tbuckley/cabot-search huggingface dataset:
Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention
Authors: Morten Lamberts, Jonas Bjerring Olesen, Martin Huth Ruwald, Carolina Malta Hansen, Deniz Karasoy, Søren Lund Kristensen, Lars Køber, Christian Torp-Pedersen, Gunnar Hilmar Gislason, Morten Lock Hansen
Journal: Circulation (2012)

Uncertainty remains over optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction and/or undergoing percutaneous coronary intervention. We investigated the risk and time frame for bleeding following myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation according to antithrombotic treatment.Patients with atrial fibrillation and admitted with myocardial infarction or for percutaneous coronary intervention between 2000 and 2009 (11 480 subjects, mean age 75.6 years [SD ±10.3], males 60.9%) were identified by individual level linkage of nationwide registries in Denmark. Fatal or nonfatal (requiring hospitalization) bleeding was determined according to antithrombotic treatment regimen: triple therapy (TT) with vitamin K antagonist (VKA)+aspirin+clopidogrel, VKA+antiplatelet, and dual antiplatelet therapy with aspirin+clopidogrel. We calculated crude incidence rates and adjusted hazard ratios by Cox regression models. Within 1 year, 728 bleeding events were recorded (6.3%); 79 were fatal (0.7%). Within 30 days, rates were 22.6, 20.3, and 14.3 bleeding events per 100 person-years for TT, VKA+antiplatelet, and dual antiplatelet therapy, respectively. Both early (within 90 days) and delayed (90-360 days) bleeding risk with TT exposure in relation to VKA+antiplatelet was increased; hazard ratio 1.47 (1.04;2.08) and 1.36 (0.95;1.95), respectively. No significant difference in thromboembolic risk was observed for TT versus VKA+antiplatelet; hazard ratio, 1.15 (0.95;1.40).High risk of bleeding is immediately evident with TT after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.
Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection
Authors: Luc English, Magali Chemali, Johanne Duron, Christiane Rondeau, Annie Laplante, Diane Gingras, Diane Alexander, David Leib, Christopher Norbury, Roger Lippé, Michel Desjardins
Journal: Nature Immunology (2009)
Nocturnal saturation improves by target-flow inspiratory muscle training in patients with COPD.
Authors: Y F Heijdra, P N Dekhuijzen, C L van Herwaarden, H T Folgering
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Nocturnal desaturations during rapid eye movement (REM) sleep, caused by nonobstructive hypoventilation, occur frequently in patients with chronic obstructive pulmonary disease (COPD). This is partly caused by decreased activity of the intercostal and accessory muscles due to a lower motor command. The diaphragm has to compensate for the diminished activity of these muscles during REM sleep. However, in patients with COPD strength and endurance of the diaphragm may be affected by its unfavorable position on the length-tension curve because of hyperinflation. The aim of this study was to establish the causal relationship between respiratory muscle function and nocturnal saturation in patients with COPD. We hypothesized that target-flow inspiratory muscle training (TF-IMT) would improve nocturnal saturation. In 20 patients with stable COPD (FEV1 35.5 +/- 14.1% of predicted) and a mean nocturnal saturation below 92% we measured maximal inspiratory pressure (PImax), transdiaphragmatic pressure (Pdi), maximal sustainable inspiratory pressure (SIPmax), endurance time, and nocturnal saturation in Weeks 0, 4, and 10. During these 10 wk 10 patients underwent TF-IMT at 60% of PImax and 10 control patients received sham TF-IMT at 10% of PImax. PImax, Pdi, SIPmax, and the endurance time as well as the nocturnal saturation improved significantly in the 60% training group (by 3.0 +/- 1.5 kPa, 3.4 +/- 1.9 kPa, 1.5 +/- 1.4 kPa, 189 +/- 149 s, and 1.9 +/- 2.2%, respectively), whereas no changes occurred in the sham training group. Also, significant correlations were observed between the changes in Pdi, SIPmax, and endurance time on the one hand and the change in nocturnal saturation on the other. We conclude that TF-IMT improves the nocturnal saturation in patients with severe COPD by increasing respiratory muscle strength and endurance.
Phosphatidylinositol 3-Kinase and Calcium-Activated Transcription Pathways Are Required for VLDL-Induced Smooth Muscle Cell Proliferation
Authors: Larissa Lipskaia, Marie-Luce Pourci, Claudine Deloménie, Laurent Combettes, Dominique Goudounèche, Jean-Louis Paul, Thierry Capiod, Anne-Marie Lompré
Journal: Circulation Research (2003)

