tbuckley/cabot-search huggingface dataset:
Efficacy of Sertraline in Preventing Relapse of Posttraumatic Stress Disorder: Results of a 28-Week Double-Blind, Placebo-Controlled Study
Authors: Jonathan Davidson, Teri Pearlstein, Peter Londborg, Kathleen T. Brady, Barbara Rothbaum, Jon Bell, Richard Maddock, Mark T. Hegel, Gail Farfel
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The study examined the efficacy of sertraline, compared with placebo, in sustaining improvement and preventing relapse over 28 weeks in patients with posttraumatic stress disorder (PTSD) who had completed a 12-week double-blind, placebo-controlled acute treatment study and a subsequent 24-week open-label study of continuation treatment with sertraline. METHOD: Ninety-six patients were randomly assigned, in a double-blind design, to 28 weeks of maintenance treatment with sertraline (50–200 mg, N=46; 78% were women) or placebo (N=50; 62% were women). Measures used in biweekly assessments included the Clinician-Administered PTSD Scale, the Impact of Event Scale, and the Clinical Global Impression severity and improvement ratings. Kaplan-Meier analyses were used to estimate time to discontinuation from the study due to relapse, relapse or study discontinuation due to clinical deterioration, and acute exacerbation. RESULTS: Continued treatment with sertraline yielded lower PTSD relapse rates than placebo (5% versus 26%). Patients who received placebo were 6.4 times as likely to experience relapse as were patients who received sertraline. Kaplan-Meier analyses confirmed the protective effect of sertraline in significantly extending time in remission. The ability of sertraline to sustain improvement was comparable across the three core PTSD symptom clusters (reexperiencing/intrusion, avoidance/numbing, and hyperarousal). A regression analysis found early response during acute treatment to be associated with a more than 16-fold reduced risk of relapse after placebo substitution. Sertraline, at a mean endpoint dose of 137 mg, was well tolerated, with no sertraline-related adverse events observed at a rate of 10% or higher. CONCLUSIONS: The results provide evidence for the ability of sertraline both to sustain improvement in PTSD symptoms and to provide prophylactic protection against relapse.
Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training
Authors: Hugh Montgomery, Peter Clarkson, Maria Barnard, Jimmy Bell, Audrey Brynes, Joseph Hajnal, Harry Hemingway, Dawn Mercer, Paul Jarman, Richard Marshall, Krishna Prasad, Mark Rayson, Nadeem Saeed, Louise Thomas, Mick Jubb, Michael World, Claire Dollery, Phillipa Talmud, Steve Humphries
Journal: The Lancet (1999)
Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation
Authors: Y GOUEFFIC, C GUILLUY, P GUERIN, P PATRA, P PACAUD, G LOIRAND
Journal: Cardiovascular Research (2006)

Hyaluronan (HA) is an important constituent of the extracellular matrix and is known to regulate cellular events through binding to CD44 and the receptor for HA-mediated motility (RHAMM). Here we investigated the role of these receptors and the signaling pathways involved in HA-mediated effects in arterial smooth muscle cells (ASMC).Effects of high-molecular weight HA (1 to 5 mg/ml) were analyzed in cultured ASMC from rat aorta.HA promoted actin stress fiber and lamellipodia formation and dose-dependently induced ASMC migration without effect on proliferation. Pull-down assay of Rho protein activity indicated that HA activated RhoA and Rac. HA-induced ASMC migration was not affected by the RhoA inhibitor Tat-C3 (10 microg/ml), the Rho kinase inhibitor Y-27632 (10 microM) and blocking anti-CD44 antibody ,but was reduced by the non-selective Rho protein inhibitor simvastatin (10 microM), the Rac inhibitor LT-toxin (1 mug/ml), small interfering RNA (siRNA) targeting Rac and the phosphatidyl inositol 3-kinase (PI3K) inhibitor LY294002 (25 microM), which also blocked HA-induced Rac activation. CD44 knockdown by siRNA inhibited HA-mediated RhoA activation without effect on ASMC migration. In contrast, siRNA targeting RHAMM inhibited both HA-induced migration and Rac activation.High-molecular weight HA independently activates RhoA and Rac through CD44 and RHAMM, respectively. HA-induced migration depends exclusively on RHAMM-mediated PI3K-dependent Rac activation.
Complete Genomic Screen in Parkinson Disease
Authors: William K. Scott, Martha A. Nance, Ray L. Watts, Jean P. Hubble, William C. Koller, Kelly Lyons, Rajesh Pahwa, Matthew B. Stern, Amy Colcher, Bradley C. Hiner, Joseph Jankovic, William G. Ondo, Fred H. Allen, Jr, Christopher G. Goetz, Gary W. Small, Donna Masterman, Frank Mastaglia, Nigel G. Laing, Jeffrey M. Stajich, Brandon Slotterbeck, Michael W. Booze, Robert C. Ribble, Evadnie Rampersaud, Sandra G. West, Rachel A. Gibson, Lefkos T. Middleton, Allen D. Roses, Jonathan L. Haines, Burton L. Scott, Jeffery M. Vance, Margaret A. Pericak-Vance
Journal: JAMA (2001)

