tbuckley/cabot-search huggingface dataset:
Developing tolerogenic dendritic cell therapy for rheumatoid arthritis: what can we learn from mouse models?
Authors: J. N. Stoop, J. H. Robinson, C. M. U. Hilkens
Journal: Annals of the Rheumatic Diseases (2011)

One of the therapeutic strategies under development for the treatment of rheumatoid arthritis is based on reinstating immune tolerance by vaccination with autologous dendritic cells with potent tolerogenic function. These tolerogenic dendritic cells (TolDC) can be generated ex vivo and have beneficial therapeutic effects in animal models of arthritis. Although experimental animal models have been instrumental in the development of this novel immunotherapeutic tool, several outstanding questions regarding the application of TolDC remain to be addressed. This paper reviews what has been learnt to date from studying the therapeutic potential of TolDC in animal models of arthritis and discusses issues relating to preventive versus curative effects of TolDC, the antigen specificity of TolDC therapy, the route, dose and frequency of TolDC administration and the safety of TolDC treatment. Lessons learnt from animal models will aid the design of clinical trials with TolDC.
Cyclosporine Treatment of Glomerular Diseases
Authors: Michael Klein, Jai Radhakrishnan, Gerald Appel
Journal: Annual Review of Medicine (1999)

Cyclosporine-A is primary therapy for organ transplantation. Its immunosuppressive effect might suggest a therapeutic role in autoimmune diseases, including several idiopathic and secondary glomerular conditions. Various forms of idiopathic nephrotic syndrome, including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy (MN), may respond well to cyclosporine in selected patients. However, frequent relapse limits its use to those who have failed to respond to, or were intolerant of, steroids or cytotoxics. Cyclosporine's efficacy in other glomerulopathies, such as IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) remains poorly studied and, given the risk of nephrotoxicity, cannot be recommended for treatment of these entities until further data are available. Cyclosporine demonstrates some efficacy in treating proliferative lupus nephritis and, based on pilot study data, membranous lupus as well. Again, given relapse rates and potential nephrotoxicity, it should be used only in combination with azathioprine and steroids, assuming cytotoxic therapy has failed. Finally, cyclosporine toxicity is briefly reviewed.
Gout: new insights into an old disease
Authors: F. Martinon
Journal: Journal of Clinical Investigation (2006)

Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Recent advances suggest that the innate immune system may drive the gouty inflammatory response to MSU. These findings prompt questions concerning how the innate immune system recognizes MSU and the identities of the receptors involved. In this issue of the JCI, Chen et al. show that the IL-1 receptor and its signaling protein myeloid differentiation primary response protein 88 (MyD88) but not the "classical" innate immune receptors, TLRs, are central for MSU-induced inflammation (see the related article beginning on page 2262).
The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis
Authors: Clara Dees, Inga Schlottmann, Robin Funke, Alfiya Distler, Katrin Palumbo-Zerr, Pawel Zerr, Neng-Yu Lin, Christian Beyer, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Activated Wnt signalling with decreased expression of endogenous inhibitors has recently been characterised as a central pathomechanism in systemic sclerosis (SSc). Aberrant epigenetic modifications also contribute to the persistent activation of SSc fibroblasts. We investigated whether increased Wnt signalling and epigenetic changes in SSc are causally linked via promoter hypermethylation-induced silencing of Wnt antagonists. <h3>Methods</h3> The methylation status of endogenous Wnt antagonists in leucocytes and fibroblasts was evaluated by methylation-specific PCR. 5-aza-2′-deoxycytidine was used to inhibit DNA methyltransferases (Dnmts) in cultured fibroblasts and in the mouse model of bleomycin-induced skin fibrosis. Activation of Wnt signalling was assessed by analysing Axin2 mRNA levels and by staining for β-catenin. <h3>Results</h3> The promoters of DKK1 and SFRP1 were hypermethylated in fibroblasts and peripheral blood mononuclear cells of patients with SSc. Promoter hypermethylation resulted in impaired transcription and decreased expression of DKK1 and SFRP1 in SSc. Treatment of SSc fibroblasts or bleomycin-challenged mice with 5-aza prevented promoter methylation-induced silencing and increased the expression of both genes to normal levels. Reactivation of DKK1 and SFRP1 transcription by 5-aza inhibited canonical Wnt signalling in vitro and in vivo and effectively ameliorated experimental fibrosis. <h3>Conclusions</h3> We demonstrate that hypermethylation of the promoters of DKK1 and SFRP1 contributes to aberrant Wnt signalling in SSc and that Dnmt inhibition effectively reduces Wnt signalling. These data provide a novel link between epigenetic alterations and increased Wnt signalling in SSc and also have translational implications because Dnmt inhibitors are already approved for clinical use.
Quality indicators for the primary care of osteoarthritis: a systematic review
Authors: J J Edwards, M Khanna, K P Jordan, J L Jordan, J Bedson, K S Dziedzic
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To identify valid and feasible quality indicators for the primary care of osteoarthritis (OA). <h3>Design</h3> Systematic review and narrative synthesis. <h3>Data sources</h3> Electronic reference databases (MEDLINE, EMBASE, CINAHL, HMIC, PsychINFO), quality indicator repositories, subject experts. <h3>Eligibility criteria</h3> Eligible articles referred to adults with OA, focused on development or implementation of quality indicators, and relevant to UK primary care. An English language restriction was used. The date range for the search was January 2000 to August 2013. The majority of OA management guidance has been published within this time frame. <h3>Data extraction</h3> Relevant studies were quality assessed using previous quality indicator methodology. Two reviewers independently extracted data. Articles were assessed through the Outcome Measures in Rheumatology filter; indicators were mapped to management guidance for OA in adults. A narrative synthesis was used to combine the indicators within themes. <h3>Results</h3> 10 853 articles were identified from the search; 32 were included in the review. Fifteen indicators were considered valid and feasible for implementation in primary care; these related to assessment non-pharmacological and pharmacological management. Another 10 indicators were considered less feasible, in various aspects of assessment and management. A small number of recommendations had no published corresponding quality indicator, such as use of topical non-steroidal anti-inflammatory drugs. No negative ('do not do') indicators were identified. <h3>Conclusions and implications of key findings</h3> There are well-developed, feasible indicators of quality of care for OA which could be implemented in primary care. Their use would assist the audit and quality improvement for this common and frequently disabling condition.
Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level.
Authors: K E Sorensen, D S Celermajer, D Georgakopoulos, G Hatcher, D J Betteridge, J E Deanfield
Journal: Journal of Clinical Investigation (1994)

Familial hypercholesterolemia is associated with premature atherosclerosis. Since endothelial dysfunction is an early event in atherogenesis, we used a noninvasive method to assess endothelial function in the systemic arteries of 30 children aged 7-17 yr (median 11) with familial hypercholesterolemia (2 homozygotes, 28 heterozygotes, total cholesterol 240-696 mg/dl) and 30 healthy age- and sex-matched controls. Using high resolution ultrasound, the diameter of the superficial femoral artery was measured at rest, in response to reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation). Flow-mediated dilation was present in the controls (7.5 +/- 0.7%) but was impaired or absent in the hypercholesterolemic children (1.2 +/- 0.4%, P < 0.0001). Total cholesterol was inversely correlated with flow-mediated dilation (r = -0.61, P < 0.0001). In the hypercholesterolemic children, flow-mediated dilation was inversely related to the lipoprotein(a) level (r = -0.61, P = 0.027) but not to other lipid fractions. Glyceryltrinitrate-induced dilation was present in all subjects but was lower in the hypercholesterolemia group (10.0 +/- 0.6% vs 12.4 +/- 0.8%, P = 0.023). Thus, impaired endothelium-dependent dilation is present in children with familial hypercholesterolemia as young as 7 yr of age and the degree of impairment is related to the lipoprotein(a) level.
YEASTS AS A CAUSE OF FALSE-POSITIVE REACTIONS IN PATCH TESTS FOR ALLERGY TO DENTURE MATERIALS
Authors: O. P. SALO, MARJA-LIISA HIRVONEN
Journal: British Journal of Dermatology (1969)