Little is known regarding the molecular mechanisms of atherogenicity of triglyceride-rich lipoproteins such as very low-density lipoproteins (VLDLs). We examined the effect of VLDL on proliferation of rat aortic smooth muscle cells, intracellular Ca2+ handling, and activity of cAMP-responsive element binding protein (CREB) and nuclear factor of activated T cells (NFAT) transcription factors. VLDL, isolated from human serum, dose- and time-dependently promoted proliferation. After 4 hours of exposure to VLDL (0.15 g/L proteins), the caffeine-induced Ca2+ release was inhibited and the IP3-sensitive Ca2+ release induced by ATP (10 micromol/L) was markedly prolonged. In quiescent cells, CREB was phosphorylated (pCREB) and NFAT was present in the cytosol, whereas in cells exposed to VLDL for 4 to 24 hours, pCREB disappeared and NFAT was translocated to the nucleus. VLDL-induced NFAT translocation and proliferation were blocked by cyclosporin A and LY294002 involving calcineurin and phosphatidylinositol 3-kinase (PI3K) pathways. Indeed, VLDLs rapidly phosphorylate protein kinase B and glycogen synthase kinase-3beta in a PI3K-dependent way. These results provide the first evidence that VLDLs induce smooth muscle cell proliferation by activating the PI3K pathway and nuclear NFAT translocation. Blockade of the Ca2+-induced Ca2+ release mechanism and dephosphorylation of pCREB contribute but were not sufficient to induce a proliferating phenotype.
Methods to Encourage the Use of Antenatal Corticosteroid Therapy for Fetal Maturation
Authors: Laura C. Leviton, Robert L. Goldenberg, C. Suzanne Baker, Rachel M. Schwartz, Margaret C. Freda, Larry J. Fish, Suzanne P. Cliver, Dwight J. Rouse, Cynthia Chazotte, Irwin R. Merkatz, James M. Raczynski
Journal: JAMA (1999)

ContextAntenatal corticosteroids for fetal maturation have been underused, despite evidence for their benefits in cases of preterm birth.ObjectiveTo evaluate dissemination strategies aimed at increasing appropriate use of this therapy.Design and SettingTwenty-seven tertiary care institutions were randomly assigned to either usual dissemination of practice recommendations (n=14) or usual dissemination plus an active, focused dissemination effort (n=13).SubjectsObstetricians and their preterm delivery cases at participating hospitals.InterventionRecommendations by a National Institutes of Health (NIH) Consensus Conference held in late February–early March 1994 were disseminated in early May 1994. Usual dissemination was publication of the recommendations and endorsement by the American College of Obstetricians and Gynecologists. Active dissemination was a year-long educational effort led by an influential physician and a nurse coordinator at each facility, consisting of grand rounds, a chart reminder system, group discussion of case scenarios, monitoring, and feedback.Main Outcome MeasureUse or nonuse of antenatal corticosteroids was abstracted from medical records of eligible women delivering at the participating hospitals in the 12 months immediately prior to release of the NIH recommendations (average number of records abstracted, 130) and in the 12 months following their release (average number of records abstracted, 122).ResultsActive dissemination significantly increased the odds of corticosteroid use after the conference. Use increased from 33.0% of eligible patients receiving corticosteroids to 57.6%, or by 75% over baseline, in usual dissemination hospitals. Use increased from 32.9% to 68.3%, or an 108% increase, in active dissemination hospitals. Gestational age and maternal diagnosis affected use of the therapy in complex ways.ConclusionAn active, focused dissemination effort increased the effectiveness of usual dissemination methods when combined with key principles to change physician practices.
MicroRNA-145, a Novel Smooth Muscle Cell Phenotypic Marker and Modulator, Controls Vascular Neointimal Lesion Formation
Authors: Yunhui Cheng, Xiaojun Liu, Jian Yang, Ying Lin, Da-Zhong Xu, Qi Lu, Edwin A. Deitch, Yuqing Huo, Ellise S. Delphin, Chunxiang Zhang
Journal: Circulation Research (2009)

