tbuckley/cabot-search huggingface dataset:
Regression of Electrocardiographic Left Ventricular Hypertrophy by Losartan Versus Atenolol
Authors: Peter M. Okin, Richard B. Devereux, Sverker Jern, Sverre E. Kjeldsen, Stevo Julius, Markku S. Nieminen, Steven Snapinn, Katherine E. Harris, Peter Aurup, Jonathan M. Edelman, Björn Dahlöf
Journal: Circulation (2003)

Background— Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. Methods and Results— Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months’ follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, −200 versus −69 mm · ms, P &lt;0.001) and Sokolow-Lyon voltage (−2.5 versus −0.7 mm, P &lt;0.001) than was atenolol-based therapy. Greater regression of ECG LVH persisted at each subsequent annual evaluation in the losartan-treated group, with between 140 and 164 mm · ms greater mean reductions in Cornell product and from 1.7 to 2.2 mm greater mean reductions in Sokolow-Lyon voltage (all P &lt;0.001). The effect of losartan was consistent across subgroups defined by gender, age, ethnicity, and diabetes. Conclusions— After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.
The role of the scavenger receptor CD36 in regulating mononuclear phagocyte trafficking to atherosclerotic lesions and vascular inflammation
Authors: Diala Harb, Kim Bujold, Maria Febbraio, Martin G. Sirois, Huy Ong, Sylvie Marleau
Journal: Cardiovascular Research (2009)

AimsCD36 has been shown to associate with non-receptor Src kinases to activate mitogen-activated protein kinases and trigger cytoskeletal remodelling, important events in foam cell formation and macrophage migration. Yet, its role in regulating circulating mononuclear phagocyte trafficking to atherosclerotic lesions has not been investigated. The aim of the present study was to investigate the role of CD36 in modulating the recruitment of mononuclear phagocytes to the arterial wall and the associated vascular inflammation, using both pharmacological and genetic approaches.
Molecular features in arsenic-induced lung tumors
Authors: Roland Hubaux, Daiana D Becker-Santos, Katey SS Enfield, David Rowbotham, Stephen Lam, Wan L Lam, Victor D Martinez
Journal: Molecular Cancer (2013)

Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer.
Phase I Clinical Study of Pertuzumab, a Novel HER Dimerization Inhibitor, in Patients With Advanced Cancer
Authors: David B. Agus, Michael S. Gordon, Charles Taylor, Ronald B. Natale, Beth Karlan, David S. Mendelson, Michael F. Press, David E. Allison, Mark X. Sliwkowski, Gracie Lieberman, Stephen M. Kelsey, Gwen Fyfe
Journal: Journal of Clinical Oncology (2005)

Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy.Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks.Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients.These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy.
Intracellular Compartmentalization of Leukotriene Biosynthesis
Authors: MARC PETERS-GOLDEN, THOMAS G. BROCK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Leukotrienes (LTs) are potent bioactive lipids derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) metabolism. Although they have been conventionally viewed as paracrine mediators of inflammatory disease processes such as asthma (1), more recent information suggests that they are also important participants in disease processes characterized by cellular proliferation and fibrogenesis (2-4), and that they subserve a homeostatic role in antimicrobial host defense (5). In view of the actions and importance of LTs, substantial effort has been directed at increasing our understanding of the regulation of their synthesis. An extensive body of research, reviewed elsewhere in this symposium, has identified three key factors that regulate LT synthesis: (1) the steady state levels of key proteins necessary for AA release and 5-LO metabolism; (2) posttranslational modifications (such as phosphorylation) that alter the catalytic activities of these proteins; and (3) the concentrations of small molecules (e.g., Ca 2+ , ATP, and glutathione) that serve as cofactors for certain of these proteins. One additional determinant of LT biosynthesis that has been recognized is the intracellular compartmentalization of these LT-forming proteins. This topic has become a focus of investigation in our own and other laboratories, and this article reviews the current state of knowledge in this area. Indeed, a number of unexpected findings that have emerged from these studies underscore the appropriateness of a perspective on LT biology that transcends conventional notions.
Emerging Viral Diseases: Confronting Threats with New Technologies
Authors: Hilary D. Marston, Gregory K. Folkers, David M. Morens, Anthony S. Fauci
Journal: Science Translational Medicine (2014)

Emerging viral diseases pose ongoing health threats, particularly in an era of globalization; however, new biomedical research technologies such as genome sequencing and structure-based vaccine and drug design have improved our ability to respond to viral threats.
Ontogeny, distribution, and possible functional implications of an unusual aquaporin, AQP8, in mouse liver
Authors: Domenico Ferri, Amelia Mazzone, Giuseppa Esterina Liquori, Grazia Cassano, Maria Svelto, Giuseppe Calamita
Journal: Hepatology (2003)