Journal Article YEASTS AS A CAUSE OF FALSE‐POSITIVE REACTIONS IN PATCH TESTS FOR ALLERGY TO DENTURE MATERIALS Get access O. P. SALO, O. P. SALO Department of Dermatology, University Central Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar MARJA‐LIISA HIRVONEN MARJA‐LIISA HIRVONEN Department of Dermatology, University Central Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 81, Issue 5, 1 May 1969, Pages 338–341, https://doi.org/10.1111/j.1365-2133.1969.tb13993.x Published: 01 May 1969 Article history Accepted: 14 October 1968 Published: 01 May 1969
Social cognition is not a special case, and the dark matter is more extensive than recognized
Authors: Fred Cummins
Journal: Behavioral and Brain Sciences (2013)

The target article's approach is applauded, but it is suggested that the "dark matter" may be much larger than even the current authors suspect. Cartesian and mechanistic assumptions infuse not only the discipline of cognitive psychology, but all societal accounts of the person. A switch to dynamical accounts in which lawfulness is observed within a given systemic context is suggested.
National Guidelines and Level of Evidence: Comments on Some of the New Recommendations in the American Society of Clinical Oncology and the College of American Pathologists Human Epidermal Growth Factor Receptor 2 Guidelines for Breast Cancer
Authors: Emad A. Rakha, Marian Pigera, Abeer Shaaban, Sandra J. Shin, Timothy D'Alfonso, Ian O. Ellis, Andrew H.S. Lee
Journal: Journal of Clinical Oncology (2015)
Determinants of Weight Gain in the Action to Control Cardiovascular Risk in Diabetes Trial
Authors: Vivian Fonseca, Roberta McDuffie, Jorge Calles, Robert M. Cohen, Patricia Feeney, Mark Feinglos, Hertzel C. Gerstein, Faramarz Ismail-Beigi, Timothy M. Morgan, Rodica Pop-Busui, Matthew C. Riddle
Journal: Diabetes Care (2013)

Identify determinants of weight gain in people with type 2 diabetes mellitus (T2DM) allocated to intensive versus standard glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.We studied determinants of weight gain over 2 years in 8,929 participants (4,425 intensive arm and 4,504 standard arm) with T2DM in the ACCORD trial. We used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit. We fit a linear regression of change in weight and A1C and used general linear models to examine the association between each medication at baseline and weight change at the 2-year visit, stratified by glycemia allocation.There was significantly more weight gain in the intensive glycemia arm of the trial compared with the standard arm (3.0 ± 7.0 vs. 0.3 ± 6.3 kg). On multivariate analysis, younger age, male sex, Asian race, no smoking history, high A1C, baseline BMI of 25-35, high waist circumference, baseline insulin use, and baseline metformin use were independently associated with weight gain over 2 years. Reduction of A1C from baseline was consistently associated with weight gain only when baseline A1C was elevated. Medication usage accounted for <15% of the variability of weight change, with initiation of thiazolidinedione (TZD) use the most prominent factor. Intensive participants who never took insulin or a TZD had an average weight loss of 2.9 kg during the first 2 years of the trial. In contrast, intensive participants who had never previously used insulin or TZD but began this combination after enrolling in the ACCORD trial had a weight gain of 4.6-5.3 kg at 2 years.Weight gain in ACCORD was greater with intensive than with standard treatment and generally associated with reduction of A1C from elevated baseline values. Initiation of TZD and/or insulin therapy was the most important medication-related factor associated with weight gain.
A statistical framework for modeling gene expression using chromatin features and application to modENCODE datasets
Authors: Chao Cheng, Koon-Kiu Yan, Kevin Y Yip, Joel Rozowsky, Roger Alexander, Chong Shou, Mark Gerstein
Journal: Genome biology (2011)

