tbuckley/cabot-search huggingface dataset:
Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials
Authors: Josef S Smolen, Daniel Aletaha, Johannes C Grisar, Tanja A Stamm, John T Sharp
Journal: Annals of the Rheumatic Diseases (2009)

Background Joint damage is an important outcome in trials of rheumatoid arthritis (RA), usually assessed by Total Sharp Score (TSS). It is currently unknown how it translates numerically into disability by the Health Assessment Questionnaire (HAQ). Objective To determine the units of HAQ score corresponding to one TSS unit. Methods A short-term observational trial of glucocorticoids in RA (the ‘BEst LIfe with Rheumatoid Arthritis’ (BELIRA) trial) was evaluated, using randomised controlled clinical trial (RCT) data for confirmation. For each trial arm HAQ, TSS and the Simplified Disease Activity Index (SDAI) were assessed. Based on the hypothesis that short-term HAQ changes will mostly be due to changes of disease activity, activity HAQ (ACT-HAQ) at end point (EP) was determined and remaining disability defined as damage related (DAM-HAQ). Using TSS at EP, the HAQ units corresponding to a TSS unit were estimated. Results In BELIRA, one TSS unit corresponded to a mean of 0.017 HAQ units; to account for other causes of irreversible disability, the 25th percentile was used: 0.011 HAQ units/TSS unit. In RCT trial arms, the HAQ/TSS were similar (0.013 and 0.015 in established and early RA, respectively; 25th percentile: 0.010). The correlation between DAM-HAQ EP and TSS was r=0.829. Over 5 years, damage would amount to an increase of irreversible HAQ of 0.33 on placebo, 0.13 on disease-modifying antirheumatic drugs (DMARDs) and 0.03 on TNF inhibitors+methotrexate (MTX). Conclusion An approach to estimate the numerical relationship between HAQ and damage as 0.01 HAQ points/TSS unit is presented, although the linear relationship may not be generally valid. This allows the assessment of functional correlates of radiographic changes in trials.
The Relative Importance of T Cell Subsets in Immunity and Immunopathology of Airborne <i>Mycobacterium tuberculosis</i> Infection in Mice
Authors: Tirsit Mogues, Mariam E. Goodrich, Lynn Ryan, Ronald LaCourse, Robert J. North
Journal: The Journal of Experimental Medicine (2001)

Wild-type (WT) and targeted-mutant mice incapable of making αβ T cells, γδ T cells, class I major histocompatibility complex (MHC), class II MHC, interferon (IFN)-γ, or inducible nitric oxide synthase (NOS2), were infected with Mycobacterium tuberculosis (Mtb) by aerosol, and monitored over time for their ability to (a) control infection, (b) develop histopathology at sites of infection, and (c) survive. WT mice acquired the ability to control and to hold infection at a stationary level from day 20 on. This was associated with the development of a macrophage-dominated alveolitis at sites of infection, with increased synthesis of IFN-γ and NOS2 mRNA, and with an median survival time (MST) of 258.5 d. In the absence of αβ T cells, Mtb grew progressively and rapidly to induce a necrotic, neutrophil-dominated lung pathology that killed mice with an MST of 48 d. In the absence of CD4-mediated immunity (class II−/− mice), progressive bacterial growth continued in the lungs and in other organs beyond day 20, resulting in an MST of 77 d. By contrast, in the absence of CD8 T cell–mediated immunity, lung infection was controlled at a 1 log higher stationary level that induced a similar histopathologic response to that of WT mice, and resulted in an MST of 232 d.
Intramural Delivery of Recombinant Apolipoprotein A-I <sub>Milano</sub> /Phospholipid Complex (ETC-216) Inhibits In-Stent Stenosis in Porcine Coronary Arteries
Authors: Sanjay Kaul, Vladimir Rukshin, Raul Santos, Babak Azarbal, Charles L. Bisgaier, Jan Johansson, Vivian T. Tsang, Kuang-Yuh Chyu, Bojan Cercek, James Mirocha, Prediman K. Shah
Journal: Circulation (2003)

