tbuckley/cabot-search huggingface dataset:
Statin Therapy and Risk of Developing Type 2 Diabetes: A Meta-Analysis
Authors: Swapnil N. Rajpathak, Dharam J. Kumbhani, Jill Crandall, Nir Barzilai, Michael Alderman, Paul M. Ridker
Journal: Diabetes Care (2009)

Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I(2) statistic.In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03-1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93-1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I(2) = 57.7%).Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.
Targeted Deletion of Nuclear Factor κB p50 Enhances Cardiac Remodeling and Dysfunction Following Myocardial Infarction
Authors: Leo Timmers, J. Karlijn van Keulen, Imo E. Hoefer, Matthijs F.L. Meijs, Ben van Middelaar, Krista den Ouden, Cees J.A. van Echteld, Gerard Pasterkamp, Dominique P.V. de Kleijn
Journal: Circulation Research (2009)

Myocardial infarction is commonly complicated by left ventricular remodeling, a process that leads to cardiac dilatation, congestive heart failure and death. The innate immune system plays a pivotal role in the remodeling process via nuclear factor (NF)-kappaB activation. The NF-kappaB transcription factor family includes several subunits (p50, p52, p65, c-Rel, and Rel B) that respond to myocardial ischemia. The function of NF-kappaB p50, however, is controversial in this process. To clarify the role of NF-kappaB p50 in postinfarct left ventricular remodeling, myocardial infarction was induced in wild-type 129Bl6 mice and NF-kappaB p50-deficient mice. Without affecting infarct size, deletion of NF-kappaB p50 markedly increased the extent of expansive remodeling (end-diastolic volume: 176+/-13 microL versus 107+/-11 microL; P=0.003) and aggravated systolic dysfunction (left ventricular ejection fraction: 16.1+/-1.5% versus 24.7+/-3.7%; P=0.029) in a 28-day time period. Interstitial fibrosis and hypertrophy in the noninfarcted myocardium was increased in NF-kappaB p50 knockout mice. In the infarct area, a lower collagen density was observed, which was accompanied by an increased number of macrophages, higher gelatinase activity and increased inflammatory cytokine expression. In conclusion, targeted deletion of NF-kappaB p50 results in enhanced cardiac remodeling and functional deterioration following myocardial infarction by increasing matrix remodeling and inflammation.
Phenotypic and Functional Analysis of Cd8+ T Cells Undergoing Peripheral Deletion in Response to Cross-Presentation of Self-Antigen
Authors: Javier Hernandez, Sandra Aung, William L. Redmond, Linda A. Sherman
Journal: The Journal of Experimental Medicine (2001)

Not all T cells specific for autoantigens are eliminated in the thymus, and therefore alternate mechanisms are required to prevent potentially autoreactive T cells from developing into effectors. Adoptive transfer of CD8+ T cells from influenza hemagglutinin-specific Clone 4 TCR transgenic mice into mice that express hemagluttinin in the pancreatic islets results in tolerance. This is preceded by activation of Clone 4 T cells that encounter antigen cross-presented in the draining lymph nodes of the pancreas. In this report we compare the phenotype, function, and costimulatory requirements of Clone 4 T cells activated by endogenous self-antigen, with Clone 4 T cells stimulated by influenza virus. The cells undergoing tolerance upregulate both CD69 and CD44, yet only partially downregulate CD62L, and do not express CD49d or CD25. Most importantly, they lack the ability to produce interferon-γ in response to antigen and show no cytolytic activity. Clone 4 T cells disappear after several cycles of division, apparently without leaving the site of initial activation. Surprisingly, despite the fact that such stimulation occurs through recognition of antigen that is cross-presented by a professional antigen-presenting cell, we find this activation is not dependent on costimulation through CD28. These data demonstrate that the recognition by naive CD8+ T cells of cross-presented self-antigen results in localized proliferation and deletion, without the production of effector cells.
The HSPGs Syndecan and Dallylike Bind the Receptor Phosphatase LAR and Exert Distinct Effects on Synaptic Development
Authors: Karl G. Johnson, Alan P. Tenney, Aurnab Ghose, April M. Duckworth, Misao E. Higashi, Karen Parfitt, Oana Marcu, Timothy R. Heslip, J. Lawrence Marsh, Thomas L. Schwarz, John G. Flanagan, David Van Vactor
Journal: Neuron (2006)
Bosentan Therapy in Patients With Eisenmenger Syndrome
Authors: Nazzareno Galiè, Maurice Beghetti, Michael A. Gatzoulis, John Granton, Rolf M.F. Berger, Andrea Lauer, Eleonora Chiossi, Michael Landzberg
Journal: Circulation (2006)

