign process is not misinterpreted as cancer, either primary or metastatic, which may prompt inappropriate treatment or investigations that are not needed. C1 Royal Grp Hosp Trust, Dept Pathol, Belfast BT12 6BL, Antrim, North Ireland. Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP McCluggage, WG (reprint author), Royal Grp Hosp Trust, Dept Pathol, Grosvenor Rd, Belfast BT12 6BL, Antrim, North Ireland. EM mccluggage@bll.n-i.nhs.uk NR 15 TC 12 Z9 12 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 J9 J CLIN PATHOL JI J. Clin. Pathol. PD FEB 1 PY 2004 VL 57 IS 2 BP 151 EP 154 DI 10.1136/jcp.2003.011338 PG 4 WC Pathology SC Pathology GA 767TA UT WOS:000188467700010 PM 14747439 ER PT J AU Papakostas, GI Petersen, TJ Nierenberg, AA Murakami, JL Alpert, JE Rosenbaum, JF Fava, M AF Papakostas, GI Petersen, TJ Nierenberg, AA Murakami, JL Alpert, JE Rosenbaum, JF Fava, M TI Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID ATYPICAL ANTIPSYCHOTIC-DRUGS; 5-HT1A RECEPTOR ACTIVATION; PLACEBO-CONTROLLED TRIAL; RAT PREFRONTAL CORTEX; SCHIZOAFFECTIVE DISORDER; DOUBLE-BLIND; ACUTE EXACERBATION; DOPAMINE RELEASE; WEIGHT-GAIN; SCHIZOPHRENIA AB Background: Due to their favorable sideeffect profile, atypical antipsychotic agents offer important therapeutic advantages in mood disorders. Ziprasidone, an atypical antipsychotic agent with strong 5-HT1A agonist activity, may be particularly useful when used in conjunction with standard antidepressants in treatment-resistant depression. The purpose of this study is to test this hypothesis in depressed outpatients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor (SSRI). Method: Twenty patients with major depressive disorder (MDD) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002. MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders. Clinical response was defined as a 50% or greater decrease in depressive symptoms during the course of the trial (baseline to endpoint), as measured by the HAM-D-17 total score. Results: Thirteen of 20 patients (65.0%) completed the trial. Using a completer analysis, 8 patients (61.5%) were classified as responders. An intent-to-treat (ITT) analysis resulted in 10 responders (50.0%). The overall proportion of remitters was 5 of 13 (38.5%) using a completer analysis and 5 of 20 (25.0%) using the ITT analysis. Ziprasidone administration appeared to be safe, with no clinically significant QTc prolongation or severe adverse events observed in any of the study participants. Conclusion: These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Depress Clin & Res Program, Boston, MA 02114 USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Depress Clin & Res Program, 15 Parkman St,WAC 812, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X NR 51 TC 106 Z9 111 U1 0 U2 1 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD FEB PY 2004 VL 65 IS 2 BP 217 EP 221 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 831JH UT WOS:000222190200012 PM 15003076 ER PT J AU Faraone, SV Spencer, T Aleardi, M Pagano, C Biederman, J AF Faraone, SV Spencer, T Aleardi, M Pagano, C Biederman, J TI Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; CLINICAL-TRIAL; DOUBLE-BLIND; ADOLESCENTS; SYMPTOMS; CHILDREN; PLACEBO; ADHD; BUPROPION AB This article reviews the efficacy of methylphenidate (MPH) for adult attention-deficit/hyperactivity disorder (ADHD). A literature search identified double-blind placebo-controlled MPH treatment studies of ADHD adults. Meta-analysis estimated the pooled effect size for MPH treatment and tested for publication bias. Meta-analysis regression assessed the influence of study design features on medication effects. Six trials met criteria and were included in this meta-analysis. These studies included a total of 140 MPH-treated ADHD adults and 113 placebo-treated ADHD adults. The mean effect size of 0.9 was statistically significant and there was no evidence of publication bias. Larger MPH effect sizes were associated with physician ratings of outcome and use of higher doses. When treatment is optimized to high doses, the effect size for MPH in adults was 1.3. We found strong support for the assertion that MPH is efficacious for treating adult ADHD. Because the degree of efficacy of MPH in treating ADHD adults is similar to what has been reported from meta-analyses of the child and adolescent literature, our work provides further assurance to clinicians that the diagnosis of ADHD can be validly applied in adulthood. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Res, Child Psychiat Serv, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA USA. RP Faraone, SV (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Res, Child Psychiat Serv, Pediat Psychopharmacol Unit, WRN 705,Fruit St, Boston, MA 02114 USA. EM sfaraone@hms.harvard.edu OI Faraone, Stephen/0000-0002-9217-3982 NR 40 TC 210 Z9 218 U1 4 U2 24 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2004 VL 24 IS 1 BP 24 EP 29 DI 10.1097/01.jcp.0000108984.11879.95 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 763NY UT WOS:000188093400005 PM 14709943 ER PT J AU Wernicke, JF Adler, L Spencer, T West, SA Allen, AJ Heiligenstein, J Milton, D Ruff, D Brown, WJ Kelsey, D Michelson, D AF Wernicke, JF Adler, L Spencer, T West, SA Allen, AJ Heiligenstein, J Milton, D Ruff, D Brown, WJ Kelsey, D Michelson, D TI Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; METHYLPHENIDATE; TRIAL AB Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued. C1 Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. NYU, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. CNS Healthcare, Orlando, FL USA. RP Wernicke, JF (reprint author), Lilly Corp Ctr, Lilly Res Labs, DC 6337, Indianapolis, IN 46285 USA. EM jfwernicke@lilly.com OI Adler, Len/0000-0002-9812-8234 NR 14 TC 33 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2004 VL 24 IS 1 BP 30 EP 35 DI 10.1097/01.jcp.0000104907.75206.c2 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 763NY UT WOS:000188093400006 PM 14709944 ER PT J AU Wilens, TE Biederman, J Lerner, M AF Wilens, TE Biederman, J Lerner, M CA Concerta Study Grp TI Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder - Results from a one-year follow-up study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID HYPERACTIVE-CHILDREN; DEFICIT HYPERACTIVITY; OROS METHYLPHENIDATE; CONTROLLED TRIAL; A-DAY; ADOLESCENTS; SPHYGMOMANOMETER; HALOPERIDOL; BEHAVIOR; LIFE AB Objective: Studies of vital signs in children and adolescents with attention-deficit/byperactivity disorder (ADHD) receiving stimulants indicate a variable effect on blood pressure (BP) and heart rate (HR). We evaluated the longer-term effects on vital signs of once-daily osmotic-release methylphenidate (MPH, Concerta) in children with ADHD. Methods: As part of a 1-year open-extension trial, we studied children with ADHD (aged 6-13 years; baseline assessment, n = 432) who were entered into an open-label study of osmotic-release MPH (18-54 mg) for up to 1 year. Subjects' BP and HR were recorded at monthly visits and, when applicable, analyses were by last observation carried forward. Results: Compared to off-drug baseline, osmotic-release MPH was associated with minor clinical, although statistically significant, changes in systolic and diastolic blood pressure (DBP) (3.3 and 1.5 min Hg, Ps < 0.001) and HR (3.9 bpm, P < 0.0001) at 12-month end point. There was no clear dose-response relationship. There was no tolerance to the pressor effects of osmotic-release MPH over the 1-year period. There was an inverse relationship between baseline vital signs and positive change in vital signs at end point. Conclusions: Over a 12-month period, osmotic-release MPH produced minor clinical, although statistically significant, changes in BP and HR in children with ADHD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Res Program Pediat Psychopharmacol, Boston, MA USA. Univ Calif Irvine, Dept Pediat, Irvine, CA 92717 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, ACC 725,15 Parkman St, Boston, MA 02114 USA. EM wilens@helix.mgh.harvard.edu FU NIDA NIH HHS [DA 1192901A2] NR 40 TC 55 Z9 58 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD FEB PY 2004 VL 24 IS 1 BP 36 EP 41 DI 10.1097/01.jcp.0000106223.36344.df PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 763NY UT WOS:000188093400007 PM 14709945 ER PT J AU Cruz, GD Shore, R Le Geros, RZ Tavares, M AF Cruz, GD Shore, R Le Geros, RZ Tavares, M TI Effect of acculturation on objective measures of oral health in Haitian immigrants in New York City SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE acculturation; oral health; immigrants ID MEXICAN-AMERICANS AB Acculturation is a complex phenomenon that can serve as a proxy for cultural norms and behaviors affecting care-seeking, prevention behaviors, and, ultimately, health outcomes. The purpose of this study was to assess the effect of acculturation on the oral health of Haitian immigrants in New York City. We hypothesized that acculturation would be a predictor of the oral health status of the participating individuals. An acculturation scale was specifically developed and validated for this study. A sample of 425 adult Haitian immigrants living in NYC was obtained through outreach activities. Oral health examinations were conducted, and a questionnaire was administered to the participants. After adjustment for age, sex, education, income, and marital status, acculturation was negatively associated with measures of decayed teeth, periodontal attachment loss of : 4 mm, and the number of missing teeth. Results suggest a positive impact of acculturation on the oral health status of these individuals. C1 NYU, Coll Dent, Dept Epidemiol & Hlth Promot, New York, NY 10010 USA. NYU, Sch Med, New York, NY USA. Forsyth Inst, Boston, MA USA. RP Cruz, GD (reprint author), NYU, Coll Dent, Dept Epidemiol & Hlth Promot, 345 E 24th St, New York, NY 10010 USA. EM gdc1@nyu.edu FU NIDCR NIH HHS [DE 10593-S1] NR 22 TC 22 Z9 22 U1 1 U2 2 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD FEB PY 2004 VL 83 IS 2 BP 180 EP 184 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 768WK UT WOS:000188593000019 PM 14742660 ER PT J AU Feuerstein, M Shaw, WS Nicholas, RA Huang, GD AF Feuerstein, M Shaw, WS Nicholas, RA Huang, GD TI From confounders to suspected risk factors: psychosocial factors and work-related upper extremity disorders SO JOURNAL OF ELECTROMYOGRAPHY AND KINESIOLOGY LA English DT Article; Proceedings Paper CT Symposium on perspectives on Musculoskeletal Disorder Causation and Control CY MAY 21-22, 2003 CL COLUMUS, OHIO DE work-related upper extremity disorders; psychosocial factors; workstyle ID MUSCULOSKELETAL DISORDERS; COMPUTER USERS; JOB STRESS; SYMPTOMS; DISEASE; FORCES; NECK AB Psychosocial variables have recently been more prominent among epidemiologic risk factors for work-related upper extremity disorders (WRUEDs),. but bio-behavioral mechanisms underlying these associations have been elusive. One reason is that the psychosocial domain has included many broad and disparate variables (e.g. mood, coping skills, job control, job satisfaction, job stress. social support), and this lack of specificity in the conceptualization of psychosocial factors has produced limited hypothesis testing opportunities. Therefore, recent research efforts have focused on identifying and conceptualizing specific psychosocial factors that might more clearly delineate plausible bio-behavioral mechanisms linking psychosocial factors to WRUEDs. One such factor is workstyle, a strategy that workers may employ for completing, responding to, or coping with job demands that might affect musculoskeletal health. Preliminary studies have provided support for measurable differences in workstyle among individual workers and an association with upper extremity pain and discomfort. An initial self-report measure of workstyle has been pilot tested among office workers and shown acceptable reliability and validity. Future studies are needed to study this construct among other working populations and to determine its relationship with other clinical endpoints. Nevertheless, early findings suggest workstyle may be a potential focus of WRUED prevention efforts. Published by Elsevier Ltd. C1 Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. Georgetown Univ, Med Ctr, Bethesda, MD 20814 USA. Univ Massachusetts, Sch Med, Hopkinton, MA 01748 USA. Liberty Mutual Ctr Disabil Res, Hopkinton, MA 01748 USA. US Dept Vet Affairs, Off Res & Dev, Bethesda, MD 20814 USA. RP Feuerstein, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mfeuerstein@usuhs.mil NR 27 TC 38 Z9 41 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1050-6411 J9 J ELECTROMYOGR KINES JI J. Electromyogr. Kinesiol. PD FEB PY 2004 VL 14 IS 1 BP 171 EP 178 DI 10.1016/j.jelekin.2003.09.016 PG 8 WC Neurosciences; Physiology; Rehabilitation; Sport Sciences SC Neurosciences & Neurology; Physiology; Rehabilitation; Sport Sciences GA 775ZC UT WOS:000189089700019 PM 14759762 ER PT J AU Pang, PS Look, RB Brown, DFM Nadel, ES AF Pang, PS Look, RB Brown, DFM Nadel, ES TI Wide complex rhythm and cardiac arrest SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material ID TISSUE-PLASMINOGEN ACTIVATOR; CARDIOPULMONARY-RESUSCITATION; HYPERKALEMIA; THERAPY C1 Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Emergency Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Nadel, ES (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD FEB PY 2004 VL 26 IS 2 BP 197 EP 200 DI 10.1016/j.jemermed.2003.12.001 PG 4 WC Emergency Medicine SC Emergency Medicine GA 775AE UT WOS:000189017900011 PM 14980344 ER PT J AU Madry, H Emkey, G Zurakowski, D Trippel, SB AF Madry, H Emkey, G Zurakowski, D Trippel, SB TI Overexpression of human fibroblast growth factor2 stimulates cell proliferation in an ex vivo model of articular chondrocyte transptantation SO JOURNAL OF GENE MEDICINE LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the Orthopaedic-Research-Society CY FEB 10-13, 2002 CL Dallas, TX SP Orthopaed Res Soc DE cartilage defects; FGF-2; transfection; chondrocytes; transplantation ID MEDIATED GENE-TRANSFER; DEFECTS IN-VIVO; CARTILAGE DEFECTS; PLATE CHONDROCYTES; MATRIX SYNTHESIS; IGF-I; TRANSPLANTATION; DELIVERY; CULTURE; TISSUE AB Background Genetically engineered chondrocytes could be used to enhance cartilage repair. Fibroblast growth factor 2 (FGF-2) is a mitogen for chondrocytes and may be a candidate for gene transfer approaches to stimulate chondrocyte proliferation. In the present study, we tested the hypothesis that human FGF-2 (hFGF-2) gene transfer into articular chondrocytes modulates cell proliferation in an ex vivo model of chondrocyte transplantation. Methods Transfection of articular chondrocytes with an expression plasmid vector carrying the cDNA for hFGF-2 under the control of the cytomegalovirus promoter/enhancer mediated transgene expression and synthesis of biologically relevant amounts of the recombinant hFGF-2 protein. Articular chondrocytes transfected with the Escherichia coli-galactosidase (lacZ) gene or a hFGF-2 cDNA were transplanted onto the surface of articular cartilage explants. Results The tissue formed by the chondrocytes expressing hFGF-2 was thicker and contained more cells than control cultures. Quantitative analysis of [H-3]thymidine and [S-35]sulfate incorporation in composite cultures revealed that hFGF-2 transfection stimulated mitogenic activity in the new tissue but did not augment matrix glycosaminoglycan synthesis. Conclusions These data support the concept that chondrocytes overexpressing a hFGF-2 cDNA selectively modulate cell proliferation in an ex vivo model of chondrocyte transplantation. These results suggest that therapeutic hFGF-2 gene transfer may be applicable for the treatment of articular cartilage disorders, such as traumatic defects in which cellular repopulation is a therapeutic goal. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Univ Saarland, Med Ctr, Dept Orthopaed Surg, Lab Expt Orthopaed, D-66421 Homburg, Germany. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Res Labs,Dept Orthopaed Surg, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Biostat & Med, Boston, MA USA. Indiana Univ, Dept Orthopaed Surg, Indianapolis, IN USA. RP Madry, H (reprint author), Univ Saarland, Med Ctr, Dept Orthopaed Surg, Lab Expt Orthopaed, D-66421 Homburg, Germany. EM hmad@hotmail.com FU NIAMS NIH HHS [AR 45749, AR 31068] NR 34 TC 39 Z9 42 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD FEB PY 2004 VL 6 IS 2 BP 238 EP 245 DI 10.1002/jgm.488 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 780BN UT WOS:000189351400011 PM 14978777 ER PT J AU Johnson, RL Saha, S Arbelaez, JJ Beach, MC Cooper, LA AF Johnson, RL Saha, S Arbelaez, JJ Beach, MC Cooper, LA TI Racial and ethnic differences in patient perceptions of bias and cultural competence in health care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE bias; cultural competence; disparities; racial and ethnic minorities ID RACIAL/ETHNIC DISPARITIES; DIVERSE POPULATIONS; TEACHING RESIDENTS; PHYSICIAN; RACE; FRAMEWORK; EDUCATION; PROVIDERS; MODEL AB OBJECTIVES: To determine: 1) whether racial and ethnic differences exist in patients' perceptions of primary care provider (PCP) and general health care system-related bias and cultural competence; and 2) whether these differences are explained by patient demographics, source of care, or patient-provider communication variables. DESIGN: Cross-sectional telephone survey. SETTING: The Commonwealth Fund 2001 Health Care Quality Survey. SUBJECTS: A total of 6,299 white, African-American, Hispanic, and Asian adults. MEASUREMENTS AND MAIN RESULTS: Interviews were conducted using random-digit dialing; oversampling respondents from communities with high racial/ethnic minority concentrations; and yielding a 54.3% response rate. Main outcomes address respondents' perceptions of their PCPs' and health care system-related bias and cultural competence; adjusted probabilities (Pr) are reported for each ethnic group. Most racial/ethnic differences in perceptions of PCP bias and cultural competence were explained by demographics, source of care, and patient-physician communication variables. In contrast, racial/ethnic differences in patient perceptions of health care system-wide bias and cultural competence persisted even after controlling for confounders: African Americans, Hispanics, and Asians remained more likely than whites (P < .001) to perceive that: 1) they would have received better medical care if they belonged to a different race/ethnic group (Pr 0.13, Pr 0.08, Pr 0.08, and Pr 0.01, respectively); and 2) medical staff judged them unfairly or treated them with disrespect based on race/ethnicity (Pr 0.06, Pr 0.04, Pr 0.06, and Pr 0.01, respectively) and how well they speak English (Pr 0.09, Pr 0.06, Pr 0.06, and Pr 0.03, respectively). CONCLUSION: While demographics, source of care, and patient-physician communication explain most racial and ethnic differences in patient perceptions of PCP cultural competence, differences in perceptions of health care system-wide bias and cultural competence are not fully explained by such factors. Future research should include closer examination of the sources of cultural bias in the US medical system. C1 Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Portland VA Med Ctr, Gen Internal Med Sect, Portland, OR USA. Oregon Hlth & Sci Univ, Dept Med, Portland, OR USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. RP Cooper, LA (reprint author), Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-500, Baltimore, MD 21205 USA. EM lisa.cooper@jhmi.edu NR 37 TC 210 Z9 210 U1 3 U2 24 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD FEB PY 2004 VL 19 IS 2 BP 101 EP 110 DI 10.1111/j.1525-1497.2004.30262.x PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 779KD UT WOS:000189293100001 PM 15009789 ER PT J AU Wu, A Yamada, K Baron, C Mathes, DW Monajati, LM Vagefi, PA Sachs, DH AF Wu, A Yamada, K Baron, C Mathes, DW Monajati, LM Vagefi, PA Sachs, DH TI Detection of regulatory cells as an assay for allograft tolerance in miniature swine SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID DISPARATE RENAL-ALLOGRAFTS; T-CELLS; TRANSPLANTATION TOLERANCE; CLASS-I; IMMUNOSUPPRESSION WITHDRAWAL; KIDNEY ALLOGRAFTS; INDUCTION; CYCLOSPORINE; ANTIGEN; RECIPIENTS AB Background: There is currently a great need for an in vitro assay to assess the presence of tolerance following allotransplantation to determine whether immunosuppressive medications can be discontinued. Our laboratory has recently developed an assay involving coculture inhibition of cell-mediated lympholysis that correlates with tolerance to allografts in swine leukocyte antigen (SLA) Class I-mismatched miniature swine. The potential for clinical application of this assay may depend on 2 important factors: (1) whether the assay can be used in the presence of immunosuppression; and (2) whether frozen-stored naive responder cells can be utilized. Methods: Long-term tolerant NIGH miniature swine that had accepted SLA Class I-mismatched kidney transplants after a 12-day course of cyclosporine or tacrolimus were studied. Two long-term tolerant and 2 naive control animals were treated with a clinically relevant dose of cyclosporine for 2 weeks (trough level 100 to 400 ng/ml) to simulate the ongoing "chronic" immunosuppression used in human recipients of allografts. Cells from tolerant or naive, recipient-matched animals were stimulated for 6 days with donor or third-party SLA. These primed cells were then cocultured with naive unstimulated recipient major histocompastibility complex (MHC)-matched responders and irradiated stimulators. Responder cells were tested both fresh and frozen. Results: Suppression of cytotoxic responses of naive responder cells was observed in all coculture assays using cells from tolerant animals primed against donor antigen in vitro, but not in assays,using similarly primed cells from naive animals. Responder cells from tolerant animals receiving, immunosuppression had a suppressive activity similar to that from cells of the same animals not receiving immunosuppression. Similar suppression was also observed in coculture assays using either fresh or frozen naive responder cells. Conclusions: This coculture assay appears to correlate with the presence of tolerance under conditions applicable to the clinical setting. The assay appears to identify peripheral regulatory mechanisms of tolerance in allogeneic transplant recipients, and therefore may provide an approach for determining an appropriate timepoint at which to test withdrawal of immunosuppressive medications. C1 Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Sch Med,MGH East, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Sch Med,MGH East, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu OI Mathes, David/0000-0003-4388-1373 FU NHLBI NIH HHS [5P01 HL18646, 5R01 HL63430]; NIAID NIH HHS [2R01 AI31046] NR 26 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2004 VL 23 IS 2 BP 210 EP 217 DI 10.1016/S1053-2498(03)00115-3 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 770YN UT WOS:000188759100008 PM 14761769 ER PT J AU Tripodi, G Messaggio, E Hamlyn, JM Sciarrone, MT Lanzani, C Murrell, JR Haupert, GT Bianchi, G Florio, M Manunta, P AF Tripodi, G Messaggio, E Hamlyn, JM Sciarrone, MT Lanzani, C Murrell, JR Haupert, GT Bianchi, G Florio, M Manunta, P TI Genes involved in the biosynthetic pathway of endogenous ouabain in human hypertension SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 20th Scientific Meeting of the International-Society-of-Hypertension CY FEB 15-19, 2004 CL Sao Paulo, BRAZIL SP Int Soc Hypertens C1 Univ Vita Salute San Raffaele, Div Nephrol Dialysis & Hypertens, Milan, 21201, Italy. Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD FEB PY 2004 VL 22 SU 1 BP S205 EP S205 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 835PR UT WOS:000222497400881 ER PT J AU Lucas, M Vargas-Cuero, AL Lauer, GM Barnes, E Willberg, CB Semmo, N Walker, BD Phillips, R Klenerman, P AF Lucas, M Vargas-Cuero, AL Lauer, GM Barnes, E Willberg, CB Semmo, N Walker, BD Phillips, R Klenerman, P TI Pervasive influence of hepatitis C virus on the phenotype of antiviral CD8+T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; LYMPHOCYTE-RESPONSES; LIVER-TRANSPLANTATION; EFFECTOR FUNCTION; IMMUNE-RESPONSE; INFECTION; CYTOMEGALOVIRUS; DIFFERENTIATION; PERSISTENCE; EXPRESSION AB Recent studies using MHC class I tetramers have shown that CD8(+) T cell responses against different persistent viruses vary considerably in magnitude and phenotype. At one extreme, hepatitis C virus (HCV)-specific CD8(+) T cell responses in blood are generally weak and have a phenotype that is perforin low and CCR7 high (early memory). At the other, specific responses to CMV are strong, perforin high, and CCR7 low (mature or effector memory). To examine the potential mechanisms behind this diversity, we compared CMV-specific responses in HCV-infected and healthy individuals. We find a striking difference in the phenotype of CMV-specific CD8(+) T cells between these groups. In the HCV-infected cohort, CMV-specific CD8(+) T cells lost markers associated with maturity; they had increased expression of CCR7 and reduced expression of Fas and perforin. They nevertheless responded to Ag in vitro in a manner similar to controls, with strong proliferation and appropriate acquisition of effector memory markers. The reduction in mature CD8 T cells in HCV-infected individuals may arise through either impairment or regulation of T cell stimulation, or through the early loss of mature T cells. Whatever the mechanism, HCV has a pervasive influence on the circulating CD8(+) T cell population, a novel feature that may be a hallmark of this infection. C1 Univ Oxford, Nuffield Dept Clin Med, Oxford OX1 3SY, England. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Royal Free Hosp, Ctr Hepatol, London NW3 2QG, England. RP Klenerman, P (reprint author), Univ Oxford, Nuffield Dept Clin Med, Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM klener@molbiol.ox.ac.uk RI Yang, Chen/G-1379-2010 NR 31 TC 76 Z9 83 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2004 VL 172 IS 3 BP 1744 EP 1753 PG 10 WC Immunology SC Immunology GA 766LW UT WOS:000188378700051 PM 14734757 ER PT J AU Ranjbar, S Ly, N Thim, S Reynes, JM Goldfeld, AE AF Ranjbar, S Ly, N Thim, S Reynes, JM Goldfeld, AE TI Mycobacterium tuberculosis recall antigens suppress HIV-1 replication in anergic donor cells via CD8(+) T cell expansion and increased IL-10 levels SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLASMA VIRAL LOAD; BIOLOGICAL PHENOTYPE; INFECTION INVITRO; TYPE-1; PROGRESSION; LYMPHOCYTES; EXPRESSION; RESPONSES; TRANSCRIPTION AB Mycobacterium tuberculosis (MTb) is the leading cause of death in the setting of AIDS. MTb enhances the pathogenicity and accelerates the course of HIV disease and, furthermore, infection with HIV-1 increases the risk of reactivation or reinfection with MTb. In this study, we show that host-specific recall responses to one pathogen, MTb, has a direct effect upon the regulation of a second pathogen, HIV-1. Using cells from immunocompetent former tuberculosis (TB) patients who displayed either a persistently positive (responsive) or negative (anergic), delayed-type hypersensitivity (DTH) reaction to intradermal injection of purified protein derivative (PPD), we investigated the effect of recall Ags to MTb upon the replication of HIV-1 primary isolates in vitro. We show that HIV-1 replication of a T cell-tropic isolate was significantly impaired in MTb-stimulated PBMC from PPD-anergic donors. Furthermore, these donors displayed a significant increase in CD8(+) T cells and IL-10 levels and lower levels of IL-2 and TNF-alpha relative to PPD-responsive donors in response to PPD stimulation. Strikingly, CD8(+) T cell depletion and blocking of IL-10 significantly increased HIV-1 replication in these PPD-anergic donors, indicating that an immunosuppressive response to MTb recall Ags inhibits HIV-1 replication in PPD-anergic individuals. Therefore, immunotherapeutic approaches aimed at recapitulating Ag-specific MTb anergy in vivo could result in novel and effective approaches to inhibit HIV-1 disease progression in MTb/HIV-1 coinfection. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Inst Pasteur Cambodge, Unite Virol, Phnom Penh, Cambodia. Cambodian Hlth Comm, Phnom Penh, Cambodia. RP Goldfeld, AE (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. EM goldfeld@cbr.med.harvard.edu RI Reynes, Jean-Marc/M-6108-2014 FU NHLBI NIH HHS [HL59838] NR 40 TC 17 Z9 17 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2004 VL 172 IS 3 BP 1953 EP 1959 PG 7 WC Immunology SC Immunology GA 766LW UT WOS:000188378700075 PM 14734781 ER PT J AU Pathak, MA AF Pathak, MA TI In memory of Thomas Bernhard Fitzpatrick SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pathak, MA (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP XX EP XXI DI 10.1046/j.1523-1747.2003.22248.x PG 2 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100007 PM 15009754 ER PT J AU Astner, S Anderson, RR AF Astner, S Anderson, RR TI Skin phototypes 2003 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. RP Astner, S (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. NR 3 TC 20 Z9 21 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP XXX EP XXXI DI 10.1046/j.1523-1747.2003.22251.x PG 2 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100012 PM 15009759 ER PT J AU Mihm, MC Sober, AJ AF Mihm, MC Sober, AJ TI Melanoma before and after Thomas B. Fitzpatrick SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item ID PROGNOSTIC FACTORS; THICKNESS; MM C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Mihm, MC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 6 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP XXXII EP XXXIII DI 10.1046/j.1523-1747.2003.22252.x PG 2 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100013 PM 15009760 ER PT J AU Shimizu, H Morgan, BA AF Shimizu, H Morgan, BA TI Wnt signaling through the beta-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE dermal papilla; wnt; hair follicle; regeneration ID HAIR FOLLICLE DEVELOPMENT; BUD DEVELOPMENT; DIFFERENTIATION; TRANSCRIPTION; ACTIVATION; EXPRESSION; PROMOTER; CYCLE AB Dermal papilla cells of the hair follicle can be maintained in an active, hair-inducing state in vitro when cocultured with cells secreting Wnt3a. By inducing cultured dermal papilla cells to secrete Wnt themselves, we demonstrate that this activity is a direct effect of Wnt signaling to dermal papilla cells. We further demonstrate that the effects of Wnt3a are exerted through activation of the beta-catenin signal transduction pathway and do not require alternative Wnt transduction cascades. Once dermal papilla cells have lost hair-inducing properties in vitro, neither treatment with Wnt nor expression of a truncated and activating form of beta-catenin is sufficient to restore these properties to the cultured cells. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Morgan, BA (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM bruce.morgan@cbrc2.mgh.harvard.edu NR 22 TC 69 Z9 72 U1 0 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP 239 EP 245 DI 10.1046/j.0022-202X.2004.22224.x PG 7 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100017 PM 15009701 ER PT J AU Kobayashi, T Kishimoto, J Hattori, S Wachi, H Shinkai, H Burgeson, RE AF Kobayashi, T Kishimoto, J Hattori, S Wachi, H Shinkai, H Burgeson, RE TI Matrix metalloproteinase 9 expression is coordinately modulated by the KRE-M9 and 12-O-tetradecanoyl-phorbol-13-acetate responsive elements SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE differentiation; fibroblast; HT1080 fibrosarcoma cell; keratinocyte ID CULTURED HUMAN KERATINOCYTES; IV COLLAGENASE EXPRESSION; TISSUE INHIBITOR; GENE-EXPRESSION; GELATINASE-B; MATRIX-METALLOPROTEINASE; 92-KD GELATINASE; EPIDERMAL-CELLS; TRANSGENIC MICE; HUMAN SKIN AB To investigate the pathophysiologic role of matrix metalloproteinase 9 (MMP-9), we analyzed the mechanism of its transcriptional regulation in keratinocytes and in HT1080 fibrosarcoma cells in culture. The KRE-M9 element, which is located between the 12-O-tetradecanoyl-phorbol-13-acetate responsive element (TRE) and the transcription initiation site in the MMP-9 promoter, is essential for MMP-9 transcription in the absence of the TRE. The KRE-M9 binding protein, however, is shown to be a repressor of transcription rather than an activator; we found several times higher transcriptional activity when the KRE-M9 element was mutated. In contrast, activator protein 1 proteins (AP-1) are shown to activate transcription of MMP-9 by binding to the TRE, which is located adjacent to the KRE-M9 element. Moreover, we found that the KRE-M9 binding protein could serve as a differentiation repressing factor 1 (DRF-1) as shown by the decrease in levels of this protein with differentiation. In addition, the TRE binding protein is able to bind to the KRE-M9 to some extent. These results indicate that the coordinated modulation of MMP-9 transcription via the TRE and the KRE-M9 elements is important in epidermal and mesenchymal tissues. Our findings could facilitate consideration of the molecular mechanism in a variety of pathophysiologic conditions with which MMP-9 is involved. C1 Chiba Univ, Sch Med, Dept Dermatol Clin Biol Extracellular Matrix F7, Chiba 280, Japan. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Dept Dermatol, Charlestown, MA USA. Nippi Res Inst Biomatrix, Tokyo, Japan. Hoshi Pharmaceut Coll, Tokyo, Japan. RP Kobayashi, T (reprint author), Chiba Univ, Sch Med, Dept Dermatol Clin Biol Extracellular Matrix F7, Chiba 280, Japan. EM tkobayas@faculty.chiba-u.jp NR 48 TC 9 Z9 10 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP 278 EP 285 DI 10.1046/j.0022-202X.2004.22210.x PG 8 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100021 PM 15009705 ER PT J AU Tsao, H Goel, V Wu, H Yang, G Haluska, FG AF Tsao, H Goel, V Wu, H Yang, G Haluska, FG TI Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE BRAF; melanoma; NRAS; PTEN ID PROTEIN-KINASE ACTIVATION; CUTANEOUS MELANOMA; RAS ONCOGENE; CONSTITUTIVE ACTIVATION; TUMOR-SUPPRESSOR; HIGH-FREQUENCY; GROWTH-FACTOR; CELL-LINES; SKIN; PROGRESSION AB Extant evidence implicates growth factor signaling in the pathogenesis of many tumor types, including cutaneous melanoma. Recently, reciprocal activating mutations of NRAS and BRAF were found in benign melanocytic nevi and cutaneous melanomas. We had previously reported a similar epistatic relationship between activating NRAS mutations and inactivating PTEN/MMAC1 alterations. We thus hypothesized that BRAF and PTEN/MMAC1 mutations may cooperate to promote melanoma tumorigenesis. Overall, 40 of 47 (85%) melanoma cell lines and 11 of 16 (69%) uncultured melanoma metastases had mutations in NRAS, BRAF, or PTEN/MMAC1. NRAS was exclusively mutated in nine of 47 (19%) cell lines and two of 16 (13%) metastases, whereas BRAF was solely mutated in 28 of 47 (60%) cell lines and nine of 16 (56%) metastases. In the 12 of 15 melanoma cell lines (80%) and two of two melanoma metastases with PTEN alterations, BRAF was also mutated. These findings suggest the existence of possible cooperation between BRAF activation and PTEN loss in melanoma development. C1 Massachusetts Gen Hosp, Melanoma Ctr, Wellman Ctr, Dept Dermatol,Wellman Labs, Boston, MA 02114 USA. Massachusetts Gen Hosp, Melanoma Ctr, Dept Med, Div Oncol, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Melanoma Ctr, Wellman Ctr, Dept Dermatol,Wellman Labs, Boston, MA 02114 USA. FU NCI NIH HHS [R01 CA095798-02, K08 CA095532, K08 CA095532-05] NR 27 TC 278 Z9 283 U1 0 U2 9 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP 337 EP 341 DI 10.1046/j.0022-202X.2004.22243.x PG 5 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100030 PM 15009714 ER PT J AU Suthamjariya, K Farinelli, WA Koh, W Anderson, RR AF Suthamjariya, K Farinelli, WA Koh, W Anderson, RR TI Mechanisms of microvascular response to laser pulses SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE laser; port wine stain; cavitation; microvessel ID PORT-WINE STAINS; DYE-LASER; ARGON-LASER; TUNABLE DYE; NM LASER; VESSELS; BLOOD; PHOTOTHERMOLYSIS; TEMPERATURE; IRRADIATION AB "Selective photothermolysis" is widely used for treating vascular lesions. In order to understand mechanisms of response, we investigated fast events during pulsed laser treatment of microvessels. A high-speed (2000 fps) CCD camera and microscope were used to image hamster cheek pouch microvessels during and after 532 nm and 1064 nm laser pulse exposures. Pulse duration and fluence were varied systematically (1-50 ms, 0-600 J per cm(2)). Threshold fluences for fast events were determined. On a millisecond time-scale, a specific series of fast events occur, which are wavelength, fluence, irradiance, and pulse duration dependent. In order of increasing fluence we observed: blood coagulation, vasoconstriction, thread-like appearance of the treated vascular segment, vessel disappearance, intravascular cavitation, bubble formation, vessel wall rupture and hemorrhage, and shrinkage of perivascular tissue. With increasing pulse duration, the threshold fluences for coagulation, vessel disappearance, and cavitation increase, and cavitation becomes less violent, conforming to the vessel lumen. Intravascular cavitation did not always rupture the vessel wall, and is not the mechanism for immediate vessel disappearance, a desired endpoint for treating vascular lesions. The apparent mechanism for immediate vessel disappearance is contraction of intravascular blood and perivascular collagen after thermal denaturation. This study suggests that detecting fast events in humans, in real time, may provide useful feedback signals for "smarter" laser devices. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA USA. RP Anderson, RR (reprint author), Wellman Labs Photomed, Dept Dermatol, BHX 630,55 Fruit St, Boston, MA 02114 USA. EM rranderson@partners.org NR 25 TC 37 Z9 39 U1 0 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD FEB PY 2004 VL 122 IS 2 BP 518 EP 525 DI 10.1046/j.0022-202X.2004.22241.x PG 8 WC Dermatology SC Dermatology GA 774PF UT WOS:000188991100055 PM 15009739 ER PT J AU Fitzgerald, ML Morris, AL Chroni, A Mendez, AJ Zannis, VI Freeman, MW AF Fitzgerald, ML Morris, AL Chroni, A Mendez, AJ Zannis, VI Freeman, MW TI ABCA1 and amphipathic apolipoproteins form high-affinity molecular complexes required for cholesterol efflux SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ATP binding cassette transporter A1; Tangier Disease; high density lipoprotein ID A-I; CELLULAR CHOLESTEROL; LIPID EFFLUX; APOA-I; TRANSPORTER; BINDING; CELLS AB Apolipoproteins, such as apolipoprotein A-I (apoA-I), can stimulate cholesterol efflux from cells expressing the ATP binding cassette transporter A1 (ABCA1). The nature of the molecular interaction between these cholesterol acceptors and ABCA1 is controversial, and models suggesting a direct protein-protein interaction or indirect association have been proposed. To explore this issue, we performed competition binding and chemical cross-linking assays using six amphipathic plasma proteins and an 18 amino acid amphipathic helical peptide. All seven proteins stimulated lipid efflux and inhibited the cross-linking of apoA-I to ABCA1. Cross-linking of apoA-I to ABCA1 was saturable and occurred at high affinity (K-d of 7.0 +/- 1.9 nM), as was cross-linking of apoA-II. After binding to ABCA1, apoA-I rapidly dissociated (half-life of 25 min) from the complex and was released back into the medium. A mutant form of ABCA1 (W590S) that avidly binds apoA-I but fails to promote cholesterol efflux released apoA-I with similar kinetics but without transfer of cholesterol to apoA-I. Thus, a high-affinity, saturable, protein-protein interaction occurs between ABCA1 and all of its amphipathic protein ligands. Dissociation of the complex leads to the cellular release of cholesterol and the apolipoprotein. However, dissociation is not dependent on cholesterol transfer, which is a clearly separable event, distinguishable by ABCA1 mutants. C1 Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. Univ Miami, Sch Med, Diabet Res Inst, Miami, FL 33101 USA. RP Freeman, MW (reprint author), Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. EM freeman@molbio.mgh.harvard.edu NR 20 TC 95 Z9 100 U1 1 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD FEB PY 2004 VL 45 IS 2 BP 287 EP 294 DI 10.1194/jlr.M300355-JLR200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 776JM UT WOS:000189112900010 PM 14617740 ER PT J AU Ogino, S Wilson, RB AF Ogino, S Wilson, RB TI Bayesian analysis and risk assessment in genetic counseling and testing SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Review ID RECURRENCE RISKS AB Risk assessment is an essential component of genetic counseling and testing, and Bayesian analysis plays a central role in genetic risk assessment. Bayesian analysis allows calculation of the probability of a particular hypothesis, either disease or carrier status, based on family information and/or genetic test results. Genetic risk should be assessed as accurately as possible for family decision making. Additional information, from the pedigree and/or from genetic testing, can often dramatically improve the accuracy of genetic risk assessment. We illustrate herein the application of Bayes' theorem and describe important basic principles in genetic risk assessment. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Penn, Ctr Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM sogino@partners.org NR 17 TC 10 Z9 10 U1 1 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD FEB PY 2004 VL 6 IS 1 BP 1 EP 9 DI 10.1016/S1525-1578(10)60484-9 PG 9 WC Pathology SC Pathology GA 768MN UT WOS:000188546900001 PM 14736820 ER PT J AU Wiren, KM Toombs, AR Zhang, XW AF Wiren, KM Toombs, AR Zhang, XW TI Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteloblasts SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; OSTEOBLASTIC CELL-LINE; BONE-CELLS; EXTRACELLULAR-MATRIX; OSTEOSARCOMA CELLS; ADRENAL ANDROGENS; RAT OSTEOBLASTS; UP-REGULATION; IN-VITRO; RECEPTOR AB Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (coIAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT. C1 Portland Vet Affairs Med Ctr, Bone & Mineral Res Unit, Portland, OR USA. Oregon Hlth & Sci Univ, Dept Med, Portland, OR USA. Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR USA. RP Wiren, KM (reprint author), Portland VA Med Ctr P3 RD39, 3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM wirenk@ohsu.edu NR 42 TC 20 Z9 20 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD FEB PY 2004 VL 32 IS 1 BP 209 EP 226 DI 10.1677/jme.0.0320209 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 804NM UT WOS:000220305400016 PM 14766003 ER PT J AU Yao, JK Cheng, P Wengenack, TM Poduslo, JF AF Yao, JK Cheng, P Wengenack, TM Poduslo, JF TI Multiplicity effects of oxidative stress in the cortex of a transgenic mouse model of Alzheimer's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 6th Biennial Meeting of the Asian-Pacific-Society-for-Neurochemistry CY FEB 04-07, 2004 CL Hong Kong, PEOPLES R CHINA SP Asian-Pacific Soc Neurochem DE Alzheimer's disease; cortex; glutathione; oxidative stress; transgenic mouse C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2004 VL 88 SU 1 BP 49 EP 49 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 775UH UT WOS:000189078700145 ER PT J AU Fink, JS Kalda, A Ryu, H Stack, EC Schwarzschild, MA Chen, JF Ferrante, RJ AF Fink, JS Kalda, A Ryu, H Stack, EC Schwarzschild, MA Chen, JF Ferrante, RJ TI Genetic and pharmacological inactivation of the adenosine A(2A) receptor attenuates 3-nitropropionic acid-induced striatal damage SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE A(2A) receptor antagonist; adenosine A(2a) eceptor; 8-C-chlorostyryl caffeine; Hntington disease; mitochondrial toxin; 3-nitropropionic acid ID TRANSGENIC MOUSE MODELS; HUNTINGTONS-DISEASE; RAT STRIATUM; PARKINSONS-DISEASE; NEURODEGENERATIVE DISEASES; INDUCED EXCITOTOXICITY; ENDOGENOUS ADENOSINE; BASAL GANGLIA; FREE-RADICALS; ANTAGONISTS AB Adenosine A(2A) receptor (A(2A)R) antagonism attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and quinolinic acid-induced excitotoxicity in the neostriatum. As A(2A)Rs are enriched in striatum, we investigated the effect of genetic and pharmacological A(2A) inactivation on striatal damage produced by the mitochondrial complex II inhibitor 3-nitropriopionic acid (3-NP). 3-NP was administered to A(2A)R knockout (KO) and wild-type (WT) littermate mice over 5 days. Bilateral striatal lesions were analyzed from serial brain tissue sections. Whereas all of the 3-NP-treated WT mice (C57BL/6 genetic background) had bilateral striatal lesions, only one of eight of the 3-NP-treated A(2A)R KO mice had detectable striatal lesions. Similar attenuation of 3-NP-induced striatal damage was observed in A(2A)R KO mice in a 129-Steel background. In addition, the effect of pharmacological antagonism on 3-NP-induced striatal neurotoxicity was tested by pre-treatment of C57Bl/6 mice with the A(2A)R antagonist 8-(3-chlorostyryl) caffeine (CSC). Although bilateral striatal lesions were observed in all mice treated either with 3-NP alone or 3-NP plus vehicle, there were no demonstrable striatal lesions in mice treated with CSC (5 mg/kg) plus 3-NP and in five of six mice treated with CSC (20 mg/kg) plus 3-NP. We conclude that both genetic and pharmacological inactivation of the A(2A)R attenuates striatal neurotoxicity produced by 3-NP. Since the clinical and neuropathological features of 3-NP-induced striatal damage resemble those observed in Huntington's disease, the results suggest that A(2A)R antagonism may be a potential therapeutic strategy in Huntington's disease patients. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. Bedford VA Med Ctr, Ctr Geriatr Res Educ & Clin, GRECC Unit, Bedford, MA 01730 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Chen, JF (reprint author), Boston Univ, Sch Med, Dept Neurol, 715 Albany St,C329, Boston, MA 02118 USA. EM chenjf@bu.edu; rjferr@bu.edu RI Kalda, Anti/H-3150-2015 FU NCCIH NIH HHS [AT00613]; NIEHS NIH HHS [ES10804]; NINDS NIH HHS [NS37403, NS35255, NS045242, NS41083] NR 51 TC 44 Z9 44 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2004 VL 88 IS 3 BP 538 EP 544 DI 10.1046/j.1471-4159.2003.02145.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 763YQ UT WOS:000188128400003 PM 14720203 ER PT J AU Liu, TB Perry, G Chan, HW Verdile, G Martins, RN Smith, MA Atwood, CS AF Liu, TB Perry, G Chan, HW Verdile, G Martins, RN Smith, MA Atwood, CS TI Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE amyloid-beta; antisense oligonucleotides; cyclin-dependent kinase 5; differentiation; tau; viability ID MICROTUBULE-ASSOCIATED PROTEIN; PERIPHERAL NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; PRECURSOR PROTEIN; OXIDATIVE STRESS; LIVING CELLS; IN-VITRO; A-BETA; NEUROFIBRILLARY TANGLES AB It has previously been reported that amyloid-beta (Abeta) peptide is neurotrophic to undifferentiated but neurotoxic to differentiated primary neurons. The underlying reasons for this differential effect is not understood. Recently, the toxicity of Abeta to neurons was shown to be dependent upon the activation of cyclin-dependent kinase 5 (Cdk5), thought to promote tau phosphorylation that leads to cytoskeletal disruption, morphological degeneration and apoptosis. Here we report that Cdk5, tau, and phosphorylated-tau (P-tau) are expressed at very low levels in undifferentiated primary neurons, but that the expression of Cdk5 and tau and the phosphorylation of tau increase markedly between 4 and 8 days of differentiation in vitro. Tau expression decreased after this time, as did the level of P-tau, to low levels by 17 days. Abeta induced tau phosphorylation of neurons only after greater than or equal to 4 days of differentiation, a time that coincides with the onset of Abeta toxicity. Blocking tau expression (and therefore tau phosphorylation) with an antisense oligonucleotide completely blocked Abeta toxicity of differentiated primary neurons, thereby confirming that tau was essential for mediating Abeta toxicity. Our results demonstrate that differentiation-associated changes in tau and Cdk-5 modulate the toxicity of Abeta and explain the opposite responses of differentiated and undifferentiated neurons to Abeta. Our results predict that only cells containing appreciable levels of tau are susceptible to Abeta-induced toxicity and may explain why Abeta is more toxic to neurons compared with other cell types. C1 Univ Wisconsin, Sch Med, Dept Med, Wm S Middleton Mem VA,GRECC 11G, Madison, WI 53705 USA. Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. Univ Western Australia, Dept Psychiat & Clin Neurosci, Perth, WA 6009, Australia. Hollywood Private Hosp, Sir James McCusker Alzheimers Dis Res Unit, Perth, WA, Australia. RP Atwood, CS (reprint author), Univ Wisconsin, Sch Med, Dept Med, Wm S Middleton Mem VA,GRECC 11G, 2500 Overlook Terrace, Madison, WI 53705 USA. EM csa@medicine.wisc.edu RI Smith, Mark/A-9053-2009; Perry, George/A-8611-2009 OI Perry, George/0000-0002-6547-0172 FU NIA NIH HHS [R01 AG19356] NR 97 TC 64 Z9 69 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2004 VL 88 IS 3 BP 554 EP 563 DI 10.1046/j.1471-4159.2003.02196.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 763YQ UT WOS:000188128400005 PM 14720205 ER PT J AU Won, JS Im, YB Khan, M Singh, AK Singh, I AF Won, JS Im, YB Khan, M Singh, AK Singh, I TI The role of neutral sphingomyelinase produced ceramide in lipopolysaccharide-mediated expression of inducible nitric oxide synthase SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE ceramide; inducible nitric oxide synthase; neutral sphingomyelinase; NF-kappa B; ras ID TUMOR-NECROSIS-FACTOR; FACTOR-KAPPA-B; ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; FACTOR-ALPHA; TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; PRIMARY ASTROCYTES; INTERFERON-GAMMA; GENE-EXPRESSION AB Lipopolysaccharide (LPS) and interferon-gamma (IFN) treatment of C6 rat glioma cells increased the intracellular ceramide level and the expression of the inducible nitric oxide synthase (iNOS) gene. To delineate the possible role of ceramide in the induction of iNOS, we examined the source of intracellular ceramide and associated signal transduction pathway(s) with the use of inhibitors of intracellular ceramide generation. The inhibitor of neutral sphingomyelinase (3-O-methylsphingomyelin, MSM) inhibited the induction of iNOS, whereas inhibitor of acidic sphingomyelinase (SR33557) or that of ceramide de novo synthesis (fumonisin B1) had no effect on the induction of iNOS. MSM-mediated inhibition of iNOS induction was reversed by the supplementation of exogenous C-8-ceramide, suggesting that ceramide production by neutral sphingomyelinase (nSMase) is a key mediator in the induction of iNOS. The MSM-mediated inhibition of iNOS gene expression correlated with the decrease in the activity of ras. Inhibition of co-transfected iNOS promoter activity by dominant negative ras supported the role of ras in the nSMase-dependent regulation of iNOS gene. NF-kappaB DNA binding activity and its transactivity were also reduced by MSM pretreatment, and were completely reversed by the supplementation of C-8-ceramide. As the dominant negative ras also reduced NF-kappaB transactivity, NF-kappaB activation may be downstream of ras. Our results suggest that ceramide generated by nSMase may be a critical mediator in the regulation of iNOS gene expression via ras-mediated NF-kappaB activation under inflammatory conditions. C1 Med Univ S Carolina, Dept Pediat, Div Dev Neurogenet, CSB 316, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, Div Dev Neurogenet, CSB 316, 171 Ashley Ave, Charleston, SC 29425 USA. EM singhi@musc.edu FU NINDS NIH HHS [NS-22576, NS-34741, NS-37766, NS-40810] NR 68 TC 36 Z9 40 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2004 VL 88 IS 3 BP 583 EP 593 DI 10.1046/j.1471-4159.2003.02165.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 763YQ UT WOS:000188128400008 PM 14720208 ER PT J AU Harada, J Foley, M Moskowitz, MA Weber, C AF Harada, J Foley, M Moskowitz, MA Weber, C TI Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE MAP kinase; neural progenitor cells; neurogenesis; Rho-associated kinase; sphingolipids; telomerase ID FIBROBLAST-GROWTH-FACTOR; SPHINGOSINE 1-PHOSPHATE RECEPTOR; PROTEIN-COUPLED RECEPTORS; CNS STEM-CELLS; LYSOPHOSPHATIDIC ACID; TELOMERASE ACTIVITY; IN-VITRO; NEURONAL DIFFERENTIATION; KINASE KINASE; NEUROGENESIS AB Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of G-protein-coupled receptors. Although the role of S1P on angiogenesis is well established, its role in neurogenesis is unknown. We examined the effects of S1P on G-protein activation in brain sections of rat embryo and on neural progenitor cells in culture. Intense S1P-stimulated [S-35]GTPgammaS labeling was observed as early as E15 in the neuroepithelium and differentiating fields throughout the brain, suggesting that functional S1P receptors are expressed in brain areas with active neurogenesis. mRNA transcripts for several S1P receptor subtypes (S1P(1), S1P(2), S1P(3) and S1P(5)) were expressed in neural progenitor cells prepared from embryonic rat hippocampus. S1P induced phosphorylation of extracellular signal-regulated kinase (ERK) and proliferation of neural progenitor cells as determined by BrdU incorporation in a pertussis toxin-sensitive manner. These effects were prevented by the ERK signaling inhibitor U0126. S1P augmented telomerase activity in neural progenitor cells with similar potency as that, of FGF-2. Furthermore, S1P induced cell-cell aggregation. This morphological change was transient and prevented by Y-27632, an inhibitor of Rho-associated kinase. These results suggest that S1P plays, a pleiotropic role in neurogenesis via pathways involving S1P receptors, MAP kinases and Rho kinase. C1 Massachusetts Gen Hosp, Dept Radiol, Stroke & Neurovasc Regulat Lab, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Weber, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Stroke & Neurovasc Regulat Lab, 149 13th St,Room 6403, Boston, MA 02129 USA. EM waeber@helix.mgh.harvard.edu RI Moskowitz, Michael/D-9916-2011; Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 FU NINDS NIH HHS [R21NS043216, P01NS035611] NR 67 TC 131 Z9 134 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD FEB PY 2004 VL 88 IS 4 BP 1026 EP 1039 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 774UK UT WOS:000189003500028 PM 14756825 ER PT J AU Gardner, B Zhu, LX Roth, MD Tashkin, DP Dubinett, SM Sharma, S AF Gardner, B Zhu, LX Roth, MD Tashkin, DP Dubinett, SM Sharma, S TI Cocaine modulates cytokine and enhances tumor growth through sigma receptors SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article; Proceedings Paper CT 9th Conference of the Society-of-NeuroImmune-Pharmacology CY OCT 02-06, 2002 CL CLEARWATER BEACH, FLORIDA SP SNIP, Univ So Florida DE cocaine; sigma receptor; tumor; cytokine; interleukin-10; immunity ID T-CELL; TGF-BETA; HABITUAL SMOKERS; AND/OR TOBACCO; NITRIC-OXIDE; DRUG-USERS; IFN-GAMMA; IN-VIVO; IL-10; MICE AB Sigma receptors are intracellular receptors that interact with a variety of psychotropic ligands, including cocaine. Administration of cocaine to mice promoted the in vivo growth of a syngeneic lung cancer cell line and identical effects were observed with PRE 084, a selective sigma, receptor agonist. Increased tumor growth was accompanied by an increase in IL-10 and a decrease in IFN-gamma production in splenocytes and at the tumor site. The tumor-promoting effects produced by both cocaine and PRE 084 were abrogated by administration of specific antibodies to IL-10, or by administration of a sigma, receptor antagonist. We conclude that sigma, receptor ligands, including cocaine, augment tumor growth via a cytokine-dependent, receptor-mediated mechanism that involves regulation of T helper l/T helper 2 cytokine balance. (C) 2003 Elsevier B.V. All rights reserved. C1 Univ Calif Los Angeles, David Geffen Sch Med, Lung Canc Res Program, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. Vet Adm Greater Los Angeles Healthcare Syst, Div Pulm & Crit Care Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Lung Canc Res Program, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Gardner, B (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Lung Canc Res Program, Div Pulm & Crit Care Med, 37-131 Ctr Hlth Sci,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM bgardner@mednet.ucla.edu; sharmasp@ucla.edu FU NCI NIH HHS [R01 CA71818]; NIDA NIH HHS [R01 DA08254]; PHS HHS [P50 90388] NR 35 TC 21 Z9 21 U1 0 U2 2 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 2004 VL 147 IS 1-2 BP 95 EP 98 DI 10.1016/j.neuroim.2003.10.020 PG 4 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 772GQ UT WOS:000188834000023 PM 14741436 ER PT J AU Smith, ER Butler, WE Barker, FG AF Smith, ER Butler, WE Barker, FG TI In-hospital mortality rates after ventriculoperitoneal shunt procedures in the United States, 1998 to 2000: relation to hospital and surgeon volume of care SO JOURNAL OF NEUROSURGERY LA English DT Article DE volume of care; ventriculoperitoneal shunt; hydrocephalus; mortality rate ID CEREBROSPINAL-FLUID SHUNT; NEW-YORK-STATE; PEDIATRIC CARDIAC-SURGERY; CONGENITAL HEART-DEFECTS; EXPERIENCE; OUTCOMES; CHILDREN; HYDROCEPHALUS; COMPLICATIONS; NEUROSURGERY AB Object. Death after ventriculoperitoneal (VP) shunt surgery is uncommon, and therefore it has been difficult to study. The authors used a population-based national hospital discharge database to examine the relationship between annual hospital and surgeon volume of VP shunt surgery in pediatric patients and in-hospital mortality rates. Methods. All children in the Nationwide Inpatient Sample (1998-2000, age 90 days-18 years) who underwent VP shunt placement or shunt revision as the principal procedure were included. Main outcome measures were in-hospital mortality rates, length of stay (LOS), and total hospital charges. Overall, 5955 admissions were analyzed (253 hospitals, 411 surgeons). Mortality rates were lower at high-volume centers and for high-volume surgeons. In terms of hospital volume, the mortality rate was 0.8% at lowest-quartile-volume centers (< 28 admissions/year) and 0.3% at highest-quartile-volume centers (> 121 admissions/year). In terms of surgeon volume, the mortality rate was 0.8% for lowest-quartile-volume providers (< nine admissions/year) and 0.1% for high est-quartile-volume providers (> 65 admissions/year). After multivariate adjustment for demographic variables, emergency admission and presence of infection, hospital volume of care remained a significant predictor of death (odds ratio [OR] for a 10-fold increase in caseload 0.38; 95% confidence interval [CI] 0.18-0.81). Surgeon volume of care was statistically significant in a similar multivariate model (OR for a 10-fold increase in caseload 0.3; 95% CI 0.13-0.69). Length of stay was slightly shorter and total hospital charges were slightly higher at higher-volume centers, but the differences were not statistically significant. Conclusions. Pediatric shunt procedures performed at high-volume hospitals or by high-volume surgeons were associated with lower in-hospital mortality rates, with no significant difference in LOS or hospital charges. C1 Massachusetts Gen Hosp, Brain Tumor Ctr, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Brain Tumor Ctr, Neurosurg Serv, Fruit St, Boston, MA 02114 USA. EM barker@helix.mgh.harvard.edu NR 42 TC 55 Z9 56 U1 1 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD FEB PY 2004 VL 100 IS 2 SU S BP 90 EP 97 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 770LK UT WOS:000188732100006 PM 14758935 ER PT J AU Walker, JC Brenner, MJ Mackinnon, SE Winograd, JM Hunter, DA AF Walker, JC Brenner, MJ Mackinnon, SE Winograd, JM Hunter, DA TI Effect of perineurial window size on nerve regeneration, blood-nerve barrier integrity, and functional recovery SO JOURNAL OF NEUROTRAUMA LA English DT Article DE collateral sprouting; end-to-side neurorrhaphy; microsurgery; nerve regeneration; perineurial window; terminolateral neurorrhaphy ID TO-SIDE NEURORRHAPHY; RAT MODEL; PERIPHERAL-NERVE; TERMINOLATERAL NEURORRHAPHY; DIFFUSION BARRIER; BRACHIAL-PLEXUS; PROTEIN TRACERS; LONG-TERM; END; MOTOR AB End-to-side neurorrhaphy is used clinically to reconstruct nerve injuries when the lack of a suitable proximal nerve stump precludes conventional approaches to microsurgical repair. In end-to-side neurorrhaphy, the distal stump of a transected nerve is sutured to the side of an intact nerve that serves as an axon donor. Prior studies suggest that this perineurial window is a prerequisite for effective nerve regeneration into the recipient nerve. However, the optimal size for this perineurial window remains uncertain. This study evaluated the effect of perineurial window size on collateral axonal sprouting, blood-nerve barrier architecture, and functional impairment of the donor nerve. One hundred twenty Lewis rats were randomized to 1 and 5 mm perineurial window groups and examined at serial time points. The 5 mm perineurial window group exhibited significantly greater fiber counts at the repair zone than the 1mm group within 4 weeks (P < 0.005). Marked breakdown of the blood-nerve barrier was present 2 week postoperatively and resolved by 4 weeks regardless of 1 versus 5 mm perineurial window size. Tibial function indices in both groups normalized between 4 and 6 weeks postoperatively. A large (5 mm) perineurial window induced greater collateral sprouting or regenerative response than a small (1 mm) perineurial window without increasing cross sectional nerve injury or delaying functional recovery. C1 Washington Univ, Sch Med, Dept Surg, Dept Orthopaed Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Surg, Dept Otolaryngol Head & Neck Surg, St Louis, MO USA. Washington Univ, Sch Med, Dept Surg, Div Plast & Reconstruct Surg, St Louis, MO USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast Surg,Dept Surg, Boston, MA 02115 USA. RP Mackinnon, SE (reprint author), Washington Univ, Sch Med, Dept Surg, Dept Orthopaed Surg, St Louis, MO 63110 USA. EM mackinnons@msnotes.wustl.edu NR 39 TC 28 Z9 31 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD FEB PY 2004 VL 21 IS 2 BP 217 EP 227 DI 10.1089/089771504322778677 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 774WB UT WOS:000189008200009 PM 15000762 ER PT J AU Erickson, JI Holm, LJ Chelminiak, L AF Erickson, JI Holm, LJ Chelminiak, L TI Keeping the nursing shortage from becoming a nursing crisis SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article C1 Massachusetts Gen Hosp, Patient Care Serv, Boston, MA 02114 USA. Partners HealthCare, Community Benefit Program, Boston, MA USA. RP Erickson, JI (reprint author), Massachusetts Gen Hosp, Patient Care Serv, 55 Fruit St,BUL 230, Boston, MA 02114 USA. EM jiveserickson@partners.org NR 5 TC 4 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD FEB PY 2004 VL 34 IS 2 BP 83 EP 87 DI 10.1097/00005110-200402000-00006 PG 5 WC Nursing SC Nursing GA 776LX UT WOS:000189118400006 PM 14770067 ER PT J AU Schierle, C Winograd, JM AF Schierle, C Winograd, JM TI Radiation-induced brachial plexopathy: review. Complication without a cure SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Article DE badiation-induced brachial plexopathy; review ID BREAST-CANCER PATIENTS; FOLLOW-UP; PLEXUS NEUROPATHY; MR; LESIONS; FIBROSIS; TUMOR; CT; DIFFERENTIATION; RADIOTHERAPY AB Radiation-induced brachial plexopathy, especially the chronic and progressive form, has become an increasingly rare entity in patients receiving radiation therapy to the chest wall and axilla. However, for the patients affected by this pathologic process, the chronic pain, decline in function, and absence of a satisfactory treatment are a continuing challenge to the reconstructive peripheral nerve surgeon. The authors have undertaken a review of the relevant literature addressing radiation-induced brachial plexopathy, and here present a summary of the current understanding of the pathophysiology, diagnosis, and treatment of this disorder. C1 Ctr Ambulatory Care, Div Plast Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Winograd, JM (reprint author), Ctr Ambulatory Care, Div Plast Surg, Suite 453,15 Parkman St, Boston, MA 02114 USA. NR 38 TC 29 Z9 31 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD FEB PY 2004 VL 20 IS 2 BP 149 EP 152 PG 4 WC Surgery SC Surgery GA 779BG UT WOS:000189275300006 PM 15011123 ER PT J AU Guenther, FH Nieto-Castanon, A Ghosh, SS Tourville, JA AF Guenther, FH Nieto-Castanon, A Ghosh, SS Tourville, JA TI Representation of sound categories in auditory cortical maps SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article DE speech perception; auditory cortex; categorical perception; perceptual magnet effect ID SPEECH-PERCEPTION; OWL MONKEYS; DISCRIMINATION; IDENTIFICATION; MRI; PROTOTYPES; LISTENERS; INFANTS; CORTEX; VOWELS AB Functional magnetic resonance imaging (fMRI) was used to investigate the representation of sound categories in human auditory cortex. Experiment 1 investigated the representation of prototypical (good) and nonprototypical (bad) examples of a vowel sound. Listening to prototypical examples of a vowel resulted in less auditory cortical activation than did listening to nonprototypical examples. Experiments 2 and 3 investigated the effects of categorization training and discrimination training with novel nonspeech sounds on auditory cortical representations. The 2 training tasks were shown to have opposite effects on the auditory cortical representation of sounds experienced during training: Discrimination training led to an increase in the amount of activation caused by the training stimuli, whereas categorization training led to decreased activation. These results indicate that the brain efficiently shifts neural resources away from regions of acoustic space where discrimination between sounds is not behaviorally important (e.g., near the center of a sound category) and toward regions where accurate discrimination is needed. The results also provide a straightforward neural account of learned aspects of perceptual distortion near sound categories: Sounds from the center of a category are more difficult to discriminate from each other than sounds near category boundaries because they are represented by fewer cells in the auditory cortical areas. C1 Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02115 USA. MIT, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Ctr Morphometr Anal, Charlestown, MA USA. RP Guenther, FH (reprint author), Boston Univ, Dept Cognit & Neural Syst, 67 Beacon St, Boston, MA 02115 USA. EM guenther@cns.bu.edu OI Ghosh, Satrajit/0000-0002-5312-6729 FU NIDCD NIH HHS [R01 DC02852] NR 38 TC 67 Z9 68 U1 0 U2 4 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 PY 2004 VL 47 IS 1 BP 46 EP 57 DI 10.1044/1092-4388(2004/005) PG 12 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 800QV UT WOS:000220043700005 PM 15072527 ER PT J AU Stelzner, M AF Stelzner, M TI Achieving balance in academic surgery SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Association-for-Academic-Surgery CY NOV 07-09, 2002 CL BOSTON, MASSACHUSETTS SP Assoc Acad Surg DE balance; surgeon-scientist; family life; research ID INTESTINE; FALLS C1 Univ Washington, Dept Surg, VAPSHCS Surg Serv 112, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Stelzner, M (reprint author), Univ Washington, Dept Surg, VAPSHCS Surg Serv 112, 1660 S Columbian Way, Seattle, WA 98108 USA. EM stelzner@u.washington.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD FEB PY 2004 VL 116 IS 2 BP 350 EP 354 DI 10.1016/j.jss.2003.09.013 PG 5 WC Surgery SC Surgery GA 774WC UT WOS:000189008300021 PM 15013375 ER PT J AU Swindells, K Burnett, N Rius-Diaz, F Gonzalez, E Mihm, MC Gonzalez, S AF Swindells, K Burnett, N Rius-Diaz, F Gonzalez, E Mihm, MC Gonzalez, S TI Reflectance confocal microscopy may differentiate acute allergic and irritant contact dermatitis in vivo SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID PATCH TEST REACTIONS; SCANNING LASER MICROSCOPY; HUMAN SKIN; HYPERSENSITIVITY REACTIONS; DOPPLER FLOWMETRY; MORPHOLOGY; HISTOLOGY; RESPONSES; TISSUE; CELLS AB Background.: Acute irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) may be difficult to distinguish by clinical or histologic assessment. Reflectance confocal microscopy (RCM) enables real-time, high-resolution skin imaging in vivo. Objective: We sought to image, characterize, and distinguish acute ACD and ICD in vivo. Methods: Volunteers with ACD were patch tested with an allergen and the irritant, sodium lauryl sulfate. RCM imaging and transepidermal water loss measurements were performed at 24 and 72 hours. Biopsy specimens were correlated with RCM images. Results: Spongiosis, epidermal inflammatory cell infiltrate, and vesicle formation were observed in ACD and ICD. Compared with ACD, ICD showed greater disruption of the stratum corneum, and more parakeratosis. There was a significantly greater increase in transepidermal water loss for ICD compared with ACD. Conclusion: RCM is a promising tool for dynamic, noninvasive assessment and may help to differentiate acute ACD and sodium lauryl sulfate-induced ICD. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Dermatol, Contact Dermatitis Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, BHX 630, Boston, MA 02115 USA. EM sgonzalez3@partners.org FU NIOSH CDC HHS [R01 OH04029] NR 37 TC 49 Z9 56 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD FEB PY 2004 VL 50 IS 2 BP 220 EP 228 DI 10.1016/j.jaad.2003.08.005 PG 9 WC Dermatology SC Dermatology GA 770EK UT WOS:000188710100008 PM 14726876 ER PT J AU Harbrecht, BG Zenati, MS Ochoa, JB Townsend, RN Puyana, JC Wilson, MA Peitzman, AB AF Harbrecht, BG Zenati, MS Ochoa, JB Townsend, RN Puyana, JC Wilson, MA Peitzman, AB TI Management of adult blunt splenic injuries: Comparison between level I and level II trauma centers SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID NONOPERATIVE MANAGEMENT; EASTERN-ASSOCIATION; SURGERY; GENDER AB BACKGROUND: The factors important in determining outcome when managing adult blunt splenic injuries continue to be debated. Whether trauma center level designation (Level I versus Level II) affects patient management has not been evaluated. STUDY DESIGN: We conducted a retrospective analysis of prospectively gathered data from the Pennsylvania Trauma Outcome Study database that collected information from 27 statewide trauma centers (Level I [15], Level II [17]). Adult patients (ages 16 years) with blunt splenic injuries (ICD-9-CM 865) were evaluated. Demographic data, injury data, and trauma center level designation were collected, and patient management, length of stay, and mortality were analyzed. RESULTS: There were 2,138 adult patients who suffered blunt splenic injuries during the study period (1998-2000). Patients treated at Level II trauma centers (n = 772) had a higher rate of operative treatment (38.2% versus 30.7%) (p < 0.001), but a shorter mean length of stay (10.1 +/- 0.4 versus 12.0 +/- 0.4 days) (p < 0.01) compared with patients in Level I trauma centers (n = 1,366). The rate of failure of nonoperative treatment was lower at Level II trauma centers (13.0% versus 17.6%) (p < 0.05), but the mortality for patients managed nonoperatively was higher (8.4% versus 4.5%) (p < 0.05). Splenorrhaphy was performed more frequently in Level I trauma centers. CONCLUSIONS: Management differences exist in the treatment of adult blunt splenic injuries between institutions of different trauma center level designation. Multicenter studies should account for this finding in design and implementation. (C) 2004 by the American College of Surgeons. C1 Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA 15213 USA. VA Pittsburgh Healthcare Syst, Surg Serv, Pittsburgh, PA USA. RP Harbrecht, BG (reprint author), Univ Pittsburgh, Med Ctr, Dept Surg, F1264-200 Lothrop St, Pittsburgh, PA 15213 USA. RI Zenati, Mazen/C-2020-2012 NR 15 TC 24 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD FEB PY 2004 VL 198 IS 2 BP 232 EP 239 DI 10.1016/j.jamcollsurg.2003.10.007 PG 8 WC Surgery SC Surgery GA 771NZ UT WOS:000188793900009 PM 14759780 ER PT J AU Sheridan, RL Tompkins, RG AF Sheridan, RL Tompkins, RG TI What's new in burns and metabolism SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Review ID ABDOMINAL COMPARTMENT SYNDROME; TOXIC EPIDERMAL NECROLYSIS; CULTURED SKIN SUBSTITUTES; SMOKE-INHALATION INJURY; HUMAN GROWTH-HORMONE; ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; FULL-THICKNESS BURNS; FREQUENCY PERCUSSIVE VENTILATION; RESUSCITATION FLUID VOLUME C1 Shriners Hosp Children, Burn Surg Serv, Dept Surg, Div Burns & Trauma,Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Sheridan, RL (reprint author), Shriners Hosp Children, Burn Surg Serv, Dept Surg, Div Burns & Trauma,Massachusetts Gen Hosp, 51 Blossom St, Boston, MA 02114 USA. NR 363 TC 27 Z9 35 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD FEB PY 2004 VL 198 IS 2 BP 243 EP 263 DI 10.1016/j.jamcollsurg.2003.11.007 PG 21 WC Surgery SC Surgery GA 771NZ UT WOS:000188793900012 PM 14759783 ER PT J AU Grillo, HC AF Grillo, HC TI Concentration versus specialization? A case study on the arteria aspera SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Review ID CONGENITAL TRACHEAL STENOSIS; SLIDE TRACHEOPLASTY; TRACHEOESOPHAGEAL FISTULA; COMPLICATING TRACHEOSTOMY; ASSISTED RESPIRATION; SUBGLOTTIC LARYNGEAL; IATROGENIC STENOSES; SURGICAL MANAGEMENT; EXTENSIVE RESECTION; CLINICAL-EXPERIENCE C1 Massachusetts Gen Hosp, Gen Thorac Surg Div, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Grillo, HC (reprint author), Massachusetts Gen Hosp, Gen Thorac Surg Div, Blake 1570,55 Fruit St, Boston, MA 02114 USA. NR 130 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD FEB PY 2004 VL 198 IS 2 BP 291 EP 301 DI 10.1016/j.jamcollsurg.2003.08.023 PG 11 WC Surgery SC Surgery GA 771NZ UT WOS:000188793900015 PM 14759787 ER PT J AU Fitzpatrick, AL Kuller, LH Ives, DG Lopez, OL Jagust, W Breitner, JCS Jones, B Lyketsos, C Dulberg, C AF Fitzpatrick, AL Kuller, LH Ives, DG Lopez, OL Jagust, W Breitner, JCS Jones, B Lyketsos, C Dulberg, C TI Incidence and prevalence of dementia in the cardiovascular health study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Alzheimer's disease; dementia; education; incidence; prevalence; race; vascular dementia ID ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; UNITED-STATES; POPULATION; DIAGNOSIS; RISK; AD; CRITERIA; PROJECT; DECLINE AB OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort. DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia. SETTING: Four U.S. communities. PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years. MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD and Alzheimer's Disease Diagnostic and Treatment Center's State of California criteria for VaD. RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0%) than men (14.7%). CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden. C1 Univ Washington, Dept Epidemiol, Seattle, WA 98115 USA. Univ Washington, Dept Biostat, Seattle, WA 98115 USA. Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Div Geriatr Psychait, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Psychiat, Winston Salem, NC USA. Johns Hopkins Univ, Sch Publ Hlth, Dept Mental Hyg, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP Fitzpatrick, AL (reprint author), Univ Washington, Dept Epidemiol, Bldg 29,Suite 310,6200 NE 74th St, Seattle, WA 98115 USA. EM fitzpal@u.washington.edu FU NHLBI NIH HHS [N01-HC-85079, N01-HC-85086]; NIA NIH HHS [5 R01 AG15928-02] NR 46 TC 186 Z9 189 U1 1 U2 15 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2004 VL 52 IS 2 BP 195 EP 204 DI 10.1111/j.1532-5415.2004.52058.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 765JR UT WOS:000188263900004 PM 14728627 ER PT J AU Asthana, S Middleton, WS AF Asthana, S Middleton, WS TI Estrogen and cognition: A true relationship? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; HEALTH INITIATIVE MEMORY; CENTRAL-NERVOUS-SYSTEM; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; PLUS PROGESTIN; TRANSDERMAL ESTROGEN; HORMONE REPLACEMENT; ALZHEIMERS-DISEASE; OLDER WOMEN C1 Univ Wisconsin, Sch Med,Sect Geriatr & Gerontol, Ctr Geriatr Res Educ & Clin, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. Wisconsin Alzheimers Inst, Madison, WI USA. RP Asthana, S (reprint author), Univ Wisconsin, Sch Med,Sect Geriatr & Gerontol, Ctr Geriatr Res Educ & Clin, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. NR 23 TC 9 Z9 10 U1 1 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2004 VL 52 IS 2 BP 316 EP 318 DI 10.1111/j.1532-5415.2004.52078.x PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 765JR UT WOS:000188263900024 PM 14728648 ER PT J AU O'Hare, AM Feinglass, J Reiber, GE Rodriguez, RA Daley, J Khuri, S Henderson, WG Johansen, KL AF O'Hare, AM Feinglass, J Reiber, GE Rodriguez, RA Daley, J Khuri, S Henderson, WG Johansen, KL TI Postoperative mortality after nontraumatic lower extremity amputation in patients with renal insufficiency SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID OF-VETERANS-AFFAIRS; GLOMERULAR-FILTRATION RATE; SERUM CREATININE; MYOCARDIAL-INFARCTION; LIMB AMPUTATION; SURGERY; RISK; POPULATION; OUTCOMES; FAILURE AB Mortality rates after lower extremity amputation are extremely high among dialysis patients. However, the impact of milder degrees of renal insufficiency on death rates after lower extremity amputation has not been carefully examined. In this study, the authors used data from the Department of Veterans Affairs' National Surgical Quality Improvement Program (NSQIP) to measure the association between renal dysfunction and 30-d mortality after nontraumatic amputation adjusted for confounders. The study population consisted of 16,994 patients undergoing their first NSQIP recorded amputation from January 1, 1994 through September 30, 2001. Thirty-five percent of all cohort patients had at least moderate renal insufficiency, and 52% of all postoperative deaths occurred in this group. Postoperative mortality was 9% in patients with moderate renal insufficiency, 15% in patients with severe renal insufficiency, and 16% in dialysis patients, compared with 6% in patients with normal or mildly reduced renal function. Renal insufficiency remained associated with death after adjustment for confounders (adjusted odds ratio [OR] 3.36, 95% confidence interval [CI] 2.75 to 4.10 [dialysis patients]; OR 2.54, CI 2.06 to 3.14 [severe renal insufficiency]; and OR 1.52, Cl 1.32 to 1.76 [moderate renal insufficiency]). In conclusion, even moderate renal insufficiency is independently associated with postoperative death after lower extremity amputation. This finding highlights the need for a targeted approach to improving the care of patients with renal insufficiency undergoing lower extremity amputation. C1 Vet Affairs Med Ctr, Dept Med, Div Nephrol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Northwestern Univ, Sch Med, Div Gen Internal Med, Chicago, IL USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. Tenet Hlth Syst, Med Affairs, Dallas, TX USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. VA Boston Healthcare Syst, Surg Serv, Boston, MA USA. Univ Colorado, Hlth Outcomes Program, Denver, CO 80202 USA. UCSF, Dept Epidemiol, San Francisco, CA USA. UCSF, Dept Biostat, San Francisco, CA USA. RP O'Hare, AM (reprint author), Vet Affairs Med Ctr, Dept Med, Div Nephrol, Box 111J,4150 Clement St, San Francisco, CA 94121 USA. EM ann.o'hare@med.va.gov NR 29 TC 32 Z9 33 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2004 VL 15 IS 2 BP 427 EP 434 DI 10.1097/01.ASN.0000105992.18297.63 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 769AQ UT WOS:000188604600021 PM 14747390 ER PT J AU McPherson, EA Luo, ZM Brown, RA Lebard, LS Corless, CC Speth, RC Bagby, SP AF McPherson, EA Luo, ZM Brown, RA Lebard, LS Corless, CC Speth, RC Bagby, SP TI Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID BLOOD-PRESSURE CONTROL; MAST-CELLS; CONVERTING-ENZYME; MYOCARDIAL-INFARCTION; FORMING PATHWAYS; RENAL-DISEASE; EXPRESSION; GENE; SYSTEM; TISSUE AB Autosomal dominant polycystic kidney disease (ADPKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of I-125-AngT to I-125-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 +/- 2.9 fmol AngII/min/mug protein with a mean maximal conversion of 55% +/- 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression. C1 Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. Portland VA Med Ctr, Portland, OR USA. Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA 99164 USA. RP Bagby, SP (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, 3314 SW US Vet Hosp Rd,Suite 262, Portland, OR 97239 USA. EM bagbys@ohsu.edu NR 41 TC 34 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2004 VL 15 IS 2 BP 493 EP 500 DI 10.1097/01.ASN.0000109782.28991.26 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 769AQ UT WOS:000188604600029 PM 14747398 ER PT J AU Stone, VE Smith, KY AF Stone, VE Smith, KY TI Improving adherence to HAART SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE adherence; HIV/AIDS; highly; active antiretroviral therapy ID ACTIVE ANTIRETROVIRAL THERAPY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. RP Stone, VE (reprint author), Massachusetts Gen Hosp, Bulfinch 130,55 Fruit St, Boston, MA 02114 USA. EM vstone@partners.org NR 16 TC 1 Z9 1 U1 0 U2 0 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD FEB PY 2004 VL 96 IS 2 SU S BP 27 EP 29 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 852FL UT WOS:000223740600008 ER PT J AU Graves, EE Culver, JP Ripoll, J Weissleder, R Ntziachristos, V AF Graves, EE Culver, JP Ripoll, J Weissleder, R Ntziachristos, V TI Singular-value analysis and optimization of experimental parameters in fluorescence molecular tomography SO JOURNAL OF THE OPTICAL SOCIETY OF AMERICA A-OPTICS IMAGE SCIENCE AND VISION LA English DT Article ID DIFFUSE OPTICAL TOMOGRAPHY; CONTRAST AGENTS; TURBID MEDIA; BREAST-CANCER; LIFETIME; TUMORS; PROBES; SYSTEM; BRAIN; LIGHT AB The advent of specific molecular markers and probes employing optical reporters has encouraged the application of in vivo diffuse tomographic imaging at greater spatial resolutions and hence data-set volumes. This study applied singular-value analysis (SVA) of the fluorescence tomographic problem to determine optimal source and detector distributions that result in data sets that are balanced between information content and size. Weight matrices describing the tomographic forward problem were constructed for a range of source and detector distributions and fields of view and were decomposed into their associated singular values. These singular-value spectra were then compared so that we could observe the effects of each parameter on imaging performance. The findings of the SVA were then confirmed by examining reconstructions of simulated and experimental data acquired with the same optode distributions as examined by SVA. It was seen that for a 20-mm target width, which is relevant to the small-animal imaging situation, the source and detector fields of view should be set at approximately 30 mm. Equal numbers of sources and detectors result in the best imaging performance in the parallel-plate geometry and should be employed when logistically feasible. These data provide guidelines for the design of small-animal diffuse optical tomographic imaging systems and demonstrate the utility of SVA as a simple and efficient means of optimizing experimental parameters in problems for which a forward model of the data collection process is available. (C) 2004 Optical Society of America. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Photon Migrat Lab, Charlestown, MA 02129 USA. Fdn Res & Technol Hellas, Inst Elect Struct & Laser, GR-71110 Iraklion, Greece. RP Ntziachristos, V (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Ctr Mol Imaging Res, 149 13th St,Room 5404, Charlestown, MA 02129 USA. EM vasilis@helix.mgh.harvard.edu RI Ripoll, Jorge/J-8134-2012 OI Ripoll, Jorge/0000-0001-8856-7738 FU NCI NIH HHS [R24 CA 92782, T32 CA 79443, R21 CA 91807, P50 CA 86355]; NIBIB NIH HHS [R01 EB 000750-1] NR 30 TC 72 Z9 74 U1 0 U2 1 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1084-7529 J9 J OPT SOC AM A JI J. Opt. Soc. Am. A-Opt. Image Sci. Vis. PD FEB PY 2004 VL 21 IS 2 BP 231 EP 241 DI 10.1364/JOSAA.21.000231 PG 11 WC Optics SC Optics GA 764CZ UT WOS:000188183900009 PM 14763766 ER PT J AU Hubel, CA Wolf, M Rajakumar, A Daftary, A Roberts, JM Ness, RB Karumanchi, SA Thadhani, R AF Hubel, CA Wolf, M Rajakumar, A Daftary, A Roberts, JM Ness, RB Karumanchi, SA Thadhani, R TI An excess of serum soluble FMS-like tyrosine kinase 1 (sFlt1) persists postpartum in women with prior preeclampsia: Relation to insulin resistance. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Univ Pittsburgh, Sch Med, Magee Womens Res Inst, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Renal Unit, Boston, MA 02215 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 571 BP 266A EP 266A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500568 ER PT J AU Rajakumar, A Brandon, HM Rajakumar, PA Hubel, CA Karumanchi, A Thadhani, R Harger, G Markovic, N AF Rajakumar, A Brandon, HM Rajakumar, PA Hubel, CA Karumanchi, A Thadhani, R Harger, G Markovic, N TI Differential expression of vascular endothelial growth factor receptor, Flt-1 in PBMCs of pregnant women. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA 15260 USA. Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 572 BP 266A EP 266A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500569 ER PT J AU Canning, J Kim, MR Pru, JK Tilly, JL AF Canning, J Kim, MR Pru, JK Tilly, JL TI Role of the pro-apoptotic executioner enzyme, caspase-6, in ovarian follicle dynamics and depletion. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA 02114 USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 598 BP 274A EP 275A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500595 ER PT J AU Henkes, LE Lynch, MP Perez, GI Rueda, BR AF Henkes, LE Lynch, MP Perez, GI Rueda, BR TI Assessing the reproductive phenotype of acid sphingomyelinase (ASMase) deficient females: Separating the steroidogenic and apoptotic effects of members of the sphincomyelin pathway. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol,Vincent Ctr, Boston, MA USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 603 BP 276A EP 277A PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500600 ER PT J AU Lee, HJ Kim, MR Tilly, JL AF Lee, HJ Kim, MR Tilly, JL TI Death receptor-drivets apoptosis in ovarian granulosa cells requires the pro-apoptotic Bcl-2 family member, Bid, as an essential mediator. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 607 BP 278A EP 278A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500604 ER PT J AU Styer, AK Luo, HW Lynch, MP Kirley, SD Zukerberg, LR Rueda, BR AF Styer, AK Luo, HW Lynch, MP Kirley, SD Zukerberg, LR Rueda, BR TI Cables deficient mice display a unique ovarian phenotype. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Vincent Ctr Reprod Biol, Boston, MA USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 614 BP 280A EP 280A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500611 ER PT J AU Ramos, MP Rueda, BR Lynch, MP Henkes, LE Leavis, PC Gonzalez, RR AF Ramos, MP Rueda, BR Lynch, MP Henkes, LE Leavis, PC Gonzalez, RR TI The inhibition of leptin receptor negatively impacts mouse implantation. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Boston Biomed Res Inst, Watertown, MA USA. Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 690 BP 307A EP 307A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500687 ER PT J AU Johnson, J Canning, J Kaneko, T Pru, JK Tilly, JL AF Johnson, J Canning, J Kaneko, T Pru, JK Tilly, JL TI Germline stem cells and follicular repopulation in the postnatal mammalian ovary. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 707 BP 313A EP 313A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500704 ER PT J AU Pru, JK Trbovich, AM AF Pru, JK Trbovich, AM TI Apoptosis gene expression profiling and evaluation of cell death-inducing cytokines during early murine gestation. SO JOURNAL OF THE SOCIETY FOR GYNECOLOGIC INVESTIGATION LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2004 CL Houston, TX SP Soc Gynecol Investigat C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Obstet & Gynecol, Boston, MA 02114 USA. NR 0 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 1071-5576 J9 J SOC GYNECOL INVEST JI J. Soc. Gynecol. Invest. PD FEB PY 2004 VL 11 IS 2 SU S MA 949 BP 395A EP 395A PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 802SZ UT WOS:000220184500945 ER PT J AU Sheridan, RL AF Sheridan, RL TI Predicting increased fluid requirements during the resuscitation of thermally injured patients - Comment SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Shriners Hosp Children, Boston, MA 02114 USA. RP Sheridan, RL (reprint author), Massachusetts Gen Hosp, Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD FEB PY 2004 VL 56 IS 2 BP 413 EP 414 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 777ZV UT WOS:000189215200030 ER PT J AU Dunn, NJ Yanasak, E Schillaci, J Simotas, S Rehm, LP Souchek, J Menke, T Ashton, C Hamilton, JD AF Dunn, NJ Yanasak, E Schillaci, J Simotas, S Rehm, LP Souchek, J Menke, T Ashton, C Hamilton, JD TI Personality disorders in veterans with posttraumatic stress disorder and depression SO JOURNAL OF TRAUMATIC STRESS LA English DT Article DE trauma; PTSD; personality disorders; depression; assessment ID ADMINISTERED PTSD SCALE; VIETNAM VETERANS; PSYCHIATRIC-DISORDERS; COMBAT VETERANS; SYMPTOMS; CLINICIAN; COMORBIDITY; PREDICTORS; PREVALENCE; EXPOSURE AB Little is known about the frequency of the full-range of personality disorders in outpatients with concurrent posttraumatic stress disorder (PTSD) and depression, a common and oftentimes treatment-resistant combination in clinical practice. In a group therapy outcome study, Axis I and II diagnoses were assessed with the Structured Clinical Interview for DSM-IV and the Clinician-Administered PTSD Scale to select 115 male combat veterans with PTSD and depressive disorder. Within this sample, 52 (45.2%) had one or more personality disorders - most commonly paranoid (17.4%), obsessive-compulsive (16.5%), avoidant (12.2%), and borderline (8.7%) - and 19 (16.5%) had two or more. Documenting a substantial frequency of personality disorders is a first step in devising appropriate interventions for this treatment-resistant combination of disorders. C1 Vet Affairs Med Ctr, Houston, TX 77030 USA. Dept Vet Affairs Med Ctr, Hlth Serv Res & Dev Serv, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. Vet Affairs S Cent Mental Illness Res Educ & Clin, Houston, TX USA. Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Univ Houston, Houston, TX USA. RP Dunn, NJ (reprint author), Vet Affairs Med Ctr, Mental Hlth Care Line 116MHCL,2002 Holcombe Blvd, Houston, TX 77030 USA. EM ndunn@bcm.tmc.edu NR 35 TC 27 Z9 27 U1 3 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD FEB PY 2004 VL 17 IS 1 BP 75 EP 82 DI 10.1023/B:JOTS.0000014680.54051.50 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 770TA UT WOS:000188745900011 PM 15027797 ER PT J AU Konety, BR Eastham, JA Reuter, VE Scardino, PT Donat, SM Dalbagni, G Russo, P Herr, HW Schwartz, L Kantoff, PW Scher, H Kelly, WK AF Konety, BR Eastham, JA Reuter, VE Scardino, PT Donat, SM Dalbagni, G Russo, P Herr, HW Schwartz, L Kantoff, PW Scher, H Kelly, WK TI Feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy for patients with high risk or locally advanced prostate cancer: Results of a phase I/II study SO JOURNAL OF UROLOGY LA English DT Article DE prostatectomy; drug therapy; prostatic neoplasms ID ESTRAMUSTINE PHOSPHATE; RADIATION-THERAPY; CHEMOTHERAPY; EXPERIENCE AB Purpose: We determined the feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy in locally advanced (stage T3 or greater) and/or high risk tumors (Gleason 8 to 10 and/or serum prostate specific antigen (PSA) greater than 20 ng/ml). Materials and Methods: Enrollment criteria included clinical stage T1 to 2 with any Gleason grade and PSA greater than 20 ng/ml, clinical stage T3 to 4 with any serum PSA or Gleason grade, or any clinical stage with biopsy Gleason grade of 8 to 10 and any serum PSA. All patients received neoadjuvant hormonal therapy during chemotherapy (4 cycles of paclitaxel and carboplatin and estramustine) followed by radical prostatectomy. Nerve sparing was decided on an individual basis and a nerve graft was offered to those who underwent unilateral or bilateral nerve resection. Perioperative morbidity, mortality and delayed complications were assessed. Results: A total of 36 patients were enrolled. After chemohormonal therapy clinical stage was less in 39% of patients and greater in 36%. Bilateral nerve sparing was performed in 3 patients and the remaining 33 underwent either unilateral or bilateral neurovascular bundle resection with nerve grafts performed in 17 (52%). Deep vein thrombosis (22%) was the most frequent complication of chemotherapy. Minor postoperative complications occurred in 6 patients. At a median followup of 29 months (range 5 to 51) after radical prostatectomy 32 (89%) were continent and 5 (15%) preoperatively potent men remained potent. The positive surgical margin rate was 22%. Of all subjects 45% remain free from biochemical recurrence. Conclusions: Neoadjuvant chemohormonal therapy followed by radical prostatectomy can be performed with low morbidity. Positive surgical margin rates are low. This approach yielded good local control of disease, however impact on tumor recurrence and survival is not known. C1 Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, New York, NY 10021 USA. Cornell Univ, Dept Urol, New York, NY USA. Cornell Univ, Dept Med, New York, NY USA. Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Eastham, JA (reprint author), Mem Sloan Kettering Canc Ctr, Dept Urol, C1071,1275 York Ave, New York, NY 10021 USA. EM easthamj@mskcc.org OI Donat, Sherri/0000-0001-7430-9236 NR 19 TC 52 Z9 54 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2004 VL 171 IS 2 BP 709 EP 713 DI 10.1097/01.ju.0000108122.36893.5a PN 1 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 765YU UT WOS:000188319300037 PM 14713792 ER PT J AU Marone, LK Clouse, WD Dorer, DJ Brewster, DC LaMuraglia, GM Watkins, MT Kwolek, CJ Cambria, RP AF Marone, LK Clouse, WD Dorer, DJ Brewster, DC LaMuraglia, GM Watkins, MT Kwolek, CJ Cambria, RP TI Preservation of renal function with surgical revascularization in patients with atherosclerotic renovascular disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the American-Association-for-Vascular-Surgery CY JUN 08-11, 2003 CL CHICAGO, ILLINOIS SP Amer Assoc Vasc Surg ID ARTERY STENOSIS; ISCHEMIC NEPHROPATHY; VASCULAR-DISEASE; FOLLOW-UP; MANAGEMENT; INSUFFICIENCY; HYPERTENSION; EXPERIENCE; SURVIVAL; FAILURE AB Objective: Clinical and anatomic factors predictive of a favorable response to renal revascularization performed for renal function salvage remain poorly defined. To clarify decision making in such patients we reviewed a contemporary experience of surgical renal artery revascularization (RAR) performed primarily for preservation of renal function. Methods: Between June 1990 and March 2001 (ensuring 1 year minimum follow-up), 96 patients with renal insufficiency (serum creatinine [Cr] concentration greater than or equal to.5 mg&/dL) and hypertension underwent RAR for preservation of renal function. Study end points included early and late renal function response, progression to dialysis dependence, and long-term survival. Variables potentially associated with these end points were assessed with univariate analysis, Cox regression analysis, and logistic regression analysis, and survival was assessed with the Kaplan-Meier method. Results: Perioperative failure of RAR occurred in 3 patients (3%), with perioperative mortality in 4 patients (4.1%); thus 92 patients were available for long-term follow-up (mean, 39 months). Mean patient age was 70+/-9 years with a mean baseline Cr of 2.6 mg/dL (range, 1.5-7.8 mg/dL). Operative management consisted of aortorenal bypass in 38% of patients, extraanatomic bypass in 38% of patients, and endarterectomy in 24% of patients; 32% of patients required combined aortic revascularization and RAP, and 27% underwent bilateral RAR At hospital discharge renal function had improved (20% decrement in Cr) in 41 (43%) patients, including 7 patients who were removed from dialysis; remained unchanged in 40 (41%) patients; and declined (20% increase in Cr) in 15 (16%) patients. At last follow-up renal function was either improved or unchanged in 72% of patients. Predictors of a favorable response to RAR at last follow-up included stable Cr at hospital discharge (odds ratio [OR], 7.1; 95% confidence interval [CI], 2.5-21.8; P=.0004) and decreased Cr at hospital discharge (OR, 16; 95% CI, 1.6-307.8; P<.0001); bilateral renal artery repair (OR, 3.1; 95% CI, 0.9-10.6; P=.07) approached clinical significance. Predictors of worsened excretory function at last follow-up included decline of renal function at hospital discharge (OR, 28.9; 95% CI, 5.0-165.4; P=.0002), intervention to treat unilateral renal artery stenosis (OR, 3.8; 95% CI, 0.8-16.6; P=.05), and level of baseline Cr (OR, 3.0; 95% CI, 1.0-4.0; P=.04). Progression to dialysis occurred in 16 (17%) patients. Dialysis-free survival at 5 years was 50%, and overall actuarial survival at 5 years was 59%. Predictors of progression to dialysis during follow-up included treatment of complete renal artery occlusion (OR, 6.2; 95%, CI, 1.3-29.5; P=.02), early failure of RAR (OR, 3.1; 95% CI, 0.7-14.2; P=.04) and baseline Cr (OR, 2.9; 95% CI, 1.3-6.1; P=.006). Conclusion: Long-term clinical success in the preservation of renal function, noted in 70% of patients, can be predicted by the initial response to RAR and by anatomic factors, in particular, bilateral repair. While extreme (mean Crgreater than or equal to3.2 mg/dL) renal dysfunction generally is predictive of poor long-term outcome, a subset of patients will experience favorable results, even to the extent of rescue from dialysis. These results may facilitate clinical decision making in the application of RAR for renal function salvage. C1 Massachusetts Gen Hosp, Boston, MA 02111 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, WAC 458,32 Fruit St, Boston, MA 02111 USA. EM rcambria@parnters.org NR 37 TC 33 Z9 36 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD FEB PY 2004 VL 39 IS 2 BP 322 EP 329 DI 10.1016/j.jvs.2003.10.023 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 768GJ UT WOS:000188535000012 PM 14743131 ER PT J AU North, PE DeAos, I Hemphill, C Waner, M Mihm, MC AF North, PE DeAos, I Hemphill, C Waner, M Mihm, MC TI Evidence for chemokine-mediated epithelial "homing" in juvenile hemangioma (JH) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Pediatric-Pathology CY MAR 06-07, 2004 CL Vancouver, CANADA SP Soc Pediat Pathol C1 Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2004 VL 84 IS 2 MA 24 BP 273 EP 273 PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 840BW UT WOS:000222833000041 ER PT J AU Lum, G AF Lum, G TI Clinical utility of magnesium measurement SO LABORATORY MEDICINE LA English DT Article ID HOSPITALIZED-PATIENTS; HYPOMAGNESEMIA; SERUM; ROUTINE; METABOLISM; FREQUENCY; SUPPLEMENTATION; HYPERMAGNESEMIA; DEFICIENCY; DISORDERS C1 VA Boston Healthcare Syst, Boston, MA USA. RP Lum, G (reprint author), VA Boston Healthcare Syst, Boston, MA USA. NR 34 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 J9 LAB MED JI Lab. Med. PD FEB PY 2004 VL 35 IS 2 BP 106 EP 111 DI 10.1309/XWP9GN4WXE90U0B PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 769QJ UT WOS:000188661000018 ER PT J AU Brown, JR Gaudet, G Friedberg, JW Neuberg, D Mauch, P Kutok, JL Takvorian, T Fisher, DC Gribben, JG Kim, H Nadler, LM Freedman, AS AF Brown, JR Gaudet, G Friedberg, JW Neuberg, D Mauch, P Kutok, JL Takvorian, T Fisher, DC Gribben, JG Kim, H Nadler, LM Freedman, AS TI Autologous bone marrow transplantation for marginal zone non-Hodgkin's lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE autologous transplant; marginal zone lymphoma ID B-CELL LYMPHOMA; HIGH-DOSE THERAPY; CIRCULATING VILLOUS LYMPHOCYTES; FOLLICULAR LYMPHOMA; MYELODYSPLASTIC SYNDROME; MALIGNANT-LYMPHOMA; SECONDARY MALIGNANCIES; LATE COMPLICATION; SPLENIC LYMPHOMA; TISSUE LYMPHOMA AB The marginal zone non-Hodgkin's lymphomas are a recently defined group of related low-grade B cell malignancies whose natural history is heterogeneous. The optimal therapy is often unclear, particularly for the subset of patients with disseminated disease that behaves aggressively. We have retrospectively analyzed the outcomes of 11 patients with chemosensitive but disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide and total body irradiation followed by bone marrow transplantation (BMT) with anti-B cell monoclonal antibody-purged autologous bone marrow between January 1994 and September 1999. All patients had stage IV disease and received multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatment-related deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease. One patient developed and died of myelodysplasia. Five patients remain in continuous complete remission at a median follow-up of 52 months (45%). The median progression-free survival for these patients was 56 months, with median overall survival 58 months. The only significant predictor of disease-free and overall survival was age at the time of transplant; no patient under 45 at the time of transplant has relapsed or died of any cause (P=0.003). Outcomes of autologous BMT in patients with disseminated marginal zone NHL are similar to those in follicular NHL, and suggest that certain patients may experience prolonged disease-free survival. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiat Therapy, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Freedman, AS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 66996] NR 41 TC 11 Z9 11 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD FEB PY 2004 VL 45 IS 2 BP 315 EP 320 DI 10.1080/10428190310001593157 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 740FW UT WOS:000186393200014 PM 15101717 ER PT J AU Friedberg, JW Dong, DA Li, SG Kim, H Stephans, K Noonan, K Neuberg, D Gribben, JG Fisher, DC Freedman, AS Takvorian, T Jurgens, R Battle, TE Frank, DA AF Friedberg, JW Dong, DA Li, SG Kim, H Stephans, K Noonan, K Neuberg, D Gribben, JG Fisher, DC Freedman, AS Takvorian, T Jurgens, R Battle, TE Frank, DA TI Oral fludarabine has significant activity in patients with previously untreated chronic lymphocytic leukemia, and leads to increased STAT1 levels in vivo SO LEUKEMIA RESEARCH LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Hematology CY DEC 06-10, 2002 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Hematol DE CLL; oral fludarabine; purine analog therapy; STAT1; flow cytometry; CD38 ID NATIONAL-CANCER-INSTITUTE; VARIABLE-REGION MUTATIONS; NON-HODGKINS-LYMPHOMA; CD38 EXPRESSION; FOLLOW-UP; PHOSPHATE; CHEMOTHERAPY; CLL; THERAPY; DISEASE AB Fifteen patients with previously untreated chronic lymphocytic leukemia (CLL) were treated with oral fludarabine. Toxicities were mainly hematologic, and the response rate was 80%. To assess the effect of fludarabine on the transcription factor STAT1, blood samples obtained on study entry were treated in vitro with fludarabine for 24 h, and the majority of samples displayed an expected decrease in STAT1. To determine whether similar changes occurred in vivo, we developed a flow cytometric assay to quantitate STAT1 levels. On completion of fludarabine cycle 1, CLL cells showed increased STAT1 in the majority of patients, in contrast to the in vitro findings. This may reflect a survival advantage for cells that express high levels of STAT1. In conclusion, oral fludarabine is highly active and merits further investigation in previously untreated patients with CLL. Larger studies are indicated to determine optimal timing of STAT1 assessment, and if changes in STAT1 represent an in vivo indicator of response to purine analog therapy. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Med Hematol, Oncol Unit, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Berlex Labs Inc, Richmond, CA USA. RP Friedberg, JW (reprint author), Univ Rochester, James P Wilmot Canc Ctr, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. EM jonathan_friedberg@urmc.rochester.edu FU NCI NIH HHS [CA79547, CA93053] NR 34 TC 14 Z9 14 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD FEB PY 2004 VL 28 IS 2 BP 139 EP 147 DI 10.1016/S0145-2126(03)00213-3 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 764RX UT WOS:000188220800008 PM 14654078 ER PT J AU Wang, VS Saab, S AF Wang, VS Saab, S TI Liver transplantation in the era of model for end-stage liver disease SO LIVER INTERNATIONAL LA English DT Review DE liver transplantation; MELD ID HEPATOCELLULAR-CARCINOMA; WAITING-LIST; MELD SCORE; ALLOCATION POLICY; SURVIVAL; MORTALITY; PREDICTORS; SEVERITY; PATIENT; DROPOUT AB Liver transplantation is challenged by organ shortage and prolonged waiting list time. The goal of the ideal organ allocation system is to transplant individuals least likely to survive without a liver transplantation, and maintain appropriate rates of postoperative survival. Currently, liver allocation in the United States is based on the model for end-stage liver disease (MELD). Studies have shown MELD to be objective and accurate in predicting short-term survival in patients with cirrhosis. C1 Univ Calif Los Angeles, Med Ctr, Div Digest Dis, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dumont UCLA Liver Transplant Ctr, Los Angeles, CA 90095 USA. RP Saab, S (reprint author), Univ Calif Los Angeles, Med Ctr, Div Digest Dis, 44-138 CHS MC 168417,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM Ssaab@mednet.ucla.edu NR 29 TC 63 Z9 70 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1478-3231 J9 LIVER INT JI Liver Int. PD FEB PY 2004 VL 24 IS 1 BP 1 EP 8 DI 10.1111/j.1478-3231.2004.00888.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 803CZ UT WOS:000220210500001 PM 15101994 ER PT J AU Mokuno, Y Berthiaume, F Tompkins, RG Balis, UJ Yarmush, ML AF Mokuno, Y Berthiaume, F Tompkins, RG Balis, UJ Yarmush, ML TI Technique for expanding the donor liver pool: Heat shock preconditioning in a rat fatty liver model SO LIVER TRANSPLANTATION LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; HEME OXYGENASE-1; ZUCKER RAT; HEPATIC STEATOSIS; COLD PRESERVATION; TRANSPLANTATION; GRAFT; GERANYLGERANYLACETONE; HEPATOCYTES; TOLERANCE AB Fatty liver is a common predisposing risk factor for postoperative liver failure and accounts for most discarded livers during triage of donors. We investigated the effect of heat shock preconditioning (HPc) on recipient survival in a rat fatty liver transplantation model. Fatty liver donor rats were exposed to brief whole-body hyperthermia (10 minutes at 42.5degreesC) and allowed to recover. HPc induced heat shock proteins (HSPs) (HSP72, HSP90, and heme oxygenase [HO] -1) in donor livers, with levels peaking 12 to 48 hours after HPc. Subsequently, donor livers were harvested 24 hours after HPc, placed in cold storage for 10 hours, and transplanted into normal rats. At 3 hours posttransplantation, HPc reduced serum liver enzymes in the recipients and almost completely suppressed the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. Histologic evaluation 3 and 24 hours after transplantation showed that HPc significantly reduced hepatic inflammation and hepatocellular necrosis without affecting the steatotic appearance of hepatocytes. One week after transplantation, control non-heat-shocked and heat-shocked fatty liver recipients exhibited survival rates of less than 10% and more than 80%, respectively. The evaluation of the survival of recipients receiving fatty livers at different times after HPc showed that the protective effect of HPc was significant when donor livers were transplanted 3 to 48 hours after HPc, with the maximum effect seen 6 to 48 hours after HPc. In conclusion, HPc is a promising avenue to salvage rejected donor fatty livers and enhance the survival rate of fatty liver recipients. We estimate that this technique could increase the annual donor pool by 600 livers. C1 Shriners Hosp Children, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med,Surg Serv, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org FU NIDDK NIH HHS [R01DK59766, R01DK43371] NR 40 TC 23 Z9 23 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD FEB PY 2004 VL 10 IS 2 BP 264 EP 272 DI 10.1002/lt.20014 PG 9 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 805NX UT WOS:000220374100015 PM 14762865 ER PT J AU Fung, CH Woo, HE Asch, SM AF Fung, CH Woo, HE Asch, SM TI Controversies and legal issues of prescribing and dispensing medications using the Internet SO MAYO CLINIC PROCEEDINGS LA English DT Review ID PRESCRIPTION DRUGS; SILDENAFIL VIAGRA; DIRECT SALE; PHARMACIES; CONSUMERS; BOARDS AB Online pharmacies fall into 3 major categories: independent Internet-only sites, online branches of "brick-and-mortar" pharmacies, and sites representing partnership among neighborhood pharmacies. Potential benefits of online pharmacies include increased access, lower transaction and product costs, and greater anonymity. However, online pharmacies have generated controversies, including the use of "cyberdoctors" on some sites, the dispensing of drugs without prescriptions from other sites, and the importation of prescription medications. Although some online pharmacies are legitimate and likely provide benefits to patients, other online pharmacies engage in questionable practices. Numerous state and federal regulations and laws have tried to address controversies surrounding rogue Internet pharmacies. Because online pharmacies are increasingly common, clinicians may encounter patients asking for advice and information about online pharmacies. We review the regulatory framework governing online pharmacies and the potential risks and benefits of using online pharmacies. C1 VA Greater Los Angeles Healthcare Syst, Div Gen Internal Med, Dept Med, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA USA. RP Fung, CH (reprint author), 11301 Wilshire Bldg 111G, Los Angeles, CA 90073 USA. NR 102 TC 24 Z9 25 U1 0 U2 6 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD FEB PY 2004 VL 79 IS 2 BP 188 EP 194 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 770HX UT WOS:000188718100008 PM 14959914 ER PT J AU Weiner, M Long, J AF Weiner, M Long, J TI Cross-sectional versus longitudinal performance assessments in the management of diabetes SO MEDICAL CARE LA English DT Article; Proceedings Paper CT Conference on Measuring and Improving Healthcare Quality CY APR 18-20, 2002 CL UNIV PENN, PHILADELPHIA, PENNSYLVANIA HO UNIV PENN DE diabetes; quality indicators; health care; quality of health care ID CARDIOVASCULAR EVENTS; PRIMARY PREVENTION; GLYCEMIC CONTROL; CANCER; COSTS; CARE AB Background: Performance assessments help to quantify the level of adherence with practice standards and are often used to measure and compare the quality of care. However, most performance assessments are based on a cross-sectional analysis of patient information, whereas patient care is inherently longitudinal. This discordance could confound the relationship between the performance measure and the true quality of care. Objective: The objective of this study was to illustrate differences in performance assessment as measured by a traditional cross-sectional analysis compared with a longitudinal analysis. Methods: We conducted a cross-sectional and longitudinal analysis of a cohort of diabetic patients in an integrated delivery system having primary care visits and hemoglobin A1c (HBA1c) testing in both 1999 and 2000. Results: In the cross-sectional analysis of 4661 patients, we found a modestly increasing proportion achieved an HBA1c level of <8.0%: 73.1% in 1999 and 75.6% in 2000. Longitudinal analysis, however, suggested that certain subsets of patients were more likely to switch from good to poor control or retain their level of poor control over the 2 years studied. In particular, compared with whites, blacks were 1.76 (95% confidence interval [CI], 1.31-2.37) times as likely to switch from good to poor control and only 0.56 (95% CI, 0.41-0.76) times as likely to switch from poor to good control. Patients aged 35 to 49 were 2.54 (95% CI, 1.79-3.45) times as likely to switch from good to poor and only 0.66 (95% CI, 0.47-0.94) times as likely to switch from poor to good control than patients over age 64 years. Conclusions: Cross-sectional performance assessments could mask changes in diabetes control among individuals belonging to a cohort and, conceptually, are poorer indicators of care process than longitudinal measures. In addition, longitudinal analyses suggest the influence of patient sociodemographic factors on the performance assessment that should be accounted for when comparing quality of care for diabetes. C1 Philadelphia VA Med Ctr, Ctr Hlth Equity & Res & Promot, Philadelphia, PA USA. Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA USA. Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Weiner, M (reprint author), 423 Guardian Dr,Rm 1116, Philadelphia, PA 19104 USA. EM mweiner@mail.med.upenn.edu NR 16 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2004 VL 42 IS 2 SU S BP 34 EP 39 DI 10.1097/01.mlr.0000109167.86509.24 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 768FN UT WOS:000188533100005 ER PT J AU O'Malley, KJ Roddey, TS Gartsman, GM Cook, KF AF O'Malley, KJ Roddey, TS Gartsman, GM Cook, KF TI Outcome expectancies, functional outcomes, and expectancy fulfillment for patients with shoulder problems SO MEDICAL CARE LA English DT Article DE outcome expectancies; shoulder function; outcomes; expectancy fulfillment ID TOTAL HIP-ARTHROPLASTY; FULL-THICKNESS TEARS; PATIENTS EXPECTATIONS; ROTATOR CUFF; LOW-BACK; PREOPERATIVE EXPECTATIONS; ARTHROSCOPIC TREATMENT; PAIN EXPECTANCIES; SELF-EFFICACY; PRIMARY-CARE AB Objectives: This study was conducted to evaluate the relationship among patient outcome expectancies, perceived shoulder function changes, and perceptions of expectancy fulfillment. Methods: Patients (n = 199) treated for shoulder problems at one orthopedic surgeon's office completed a baseline survey comprised of measures of outcome expectancies, shoulder function, health status, and demographics. At I month, 2 months, and 3 months, patients completed a mailed follow-up survey comprised of all baseline measures except demographic variables. At 3 months, a measure of expectancy fulfillment was added. A general linear modeling approach was used to assess the significance and effect size of 1) outcome expectancies on changes in shoulder function; and (2) outcome expectancies, shoulder function changes, and their interaction on perceptions of expectancy fulfillment. Results: Outcome expectancies significantly predicted changes in shoulder function and accounted for 10% of the variance in functional improvement. The improvement difference between patients with high expectancies compared with those with low expectancies was clinically relevant (4.57 points), as it was greater than the minimal clinically important difference (3.02 points). Outcome expectancies and shoulder function changes significantly predicted patients' perceptions of fulfilled expectancies, but their interaction was not statistically significant. Conclusions: Results highlight the importance of patient expectancy in medical encounters. The findings suggest the need for interventions targeting patient expectancies such as including discussions about expectancy in patient-physician negotiations of therapeutic plans. Results also underscore the need for the development of better measures of outcome expectancies and expectancy fulfillment. C1 Baylor Coll Med, Houston VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Dept Med,Sect Hlth Serv Res, Houston, TX 77030 USA. Texas Womans Univ, Dept Phys Therapy, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Fondren Orthoped Grp, Houston, TX USA. VA Med Ctr, Parkinsons Dis Res, Educ & Clin Ctr, Houston, TX USA. RP O'Malley, KJ (reprint author), 905 W Howard Lane, Austin, TX 78753 USA. EM kimberly.omalley@pearson.com NR 47 TC 16 Z9 16 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2004 VL 42 IS 2 BP 139 EP 146 DI 10.1097/01.mlr.0000108766.00294.92 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 767GP UT WOS:000188432100007 PM 14734951 ER PT J AU Marxen, M Thornton, MM Chiarot, CB Klement, G Koprivnikar, J Sled, JG Henkelman, RM AF Marxen, M Thornton, MM Chiarot, CB Klement, G Koprivnikar, J Sled, JG Henkelman, RM TI MicroCT scanner performance and considerations for vascular specimen imaging SO MEDICAL PHYSICS LA English DT Article ID 3-DIMENSIONAL RECONSTRUCTION; ALGORITHM; NETWORKS; MODEL; POWER; CT AB Obtaining three-dimensional geometrical data of vascular systems is of major importance to a number of research areas in medicine and biology. Examples are the characterization of tumor vasculature, modeling blood flow, or genetic effects on vascular development. The performance of the General Electric Medical Systems MS8 microCT scanner is examined in the context of these applications. The system is designed to acquire high-resolution images of specimens up to 5 cm in diameter. A maximum resolution of 38 1p/mm at the 10% modulation transfer function level or 22,urn full width at half maximum of the plane spread function can be achieved with 8.5 mum voxels and a 17 mm field of view. Three different contrast agents are discussed and applied for imaging of small animal vasculature: corrosion casting material Batson's No. 17 with an added lead pigment, silicon rubber MICROFIL MV122, and a suspension of barium sulfate (Baritop) in gelatin. Contrast for all of these agents was highly variable in different vessels as well as within the same vessel. Imaging of PMMA tubing filled with MICROFIL shows that even vessels below 20 mum in diameter are detectable and that diameter estimation of vessels based on thresholding is possible with a precision of 2-3 pixels. (C) 2004 American Association of Physicists in Medicine. C1 Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Dept Med Biophys, Toronto, ON, Canada. Gen Elect Med Syst, London, ON, Canada. Univ Hlth Network, Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON, Canada. Univ Hlth Network, Princess Margaret Hosp, Dept Clin Phys, Toronto, ON, Canada. Univ Hlth Network, Princess Margaret Hosp, Dept Radiat Med Phys, Toronto, ON, Canada. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Vasc Anomalies Clin, Boston, MA USA. Univ Toronto, Dept Zool, Mississauga, ON L5L 1C6, Canada. Univ Toronto, Hosp Sick Children, Sunnybrook & Womens Coll Hlth Sci Ctr, Mouse Imaging Ctr,Dept Med Biophys, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Med Imaging, Toronto, ON M5G 1X8, Canada. RP Marxen, M (reprint author), Univ Toronto, Sunnybrook & Womens Coll Hlth Sci Ctr, Dept Med Biophys, Toronto, ON, Canada. RI Sled, John/D-8268-2012; Henkelman, Mark/F-3662-2011 OI Sled, John/0000-0002-4461-283X; NR 23 TC 89 Z9 89 U1 0 U2 17 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD FEB PY 2004 VL 31 IS 2 BP 305 EP 313 DI 10.1118/1.1637971 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 775CU UT WOS:000189023800016 PM 15000616 ER PT J AU Pan, T Lee, TY Rietzel, E Chen, GTY AF Pan, T Lee, TY Rietzel, E Chen, GTY TI 4D-CT imaging of a volume influenced by respiratory motion on multi-slice CT SO MEDICAL PHYSICS LA English DT Article DE 4D-CT; motion artifacts; motion characterization; gating and gated imaging ID SPIRAL CT; LUNG-CANCER; RECONSTRUCTION; SCANS; HEART AB We propose a new scanning protocol for generating 4D-CT image data sets influenced by respiratory motion. A cine scanning protocol is used during data acquisition, and two registration methods are used to sort images into temporal phases. A volume is imaged in multiple acquisitions of 1 or 2 cm length along the cranial-caudal direction. In each acquisition, the scans are continuously acquired for a time interval greater than or equal to the average respiratory cycle plus the duration of the data for an image reconstruction. The x ray is turned off during CT table translation and the acquisition is repeated until the prescribed volume is completely scanned. The scanning for 20 cm coverage takes about 1 min with an eight-slice CT or 2 mins with a four-slice CT. After data acquisition, the CT data are registered into respiratory phases based on either an internal anatomical match or an external respiratory signal. The internal approach registers the data according to correlation of anatomy in the CT images between two adjacent locations in consecutive respiratory cycles. We have demonstrated the technique with ROIs placed in the region of diaphragm. The external approach registers the image data according to an externally recorded respiratory signal generated by the Real-Time Position Management (RPM) Respiratory Gating System (Varian Medical Systems, Palo Alto, CA). Compared with previously reported prospective or retrospective imaging of the respiratory motion with a single-slice or multi-slice CT, the 4D-CT method proposed here provides (1) a shorter scan time of three to six times faster than the single-slice CT with prospective gating; (2) a shorter scan time of two to four times improvement over a previously reported multi-slice CT implementation, and (3) images over all phases of a breathing cycle. We have applied the scanning and registration methods on phantom, animal and patients, and initial results suggest the applicability of both the scanning and the registration methods. 0 2004 American Association of Physicists in Medicine. C1 GE Med Syst, Waukesha, WI USA. Univ Western Ontario, London, ON, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pan, T (reprint author), GE Med Syst, Waukesha, WI USA. EM tpan@di.mdacc.tmc.edu RI Lee, Ting-Yim/M-1721-2013 NR 18 TC 366 Z9 373 U1 1 U2 22 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD FEB PY 2004 VL 31 IS 2 BP 333 EP 340 DI 10.1118/1.1639993 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 775CU UT WOS:000189023800019 PM 15000619 ER PT J AU Ozen, M Medreano, EE Ittmann, M AF Ozen, M Medreano, EE Ittmann, M TI Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor SO MELANOMA RESEARCH LA English DT Article DE melanoma; fibroblast growth factors; receptors; G(2); cytokinesis; adenovirus ID NORMAL HUMAN MELANOCYTES; DNA-DAMAGE; TRANSFORMED PHENOTYPE; MALIGNANT-MELANOMA; PROSTATE-CANCER; KINASE; PROGRESSION; INVOLVEMENT; SUPPRESSION; INDUCTION AB Melanoma is the most deadly cutaneous malignancy; its incidence has risen significantly over the last 30 years and there is no effective treatment for advanced melanoma. Autocrine expression of fibroblast growth factors (FGFs) is a common event in malignant melanoma. We therefore sought to inhibit the proliferation and survival of melanoma cells as an approach to melanoma therapy by disrupting FGF signalling via adenoviral-mediated expression of a dominant negative FGF receptor. We tested three melanoma cell lines (A375, IIB and UCD) that express FGF2 and respond to exogenous FGF2 with increased proliferation. In all three cell lines, there was a significant decrease in net proliferation, and in two (A375 and UCD) an increase in cell death, associated with expression of the dominant negative FGF receptor. In these two cell lines, expression of the dominant negative FGF receptor resulted in the accumulation of p21 (WAF1/cip1), decreased cell division cycle-2 (cdc2) kinase activity, an increase in the percentage of cells in the G(2) phase of the cell cycle, and inhibition of cytokinesis, with accumulation of binucleated cells. These studies reveal that inhibition of FGF signalling can markedly decrease the net proliferation of melanoma cells by a novel mechanism involving a decrease in cdc2 kinase activity, an increase in p21 expression, inhibition of G(2) progression, inhibition of cytokinesis and increased cell death. In contrast, disruption of FGF signalling had only slight effects on normal melanocytes. Disruption of FGF signalling via the expression of the dominant negative FGF receptor is, therefore, a potential therapeutic approach in human melanoma. C1 Baylor Coll Med, Texas Med Ctr, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Texas Med Ctr, Dept Mol & Cell Biol, Houston, TX 77030 USA. Dept Vet Affairs, VA Med Ctr, Houston, TX USA. RP Ittmann, M (reprint author), Houston VAMC, Res Serv, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM mittmann@bcm.tmc.edu FU NCI NIH HHS [R0-1 CA-84282] NR 31 TC 19 Z9 20 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD FEB PY 2004 VL 14 IS 1 BP 13 EP 21 DI 10.1097/01.cmr.0000114316.54394.3c PG 9 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 809WY UT WOS:000220668000002 PM 15091189 ER PT J AU Economides, PA Caselli, A Zuo, CS Sparks, C Khaodhiar, L Katsilambros, N Horton, ES Veves, A AF Economides, PA Caselli, A Zuo, CS Sparks, C Khaodhiar, L Katsilambros, N Horton, ES Veves, A TI Kidney oxygenation during water diuresis and endothelial function in patients with type 2 diabetes and subjects at risk to develop diabetes SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID INTRARENAL OXYGENATION; NITRIC-OXIDE; DYSFUNCTION; MICROCIRCULATION; VASODILATION; NEPHROPATHY; MELLITUS; MRI AB The aim of the present study was to examine the relationship among water diuresis-induced changes in renal oxygenation, endothelial function, and various metabolic parameters in type 2 diabetic patients and healthy subjects at risk of type 2 diabetes. Thirty-eight subjects with type 2 diabetes (D: age, 54 +/- 10 years, mean +/- SD, 24 men) and 7 healthy subjects with parental history of type 2 diabetes or with impaired glucose tolerance (IGT) (relatives [R]: age 46 +/- 11 years, 4 men) were included. Laser Doppler imaging scanning was used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach) and 1% sodium nitroprusside (SNP), and ultrasound was used to measure the flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) in the brachial artery. Renal oxygenation was assessed by magnetic resonance imaging (MRI) before and during water diuresis. A decrease in the magnetic parameter R2* implies an increase in oxygenation. Renal medullary oxygenation did not improve with diuresis in either group (D: -0.5 +/- 1.9, R: -0.4 +/- 2.1, P = not significant [NS]). The renal cortical oxygenation showed a small, but statistically significant, improvement after diuresis in the 2 groups (D: -0.6 +/- 1.1, R: -0.5 +/- 0.5, P < .05). There were no correlations between the change in cortical R2* (R2* post-minus R2* prewater diuresis) and the micro- and macrovascular reactivity. The postdiuresis renal cortical R2* was negatively correlated with both the Ach- and SNP-induced skin vasodilation (% change over baseline)(r = -.40, P < .01 and r = -.39, P < .05, respectively), while no correlation existed with the FMD and NID. The baseline renal cortical oxygenation was also negatively correlated with the SNP-induced skin vasodilation (r = .36, P < .05) and positively correlated with the fasting plasma glucose, total cholesterol, and vascular cell adhesion molecule (VCAM) concentrations (r = .34, P < .05, r = .31, P < .05 and r = .37, P < .05, respectively). These preliminary findings suggest an association between the kidney cortical oxygenation and the skin microvascular reactivity, glycemia, and lipidemia. Water diuresis failed to produce an improvement in renal medullary oxygenation in both patients with diabetes and subjects at risk for diabetes. (C) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, Microcirculat Lab, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. Harvard Univ, Dept Radiol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Univ Athens, Sch Med, Dept Propaedeut Med 1, GR-11527 Athens, Greece. RP Veves, A (reprint author), Harvard Univ, Microcirculat Lab, Beth Israel Deaconess Med Ctr, Sch Med, Palmer 317,West Campus,1 Deaconess Rd, Boston, MA 02215 USA. FU NCRR NIH HHS [RR 01032] NR 20 TC 19 Z9 20 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD FEB PY 2004 VL 53 IS 2 BP 222 EP 227 DI 10.1016/j.metabol.2003.09.019 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 771QK UT WOS:000188797400016 PM 14767875 ER PT J AU Schechter, NM Plotnick, MI AF Schechter, NM Plotnick, MI TI Measurement of the kinetic parameters mediating protease-serpin inhibition SO METHODS LA English DT Article DE serpins; inhibition; serine protease; kinetics; pseudo-first order; second order; progress curve; complex breakdown; stoichiometry of inhibition ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; REACTIVE-CENTER LOOP; PLASMA PROTEINASE-INHIBITORS; ANTITHROMBIN-III; CONFORMATIONAL DISEASE; SUBSTRATE-SPECIFICITY; MICHAELIS COMPLEX; HUMAN CHYMASE; MECHANISM; ALPHA(1)-ANTICHYMOTRYPSIN AB Serine protease inhibition by proteins of the serpin family is a unique and complex process involving physical, chemical, and conformational changes. After encounter with the reactive site of inhibitor, the protease is conformationally trapped as a covalent complex resembling the acyl-protease intermediate of catalysis. The stability of the trap is not permanent and may vary for different proteases. In addition, the trapping mechanism is not 100% efficient and a fraction of the serpin may be consumed like a substrate before inactivation is complete. Characterization of protease-serpin inhibition therefore requires the measurement of three parameters: the apparent second order rate constant of inhibition (k(inh)), the stoichiometry of inhibition (SI), and the rate of complex breakdown (k(brkdn)). The basic kinetic methods to establish these parameters are described. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Univ Penn, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Schechter, NM (reprint author), Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. EM schechte@mail.med.upenn.edu; mplotnic@mail.med.upenn.edu FU NHLBI NIH HHS [HL50523]; NIAMS NIH HHS [AR39674] NR 56 TC 33 Z9 33 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD FEB PY 2004 VL 32 IS 2 BP 159 EP 168 DI 10.1016/S1046-2023(03)00207-X PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 762ZV UT WOS:000188043600009 PM 14698628 ER PT J AU Page, RN King, R Mihm, MC Googe, PB AF Page, RN King, R Mihm, MC Googe, PB TI Microphthalmia transcription factor and NKI/C3 expression in cellular neurothekeoma SO MODERN PATHOLOGY LA English DT Article DE neurothekeoma; microphthalmia transcription factor; NKIC3; immunohistochemistry ID NERVE SHEATH MYXOMA; IMMUNOHISTOCHEMICAL ANALYSIS; RENAL ANGIOMYOLIPOMA; MYOMELANOCYTIC TUMOR; EPITHELIOID VARIANT; MELANOMA MARKERS; S-100 PROTEIN; DIAGNOSIS; SPECTRUM; BENIGN AB While the usual or myxoid-type neurothekeoma has been reasonably well established as being a tumor of neural origin, the cellular neurothekeoma remains in disputed histogenesis. We studied a series of 11 cellular neurothekeomas using paraffin immunoperoxidase staining with microphthalmia transcription factor (Mitf), NKI/C3, and S-100. The majority of the tumors in our series stained with NKI/C3 (9/11) and Mitf (9/11). All failed to stain with S-100. Furthermore, we divided our series of cellular neurothekeomas according to cytomorphology; tumors demonstrating predominantly spindled morphology, predominantly epithelioid morphology, and mixed spindle and epithelioid morphology. The two tumors that failed to stain with NKI/C3 both demonstrated predominantly spindled morphology. One of the tumors that failed to stain with Mitf showed exclusive spindled morphology, while the other showed mixed morphology (spindle and epithelioid). Two of the tumors, which stained strongly with Mitf, however, showed exclusive epithelioid morphology. This current study furthers the concept that cellular neurothekeoma is a tumor of neuroectodermal origin, and further suggests that it may express some component of melanocytic differentiation. C1 Univ Tennessee, Knoxville Dermatopathol Lab, Knoxville, TN 37919 USA. Univ Tennessee, Dept Pathol, Knoxville, TN 37919 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Vanderbilt Univ, Dept Pathol, Nashville, TN USA. RP Page, RN (reprint author), Univ Tennessee, Knoxville Dermatopathol Lab, Knoxville, TN 37919 USA. EM rpage@labpath.com OI Googe, Paul/0000-0002-9185-3548 NR 26 TC 34 Z9 34 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 2004 VL 17 IS 2 BP 230 EP 234 DI 10.1038/modpathol.3800043 PG 5 WC Pathology SC Pathology GA 856DZ UT WOS:000224027200012 PM 14685254 ER PT J AU North, PE DeAos I Hemphill, C Waner, M Mihm, MC AF North, PE DeAos, I Hemphill, C Waner, M Mihm, MC TI Evidence for chemokine-mediated epithelial "homing" in juvenile hemangioma SO MODERN PATHOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Pediatric-Pathology CY MAR 06-07, 2004 CL Vancouver, CANADA SP Soc Pediat Pathol C1 Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Arkansas Childrens Hosp, Little Rock, AR 72202 USA. Harvard Univ, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 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 2004 VL 17 IS 2 MA 24 BP 271 EP 271 PG 1 WC Pathology SC Pathology GA 856DZ UT WOS:000224027200043 ER PT J AU Smith, ED Xu, YF Tomson, BN Leung, CG Fujiwara, Y Orkin, SH Crispino, JD AF Smith, ED Xu, YF Tomson, BN Leung, CG Fujiwara, Y Orkin, SH Crispino, JD TI More than blood, a novel gene required for mammalian postimplantation development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EARLY EMBRYONIC LETHALITY; TARGETED DISRUPTION; PERIIMPLANTATION LETHALITY; MOUSE DEVELOPMENT; MICE LACKING; STEM-CELLS; S-PHASE; TRANSCRIPTION; LEADS; ATR AB More than blood (Mtb) is a novel gene that is widely expressed in mouse embryos prior to gastrulation but is subsequently restricted to specific tissues, including the developing central nervous system and hematopoietic organs. Since MTB is highly expressed in the fetal liver and developing thymus, we predicted that MTB would be required for hematopoiesis and that embryos deficient in MTB would die of anemia. Surprisingly, embryos with a targeted disruption of Mtb died prior to the initiation of blood cell development, immediately following implantation. This lethality is due to a defect in expansion of the inner cell mass (ICM), as Mtb(-/-) blastocysts failed to exhibit outgrowth of the ICM, both in vitro and in vivo. Furthermore, Mtb(-/-) blastocysts exhibited a higher frequency of apoptotic cells than wild-type or heterozygous blastocysts. These findings demonstrate that Mtb is a novel gene that is essential for early embryonic development. C1 Univ Chicago, Gwen Knapp Ctr, Ben May Inst Canc Res, Chicago, IL 60637 USA. Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA. Dana Farber Canc Ctr, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Crispino, JD (reprint author), Univ Chicago, Gwen Knapp Ctr, Ben May Inst Canc Res, Room R116,924 E 57th St, Chicago, IL 60637 USA. EM crispino@huggins.bsd.uchicago.edu OI Crispino, John/0000-0002-8182-8306 FU NIDDK NIH HHS [R01 DK061464, DK61464-01, R01 DK061464-04] NR 31 TC 8 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2004 VL 24 IS 3 BP 1168 EP 1173 DI 10.1128/MCB.24.3.1168-1173.2004 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 764MW UT WOS:000188211500020 PM 14729962 ER PT J AU Tian, M Shinkura, R Shinkura, N Alt, FW AF Tian, M Shinkura, R Shinkura, N Alt, FW TI Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PIGMENTOSUM GROUP-F; XERODERMA-PIGMENTOSUM; NUCLEAR ABNORMALITIES; SWITCH REGIONS; ULTRAVIOLET-B; ERCC1; GENE; ENDONUCLEASE; RECOMBINATION; LACKING AB Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5' to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU PHS HHS [A13154, A107512] NR 40 TC 103 Z9 105 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2004 VL 24 IS 3 BP 1200 EP 1205 DI 10.1128/MCB.24.3.1200-1205.2004 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 764MW UT WOS:000188211500023 PM 14729965 ER PT J AU Safi, A Vandromme, M Caussanel, S Valdacci, L Baas, D Vidal, M Brun, G Schaeffer, L Goillot, E AF Safi, A Vandromme, M Caussanel, S Valdacci, L Baas, D Vidal, M Brun, G Schaeffer, L Goillot, E TI Role for the pleckstrin homology domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase-regulated muscle differentiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR-II; SKELETAL-MUSCLE; KINASE-B; IGF-I; MYOGENIN EXPRESSION; SIGNALING PATHWAY; 3-KINASE; CELLS; MYOBLASTS; MICE AB In this work, we report the implication of the pleckstrin homology (PH) domain-containing protein CKIP-1 in phosphatidytinositol 3-kinase (PI3-K) -regulated muscle differentiation. CKIP-1 is upregulated during muscle differentiation in C2C12 cells. We show that CKIP-1 binds to phosphatidylinositol 3-phosphate through its PH domain and localizes to the plasma membrane in a P13-K-dependent manner. Activation of P13-K by insulin or expression of an active form of P13-K p110 induces a rapid translocation of CKIP-1 to the plasma membrane. Conversely, expression of the 3-phosphoinositide phosphatase myotubularin or P13-K inhibition by LY294002, wortmannin, or mutant p85 abolishes CKIP-1 binding to the membrane. Upon induction of differentiation in low-serum medium, CKIP-1 overexpression in C2C12 myoblasts first promotes proliferation and then stimulates the expression of myogenin and cell fusion in a manner reminiscent of the dual positive effect of insulin-like growth factors on muscle cells. Interference with the P13-K pathway impedes the effect of CKIP-1 on C2C12 cell differentiation. Finally, silencing of CKIP-1 by RNA interference abolishes proliferation and delays myogenin expression. Altogether, these data strongly implicate CKIP-1 as a new component of P13-K signaling in muscle differentiation. C1 Ecole Normale Super Lyon, CNRS, LBMC, UMR 5665,IFR128 Biosci Lyon Gerland,Equipe Biol R, F-69364 Lyon 07, France. Ecole Normale Super Lyon, CNRS, LBMC, UMR 5665,IFR128 Biosci Lyon Gerland,Equipe Differ, F-69364 Lyon, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Goillot, E (reprint author), Ecole Normale Super Lyon, CNRS, LBMC, UMR 5665,IFR128 Biosci Lyon Gerland,Equipe Biol R, 46 Allee Italie, F-69364 Lyon 07, France. EM Evelyne.Goillot@ens-lyons.fr NR 37 TC 29 Z9 31 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2004 VL 24 IS 3 BP 1245 EP 1255 DI 10.1128/MCB.24.3.1245-1255.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 764MW UT WOS:000188211500027 PM 14729969 ER PT J AU Moseley, JB Sagot, I Manning, AL Xu, YW Eck, J Pellman, D Goode, BL AF Moseley, JB Sagot, I Manning, AL Xu, YW Eck, J Pellman, D Goode, BL TI A conserved mechanism for Bni1-and mDia1-induced actin assembly and dual regulation of Bni1 by Bud6 and profilin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FORMIN HOMOLOGY PROTEIN; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; CAPPING PROTEIN; CELL POLARITY; IN-VIVO; ACANTHAMOEBA PROFILIN; BINDING PROTEIN; BUDDING YEAST; FH PROTEINS AB Formins have conserved roles in cell polarity and cytokinesis and directly nucleate actin filament assembly through their FH2 domain. Here, we define the active region of the yeast formin Boil FH2 domain and show that it dimerizes. Mutations that disrupt dimerization abolish actin assembly activity, suggesting that dimers are the active state of FH2 domains. The Bni1 FH2 domain protects growing barbed ends of actin filaments from vast excesses of capping protein, suggesting that the dimer maintains a persistent association during elongation. This is not a species-specific mechanism, as the activities of purified mammalian formin mDia1 are identical to those of Bni1. Further, mDia1 partially complements BNI1 function in vivo, and expression of a dominant active mDia1 construct in yeast causes similar phenotypes to dominant active Bni1 constructs. In addition, we purified the Bni1-interacting half of the cell polarity factor Bud6 and found that it binds specifically to actin monomers and, like profilin, promotes rapid nucleotide exchange on actin. Bud6 and profilin show additive stimulatory effects on Bni1 activity and have a synthetic lethal genetic interaction in vivo. From these results, we propose a model in which Bni1 FH2 dimers nucleate and processively cap the elongating barbed end of the actin filament, and Bud6 and profilin generate a local flux of ATP-actin monomers to promote actin assembly. C1 Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. Harvard Univ, Sch Med, Childrens Hosp,Dept Pediat Oncol, Dana Farber Canc Inst & Pediat Hematol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Goode, BL (reprint author), Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. EM goode@brandeis.edu FU NCI NIH HHS [R01 CA116020]; NIGMS NIH HHS [GM63691, GM61345, R37 GM061345, R01 GM061345, R01 GM063691] NR 60 TC 164 Z9 168 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2004 VL 15 IS 2 BP 896 EP 907 DI 10.1091/mbc.E03-08-0621 PG 12 WC Cell Biology SC Cell Biology GA 770JF UT WOS:000188718900045 PM 14657240 ER PT J AU Zimmer, M Doucette, D Siddiqui, N Iliopoulos, O AF Zimmer, M Doucette, D Siddiqui, N Iliopoulos, O TI Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors SO MOLECULAR CANCER RESEARCH LA English DT Article ID HIPPEL-LINDAU PROTEIN; RNA-POLYMERASE-II; POSTTRANSCRIPTIONAL REGULATION; PROLINE HYDROXYLATION; GENE-EXPRESSION; FACTOR 1-ALPHA; HIF-ALPHA; HIF-1-ALPHA; HIF-2-ALPHA; TARGET AB The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate receptor for the mammalian SCF-2 E3 ubiquitin ligase complex that targets several substrates for ubiquitination and proteasomal degradation. Among these targets are the alpha-regulatory subunits of the hypoxia-Inducible factor (HIF). VHL-/- cells constitutively overexpress hypoxia-inducible genes through both transcriptional and posttranscriptional mechanisms and form tumors when injected into nude mice. Reintroduction of pVHL into VHL-/- cell lines restores normal oxygen-dependent regulation of these genes and suppresses tumor formation in the mouse xenograft assay. We report here that short hairpin RNA-mediated inactivation of HIF phenocopies the effects of pVHL reintroduction with respect to decreased expression of hypoxia-inducible genes, decreased ability to promote vascular endothelial cell proliferation in vitro, and tumor growth suppression in vivo. In addition, HIF inactivation abrogated the cellular response to hypoxia, indicating that HIF is the only pVHL target required for this response. These data suggest that deregulation of hypoxia-inducible genes in VHL-/- cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target. C1 Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, 55 Fruit St,GRJ904, Boston, MA 02114 USA. EM oiliopoulos@partners.org FU NCI NIH HHS [R29 CA78358-06] NR 39 TC 162 Z9 165 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2004 VL 2 IS 2 BP 89 EP 95 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 779RG UT WOS:000189313800003 PM 14985465 ER PT J AU Wucherpfennig, KW AF Wucherpfennig, KW TI T cell receptor crossreactivity as a general property of T cell recognition SO MOLECULAR IMMUNOLOGY LA English DT Article DE T cell receptor; crossreactivity; molecular mimicry; autoimmunity ID MYELIN BASIC-PROTEIN; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CLASS-II MOLECULES; STRUCTURAL REQUIREMENTS; PEPTIDE RECOGNITION; ANTIGENIC PEPTIDE; CRYSTAL-STRUCTURE; VIRAL PEPTIDE; SELF-PEPTIDE; MIMICRY AB TCR recognition of MHC/peptide complexes directs many aspects of T cell biology, including thymic selection, survival of naive T cells and differentiation into effector and memory T cells. It was widely thought that TCR recognition is highly specific, with an individual T cell being capable of only recognizing a particular peptide and closely related sequence variants. By considering the structural requirements for peptide binding to MHC molecules and TCR recognition of MHC/peptide complexes, we demonstrated that T cell clones could recognize a number of peptides from different organisms that are remarkably distinct in their primary sequence. These peptides are particularly diverse at those sequence positions buried in pockets of the MHC binding site, while a higher degree of similarity is present at a limited number of peptide residues that create the interface with the TCR. Many examples have now been documented for human and murine T cells, indicating that TCR crossreactivity represents a general feature of TCR recognition. (C) 2003 Elsevier Ltd. All rights reserved. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Wucherpfennig, KW (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM wucherpf@mbcrr.harvard.edu FU NINDS NIH HHS [R01 NS39096] NR 45 TC 45 Z9 48 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB PY 2004 VL 40 IS 14-15 BP 1009 EP 1017 DI 10.1016/j.molimm.2003.11.003 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 800BB UT WOS:000220002800006 PM 15036904 ER PT J AU Sklar, P Pato, MT Kirby, A Petryshen, TL Medeiros, H Carvalho, C Macedo, A Dourado, A Coelho, I Valente, J Soares, MJ Ferreira, CP Lei, M Verner, A Hudson, TJ Morley, CP Kennedy, JL Azevedo, MH Lander, E Daly, MJ Pato, CN AF Sklar, P Pato, MT Kirby, A Petryshen, TL Medeiros, H Carvalho, C Macedo, A Dourado, A Coelho, I Valente, J Soares, MJ Ferreira, CP Lei, M Verner, A Hudson, TJ Morley, CP Kennedy, JL Azevedo, MH Lander, E Daly, MJ Pato, CN TI Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis SO MOLECULAR PSYCHIATRY LA English DT Article DE schizophrenia; bipolar disorder; linkage; genetic ID BIPOLAR DISORDER PEDIGREES; LINKAGE ANALYSIS; GENETIC-VARIATION; 6P22.3 GENE; DISEASE; METAANALYSIS; REVEALS; NEUREGULIN-1; AGGREGATION; ASSOCIATION AB Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31 - 5q35 with strong linkage (NPL = 3.09, P = 0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL = 3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL = 3.28 ( P = 0.00066) at markers D5S2112 D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia ( peak NPL = 3.03, P = 0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases. C1 Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Charlestown, MA USA. Broad Inst, Cambridge, MA USA. Vet Adm, Syracuse, NY USA. SUNY Upstate Med Univ, Ctr Psychiat & Mol Genet, Syracuse, NY USA. Univ Coimbra, Coimbra, Portugal. Psychiat Serv, Azores, Portugal. McGill Univ, Montreal, PQ H3A 1A4, Canada. Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. Ctr Addict & Mental Hlth, Clarke Div, Toronto, ON, Canada. RP Sklar, P (reprint author), Psychiat & Neurodev Genet Unit, 149 13th St, Charlestown, MA 02129 USA. EM sklar@psych.mgh.harvard.edu RI macedo santos, antonio/M-5737-2013; Morley, Christopher P/K-1907-2014; OI macedo santos, antonio/0000-0003-2180-2718; Morley, Christopher P/0000-0003-0185-7148; de Oliveira Barreto Coimbra Carvalho, Celia Maria/0000-0003-4453-8139 FU NIMH NIH HHS [MH52618, MH058693] NR 37 TC 81 Z9 81 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2004 VL 9 IS 2 BP 213 EP 218 DI 10.1038/sj.mp.4001418 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 774GN UT WOS:000188971600016 PM 14699422 ER PT J AU Cheng, EM Siderowf, A Swarztrauber, K Eisa, M Lee, M Vickrey, BG AF Cheng, EM Siderowf, A Swarztrauber, K Eisa, M Lee, M Vickrey, BG TI Development of quality of care indicators for Parkinson's disease SO MOVEMENT DISORDERS LA English DT Review DE quality indicators; Parkinson's disease; quality of health care; health services research ID VULNERABLE ELDERS; HEALTH-CARE; DEPRESSION; CRITERIA; APPROPRIATENESS; SPECIALTY; EXPLICIT; RATINGS AB Parkinson's disease (PD) is a major cause of disability. To date, there have been no large-scale efforts to measure the quality of PD care because of a lack of quality indicators for conducting an explicit review of PD care processes. We present a set of quality indicators for PD care. Based on a structured review of the medical literature, 79 potential indicators were drafted. Through a two-round modified Delphi process, an expert panel of seven movement disorders specialists rated each indicator on criteria of validity, feasibility, impact on outcomes, room for improvement, and overall utility. Seventy-one quality indicators met validity and feasibility thresholds. Applying thresholds for impact on out-comes, room for improvement, and overall utility, a subset of 29 indicators was identified, spanning dopaminergic therapy, assessment of functional status, assessment and treatment of depression, coordination of care, and medication use. Multivariable analysis showed that overall utility ratings were driven by validity and impact on outcomes (P < 0.01). An expert panel can reach consensus on a set of highly rated quality indicators for PD care, which can be used to assess quality of PD care and guide the design of quality improvement projects. (C) 2003 Movement Disorder Society C1 VA Greater Los Angeles Healthcare Syst, Parkinsons Dis Res Educ & Clin Ctr, Dept Neurol, Los Angeles, CA 90073 USA. Philadelphia Vet Affairs Med Ctr, PADRECC, Philadelphia, PA USA. Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Oregon Hlth Sci Univ, Vet Affairs Med Ctr, PADRECC, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. Yale Univ, Dept Neurol, New Haven, CT USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. RP Cheng, EM (reprint author), VA Greater Los Angeles Healthcare Syst, Parkinsons Dis Res Educ & Clin Ctr, Dept Neurol, 11301 Wilshire Blvd,B500,ML 127, Los Angeles, CA 90073 USA. EM eric.cheng@med.va.gov FU AHRQ HHS [K-08 HS000004] NR 39 TC 28 Z9 28 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2004 VL 19 IS 2 BP 136 EP 150 DI 10.1002/mds.10664 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA 777DR UT WOS:000189160700002 PM 14978668 ER PT J AU Kock, N Kasten, M Schule, B Hedrich, K Wiegers, K Kabakci, K Hagenah, J Pramstaller, PP Nitschke, MF Munchau, A Sperner, J Klein, C AF Kock, N Kasten, M Schule, B Hedrich, K Wiegers, K Kabakci, K Hagenah, J Pramstaller, PP Nitschke, MF Munchau, A Sperner, J Klein, C TI Clinical and genetic features of myoclonus-dystonia in 3 cases: A video presentation SO MOVEMENT DISORDERS LA English DT Article DE myoclonus-dystonia; SGCE gene; genetic heterogeneity ID EPSILON-SARCOGLYCAN MUTATIONS; CHROMOSOME 7Q; MAJOR LOCUS AB Many cases of myoclonus-dystonia (M-D) are caused by mutations in the epsilon-sarcoglycan (SGCE) gene. We describe 3 children with a similar clinical picture of autosomal dominant M-D and an SGCE mutation in only one of them, suggesting that M-D is genetically heterogeneous. (C) 2004 Movement Disorder Society C1 Univ Schleswig Holstein, Dept Neurol, Lubeck, Germany. Univ Schleswig Holstein, Dept Human Genet, Lubeck, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. Gen Hosp Bolzano, Dept Neurol, Bolzano, Italy. Univ Hamburg, Dept Neurol, Hamburg, Germany. Med Univ Lubeck, Dept Pediat, D-23538 Lubeck, Germany. RP Klein, C (reprint author), Med Univ Lubeck, Dept Neurol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM klein_ch@neuro.mu-luebeck.de RI Pramstaller, Peter/C-2357-2008 NR 16 TC 11 Z9 12 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB PY 2004 VL 19 IS 2 BP 231 EP 234 DI 10.1002/mds.10635 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 777DR UT WOS:000189160700019 PM 14978685 ER PT J AU Weiner, HL AF Weiner, HL TI Multiple sclerosis: A disease of immune dysregulation SO MULTIPLE SCLEROSIS LA English DT Article; Proceedings Paper CT 8th Annual Meeting of Americas-Committee-for-Treatment-and-Resarch-in-Multiple-Sclerosis CY OCT 19, 2003 CL SAN FRANCISCO, CALIFORNIA SP Amer Comm Treatment & Res Multiple Sclerosis DE cyclophosphamide; IFN-gamma; IL-12; IL-15; IL-18; T cells ID CD4(+) T-CELLS; INTERLEUKIN-12; LESIONS; LIGAND C1 Harvard Univ, Sch Med, Brigham & Womens Massachusetts Gen Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. RP Weiner, HL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Massachusetts Gen Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD FEB PY 2004 VL 10 IS 1 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 764YV UT WOS:000188239500019 ER PT J AU Hermjakob, H Montecchi-Palazzi, L Bader, G Wojcik, R Salwinski, L Ceol, A Moore, S Orchard, S Sarkans, U von Mering, C Roechert, B Poux, S Jung, E Mersch, H Kersey, P Lappe, M Li, YX Zeng, R Rana, D Nikolski, M Husi, H Brun, C Shanker, K Grant, SGN Sander, C Bork, P Zhu, WM Pandey, A Brazma, A Jacq, B Vidal, M Sherman, D Legrain, P Cesareni, G Xenarios, L Eisenberg, D Steipe, B Hogue, C Apweiler, R AF Hermjakob, H Montecchi-Palazzi, L Bader, G Wojcik, R Salwinski, L Ceol, A Moore, S Orchard, S Sarkans, U von Mering, C Roechert, B Poux, S Jung, E Mersch, H Kersey, P Lappe, M Li, YX Zeng, R Rana, D Nikolski, M Husi, H Brun, C Shanker, K Grant, SGN Sander, C Bork, P Zhu, WM Pandey, A Brazma, A Jacq, B Vidal, M Sherman, D Legrain, P Cesareni, G Xenarios, L Eisenberg, D Steipe, B Hogue, C Apweiler, R TI The HUPOPSI's Molecular Interaction format - a community standard for the representation of protein interaction data SO NATURE BIOTECHNOLOGY LA English DT Article ID EXCHANGING PROTEOMICS DATA; COMMON STANDARDS; SYSTEMS BIOLOGY; MICROARRAY DATA; DATA-BANK; RESOURCE; BIND AB A major goal of proteomics is the complete description of the protein interaction network underlying cell physiology. A large number of small scale and, more recently, large-scale experiments have contributed to expanding our understanding of the nature of the interaction network. However, the necessary data integration across experiments is currently hampered by the fragmentation of publicly available protein interaction data, which exists in different formats in databases, on authors' websites or sometimes only in print publications. Here, we propose a community standard data model for the representation and exchange of protein interaction data. This data model has been jointly developed by members of the Proteomics Standards Initiative (PSI), a work group of the Human Proteome Organization (HUPO), and is supported by major protein interaction data providers, in particular the Biomolecular Interaction Network Database (BIND), Cellzome (Heidelberg, Germany), the Database of Interacting Proteins (DIP), Dana Farber Cancer Institute (Boston, MA, USA), the Human Protein Reference Database (HPRD), Hybrigenics (Paris, France), the European Bioinformatics Institute's (EMBL-EBI, Hinxton, UK) IntAct, the Molecular Interactions (MINT, Rome, Italy) database, the Protein-Protein Interaction Database (PPID, Edinburgh, UK) and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING, EMBL, Heidelberg, Germany). C1 European Bioinformat Inst, EBI Hinxton, Cambridge CB10 1SD, England. Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy. Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10021 USA. Hybrigen SA, F-75012 Paris, France. Univ Calif Los Angeles, Howard Hughes Med Inst, DOE Inst Gen & Prote, Los Angeles, CA 90095 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. European Mol Biol Lab, Struct & Computat Biol Program, D-69117 Heidelberg, Germany. Max Delbruck Ctr Mol Med, Dept Bioinformat, D-13092 Berlin, Germany. Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. LG Informat, Aventis Pharma Deutschland, D-65812 Bad Soden, Germany. Univ Bielefeld, Fac Technol, D-33615 Bielefeld, Germany. Chinese Acad Sci, Shanghai Inst Biol Sci, Bioinformat Ctr, Shanghai 200031, Peoples R China. Chinese Acad Sci, Shanghai Inst Biol Sci, Prote Ctr, Shanghai 200031, Peoples R China. Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. CNRS, Lab Genet & Physiol Dev, IBDM, F-13402 Marseille 9, France. Univ Edinburgh, Div Neurosci, Edinburgh EH8 9JZ, Midlothian, Scotland. Inst Bioinformat, Bangalore 560066, Karnataka, India. Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD 21287 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. CNRS, Lab Bordelais Rech Informat, UMR 5800, F-33405 Talence, France. Serono Int SA, CH-1228 Geneva, Switzerland. Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada. RP Hermjakob, H (reprint author), European Bioinformat Inst, EBI Hinxton, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. EM hhe@ebi.ac.uk RI Kalyana-Sundaram, Shanker/F-6860-2012; Bork, Peer/F-1813-2013; Ceol, Arnaud/H-3386-2012; Brun, Christine/B-4922-2008; Lappe, Michael/A-5505-2008; von Mering, Christian/B-3300-2008; Pandey, Akhilesh/B-4127-2009; Bader, Gary/C-1176-2009; Hogue, Christopher/B-6726-2008; sander, chris/H-1452-2011 OI Orchard, Sandra/0000-0002-8878-3972; Kersey, Paul/0000-0002-7054-800X; Hermjakob, Henning/0000-0001-8479-0262; Xenarios, Ioannis/0000-0002-3413-6841; Poux, Sylvain/0000-0001-7299-6685; Brazma, Alvis/0000-0001-5988-7409; Bork, Peer/0000-0002-2627-833X; Ceol, Arnaud/0000-0001-9533-4246; Brun, Christine/0000-0002-5563-6765; Apweiler, Rolf/0000-0001-7078-200X; Sarkans, Ugis/0000-0001-9227-8488; von Mering, Christian/0000-0001-7734-9102; Pandey, Akhilesh/0000-0001-9943-6127; Bader, Gary/0000-0003-0185-8861; FU Telethon [GTF02011] NR 29 TC 358 Z9 374 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2004 VL 22 IS 2 BP 177 EP 183 DI 10.1038/nbt926 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 770KT UT WOS:000188730500016 PM 14755292 ER PT J AU Liu, XQ Zhao, Y Gao, JG Pawlyk, B Starcher, B Spencer, JA Yanagisawa, H Zuo, J Li, TS AF Liu, XQ Zhao, Y Gao, JG Pawlyk, B Starcher, B Spencer, JA Yanagisawa, H Zuo, J Li, TS TI Elastic fiber homeostasis requires lysyl oxidase-like 1 protein SO NATURE GENETICS LA English DT Article ID BINDING PROTEIN; AORTIC-ANEURYSMS; PELVIC FLOOR; MICE; EMPHYSEMA; TROPOELASTIN; CELL AB Elastic fibers are components of the extracellular matrix and confer resilience(1). Once laid down, they are thought to remain stable(2), except in the uterine tract where cycles of active remodeling occur(3). Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema(4-7). Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance(8), but little is known about the role of renewal. Here we show that mice lacking the protein lysyl oxidase like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. Thus elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a cross-linking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin. C1 Harvard Univ, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. Univ Texas Hlth Ctr, Dept Biochem, Tyler, TX 75708 USA. Univ Texas, SW Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA. RP Li, TS (reprint author), Harvard Univ, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. EM tli@meei.harvard.edu NR 30 TC 327 Z9 342 U1 1 U2 16 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 2004 VL 36 IS 2 BP 178 EP 182 DI 10.1038/ng1297 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 768KT UT WOS:000188542700021 PM 14745449 ER PT J AU Livingston, DM AF Livingston, DM TI EMSY, a BRCA-2 partner in crime SO NATURE MEDICINE LA English DT Editorial Material ID SPORADIC BREAST; METHYLATION; LYSINE-9; CANCER AB Sporadic breast cancers only rarely contain BRCA2 or BRCA1 mutations, despite the presence of such mutations in inherited breast and ovarian cancers. The identification of a new binding partner for BRCA-2 sheds light on this incongruity. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Livingston, DM (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM David_Livingston@dfci.harvard.edu NR 8 TC 9 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2004 VL 10 IS 2 BP 127 EP 128 DI 10.1038/nm0204-127 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 770JN UT WOS:000188719600020 PM 14760417 ER PT J AU Willett, CG Boucher, Y di Tomaso, E Duda, DG Munn, LL Tong, RT Chung, DC Sahani, DV Kalva, SP Kozin, SV Mino, M Cohen, KS Scadden, DT Hartford, AC Fischman, AJ Clark, JW Ryan, DP Zhu, AX Blaszkowsky, LS Chen, HX Shellito, PC Lauwers, GY Jain, RK AF Willett, CG Boucher, Y di Tomaso, E Duda, DG Munn, LL Tong, RT Chung, DC Sahani, DV Kalva, SP Kozin, SV Mino, M Cohen, KS Scadden, DT Hartford, AC Fischman, AJ Clark, JW Ryan, DP Zhu, AX Blaszkowsky, LS Chen, HX Shellito, PC Lauwers, GY Jain, RK TI Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer SO NATURE MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANGIOGENESIS; THERAPY; CELLS AB The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, AIDS Res Ctr Expt Hematol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NCI, Canc Therapy Evaluat Program, Rockville, MD 20852 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU NCI NIH HHS [P01 CA080124-01A19001, P01 CA080124, P01 CA080124-01A10002, P01 CA080124-01A1S10002, P01 CA080124-01A1S19001, P01 CA080124-020002, P01 CA080124-029001, P01 CA080124-030002, P01 CA080124-039001, P01 CA080124-040002, P01 CA080124-049001, P01 CA080124-050002, P01 CA080124-059001, P01 CA080124-06A20006, P01 CA080124-06A29001, P01 CA080124-070006, P01 CA080124-079001, P01 CA080124-080006, P01 CA080124-089001, P01 CA80124, R21 CA099237, R21 CA099237-02] NR 15 TC 1251 Z9 1329 U1 8 U2 74 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2004 VL 10 IS 2 BP 145 EP 147 DI 10.1038/nm988 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 770JN UT WOS:000188719600032 PM 14745444 ER PT J AU Alexandrakis, G Brown, EB Tong, RT McKee, TD Campbell, RB Boucher, Y Jain, RK AF Alexandrakis, G Brown, EB Tong, RT McKee, TD Campbell, RB Boucher, Y Jain, RK TI Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors SO NATURE MEDICINE LA English DT Article ID IN-VIVO MEASUREMENT; CORRELATION SPECTROSCOPY; PHOTOBLEACHING RECOVERY; HYALURONIC-ACID; DIFFUSION; MACROMOLECULES; INTERSTITIUM; COLLAGEN; ANGIOGENESIS; CONVECTION AB Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. MIT, Biol Engn Div, Cambridge, MA 02139 USA. Northeastern Univ, Bouve Coll Hlth Sci, Dept Pharmaceut Sci, Boston, MA 02115 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu OI McKee, Trevor/0000-0002-2195-6146 FU NCI NIH HHS [T32CA73479, F32 CA097818, F32CA97818, P01CA80124, R24CA85140] NR 30 TC 109 Z9 110 U1 2 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2004 VL 10 IS 2 BP 203 EP 207 DI 10.1038/nm981 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 770JN UT WOS:000188719600042 PM 14716306 ER PT J AU Kau, TR Way, JC Silver, PA AF Kau, TR Way, JC Silver, PA TI Nuclear transport and cancer: From mechanism to intervention SO NATURE REVIEWS CANCER LA English DT Review ID FORKHEAD TRANSCRIPTION FACTOR; NF-KAPPA-B; PROTEIN-KINASE-B; TUMOR-SUPPRESSOR PROTEIN; SEGREGATION GENE CSE1; WILD-TYPE P53; APOPTOSIS SUSCEPTIBILITY GENE; RING-FINGER DOMAIN; CELL-CYCLE ARREST; BREAST-CANCER AB Nuclear-cytoplasmic transport, which occurs through special structures called nuclear pores, is an important aspect of normal cell function, and defects in this process have been detected in many different types of cancer cells. These defects can occur in the signal-transduction pathways that regulate the transfer of factors such as p53 and beta-catenin in and out of the nucleus, or in the general nuclear import and export machinery itself. In some cases, nuclear transport factors are overproduced, whereas in others, chromosomal translocations disrupt the structural proteins that make up the nuclear pore, leading to cell transformation. How does disruption of nuclear-cytoplasmic transport promote transformation, and is this process a viable therapeutic target? C1 Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EMD Lexigen Res Ctr, Billerica, MA 01821 USA. RP Silver, PA (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM pamela_silver@dfci.harvard.edu NR 126 TC 247 Z9 251 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2004 VL 4 IS 2 BP 106 EP 117 DI 10.1038/nrc1274 PG 12 WC Oncology SC Oncology GA 768ZF UT WOS:000188600800012 PM 14732865 ER PT J AU Roberts, CWM Orkin, SH AF Roberts, CWM Orkin, SH TI The SWI/SNF complex - Chromatin and cancer SO NATURE REVIEWS CANCER LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; ATYPICAL TERATOID/RHABDOID TUMORS; MALIGNANT RHABDOID TUMORS; CELL-CYCLE ARREST; REMODELING COMPLEXES; SACCHAROMYCES-CEREVISIAE; HSNF5/INI1 GENE; BRAIN-TUMORS; C-MYC; TRANSCRIPTIONAL ACTIVATION AB The SWI/SNF complex is an evolutionarily conserved multi-subunit chromatin-remodelling complex, which uses the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin. Increasing evidence supports a role for this complex in cancer development, as several subunits possess intrinsic tumour-suppressor activity or are required for the activity of other tumour-suppressor genes. For example, conditional inactivation of the Snf5 gene resulted in a highly penetrant cancer phenotype in mice. So, what are the links between the SWI/SNF complex and cancer, and what mechanisms might facilitate its involvement in oncogenesis? C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM charles_roberts@dfci.harvard.edu NR 78 TC 339 Z9 353 U1 3 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2004 VL 4 IS 2 BP 133 EP 142 DI 10.1038/nrc1273 PG 10 WC Oncology SC Oncology GA 768ZF UT WOS:000188600800014 PM 14964309 ER PT J AU Steere, AC Glickstein, L AF Steere, AC Glickstein, L TI Elucidation of Lyme arthritis SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID OUTER SURFACE PROTEIN; SEVERE COMBINED IMMUNODEFICIENCY; BORRELIA-BURGDORFERI INFECTION; ERYTHEMA CHRONICUM MIGRANS; POLYMERASE-CHAIN-REACTION; DELTA T-CELLS; MHC CLASS-II; TREATMENT-RESISTANT; SYNOVIAL-FLUID; ANTIBIOTIC-TREATMENT AB Before the first description of Lyme arthritis in 1976, patients with this disease were often thought to have juvenile or adult rheumatoid arthritis. It is now known that Lyme arthritis is caused by a tick-borne spirochete that disseminates to joints, where it induces marked pro-inflammatory responses. In most patients, the arthritis resolves with antibiotic treatment. However, in the United States, about 10% of patients with Lyme arthritis develop persistent synovitis, which lasts for months or even several years after the apparent eradication of the spirochete from the joint with antibiotic therapy. The elucidation of Lyme arthritis, from acute infection to chronic synovitis, might help in our understanding not only of this entity, but also of other forms of chronic inflammatory arthritis, including rheumatoid arthritis. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02114 USA. RP Steere, AC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02114 USA. EM asteere@partners.org NR 116 TC 139 Z9 143 U1 6 U2 21 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 2004 VL 4 IS 2 BP 143 EP 152 DI 10.1038/nri1267 PG 10 WC Immunology SC Immunology GA 768ZU UT WOS:000188602200016 PM 15040587 ER PT J AU Lipsky, BA Hirschmann, JV AF Lipsky, BA Hirschmann, JV TI Pneumococcal polysaccharide vaccines do not protect the elderly from pneumococcal infections SO NETHERLANDS JOURNAL OF MEDICINE LA English DT Editorial Material ID COST-EFFECTIVENESS; CLINICAL EFFECTIVENESS; EFFICACY; VACCINATION; ADULTS; PEOPLE; METAANALYSIS; PNEUMONIA; OLDER; COUNTRIES C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98108 USA. RP Lipsky, BA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Benjamin.Lipsky@med.va.gov OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 28 TC 10 Z9 10 U1 0 U2 0 PU VAN ZUIDEN COMMUNICATIONS PI ALPHEN AAN DE RIJN PA HENRY DUNANTWEG 40A, 2402 NR ALPHEN AAN DE RIJN, NETHERLANDS SN 0300-2977 J9 NETH J MED JI Neth. J. Med. PD FEB PY 2004 VL 62 IS 2 BP 33 EP 35 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 803NP UT WOS:000220238100001 PM 15127828 ER PT J AU Barbieri, R Frank, LM Nguyen, DP Quirk, MC Solo, V Wilson, MA Brown, EN AF Barbieri, R Frank, LM Nguyen, DP Quirk, MC Solo, V Wilson, MA Brown, EN TI Dynamic analyses of information encoding in neural ensembles SO NEURAL COMPUTATION LA English DT Article ID HIPPOCAMPAL PLACE CELLS; LATERAL GENICULATE-NUCLEUS; RETINAL GANGLION-CELLS; VISUAL INFORMATION; CORTICAL-NEURONS; SPIKING ACTIVITY; POPULATION; RECONSTRUCTION; CODE; CONSTRUCTION AB Neural spike train decoding algorithms and techniques to compute Shannon mutual information are important methods for analyzing how neural systems represent biological signals. Decoding algorithms are also one of several strategies being used to design controls for brain-machine interfaces. Developing optimal strategies to design decoding algorithms and compute mutual information are therefore important problems in computational neuroscience. We present a general recursive filter decoding algorithm based on a point process model of individual neuron spiking activity and a linear stochastic state-space model of the biological signal. We derive from the algorithm new instantaneous estimates of the entropy, entropy rate, and the mutual information between the signal and the ensemble spiking activity. We assess the accuracy of the algorithm by computing, along with the decoding error, the true coverage probability of the approximate 0.95 confidence regions for the individual signal estimates. We illustrate the new algorithm by reanalyzing the position and ensemble neural spiking activity of CA1 hippocampal neurons from two rats foraging in an open circular environment. We compare the performance of this algorithm with a linear filter constructed by the widely used reverse correlation method. The median decoding error for Animal 1 (2) during 10 minutes of open foraging was 5.9 (5.5) cm, the median entropy was 6.9 (7.0) bits, the median information was 9.4 (9.4) bits, and the true coverage probability for 0.95 confidence regions was 0.67 (0.75) using 34 (32) neurons. These findings improve significantly on our previous results and suggest an integrated approach to dynamically reading neural codes, measuring their properties, and quantifying the accuracy with which encoded information is extracted. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,Neurosci Stat Res Lab, Boston, MA 02114 USA. Harvard Med Sch MIT, Div Hlth Sci & Technol, Boston, MA 02114 USA. MIT, Dept Brain & Cognit Sci, Riken MIT Neurosci Res Ctr, Picower Ctr Learning & Memory, Cambridge, MA 02139 USA. Univ New S Wales, Sch Elect Engn & Telecommun, Sydney, NSW 2052, Australia. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Barbieri, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,Neurosci Stat Res Lab, Boston, MA 02114 USA. EM barbieri@neurostat.mgh.harvard.edu; loren@neurostat.mgh.harvard.edu; dpnguyen@neurostat.mgh.harvard.edu; mquirk@ladyday.mwl.ai.mit.edu; vic@nmr.mgh.harvard.edu; mwilson@mit.edu; brown@neurostat.mgh.harvard.edu OI Barbieri, Riccardo/0000-0001-9381-3833; Frank, Loren/0000-0002-1752-5677 FU NIDA NIH HHS [DA015644]; NIMH NIH HHS [MH59733, MH61637, MH65018] NR 53 TC 81 Z9 82 U1 1 U2 7 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD FEB PY 2004 VL 16 IS 2 BP 277 EP 307 DI 10.1162/089976604322742038 PG 31 WC Computer Science, Artificial Intelligence SC Computer Science GA 761KF UT WOS:000187907400003 PM 15006097 ER PT J AU Bai, L Hof, PR Standaert, DG Xing, YD Nelson, SE Young, AB Magnusson, KR AF Bai, L Hof, PR Standaert, DG Xing, YD Nelson, SE Young, AB Magnusson, KR TI Changes in the expression of the NR2B subunit during aging in macaque monkeys SO NEUROBIOLOGY OF AGING LA English DT Article DE NMDA receptor; N-methyl-D-aspartate receptor; epsilon2 subunit; glutamate; frontal cortex; striatum; hippocampus ID ASPARTATE RECEPTOR ANTAGONIST; SPATIAL MEMORY PERFORMANCE; LONG-TERM POTENTIATION; MESSENGER-RNA LEVELS; MORRIS WATER MAZE; NMDA RECEPTOR; GLUTAMATE RECEPTORS; PREFRONTAL CORTEX; WORKING-MEMORY; ELDERLY ADULTS AB Humans, non-human primates and rodents show declines in spatial memory abilities with increased age. Some of these declines in mice are related to changes in the expression of the epsilon2 (epsilon2) (NR2B) subunit of the N-methyl-D-aspartate receptor. The purpose of this study was to determine whether primates show changes during aging in the mRNA expression of the NR2B subunit. In situ hybridization was performed on tissue sections from three different ages of Rhesus monkeys (Macaca mulatta; 6-8, 10-12, and 24-26 years). There was a significant decrease in the mRNA expression of the NR2B subunit overall in the prefrontal cortex and in the caudate nucleus between young and old monkeys. There were no significant changes in NR2B mRNA expression in the hippocampus or the parahippocampal gyrus. The results in the prefrontal cortex, caudate and hippocampus were similar to those seen previously in C57BL/6 mice during aging, which suggests that mice may be useful as a model for primates to further examine the age-related changes in the expression of the NR2B subunit of the NMDA receptor in several important regions of the brain. (C) 2003 Elsevier Science Inc. All rights reserved. C1 Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Biomed Sci, Program Mol Cellular & Integrat Neurosci, Ft Collins, CO 80523 USA. Mt Sinai Sch Med, Dept Geriatr & Adult Dev, Dept Ophthalmol, Kastor Neurobiol Aging Labs, New York, NY 10029 USA. Mt Sinai Sch Med, Fishberg Res Ctr Neurobiol, New York, NY 10029 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Magnusson, KR (reprint author), Univ Idaho, Coll Sci, Dept Biol Sci, Moscow, ID 83844 USA. EM kmagnuss@uidaho.edu OI Standaert, David/0000-0003-2921-8348 FU NIA NIH HHS [AG 16322, AG05138]; NINDS NIH HHS [NS34361] NR 62 TC 31 Z9 33 U1 5 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2004 VL 25 IS 2 BP 201 EP 208 DI 10.1016/S0197-4580(03)00091-5 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 772LU UT WOS:000188844200008 PM 14749138 ER PT J AU Johnson, K Jones, K Killiany, R Becker, JA Hilson, J Albert, M AF Johnson, K Jones, K Killiany, R Becker, JA Hilson, J Albert, M TI Cerebral perfusion as a predictor of stability, decline and conversion to AD SO NEUROBIOLOGY OF AGING LA English DT Meeting Abstract CT 2nd Meeting of the Alzheimers Imaging Consortium CY JUL 20, 2002 CL STOCKHOLM, SWEDEN C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2004 VL 25 IS 2 MA 59 BP 268 EP 269 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 772LU UT WOS:000188844200071 ER PT J AU Caplan, D Moo, L AF Caplan, D Moo, L TI Cognitive conjunction and cognitive functions SO NEUROIMAGE LA English DT Article DE cognitive conjunction; functional neuroimaging techniques; subtraction analyses ID COMPREHENSION AB We argue that conjunction analysis does not solve the problems with subtraction analyses that it sets out to solve and that it has additional problems of its own. We argue that detailed analyses of the tasks set to identify cognitive functions are required for both conjunction and subtraction analyses to achieve their goals of localizing cognitive operations using functional neuroimaging techniques. (C) 2003 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, Vincent Burnham 827,Fruit St, Boston, MA 02114 USA. EM dcaplan@partners.org FU NIDCD NIH HHS [DC02146, DC05068] NR 11 TC 21 Z9 21 U1 3 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2004 VL 21 IS 2 BP 751 EP 756 DI 10.1016/j.neuroimage.2003.09.061 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 778QM UT WOS:000189252300028 PM 14980578 ER PT J AU Myrick, H Anton, RF Li, XB Henderson, S Drobes, D Voronin, K George, MS AF Myrick, H Anton, RF Li, XB Henderson, S Drobes, D Voronin, K George, MS TI Differential brain activity in alcoholics and social drinkers to alcohol cues: Relationship to craving SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE neuroimaging; alcoholism; craving ID COMPULSIVE DRINKING SCALE; HUMAN PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; ORBITOFRONTAL CORTEX; GUSTATORY NEOCORTEX; ANTERIOR CINGULATE; VENTRAL STRIATUM; DRUG-ABUSE; COCAINE; REWARD AB Using fMRI, our group previously found that after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. This study extends this earlier work with several improvements including imaging the entire brain (rather than the anterior half previously) and recording craving, while the subjects viewed images within the scanner. In a Philips 1.5T MRI scanner, 10 nontreatment-seeking alcoholics and 10 age-matched healthy social drinkers were given a sip of alcohol before viewing a 12 min randomized presentation of pictures of alcoholic beverages, nonalcoholic beverages, and two different visual control tasks, During picture presentation, changes in regional brain activity were measured in 15 transverse T2*-weighted blood oxygen level dependent slices. Subjects rated their urge to drink after each picture sequence. After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. This study suggests, as did our earlier study, that alcoholics and not social drinkers, when exposed to alcohol cues. have increased brain activity in areas that reportedly subserve craving for other addictive substances. C1 Med Univ S Carolina, Inst Psychiat 4N, Dept Psychiat & Behav Sci, Alcohol Res Ctr, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Res & Dev Serv, Charleston, SC 29401 USA. MUSC, CAIR, Charleston, SC 29425 USA. RP Myrick, H (reprint author), Med Univ S Carolina, Inst Psychiat 4N, Dept Psychiat & Behav Sci, Alcohol Res Ctr, 67 President St, Charleston, SC 29425 USA. EM myrickh@musc.edu FU NIAAA NIH HHS [K23 AA00314, 2 P50 AA10761-03] NR 52 TC 219 Z9 225 U1 9 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2004 VL 29 IS 2 BP 393 EP 402 DI 10.1038/sj.npp.1300295 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 771DD UT WOS:000188769600018 PM 14679386 ER PT J AU Yehuda, R Yang, RK Golier, JA Tischler, L Liong, B Decker, K AF Yehuda, R Yang, RK Golier, JA Tischler, L Liong, B Decker, K TI Effect of topiramate on glucocorticoid receptor mediated action SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE topiramate; glucocorticoid receptors; lysozyme activity; post-traumatic stress disorder; depression; mononuclear leukocytes ID POSTTRAUMATIC-STRESS-DISORDER; CULTURED HIPPOCAMPAL-NEURONS; MDR1A P-GLYCOPROTEIN; COMBAT VETERANS; DEXAMETHASONE; CORTISOL; RELEVANCE; EFFICACY; ABSENCE; ATROPHY AB This study examined the effects of topiramate (TPM) on glucocorticoid receptors (GRs) in mononuclear leukocytes of nine men and four women with chronic and recurring post-traumatic stress disorder (PTSD) and a group of comparison subjects (nine men, four women). A measure of 60 ml of blood was withdrawn by venipuncture at 0800 and mononuclear leukocytes were isolated. The cells were incubated with a series of concentrations of dexamethasone (DEX) without or with 50 mumol/l of TPM to evaluate the effects of DEX to inhibit lysozyme activity and the effect of TPM on it. ANCOVA compared the IC50 for lysozyme inhibition under conditions of DEX only and TPM + DFX. TPM affected lysozyme IC50 in the direction of increasing the sensitivity of the receptor in the sample as a whole. This effect was more pronounced in the mononuclear leukocytes from participants in the PTSD group, particularly in cells from subjects whose pretreatment lysozyme IC50 was relatively higher (eg, reflecting decreased glucococorticoid receptor responsiveness), compared to the rest of the sample. In conclusion, further investigation of the actions of TPM on GR and other neuroendocrine systems may prove useful in understanding some of the other established clinical effects of this agent. C1 Bronx Vet Affairs Med Ctr, Bronx, NY USA. Mt Sinai Sch Med, Dept Psychiat, Traumat Stress Studies Program, Bronx, NY USA. RP Yehuda, R (reprint author), Bronx Vet Affairs, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM rachel.yehuda@med.va.gov NR 30 TC 14 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2004 VL 29 IS 2 BP 433 EP 439 DI 10.1038/sj.npp.1300331 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 771DD UT WOS:000188769600023 PM 14666121 ER PT J AU Frederickson, CJ Maret, W Cuajungco, MP AF Frederickson, CJ Maret, W Cuajungco, MP TI Zinc and excitotoxic brain injury: A new model SO NEUROSCIENTIST LA English DT Article DE nitric oxide; oxidative stress; cerebral ischemia; metal chelator; zinc ID SYNAPTICALLY-RELEASED ZINC; HIPPOCAMPAL MOSSY FIBERS; LONG-TERM POTENTIATION; METAL CHELATING-AGENTS; NITRIC-OXIDE SYNTHASE; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; CEREBRAL-ISCHEMIA; KAINIC ACID; IN-VIVO AB It has been nearly 15 years since the suggestion that synaptically released Zn2+ might contribute to excitotoxic brain injury after seizures, stroke, and brain trauma. In the original "zinc-translocation" model, it was proposed that synaptically released Zn2+ ions penetrated postsynaptic neurons, causing injury. According to the model, chelating zinc in the cleft was predicted to be neuroprotective. This proved to be true: zinc chelators have proved to be remarkably potent at reducing excitotoxic neuronal injury in many paradigms. Promising new zinc-based therapies for stroke, head trauma, and epileptic brain injury are under development. However, new evidence suggests that the original translocation model was incomplete. As many as three sources of toxic zinc ions may contribute to excitotoxicity: presynaptic vesicles, postsynaptic zinc-sequestering proteins, and (more speculatively) mitochondrial pools. The authors present a new model of zinc currents and zinc toxicity that offers expanded opportunities for zinc-selective therapeutic chelation interventions. C1 NeuroBioTex Inc, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Biomed Engn, Galveston, TX 77550 USA. Harvard Univ, Sch Med, Ctr Biochem & Biol, Cambridge, MA 02138 USA. Harvard Univ, Massachusetts Gen Hosp, Inst Human Genet, Mol Neurogenet Lab, Cambridge, MA 02138 USA. RP Frederickson, CJ (reprint author), NeuroBioTex Inc, 101 Christopher Columbus Blvd, Galveston, TX 77550 USA. EM chris@neurobiotex.com RI Cuajungco, Math/B-2647-2008 OI Cuajungco, Math/0000-0003-0749-9564 FU NINDS NIH HHS [NS042882, NS38585, NS40215, NS41682] NR 74 TC 69 Z9 73 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD FEB PY 2004 VL 10 IS 1 BP 18 EP 25 DI 10.1177/1073858403255840 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 764YC UT WOS:000188233400010 PM 14987444 ER PT J AU Adelson, DW Million, M AF Adelson, DW Million, M TI Tracking the moveable feast: Sonomicrometry and gastrointestinal motility SO NEWS IN PHYSIOLOGICAL SCIENCES LA English DT Article ID LOWER ESOPHAGEAL SPHINCTER; CHOLECYSTOKININ-OCTAPEPTIDE; SMALL-INTESTINE; RATS AB Ultrasonomicrometry measures distance between piezoelectric crystals based on transmission time of ultrasound bursts. It allows monitoring of coordinated motion of small and delicate tissues, including gastrointestinal sphincters. Its suitability for motility studies in small animals such as mice suggests that its use in gastrointestinal studies will increase in coming years. C1 W Los Angeles Vet Affairs Med Ctr, Vet Affairs Greater Los Angeles Area Hlth Syst, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Vet Affairs Greater Los Angeles Area Hlth Syst, Ctr Neurovisceral Sci & Womens Hlth, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. RP Adelson, DW (reprint author), W Los Angeles Vet Affairs Med Ctr, Vet Affairs Greater Los Angeles Area Hlth Syst, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. OI Adelson, David/0000-0002-4623-6030 FU NIDDK NIH HHS [DK-57328-01A1S1, DK-41301] NR 20 TC 10 Z9 11 U1 0 U2 0 PU NEWS IN PHYSIOLOGICAL SCIENCES PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0886-1714 J9 NEWS PHYSIOL SCI JI News Physiol. Sci. PD FEB PY 2004 VL 19 BP 27 EP 32 DI 10.1152/nips.01439.2003 PG 6 WC Physiology SC Physiology GA 774EB UT WOS:000188965800006 PM 14739400 ER PT J AU Hsieh, AC Bo, RH Manola, J Vazquez, F Bare, O Khvorova, A Scaringe, S Sellers, WR AF Hsieh, AC Bo, RH Manola, J Vazquez, F Bare, O Khvorova, A Scaringe, S Sellers, WR TI A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE-STRANDED-RNA; TUMOR-SUPPRESSOR; INTERFERENCE; PROTEIN; DROSOPHILA; MICRORNAS; PHOSPHORYLATION; CLEAVAGE AB Gene silencing through RNA interference (RNAi) has been established as a means of conducting reverse genetic studies. In order to better understand the determinants of short interfering RNA (siRNA) knockdown for use in high-throughput cell-based screens, 148 siRNA duplexes targeting 30 genes within the PI3K pathway were selected and synthesized. The extent of RNA knockdown was measured for 22 genes by quantitative real-time PCR. Analysis of the parameters correlating with effective knockdown showed that (1) duplexes targeting the middle of the coding sequence silenced significantly poorer, (ii) silencing by duplexes targeting the 3' UTR was comparable with duplexes targeting the coding sequence, (iii) pooling of four or five duplexes per gene was remarkably efficient in knocking down gene expression and (iv) among duplexes that achieved a >70% knockdown of the mRNA there were strong nucleotide preferences at specific positions, most notably positions 11 (G or C) and 19 (T) of the siRNA duplex. Finally, in a proof-of-principle pathway-wide cell-based genetic screen, conducted to detect negative genetic regulators of Akt S473 phosphorylation, both known negative, regulators of this phosphorylation, PTEN and PDKA, were found. These data help to lay the foundation for genome-wide siRNA screens in mammalian cells. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Dharmacon Inc, Lafayette, CO 80026 USA. RP Sellers, WR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM william_sellers@dfci.harvard.edu FU NCI NIH HHS [CA85912, R01 CA085912] NR 25 TC 157 Z9 171 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2004 VL 32 IS 3 BP 893 EP 901 DI 10.1093/nar/gkh238 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 807GQ UT WOS:000220490400004 PM 14769947 ER PT J AU Farahani, P Fisler, JS Wong, H Diament, AL Yi, NJ Warden, CH AF Farahani, P Fisler, JS Wong, H Diament, AL Yi, NJ Warden, CH TI Reciprocal hemizygosity analysis of mouse hepatic lipase reveals influence on obesity SO OBESITY RESEARCH LA English DT Article DE genetics; percentage body fat; cholesterol; hepatic lipase activity; food intake ID INTRAABDOMINAL FAT; GENETIC-LOCI; LIPOPROTEIN METABOLISM; LIPID-METABOLISM; BODY-COMPOSITION; OLDER MEN; MODEL; MICE; LDL; CHOLESTEROL AB Objectives: We previously demonstrated coincident quantitative trait loci (QTLs) for percentage body fat, plasma hepatic lipase (HL) activity, and plasma cholesterol on mouse chromosome 7. In the present study, we investigated whether hepatic lipase (Lipc) is an obesity gene, whether Lipc interacts with an unknown gene on chromosome 7, and how HL activity is linked to the chromosome 7 locus. Research Methods and Procedures: BSB mice are a model of complex obesity due to interactions among genes from C57BL/6J and Mus spretus (SPRET) in (C57BL/6J X SPRET) X C57BL/6J backcross mice. Five crosses tested the impact on obesity of combinations of inactive (knockout) and wild-type Lipc alleles from C57BL/6J or SPRET in a reciprocal hemizygosity analysis. Results: The combined data from this allelic series suggest that Lipc alleles, and not alleles from a gene linked to Lipc, influence obesity. No interaction between Lipc and chromosome 7 was demonstrated. We confirmed the chromosome 7 QTLs for obesity, HL activity, and cholesterol. Because obesity and HL activity are not consistently associated in the BSB model, linkage of HL activity to chromosome 7 is not secondary to obesity per se. We also report, for the first time to our knowledge, a QTL in mammals for food intake. Discussion: This use of reciprocal hemizygosity analysis in mammals, which, to our knowledge, is the first reported, reveals its power to detect previously unknown effects of Lipc on obesity. C1 Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. Univ Calif Davis, Sect Neurobiol Physiol & Behav, Davis, CA 95616 USA. W Los Angeles VA Med Ctr, Lipid Res Lab, Los Angeles, CA USA. Univ Alabama, Dept Biostat, Birmingham, AL USA. RP Warden, CH (reprint author), Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. EM chwarden@ucdavis.edu FU NIDDK NIH HHS [R01 DK53993, DK35747, DK07355] NR 34 TC 19 Z9 19 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD FEB PY 2004 VL 12 IS 2 BP 292 EP 305 DI 10.1038/oby.2004.37 PG 14 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 779TX UT WOS:000189318000015 PM 14981222 ER PT J AU Baykal, A Thompson, JA Xu, XC Hahn, WC Deavers, MT Malpica, A Gershenson, DM Silva, EG Liu, JS AF Baykal, A Thompson, JA Xu, XC Hahn, WC Deavers, MT Malpica, A Gershenson, DM Silva, EG Liu, JS TI In situ human telomerase reverse transcriptase expression pattern in normal and neoplastic ovarian tissues SO ONCOLOGY REPORTS LA English DT Article DE ovarian tumors of low malignant potential; ovarian carcinoma; in situ hybridization; early detection marker ID CATALYTIC SUBUNIT GENE; REGULATED EXPRESSION; CERVICAL-CANCER; MESSENGER-RNA; HUMAN-CELLS; HTERT; TUMORS; DNA; EXTENSION; CARCINOMA AB Telomerase is a ribonuclear protein reverse transcriptase that maintains telomere length in eukaryotic cells. Activation of telomerase has been implicated in human cellular immortalization and carcinogenesis. Telomerase activity in ovarian neoplasm has been studied using polymerase chain reaction (PCR)-based methods and shown to be correlated with malignancy. However, we believe those results must be interpreted with caution because such studies used a heterogeneous mix of cells, including normal cell type known to express telomerase when activated. The present study used in situ hybridization that allows determination of the type of cells expressing telomerase, as well as the intensity of that expression, in ovarian neoplasms. A total of 75 specimens were studied. Epithelial telomerase reverse transcriptase mRNA expression was detected in 28 of 31 epithelial ovarian carcinomas, 1 of 1 malignant granulosa cell tumor, 7 of 9 serous borderline ovarian tumors, 11 of 11 mucinous borderline ovarian tumors, 4 of 5 serous cyst-adenofibromas, 2 of 4 serous cystadenomas, 8 of 8 mucinous cystadenomas, and 0 of 6 normal ovaries except the corpus luteum. Telomerase expression is heterogeneously found in both benign and malignant epithelial tissues. We conclude that human telomerase reverse transcriptase mRNA expression does not seem to be a reliable marker for clinical use in differentiating between benign and malignant tumors. C1 Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Div Pathol & Lab Med, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Liu, JS (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Div Pathol & Lab Med, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM jliu@mdanderson.org FU NCI NIH HHS [P01 CA 64602-01] NR 32 TC 12 Z9 12 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD FEB PY 2004 VL 11 IS 2 BP 297 EP 302 PG 6 WC Oncology SC Oncology GA 764YE UT WOS:000188233600007 PM 14719058 ER PT J AU Haimovici, R Koh, S Gagnon, DR Lehrfeld, T Wellik, S AF Haimovici, R Koh, S Gagnon, DR Lehrfeld, T Wellik, S CA Cent Serous Chorioretinopathy Case TI Risk factors for central serous chorioretinopathy - A case-control study SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT 105th Annual Meeting of the American-Academy-of-Ophthalmology CY NOV 11-14, 2001 CL NEW ORLEANS, LOUISIANA SP Amer Acad Ophthalmol ID SYSTEMIC LUPUS-ERYTHEMATOSUS; ALCOHOL-CONSUMPTION; PSYCHOLOGICAL STRESS; DEPENDENT DILATATION; RETINAL-DETACHMENT; RETINOPATHY; SMOKING; MICE; SUSCEPTIBILITY; EXPRESSION AB Purpose: To identify systemic factors associated with the development of central serous chorioretinopathy(CSCR). Design: Retrospective, case-control study. Participants and controls: 312 cases and 312 controls. Results: By use of a multivariate analysis, the previously described risk factors, systemic steroid use (odds ratio [OR], 37.1; 95% confidence interval [CI], 6.2-221.8), and pregnancy (OR, 7.1; 95% CI, 1.0-50.7), were strongly associated with CSCR. Additional risk factors identified by this study include antibiotic use (OR, 6.2; 95% CI, 1.0-37.9), alcohol use (OR, 4.9; 95% CI, 1.5-16.3), untreated hypertension (OR, 3.3; 95% CI, 1.3-8.5), and allergic respiratory disease (OR, 2.5; 95% CI, 1.2-5.1). Conclusions: A wide variety of systemic factors are associated with CSCR. Prospective studies are warranted to evaluate the nature and significance of these associations further. (C) 2004 by the American Academy of Ophthalmology. C1 Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. MAVERIC, Boston, MA USA. RP Koh, S (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. OI Gagnon, David/0000-0002-6367-3179 NR 44 TC 124 Z9 130 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2004 VL 111 IS 2 BP 244 EP 249 DI 10.1016/j.ophtha.2003.09.024 PG 6 WC Ophthalmology SC Ophthalmology GA 771UU UT WOS:000188805100008 PM 15019370 ER PT J AU Stewart, MG Witsell, DL Smith, TL Weaver, EM Yueh, B Hannley, MT AF Stewart, MG Witsell, DL Smith, TL Weaver, EM Yueh, B Hannley, MT TI Development and validation of the Nasal Obstruction Symptom Evaluation (NOSE) Scale SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID CHRONIC SINUSITIS; SEPTAL SURGERY; HEALTH-STATUS; OUTCOMES; SEPTOPLASTY AB OBJECTIVE: The study goal was to validate a disease-specific health status instrument for use in patients with nasal obstruction. DESIGN, SETTINGS, AND PATIENTS: The study consisted of a prospective instrument validation conducted at 4 academic medical centers with 32 adults with nasal septal deformity. METHODS: Prospective instrument validation occurred in 2 stages. Stage 1 was the development of a preliminary (alpha-version) instrument of potential items. Stage 2 was a test of the alpha-version for item performance, internal consistency, and test-retest reliability; construct, discriminant, criterion validity, and responsiveness; and creation of the final instrument. RESULTS: Items with poor performance were eliminated from the alpha-version instrument. In testing the final instrument, test-retest reliability was adequate at 0.702; internal consistency reliability was also adequate at 0.785. Validity was confirmed using correlation and comparison analysis, and response sensitivity was excellent. CONCLUSIONS: The Nasal Obstruction Symptom Evaluation Scale is a valid, reliable, and responsive instrument that is brief and easy to complete and has potential use for outcomes studies in adults with nasal obstruction. C1 Baylor Coll Med, Bobby R Alford Dept Otolarynogol & Communicat Sci, Houston, TX 77030 USA. Duke Univ, Dept Surg, Div Otolaryngol Head & Neck Surg, Durham, NC 27706 USA. Med Coll Wisconsin, Dept Otolaryngol & Commun Sci, Milwaukee, WI 53226 USA. Univ Washington, Sch Med, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Surg & Perioperat Care Serv, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Serv, Seattle, WA USA. Amer Acad Otolaryngol Head & Neck Surg Fdn, Alexandria, VA 22314 USA. RP Stewart, MG (reprint author), Baylor Coll Med, Bobby R Alford Dept Otolarynogol & Communicat Sci, 6550 Fannin St,Suite 1727, Houston, TX 77030 USA. EM mgstew@bcm.tmc.edu OI Yueh, Bevan/0000-0003-1380-1053 FU NHLBI NIH HHS [K23 HL068849-01A2, K23 HL068849]; ODCDC CDC HHS [CD-98318] NR 22 TC 217 Z9 225 U1 0 U2 7 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD FEB PY 2004 VL 130 IS 2 BP 157 EP 163 DI 10.1016/j.otohns.2003.09.016 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 779TP UT WOS:000189317300001 PM 14990910 ER PT J AU Kalso, E AF Kalso, E TI Biomarkers for pain SO PAIN LA English DT Editorial Material ID CYSTEINE-PROTEINASE-INHIBITOR; HUMAN CYSTATIN-C; SPINAL-CORD; CATHEPSIN-B; CEREBROSPINAL-FLUID; EXPRESSION; GENE; MARKER; RAT C1 Univ Helsinki, Cent Hosp, Dept Anaesthesia & Intens Care Med, Helsinki 00029, Finland. Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Pain Ctr, Boston, MA USA. RP Kalso, E (reprint author), Univ Helsinki, Cent Hosp, Dept Anaesthesia & Intens Care Med, POB 340, Helsinki 00029, Finland. EM eija.kalso@hus.fi NR 19 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD FEB PY 2004 VL 107 IS 3 BP 199 EP 201 DI 10.1016/j.pain.2003.12.009 PG 3 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 773GA UT WOS:000188888300001 PM 14736580 ER PT J AU Harrison, TH Thomas, SH Wedel, SK AF Harrison, TH Thomas, SH Wedel, SK TI Success rates of pediatric intubation by a non-physician-staffed critical care transport service SO PEDIATRIC EMERGENCY CARE LA English DT Article DE endotracheal intubation; neuromuscular blockade; prehospital airway management ID AIR MEDICAL TRANSPORT; ENDOTRACHEAL INTUBATION; CHILDREN; PARAMEDICS AB Objectives: Previous researchers have found that institution of an endotracheal intubation (ETI) protocol into a large urban paramedic program resulted in low success rates and had no beneficial effects. The primary goal of the current study was to assess ETI success rates achieved by a small cadre of nonphysician critical care transport (CCT) providers. A secondary objective was to assess for association between ETI success and factors such as age group or ETI setting (eg, in-hospital, in-aircraft). Design: This retrospective study analyzed transport records of consecutive pediatric patients (younger than 13 years) in whom ETI was attempted by a nurse/paramedic (RN/EMTP) CCT crew working under protocols which included neuromuscular blockade (NMB)-facilitated ETI. The CCT service performs scene and interfacility transports in helicopter, fixed-wing (airplane), and ground critical care vehicles; pediatric patients are transferred to 4 receiving tertiary care centers. chi(2) test, Fisher exact test, and logistic regression analysis (P = 0.05) examined ETI success rates and assessed for association between ETI success and various characteristics (eg, age group, ETI setting). Results: The CCT crew attempted ETI in 143 patients, with success in 136 cases (95.1%). There were no unrecognized esophageal intubations. ETI success was of similar likelihood across pediatric age groups (P = 0.19) and in different ETI settings (P = 0.57). Conclusions: CCT crew airway management success was very high in all practice settings. These data support contentions that, with a high level of initial and ongoing training, nonphysician CCT crew can successfully manage pediatric airways in a variety of circumstances. C1 Massachusetts Gen Hosp, Dept Emergency Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston MedFlight Crit Care Transport Serv, Boston, MA USA. Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. RP Thomas, SH (reprint author), Massachusetts Gen Hosp, Dept Emergency Serv, Clin Bldg 115,55 Fruit St, Boston, MA 02114 USA. EM thomas.stephen@mgh.harvard.edu NR 13 TC 10 Z9 10 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD FEB PY 2004 VL 20 IS 2 BP 101 EP 107 DI 10.1097/01.pec.0000113879.10140.7f PG 7 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 775GR UT WOS:000189032800005 PM 14758307 ER PT J AU Oh, J Reiser, J Mundel, P AF Oh, J Reiser, J Mundel, P TI Dynamic (re)organization of the podocyte actin cytoskeleton in the nephrotic syndrome SO PEDIATRIC NEPHROLOGY LA English DT Review DE podocytes; foot process effacement; proteinuria; integrins; glomerular basement membrane; dystroglycan ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR SLIT DIAPHRAGM; DIABETIC-NEPHROPATHY; MICE LACKING; ALPHA-3-BETA-1 INTEGRIN; MOLECULAR-ORGANIZATION; LUNG ORGANOGENESIS; EPITHELIAL-CELLS; RENAL-DISEASE; RAT-KIDNEY AB The visceral glomerular epithelial cell, also known as the podocyte, plays an important role in the maintenance of renal glomerular function. This cell type is highly specialized and its foot processes together with the interposed slit diaphragm (SD) form the final barrier to urinary protein loss. Effacement of foot processes is associated with the development of proteinuria and-if not reversed in a certain time-with permanent deterioration of the glomerular filter. To maintain an intact glomerular filter barrier, podocyte-podocyte interactions and podocyte interactions with the glomerular basement membrane (GBM) are essential. Recent years have highlighted podocyte functions by unraveling the molecular composition of the SD, but have also clarified the important role of the podocyte actin cytoskeleton, and the podocyte-GBM interaction in the development of foot process (FP) effacement. This review provides an update of podocyte functions with respect to novel podocyte-specific proteins and also focuses on the dynamic interaction between the actin cytoskeleton of podocytes, their cell surface receptors and the GBM. C1 Yeshiva Univ Albert Einstein Coll Med, Div Nephrol, Bronx, NY 10461 USA. Univ Heidelberg, Childrens Hosp, Div Pediat Nephrol, D-6900 Heidelberg, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA USA. RP Mundel, P (reprint author), Yeshiva Univ Albert Einstein Coll Med, Div Nephrol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM mundel@aecom.yu.edu NR 103 TC 52 Z9 64 U1 2 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD FEB PY 2004 VL 19 IS 2 BP 130 EP 137 DI 10.1007/s00467-003-1367-y PG 8 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 765AE UT WOS:000188243700003 PM 14673634 ER PT J AU Abdelwahid, E Pelliniemi, LJ Szucsik, JC Lessard, JL Jokinen, E AF Abdelwahid, E Pelliniemi, LJ Szucsik, JC Lessard, JL Jokinen, E TI Cellular disorganization and extensive apoptosis in the developing heart of mice that lack cardiac muscle alpha-actin: Apparent cause of perinatal death SO PEDIATRIC RESEARCH LA English DT Article ID FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; STRIATED-MUSCLE; GENE TRANSCRIPTS; SKELETAL-MUSCLE; MOUSE HEART; CELLS; EXPRESSION; FAILURE; DIFFERENTIATION; RAT AB Mice that lack cardiac muscle alpha-actin die during the perinatal period. Approximately 56% of mice that are homozygous null (-/-) for a functional cardiac alpha-actin gene do not survive to term, and the remainder generally die within 2 wk of birth. We found that there were neither morphologic differences nor differences in the extent of apoptosis between the mutant and normal hearts on embryonic day (E) 12 and E14 of development. However, apoptosis was greater in the hearts of homozygous null mice on E17 and postnatal day I when compared with wild-type hearts. The antiapoptotic factor Bcl-x/(L), was localized in regions adjacent to where apoptosis was detected. The distribution patterns of the apoptosis triggering protein p53 were similar to those of apoptotic cells. The growth of the prenatal and postnatal hearts of the cardiac alpha-actin-deficient mice was retarded, and the cytoplasmic filaments were disorganized. Although apoptotic cells were observed in both the atria and ventricles in the hearts of the homozygous null animals, the frequency was greater in the ventricles than in the atria. Our results indicate that the functional and structural disturbances in the mice with a homozygous lack of cardiac alpha-actin seem to be due to disorganized development of acto-myosin filaments in the affected cardiomyocytes. Other actin isoforms cannot compensate for the lack of cardiac alpha-actin, and this seems to induce apoptosis in defective cardiac myocytes, which are not able to cope with the increased workload in the perinatal phase. C1 Univ Turku, Dept Pediat, FIN-20520 Turku, Finland. Univ Turku, MediCity Res Labs, FIN-20520 Turku, Finland. Univ Turku, Electron Microscopy Lab, FIN-20520 Turku, Finland. Univ Cincinnati, Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Univ Helsinki, Dept Pediat, FIN-00290 Helsinki, Finland. RP Abdelwahid, E (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bldg 149,13th Str, Boston, MA 02129 USA. EM eltyeb.abdelwahid@cbrc2.mgh.harvard.edu FU NHLBI NIH HHS [R01 HL57291] NR 41 TC 9 Z9 14 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD FEB PY 2004 VL 55 IS 2 BP 197 EP 204 DI 10.1203/01.PDR.0000100900.56627.E1 PG 8 WC Pediatrics SC Pediatrics GA 767QX UT WOS:000188465100004 PM 14605248 ER PT J AU Yovel, I Mineka, S AF Yovel, I Mineka, S TI Hierarchical models of emotional disorders and emotion-congruent cognitive biases SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE models; anxiety; depression (emotion); selective attention; memory; cognitive processes ID EXPLICIT MEMORY; ANXIETY DISORDERS; TRIPARTITE MODEL; STROOP TASK; DEPRESSION; MOOD; INFORMATION; AWARENESS; WORDS; TRAIT AB Based on hierarchical models of emotional disorders, relationships between higher- and lower-order components of anxiety and depression and emotion-congruent cognitive biases were examined. Two groups of participants (n = 189) were selected based on their scores on General Distress (the nonspecific factor of anxiety and depression). They performed an explicit memory test of incidentally-learned self-referenced material and an emotional Stroop interference task, using three types of stimuli: anxiety-related, depression-related and neutral non-valenced words. It was hypothesized that an attentional bias for anxiety-relevant words and a memory bias for depression-relevant words would be best predicted by anxiety-related and depression-related measures, respectively. Strengthening the notion that demonstration of these types of biases is not reliable in subclinical populations, both a correlational analysis as well as a more powerful extreme group analysis could not detect the existence of any emotion-related cognitive biases. (C) 2003 Elsevier Ltd. All rights reserved. C1 Northwestern Univ, Dept Psychol, Evanston, IL 60208 USA. RP Yovel, I (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,ACC 812, Boston, MA 02114 USA. EM iyovel@partners.org NR 45 TC 22 Z9 23 U1 6 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD FEB PY 2004 VL 36 IS 3 BP 679 EP 694 DI 10.1016/S0191-8869(03)00125-9 PG 16 WC Psychology, Social SC Psychology GA 770LW UT WOS:000188733100014 ER PT J AU Mount, DB Romero, MF AF Mount, DB Romero, MF TI The SLC26 gene family of multifunctional anion exchangers SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review DE bicarbonate; chondrodysplasia; cystic fibrosis; deafness; diarrhea; oxalate; proximal tubule; chloride ID DYSPLASIA SULFATE-TRANSPORTER; ADENOMA DRA GENE; PENDRED-SYNDROME GENE; TRANSMEMBRANE CONDUCTANCE REGULATOR; CONGENITAL CHLORIDE DIARRHEA; SENSORINEURAL HEARING-LOSS; APICAL CL-/HCO3-EXCHANGER; NHE3 NA+/H+ EXCHANGER; OUTER HAIR-CELLS; DIASTROPHIC DYSPLASIA AB The ten-member SLC26 gene family encodes anion exchangers capable of transporting a wide variety of monovalent and divalent anions. The physiological role(s) of individual paralogs is evidently due to variation in both anion specificity and expression pattern. Three members of the gene family are involved in genetic disease; SLC26A2 in chondrodysplasias, SLC26A3 in chloride-losing diarrhea, and SLC26A4 in Pendred syndrome and hereditary deafness (DFNB4). The analysis of Slc26a4-null mice has significantly enhanced the understanding of the roles of this gene in both health and disease. Targeted deletion of Slc26a5 has in turn revealed that this paralog is essential for electromotor activity of cochlear outer hair cells and thus for cochlear amplification. Anions transported by the SLC26 family, with variable specificity, include the chloride, sulfate, bicarbonate, formate, oxalate and hydroxyl ions. The functional versatility of SLC26A6 identifies it as the primary candidate for the apical Cl--formate/oxalate and Cl--base exchanger of brush border membranes in the renal proximal tubule, with a central role in the reabsorption of Na+-Cl- from the glomerular ultrafiltrate. At least three of the SLC26 exchangers mediate electrogenic Cl--HCO3- and Cl--OH- exchange; the stoichiometry of Cl--HCO3- exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports greater than or equal to2 Cl- ions per HCO3- ion, whereas SLC26A6 transports greater than or equal to2 HCO3- ions per Cl- ion. SLC26 Cl--HCO3- and Cl--OH- exchange is activated by the cystic fibrosis transmembrane regulator (CFTR), implicating defective regulation of these exchangers in the reduced HCO3- transport seen in cystic fibrosis and related disorders; CFTR-independent activation of these exchangers is thus an important and novel goal for the future therapy of cystic fibrosis. C1 VA Boston Healthcare Syst, Div Renal, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, Boston, MA 02115 USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. RP Mount, DB (reprint author), VA Boston Healthcare Syst, Div Renal, Boston, MA 02115 USA. EM dmount@rics.bwh.harvard.edu; mfr@pop.cwru.edu FU NIDDK NIH HHS [DK60845, DK56218, R01-DK57708] NR 105 TC 333 Z9 346 U1 3 U2 16 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD FEB PY 2004 VL 447 IS 5 BP 710 EP 721 DI 10.1007/s00424-003-1090-3 PG 12 WC Physiology SC Physiology GA 772HV UT WOS:000188837300027 PM 12759755 ER PT J AU Glowacki, J Shusterman, EM Troulis, M Holmes, R Perrott, D Kaban, LB AF Glowacki, J Shusterman, EM Troulis, M Holmes, R Perrott, D Kaban, LB TI Distraction osteogenesis of the porcine mandible: Histomorphometric evaluation of bone SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article; Proceedings Paper CT 81st Annual Meeting of the American-Association-of-Oral-and-Maxillofacial-Surgeons CY SEP 29, 1999 CL BOSTON, MASSACHUSETTS SP Amer Assoc Oral & Maxillofacial Surgeons ID GRADUAL DISTRACTION; GROWTH; TISSUES; GENESIS; LATENCY AB Distraction osteogenesis is a technique for skeletal lengthening that exploits the body's innate capacity for bone formation in response to tension forces on the repair callus. The authors developed a distraction osteogenesis model with a semiburied device in the Yucatan minipig mandible because of similarities between human and porcine mandibular anatomy, temporomandibular function, chewing patterns, and bone turnover rates. The purpose of this study was to measure histomorphometric bone fill after different latency periods, rates of distraction, and duration of neutral fixation in the minipig mandible. In addition, the relationship between histomorphometric bone fill and clinical stability was investigated. Mandibular osteotomies in 20 female Yucatan minipigs weighing 25 to 30 kg were distracted with modified semiburied distraction devices. Variables included 0-day or 4-day latency; 1-mm, 2-mm, or 4-mm daily distraction rates; gap size of 7 or 12 mm; and evaluation after neutral fixation for various lengths of time. Specimens were fixed in 2% paraformaldehyde, pH 7.4, before being embedded in methylmethacrylate. Sections were prepared from the region just below the inferior alveolar canal. The area of new bone formation within the gap was measured and expressed as a percentage of the total area of the distraction gap. Bone fill ranged from 0 to 100 percent. A pilot study with 7-mm advancements showed similar bone fill with 0-day or 4-day latency, but with poor reproducibility. Mandibles that were distracted to 12 min at 1 mm per day exhibited nearly complete bone fill, either with 0-day latency (average, 93 percent) or 4-day latency (average, 100 percent). Mandibles that had been distracted for 3 days at 4 mm per day showed moderate osteogenesis and clinical stability with increasing time of neutral fixation. Bone fill was significantly correlated with clinical stability (Spearman r = 0.801, p = 0.001). Histological examination showed exuberant periosteal osteogenesis in distracted mandibles, even in those that showed poor bone fill and clinical stability. Thus, the periosteum appears to be a major source of new bone formation. These results show that osteogenesis was nearly complete with I mm per day and 0-day or 4-day latency. These results are consistent with the authors' previously reported clinical and radiographic observations that a latency period is not necessary for successful healing of the mandibular distraction osteogenesis wound. C1 Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg,Skeletal Biol Res, Boston, MA 02115 USA. Univ Calif San Diego, Div Plast Surg, San Diego, CA 92103 USA. RP Glowacki, J (reprint author), Brigham & Womens Hosp, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. EM jglowacki@rics.bwh.harvard.edu NR 26 TC 37 Z9 38 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD FEB PY 2004 VL 113 IS 2 BP 566 EP 573 DI 10.1097/01.PRS.0000101061.99577.09 PG 8 WC Surgery SC Surgery GA 800YJ UT WOS:000220063300015 PM 14758219 ER PT J AU Rivas-Vazquez, RA Saffa-Biller, D Ruiz, I Blais, MA Rivas-Vazquez, A AF Rivas-Vazquez, RA Saffa-Biller, D Ruiz, I Blais, MA Rivas-Vazquez, A TI Current issues in anxiety and depression: Comorbid, mixed, and subthreshold disorders SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article ID MAJOR DEPRESSION; PRIMARY-CARE; MENTAL-DISORDERS; ANXIOUS DEPRESSION; COGNITIVE THERAPY; MEDICAL OUTCOMES; DOUBLE-BLIND; FOLLOW-UP; SYMPTOMS; STATES AB Recent attention has been given to the high frequency of coexisting anxiety and depressive symptoms that has served to challenge the more traditional view that these two disorders are typically discrete syndromes. Furthermore, research suggests that less severe states of anxiety and depression continue to be overlooked, despite their capacity to produce significant psychosocial impairment. Given the implications for diagnostic and treatment outcome, psychologists need to be aware of the epidemiology, clinical presentations, and treatment strategies surrounding comorbid and subthreshold anxiety and depression. We review the literature, present issues related to these syndromes, and discuss the implications for diagnostic and clinical activities. C1 Univ Miami, Sch Med, Coral Gables, FL 33124 USA. Weston Ctr Psychol Serv, Weston, FL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Rivas-Vazquez, A (reprint author), 8340 N Kendell Dr,Suite 802 E, Miami, FL 33176 USA. EM rafrv@bellsouth.net NR 73 TC 34 Z9 36 U1 2 U2 21 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 2004 VL 35 IS 1 BP 74 EP 83 DI 10.1037/0735-7028.35.1.74 PG 10 WC Psychology, Multidisciplinary SC Psychology GA 768FV UT WOS:000188533700009 ER PT J AU Thrall, JH AF Thrall, JH TI Nanotechnology and medicine SO RADIOLOGY LA English DT Editorial Material DE perspectives; radiology and radiologists, research; technology assessment ID HIV-1 PROTEASE; GENE DELIVERY; NANOPARTICLES; SYSTEM; DNA; INHIBITORS; PLATFORM; THERAPY; BINDING; CANCER C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 14 Fruit St,MZ-FND 216, Boston, MA 02114 USA. EM thrall.james@mgh.harvard.edu NR 39 TC 34 Z9 38 U1 0 U2 4 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 2004 VL 230 IS 2 BP 315 EP 318 DI 10.1148/radiol.2302031698 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 767QG UT WOS:000188463700003 PM 14752175 ER PT J AU Dachman, AH Zalis, ME AF Dachman, AH Zalis, ME TI Quality and consistency in CT colonography and research reporting SO RADIOLOGY LA English DT Editorial Material DE colon, CT; colon neoplasms, CT; colon neoplasms, diagnosis; colonoscopy; editorials ID VIRTUAL COLONOSCOPY; COLORECTAL POLYPS; CONVENTIONAL COLONOSCOPY; DIAGNOSTIC PERFORMANCE; MULTICENTER; CANCER; GUIDELINES; ADENOMAS; COLON C1 Univ Chicago, Dept Radiol, Chicago, IL 60645 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Dachman, AH (reprint author), Univ Chicago, Dept Radiol, MC 2026,5841 S Maryland Ave, Chicago, IL 60645 USA. EM ahdachma@uchicago.edu NR 31 TC 43 Z9 43 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD FEB PY 2004 VL 230 IS 2 BP 319 EP 323 DI 10.1148/radiol.2302031113 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 767QG UT WOS:000188463700004 PM 14752176 ER PT J AU Arroyo, JG Bula, DV AF Arroyo, JG Bula, DV TI Immunohistochemical study of the internal limiting membrane in Terson syndrome SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE glial fibrillary acidic protein; internal limiting membrane; neuron-specific enolase; synaptophysin; Terson syndrome; vitreous hemorrhage ID HEMORRHAGE C1 Brigham & Womens Hosp, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Arroyo, JG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Retina Serv, 12th Floor,243 Charles St, Boston, MA 02114 USA. EM jarroyo@bidmc.harvard.edu NR 4 TC 6 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2004 VL 24 IS 1 BP 155 EP 157 DI 10.1097/00006982-200402000-00023 PG 3 WC Ophthalmology SC Ophthalmology GA 778HU UT WOS:000189234200023 PM 15076959 ER PT J AU Csernok, E Holle, J Hellmich, B Willem, J Tervaert, C Kallenberg, CGM Limburg, PC Niles, J Pan, GL Specks, U Westman, K Wieslander, J De Groot, K Gross, WL AF Csernok, E Holle, J Hellmich, B Willem, J Tervaert, C Kallenberg, CGM Limburg, PC Niles, J Pan, GL Specks, U Westman, K Wieslander, J De Groot, K Gross, WL TI Evaluation of capture ELISA for detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 in Wegener's granulomatosis: first results from a multicentre study SO RHEUMATOLOGY LA English DT Article DE ANCA; ELISA; IFT; proteinase 3; Wegener's granulomatosis ID DIAGNOSTIC-VALUE; MYELOPEROXIDASE; PREVALENCE; ANCA; AUTOANTIBODIES; VASCULITIS; DISEASE; PR3 AB Objective: To evaluate the performance characteristics of direct and capture ELISA for the detection of PR3-ANCA in Wegener's granulomatosis (WG) in international ANCA reference laboratories. Methods: Serum samples were derived from patients with histological and clinical diagnosis of WG (n = 60), rheumatoid arthritis (RA) (n = 30) and healthy controls (n = 30). Each of them was tested for the presence of ANCA by indirect immunofluorescence technique (IFT), direct and capture ELISA in six international reference laboratories (Massachusetts General Hospital, Boston; Wieslab AB, Lund; University of Maastricht; University Hospital Groningen; Mayo Clinic, Rochester; Rheumaklinik Bad Bramstedt/University of Schleswig-Holstein Campus Lubeck). Each centre tested the sera according to their house protocols of IFT and ELISA. The diagnostic performance of each test was estimated by receiver operating characteristic curve analysis and sensitivity and specificity in detection of ANCA/PR3-ANCA were calculated for the respective methods. Results: In patients histologically and clinically known as WG, the detection of ANCA by IFT varied between 52 and 83% among the participating centres. PR3-ANCA positivity with the different ELISAs ranged from 53 to 80% in direct ELISA and from 72 to 76% in capture ELISA. While most capture ELISAs successfully detected PR3-ANCA, there were significant differences between IFT and direct ELISA results between laboratories. ROC curve analysis demonstrated that in five of six laboratories the overall diagnostic performance of capture ELISA was superior to IFT and direct ELISA, respectively. Conclusion: Capture ELISA is a highly sensitive assay for detection of PR3-ANCA in WG and should be used in conjunction with compatible clinical picture and histological evidence. C1 Med Univ Lubeck, Dept Rheumatol, D-23538 Lubeck, Germany. Rheumaklin Bad Bramstedt, Bad Bramstedt, Germany. Univ Hosp Maastricht, Dept Clin & Expt Immunol, Maastricht, Netherlands. Univ Groningen Hosp, Groningen, Netherlands. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Div Pulm & Crit Care, Rochester, MN USA. Wieslab AB, Lund, Sweden. Univ Hannover, Dept Nephrol, D-30167 Hannover, Germany. RP Csernok, E (reprint author), Oskar Alexander Str 26, D-24576 Bad Bramstedt, Germany. EM csernok@rheuma-zentrum.de RI Gross, Wolfgang Ludwig/C-8733-2011; Holle, Julia/G-6138-2012 NR 19 TC 65 Z9 67 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD FEB PY 2004 VL 43 IS 2 BP 174 EP 180 DI 10.1093/rheumatology.keh028 PG 7 WC Rheumatology SC Rheumatology GA 772PG UT WOS:000188850000009 PM 14585921 ER PT J AU Ihlemann, N Rask-Madsen, C Kober, L Torp-Pedersen, C AF Ihlemann, N Rask-Madsen, C Kober, L Torp-Pedersen, C TI Vascular insulin response is preserved in non-diabetic patients with coronary artery disease, despite endothelial dysfunction SO SCANDINAVIAN CARDIOVASCULAR JOURNAL LA English DT Article DE coronary artery disease; endothelial function; insulin resistance ID NITRIC-OXIDE; CARDIOVASCULAR MORBIDITY; RESISTANCE; CELLS; ATHEROSCLEROSIS; VASODILATION; INHIBITION; SEVERITY; GLUCOSE; RISK AB Background - Patients with coronary artery disease ( CAD) are often insulin resistant, a state that predisposes to increased atherosclerosis. Recently, it was suggested that a " vascular insulin resistance" could explain this association, causing endothelial dysfunction and hence atherosclerosis. We therefore studied the vascular insulin response in patients with CAD. Materials and methods - Nine non- diabetic patients with documented CAD and 31 lean healthy controls were examined. Forearm blood flow was measured by venous occlusion plethysmography. Dose - response studies of acetylcholine ( ACh) and sodium nitroprusside ( SNP) elicited endothelium- dependent and - independent vasodilation and were repeated during intraarterial insulin infusion. Results - Patients were insulin resistant as determined by HOMA index. Insulin infusion resulted in high physiological levels of insulin in the forearm without systemic effects. Patients had a reduced ACh response but insulin infusion increased the ACh response equally in patients and controls ( a mean increase of 74 +/- 37 vs 57 +/- 24%, patients vs controls, p = 0.12). A minor increase of the SNP response was also noted during insulin infusion. Conclusion - Vascular insulin response is intact in non- diabetic CAD patients in spite of insulin resistance and endothelial dysfunction. C1 Bispebjerg Univ Hosp, Dept Cardiol, DK-2400 Copenhagen NV, Denmark. Joslin Diabet Ctr, Boston, MA 02215 USA. Rigshosp, Dept Cardiol, DK-2100 Copenhagen, Denmark. RP Ihlemann, N (reprint author), Bispebjerg Univ Hosp, Dept Cardiol, Bldg 40,Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. EM nihl@heart.dk RI Torp-Pedersen, Christian/E-5931-2013 NR 26 TC 3 Z9 4 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 1401-7431 J9 SCAND CARDIOVASC J JI Scand. Cardiovasc. J. PD FEB PY 2004 VL 38 IS 1 BP 22 EP 27 DI 10.1080/14017430310016397 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 804UX UT WOS:000220324700005 PM 15204243 ER PT J AU Bleuming, SA Peppelenbosch, MP van den Brink, GR Roberts, DJ AF Bleuming, SA Peppelenbosch, MP van den Brink, GR Roberts, DJ TI Homeostasis of the adult colonic epithelium: a role for morphogens SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID KERATINOCYTE GROWTH-FACTOR; INFLAMMATORY BOWEL-DISEASE; GASTROINTESTINAL-TRACT; TRANSCRIPTION FACTORS; CELL DIFFERENTIATION; FORCED EXPRESSION; BETA-CATENIN; CYCLIN D1; MOUSE; INTESTINE C1 Univ Amsterdam, Acad Med Ctr, Dept Expt Internal Med, Amsterdam, Netherlands. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP van den Brink, GR (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Expt Internal Med, Room G2-130, Amsterdam, Netherlands. NR 46 TC 2 Z9 2 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD FEB PY 2004 VL 39 IS 2 BP 93 EP 98 DI 10.1080/00365520310005451 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 776YL UT WOS:000189146900001 PM 15000268 ER PT J AU Schumacher, HR Habre, W Meador, R Hsia, EC AF Schumacher, HR Habre, W Meador, R Hsia, EC TI Predictive factors in early arthritis: Long-Term follow-up SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE unclassified arthritis; transient arthritis; rheumatoid arthritis; spondyloarthropathy; hands; polyarthritis ID EARLY RHEUMATOID-ARTHRITIS; SYNOVIAL MEMBRANE; RECENT-ONSET; INFLAMMATORY POLYARTHRITIS; CLASSIFICATION CRITERIA; CLINICAL-FEATURES; DISEASE; DISABILITY; SPONDYLOARTHROPATHIES; OLIGOARTHRITIS AB Background. Because recent-onset inflammatory arthritis exhibits considerable clinical and prognostic variability, it is important to attempt to predict which patients are likely to have a poor prognosis as early as possible. Most prognostic studies have looked at patients who fulfilled proposed criteria for a definite diagnosis of rheumatoid arthritis (RA) or other well-defined conditions; less information exists concerning predictive factors for other types of early arthritis. Objectives: To examine prognosis in early arthritis, the authors assessed the long-term outcome in a cohort of patients who presented with inflammatory arthritis of short duration. Associations between outcome and patient clinical characteristics were analyzed to determine possible prognostic factors. Methods: Since 1968, patients were selected to be followed up in 2 early-arthritis clinics if they had evidence of inflammatory joint disease and symptom duration was < 1 year. Length of follow-up was variable, but was at least 1 year. At last follow-up, patients were classified as being in remission or as having persistent disease. Factors associated with a poor outcome were identified by using formal statistical methods. Results: A total of 121 patients were included in this analysis. Mean disease duration to the first evaluation was 3 months, and median follow-up was 5 years (range, 1 to 30 months). Twenty-one patients (17%) had transient disease defined as total duration of < 6 weeks. Sixty-three patients (52%) were in remission at final follow-up, with unclassified patients doing the best. Patients meeting criteria for RA or spondylarthropathies had more persistent disease. Polyarticular disease predicted more persistent disease (P < .05). In multivariable analyses, patients with initial hand involvement were much less likely to achieve remission of their disease (odds ratio, 0.18; 95% confidence interval, 0.05 to 0.66). Only 4 patients had either class 4 function or joint replacement. Conclusions: Our findings indicate that prognosis in early inflammatory arthritis is generally good, with more than half of all patients achieving remission in our cohort. Patients with unclassified arthritis fared better than those meeting criteria for RA or spondylarthropathy. Of the many clinical variables examined as possible prognostic factors, hand involvement was the strongest predictor of a poor outcome. Relevance: The long follow-up of these patients with early arthritis provides clues for the clinician to the likely course and shows that many patients will do well. (C) 2004 Elsevier Inc. All rights reserved. C1 Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. RP Schumacher, HR (reprint author), Vet Affairs Med Ctr, 151K,Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM schumacr@mail.med.upenn.edu NR 55 TC 25 Z9 28 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0049-0172 J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD FEB PY 2004 VL 33 IS 4 BP 264 EP 272 DI 10.1053/S0049-0172(03)00130-6 PG 9 WC Rheumatology SC Rheumatology GA 777GD UT WOS:000189166900005 PM 14978664 ER PT J AU Koerner, FC AF Koerner, FC TI A brief historical perspective on the pathology of the breast: From Cheatle to Azzopardi and beyond SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE history; breast pathology; Cheatle; Azzopardi AB The modern pathological study of disorders of the breast begins with the intraoperative macroscopical examinations of such late-nineteenth-century American and British surgeons as Drs. John Collins Warren, Joseph Colt Bloodgood, and Sir George Lenthal Cheatle. Technical advances in the fields of microscopy and histology led to a shift in the nature and conduct of pathological studies in the first part of the twentieth century. Microscopical examination became the primary method of study, and pathologists assumed the leading role in this line of research. With the studies of Drs. Frank W. Foote, Fred W. Stewart, and Arthur Purdy Stout, pathologists began to explore the territory of breast pathology in detail, describing the microscopical features of breast lesions and developing theories regarding their pathogenesis. The spread of the use of biopsy procedures to establish diagnoses led pathologists of the mid-twentieth century to. assume the new role of clinical diagnostician. Exemplified by the work of Dr. John G. Azzopardi, pathological research of the latter half of the twentieth century came to emphasize microscopical diagnostic criteria and differential diagnosis. With ever more sophistication and increasingly powerful techniques, this trend continues to this day. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Koerner, FC (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM FKOERNER@PARTNERS.ORG NR 29 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 3 EP 9 DI 10.1053/j.semdp.2003.10.008 PG 7 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200002 PM 15074553 ER PT J AU Koerner, FC AF Koerner, FC TI Epithelial proliferations of ductal type SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE ductal hyperplasia; atypical ductal hyperplasia; ductal carcinoma in situ ID MALIGNANT INTRADUCTAL PROLIFERATIONS; TERM FOLLOW-UP; BREAST; CARCINOMA; 34-BETA-E12; HYPERPLASIA; DIAGNOSIS; LESIONS AB The diagnosis of ductal proliferations requires analysis of both architectural and cytological features. Architectural characteristics of conventional ductal hyperplasia include persistence of the duct lumen as peripheral, crescent shaped spaces; streaming of cells; formation of irregular, slit-like fenestrations; and "maturation." Hyperplastic ductal cells exhibit indistinct cell borders, irregular placement of nuclei, irregular nuclear shapes, granular chromatin, and uniform small nucleoli. The cells do not show polarization or dishesion. Low-grade ductal carcinoma in-situ exhibits both architectural and cytological atypicality. The architectural atypicality takes two forms: the formation of cribriform spaces or their variants and the regular arrangement of cells. The former reflects the polarization of the carcinoma cells and the latter their dishesion. Cytological atypicality includes distinct cell borders; smoothly contoured, oval or round nuclei; homogeneous chromatin; and inconspicuous nucleoli. Atypical ductal hyperplasia shows low-grade cytological atypicality but lacks the architectural atypicality of ductal carcinoma in situ. Proliferations lacking cytological atypicality do not merit the diagnosis of atypical ductal hyperplasia whatever their architectural characteristics. Although not usually necessary, immunohistochemical staining for high molecular weight keratin can help resolve difficult cases. Current evidence does not support the belief that conventional ductal hyperplasia represents an obligate precursor to ductal carcinoma in situ. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Koerner, FC (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM FKOERNER@PARTNERS.ORG NR 17 TC 8 Z9 11 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 10 EP 17 DI 10.1053/j.semdp.2003.10.010 PG 8 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200003 PM 15074554 ER PT J AU Nasser, SM AF Nasser, SM TI Columnar cell lesions: Current classification and controversies SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article ID CARCINOMA-IN-SITU; BREAST-CONSERVING THERAPY; ATYPICAL CYSTIC LOBULES; TERM FOLLOW-UP; CORE BIOPSY; TUBULAR CARCINOMA; CANCER; HYPERPLASIA; MICROCALCIFICATIONS; CANCERIZATION AB "Columnar cell lesions" is a general descriptive term referring to disparate lesions having in common cells with a columnar configuration but not necessarily identical histologic or biologic characteristics. Within this large category, a group of lesions having in common a population of atypical cells (frequently columnar shaped) is emerging as early neoplastic lesions. This article reviews the histological features, differential diagnosis, associated lesions, biologic potential, clinical significance, and management of atypical columnar cell lesions. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Nasser, SM (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. NR 31 TC 21 Z9 22 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 18 EP 24 DI 10.1053/j.semdp.2003.10.006 PG 7 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200004 PM 15074555 ER PT J AU Oyama, T Koerner, FC AF Oyama, T Koerner, FC TI Noninvasive papillary proliferations SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE papilloma; papillary carcinoma; micropapillary hyperplasia; micropapillary ductal carcinoma in situ ID INTRADUCTAL PAPILLOMA; BREAST-CANCER; FOLLOW-UP; CARCINOMA; DIAGNOSIS; BENIGN; BIOPSY; RISK; SUBSEQUENT; ATYPIA AB The diagnosis of noninvasive papillary tumors begins with categorization of the lesions as macropapillary or micropapillary. Macropapillary lesions include papilloma, papillary carcinoma, and papilloma harboring carcinoma. Papillomas consist of a few broad fronds, abundant stroma, and an epithelium containing both luminal and myoepithelial cells. Papillary carcinomas have many irregular fronds, small amounts of stroma, and a uniform population of malignant glandular cells. Papillomas can give rise to both conventional ductal hyperplasia and carcinomas. One analyzes proliferations on the surface of a papilloma as one would analyze those in a duct. Proliferations within the stalk of a papilloma require especially careful attention; one must observe large masses of cells demonstrating both cytological and architectural atypicality and devoid of intervening stroma to make the diagnosis of low-grade ductal carcinoma in-situ involving the stalk of a papilloma. Micropapillary proliferations represent either ductal hyperplasia or ductal carcinoma in situ. The former shows slight dilatation of ducts, micropapillae of similar size and shape, maturation of cells, lack of dishesion and necrosis, and lack of cytological atypicality. Micropapillary ductal carcinoma in situ exhibits extreme dilatation of ducts and lobules, micropapillae varying in size and shape, lack of maturation, dishesion and necrosis, and cytological atypicality. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Gunma Univ, Grad Sch Med, Dept Tumor Pathol, Maebashi, Gumma 371, Japan. Harvard Univ, Sch Med, Boston, MA USA. RP Koerner, FC (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM FKOERNER@PARTNERS.ORG NR 26 TC 10 Z9 15 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 32 EP 41 DI 10.1053/j.semdp.2003.10.011 PG 10 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200006 PM 15074557 ER PT J AU Rabban, JT Sgroi, DC AF Rabban, JT Sgroi, DC TI Sclerosing lesions of the breast SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE radial scar; nipple adenoma; sclerosing lesions; breast; tubular carcinoma ID RADIAL SCARS; FLORID PAPILLOMATOSIS; FEMALE BREAST; SYRINGOMATOUS ADENOMA; MAMMARY-CARCINOMA; PAPILLARY ADENOMA; NIPPLE; BENIGN; CANCER; HYPERPLASIA AB Sclerosing lesions of the breast often mimic invasive carcinoma at the gross and microscopic levels and can pose a significant diagnostic challenge for surgical pathologists. This brief review is devoted to the histopathological characterization of 2 such sclerosing lesions of the breast: radial scars and sclerosing nipple adenomas. Microscopically, these lesions show similar morphological features: a zonal architectural pattern consisting of a central sclerotic region with entrapped distorted glands and a corona-like peripheral region with associated nonproliferative and proliferative fibrocystic changes. Important diagnostic features of these lesions are highlighted and contrasted with those of invasive carcinoma. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Mol Pathol Unit, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sgroi, DC (reprint author), MGH E, Mol Pathol Unit, 149 13th St, Charlestown, MA 02129 USA. EM DSGROI@PARTNERS.ORG NR 33 TC 12 Z9 14 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 42 EP 47 DI 10.1053/j.semdp.2003.10.004 PG 6 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200007 PM 15074558 ER PT J AU Lerwill, MF AF Lerwill, MF TI Biphasic lesions of the breast SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE fibroadenoma; phyllodes tumor; fibroadenoma variant; hamartoma; pseudoangiomatous stromal hyperplasia ID STROMAL GIANT-CELLS; CYSTOSARCOMA-PHYLLODES; TUMOR; HYPERPLASIA; NEOPLASMS; BEHAVIOR AB Biphasic lesions of the breast are characterized by integral epithelial and stromal components. Determination of the stromal composition facilitates diagnosis. Lesions with predominantly specialized stroma include fibroadenoma and phyllodes tumor, and lesions with a mixture of nonspecialized and specialized stroma include fibroadenoma variant, hamartoma, and pseudoangiomatous stromal hyperplasia. Diagnostic difficulty may be encountered when a biphasic lesion has cellular stroma, raising the differential diagnosis of phyllodes tumor. Distinctive histologic features of phyllodes tumor include architectural frond formation, stromal cytological atypia, stromal mitotic activity, irregular gland dilatation, and morphologic heterogeneity. These histologic features contrast with those of other biphasic lesions. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lerwill, MF (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM MLERWILL@PARTNERS.ORG NR 32 TC 11 Z9 12 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 48 EP 56 DI 10.1053/j.semdp.2003.10.003 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200008 PM 15074559 ER PT J AU Eichhorn, JH AF Eichhorn, JH TI Medullary carcinoma, provocative now as then SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE medullary carcinoma; atypical medullary carcinoma; medullary features; solid circumscribed carcinoma; BRCA1 ID TUMOR-INFILTRATING LYMPHOCYTES; EPIDEMIOLOGIC RISK-FACTORS; LOBULAR BREAST CARCINOMAS; ESTROGEN-RECEPTOR; PROGNOSTIC IMPORTANCE; IMMUNOHISTOCHEMICAL DETECTION; INTRAOBSERVER VARIABILITY; HISTOLOGIC FEATURES; MAMMARY-CARCINOMA; FLOW-CYTOMETRY AB The recent observation that studies of BRCA1-associated tumors contain a high proportion of medullary carcinomas and ductal carcinomas with medullary features has re-introduced pathologists to an old diagnostic problem. The term "medullary carcinoma" dates to the 19th century, but the modern entity was introduced in 1949 by Moore and Foote, who described a carcinoma with a lymphoid infiltrate, a favorable prognosis, and low frequency of metastasis. Almost three decades later, Ridolfi et al proposed specific criteria for diagnosis, resulting in an entity with an even more favorable prognosis and a lower incidence. The reproducibility and clinical relevance of the diagnosis have been questioned recently, and new criteria have been proposed and compared. The tumors typically express cytokeratin 7, often vimentin and S100-protein, but not cytokeratin 20. The usual ones are positive for p53 and negative for estrogen receptor, Her2/neu, and bcl-2. Medullary carcinomas express e-cadherin and beta-catenin more often than ordinary high-grade ductal carcinomas, and the former have genetic differences from the latter. The lymphoid infiltrate of medullary carcinomas is related to beta-actin fragments exposed by apoptotic cells. The present review discusses historical and recent developments and emphasizes diagnostic criteria. (C) 2004 Elsevier Inc. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Eichhorn, JH (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM JEICHHORN@PARTNERS.ORG NR 69 TC 16 Z9 19 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD FEB PY 2004 VL 21 IS 1 BP 65 EP 73 DI 10.1053/j.semdp.2003.10.005 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 802VY UT WOS:000220192200010 PM 15074561 ER PT J AU Murray, N Salgia, R Fossella, FV AF Murray, N Salgia, R Fossella, FV TI Targeted molecules in small cell lung cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID SIGNAL-TRANSDUCTION; C-KIT; GROWTH; INHIBITION; MAYTANSINOIDS; BIOLOGY C1 British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Dana Farber Canc Inst, Div Med Oncol, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. Univ Texas, MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA. RP Murray, N (reprint author), British Columbia Canc Agcy, 600 W 10th Ave, Vancouver, BC V5Z 4E6, Canada. NR 20 TC 31 Z9 33 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD FEB PY 2004 VL 31 IS 1 SU 1 BP 106 EP 111 DI 10.1016/j.seminoncol.2003.12.021 PG 6 WC Oncology SC Oncology GA 778QT UT WOS:000189252800014 PM 14981588 ER PT J AU Jensen, ST Liu, XS Zhou, Q Liu, JS AF Jensen, ST Liu, XS Zhou, Q Liu, JS TI Computational discovery of gene regulatory binding motifs: A Bayesian perspective SO STATISTICAL SCIENCE LA English DT Article DE gene regulation; motif discovery; Bayesian models; scoring functions; optimization; Markov chain Monte Carlo ID UNALIGNED DNA FRAGMENTS; EXPRESSION PATTERNS; NONCODING SEQUENCES; SITES; RECOGNITION; ALGORITHM; IDENTIFICATION; DICTIONARY; ALIGNMENTS; MICROARRAY AB The Bayesian approach together with Markov chain Monte Carlo techniques has provided an attractive solution to many important bioinformatics problems such as multiple sequence alignment, microarray analysis and the discovery of gene regulatory binding motifs. The employment of such methods and, more broadly, explicit statistical modeling, has revolutionized the field of computational biology. After reviewing several heuristics-based computational methods, this article presents a systematic account of Bayesian formulations and solutions to the motif discovery problem. Generalizations are made to further enhance the Bayesian approach. Motivated by the need of a speedy algorithm, we also provide a perspective of the problem from the viewpoint of optimizing a scoring function. We observe that scoring functions resulting from proper posterior distributions, or approximations to such distributions, showed the best performance and can be used to improve upon existing motif-finding programs. Simulation analyses and a real-data example are used to support our observation. C1 Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Jensen, ST (reprint author), Harvard Univ, Dept Stat, 1 Oxford St, Cambridge, MA 02138 USA. EM jensen@stat.harvard.edu; xsliu@jimmy.harvard.edu; zhou@stat.harvard.edu; jliu@stat.harvard.edu NR 45 TC 54 Z9 59 U1 1 U2 8 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD FEB PY 2004 VL 19 IS 1 BP 188 EP 204 DI 10.1214/088342304000000107 PG 17 WC Statistics & Probability SC Mathematics GA 842OE UT WOS:000223012900018 ER PT J AU Lo, EH Broderick, JP Moskowitz, MA AF Lo, EH Broderick, JP Moskowitz, MA TI TPA and proteolysis in the neurovascular unit SO STROKE LA English DT Article DE Advances in Stroke; blood-brain barrier; matrix metalloproteinase; proteolysis; reperfusion injury; tissue plasminogen activator ID TISSUE-PLASMINOGEN ACTIVATOR; ACUTE ISCHEMIC-STROKE; BLOOD-BRAIN-BARRIER; FOCAL CEREBRAL-ISCHEMIA; SMOOTH-MUSCLE-CELLS; MATRIX METALLOPROTEINASES; HEMORRHAGIC TRANSFORMATION; NEURONAL DAMAGE; MATRIX-METALLOPROTEINASE-9; EXPRESSION C1 Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Charlestown, MA USA. Harvard Univ, Sch Med, Program Neurosci, Charlestown, MA USA. Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neurovasc Regulat & Stroke Lab, Charlestown, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg,Neurovasc Regulat & Stroke Lab, Charlestown, MA USA. RP Lo, EH (reprint author), Harvard Univ, Sch Med, Neuroprotect Res Lab, MGH E 149-2401, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu RI Moskowitz, Michael/D-9916-2011 FU NINDS NIH HHS [P50-NS10828, R01-NS37074, R01-NS38731, R01-NS40529] NR 36 TC 107 Z9 123 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2004 VL 35 IS 2 BP 354 EP 356 DI 10.1161/01.STR.0000115164.80010.8A PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 769VB UT WOS:000188669500006 PM 14757877 ER PT J AU Greer, DM Koroshetz, WJ Cullen, S Gonzalez, RG Lev, MH AF Greer, DM Koroshetz, WJ Cullen, S Gonzalez, RG Lev, MH TI Magnetic resonance imaging improves detection of intracerebral hemorrhage over computed tomography after intra-arterial thrombolysis SO STROKE LA English DT Article DE computed tomography; intracerebral hemorrhage; magnetic resonance imaging; stroke, ischemic; thrombolysis ID HYPERACUTE PARENCHYMAL HEMORRHAGE; ACUTE ISCHEMIC-STROKE; INTRACRANIAL HEMORRHAGE; CEREBRAL-HEMORRHAGE; WEIGHTED MRI; PROACT II; TRANSFORMATION; SEQUENCES/; PREDICTORS; DIAGNOSIS AB Background and Purpose - Unenhanced CT is routinely performed after intra-arterial (IA) thrombolysis. The presence of residual contrast causing staining of injured brain may mimic intracerebral hemorrhage (ICH). We evaluated MRI with diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) for detection of ICH after IA thrombolysis, specifically in equivocal areas of hyperdensity seen on postprocedure CT, to help guide the decision to use anticoagulation or antiplatelet therapy after the IA thrombolysis. Methods - We performed a retrospective analysis of 15 consecutive patients who underwent IA thrombolysis for acute stroke between September 2000 and March 2003. Inclusion criteria required an immediate postprocedure CT with a questionable hyperdensity and, within the next 48 hours, an MRI with DWI and/or SWI. Results - All patients had CT regions of hyperdensity that were equivocal for the presence of ICH. All patients subsequently underwent DWI, and 11 also underwent SWI. Eleven of 15 patients had magnetic susceptibility-induced hypointensity in DWI hyperintensity regions, signifying the presence of acute deoxyhemoglobin. Nine of these patients also received SWI, which confirmed the presence of blood within these regions. Follow-up CT on all 11 patients confirmed ICH. In the 4 patients without DWI susceptibility change, 0 were found to have ICH on either SWI (performed in 2 patients) or follow-up CT. MRI reliably detected the presence of ICH in all patients, whereas CT failed to differentiate contrast staining from hemorrhage in 4 of the 15 patients. Conclusions - MRI is an effective means to detect the presence of blood within an equivocal region on post-IA thrombolysis CT. This may influence the decision to use anticoagulation or antiplatelet therapy. C1 Massachusetts Gen Hosp, Dept Neurol, ACC 835, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. RP Greer, DM (reprint author), Massachusetts Gen Hosp, Dept Neurol, ACC 835, 55 Fruit St, Boston, MA 02114 USA. EM dgreer@partners.org NR 16 TC 26 Z9 36 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2004 VL 35 IS 2 BP 491 EP 495 DI 10.1161/01.STR.0000114201.11353.C5 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 769VB UT WOS:000188669500039 PM 14739411 ER PT J AU Dec, GW AF Dec, GW TI Management of heart failure: crossing boundary over to the surgical country SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID PARTIAL LEFT VENTRICULECTOMY; INTRAVENTRICULAR-CONDUCTION DELAY; MECHANICAL CIRCULATORY SUPPORT; DILATED CARDIOMYOPATHY; CARDIAC RESYNCHRONIZATION; MYOBLAST TRANSPLANTATION; MYOCARDIAL-INFARCTION; RECEPTOR BLOCKERS; RANDOMIZED-TRIAL; ASSIST DEVICE AB As the population ages and individuals survive previously fatal myocardial infarctions, heart failure has emerged as a worldwide health epidemic. Surveillance data from the United States indicate a prevalence of approximately 5 million cases and an incidence of over 450,000 new cases per year. In the Framingham Heart Study, the incidence of new cases doubles with each decade of age. Below age 65, there is a slight male predominance in heart failure incidence, due largely to the greater prevalence of coronary artery disease; however, beyond age 75 years, women predominate. The current lifetime risk of developing heart failure is I in 5 for both men and women. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Bigelow 842,55 Fruit St, Boston, MA 02114 USA. EM gdec@partners.org NR 48 TC 2 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD FEB PY 2004 VL 84 IS 1 BP 1 EP + DI 10.1016/S0039-6109(03)00217-2 PG 26 WC Surgery SC Surgery GA 802IV UT WOS:000220158100002 PM 15053180 ER PT J AU Chaudhri, BB del Monte, F Harding, SE Hajjar, RJ AF Chaudhri, BB del Monte, F Harding, SE Hajjar, RJ TI Gene transfer in cardiac myocytes SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID HUMAN HEART-FAILURE; SARCOPLASMIC-RETICULUM CA2+-ATPASE; FAILING HUMAN-HEART; HUMAN DILATED CARDIOMYOPATHY; BETA-ADRENERGIC STIMULATION; VENTRICULAR MYOCYTES; IN-VIVO; INSUFFICIENCY BISOPROLOL; MYOCARDIAL-CONTRACTILITY; COLLATERAL DEVELOPMENT AB Congestive heart failure (CHF) represents an enormous clinical problem and remains a leading cause of death despite advances in treatment. New treatments significantly impact mortality and disease course; they do not cure the underlying pathology. Gene transfer, the ability to genetically reprogram the heart in relevant cardiovascular disease models, allows testing the role of specific molecular pathways in disease pathogenesis. Potential therapeutic intervention targets can be then identified and approached with the full spectrum of therapeutic options, including traditional pharmacology, targeted synthesis of small molecule agonists or antagonists, biological agents (cells, antibodies, genetic material), or gene-based therapy. Lessons gleaned from gene transfer experiments on local modulation of cardiac genetic programs will guide attempts to transform early investigations into established therapy. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr,Heart Failure & Cardiac Transp, Charlestown, MA 02129 USA. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. RP Hajjar, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr,Heart Failure & Cardiac Transp, 149 13th St CNY-4,4215, Charlestown, MA 02129 USA. EM rhajjar@partners.org NR 77 TC 9 Z9 9 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD FEB PY 2004 VL 84 IS 1 BP 141 EP + DI 10.1016/S0039-6109(03)00209-3 PG 21 WC Surgery SC Surgery GA 802IV UT WOS:000220158100009 PM 15053187 ER PT J AU Hoerbelt, R Madsen, JC AF Hoerbelt, R Madsen, JC TI Feasibility of xeno-transplantation SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Review ID NF-KAPPA-B; CLASS-II GENES; HEMATOPOIETIC-CELL TRANSPLANTATION; MEDIATED XENOGRAFT REJECTION; PORCINE ENDOTHELIAL-CELLS; ACUTE VASCULAR REJECTION; TO-BABOON MODEL; MINIATURE SWINE; THYMIC TRANSPLANTATION; HYPERACUTE REJECTION AB The study of xeno-transplantation as a viable treatment for endstage heart disease is at an exciting juncture. Advances in the biology of nuclear transfer cloning in the last few years have catapulted the field forward with the creation of a group of cloned swine that have had certain genes "knocked out," resulting in more "humanized" pigs. In addition, new strategies aimed at inducing immunological tolerance to xenogeneic antigens have proven successful in small animal models. Within a very short time, organs from cloned, knockout pigs will be transplanted into nonhuman primate recipients (acting as surrogate humans) that have been conditioned to induce tolerance. The results of those experiments will determine whether xeno-transplantation will be feasible in the near future. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Cardiac Surg, Boston, MA 02114 USA. RP Madsen, JC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. EM madsen@helix.mgh.harvard.edu FU NHLBI NIH HHS [R01 HL54211, P01 HL18646]; NIAID NIH HHS [P01 AI50157] NR 117 TC 9 Z9 11 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD FEB PY 2004 VL 84 IS 1 BP 289 EP + DI 10.1016/S0039-6109(03)00208-1 PG 20 WC Surgery SC Surgery GA 802IV UT WOS:000220158100016 PM 15053194 ER PT J AU Hadidi, S Gorczynski, RM AF Hadidi, S Gorczynski, RM TI MD-1 expression regulates direct and indirect allorecognition SO TISSUE ANTIGENS LA English DT Article DE costimulation; direct/indirect recognition; MD-1; transplantation ID T-CELL-ACTIVATION; MURINE MD-1; CORNEAL TRANSPLANTATION; INDIRECT RECOGNITION; DENDRITIC CELLS; SKIN-GRAFTS; B-CELLS; REJECTION; MECHANISMS; TOLERANCE AB Expression of the molecule MD-1 was previously described to regulate allogeneic and xenogeneic skin graft survival, as documented by the decrease in rejection seen following functional blockade of MD-1 expression in vivo, using antisense oligodeoxynucleotides (ODNs) or anti-MD-1 antibodies. It was unclear from these data whether blockade of expression of MD-1 on donor or recipient cells was crucial. We have investigated the effect on allorecognition of treating skin graft donors, and/or recipients, of either fully major histocompatibility complex (MHC)-mismatched allogeneic skin grafts (C3H with C57BL/6 grafts and vice versa) or grafts differing at only multiple minor alloantigens (C3H with B10.BR grafts; C57BL/6 with C3H.SW), with antisense ODNs to MD-1, or in some cases, following transplantation of class II-deficient cells into class I-deficient mice. Graft-specific cytotoxic T lymphocytes (CTLs) were measured in spleen cells recovered at sacrifice of recipients and following donor-specific restimulation in vitro. In the latter case, we also measured cell proliferation and (by enzyme-linked immunosorbent assay) production of interleukin-2 (IL-2)/interferon-gamma (IFN-gamma) or IL-4/IL-10 in vitro (nominal type-1 vs type-2 cytokines). CTL responses to minor-incompatible grafts were diminished, only if graft recipients were treated with ODNs. However, treatment of graft donor and/or recipient of MHC-incompatible grafts produced inhibition of CTL production. Optimal inhibition came from treating both. Specific suppression of CTL production coincided with inhibition of proliferation and preferential production of IL-4 and IL-10 at the expense of IL-2 and IFN-gamma. Our data are consistent with the hypothesis that MD-1 expression regulates both the direct and indirect pathways of allorecognition and that regulation of MD-1 expression may thus help regulate clinical graft rejection. C1 Toronto Hosp, Transplant Res Div, Toronto, ON M5T 2S8, Canada. Harvard Univ, Sch Med, Boston, MA USA. RP Hadidi, S (reprint author), Massachusetts Gen Hosp, BMT TBRC, MGHE,Bldg 149,13th St,Room 5102, Boston, MA 02129 USA. NR 25 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD FEB PY 2004 VL 63 IS 2 BP 132 EP 141 DI 10.1111/j.1399-0039.2004.00132.x PG 10 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 760QX UT WOS:000187846700004 PM 14705984 ER PT J AU Zubair, AC Zahrieh, D Daley, H Schott, D Gribben, JG Alyea, EP Schlossman, R Freedman, A Antin, JH Soiffer, RJ Neuberg, D Ritz, J AF Zubair, AC Zahrieh, D Daley, H Schott, D Gribben, JG Alyea, EP Schlossman, R Freedman, A Antin, JH Soiffer, RJ Neuberg, D Ritz, J TI Engraftment of autologous and allogeneic marrow HPCs after myeloablative therapy SO TRANSFUSION LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROGENITOR-CELL TRANSPLANTATION; VERSUS-HOST DISEASE; BONE-MARROW; NEUTROPHIL RECOVERY; DEPLETION; TRIAL; RECONSTITUTION; CHEMOTHERAPY; COMPLEMENT C1 Dana Farber Canc Inst, Connell OReilly Cell Manipulat Core Facil, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Mayo Clin, Jacksonville, FL 32224 USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, Connell OReilly Cell Manipulat Core Facil, 44 Binney St,M530, Boston, MA 02115 USA. EM jerome_ritz@dfci.harvard.edu RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA102824]; NHLBI NIH HHS [5T32-HL66987, HL04095, HL070149]; NIAID NIH HHS [AI29530] NR 28 TC 7 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD FEB PY 2004 VL 44 IS 2 BP 253 EP 261 DI 10.1111/j.1537-2995.2004.00666.x PG 9 WC Hematology SC Hematology GA 775RH UT WOS:000189055900016 PM 14962317 ER PT J AU Ostrow, JD Pascolo, L Brites, D Tiribelli, C AF Ostrow, JD Pascolo, L Brites, D Tiribelli, C TI Molecular basis of bilirubin-induced neurotoxicity SO TRENDS IN MOLECULAR MEDICINE LA English DT Article ID RESISTANCE-ASSOCIATED PROTEIN; ANION-TRANSPORTING POLYPEPTIDES; DEVELOPING RAT-BRAIN; MICROVESSEL ENDOTHELIAL-CELLS; FIBROBLAST-GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; UNCONJUGATED BILIRUBIN; CHOROID-PLEXUS AB Unconjugated bilirubin (UCB), at slightly elevated unbound concentrations, is toxic to astrocytes and neurons, damaging mitochondria (causing impaired energy metabolism and apoptosis) and plasma membranes (causing oxidative damage and disrupting transport of neurotransmitters). Accumulation of UCB in the CSF and CNS is limited by its active export, probably mediated by MRP1/Mrp1 present in choroid plexus epithelia, capillary endothelia, astrocytes and neurons. Upregulation of MRP1/Mrp1 protein levels by UCB might represent an important adaptive mechanism that protects the CNS from UCB toxicity. These concepts could explain the varied susceptibility of newborns to bilirubin neurotoxicity and the occurrence of neurological damage at plasma UCB concentrations well below therapeutic guidelines, and are relevant to the increasing prevalence of bilirubin encephalopathy in newborns. C1 Univ Trieste, Liver Res Ctr, I-34012 Trieste, Italy. VA Puget Sound Hlth Care Syst, Seattle Div, Res Serv, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Med, GI Hepatol Div, Seattle, WA 98108 USA. Univ Trieste, Dept BBCM, I-34012 Trieste, Italy. Univ Lisbon, Fac Pharm, Ctr Mol Pathogenesis, P-1649019 Lisbon, Portugal. RP Tiribelli, C (reprint author), Univ Trieste, Liver Res Ctr, AREA Sci Pk, I-34012 Trieste, Italy. EM ctliver@csfunits.it RI Brites, Dora/M-8293-2013; iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, NeuronGliaBiol /B-5403-2014 OI Brites, Dora/0000-0002-3024-9777; NR 70 TC 100 Z9 107 U1 3 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD FEB PY 2004 VL 10 IS 2 BP 65 EP 70 DI 10.1016/j.molmed.2003.12.003 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 780BE UT WOS:000189350600005 PM 15102359 ER PT J AU George, DJ Regan, MM Oh, WK Tay, MH Manola, J DeCalo, N Duggan, S DeWolf, WC Kantoff, PW Bubley, GJ AF George, DJ Regan, MM Oh, WK Tay, MH Manola, J DeCalo, N Duggan, S DeWolf, WC Kantoff, PW Bubley, GJ TI Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer SO UROLOGY LA English DT Article ID CLINICAL-SIGNIFICANCE; VENTRAL PROSTATE; SERUM-LEVELS; ANGIOGENESIS; PROGRESSION; CARCINOMA; SURVIVAL; DENSITY; SURGERY AB Objectives. To measure the change in plasma vascular endothelial growth factor (VEGF) levels after radical prostatectomy (RP) and to examine the association of pre-RP VEGF levels with known prognostic factors. Methods. Plasma was collected from patients in two separate cohorts. The first cohort included 86 patients who consented to give blood before and after RP. The second cohort consisted of 280 plasma samples, obtained from untreated patients with clinically localized prostate cancer. Plasma VEGF levels were measured by enzyme-linked immunosorbent assay. The change in plasma VEGF before and 6 to 8 weeks after RP was analyzed using a Wilcoxon signed rank test. The associations between the pre-RP VEGF levels and prognostic factors were assessed with the Spearman correlation coefficient and the Kruskal-Wallis test. Results. In a cohort of 86 patients with clinically localized prostate cancer, the median preoperative VEGF level was 49.8 pg/mL. The median level 1 month after surgery was significantly lower at 39.1 pg/mL (P = 0.006, 20% decrease). A repeat analysis 6 months or more after surgery demonstrated that the percentage of decrease in the plasma VEGF levels persisted. Plasma VEGF levels were also measured in a separate cohort of 280 patients with localized prostate cancer and demonstrated no statistically significant association with risk groups or known tumor-associated prognostic factors. Conclusions. These results suggest that the prostate gland itself may be a significant source of systemic VEGF and raises the possibility that elevated plasma VEGF levels could be a reflection of prostatic VEGF production. (C) 2004 Elsevier Inc. C1 Beth Israel Deaconess Med Ctr, Dept Med, Div Oncol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Div Solid Tumor Oncol, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP George, DJ (reprint author), Duke Clin Res Inst, Box 3850 DUMC, Durham, NC 27710 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 24 TC 20 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD FEB PY 2004 VL 63 IS 2 BP 327 EP 332 DI 10.1016/j.urology.2003.09.059 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 774QU UT WOS:000188995300027 PM 14972483 ER PT J AU Bloom, KD Richie, JP Schultz, D Renshaw, A Saegaert, T D'Amico, AV AF Bloom, KD Richie, JP Schultz, D Renshaw, A Saegaert, T D'Amico, AV TI Invasion of seminal vesicles by adenocarcinoma of the prostate: PSA outcome determined by preoperative and postoperative factors SO UROLOGY LA English DT Article ID RADICAL PROSTATECTOMY; CANCER; ANTIGEN; RECURRENCE; IMMEDIATE; FAILURE; PREDICT AB Objectives. To determine which preoperative and postoperative factors were predictive of the time to prostate-specific antigen (PSA) failure after radical retropubic prostatectomy (RRP) for patients with seminal vesicle invasion (SVI). SVI by prostate cancer is associated with high PSA failure rates after RRP and subsequent distant metastases. Methods. Between 1988 and 2002, 1697 patients with prostate cancer underwent RRP at Brigham and Women's Hospital, of whom 103 (6%) had SVI. Cox regression multivariable analysis was used to determine whether the preoperative PSA level, prostatectomy Gleason score, margin status, or presence of extraprostatic extension was predictive of the time to postoperative PSA failure. Estimates of PSA outcome were made using the actuarial method of Kaplan and Meier for patients who had none, all, or at least one of the factors that predicted for the time to postoperative PSA failure. Results. The statistically significant categorical predictors of the time to PSA failure after RRP in patients with SVI included prostatectomy Gleason score of 4 + 3 or greater (P = 0.009), preoperative PSA level greater than 20 ng/dL when evaluated as a categorical or as a continuous variable (P = 0.002 and P = 0.001, respectively), and margin positivity (P = 0.075) which was of borderline significance. The 3-year estimate of PSA control was 52% to 100%, 28%, and 0% for patients with negative margins, preoperative PSA less than 20 ng/dL, and prostatectomy Gleason score of 3 + 4 or less versus having one to two or all three predictors of the time to postoperative PSA failure. Conclusions. The PSA outcome after RRP for patients with SVI varies depending on the preoperative PSA level, prostatectomy Gleason score, and margin status. (C) 2004 Elsevier Inc. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Millersville Univ Pennsylvania, Millersville, PA 17551 USA. RP Bloom, KD (reprint author), Div Urol, 75 Francis St, Boston, MA 02115 USA. NR 15 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD FEB PY 2004 VL 63 IS 2 BP 333 EP 336 DI 10.1016/j.urology.2003.09.042 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 774QU UT WOS:000188995300028 PM 14972484 ER PT J AU Levin, M AF Levin, M TI A novel immunohistochemical method for evaluation of antibody specificity and detection of labile targets in biological tissue SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE serotonin; immunohistochemistry; melatonin; 5HT; antibody specificity ID SEROTONIN-LIKE IMMUNOREACTIVITY; DEVELOPING RETINA; RANA-PIPIENS; OPTIC-NERVE; INNERVATION; MOUSE; LOCALIZATION; EXPRESSION; NEURONS; SYSTEM AB Immunohistochemistry is a key tool for analyzing target molecule localization within tissues. However, accurate results require an antibody that can distinguish between similar compounds. We present a simple immunohistochemical method that can also be used to rapidly evaluate antibodies' specificities. We demonstrate this technique with serotonin, an extremely labile compound. Serotonin (5-hydroxytryptamine, 5HT) is an important neurotransmitter regulating normal cognition and several mental disorders, as well as tumor growth, cardiopathology, and embryogenesis. In-imunohistochemical detection of serotonin is commonly used as a neuronal cell marker and to provide crucial information on serotonin's role as an embryonic morphogen. It is necessary to be able to distinguish serotonin from closely related molecules with significantly different biological activity. Using our method, we identify antibodies that are specific for serotonin and show that some commercial 5HT antibodies often used to identify serotonergic cells in published papers are not 5HT-specific. These data demonstrate the necessity of specifically testing antibodies (especially in areas of high clinical relevance such as 5HT). We also illustrate detection of serotonergic cells in embryonic tissue using our technique. This method offers a number of general advantages for testing specificity of antibodies to any biological molecule, and helps avoid false positives and negatives during imimmohistochernistry. (C) 2003 Published by Elsevier B.V. C1 Forsyth Inst, Cytokine Biol Dept, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Oral & Dev Biol, Boston, MA 02115 USA. RP Levin, M (reprint author), Forsyth Inst, Cytokine Biol Dept, 140 Fenway, Boston, MA 02115 USA. EM mlevin@forsyth.org NR 45 TC 28 Z9 28 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD JAN 30 PY 2004 VL 58 IS 1 BP 85 EP 96 DI 10.1016/S0165-022X(03)00149-0 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 761ZZ UT WOS:000187946500009 PM 14597192 ER PT J AU Lynch, M Fitzgerald, C Johnston, KA Wang, SP Schmidt, EV AF Lynch, M Fitzgerald, C Johnston, KA Wang, SP Schmidt, EV TI Activated eIF4E-binding protein slows G(1) progression and blocks transformation by c-myc without inhibiting cell growth SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION-FACTOR 4E; TARGETED HOMOLOGOUS RECOMBINATION; MESSENGER-RNA TRANSLATION; ORNITHINE DECARBOXYLASE; FACTOR EIF-4E; NEOPLASTIC TRANSFORMATION; RPS6 PHOSPHORYLATION; SIGNALING PATHWAY; INDUCED APOPTOSIS; CYCLE AB Translation initiation is poised between global regulation of cell growth and specific regulation of cell division. The mRNA cap-binding protein (eIF4E) is a critical integrator of cell growth and division because it is rate-limiting for translation initiation and is also rate-limiting for G(1) progression. Translation initiation factor eIF4E is also oncogenic and a candidate target of c-myc. Recently, an activated inhibitory 4E-binding protein (4EBP) that blocks eIF4E was used to study its regulation of Drosophila growth. We adopted this approach in mammalian cells after identifying an autosensing mechanism that protects against increased levels of 4EBP1. Increased 4EBP1 induced a quantitative increase in the inactivated phosphorylated form of 4EBP1 in vitro and in vivo. To overcome this protective mechanism, we introduced alanine substitutions at four phosphorylation/inactivation sites in 4EBP1 to constitutively activate a 4EBPmu to block eIF4E. Overexpression of activated 4EBPmu inhibited cell proliferation and completely blocked transformation by both eIF4E and c-myc, although it did not block all tested oncogenes. Surprisingly, expression of the activated 4EBPmu increased cell size and protein content. Activated 4EBPmu blocked both cell proliferation and c-myc transformation by inhibiting G(1) progression and increasing apoptosis, without decreasing protein synthesis. Our results identify mammalian eIF4E as rate-limiting for cell cycle progression before it regulates cell growth. It further identifies G(1) control by translation initiation factors as an essential genetic target of c-myc that is necessary for its ability to transform cells. C1 Massachusetts Gen Hosp, Serv Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Schmidt, EV (reprint author), Massachusetts Gen Hosp, Serv Pediat, Fruit St, Boston, MA 02114 USA. EM Schmidt@helix.mgh.harvard.edu FU NCI NIH HHS [R01-CA63117] NR 80 TC 43 Z9 45 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 30 PY 2004 VL 279 IS 5 BP 3327 EP 3339 DI 10.1074/jbc.M310872200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 766MF UT WOS:000188379600024 PM 14607835 ER PT J AU Giraud, J Leshan, R Lee, YH White, MF AF Giraud, J Leshan, R Lee, YH White, MF TI Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID P70 S6 KINASE; TYROSINE PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN-KINASE; SERINE/THREONINE PHOSPHORYLATION; JUXTAMEMBRANE REGION; TARGETED DISRUPTION; REGULATORY SUBUNIT; 3T3-L1 ADIPOCYTES; IRS-1 AB Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. We used a sequence-specific polyclonal antibody directed against phosphorylated Ser(302) to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. Wortmannin or rapamycin inhibited Ser(302) phosphorylation, and amino acids or glucose stimulated Ser(302) phosphorylation, suggesting a role for the mTOR cascade. The Ser(302) kinase associates with IRS-1 during immunoprecipitation, but its identity is unknown. The NH2-terminal c-Jun kinase did not phosphorylate Ser(302). Replacing Ser(302) with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70(S6K), ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3beta phosphorylation. Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst,Dept Physiol, Boston, MA 02215 USA. RP White, MF (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst,Dept Physiol, 1 Joslin Pl,Rm 620, Boston, MA 02215 USA. EM morris.white@joslin.harvard.edu FU NIDDK NIH HHS [DK 38712] NR 53 TC 70 Z9 73 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 30 PY 2004 VL 279 IS 5 BP 3447 EP 3454 DI 10.1074/jbc.M308631200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 766MF UT WOS:000188379600040 PM 14623899 ER PT J AU Seijffers, R Woolf, CJ AF Seijffers, R Woolf, CJ TI Utilization of an HSV-based amplicon vector encoding the axonal marker hPLAP to follow neurite outgrowth in cultured DRG neurons SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE herpes simplex virus; human placental alkaline phosphatase; enhanced green fluorescent protein; dorsal root ganglion neurons; gene delivery; growth associated protein-43; bicistronic expression ID GROWTH-ASSOCIATED PROTEIN; BACTERIAL ARTIFICIAL CHROMOSOME; NERVOUS-SYSTEM; GENE-TRANSFER; SPINAL-CORD; TRANSGENIC MICE; ADULT NEURONS; GAP-43; REGENERATION; CNS AB Delivery of genes into DRG neurons by viral vectors is a powerful tool for the study of axonal outgrowth. In order to achieve efficient transfer of growth-related genes and simultaneously label neuronal processes, we have utilized the HSV-based amplicon vector system. A bicistronic expression cassette encoding the growth associated protein-43 (GAP-43) and the axonal marker human placental alkaline phosphatase (hPLAP) reporter gene under translation control of an internal ribosomal entry site was cloned into the HGCX amplicon vector. This hPLAP reporter enabled efficient labeling of neurites in both dissociated adult DRG neurons and embryonic DRG explants. Using this reporter, the effect of GAP-43 on neurite outgrowth in transduced DRG neurons could be demonstrated. HSV-based amplicon vectors can contribute to the study of axonal growth and guidance in cultured neurons. (C) 2003 Elsevier B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, 149 13th St,Room 4309, Boston, MA 02129 USA. EM rseijffers@partners.org; woolf.clifford@mgh.harvard.edu FU NICHD NIH HHS [HD038533-04]; NINDS NIH HHS [NS38253] NR 35 TC 1 Z9 2 U1 0 U2 0 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 2004 VL 132 IS 2 BP 169 EP 176 DI 10.1016/j.jneumeth.2003.09.027 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 767XZ UT WOS:000188500300006 PM 14706714 ER PT J AU Yusufzai, TM Tagami, H Nakatani, Y Felsenfeld, G AF Yusufzai, TM Tagami, H Nakatani, Y Felsenfeld, G TI CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species SO MOLECULAR CELL LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; HISTONE ACETYLATION; IN-VIVO; PROTEIN CTCF; METHYLATION; DNA; LOCALIZATION; PROTECTION; BOUNDARIES; COMPLEX AB Insulators can block an enhancer of one gene from activating a promoter on another nearby gene. Almost all described vertebrate insulators require binding of the regulatory protein CTCF for their activity. We show that CTCF copurifies with the nucleolar protein nucleophosmin and both are present at insulator sites in vivo. Furthermore, exogenous insulator sequences are tethered to the nucleolus in a CTCF-dependent manner. These interactions, quite different from those of the gypsy insulator element in Drosophila, may generate similar loop structures, suggesting a common theme and model for enhancer-blocking insulator action. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov NR 23 TC 298 Z9 310 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 30 PY 2004 VL 13 IS 2 BP 291 EP 298 DI 10.1016/S1097-2765(04)00029-2 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 771QN UT WOS:000188797700012 PM 14759373 ER PT J AU Lange, C Blacker, D Laird, NM AF Lange, C Blacker, D Laird, NM TI Family-based association tests for survival and times-to-onset analysis SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 2nd International Conference on Statistical Methodology on Alzheimers Disease Research CY MAY 10-12, 2002 CL LEXINGTON, KENTUCKY DE family-based association tests; FBATs; FBAT-logrank; FBAT-Wilcoxon ID SIB-TRANSMISSION/DISEQUILIBRIUM-TEST; QUANTITATIVE TRAITS; ALZHEIMER-DISEASE; GENERAL-CLASS; UNIFIED APPROACH; SIBSHIP TEST; LINKAGE; POWER; ALPHA-2-MACROGLOBULIN; DISEQUILIBRIUM AB In this paper, we discuss family-based association test (FBATs) relating genetic data to survival and time-to-onset data. We show how the standard logrank and Wilcoxon statistics can be used with family data to develop tests of association. We prove that the FBAT-logrank approach can be identical to the proportional hazard approach discussed in Mokliatchouk et al. (2000). Further, using simulation studies, we compare the power of the logrank, Wilcoxon and an approach developed for censored exponential data (Euro J Hum Gen 2001; 9:301-306). Based on the results of the simulation study, we suggest rules of thumb about which statistics to use in a given situation. An application of all three tests to an Alzheimer study illustrates the practical relevance of our discussion. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Med Sch, Charlestown, MA 02129 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Lange, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA. EM clange@hsph.harvard.edu NR 26 TC 33 Z9 33 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2004 VL 23 IS 2 BP 179 EP 189 DI 10.1002/sim.1707 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 763TW UT WOS:000188117400003 PM 14716720 ER PT J AU Zhou, XH Castelluccio, P AF Zhou, XH Castelluccio, P TI Adjusting for non-ignorable verification bias in clinical studies for Alzheimer's disease SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 2nd International Conference on Statistical Methodology on Alzheimers Disease Research CY MAY 10-12, 2002 CL LEXINGTON, KENTUCKY DE Alzheimer's disease; ROC curves; verification bias; profile likelihood; non-ignorability ID DIAGNOSTIC-TESTS AB A common problem for comparing the relative accuracy of two screening tests for Alzheimer's disease (AD) in a two-stage design study is verification bias. If the verification bias can be assumed to be ignorable, Zhou and Higgs have proposed a maximum likelihood approach to compare the relative accuracy of screening tests in a two-stage design study. However, if the verification mechanism also depends on the unobserved disease status, the ignorable assumption does not hold. In this paper, we discuss how to use a profile likelihood approach to compare the relative accuracy of two screening tests for AD without assuming the ignorable verification bias mechanism. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Univ Washington, Dept Biostat, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, NW HSR&d Ctr Excellence, Seattle, WA 98108 USA. Purdue Univ, Dept Stat, W Lafayette, IN 47907 USA. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, F600 HSB Box 357232, Seattle, WA 98195 USA. EM azhou@u.washington.edu FU AHRQ HHS [R29HS08559] NR 7 TC 9 Z9 9 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2004 VL 23 IS 2 BP 221 EP 230 DI 10.1002/sim.1711 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 763TW UT WOS:000188117400007 PM 14716724 ER PT J AU Lange, N Lake, S Sperling, R Brown, J Routledge, C Albert, M Heckers, S AF Lange, N Lake, S Sperling, R Brown, J Routledge, C Albert, M Heckers, S TI Two macroscopic and microscopic brain imaging studies of human hippocampus in early Alzheimer's disease and schizophrenia research SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 2nd International Conference on Statistical Methodology on Alzheimers Disease Research CY MAY 10-12, 2002 CL LEXINGTON, KENTUCKY DE FMRI; hippocampus; imaging; microscopy; mixed effects; stereology ID FALSE DISCOVERY RATE; SYSTEMATIC BIAS; RHESUS-MONKEY; MEMORY; FMRI; PET; SCOPOLAMINE; RETRIEVAL; VOLUME; INTERNEURONS AB Among the many diseases that affect the hippocampus, a small yet highly important brain region responsible for memory and identity, Alzheimer's disease and schizophrenia are among the most devastating. We describe a two-stage, region-of-interest based linear mixed model approach to the analysis of a longitudinal functional magnetic resonance (FMRI) study of human memory function under several drug challenges. We then describe a Monte Carlo approach to testing members of nested hierarchies of linear models in a stereological study of different types and locations of human hippocampal neurons. Last, we attempt to draw the attention of the biostatistical community interested in imaging neuroscience to the intriguing complexities of human hippocampal research in early Alzheimer's disease, schizophrenia and other brain diseases via brain imaging methods. Copyright (C) 2004 John Wiley Sons, Ltd. C1 McLean Hosp, Mailman Res Ctr, Lab Stat Neuroimaging, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EigenStat, Boston, MA USA. Channing Labs, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Gerontol Res Unit, Charlestown, MA USA. Glaxo Smith Kline, Harlow, Essex, England. RP Lange, N (reprint author), McLean Hosp, Mailman Res Ctr, Lab Stat Neuroimaging, 115 Mill St, Belmont, MA 02478 USA. EM nlange@hms.harvard.edu RI Heckers, Stephan/F-3051-2010 OI Heckers, Stephan/0000-0003-3601-9910 FU NIMH NIH HHS [MH60450]; NINDS NIH HHS [NS37483] NR 78 TC 2 Z9 3 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 30 PY 2004 VL 23 IS 2 BP 327 EP 350 DI 10.1002/sim.1720 PG 24 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 763TW UT WOS:000188117400016 PM 14716733 ER PT J AU Yock, T Schaefer, PW Hoch, BL Friedmann, AM Tarbell, NJ Rosenberg, AE Harris, NL AF Yock, T Schaefer, PW Hoch, BL Friedmann, AM Tarbell, NJ Rosenberg, AE Harris, NL TI A nine-month-old boy with an orbital rhabdomyosarcoma - Rhabdomyosarcoma of the orbit. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INTERGROUP RHABDOMYOSARCOMA; RADIATION-THERAPY; PROTON-BEAMS; GENE FUSIONS; STUDY-II; TUMORS; CHEMOTHERAPY; RADIOTHERAPY; ONCOLOGY; CHILDREN C1 Massachusetts Gen Hosp, Div Pediat Hematol Oncol, Serv Pediat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Yock, T (reprint author), Massachusetts Gen Hosp, Div Pediat Hematol Oncol, Serv Pediat, Boston, MA 02114 USA. NR 28 TC 3 Z9 3 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 29 PY 2004 VL 350 IS 5 BP 494 EP 502 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 767QJ UT WOS:000188463900014 PM 14749459 ER PT J AU Nathan, DG Wilson, JD AF Nathan, DG Wilson, JD TI NIH report card - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 29 PY 2004 VL 350 IS 5 BP 516 EP 516 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 767QJ UT WOS:000188463900019 ER PT J AU Marsit, CJ Liu, M Nelson, HH Posner, M Suzuki, M Kelsey, KT AF Marsit, CJ Liu, M Nelson, HH Posner, M Suzuki, M Kelsey, KT TI Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival SO ONCOGENE LA English DT Article DE methylation; NSCLC; HNSCC; Fanconi anemia; BRCA ID PROMOTER HYPERMETHYLATION; DNA METHYLATION; OVARIAN-TUMORS; BRCA1 PROMOTER; CPG ISLANDS; GENE; SUSCEPTIBILITY; EXPOSURE; BREAST; ASSOCIATION AB Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P = 0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% Cl 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients. C1 Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX USA. RP Kelsey, KT (reprint author), Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, 665 Huntington Ave, Boston, MA 02115 USA. EM kelsey@hsph.harvard.edu RI Kelsey, Karl/I-1252-2014; OI Marsit, Carmen/0000-0003-4566-150X FU NCI NIH HHS [CA78609, T32CA09078]; NIEHS NIH HHS [ES00002] NR 26 TC 151 Z9 157 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 29 PY 2004 VL 23 IS 4 BP 1000 EP 1004 DI 10.1038/sj.onc.1207256 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 767UV UT WOS:000188486600016 PM 14647419 ER PT J AU Ganesan, S Silver, DP Drapkin, R Greenberg, R Feunteun, J Livingston, DM AF Ganesan, S Silver, DP Drapkin, R Greenberg, R Feunteun, J Livingston, DM TI Association of BRCA1 with the inactive X chromosome and XIST RNA SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Royal-Society Discussion Meeting on Replicating and Reshaping DNA CY APR 23-24, 2003 CL ROYAL SOC, LONDON, ENGLAND HO ROYAL SOC DE BRCA1; XIST; X chromosome inactivation; heterochromatin; breast cancer ID BREAST-CANCER; BARR BODY; TRANSCRIPTION; EXPRESSION; MUTATION; MEIOSIS; PROTEIN; REPAIR; CELLS AB Breast cancer, early onset 1 (BRCA1) encodes a nuclear protein that participates in breast and ovarian cancer suppression. The molecular basis for the gender and tissue specificity of the BRCA1 cancer syndrome is unknown. Recently, we observed that a fraction of BRCA1 in female cells is localized on the inactive X chromosome (Xi). Chromatin immunoprecipitation (ChIP) experiments have demonstrated that BRCA1 physically associates with Xi-specific transcript (XIST) RNA, a non-coding RNA known to coat Xi and to participate in the initiation of its inactivation during early embryogenesis. Cells lacking wildtype BRCA1 show abnormalities in Xi, including lack of proper XIST RNA localization. Reintroduction of wild-type, but not mutant, BRCA1 can correct this defect in XIST localization in these cells. Depletion of BRCA1 in female diploid cells led to a defect in proper XIST localization on Xi and in the development of normal Xi heterchromatic superstructure. Moreover, depletion of BRCA1 led to an increased likelihood of re-expression of a green fluorescent protein (GFP) reporter gene embedded on Xi. Taken together, these findings are consistent with a model in which BRCA1 function contributes to the maintenance of proper Xi heterochromatin superstructure. Although the data imply a novel gender-specific consequence of BRCA1 loss, the relevance of the BRCA1/Xi function to the tumour suppressor activity of BRCA1 remains unclear and needs to be tested. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Inst Gustave Roussy, Lab Genet & Transfert Gene, F-94805 Villejuif, France. RP Livingston, DM (reprint author), Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM david-livingston@dcfi.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 36 TC 21 Z9 22 U1 0 U2 2 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD JAN 29 PY 2004 VL 359 IS 1441 BP 123 EP 128 DI 10.1098/rstb.2003.1371 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 767DR UT WOS:000188425400015 PM 15065664 ER PT J AU Tsomaia, N Pellegrini, M Hyde, K Gardella, TJ Mierke, DF AF Tsomaia, N Pellegrini, M Hyde, K Gardella, TJ Mierke, DF TI Toward parathyroid hormone minimization: Conformational studies of cyclic PTH(1-14) analogues SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; RECEPTOR INTERACTIONS; DISTANCE CONSTRAINTS; COUPLING-CONSTANTS; MOLECULAR-DYNAMICS; PROTEIN; RESTRAINTS; FRAGMENTS; EXCHANGE AB The N-terminal fragment of PTH(1-34) is critical for PTH1 receptor activation. Various modifications of PTH(1-14) have been shown to result in a considerable increase in signaling potency [Shimizu et al. (2000) J. Biol. Chem. 275, 21836-2184.3]. Our structural investigations revealed an unusually stable helical structure of the signaling domain (1-14), where residues 6 (Gln) and 10 (Gln or Asn) were located on the same face of the alpha-helix. To test whether a stable N-terminal alpha-helix is required for productive interaction with PTH1 receptor, we designed two conformationally restricted PTH(1 - 14) analogues, each containing a lactam bridge at positions 6 and 10. Specifically, substitutions Gln(6) --> Glu(6) and Asn(10) --> Lys(10) were introduced into the most potent [Ala(1,3,12),Gln(10),Har(11),Trp(14)]PTH(1 - 14)NH2 agonist. Both the Glu(6)-Lys(10) and Lys(6)-Glu(10) lactam-bridged analogues were characterized to examine the importance of orientation of the lactam. According to biological studies [Shimizu et al. (2003) Biochemistry 42, 2282-2290], none of the 6/10 substituted analogues (linear or cyclic) remained as active as the parent peptide. However, relative to their corresponding linear peptides, lactam-bridged analogues either maintained potency or showed 6-fold improvement. High-resolution structures as determined by H-1 NMR and NOE-restrained molecular dynamics simulations clearly illustrate the structural differences between the linear and cyclic PTH(1-14) fragments, supporting the hypothesis that an alpha-helix is the preferred bioactive conformation of the N-terminal fragment of PTH. In addition, our results demonstrate that the structural order of the very first residues (1-4) of the signaling domain plays a significant role in PTH action. C1 Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Providence, RI 02912 USA. Brown Univ, Dept Chem, Providence, RI 02912 USA. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Mierke, DF (reprint author), Brown Univ, Dept Mol Pharmacol, Div Biol & Med, Providence, RI 02912 USA. EM Dale_Mierke@Brown.edu OI Pellegrini, Maria/0000-0003-3817-4412 NR 45 TC 31 Z9 31 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 27 PY 2004 VL 43 IS 3 BP 690 EP 699 DI 10.1021/bi035703i PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 766BR UT WOS:000188326000012 PM 14730973 ER PT J AU Bertram, L Menon, R Mullin, K Parkinson, M Bradley, ML Blacker, D Tanzi, RE AF Bertram, L Menon, R Mullin, K Parkinson, M Bradley, ML Blacker, D Tanzi, RE TI PEN2 is not a genetic risk factor for Alzheimer's disease in a large family sample SO NEUROLOGY LA English DT Article ID ASSOCIATION TESTS; ONSET; GENOME; APH-1 AB PEN2 is a reasonable Alzheimer's disease (AD) candidate gene because it is a necessary component of the gamma-secretase complex that generates beta-amyloid peptide. Moreover, its gene (PEN2) maps to a highly significant linkage region on chromosome 19q13. Four common polymorphisms in PEN2 were tested for genetic association with AD in a large and carefully ascertained AD family sample (789 subjects from 202 nuclear families) using single-locus and haplotype-based analyses. These results do not suggest PEN2 to be a major AD risk factor. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Neurol, Ctr Aging Genet & Neurodegenerat,Genet & Aging Re, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Gerontol Res Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Tanzi, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Neurol, Ctr Aging Genet & Neurodegenerat,Genet & Aging Re, CNY 114,16 St, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X NR 10 TC 9 Z9 11 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 27 PY 2004 VL 62 IS 2 BP 304 EP 306 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 767KT UT WOS:000188439300032 PM 14745076 ER PT J AU Cotsiki, M Lock, RL Cheng, Y Williams, GL Zhao, J Perera, D Freire, R Entwistle, A Golemis, EA Roberts, TM Jat, PS Gjoerup, OV AF Cotsiki, M Lock, RL Cheng, Y Williams, GL Zhao, J Perera, D Freire, R Entwistle, A Golemis, EA Roberts, TM Jat, PS Gjoerup, OV TI Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SV40 LARGE-T; LARGE TUMOR-ANTIGEN; ANCHORAGE-INDEPENDENT GROWTH; PRB-RELATED PROTEINS; SIMIAN VIRUS-40; HUMAN-CELLS; J-DOMAIN; KINETOCHORE LOCALIZATION; SV40-TRANSFORMED CELLS; MITOTIC CHECKPOINTS AB The mitotic spindle checkpoint protein Bub1 has been found to be mutated at low frequency in certain human cancers characterized by aneuploidy. Simian virus 40 large T antigen efficiently immortalizes rodent cells and occasionally transforms them to tumorigenicity. T antigen can also cause genomic instability, inducing chromosomal aberrations and aneuploidy. Here, we report an interaction between Bub1 and T antigen. T antigen coimmunoprecipitates with endogenous Bub1 and Bub3, another component of the spindle checkpoint complex. Genetic analysis demonstrates that the interaction of T antigen with Bub1 is not required for immortalization but is closely correlated with transformation. T antigen induces an override of the spindle checkpoint dependent on Bub1 binding. This interaction with proteins of the spindle checkpoint machinery suggests another role for T antigen and provides insight into its ability to cause chromosomal aberrations, aneuploidy, and transformation. C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Hosp Univ Canarias, Unidad Invest, Tenerife 38320, Spain. Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England. Royal Free & Univ Coll Med Sch, Sch Med, Ludwig Inst Canc Res, London W1W 7BS, England. RP Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM thomas.roberts@dfci.harvard.edu FU NCI NIH HHS [R01 CA030002, P01-CA50661, CA30002, R37 CA030002, P01 CA050661] NR 43 TC 75 Z9 77 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 27 PY 2004 VL 101 IS 4 BP 947 EP 952 DI 10.1073/pnas.0308006100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 768FU UT WOS:000188533600010 PM 14732683 ER PT J AU Pal, S Cantor, AB Johnson, KD Moran, TB Boyer, ME Orkin, SH Bresnick, EH AF Pal, S Cantor, AB Johnson, KD Moran, TB Boyer, ME Orkin, SH Bresnick, EH TI Coregulator-dependent facilitation of chromatin occupancy by GATA-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; ZINC-FINGER PROTEIN; EMBRYONIC STEM-CELLS; DNA-BINDING; ERYTHROID-DIFFERENTIATION; CONTROL REGION; MICE LACKING; IN-VIVO; GENE; EXPRESSION AB Coregulator recruitment by DNA-bound factors results in chromatin modification and protein-protein interactions, which regulate transcription. However, the mechanism by which the Friend of GATA (FOG) coregulator mediates GATA factor-dependent transcription is unknown. We showed previously that GATA-1 replaces GATA-2 at an upstream region of the GATA-2 locus, and that this GATA switch represses GATA-2. Genetic complementation analysis in FOG-1-null hematopoietic precursors revealed that FOG-1 is not required for establishment or maintenance of the active GATA-2 domain, but is critical for the GATA switch. Analysis of GATA factor binding to additional loci also revealed FOG-1-dependent GATA switches. Thus, FOG-1 facilitates chromatin occupancy by GATA-1 at sites bound by GATA-2. We propose that FOG-1 is a prototype of a new class of coregulators termed chromatin occupancy facilitators, Which confer coregulation in certain contexts via enhancing trans-acting factor binding to chromatin in vivo. C1 Univ Wisconsin, Sch Med, Dept Pharmacol, Mol & Cellular Pharmacol Program, Madison, WI 53706 USA. Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Bresnick, EH (reprint author), Univ Wisconsin, Sch Med, Dept Pharmacol, Mol & Cellular Pharmacol Program, 1300 Univ Ave,383 Med Sci Ctr, Madison, WI 53706 USA. EM ehbresni@facstaff.wisc.edu FU NCI NIH HHS [K08 CA82175-05]; NHLBI NIH HHS [T32 HL007899, T32 HL007936, T32 HL07899, T32 HL07936]; NIDDK NIH HHS [DK50107, DK55700, R01 DK050107, R01 DK055700, R37 DK050107] NR 46 TC 111 Z9 113 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 27 PY 2004 VL 101 IS 4 BP 980 EP 985 DI 10.1073/pnas.0307612100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 768FU UT WOS:000188533600016 PM 14715908 ER PT J AU Kaye, J Bagley, J Malkowski, D Iacomini, J AF Kaye, J Bagley, J Malkowski, D Iacomini, J TI The role of complement receptors in production of antibodies specific for Gal alpha 1,3Gal SO TRANSPLANTATION LA English DT Article ID INHIBITION; ANTIGEN; CELLS AB By using a-galactosyl transferase knockout (GT(-/-)) mice, which make natural alphaGal-reactive antibodies, we examined the role of complement receptors in the production of alphaGal-specific antibodies. GT(-/-) mice were crossed with complement receptor 2 loci knockout mice to generate double knockout (DKO) mice. alphaGal-specific natural antibodies were detectable by enzyme-linked immunosorbent assay in the serum of GT(-/-) mice by 9 weeks of age. In contrast, only low titers of alphaGal-specific natural antibodies were detectable only in the serum of older DKO mice. Serum titers of alphaGal-reactive antibodies in GT(-/-) mice increased significantly after immunization with pig cells. In contrast, immunization had little effect on alphaGal-reactive antibody levels in DKO mice. Similarly, pretreatment of GT(-/-) mice with a blocking antibody to CD21 and CD35 inhibited production of alphaGal-reactive antibodies after immunization. However, DKO mice were able to make aGal-specific antibodies after secondary immunization. Thus, Cr2 loci-encoded receptors seem to be directly involved in the production of primary alphaGal-reactive antibodies. C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Iacomini, J (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH E,Bldg 149,13th St, Boston, MA 02129 USA. EM john.iacomini@tbrc.mgh.harvard.edu FU NIAID NIH HHS [R01 AI44268, T32 AI07529] NR 10 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2004 VL 77 IS 2 BP 314 EP 316 DI 10.1097/01.TP.0000101008.13282.FD PG 3 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 770CJ UT WOS:000188705400026 PM 14743001 ER PT J AU Fischer, ME Vitek, ME Hedeker, D Henderson, WG Jacobsen, SJ Goldberg, J AF Fischer, ME Vitek, ME Hedeker, D Henderson, WG Jacobsen, SJ Goldberg, J TI A twin study of erectile dysfunction SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INTERNATIONAL INDEX; CORPUS CAVERNOSUM; EJACULATORY DYSFUNCTION; PENILE ERECTION; UNITED-STATES; NITRIC-OXIDE; RISK-FACTORS; PREVALENCE; EXPRESSION; IMPOTENCE AB Background: The extent of genetic influence on erectile dysfunction (ED) is unknown. This study determines the contribution of heredity to ED in a sample of middle-aged men. Methods: A classical twin study was conducted in the Vietnam Era Twin Registry, a national sample of male-male pairs (mean birth year, 1949) who served on active duty during the Vietnam era (1965-1975). A 1999 male health survey was completed by 890 monozygotic (MZ) and 619 dizygotic (DZ) pairs. The prevalence and heritability of 2 self-report indicators of ED, difficulty in having an erection and in maintaining an erection, are estimated. Results: The prevalence of difficulty in having an erection is 23.3% and in maintaining an erection is 26.7%. Twin correlations for dysfunction in having an erection are 0.35 (95% confidence interval [CI], 0.28-0.41) in MZ and 0.17 (95% Cl, 0.09-0.27) in DZ pairs. For dysfunction in maintaining an erection, the twin correlations in MZ and DZ pairs are 0.39 (95% Cl, 0.32-0.45) and 0.18 (95% Cl, 0.09-0.27), respectively. The estimated heritability of liability for dysfunction in having an erection is 35% and in maintaining an erection is 42%. The heritable influence on ED remained significant after adjustment for ED risk factors. Conclusions: The present study demonstrates an ED-specific genetic component that is independent of genetic influences from numerous ED risk factors. The results suggest that future molecular genetic studies to identify ED-related polymorphisms are warranted. C1 VA Puget Sound Hlth Care Syst, VET Registry Seattle ERIC, Seattle, WA 98108 USA. Vet Affairs Edward Hines Jr Hosp, Coordinating Ctr, Cooperat Studies Program, Hines, IL USA. Univ Illinois, Epidemiol Biostat Div, Chicago, IL USA. Mayo Clin & Mayo Fdn, Div Epidemiol, Rochester, MN 55905 USA. RP Goldberg, J (reprint author), VA Puget Sound Hlth Care Syst, VET Registry Seattle ERIC, MS 152E,1660 S Columbian Way, Seattle, WA 98108 USA. EM goldie1@u.washington.edu NR 38 TC 12 Z9 12 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 26 PY 2004 VL 164 IS 2 BP 165 EP 168 DI 10.1001/archinte.164.2.165 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 769LY UT WOS:000188652600006 PM 14744839 ER PT J AU Nishiguchi, KM Berson, EL Dryja, TP AF Nishiguchi, KM Berson, EL Dryja, TP TI Mutation screening of the phosducin gene PDC in patients with retinitis pigmentosa and allied diseases SO MOLECULAR VISION LA English DT Article ID MACULAR DEGENERATION; LARGE FAMILY; TRANSDUCIN; PROTEIN; BINDING; PHOSPHORYLATION; SEGMENTS; BOVINE AB PURPOSE: To search for a phenotype associated with mutations in the phosducin gene PDC. METHODS: We screened 853 patients with retinitis pigmentosa or an allied disease diseases, including groups of 61 to 212 patients, each with dominant retinitis pigmentosa (RP), recessive RP, Leber congenital amaurosis, or cone-rod degeneration, for mutations in the PDC gene using direct genomic sequencing of the three coding exons and their flanking intron splice sites. RESULTS: We found one polymorphism in the 5' untranslated region (minor allele frequency of 0.149) and three rare single-base sequence variants (one missense change, one isocoding change, and one in the 3' untranslated region). The rare variants were found in one heterozygous patient each and none was interpreted as pathogenic. CONCLUSIONS: Phosducin mutations are not a major cause of dominant or recessive RP, Leber congenital amaurosis, or cone-rod degeneration. The human phenotype associated with phosducin defects remains unknown. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. EM thaddeus_dryja@meei.harvard.edu FU NEI NIH HHS [EY00169, EY08683] NR 22 TC 3 Z9 3 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JAN 26 PY 2004 VL 10 IS 7-9 BP 62 EP 64 PG 3 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 769MG UT WOS:000188653400003 PM 14758335 ER PT J AU He, X Batchelor, TT Grossman, S Supko, JG AF He, X Batchelor, TT Grossman, S Supko, JG CA New Approaches Brain Tumor Therapy TI Determination of procarbazine in human plasma by liquid chromatography with electrospray ionization mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE procarbazine ID RAT-LIVER; METABOLITES; METHYLAZOXYPROCARBAZINE; HYDROCHLORIDE; ACTIVATION; OXIDATION; LEUKEMIA; PRODUCTS; AGENTS; CELLS AB Procarbazine is a cytotoxic chemotherapeutic agent used in the treatment of lymphomas and brain tumors. Its pharmacokinetic behavior remains poorly understood even though more than 30 years have elapsed since the drug was approved for clinical use. To characterize the pharmacokinefics of procarbazine in brain cancer patients during a phase I trial, a method for determining the drug in human plasma by reversed-phase high-performance liquid chromatography (HPLC) with electrospray ionization mass spectrometry (ESI-MS) was developed and thoroughly validated. Plasma samples were prepared for analysis by precipitating proteins with trichloroacetic acid and washing the protein-free supernatant with methyl tert-butyl ether to remove excess acid. The solution was separated on a Luna C-18 analytical column using methanol-25 mM ammonium acetate buffer, pH 5.1 (22:78, v/v) as the mobile phase at 10 ml/min. A single-quadrupole mass spectrometer with an electrospray interface was operated in the selected-ion monitoring mode to detect the [M + H](+) ions at m/z 222.2 for procarbazine and at m/z 192.1 for the internal standard (3-dimethylamino-2-methylpropiophenone). Procarbazine and the internal standard eluted as sharp, symmetrical peaks with retention times (mean +/- S.D.) of 6.3 +/- 0.1 and 9.9 +/- 0.3 min, respectively. Calibration curves of procarbazine hydrochloride in human plasma at concentrations ranging from 0.5 to 50 ng/ml exhibited excellent linearity. The mean absolute recovery of the drug from plasma was 102.9 +/- 1.0%. Using a sample volume of 150 mul, procarbazine was determined at the 0.5 ng/ml (1.9 nM) lower limit of quantitation with a mean accuracy of 105.2% and an interday precision of 3.60% R.S.D. on 11 different days over 5 weeks. During this same time interval, the between-day accuracy for determining quality control solutions of the drug in plasma at concentrations of 2.0, 15 and 40 ng/ml ranged from 97.5 to 98.2% (mean +/- S.D., 97.9 +/- 0.4%) and the precision was 3.8-6.2% (mean +/- S.D., 5.1 +/- 1.2%). Stability characteristics of the drug were thoroughly evaluated to establish appropriate conditions to process, store and prepare clinical specimens for chromatographic analysis without inducing significant chemical degradation. The sensitivity achieved with this assay permitted the plasma concentration-time profile of the parent drug to be accurately defined following oral administration of standard doses to brain cancer patients. (C) 2003 Elsevier B.V. All rights reserved. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. Johns Hopkins Univ, Sch Med, Dept Med Oncol, Baltimore, MD 21287 USA. RP Supko, JG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 55 Fruit St,GRJ 1025, Boston, MA 02114 USA. FU NCI NIH HHS [P30-CA0516, U01-CA62406, UO1-CA-62475] NR 26 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD JAN 25 PY 2004 VL 799 IS 2 BP 281 EP 291 DI 10.1016/j.jchromb.2003.10.061 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 758VB UT WOS:000187670500012 PM 14670747 ER PT J AU Peppercorn, JM Weeks, JC Cook, EF Joffe, S AF Peppercorn, JM Weeks, JC Cook, EF Joffe, S TI Comparison of outcomes in cancer patients treated within and outside clinical trials: Conceptual framework and structured review SO LANCET LA English DT Review ID CELL LUNG-CANCER; ACUTE LYMPHOBLASTIC-LEUKEMIA; LONG-TERM SURVIVAL; ADJUVANT CHEMOTHERAPY; TREATMENT PROTOCOLS; RANDOMIZED TRIALS; HODGKINS-DISEASE; MULTIPLE-MYELOMA; SELECTION BIAS; BREAST-CANCER AB Background Many oncologists believe that patients with cancer who enrol in clinical trials have better outcomes than those who do not enrol. We aimed to assess the empirical evidence that such a trial effect exists. Methods We developed a conceptual framework for comparison of trial and non-trial patients. We then did a comprehensive literature search to identify studies that compared outcomes between these groups. We critically evaluated these studies to assess whether they provide valid and generalisable support for a trial effect. Findings We identified 26 comparisons, from 24 published articles, of outcomes among cancer patients enrolled and not enrolled in clinical trials. 21 comparisons used retrospective cohort designs. 14 comparisons provided some evidence that patients enrolled in trials have improved outcomes. However, strategies to control for potential confounding factors were inconsistent and frequently inadequate. Only eight comparisons restricted non-trial patients to those meeting trial eligibility criteria. Of these, three noted better outcomes in trial patients than in non-trial patients. Children with cancer, patients with haematological malignant disease, and patients treated before 1986 were disproportionately represented in positive studies. Interpretation Despite widespread belief that enrolment in clinical trials leads to improved outcomes in patients with cancer, there are insufficient data to conclude that such a trial effect exists. Until such data are available, patients with cancer should be encouraged to enrol in clinical trials on the basis of trials' unquestioned role in improving treatment for future patients. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Joffe, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 FU NCI NIH HHS [K01 CA96872] NR 52 TC 200 Z9 203 U1 1 U2 8 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JAN 24 PY 2004 VL 363 IS 9405 BP 263 EP 270 DI 10.1016/S0140-6736(03)15383-4 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 766FQ UT WOS:000188361400007 PM 14751698 ER PT J AU Ganesh, S Tsurutani, N Suzuki, T Hoshii, Y Ishihara, T Delgado-Escueta, AV Yamakawa, K AF Ganesh, S Tsurutani, N Suzuki, T Hoshii, Y Ishihara, T Delgado-Escueta, AV Yamakawa, K TI The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE epilepsy; polyglucosan inclusion; carpora amylacea; neurodegeneration; phosphatase; carbohydrate binding ID PROGRESSIVE MYOCLONUS EPILEPSY; GLYCATION END-PRODUCTS; EPM2A GENE; CORPORA-AMYLACEA; PHOSPHATASE; MUTATIONS; IDENTIFICATION; MYOCARDIUM; SPECTRUM; GLYCOGEN AB Lafora's disease (LD) is an amosomal recessive and fatal form of epilepsy with onset in late childhood or adolescence. One of the characteristic features of LD pathology is the presence of periodic acid-Schiff (PAS) positive Lafora inclusion bodies. Lafora bodies are present primarily in neurons, but they have also been found in other organs. Histochemical and biochemical studies have indicated that Lafora bodies are composed mainly of polysaccharides. The LD gene, EPM2A, encodes a 331 amino acid long protein named laforin that contains an N-terminal carbohydrate-binding domain (CBD) and a C-terminal dual-specificity phosphatase domain (DSPD). Here we demonstrate that the CBD of laforin targets the protein to Lafora inclusion bodies and this property could be evolutionarily conserved. We also tested in vitro the effects of five LD missense mutations on laforin's affinity to Lafora body. While the missense mutant W32G failed to bind to purified Lafora body, four other mutants (S25P, E28L, F88L, and R108C) did not show any effect on the binding affinity. Based on these observations we propose the existence of a laforin-mediated glycogen metabolic pathway regulating the disposal of pathogenic polyglucosan inclusions. This is the first report demonstrating a direct association between the LD gene product and the disease-defining storage product, the Lafora bodies. (C) 2003 Elsevier Inc. All rights reserved. C1 Indian Inst Technol, Dept Biol Sci & Bioengn, Kanpur 208016, Uttar Pradesh, India. RIKEN, Brain Sci Inst, Neurogenet Lab, Wako, Saitama 35101, Japan. Yamaguchi Univ, Sch Med, Dept Pathol 1, Yamaguchi, Japan. Univ Calif Los Angeles, Sch Med, Comprehens Epilepsy Program, Epilepsy Genet Genom Labs, Los Angeles, CA USA. VA GLAHS W Los Angeles Med Ctr, Los Angeles, CA USA. RP Ganesh, S (reprint author), Indian Inst Technol, Dept Biol Sci & Bioengn, Kanpur 208016, Uttar Pradesh, India. EM sganesh@iitk.ac.in; yamakawa@brain.riken.go.jp RI Ganesh, Subramniam/B-4131-2009; Yamakawa, Kazuhiro/N-5050-2015; OI Delgado-Escueta, Antonio V./0000-0002-1581-6999 NR 29 TC 53 Z9 54 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 23 PY 2004 VL 313 IS 4 BP 1101 EP 1109 DI 10.1016/j.bbrc.2003.12.043 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 762TF UT WOS:000187997700041 PM 14706656 ER PT J AU Danial, NN Korsmeyer, SJ AF Danial, NN Korsmeyer, SJ TI Cell death: Critical control points SO CELL LA English DT Review ID CYTOCHROME-C RELEASE; APOPTOSIS-INDUCING FACTOR; MITOCHONDRIAL PERMEABILITY TRANSITION; BCL-2 FAMILY MEMBERS; CAENORHABDITIS-ELEGANS; ENDOPLASMIC-RETICULUM; STRUCTURAL BASIS; CASPASE ACTIVATION; GRANZYME-B; CHROMOSOMAL BREAKPOINT AB Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics. C1 Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. RP Korsmeyer, SJ (reprint author), Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. EM stanley_korsmeyer@dfci.harvard.edu NR 162 TC 2910 Z9 3082 U1 51 U2 412 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 23 PY 2004 VL 116 IS 2 BP 205 EP 219 DI 10.1016/S0092-8674(04)00046-7 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 768KG UT WOS:000188541700011 PM 14744432 ER PT J AU Jung, D Alt, FW AF Jung, D Alt, FW TI Unraveling V(D)J recombination: Insights into gene regulation SO CELL LA English DT Review ID SITE-SPECIFIC RECOMBINATION; DEPENDENT PROTEIN-KINASE; VARIABLE-REGION GENES; DOUBLE-STRAND BREAKS; B-CELL DEVELOPMENT; LIGHT-CHAIN GENES; TCR-BETA LOCUS; ALLELIC EXCLUSION; IMMUNOGLOBULIN GENE; IMMUNE-SYSTEM AB V(D)J recombination assembles antigen receptor genes from component gene segments. We review findings that have shaped our current understanding of this remarkable mechanism, with a focus on two major reports-the first detailed comparison of germline and rearranged antigen receptor loci and the discovery of the recombination activating gene-1. C1 Harvard Univ, Howard Hughes Med Inst, Childrens Hosp, CBR Inst Biomed Res Inc,Med Sch, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Howard Hughes Med Inst, Childrens Hosp, CBR Inst Biomed Res Inc,Med Sch, Boston, MA 02115 USA. EM alt@rascal.med.harvard.edu NR 117 TC 179 Z9 184 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 23 PY 2004 VL 116 IS 2 BP 299 EP 311 DI 10.1016/S0092-8674(04)00039-X PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 768KG UT WOS:000188541700018 PM 14744439 ER PT J AU Gera, JF Mellinghoff, IK Shi, YJ Rettig, MB Tran, C Hsu, JH Sawyers, CL Lichtenstein, AK AF Gera, JF Mellinghoff, IK Shi, YJ Rettig, MB Tran, C Hsu, JH Sawyers, CL Lichtenstein, AK TI AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EIF2-ALPHA KINASE GCN2; TRANSLATION INITIATION; MESSENGER-RNA; SIGNALING PATHWAY; CELL-SURVIVAL; CANCER-CELLS; TOR; IRES; GROWTH; HYPOTHESIS AB Prior work demonstrates that AKT activity regulates sensitivity of cells to G(1) arrest induced by mammalian target of rapamycin (mTOR) inhibitors such as rapamycin and CCI-779. To investigate this, a novel high-throughput microarray polysome analysis was performed to identify genes whose mRNA translational efficiency was differentially affected following mTOR inhibition. The analysis also allowed the assessment of steady-state transcript levels. We identified two transcripts, cyclin D1 and c-myc, which exhibited differential expression in an AKT-dependent manner: High levels of activated AKT resulted in rapamycin-induced down-regulation of expression, whereas low levels resulted in up-regulation of expression. To ectopically express these proteins we exploited the finding that the p27(kip1) mRNA was efficiently translated in the face of mTOR inhibition irrespective of AKT activity. Thus, the p27(kip1) 5'-untranslated region was fused to the cyclin D1 and c-myc coding regions and these constructs were expressed in cells. In transfected cells, expression of cyclin D1 or c-myc was not decreased by rapamycin. Most importantly, this completely converted sensitive cells to a phenotype resistant to G(1) arrest. Furthermore, the AKT-dependent differential expression patterns of these two genes was also observed in a mouse xenograft model following in vivo treatment with CCI-779. These results identify two critical downstream molecular targets whose expression is regulated by AKT activity and whose down-regulation is required for rapamycin/CCI-779 sensitivity. C1 Univ Calif Los Angeles, Med Ctr, W Los Angeles Vet Adm, Dept Med,Div Hematol & Oncol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Jonsson Comprehens Canc Ctr, Howard Hughes Med Inst,Mol Biol Inst, Los Angeles, CA 90073 USA. RP Gera, JF (reprint author), Univ Calif Los Angeles, Med Ctr, W Los Angeles Vet Adm, Dept Med,Div Hematol & Oncol, Los Angeles, CA 90073 USA. EM gera@ucla.edu RI Sawyers, Charles/G-5327-2016 FU NCI NIH HHS [CA096920] NR 36 TC 232 Z9 242 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 23 PY 2004 VL 279 IS 4 BP 2737 EP 2746 DI 10.1074/jbc.M309999200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 764MU UT WOS:000188211300051 PM 14576155 ER EF