Aquaporins are channel proteins widely expressed in nature and known to facilitate the rapid movement of water across numerous cell membranes. A mammalian aquaporin, AQP8, was recently discovered and found to have a very distinct evolutionary pathway. To understand the reason for this divergence, here we define the ontogeny and exact subcellular localization of AQP8 in mouse liver, a representative organ transporting large volumes of water for secretion of bile. Northern blotting showed strong AQP8 expression between fetal day 17 and birth as well as at weaning and thereafter. Interestingly, this pattern was confirmed by immunohistochemistry and coincided both temporally and spatially with that of hepatic glycogen accumulation. As seen by reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, fasting was accompanied by remarkable down-regulation of hepatic AQP8 that paralleled the expected depletion of glycogen content. The level of hepatic AQP8 returned to be considerable after refeeding. Immunoelectron microscopy confirmed AQP8 in hepatocytes where labeling was over smooth endoplasmic reticulum (SER) membranes adjacent to glycogen granules and in canalicular membranes, subapical vesicles, and some mitochondria. In conclusion, in addition to supporting a role for AQP8 in canalicular water secretion, these findings also suggest an intracellular involvement of AQP8 in preserving cytoplasmic osmolality during glycogen metabolism and in maintaining mitochondrial volume. AQP8 may have evolved separately to feature these intracellular roles as no other known aquaporin shows this specialization. (Hepatology 2003;38:947–957).
Inhibition of the Spontaneous Rate of Contraction of Neonatal Cardiac Myocytes by Protein Kinase C Isozymes
Authors: John A. Johnson, Daria Mochly-Rosen
Journal: Circulation Research (1995)

Abstract Protein kinase C (PKC) enzymes regulate numerous cardiac functions. In the present study, we determined the effects of the PKC-activating drug 4-β phorbol 12-myristate 13-acetate (4-β PMA) on the rate of contraction and correlated these changes with the distribution and levels of α-, β-, δ-, ε-, and ζ-PKC isozymes by using neonatal rat cardiac myocytes in culture. Treatment with 0.3 to 100 nmol/L 4-β PMA caused negative chronotropic effects on contraction. This effect was maximal at a concentration of 3 nmol/L 4-β PMA and correlated with redistribution of the α- and ε-PKC isozymes from the cytosolic to the particulate cell fraction. After a 1-hour treatment with 100 nmol/L PMA, the α- and β-PKC isozymes and an 80-kD ζ-like PKC isozyme were greatly diminished (downregulated), yet the negative chronotropic effect was sustained. Therefore, our results are most consistent with a role for the ε-PKC isozyme in suppressing the contraction rate of neonatal rat cardiac myocytes. Understanding the role(s) of individual PKC isozymes in the modulation of cardiac functions may ultimately yield more selective targets for therapies of cardiac disorders.
The Patient With Syncope
Authors: R. Joe Noble
Journal: JAMA (1977)

SYNCOPE, which is a sudden transient loss of consciousness, results from an impairment in cerebral metabolism, which is the consequence of a brief deprivation in essential energy substrates, specifically oxygen and glucose. This deprivation in energy substrates may originate from one of only four levels (Fig 1): (1) from decrease or loss of intrinsic cerebral circulation, (2) from the heart, as a result of a transient decrease in cardiac output, (3) from a decrease in systemic arterial pressure to values inadequate to perfuse the brain, or (4) from insufficient energy substrates contained in the blood delivered to the brain. After reviewing the physiological mechanisms of syncope involved at each of these levels of potential abnormality, this article will attempt to simplify and organize the diagnostic approach to syncope into a conveniently manageable scheme. <h3>PHYSIOLOGICAL MECHANISM Obstruction to Cerebral Blood Flow</h3> At this level, the mechanism of the reduction in cerebral
Psychological and pharmacological interventions for social anxiety disorder in adults: a systematic review and network meta-analysis
Authors: Evan Mayo-Wilson, Sofia Dias, Ifigeneia Mavranezouli, Kayleigh Kew, David M Clark, A E Ades, Stephen Pilling
Journal: The Lancet Psychiatry (2014)