We have previously demonstrated vasculoprotective effects after repeated intravenous administration of recombinant apolipoprotein A-IMilano (apoA-Im)/phospholipid complex. In this study, we sought to determine the effects of local recombinant apoA-Im/1-palmitoyl,2-oleoyl phosphatidylcholine complex (ETC-216) delivered intramurally via the Infiltrator catheter on luminal narrowing in a porcine coronary artery stent overstretch injury model.In twelve domestic swine ( approximately 25 kg), two arteries each were infiltrated with 0.4 mL ETC-216 (14 mg/mL) or vehicle control immediately before deployment of GFX stents (stent:artery ratio=1.3:1). Animals were euthanized at day 28, and evaluation by QCA revealed a significant improvement in mean lumen loss index with ETC-216 treatment (21+/-22% versus 43+/-13% lumen loss; P=0.01). Histomorphometric analysis showed that ETC-216 treatment significantly reduced the intimal area (6.7+/-1.5 versus 5.2+/-1.4 mm2, -22%; P=0.02) and the stenosis index (0.76+/-0.15 versus 0.59+/-0.15; P=0.01), and increased the lumen area (2.1+/-1.4 versus 3.7+/-1.8 mm2, +76%; P=0.02). Regression analysis showed significant differences in lumen area (P=0.004), neointimal area (P=0.003), stenosis index (P=0.001), and neointimal thickness (P=0.003) adjusted for injury score in favor of ETC-216.A single intramural administration of ETC-216 significantly inhibited injury-induced luminal narrowing in the porcine stent overstretch model through reduction of intimal hyperplasia. These data show that local intracoronary delivery of ETC-216 may be useful to prevent restenosis after coronary stenting.
学习、推动、落实全科医生制度建立
Authors: 贾明艳
Journal: BMJ (2011)

《国务院关于建立全科医生制度的指导意见》(《指导意见》)的正式发布标志着我国全科医学发展、全科医生队伍建设和医药卫生体制改革进程迈入一个崭新阶段.《指导意见》对建立我国全科医生制度提出了一系列重大改革措施和制度创新任务.但能否真正“落地”、“落实”,也给卫生界和社会相关领域带来巨大的压力和前所未有的挑战。
The expression and phosphorylation of eukaryotic initiation factor 4E are increased in lesional psoriatic skin
Authors: R.B. Kjellerup, L. Iversen, K. Kragballe, C. Johansen
Journal: British Journal of Dermatology (2009)

Overexpression of the eukaryotic initiation factor (eIF) 4E results in increased translation of mRNAs encoding proteins involved in cell cycle control, proliferation, apoptosis and angiogenesis. Phosphorylation of eIF4E is conducted by MAP kinase interacting serine/threonine kinase 1 and 2, and phosphorylation of eIF4E has previously been associated with increased release of proinflammatory cytokines from keratinocytes. The actions of eIF4E are counteracted by the eIF4E-binding protein 1 (4E-BP1).To characterize the mRNA and protein expression of eIF4E, as well as the phosphorylation of eIF4E in psoriatic skin.Biopsies were collected from patients with psoriasis. mRNA expression and protein levels of eIF4E were evaluated by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. eIF4E distribution was determined by immunofluorescence analysis.We found a significant increase in mRNA expression and protein level of eIF4E in lesional as compared with nonlesional psoriatic skin. Immunofluorescence analysis demonstrated that eIF4E was located throughout the epidermis and was primarily cytoplasmic in distribution. The level of phosphorylated eIF4E protein was found to be strongly upregulated, and 4E-BP1 expression was also increased.We have demonstrated for the first time that the level of total and phosphorylated eIF4E and the expression of 4E-BP1 are increased in lesional psoriatic skin. As eIF4E-regulated proteins have been reported to be upregulated in psoriasis, it appears that the increase in eIF4E is only incompletely counteracted by 4E-BP1. Therefore, eIF4E might contribute to the pathogenesis of psoriasis.
Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis
Authors: Maria E C Sandberg, Camilla Bengtsson, Henrik Källberg, Annmarie Wesley, Lars Klareskog, Lars Alfredsson, Saedis Saevarsdottir
Journal: Annals of the Rheumatic Diseases (2014)