ContextThe relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD.ObjectiveTo identify genetic risk factors for idiopathic PD.Design, Setting, and ParticipantsGenetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status.Main Outcome MeasuresLogarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis.ResultsTwo-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients.ConclusionsOur data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.
Intake of very long chain n‐3 fatty acids from fish and the incidence of heart failure: the Rotterdam Study
Authors: S. Coosje Dijkstra, Ingeborg A. Brouwer, Frank J.A. van Rooij, Albert Hofman, Jacqueline C.M. Witteman, Johanna M. Geleijnse
Journal: European Journal of Heart Failure (2009)
Comprehensive diagnostic ability of endocytoscopy compared with biopsy for colorectal neoplasms: a prospective randomized noninferiority trial
Authors: Y. Mori, S. Kudo, N. Ikehara, K. Wakamura, Y. Wada, M. Kutsukawa, M. Misawa, T. Kudo, Y. Kobayashi, H. Miyachi, F. Yamamura, K. Ohtsuka, H. Inoue, S. Hamatani
Journal: Endoscopy (2013)

<b>Background and study aims:</b> Endocytoscopy enables observation at 450-fold magnification during gastrointestinal endoscopy, allowing on-site “optical biopsy.” We compared the accuracies of endocytoscopy and standard biopsy for the diagnosis of colorectal neoplasms. <b>Patients and methods:</b> We performed a randomized, controlled, open-label trial of patients with colorectal lesions ( ≥ 5 mm) detected during colonoscopy in a tertiary referral center. We randomly assigned the 203 detected lesions of 170 eligible patients to either the endocytoscopy or standard biopsy group. An on-site endoscopist assessed the histopathology of the endocytoscopy group lesions according to the endocytoscopic findings, whereas a pathologist later assessed standard biopsy group lesions by microscopic examination of the biopsy specimens. We calculated the diagnostic accuracies in both groups with reference to the final histopathology of the resected specimens. The primary endpoint was to determine whether the diagnostic accuracy of endocytoscopy for neoplastic lesions was noninferior to that of standard biopsy (with a predefined noninferiority margin of 10 %). Analyses were by intention-to-treat and per-protocol. The study is registered, number UMIN000003923. <b>Results:</b> Overall, 102 lesions in the endocytoscopy group and 101 in the standard biopsy group were available for primary outcome analysis. There were no complications. The diagnostic accuracy of endocytoscopy for the discrimination of neoplastic lesions was 94.1 % (95 % confidence interval 87.6 % to 97.8 %), whereas that of standard biopsy was 96.0 % (90.2 % to 98.9 %), which is within the noninferiority margin (absolute difference − 1.9 %, − 8.6 % to + 5.0 %). <b>Conclusions:</b> Endocytoscopy is noninferior to standard biopsy for the discrimination of neoplastic lesions. With its advantage of providing an on-site diagnosis, endocytoscopy could provide a novel alternative to standard biopsy in routine colonoscopy.
Genetic basis of viral persistence: single amino acid change in the viral glycoprotein affects ability of lymphocytic choriomeningitis virus to persist in adult mice.
Authors: M Matloubian, T Somasundaram, S R Kolhekar, R Selvakumar, R Ahmed
Journal: The Journal of Experimental Medicine (1990)