BackgroundSocial anxiety disorder—a chronic and naturally unremitting disease that causes substantial impairment—can be treated with pharmacological, psychological, and self-help interventions. We aimed to compare these interventions and to identify which are most effective for the acute treatment of social anxiety disorder in adults.MethodsWe did a systematic review and network meta-analysis of interventions for adults with social anxiety disorder, identified from published and unpublished sources between 1988 and Sept 13, 2013. We analysed interventions by class and individually. Outcomes were validated measures of social anxiety, reported as standardised mean differences (SMDs) compared with a waitlist reference. This study is registered with PROSPERO, number CRD42012003146.FindingsWe included 101 trials (13 164 participants) of 41 interventions or control conditions (17 classes) in the analyses. Classes of pharmacological interventions that had greater effects on outcomes compared with waitlist were monoamine oxidase inhibitors (SMD −1·01, 95% credible interval [CrI] −1·56 to −0·45), benzodiazepines (−0·96, −1·56 to −0·36), selective serotonin-reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors (SSRIs and SNRIs; −0·91, −1·23 to −0·60), and anticonvulsants (−0·81, −1·36 to −0·28). Compared with waitlist, efficacious classes of psychological interventions were individual cognitive–behavioural therapy (CBT; SMD −1·19, 95% CrI −1·56 to −0·81), group CBT (−0·92, −1·33 to −0·51), exposure and social skills (−0·86, −1·42 to −0·29), self-help with support (−0·86, −1·36 to −0·36), self-help without support (−0·75, −1·25 to −0·26), and psychodynamic psychotherapy (−0·62, −0·93 to −0·31). Individual CBT compared with psychological placebo (SMD −0·56, 95% CrI −1·00 to −0·11), and SSRIs and SNRIs compared with pill placebo (−0·44, −0·67 to −0·22) were the only classes of interventions that had greater effects on outcomes than appropriate placebo. Individual CBT also had a greater effect than psychodynamic psychotherapy (SMD −0·56, 95% CrI −1·03 to −0·11) and interpersonal psychotherapy, mindfulness, and supportive therapy (−0·82, −1·41 to −0·24).InterpretationIndividual CBT (which other studies have shown to have a lower risk of side-effects than pharmacotherapy) is associated with large effect sizes. Thus, it should be regarded as the best intervention for the initial treatment of social anxiety disorder. For individuals who decline psychological intervention, SSRIs show the most consistent evidence of benefit.FundingNational Institute for Health and Care Excellence.
Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema
Authors: Bruce L. Zuraw, Paula J. Busse, Martha White, Joshua Jacobs, William Lumry, James Baker, Timothy Craig, J. Andrew Grant, David Hurewitz, Leonard Bielory, William. E. Cartwright, Majed Koleilat, Walter Ryan, Oren Schaefer, Michael Manning, Pragnesh Patel, Jonathan A. Bernstein, Roger A. Friedman, Robert Wilkinson, David Tanner, Gary Kohler, Glenne Gunther, Robyn Levy, James McClellan, Joseph Redhead, David Guss, Eugene Heyman, Brent A. Blumenstein, Ira Kalfus, Michael M. Frank
Journal: New England Journal of Medicine (2010)

Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening.
Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome
Authors: None Choquet-Kastylevsky, None Intrator, None Chenal, None Bocquet, None Revuz, None Roujeau
Journal: British Journal of Dermatology (1998)

Hypersensitivity syndrome (HSS) usually refers to severe drug eruption associated with systemic symptoms and eosinophilia. Interleukin (IL)-5 regulates eosinophil counts with the help of IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Blood IL-5 levels have been reported to be increased in patients with eosinophilia secondary to parasitic infections or idiopathic eosinophilia, but have never been evaluated in drug-induced eosinophilia. The aim of our study was to determine whether IL-5, IL-3 and GM-CSF are involved in eosinophilia in patients with drug-induced HSS. Plasma levels of IL-3, IL-5 and GM-CSF were assayed by ELISA in seven patients with drug-induced HSS, in eight patients with cutaneous adverse drug reactions not associated with eosinophilia, and in five patients with eosinophilia unrelated to drug treatment. IL-5 levels were normal in all eight patients with drug eruptions without eosinophilia, and increased in five of the seven patients with HSS. In the latter patients, IL-5 levels peaked several days before highest eosinophil counts were noted, and returned to normal within a few days, even when eosinophilia persisted. In patients with eosinophilia unrelated to drug treatment, IL-5 levels, although significantly increased remained lower than in HSS patients. IL-3 and GM-CSF could not be detected in any group, at any time. Our results show that IL-5 is involved in drug-related eosinophilia. As IL-5 production was only involved in the early stages of the reaction, it is suggested that IL-5 mainly derives from activated lymphocytes rather than eosinophils. Our results support the clinical relevance of previous in vitro findings. Further studies are needed to test whether assays of IL-5 production by lymphocytes of patients stimulated by the suspected drug and/or its metabolites, are useful in establishing causality in drug-induced reactions associated with eosinophilia.
STEATOSIS IN CHRONIC HEPATITIS C: WHY DOES IT REALLY MATTER?
Authors: T Asselah
Journal: Gut (2005)