To investigate whether overweight/obesity at diagnosis affects the chances of decrease in disease activity and pain in early rheumatoid arthritis (RA).We investigated incident RA cases from the population-based Epidemiological Investigation of risk factors for Rheumatoid Arthritis (EIRA) study (2006-2009, N=495) with clinical follow-up in the Swedish Rheumatology Quality Register. At diagnosis, 93% received disease-modifying antirheumatic drugs (DMARDs) (86% methotrexate). The odds of achieving a good response according to the DAS28-based European League Against Rheumatism (EULAR) criteria, low disease activity (DAS28<3.2), remission (DAS28<2.6) or pain remission (visual analogue scale ≤20 mm) at 3-months and 6-months follow-up, were calculated using logistic regression, adjusting for potential confounders.Significant dose-response relationships were found between Body Mass Index (BMI) and change of disease activity as well as pain at both time points. Patients with BMI ≥25 had 51% lower odds of achieving low disease activity (odds ratio (OR=0.49 (95% CI 0.31 to 0.78)) and 42% lower odds of remission (OR=0.58 (95% CI 0.37 to 0.92)) at the 6-months visit, compared to normal-weight patients. This effect was also present at 3 months, where we also found a 43% decreased odds of pain remission (OR=0.57 (95% CI 0.37 to 0.88)). No effect modification was found for anti-citrullinated protein antibody (CCP)-status, sex, prednisolone treatment or DAS28 at diagnosis.Overweight at diagnosis significantly decreases the chance of achieving good disease control during the early phase of RA.
Patient and Cellular Characteristics Determine Efficacy of Cell Therapy
Authors: Marc S. Penn
Journal: Circulation Research (2007)

ecent clinical trials have demonstrated the safety and potential benefits of the stem cell based therapies for the preservation and treatment of cardiac dysfunction following acute myocardial infarction. 1,2More recently Assmus and colleagues published the TOPCARE-CHD trial in which they compared the effects of infusing circulating progenitor cells to bone marrow mononuclear cells in patients at a time remote from acute myocardial infarction (average time from AMI to infusion, 6 to7 years). 3Using a crossover clinical trial design that study demonstrated that circulating progenitor cells offered no benefit, where as infusion of whole bone marrow mononuclear cells resulted in an increase of 2.9% in the ejection fraction compared with a loss of 1.2% in control patients. 3he observation that circulating progenitor cells and bone marrow mononuclear cells lead to improved function in acute myocardial infarction, 4 but only bone marrow derived progenitor cells led to improvement at times significantly remote from AMI suggest that different cell populations or delivery strategies may be efficacious in one setting but not another.For example, CD34 ϩ cells are present in both circulating progenitor cells and whole bone marrow mononuclear preparations, mesenchymal stem cells are only present in the bone derived progenitor cell preparations.Similarly, the literature to date has demonstrated critical differences between myocardial tissue immediately after and that at times remote from an acute ischemic event with respect to the expression of stem cell homing factors, inflammatory infiltrates and putative differentiation factors. 5,6,7hus, although CD34 ϩ cells may be able to home to myocardial tissue in the periinfarct period, 5,6 CD34 ϩ cells may require direct injection into the myocardial tissue at times remote from acute myocardial infarction. 3,8learly there are numerous technical and biological questions that are yet to be resolved regarding cell based therapies for the prevention and treatment of cardiac dysfunction including optimal cell type, timing of delivery, dosing and the mechanisms of benefit.However,
Field tests for rational drug use in twelve developing countries
Authors: H.V. Hogerzeil, None Bimo, D. Ross-Degnan, R.O. Laing, D. Ofori-Adjei, B. Santoso, A.K. Azad Chowdhury, A.M. Das, K.K. Kafle, A.F.B. Mabadeje, A.Y. Massele
Journal: The Lancet (1993)
Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice
Authors: Michael Look, Eric Stern, Qin A. Wang, Leah D. DiPlacido, Michael Kashgarian, Joe Craft, Tarek M. Fahmy
Journal: Journal of Clinical Investigation (2013)