Background— Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia. Methods and Results— The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, −0.7 to 2.8), demonstrating that bosentan did not worsen oxygen saturation. Compared with placebo, bosentan reduced pulmonary vascular resistance index (−472.0 dyne · s · cm −5 ; P =0.0383). The mean pulmonary arterial pressure decreased (−5.5 mm Hg; P =0.0363), and the exercise capacity increased (53.1 m; P =0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the bosentan group and 2 (12%) in the placebo group. Conclusions— In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.
Genetic Variation in Vascular Endothelial Growth Factor-A and Lung Function
Authors: Angela Simpson, Adnan Custovic, Robert Tepper, Penelope Graves, Debra A. Stern, Marcus Jones, Jenny Hankinson, John A. Curtin, Jiakai Wu, Mario Blekic, Blazenka Kljaic Bukvic, Neda Aberle, Susana Marinho, Danielle Belgrave, Wayne J. Morgan, Fernando D. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function.The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood.Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A(165b)/panVEGF-A(165) among homozygotes.In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow(50), and forced expiratory flow(25-75) compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV(1)/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A(165b)/panVEGF-A(165) was significantly higher among CC versus GG homozygotes (P ≤ 0.02) at birth, in school-age children, and in adults.We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A(165), which may be determined by alternative splicing.
Mild renal insufficiency is associated with increased left ventricular mass in men, but not in women: An arterial stiffness-related phenomenon—The Hoorn Study
Authors: Ronald M.A. Henry, Otto Kamp, Piet J. Kostense, Annemieke M.W. Spijkerman, Jacqueline M. Dekker, Giel Nijpels, Robert J. Heine, Lex M. Bouter, Coen D.A. Stehouwer
Journal: Kidney International (2005)
Magnetic, fluorescent, and thermo-responsive Fe3O4/rare earth incorporated poly(St-NIPAM) core–shell colloidal nanoparticles in multimodal optical/magnetic resonance imaging probes
Authors: Haie Zhu, Juan Tao, Wenhao Wang, Yingjie Zhou, Penghui Li, Zheng Li, Kai Yan, Shuilin Wu, Kelvin W.K. Yeung, Zushun Xu, Haibo Xu, Paul K. Chu
Journal: Biomaterials (2012)
Delineation of Prevalence and Risk Factors for Early Coronary Artery Disease by Electron Beam Computed Tomography in Young Adults With Type 1 Diabetes
Authors: Harold S. Starkman, Gregory Cable, Virginia Hala, Harvey Hecht, Christine M. Donnelly
Journal: Diabetes Care (2003)

Type 1 diabetes increases the risk for coronary artery disease (CAD), but limited information is available regarding the early natural history of this process. Electron beam tomography (EBT) can measure coronary artery calcification (CAC), an early marker for CAD. This study was designed to assess the prevalence and risk factors for CAC in young adults with established type 1 diabetes.A total of 101 subjects aged 17-28 years with type 1 diabetes of over 5 years' duration and no history of heart disease underwent cardiac EBT with calcium scoring. Medical histories were obtained and physical examinations were conducted to document the presence of cardiac risk factors as well as evidence of microvasculopathy and diabetic arthropathy. Laboratory evaluation included measurement of fasting lipoproteins, homocysteine concentration, lipoprotein(a) [Lp(a)], urinary microalbumin, and HbA(1c). Contingency table analysis was used to assess bivariate relationships. Logistic regression was employed to construct a parsimonious model of independent risk factors.Eleven subjects (10.9%) had CAC. Smokers were nearly five times more likely than nonsmokers to have CAC (P = 0.03). In addition, each 0.36-mm/l increment of Lp(a) was associated with a 10% increased risk for CAC (P = 0.05) after controlling for potentially confounding factors. There was no association of other CAD or diabetes risk factors studied with CAC.The prevalence of early CAD as evidenced by CAC in young adults with type 1 diabetes is significant. Smoking and Lp(a) levels independently predict the presence of CAC. Additional study is necessary to delineate the natural history of CAC and the role of risk factor modification to prevent progression of CAD in this high-risk population.
Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists
Authors: H J van der Woude
Journal: Thorax (2001)

In vitro the long acting beta2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other beta2 agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting beta2 agonists.A randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV1 of 20% or more (PC(20)) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 microg twice daily by Turbuhaler), salmeterol (100 microg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 microg) was administered immediately thereafter, followed by ipratropium bromide (40 microg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation.There was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV1 of > or = 30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p<0.0003 for both). Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV1 after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV1 had returned to baseline values in all three treatment groups.Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vivo. Irrespective of this, prior long term treatment with both long acting beta2 agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting beta2 agonists should be made aware that an additional single dose of a short acting beta2 agonist may become less effective.
The Relationship Between Asthma Control, Impact Of Co-morbid Rhinitis And Health Related Quality Of Life: A Real Life Study.
Authors: F. Braido, I. Baiardini, S. Balestracci, V. Ghiglione, E. Stagi, E. Ridolo, R. Nathan, G.W. Canonica
Journal: Journal of Allergy and Clinical Immunology (2009)
An 86-Year-Old Woman With Cardiac Cachexia Contemplating the End of Her Life
Authors: Jean S. Kutner
Journal: JAMA (2010)

