Autoimmunity and Extrahepatic Manifestations in Treatment-Naïve Children with Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection has been associated with autoimmunity and extrahepatic manifestations in adults. Few data are available on these topics in children. Nonorgan specific auto-antibodies development is part of the natural course of chronic hepatitis C in children. Smooth muscle autoantibody is the most common autoantibody found, while liver-kidney microsomal type-1 antibody positivity is the most peculiar autoimmune feature of children with HCV infection. The clinical significance of non-organ specific autoantibodies in the course of paediatric chronic hepatitis C is still debated. Autoantibody positivity can be considered neutral for most patients, while it can be associated with negative connotations for others, especially those positive for liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not autoimmune thyroiditis has been demonstrated in HCV infection in children, while only few cases of HCV-associated membranoproliferative glomerulonephritis have been described. Single reports are available in the literature reporting the anecdotal association between chronic hepatitis C and other extrahepatic manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the low incidence of extrahepatic manifestations of chronic hepatitis C in children, overall, available data suggest a careful monitoring

Investigation on the Origin of Sperm DNA Fragmentation: Role of Apoptosis, Immaturity and Oxidative Stress

Sperm DNA fragmentation (sDF) represents a threat to male fertility, human reproduction and the health of the offspring. The causes of sDF are still unclear, even if apoptosis, oxidative assault and defects in chromatin maturation are hypothesized. Using multicolor flow cytometry and sperm sorting, we challenged the three hypothesized mechanisms by simultaneously evaluating sDF and signs of oxidative damage (8-hydroxy, 2′-deoxyguanosine [8-OHdG] and malondialdehyde [MDA]), apoptosis (caspase activity and cleaved poly[ADP-ribose] polymerase [cPARP]) and sperm immaturity (creatine phosphokinase [CK] and excess of residual histones). Active caspases and c-PARP were concomitant with sDF in a high percentage of spermatozoa (82.6% ± 9.1% and 53.5% ± 16.4%, respectively). Excess of residual histones was significantly higher in DNA-fragmented sperm versus sperm without DNA fragmentation (74.8% ± 17.5% and 37.3% ± 16.6%, respectively, p < 0.005), and largely concomitant with active caspases. Conversely, oxidative damage was scarcely concomitant with sDF in the total sperm population, at variance with live sperm, where 8-OHdG and MDA were clearly associated to sDF. In addition, most live cells with active caspase also showed 8-OHdG, suggesting activation of apoptotic pathways in oxidative-injured live cells. This is the first investigation on the origin of sDF directly evaluating the simultaneous presence of the signs of the hypothesized mechanisms with DNA breaks at the single cell level. The results indicate that the main pathway leading to sperm DNA breaks is a process of apoptosis, likely triggered by an impairment of chromatin maturation in the testis and by oxidative stress during the transit in the male genital tract. These findings are highly relevant for clinical studies on the effects of drugs on sDF and oxidative stress in infertile men and for the development of new therapeutic strategies

Th17 transcription factor RORC2 is inversely correlated with FOXP3 expression in the joints of children with juvenile idiopathic arthritis

Objective. To investigate the relationship between interleukin 17 (IL-17) producing T cells (Th17) and CD4+CD25+FOXP3+ regulatory T cells (Tregs) in blood and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA). Methods. Sixty-five children with JIA (18 males and 47 females, median age 6.2 yrs; 45 with oligoarticular and 20 with polyarticular course) and 75 age- and sex-matched healthy controls were studied. Flow cytometry was used to analyze the forkhead box P3 (FOXP3)-positive Treg cells in peripheral blood (PB) and synovial fluid mononuclear cells (SFMC). FOXP3 and retinoic-acid related orphan receptor C isoform 2 (RORC2) messenger RNA (mRNA) were assessed by real-time polymerase chain reaction analysis. Cytokines (IL-17 and Th1/Th2 related cytokines) were measured in culture supernatants of 11 paired PBMC and SFMC activated with PMA and ionomycin. Results. FOXP3+ T cells and FOXP3 mRNA amounts were significantly lower in PB of children with JIA as compared with controls (p = 0.0002 and p = 0.001, respectively) and a higher percentage of Treg cells with concomitant higher level of FOXP3 transcript levels were observed in SF when compared with their PB counterparts (both p < 0.0001). SF CD4+FOXP3+ T cells were characterized by higher amounts of FOXP3 protein per cell when compared with peripheral CD4+FOXP3+ T cells, as revealed by the difference in FOXP3 median fluorescence intensity (median ± SD, arbitrary units, 54 ± 22.6 vs 19.5 ± 4.2; p < 0.001). RORC2 transcript levels were higher in JIA joints when compared with matched PB samples (median fold increase 3.9, p < 0.0001) but negatively correlated with FOXP3 mRNA levels (r = -0.623, p = 0.04). Stimulated SFMC displayed an impaired ability to produce IL-17 when compared with PBMC and, interestingly, an inverse relationship between IL-17 levels and the percentage of CD4+CD25+FOXP3+ SF T cells (r = -0.510, p = 0.047) was seen. Conclusion. We demonstrated for the first time an increased synovial expression of the transcription factor of Th17, RORC2, in JIA, and its inverse relationship with FOXP3 mRNA. These results extend research on "Th17" and Tregs in JIA. The Journal of Rheumatology Copyright © 2009. All rights reserved

HEDGEHOG-GLI Signaling Drives Self-Renewal and Tumorigenicity of Human Melanoma-Initiating Cells

status: publishe

Measurements of W gamma and Z gamma production in pp collisions at root s=7 TeV with the ATLAS detector at the LHC

"The integrated and differential fiducial cross sections for the production of a W or Z boson in association with a high-energy photon are measured using pp collisions at root s = 7 TeV. The analyses use a data sample with an integrated luminosity of 4.6 fb(-1) collected by the ATLAS detector during the 2011 LHC data-taking period. Events are selected using leptonic decays of the W and Z bosons [W(e nu, mu nu) and Z(e(+)e(-), mu(+)mu(-), nu(nu) over bar)] with the requirement of an associated isolated photon. The data are used to test the electroweak sector of the Standard Model and search for evidence for new phenomena. The measurements are used to probe the anomalous WW gamma, ZZ gamma, and Z gamma gamma triple-gauge-boson couplings and to search for the production of vector resonances decaying to Z gamma and W gamma. No deviations from Standard Model predictions are observed and limits are placed on anomalous triple-gauge-boson couplings and on the production of new vector meson resonances.

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using 4:7 fb(-1) of root s=7 TeV proton-proton collision data

"A search for squarks and gluinos in final states containing jets, missing transverse momentum and no high-p(T) electrons or muons is presented. The data represent the complete sample recorded in 2011 by the ATLAS experiment in 7 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 4.7 fb(-1). No excess above the Standard Model background expectation is observed. Gluino masses below 860 GeV and squark masses below 1320 GeV are excluded at the 95% confidence level in simplified models containing only squarks of the first two generations, a gluino octet and a massless neutralino, for squark or gluino masses below 2 TeV, respectively. Squarks and gluinos with equal masses below 1410 GeV are excluded. In minimal supergravity\/constrained minimal supersymmetric Standard Model models with tan beta = 10, A(0) = 0 and mu > 0, squarks and gluinos of equal mass are excluded for masses below 1360 GeV. Constraints are also placed on the parameter space of supersymmetric models with compressed spectra. These limits considerably extend the region of supersymmetric parameter space excluded by previous measurements with the ATLAS detector.