tbuckley/cabot-search huggingface dataset:
Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury
Authors: Jürgen Borlak, Bijon Chatterji, Kishor B Londhe, Paul B Watkins
Journal: Genome Medicine (2013)

Abstract Background Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI). Methods Healthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays. Results One-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs labeled as no- (n = 8), low- (n = 45) or most-DILI-concern (n = 39) confirmed regulation of the identified biomarkers to demonstrate utility in predicting risk for liver injury. Conclusions The significant regulation of acute phase reactants points to an important link between AILI and the immune system. Monitoring of serum acute phase reactants prior to drug treatment may contribute to prevention and management of AILI, and may also be of utility for other drugs with known liver liabilities.
Phagocytic potential of pulmonary alveolar epithelium with particular reference to surfactant metabolism
Authors: B. Corrin
Journal: Thorax (1970)

Finely divided thorium and carbon were injected into the rat lung via the trachea and their uptake was studied electron microscopically. Small amounts of thorium were found in the lamellar vacuoles of the granular pneumocytes. Their presence was maximal at 24 hours and they later disappeared from these cells. This phenomenon is thought to represent a passive inflow as the vacuoles open on to the alveolar surface to discharge their content of surfactant, rather than evidence that the granular pneumocyte is concerned in surfactant disposal. An explanation reconciling the secretory nature of the vacuoles with their previously demonstrated content of lysosomal enzymes is advanced. Small quantities of thorium dioxide were ingested by the squamous pneumocytes and a little transferred to interstitial macrophages, but this is a minor route of disposal, the bulk of the material being ingested by alveolar macrophages. The limited phagocytic potential of the alveolar epithelium contrasts with that of the alveolar macrophages and is not taken to support the concept of an epithelial derivation of alveolar macrophages.
Effects of inspiratory muscle training on respiratory function and repetitive sprint performance in wheelchair basketball players
Authors: V Goosey-Tolfrey, E Foden, C Perret, H Degens
Journal: British Journal of Sports Medicine (2008)

There is considerable evidence that respiratory muscle training improves pulmonary function, quality of life and exercise performance in healthy athletic populations. The benefits for wheelchair athletes are less well understood. Therefore, in the present study, influence of inspiratory muscle training (IMT) on respiratory function and repetitive propulsive sprint performance in wheelchair basketball players was examined.Using a placebo-controlled design, 16 wheelchair athletes were divided to an experimental (IMT; n=8) or placebo (sham-IMT; n=8) group based on selective grouping criteria. 30 dynamic breaths were performed by the IMT group twice daily at a resistance equivalent to 50% maximum inspiratory pressure (MIP), and 60 slow breaths were performed by the sham-IMT group once a day at 15% MIP for a period of 6 weeks.In the IMT group, both MIP and maximum expiratory pressure (17% and 23%, respectively; p< or =0.03) were improved. Similar improvements were noted for the sham-IMT group with 23% and 33% from baseline for MIP and maximum expiratory pressure, respectively (p< or =0.03). There were no significant changes in pulmonary function at rest and any of the performance parameters associated with the repetitive sprint test (sprint and recovery times, peak heart rate and peak blood lactate concentration). Reported experiences of using the IMT training device suggested "less breathlessness" and "less tightness in the chest during the training".Although there was no improvement in sprint performance, an improved respiratory muscle function and quality of life were reported by participants in both the IMT and sham-IMT groups.
WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity
Authors: Shirly Becker-Herman, Almut Meyer-Bahlburg, Marc A. Schwartz, Shaun W. Jackson, Kelly L. Hudkins, Chaohong Liu, Blythe D. Sather, Socheath Khim, Denny Liggitt, Wenxia Song, Gregg J. Silverman, Charles E. Alpers, David J. Rawlings
Journal: The Journal of Experimental Medicine (2011)

Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of the WAS gene results in B cells that are hyperresponsive to B cell receptor and Toll-like receptor (TLR) signals in vitro, thereby promoting a B cell–intrinsic break in tolerance. Whereas this defect leads to autoantibody production in WAS protein–deficient (WASp−/−) mice without overt disease, chimeric mice in which only the B cell lineage lacks WASp exhibit severe autoimmunity characterized by spontaneous germinal center formation, class-switched autoantibodies, renal histopathology, and early mortality. Both T cell help and B cell–intrinsic TLR engagement play important roles in promoting disease in this model, as depletion with anti-CD4 antibodies or generation of chimeric mice with B cells deficient in both WASp and MyD88 prevented development of autoimmune disease. These data highlight the potentially harmful role for cell-intrinsic loss of B cell tolerance in the setting of normal T cell function, and may explain why WAS patients with mixed chimerism after stem cell transplantation often develop severe humoral autoimmunity.
Effects of training period on haemorheological variables in regularly trained footballers
Authors: Y Karakoc, H Duzova, A Polat, M H Emre, I Arabaci
Journal: British Journal of Sports Medicine (2005)

Objective: To investigate the effects of one football training period on haemorheological variables in regularly trained footballers. Method: Ten subjects were randomly selected from the reserve team of a football club in the Turkish Premier League. During the last week of the football season, one day before a standard training session and two days after the previous league match, venous blood samples were taken (pre-exercise). After 90 minutes of standard training, further blood samples were taken (post-exercise). Blood lactate, blood viscosity, plasma fibrinogen, blood clotting time, acid-base variables, and plasma Na + , K + , and Ca 2+ were determined. Results: Haemoglobin, packed cell volume, and mean corpuscular volume were all significantly decreased, whereas white blood cells and platelets were both increased after training. Blood viscosity decreased but the reduction was not significant. Blood lactate, plasma glucose, and Na + content were significantly increased, but standard bicarbonate, actual bicarbonate, and Ca 2+ were significantly decreased. Blood clotting time had shortened significantly after training. Blood viscosity was inversely correlated with plasma glucose concentration ( r = −0.48 and p = 0.032). Conclusions: The results show that blood viscosity tends to decrease as the result of this type of training. This is due to a reduction in packed cell volume and mean corpuscular volume. The increased blood lactate does not have an adverse effect on the blood viscosity of these subjects because protective mechanisms develop with regular training throughout the season.
Novel findings of Langerhans cells and interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis
Authors: E. Hagforsen, H. Hedstrand, F. Nyberg, G. Michaëlsson
Journal: British Journal of Dermatology (2010)

Journal Article Novel findings of Langerhans cells and interleukin‐17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis Get access E. Hagforsen, E. Hagforsen Department of Medical Sciences, University of Uppsala, SE‐751 85 Uppsala, Sweden Eva Hagforsen. E‐mail:eva.hagforsen@medsci.uu.se Search for other works by this author on: Oxford Academic Google Scholar H. Hedstrand, H. Hedstrand Department of Medical Sciences, University of Uppsala, SE‐751 85 Uppsala, Sweden Search for other works by this author on: Oxford Academic Google Scholar F. Nyberg, F. Nyberg Department of Dermatology, University of Uppsala, Uppsala, SwedenInstitution for Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden Search for other works by this author on: Oxford Academic Google Scholar G. Michaëlsson G. Michaëlsson Department of Medical Sciences, University of Uppsala, SE‐751 85 Uppsala, Sweden Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 163, Issue 3, 1 September 2010, Pages 572–579, https://doi.org/10.1111/j.1365-2133.2010.09819.x Published: 01 September 2010
Bronchial obstruction due to respiratory mucosal sloughing in toxic epidermal necrolysis.
Authors: A Dasgupta, J O'Malley, R Mallya, J G Williams
Journal: Thorax (1994)

A 17 year old woman is described who nearly asphyxiated because of sloughing of the bronchial mucosa as a result of toxic epidermal necrolysis. Bronchoscopic aspiration of bronchial slough proved life saving.
Involvement of Lat, Gads, and Grb2 in Compartmentation of Slp-76 to the Plasma Membrane
Authors: Masamichi Ishiai, Mari Kurosaki, Kazunori Inabe, Andrew C. Chan, Kazuo Sugamura, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2000)