Mrs H is an 86-year-old woman with progressive congestive heart failure and multiple chronic conditions who is experiencing worsening function and quality of life despite maximum medical therapies. She seeks advice regarding control over the circumstances of the end of her life, be it by suicide or under hospice care. Typical of US populations older than 65 years with multiple chronic health conditions and functional decline who are facing the end of life, Mrs H's concerns are particularly about quality of life, not being a burden on loved ones, and maintaining control. As she demonstrates, psychological, existential, and social factors, particularly fear of being a burden, are more common reasons for desiring hastened death than those related directly to physical symptoms. Hospice, which provides a multidisciplinary approach to care at the end of life, can assist Mrs H and her family in making decisions that are consistent with her goals.
Upper Endoscopy for Gastroesophageal Reflux Disease: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians
Authors: Nicholas J. Shaheen, David S. Weinberg, Thomas D. Denberg, Roger Chou, Amir Qaseem, Paul Shekelle
Journal: Annals of Internal Medicine (2012)

Also available: Consumer Reports Patient Resource on High-Value Care for GERD Background: Upper endoscopy is commonly used in the diagnosis and management of gastroesophageal reflux disease (GERD). Evidence demonstrates that it is indicated only in certain situations, and inappropriate use generates unnecessary costs and exposes patients to harms without improving outcomes. Methods: The Clinical Guidelines Committee of the American College of Physicians reviewed evidence regarding the indications for, and yield of, upper endoscopy in the setting of GERD, and to highlight how clinicians can increase the delivery of high-value health care. Best Practice Advice 1: Upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting). Best Practice Advice 2: Upper endoscopy is indicated in men and women with: Typical GERD symptoms that persist despite a therapeutic trial of 4 to 8 weeks of twice-daily proton-pump inhibitor therapy. Severe erosive esophagitis after a 2-month course of proton-pump inhibitor therapy to assess healing and rule out Barrett esophagus. Recurrent endoscopy after this follow-up examination is not indicated in the absence of Barrett esophagus. History of esophageal stricture who have recurrent symptoms of dysphagia. Best Practice Advice 3: Upper endoscopy may be indicated: In men older than 50 years with chronic GERD symptoms (symptoms for more than 5 years) and additional risk factors (nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intra-abdominal distribution of fat) to detect esophageal adenocarcinoma and Barrett esophagus. For surveillance evaluation in men and women with a history of Barrett esophagus. In men and women with Barrett esophagus and no dysplasia, surveillance examinations should occur at intervals no more frequently than 3 to 5 years. More frequent intervals are indicated in patients with Barrett esophagus and dysplasia.
Inhibition of Nuclear Translocation of Nuclear Factor-κB Despite Lack of Functional IκBα Protein Overcomes Multiple Defects in Apoptosis Signaling in Human B-Cell Malignancies
Authors: Roman K. Thomas, Martin L. Sos, Thomas Zander, Özlem Mani, Alexey Popov, Daniel Berenbrinker, Sigrun Smola-Hess, Joachim L. Schultze, Jürgen Wolf
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Defective apoptosis signaling is a typical feature of classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. In these malignancies, the transcription factor nuclear factor-κB (NF-κB) is a critical mediator of apoptosis resistance and oncogenic growth, making it an attractive therapeutic target. Here, we sought to determine how to overcome apoptosis resistance experimentally in these malignancies by targeting NF-κB. Experimental Design: We investigated the effect of different inhibitors of NF-κB on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively. Results: The cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2, a known inhibitor of NF-κB, induced caspase-dependent apoptosis; it restored mitochondrial apoptotic signaling by down-regulation of X-linked inhibitor of apoptosis protein and heat shock protein 27 and led to breakdown of the mitochondrial membrane potential and, finally, cleavage of caspase-3 irrespective of IκBα mutational status. Surprisingly, 15-deoxy-Δ12,14-prostaglandin J2 and the IκB kinase inhibitor curcumin both reduced nuclear levels of p65 in cell lines lacking IκBα, suggesting that inhibition of nuclear translocation of NF-κB can occur in the absence of IκBα. Finally, a synthetic peptide that specifically abrogates the assembly of the IκB kinase complex killed IκBα-defective cells by induction of apoptosis, paralleled by reduction of nuclear NF-κB. Conclusions: These results show that molecular defects in apoptotic signaling, such as IκBα mutations, can be circumvented by targeting NF-κB through inhibition of the IκB kinase complex followed by induction of apoptosis in classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. Thus, targeting IκB kinases may represent an attractive therapeutic approach against these malignancies regardless of the mutational status of IκBα.