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA (miRNA) miR-145 is the most abundant miRNA in normal vascular walls and in freshly isolated VSMCs; however, the role of miR-145 in VSMC phenotypic modulation and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs. More importantly, both in cultured rat VSMCs in vitro and in balloon-injured rat carotid arteries in vivo, we demonstrate that the noncoding RNA miR-145 is a novel phenotypic marker and a novel phenotypic modulator of VSMCs. VSMC differentiation marker genes such as SM alpha-actin, calponin, and SM-MHC are upregulated by premiR-145 or adenovirus expressing miR-145 (Ad-miR-145) but are downregulated by the miR-145 inhibitor 2'OMe-miR-145. We have further identified that miR-145-mediated phenotypic modulation of VSMCs is through its target gene KLF5 and its downstream signaling molecule, myocardin. Finally, restoration of miR-145 in balloon-injured arteries via Ad-miR-145 inhibits neointimal growth. We conclude that miR-145 is a novel VSMC phenotypic marker and modulator that is able of controlling vascular neointimal lesion formation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases.
Suppression of Helicobacter pylori reduces gastrin releasing peptide stimulated gastrin release in duodenal ulcer patients.
Authors: K Beardshall, S Moss, J Gill, S Levi, P Ghosh, R J Playford, J Calam
Journal: Gut (1992)

Helicobacter pylori increases gastrin release in duodenal ulcer patients. This may be through disruption or changes in the mucus layer affecting the access of luminal stimulants to gastrin releasing cells. The effect of suppressing H pylori on gastrin release stimulated by a non-luminal stimulus, gastrin releasing peptide (GRP), was examined. Eleven patients with active duodenal ulcer disease and colonised with H pylori received an intravenous infusion of GRP (2.9 pmol/kg/minute for 30 minutes) and the plasma gastrin response was measured. Basal and peak pentagastrin stimulated acid output were also determined. Patients were treated with tripotassium dicitratobismuthate (De-Nol) and metronidazole to suppress H pylori and the tests were repeated. Suppression of H pylori decreased plasma gastrin concentrations during GRP infusion, but acid output was not affected. Chromatographic analysis of the forms of gastrin in plasma showed a significant fall in gastrin 17, the predominant form found in the gastric antrum. Gastrin 34 did not fall significantly. This study shows that suppression of H pylori decreases the hypergastrinaemia caused by the nonluminal stimulant, GRP, mainly via decreasing gastrin 17.
The Community Adjustment and Criminal Activity of the Baxstrom Patients: 1966-1970
Authors: HENRY J. STEADMAN, GARY KEVELES
Journal: American Journal of Psychiatry (1972)

This research examines what happened to the nearly 1,000 patients transferred from two New York State hospitals for the criminally insane to civil mental hospitals in 1966 as the result of a Supreme Court decision. Four years later, about half were in civil mental hospitals, 27 percent in the community, and 14 percent dead. Only three percent were in a correctional facility or hospital for the criminally insane. The authors stress the need for more longitudinal research on the characteristics of the criminally insane to aid in the clinical determination of dangerousness.
Synergistic Killing Effect between Vorinostat and Target of CD146 in Malignant Cells
Authors: Xiaoli Ma, Jia Liu, Jiang Wu, Xiyun Yan, Peng Wu, Yong Liu, Shuang Li, Yuan Tian, Yang Cao, Gang Chen, Li Meng, Gang Xu, Shixuan Wang, Yunping Lu, Ding Ma, Jianfeng Zhou
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Although histone deacetylase inhibitors (HDACi) are emerging as a new class of anticancer agents, one of the most significant concerns is that interactions with a wide array of substrates using these agents might initiate both therapeutic and undesired protective responses. Here, we sought to identify the potential protective reactions initiated by HDACi and determine whether targeting these reactions would enhance the antitumoral activity of HDACi. Experimental Design: Gene expression profiles were analyzed by cDNA microarray in Molt-4 cells before and after treatment of vorinostat. Induction of CD146 by vorinostat was examined in a wide range of tumors and nonmalignant cells. AA98, an anti-CD146 monoclonal antibody, was used to target CD146 function. Synergistic antitumoral and antiangiogenic effects between AA98 and vorinostat were examined both in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the AKT pathway was determined by Western blotting. Results: The induction of CD146 is a common phenomenon in vorinostat-treated cancer but not in nonmalignant cells. Targeting of CD146 with AA98 substantially enhanced vorinostat-induced killing via the suppression of activation of AKT pathways in cancer cells. Moreover, AA98 in combination with vorinostat significantly inhibited angiogenesis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and metastasis. Conclusion: The present study provided the first evidence that an undesired induction of CD146 could serve as a protective response to offset the antitumor efficacy of vorinostat. On the other hand, targeting CD146 in combination with vorinostat could be exploited as a novel strategy to more effectively kill cancer cells. Clin Cancer Res; 16(21); 5165–76. ©2010 AACR.
Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition
Authors: J. Zoll, V. Fontaine, P. Gourdy, V. Barateau, J. Vilar, A. Leroyer, I. Lopes-Kam, Z. Mallat, J.-F. Arnal, P. Henry, G. Tobelem, A. Tedgui
Journal: Cardiovascular Research (2007)