This study has identified a single amino acid change in the viral glycoprotein that profoundly affects the ability of lymphocytic choriomeningitis virus (LCMV) to persist in its natural host. Adult immunocompetent mice infected with a variant of the Armstrong strain, spleen isolate clone 13 (svA/svA), harbor virus for several months and exhibit suppressed T cell responses. In contrast, adult mice infected with a reassortant virus (svA/wtA) that contains the L segment of the spleen variant and the S segment of the parental wt Armstrong, make potent LCMV-specific CTL responses and clear the infection within 2-4 wk. These two viruses, spleen variant clone 13 and the reassortant svA/wtA, are identical in their noncoding regions and show no amino acid changes in any of their viral genes except for one substitution in the glycoprotein. The reassortant virus svA/wtA has a phenylalanine at amino acid residue 260 of the glycoprotein, whereas the spleen variant clone 13 has a leucine at this position. This study constitutes one of the first reports defining the genetic basis of viral persistence at the whole animal level, and identifying a single mutation that markedly increases the ability of a virus to persist in its natural host.
(E)-5-(2-bromovinyl)-2?-deoxyuridine (BVDU)
Authors: Erik De Clercq
Journal: Medicinal Research Reviews (2004)

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, Brivudin, Zostex, Zerpex, Zonavir), now more than 20 years after its discovery, still stands out as a highly potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections. It has been used in the topical treatment of herpetic keratitis and recurrent herpes labialis and the systemic (oral) treatment of herpes zoster (zona, shingles). The high selectivity of BVDU towards HSV-1 and VZV depends primarily on a specific phosphorylation of BVDU to its 5'-diphosphate (DP) by the virus-encoded thymidine kinase (TK). After further phosphorylation (by cellular enzymes), to the 5'-triphosphate (TP), the compound interferes as a competitive inhibitor/alternate substrate with the viral DNA polymerase. The specific phosphorylation by the HSV- and VZV-induced TK also explains the marked cytostatic activity of BVDU against tumor cells that have been transduced by the viral TK genes. This finding offers considerable potential in a combined gene therapy/chemotherapy approach for cancer. To the extent that BVDU or its analogues (i.e., BVaraU) are degraded (by thymidine phosphorylase) to (E)-5-(2-bromovinyl)uracil (BVU), they may potentiate the anticancer potency, as well as toxicity, of 5-fluorouracil. This ensues from the direct inactivating effect of BVU on dihydropyrimidine dehydrogenase, the enzyme that initiates the degradative pathway of 5-fluorouracil. The prime determinant in the unique behavior of BVDU is its (E)-5-(2-bromovinyl) substituent. Numerous BVDU analogues have been described that, when equipped with this particular pharmacophore, demonstrate an activity spectrum characteristic of BVDU, including selective anti-VZV activity.
Health effects of passive smoking bullet 7: Parental smoking, bronchial reactivity and peak flow variability in children
Authors: D. G Cook, D. P Strachan
Journal: Thorax (1998)