B cell linker protein (BLNK) and Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76) are adaptor proteins required for B cell receptor (BCR) and T cell receptor function, respectively. Here, we show that expression of SLP-76 cannot reconstitute BCR function in Zap-70+BLNK− B cells. This could be attributable to inability of SLP-76 to be recruited into glycolipid-enriched microdomains (GEMs) after antigen receptor cross-linking. Supporting this idea, the BCR function was restored when a membrane-associated SLP-76 chimera was enforcedly localized to GEMs. Moreover, we demonstrate that addition of both linker for activation of T cells (LAT) and Grb2-related adaptor downstream of Shc (Gads) to SLP-76 allow SLP-76 to be recruited into GEMs, whereby the BCR function is reconstituted. The Gads function was able to be replaced by overexpression of Grb2. In contrast to SLP-76, BLNK did not require Grb2 families for its recruitment to GEMs. Hence, these data suggest a functional overlap between BLNK and SLP-76, while emphasizing the difference in requirement for additional adaptor molecules in their targeting to GEMs.
An intensive lifestyle intervention increased remission from type 2 diabetes in overweight adults
Authors: Ma P. Kyithar, Sean F. Dinneen
Journal: Annals of Internal Medicine (2013)

Source Citation Gregg EW, Chen H, Wagenknecht LE, et al; Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012;308:2489-96. 23288372
Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium
Authors: Christophe Depre, Song-Jung Kim, Anna S. John, Yanhong Huang, Ornella E. Rimoldi, John R. Pepper, Gilles D. Dreyfus, Vinciane Gaussin, Dudley J. Pennell, Dorothy E. Vatner, Paolo G. Camici, Stephen F. Vatner
Journal: Circulation Research (2004)

Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death. Accordingly, we measured the expression of survival genes in hibernating myocardium, both in patients surgically treated for hibernation and in a chronic swine model of repetitive ischemia reproducing the features of hibernation. Human hibernating myocardium was characterized by an upregulation of genes and corresponding proteins involved in anti-apoptosis (IAP), growth (VEGF, H11 kinase), and cytoprotection (HSP70, HIF-1α, GLUT1). In the swine model, the same genes and proteins were upregulated after repetitive ischemia, which was accompanied by a concomitant decrease in myocyte apoptosis. These changes characterize viable tissue, because they were not found in irreversibly injured myocardium. Our report demonstrates a novel mechanism by which the activation of an endogenous gene program of cell survival underlies the sustained viability of the hibernating heart. Potentially, promoting such a program offers a novel opportunity to salvage postmitotic tissues in conditions of ischemia.
A Simplified Approach to Meningococcal Disease Prophylaxis
Authors: Jay A. Jacobson
Journal: JAMA (1976)

ALTHOUGH meningococcal disease is presently uncommon in the United States, the suddenness and severity with which it strikes and its epidemic potential frequently produce considerable anxiety in patient contacts. This may lead concerned physicians to take measures that are inappropriate or unnecessary. A recent editorial<sup>1</sup>defines in detail the type of contact associated with increased risk and reviews the prophylactic measures appropriate for reducing this risk. However, a study by the Meningococcal Disease Surveillance Group<sup>2</sup>indicates that physicians often do not administer antimicrobial prophylaxis to persons at increased risk and do administer prophylaxis to persons not shown to be at risk. The same study showed that when physicians give antibiotics, they often select ineffective ones. Additionally, it showed that considerable time and money are spent doing useless culture surveys of contacts. Because of this evident confusion about who would benefit from meningococcal prophylaxis, about what agents should be
Akt1 in the cardiovascular system: friend or foe?
Authors: B. T. O'Neill
Journal: Journal of Clinical Investigation (2005)

Akt is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. Akt activation has been proposed as a potential strategy for increasing cardiomyocyte survival following ischemia. In mammalian cells, 3 distinct isoforms of Akt exist, but their precise roles in cardiovascular biology were previously unknown. Three separate studies published in this issue of the JCI now provide important new insight into the central role of Akt1 in the regulation of angiogenesis and the maladaptive or deleterious consequences of chronic unregulated Akt activation in the heart (see the related articles beginning on pages 2108, 2119, and 2128). Here we discuss the implications of these exciting new studies.
Oral antiviral therapy for HBeAg negative chronic hepatitis B: better stop or continue?
Authors: Pietro Lampertico
Journal: Gut (2014)