We analysed the possible protective role of human endothelial (EPCs) and smooth muscle (SPCs) progenitor cells on atherosclerosis development in apoE(-/-)RAG2(-/-) mice. We determined plasma levels of SPCs in coronary patients.ApoE(-/-)RAG2(-/-) mice received four intravenous injections of saline, 5 x 10(5) SPCs, or 5 x 10(5) EPCs every other week, one (preventive approach) or 12(curative approach) weeks after starting a high fat diet. Derived-SPC levels were quantified from blood mononuclear cells of patients with stable angina (n = 10) and acute coronary syndromes (ACS, n = 9). SPCs reduced atherosclerosis development by 42% (P < 0.001), but had no effect on lesion progression. In the SPC group, collagen and smooth muscle cell content were increased (+80%, P < 0.001, +46%, P < 0.05, respectively), and macrophage content was decreased (-41%, P < 0.05). In the curative approach, macrophage content decreased by 40.5% (P < 0.05) after SPC injection. EPC injection had no effect on atherosclerosis development or progression. Peripheral blood-derived SPC levels were reduced in patients with ACS compared with stable angina patients (P < 0.05).We demonstrate that SPCs limit plaque development and promote changes in plaque composition towards a stable phenotype in mice. Our finding in patients suggests that reduced peripheral blood-derived SPC levels might represent a mechanism contributing to plaque destabilization.
Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma with Fluorouracil, Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie
Authors: Salah-Eddin Al-Batran, Joerg Thomas Hartmann, Stephan Probst, Harald Schmalenberg, Stephan Hollerbach, Ralf Hofheinz, Volker Rethwisch, Gernot Seipelt, Nils Homann, Gerhard Wilhelm, Gunter Schuch, Jan Stoehlmacher, Hans Günter Derigs, Susanna Hegewisch-Becker, Johannes Grossmann, Claudia Pauligk, Akin Atmaca, Carsten Bokemeyer, Alexander Knuth, Elke Jäger
Journal: Journal of Clinical Oncology (2008)

This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer.Patients with previously untreated advanced adenocarcinoma of the stomach or esophagogastric junction were randomly assigned to receive either fluorouracil 2,600 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2), and oxaliplatin 85 mg/m(2) (FLO) every 2 weeks or fluorouracil 2,000 mg/m(2) via 24-hour infusion, leucovorin 200 mg/m(2) weekly, and cisplatin 50 mg/m(2) every 2 weeks (FLP). The primary end point was progression-free survival (PFS).Two hundred twenty patients (median age, 64 years; metastatic, 94%) were randomly assigned. FLO was associated with significantly less (any grade) anemia (54% v 72%), nausea (53% v 70%), vomiting (31% v 52%), alopecia (22% v 39%), fatigue (19% v 34%), renal toxicity (11% v 34%), thromboembolic events (0.9% v 7.8%), and serious adverse events related to the treatment (9% v 19%). FLP was associated with significantly less peripheral neuropathy (22% v 63%). There was a trend toward improved median PFS with FLO versus FLP (5.8 v 3.9 months, respectively; P = .077) and no significant difference in median overall survival (10.7 v 8.8 months, respectively). However, in patients older than 65 years (n = 94), treatment with FLO resulted in significantly superior response rates (41.3% v 16.7%; P = .012), time to treatment failure (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029) and an improved OS (13.9 v 7.2 months) as compared with FLP, respectively.FLO reduced toxicity as compared with FLP. In older adult patients, FLO also seemed to be associated with improved efficacy.
Training Translators for Smart Drug Discovery
Authors: Carsten Skarke, Garret A. FitzGerald
Journal: Science Translational Medicine (2010)