The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ–positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.
Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome
Authors: Andrea Frustaci, Silvia G. Priori, Maurizio Pieroni, Cristina Chimenti, Carlo Napolitano, Ilaria Rivolta, Tommaso Sanna, Fulvio Bellocci, Matteo Antonio Russo
Journal: Circulation (2005)

Background— The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in Brugada syndrome is still debated. Methods and Results— We studied 18 consecutive patients (15 males, 3 females; mean age 42.0±12.4 years) with clinical phenotype of Brugada syndrome and normal cardiac structure and function on noninvasive examinations. Clinical presentation was ventricular fibrillation in 7 patients, sustained polymorphic ventricular tachycardia in 7, and syncope in 4. All patients underwent cardiac catheterization, coronary and ventricular angiography, biventricular endomyocardial biopsy, and DNA screening of the SCN5A gene. Biopsy samples were processed for histology, electron microscopy, and molecular screening for viral genomes. Microaneurysms were detected in the right ventricle in 7 patients and also in the left ventricle in 4 of them. Histology showed a prevalent or localized right ventricular myocarditis in 14 patients, with detectable viral genomes in 4; right ventricular cardiomyopathy in 1 patient; and cardiomyopathic changes in 3. Genetic studies identified 4 carriers of SCN5A gene mutations that cause in vitro abnormal function of mutant proteins. In these patients, myocyte cytoplasm degeneration was present at histology, whereas terminal dUTP nick end-labeling assay showed a significant increase of apoptotic myocytes in right and left ventricle versus normal controls ( P =0.014 and P =0.013, respectively). Conclusions— Despite an apparently normal heart at noninvasive evaluation, endomyocardial biopsy detected structural alterations in all 18 patients with Brugada syndrome. Mutations in the SCN5A gene, identified in 4 of the 18 patients, may have induced concealed structural abnormalities of myocardiocytes that accounted for paroxysmal arrhythmic manifestations.
Role of Chemotherapy and the Receptor Tyrosine Kinases KIT, PDGFRα, PDGFRβ, and Met in Large-Cell Neuroendocrine Carcinoma of the Lung
Authors: Giulio Rossi, Alberto Cavazza, Alessandro Marchioni, Lucia Longo, Mario Migaldi, Giuliana Sartori, Nazzarena Bigiani, Laura Schirosi, Christian Casali, Uliano Morandi, Nicola Facciolongo, Antonio Maiorana, Mario Bavieri, Leonardo M. Fabbri, Elisabeth Brambilla
Journal: Journal of Clinical Oncology (2005)

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets.We reviewed 83 patients with pure pulmonary LCNEC to investigate their clinicopathologic features, therapeutic strategy, and immunohistochemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFRalpha, PDGFRbeta, and Met.LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRalpha in 60.2%, PDGFRbeta in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (> or = 3 cm) and Met expression were significantly correlated with survival. At univariate and multivariate analysis, SCLC-based chemotherapy (platinum-etoposide) was the most important variable correlating with survival, both in the adjuvant and metastatic settings (P < .0001).Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide-based chemotherapy. Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFRalpha, PDGFRbeta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.
Renal impairment in cystic fibrosis
Authors: R Mukherjee, J Whitehouse, D Honeybourne
Journal: Thorax (2008)

We read with interest the paper by Bertenshaw et al 1 on the incidence of acute renal failure (ARF) in patients with cystic fibrosis (CF) and would like to supplement these results with our findings. With increasing survival and therefore consideration for lung transplantation, monitoring adult patients with CF for renal impairment is assuming increasing importance (creatinine clearance <50 mg/ml/min is a contraindication to lung transplantation).2

We examined …
Gelsolin in idiopathic pulmonary fibrosis: a new target supports a central role for epithelial injury in disease pathogenesis
Authors: M. Whyte
Journal: Thorax (2009)

Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous condition and is likely to be initiated by many different forms of lung injury. Injury to the alveolar epithelium followed by aberrant repair is, however, recognised to be a central pathogenic mechanism in IPF.1 Histologically, there is evidence of epithelial cell hyperplasia and proliferation, particularly adjacent to fibroblastic foci, but also areas of epithelial apoptosis and denudation.2 In murine models of pulmonary fibrosis, inhibition of components of apoptotic signalling pathways abrogates both alveolar epithelial cell death and fibrosis. This has been achieved by treatment with caspase inhibitors or with antibody blockade of the Fas death receptor, these results being confirmed in mice deficient in murine Fas (lpr) or its ligand, gld.3 4 The mechanisms of epithelial cell apoptosis in human IPF are not clearly defined, although there is evidence that the Fas pathway may be upregulated resulting in caspase-dependent apoptosis.5 A recent paper has shown that apoptosis of epithelial cells derived from patients with IPF is specifically associated with markers of endoplasmic reticulum stress.6

In this issue of Thorax , Oikonomou and colleagues ( see page 467 ) show that …
NHS review: the first three months.
Authors: J. R. Butler
Journal: BMJ (1989)

lymphocytes of one of the patients but not in bladder epithelial cells or hair.'7Effective treatment of the mitochondrial myopathies remains limited.Acute exacerbations with severe lactic acidosis precipitated by exercise, infection, or alcohol may be improved by correcting the acidosis with a slow infusion of sodium bicarbonate.Patients with carnitine deficiency associated with a respiratory chain defect may improve with oral carnitine.Ubiquinone, ascorbic acid, menadione, and steroids have all been tried with varying success.Clearer.understanding ofthe molecular mechanisms underlying these metabolic defects may lead to more effective treatment.
Case of Lumbar Spina Bifida; Injection of Morton'S Iodo-Glycerine Solution; Cure. A New Instrument for the Operation
Authors: J. C. Voigt
Journal: BMJ (1887)

returned to the fingers.I used the galvanic battery for some weeks afterWards At first, owing to the wasting of the anterior interosei, which are supplied by the ulnar nerve, when he attempted
Improvement of Endocardial and Vascular Endothelial Function on Myocardial Performance by Captopril Treatment in Postinfarct Rat Hearts
Authors: Xiu-Ling Qi, Duncan J. Stewart, Hugues Gosselin, Azar Azad, Pierre Picard, Luc Andries, Stanislas U. Sys, Dirk L. Brutsaert, Jean L. Rouleau
Journal: Circulation (1999)

Background —Endocardial (EE) and myocardial capillary vascular endothelial (myocap VE) cells have been shown to modulate the contractile characteristics of myocardium in a calcium-dependent manner. We evaluated the endothelial-myocardial interaction in the rat postinfarction myocardial infarction (MI) model and the effects of captopril. Methods and Results —Wistar rats were divided into 4 groups treated for 4 weeks: (1) control; (2) infarcted controls (left anterior coronary artery ligation); (3) infarcted+captopril 2 g/L in drinking water; and (4) infarct+captopril+triton intracoronary injection. Coronary VE function was evaluated by infusion of serotonin in Langendorff preparations (n=31), and the myocardial contractile characteristics were investigated by use of isolated papillary muscles (n=44). Cardiac mRNA for endothelial constitutive nitric oxide synthase (ecNOS) was measured, and its cellular location was evaluated by immunohistochemistry. Serotonin-induced increase in coronary flow was decreased in infarct controls compared with controls (4.6% versus 53.4%, P &lt;0.01) but not in the 2 infarct+captopril groups. Intracoronary triton injection decreased serotonin-induced coronary flow in the infarct+captopril+triton group. All MI groups had decreased total tension in isolated papillary muscles. EE removal by triton immersion decreased total tension in all groups except for infarct controls (3.3 versus 3.2 g/mm 2 ). Cardiac ecNOS mRNA decreased in the control infarct group but remained normal in the infarct+captopril group. Conclusions —Chronic postinfarction endothelium-induced coronary vasodilatation is impaired, and both EE and myocap VE dysfunction contribute to myocardial depression. Captopril use prevents these abnormalities and the reduction of cardiac ecNOS mRNA.