We develop a statistical framework to study the relationship between chromatin features and gene expression. This can be used to predict gene expression of protein coding genes, as well as microRNAs. We demonstrate the prediction in a variety of contexts, focusing particularly on the modENCODE worm datasets. Moreover, our framework reveals the positional contribution around genes (upstream or downstream) of distinct chromatin features to the overall prediction of expression levels.
Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin
Authors: Davide Ferrari, Paola Chiozzi, Simonetta Falzoni, Stefania Hanau, Francesco Di  Virgilio
Journal: The Journal of Experimental Medicine (1997)

Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.
Regulation of the cardiac sodium channel Nav1.5 by utrophin in dystrophin-deficient mice
Authors: Maxime Albesa, Jakob Ogrodnik, Jean-Sébastien Rougier, Hugues Abriel
Journal: Cardiovascular Research (2010)

Duchenne muscular dystrophy (DMD) is a severe striated muscle disease due to the absence of dystrophin. Dystrophin deficiency results in dysfunctional sodium channels and conduction abnormalities in hearts of mdx mice. Disease progression in the mdx mouse only modestly reflects that of DMD patients, possibly due to utrophin up-regulation. Here, we investigated mice deficient in both dystrophin and utrophin [double knockout (DKO)] to assess the role of utrophin in the regulation of the cardiac sodium channel (Nav1.5) in mdx mice. Co-immunoprecipitation studies in HEK293 cells showed that utrophin interacts with Nav1.5 via syntrophin proteins, an interaction abolished by deletion of the PDZ (PSD-95, Dlg, and Zona occludens) domain-binding motif of Nav1.5. We also provide evidence for such interaction in mouse heart using Nav1.5 C-terminus fusion proteins. In hearts of DKO mice, Nav1.5 protein levels were decreased by 25 ± 8%, together with a 42 ± 12% reduction of syntrophins compared with mdx, where utrophin was up-regulated by 52 ± 9% compared with C57BL/10 control mice. Sodium current was found to be reduced by 41 ± 5% in DKO cardiomyocytes compared with mdx, representing a loss of 63 ± 3% when compared with C57BL/10 wild-type control mice. Decreased Nav1.5 protein and current in DKO were reflected in a significant slowing of 27 ± 6% of maximal upstroke velocity of the cardiac action potential compared with mdx. Utrophin plays a central role in the regulation of Nav1.5 in mdx mice. These findings provide support for therapeutic strategies aimed at overexpressing utrophin in the hopes of reducing cardiac pathology in DMD patients.
Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome
Authors: Giulio Marchesini, Elisabetta Bugianesi, Gabriele Forlani, Fernanda Cerrelli, Marco Lenzi, Rita Manini, Stefania Natale, Ester Vanni, Nicola Villanova, Nazario Melchionda, Mario Rizzetto
Journal: Hepatology (2003)

Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin–resistance syndrome, at present defined as the metabolic syndrome, whose limits were recently set. We assessed the prevalence of the metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes, on the basis of 3 or more criteria out of 5 defined by the U.S. National Institutes of Health (waist circumference, glucose, high–density lipoprotein [HDL]–cholesterol, triglycerides, and arterial pressure). The prevalence of the metabolic syndrome increased with increasing body mass index, from 18% in normal–weight subjects to 67% in obesity. Insulin resistance (Homeostasis Model Assessment method) was significantly associated with the metabolic syndrome (odds ratio [OR], 2.5; 95% CI, 1.5–4.2; P &lt; .001). Liver biopsy was available in 163 cases (54%). A total of 120 patients (73.6%) were classified as having nonalcoholic steatohepatitis (NASH); 88% of them had a metabolic syndrome (vs. 53% of patients with pure fatty liver; P &lt; .0001). Logistic regression analysis confirmed that the presence of metabolic syndrome carried a high risk of NASH among NAFLD subjects (OR, 3.2; 95% CI, 1.2–8.9; P = .026) after correction for sex, age, and body mass. In particular, the syndrome was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1–11.2; P = .032). In conclusion, the presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease. The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades. (Hepatology 2003;37:917–923.)
Precut Sphincterotomy for Biliary Cannulation: If you Fail, Give it Another Try
Authors: A. Barnabas, A. A. Bailey, J. Collier, J. Phillips-Hughes, R. W. Chapman, B. Braden
Journal: Gut (2011)