Hepatic steatosis is a common histological feature of chronic hepatitis C. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, diabetes type II, and hyperlipidaemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In humans, hepatitis C virus (HCV) genotype 3 is more commonly associated with steatosis. In vitro studies and the transgenic mouse model have suggested that the HCV core protein (genotype 1) can induce lipid accumulation within hepatocytes. However, what is the relevance of steatosis in chronic hepatitis C? It seems that in certain populations, steatosis may be associated with fibrosis progression and this may be genotype specific. The mechanisms underlying this association are unknown; neither is it clear whether this holds true for all patients or only a subgroup. Indeed, after antiviral treatment, virus related steatosis disappears whereas the host associated steatosis remains unaffected. This review describes and discusses the basic and clinical aspects of the relationship between steatosis and progression of fibrosis, and response to treatment in patients with chronic hepatitis C.
Genetic anticipation in Behcet's syndrome
Authors: I Fresko, M Soy, V Hamuryudan, S Yurdakul, Z Tumer, H Yazici
Journal: Annals of the Rheumatic Diseases (1998)

To examine the presence of genetic anticipation in families with Behçet's syndrome (BS).A total of 18 families with 40 affected members in two successive generations were evaluated by interviewing them for their ages at the onset of the first symptom of BS and for their ages at the time they fulfilled the diagnostic criteria.It was noted that the age of onset of the first symptom was lower in the second generation in 14 families (p = 0.01) with a mean (SD) age of 20.57 (7.47) years in the children compared with 33.29 (9.92) years in the parents (t = 7.79, p < 0.0001), whereas the diagnostic criteria were fulfilled at an earlier age in the children in 15 families (p = 0.01) with a mean age of 21.2 (6.74) years in the children compared with 36.4 (9.55) years in the parents (t = 7.41, p < 0.0001).Genetic anticipation was present in 15 of 18 (84%) of the families with BS in the form of earlier disease onset in the children compared with their parents.
The psychological factor ‘self-blame’ predicts overuse injury among top-level Swedish track and field athletes: a 12-month cohort study
Authors: Toomas Timpka, Jenny Jacobsson, Örjan Dahlström, Jan Kowalski, Victor Bargoria, Joakim Ekberg, Sverker Nilsson, Per Renström
Journal: British Journal of Sports Medicine (2015)

Background Athletes’ psychological characteristics are important for understanding sports injury mechanisms. We examined the relevance of psychological factors in an integrated model of overuse injury risk in athletics/track and field. Methods Swedish track and field athletes (n=278) entering a 12-month injury surveillance in March 2009 were also invited to complete a psychological survey. Simple Cox proportional hazards models were compiled for single explanatory variables. We also tested multiple models for 3 explanatory variable groupings: an epidemiological model without psychological variables, a psychological model excluding epidemiological variables and an integrated (combined) model. Results The integrated multiple model included the maladaptive coping behaviour self-blame (p=0.007; HR 1.32; 95% CI 1.08 to 1.61), and an interaction between athlete category and injury history (p&lt;0.001). Youth female (p=0.034; HR 0.51; 95% CI 0.27 to 0.95) and youth male (p=0.047; HR 0.49; 95% CI 0.24 to 0.99) athletes with no severe injury the previous year were at half the risk of sustaining a new injury compared with the reference group. A training load index entered the epidemiological multiple model, but not the integrated model. Conclusions The coping behaviour self-blame replaced training load in an integrated explanatory model of overuse injury risk in athletes. What seemed to be more strongly related to the likelihood of overuse injury was not the athletics load per se, but, rather, the load applied in situations when the athlete's body was in need of rest.
Oral cholera vaccine protects against endemic disease, real life trial shows:
Authors: Susan Mayor
Journal: BMJ (2015)

An oral cholera vaccine given as part of routine healthcare protects against severe cholera in children and adults in urban Bangladesh, where the disease is endemic, a real life trial of the vaccine has shown.1

The open label study, reported in the Lancet and funded by the Bill and Melinda Gates Foundation, included almost 270 000 people aged 1 and over living in the urban slums of Mirpur in Dhaka, Bangladesh. Researchers randomly assigned 90 geographical clusters of people to three groups: vaccination with a killed whole cell oral cholera vaccine (Shanchol); vaccination and behaviour change promoting handwashing …