<h3>BACKGROUND</h3> A systematic quantitative review was conducted of the evidence relating environmental tobacco smoke to bronchial hyperresponsiveness (BHR) during childhood. <h3>METHODS</h3> Twenty nine relevant studies were identified after consideration of 1593 articles selected by electronic search of the Embase and Medline databases using keywords relevant to passive smoking in children. The search was completed in April 1997. <h3>RESULTS</h3> Of 19 studies using challenge tests in children of school age, 10 (5759 children) could be summarised as the odds ratio of being bronchial hyperreactive in children exposed to environmental tobacco smoke compared with those not exposed. The pooled odds ratio for maternal smoking was 1.29 (95% confidence limits 1.10 to 1.50) with no evidence of heterogeneity between studies. However, in five further studies of 3531 children providing some evidence, but not odds ratios, none were statistically significant. A further four studies on 5233 children have collected data but are not published. In contrast, all four studies of circadian variation in peak expiratory flow found increased variation in children exposed to environmental tobacco smoke. <h3>CONCLUSIONS</h3> A clear effect of exposure to environmental tobacco smoke on BHR in the general population has not been established. While the meta-analysis suggests a small but real increase in BHR in school aged children, it seems likely that this estimate is biased upwards due to publication bias. In contrast, limited evidence suggests greater variation in peak expiratory flow in children of smoking parents.
Amrinone activates K+-depolarized atrial and ventricular myocardium of guinea pigs.
Authors: H R Adams, J Rhody, J L Sutko
Journal: Circulation Research (1982)

Amrinone is a new synthetic drug that increases contractile strength of mammalian heart muscle; however, its mechanism of positive inotropic action has not been determined. We now report that amrinone (0.053-5.3 mM) consistently restores typical slow response electromechanical activity fo K+-depolarized atrial and ventricular myocardial preparations from guniea pigs. This action was blocked in both tissues by D-600 (1 microM), but it was not significantly inhibited by either tetrodotoxin (23.5 microM), d,l-propranolol (1 microM), or phentolamine (10 microM). Cimetidine (3 microM) or metiamide (10 microM) slightly inhibited amrinone's effect only in the ventricle, whereas pyrilamine (10 microM) slightly inhibited amrinone's response only in the atrium. These data indicate that amrinone's positive inotropic action may involve augmented Ca++ influx via the slow inward Ca++ current, and that although this action is independent of adrenoceptor mechanisms, it seems to include a small histaminergic component.
Overview of the Symposium on Public Health Significance of Genomics and Eco-Genetics
Authors: Gilbert S. Omenn
Journal: Annual Review of Public Health (2009)

Genomic and genetic information is rapidly becoming a major element in public health research and emerging public health practice. This symposium reviews the methods, findings, and significance of genome-wide association studies from epidemiological and statistical points of view. We examine infectious and inflammatory components of gene-environment interaction in the respiratory system. We note the need for nutrient and dietary data and many other kinds of environmental exposure data in population-based genomic studies. Then we explore the sufficiency of a well-informed family history for public health and family counseling purposes. Finally, in an era of direct-to-consumer genomic test promotion, we review the evidence on the critical question, will genetic risk profiles motivate individuals and families to choose more healthful behaviors? This symposium builds on the foundation of the symposium on Public Health Genetics in Volume 21 (2000) of the Annual Review of Public Health.
18-Fluorodeoxyglucose Positron Emission Tomography Does Not Aid in Diagnosis of Pancreatic Ductal Adenocarcinoma
Authors: Ippei Matsumoto, Sachiyo Shirakawa, Makoto Shinzeki, Sadaki Asari, Tadahiro Goto, Tetsuo Ajiki, Takumi Fukumoto, Kazuhiko Kitajima, Yonson Ku
Journal: Clinical Gastroenterology and Hepatology (2013)
Infective Endocarditis
Authors: Larry M. Baddour, Walter R. Wilson, Arnold S. Bayer, Vance G. Fowler, Ann F. Bolger, Matthew E. Levison, Patricia Ferrieri, Michael A. Gerber, Lloyd Y. Tani, Michael H. Gewitz, David C. Tong, James M. Steckelberg, Robert S. Baltimore, Stanford T. Shulman, Jane C. Burns, Donald A. Falace, Jane W. Newburger, Thomas J. Pallasch, Masato Takahashi, Kathryn A. Taubert
Journal: Circulation (2005)