Treatment cessation is one of the few challenges left to clinicians to deal with after the marketing and widespread use of third generation oral analogues (nucleos(t)ide analogue (NUC)), entecavir (ETV) and tenofovir (TDF) for the treatment of HBeAg negative chronic hepatitis B (CHB). Treatment efficacy is in fact unquestioned as more than 95% of patients, including NUC experienced and resistant ones, achieve complete suppression of viral replication and improvement of hepatic inflammation and fibrosis within the first 5 years of treatment.1–3 As a consequence, in a majority of patients, progression to cirrhosis is prevented, and clinical decompensation and portal hypertension either improved or prevented, with hepatocellular carcinoma (HCC) remaining the only complication in HBeAg negative patients long-term treated for with ETV or TDF.4 Indeed, the yearly attack rates of HCC range between 0.5% and 1% among non-cirrhotics and 2.5% and 4% among compensated cirrhotics, incidence rates not very different from what is expected in untreated patients.4 ,5 In these patients, the recommended stopping rule of NUC therapy is HBsAg seroconversion, defined as HBsAg loss and anti-HBs titres >100–200 IU/L,6–8 which has been proven to be safe in any clinical situation including patients with advanced liver disease, though a minority of patient clearing HBsAg following NUC therapy do not seroconvert to anti-HBs.9 ,10

One major caveat of this stopping rule is the small number of HBeAg negative patients who achieve HBsAg seroconversion, no more than 1% after 5 years and 5% after 10 years of continuous treatment, thereby questioning whether it is appropriate to stop NUC therapy before achieving HBsAg seronegativity. Asian Pacific Association for the Study of the Liver (APASL) guidelines indeed suggest this, but so far clinical evidence supporting these recommendations is more than scanty.

In the study by Seto et al ,11 treatment cessation …
GRADE: an emerging consensus on rating quality of evidence and strength of recommendations
Authors: Gordon H Guyatt, Andrew D Oxman, Gunn E Vist, Regina Kunz, Yngve Falck-Ytter, Pablo Alonso-Coello, Holger J Schünemann
Journal: BMJ (2008)

Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide
Poly(ADP-Ribose) Polymerase Inhibition Reduces Reperfusion Injury After Heart Transplantation
Authors: Gábor Szabó, Susanne Bährle, Nicole Stumpf, Karin Sonnenberg, Éva Szabó, Pál Pacher, Tamás Csont, Richard Schulz, Thomas J. Dengler, Lucas Liaudet, Prakash G. Jagtap, Garry J. Southan, Christian F. Vahl, Siegfried Hagl, Csaba Szabó
Journal: Circulation Research (2002)

The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 ( N -(6-oxo-5,6-dihydro-phenanthridin-2-yl)- N , N -dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure–volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction.
Cost-Effectiveness of Cardioversion and Antiarrhythmic Therapy in Nonvalvular Atrial Fibrillation
Authors: Edward Catherwood
Journal: Annals of Internal Medicine (1999)

Background: Physicians managing patients with nonvalvular atrial fibrillation must consider the risks, benefits, and costs of treatments designed to restore and maintain sinus rhythm compared with those of rate control with antithrombotic prophylaxis. Objective: To compare the cost-effectiveness of cardioversion, with or without antiarrhythmic agents, with that of rate control plus warfarin or aspirin. Design: A Markov decision-analytic model was designed to simulate long-term health and economic outcomes. Data Sources: Published literature and hospital accounting information. Target Population: Hypothetical cohort of 70-year-old patients with different baseline risks for stroke. Time Horizon: 3 months. Perspective: Societal. Intervention: Therapeutic strategies using different combinations of cardioversion alone, cardioversion plus amiodarone or quinidine therapy, and rate control with antithrombotic treatment. Outcome Measures: Expected costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. Results of Base-Case Analysis: Strategies involving cardioversion alone were more effective and less costly than those not involving this option. For patients at high risk for ischemic stroke (5.3% per year), cardioversion alone followed by repeated cardioversion plus amiodarone therapy on relapse was most cost-effective ($9300 per QALY) compared with cardioversion alone followed by warfarin therapy on relapse. This strategy was also preferred for the moderate-risk cohort (3.6% per year), but the benefit was more expensive ($18 900 per QALY). In the lowest-risk cohort (1.6% per year), cardioversion alone followed by aspirin therapy on relapse was optimal. Results of Sensitivity Analysis: The choice of optimal strategy and incremental cost-effectiveness was substantially influenced by the baseline risk for stroke, rate of stroke in sinus rhythm, efficacy of warfarin, and costs and utilities for long-term warfarin and amiodarone therapy. Conclusions: Cardioversion alone should be the initial management strategy for persistent nonvalvular atrial fibrillation. On relapse of arrhythmia, repeated cardioversion plus low-dose amiodarone is cost-effective for patients at moderate to high risk for ischemic stroke.