To achieve advances in clinical medicine, we need investigators with a sophisticated understanding of medicine and pharmacology who are capable of projecting their preclinical research across the translational divide. Such expertise in translational medicine and therapeutics has become scant in academia, industry, and regulatory bodies. Here we discuss strategies for addressing this deficit in human capital.
The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region
Authors: Susumu Goyama, Yuko Yamaguchi, Yoichi Imai, Masahito Kawazu, Masahiro Nakagawa, Takashi Asai, Keiki Kumano, Kinuko Mitani, Seishi Ogawa, Shigeru Chiba, Mineo Kurokawa, Hisamaru Hirai
Journal: Blood (2004)
Bundle branch reentry: a possible mechanism of ventricular tachycardia.
Authors: P Touboul, G Kirkorian, G Atallah, P Moleur
Journal: Circulation (1983)

Electrophysiologic studies were performed in three patients suffering from attacks of paroxysmal tachycardia with wide QRS complexes. Two patients had atrioventricular dissociation. The arrhythmia could be initiated and terminated by premature ventricular stimulation in all three patients. One patient developed the arrhythmia after rapid atrial stimulation. In each subject, the QRS complexes during tachycardia were identical to recorded supraventricular beats (left bundle branch block pattern in two cases and right bundle branch block pattern in one). A His bundle potential was noted before the QRS complex; the HV interval was equal to or longer than that of the sinus beats. The following observations suggested the presence of a bundle branch reentry mechanism: (1) the relationship between bundle branch block development and tachycardia initiation; (2) the occurrence of tachycardia after electrically induced His-Purkinje reentry; (3) the ability of premature ventricular stimulation during tachycardia to advance the timing of the His deflection and QRS complex, with an unchanged or slightly increased HV interval; and (4) the termination of arrhythmia by premature ventricular depolarization blocked within the bundle branch system. Our results support the idea that bundle branch reentry can play a role in the genesis of ventricular tachycardia.
The Role of Ethanol in Cardiac Disease
Authors: T J Regan, P O Ettinger, B Haider, S S Ahmed, H A Oldewurtel, M M Lyons
Journal: Annual Review of Medicine (1977)

The widespread use of ethyl alcohol suggests its potential importance in clinical medicine. There is no proven therapeutic effect in cardiac patients and its role as an etiologic factor in heart disease has been disputed over the years and attributed to coexistent malnutrition. The latter factor, however, has been dissociated from ethanol use in many patients with the cardiomyopathic form of heart failure. Major support for the role of ethanol as a toxic agent when used in large amounts for a prolonged period has been obtained in various species of animals, including the subhuman primate. Abnormalities include depression of ventricular function, and metabolic and morphologic changes that parallel the changes in humans with preclinical malfunction of the heart. While the mechanism of progression to heart failure or arrhythmias is not known, several factors may be associated. These include, particularly in males, the cumulative effects of ethanol alone or after intensified drinking episodes, simultaneous exposure to trace metals in excess, and occasional specific nutritional deficiency or superimposed infection. The low prevalence of clinical nutritional deficiency in patients with alcoholic cardiomyopathy and the infrequency of heart disease in patients with cirrhosis or neuropathy supports the view that the cardiac abnormality is commonly not dependent on malnutrition. Clinical data indicate that the cessation of alcohol intake may reverse the disease or interrupt its progression in many patients. However, the pathogenic process may continue unabated in some patients who become abstinent.