Background— Despite advances in medical, surgical, and critical care interventions, infective endocarditis remains a disease that is associated with considerable morbidity and mortality. The continuing evolution of antimicrobial resistance among common pathogens that cause infective endocarditis creates additional therapeutic issues for physicians to manage in this potentially life-threatening illness. Methods and Results— This work represents the third iteration of an infective endocarditis “treatment” document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. A multidisciplinary committee of experts drafted this document to assist physicians in the evolving care of patients with infective endocarditis in the new millennium. This extensive document is accompanied by an executive summary that covers the key points of the diagnosis, antimicrobial therapy, and management of infective endocarditis. For the first time, an evidence-based scoring system that is used by the American College of Cardiology and the American Heart Association was applied to treatment recommendations. Tables also have been included that provide input on the use of echocardiography during diagnosis and treatment of infective endocarditis, evaluation and treatment of culture-negative endocarditis, and short-term and long-term management of patients during and after completion of antimicrobial treatment. To assist physicians who care for children, pediatric dosing was added to each treatment regimen. Conclusions— The recommendations outlined in this update should assist physicians in all aspects of patient care in the diagnosis, medical and surgical treatment, and follow-up of infective endocarditis, as well as management of associated complications. Clinical variability and complexity in infective endocarditis, however, dictate that these guidelines be used to support and not supplant physician-directed decisions in individual patient management.
OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients
Authors: Brendan D. Curti, Magdalena Kovacsovics-Bankowski, Nicholas Morris, Edwin Walker, Lana Chisholm, Kevin Floyd, Joshua Walker, Iliana Gonzalez, Tanisha Meeuwsen, Bernard A. Fox, Tarsem Moudgil, William Miller, Daniel Haley, Todd Coffey, Brenda Fisher, Laurie Delanty-Miller, Nicole Rymarchyk, Tracy Kelly, Todd Crocenzi, Eric Bernstein, Rachel Sanborn, Walter J. Urba, Andrew D. Weinberg
Journal: Cancer Research (2013)

Abstract OX40 is a potent costimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells. Preclinical studies have shown that OX40 agonists increase antitumor immunity and improve tumor-free survival. In this study, we performed a phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12 of 30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4+ FoxP3+ regulatory T cells in tumor-infiltrating lymphocytes, and increased the antitumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in patients with cancer, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells, and intratumoral regulatory T cells. Cancer Res; 73(24); 7189–98. ©2013 AACR.
Anti–Mesothelin Immunotoxin SS1P in Combination with Gemcitabine Results in Increased Activity against Mesothelin-Expressing Tumor Xenografts
Authors: Raffit Hassan, V. Courtney Broaddus, Shannon Wilson, David J. Liewehr, Jingli Zhang
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To determine the antitumor activity of the anti–mesothelin immunotoxin SS1P in combination with gemcitabine against mesothelin-expressing tumor xenografts. Experimental Design: The in vitro activity of SS1P in combination with gemcitabine against the mesothelin-expressing cell line A431/K5 was evaluated using cytotoxicity and apoptosis assays. The antitumor activity of this combination was evaluated in nude mice bearing A431/K5 tumor xenografts. Tumor-bearing mice were treated with different doses and schedules of gemcitabine alone, SS1P alone (0.2 mg/kg i.v. every other day × three doses), or with both agents together, and tumor volumes were measured over time. Results: In vitro studies failed to show the synergy of SS1P plus gemcitabine against the mesothelin-expressing A431/K5 cells. In contrast, in the in vivo setting, there was a marked synergy when SS1P was combined with gemcitabine for the treatment of mesothelin-expressing tumor xenografts. This synergy was present using different doses and schedules of gemcitabine administration. In mice treated with fractionated doses of gemcitabine in combination with SS1P, complete tumor regression was observed in all mice and was long-lasting in 60% of the animals. Also, this antitumor activity was specific to SS1P because HA22, an immunotoxin targeting CD22 not expressed on A431/K5 cells, did not increase the efficacy of gemcitabine. Conclusions: SS1P in combination with gemcitabine results in marked antitumor activity against mesothelin-expressing tumors. This combination could be potentially useful for the treatment of human cancers that express mesothelin and are responsive to gemcitabine therapy.