Interleukin-10 enhances the intestinal epithelial barrier in the presence of corticosteroids through p38 MAPK activity in Caco-2 monolayers : a possible mechanism for steroid responsiveness in ulcerative colitis

Altres ajuts: 2012 Spanish Gastroenterological Association i CIBER G0034Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis

Angular and Current-Target Correlations in Deep Inelastic Scattering at HERA

Correlations between charged particles in deep inelastic ep scattering have been studied in the Breit frame with the ZEUS detector at HERA using an integrated luminosity of 6.4 pb-1. Short-range correlations are analysed in terms of the angular separation between current-region particles within a cone centred around the virtual photon axis. Long-range correlations between the current and target regions have also been measured. The data support predictions for the scaling behaviour of the angular correlations at high Q2 and for anti-correlations between the current and target regions over a large range in Q2 and in the Bjorken scaling variable x. Analytic QCD calculations and Monte Carlo models correctly describe the trends of the data at high Q2, but show quantitative discrepancies. The data show differences between the correlations in deep inelastic scattering and e+e- annihilation.Comment: 26 pages including 10 figures (submitted to Eur. J. Phys. C

Diagnosing mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Metastatic skull tumors: MRI features and a new conventional classification

Skull metastases are malignant bone tumors which are increasing in incidence. The objectives of this study were to characterize the MR imaging features, locations, and extent of metastatic skull tumors to determine the frequency of the symptomatic disease, and to assess patient outcomes. Between September 2002 and March 2008, 175 patients undergoing routine head MR imaging were found to have metastatic skull tumors. Contrast-enhanced study with fat suppression was used in some cases when required. Classification of metastases was simplified to three yes/no questions: first, with regard to location (either in the calvarium or in the cranial base); second, with regard to distribution within the plane of the cranial bone (either “circumscribed” meaning clearly demarcated and confined to one bone, or “diffuse” and likely to spread across a suture to another bone); and third, with regard to invasion (“intraosseous” in cranial bones only, or “invasive” spreading from the skull, either out into the scalp or inward to the dura and perhaps further in). Primary sites were breast cancer (55%), lung cancer (14%), prostate cancer (6%), malignant lymphoma (5%), and others (20%). The mean time from primary diagnosis to skull metastasis diagnosis was 71 months for cases of breast cancer, 26 months for prostate cancer, 9 months for lung cancer, and 4 months for malignant lymphoma. Calvarial circumscribed intraosseous metastases were found most frequently (27%). The patients were mainly asymptomatic. However, some patients suffered from local pain or cranial nerve palsies that harmed their quality of life. Treatment, mainly for symptomatic cases, was by local or whole-skull irradiation. Metastatic skull tumors are not rare, and most are calvarial circumscribed intraosseous tumors. MR images contribute to understanding their type, location, and multiplicity, and their relationship to the brain, cranial nerves, and dural sinuses. Radiation therapy improved the QOL of patients with neurological symptoms

Interleukin-15 Treatment Induces Weight Loss Independent of Lymphocytes

Obesity is a chronic inflammatory condition characterized by activation and infiltration of proinflammatory immune cells and a dysregulated production of proinflammatory cytokines. While known as a key regulator of immune natural killer (NK) cell function and development, we have recently demonstrated that reduced expression of the cytokine Interleukin-15 (IL-15) is closely linked with increased body weight and adiposity in mice and humans. Previously, we and others have shown that obese individuals have lower circulating levels of IL-15 and NK cells. Lean IL-15 overexpressing (IL-15 tg) mice had an accumulation in adipose NK cells compared to wildtype and NK cell deficient obese IL-15−/− mice. Since IL-15 induces weight loss in IL-15−/− and diet induced obese mice and has effects on various lymphocytes, the aim of this paper was to determine if lymphocytes, particularly NK cells, play a role in IL-15 mediated weight loss. Acute IL-15 treatment resulted in an increased accumulation of NK, NKT, and CD3+ T cells in adipose tissue of B6 mice. Mice depleted of NK and NKT cells had similar weight loss comparable to controls treated with IL-15. Finally, IL-15 treatment induces significant weight loss in lymphocyte deficient RAG2−/−γc−/− mice independent of food intake. Fat pad cross-sections show decreased pad size with cytokine treatment is due to adipocyte shrinkage. These results clearly suggest that IL-15 mediates weight loss independent of lymphocytes

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis

<p>Abstract</p> <p>Background</p> <p>Mannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the <it>MRC1 </it>gene with sarcoidosis.</p> <p>Methods</p> <p>Nine single nucleotide polymorphisms (SNPs), encompassing the <it>MRC1 </it>gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls.</p> <p>Results</p> <p>Suggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (<it>P </it>= 0.001).</p> <p>Conclusions</p> <p>These results suggest that <it>MRC1 </it>is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in <it>MRC1</it>, a major member of the C-type lectin, contribute to the development of sarcoidosis.</p