<h3>Introduction</h3> Precut sphincterotomy facilitates selective bile duct access during endoscopic retrograde choliangiopancreaticography (ERCP) in patients in whom conventional cannulation has failed. However, it is associated with a higher complication rate and does not always facilitate successful initial cannulation. If biliary cannulation is not successful immediately after precut many endoscopists repeat the ERCP after an interval to allow papillary oedema to improve. The safety and efficacy of this practice is not well reported. We investigated the biliary cannulation success and complication rates of initial and repeat ERCPs requiring precut sphincterotomy for biliary cannulation. <h3>Methods</h3> We retrospectively analysed 895 consecutive ERCPs from our endoscopy reporting database for use of precut sphincterotomy, biliary access rate, repeat ERCP rate and complications. <h3>Results</h3> In 87 patients (9.7%) a precut sphincterotomy was performed to facilitate biliary cannulation. In 31 of these patients (35.6%) biliary cannulation was achieved directly during the first ERCP. We repeated the ERCP in 46 of the 56 patients with failed precut sphincterotomy after a median of 4 days following the initial precut sphincterotomy allowing successful biliary cannulation in 34/46 patients (73.9%). The overall cannulation success rate was 65/87 (74.7%) or 65/77 (84.4%) excluding the 10 patients who did not undergo a second ERCP. Complications observed after precut sphincterotomy were pancreatitis (12.7%), retroperitoneal perforation (2.3%) and bleeding (1.1%). <h3>Conclusion</h3> The high success rate of biliary cannulation at a second attempt justifies repeating the ERCP after unsuccessful immediate cannulation following precut sphincterotomy before more invasive approaches such as percutaneous cholangiography or surgery are considered. <h3>Competing interests</h3> None.
Leptin and exercise: new directions
Authors: J L Durstine, R W Thompson, K L Drowatzky, W P Bartoli
Journal: British Journal of Sports Medicine (2001)

Initial information on the newly discovered hormone leptin suggests a primary role in energy balance and body weight maintenance. Recent published information suggests that leptin has an impact on several physiological systems, including neuroendocrine and immune function, as well as being involved in growth and development. Although the role of leptin in these areas is only partially understood at best, even less is known about the effect of exercise on plasma leptin concentrations. Further, if exercise has an impact on leptin concentration, how then does exercise affect overall leptin function? This article considers leptin function and the impact that exercise has on blood leptin concentrations, and suggests future directions for research on exercise and leptin.

Leptin, a hormone synthesized primarily by adipose tissue and secreted into the circulatory system, is a purported satiety factor with receptors in the hypothalamus. Human leptin is a relatively small protein (16 kDa) which shares a high degree of homology with other species such as mice (84%) and rats (83%). Although rare in humans, leptin mutations in mice result in leptin deficiency and lead to early onset obesity, hyperphagia, and hypothalamic hypogonadism. Unlike leptin deficient mice, humans deficient in leptin do not suffer from hyperinsulinaemia, hyperglycaemia, hypercorticism, or hypothermia. Although regulation of leptin synthesis and release is poorly understood, a distinct circadian pattern for plasma leptin concentrations has been observed and is similar to that of prolactin and thyroid stimulating hormone.1 Conflicting …