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Background: Although epinephrine is essential for successful return of spontaneous circulation (ROSC), the influence of this drug on recovery during the post-cardiac arrest phase is debatable., Objectives: This study sought to investigate the relationship between pre-hospital use of epinephrine and functional survival among patients with out-of-hospital cardiac arrest (OHCA) who achieved successful ROSC., Methods: We included all patients with OHCA who achieved successful ROSC admitted to a cardiac arrest center from January 2000 to August 2012. Use of epinephrine was coded as yes/no and by dose (none, 1 mg, 2 to 5 mg, >5 mg). A favorable discharge outcome was coded using a Cerebral Performance Category 1 or 2. Analyses incorporated multivariable logistic regression, propensity scoring, and matching methods., Results: Of the 1,556 eligible patients, 1,134 (73%) received epinephrine; 194 (17%) of these patients had a good outcome versus 255 of 422 patients (63%) in the nontreated group (p < 0.001). This adverse association of epinephrine was observed regardless of length of resuscitation or in-hospital interventions performed. Compared with patients who did not receive epinephrine, the adjusted odds ratio of intact survival was 0.48 (95% confidence interval [CI]: 0.27 to 0.84) for 1 mg of epinephrine, 0.30 (95% CI: 0.20 to 0.47) for 2 to 5 mg of epinephrine, and 0.23 (95% CI: 0.14 to 0.37) for >5 mg of epinephrine. Delayed administration of epinephrine was associated with worse outcome., Conclusions: In this large cohort of patients who achieved ROSC, pre-hospital use of epinephrine was consistently associated with a lower chance of survival, an association that showed a dose effect and persisted despite post-resuscitation interventions. These findings suggest that additional studies to determine if and how epinephrine may provide long-term functional survival benefit are needed., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background & Aims: To determine the characteristics of hepatitis C (HCV)- infected patients in 2010 and compare this survey with those reported in 1995 and 2001., Patients and Methods: Observational multicentre study conducted in 2010 in French internal medicine, infectious diseases and hepatology departments., Results: A total of 1621 HCV infected patients (mean age 50.1 ± 10.7 years; sex ratio M/F 1.8; genotype 1: 55.7%) were included. Of these, 910 (56.1%) were HIV–HCV co-infected, 463 (40.4%) were asymptomatic and 184 (16.1%) had cirrhosis at inclusion in this study. Positive viraemia was found in 1,025 patients (65.5%) at inclusion in this study. A complete pretreatment evaluation including investigation for HCV RNA, genotype determination and liver fibrosis was performed in 96.5, 80.5 and 68.7% of the 1,621 patients respectively. Previous and ongoing HCV treatments were noted in 49.6% and 20.1% of patients respectively. A sustained virological response (SVR) was observed in 271/801 (38.3%) patients, i.e. 44.1% and 30.7% in co-infected and mono-infected patients respectively. Cirrhosis was more frequent in the 2010 than in the 2001 and 1995 surveys (16.1% vs. 10.4% and 7.4% respectively; P < 0.0001). A complete pretreatment evaluation was performed in 57.9% and 50.9% of patients in 2010 and 2001 (P < 0.0001). Liver fibrosis evaluation was more frequent in 2010 than in the 2001 and 1995 surveys (68.7% vs. 62.7% and 28.7%, respectively, P < 0.0001)., Conclusion: The care of HCV-infected patients has changed significantly in ‘real life’ through an improvement of pretreatment evaluation before the antiviral introduction and the increased use of antivirals. New HCV therapy combinations including protease inhibitors are warranted to increase the SVR rate.

Introduction: The influence of blood glucose (BG) level during the post-resuscitation period after out-of-hospital cardiac arrest (OHCA) is still debated. To evaluate the relationship between blood glucose level and outcome, we included the median glycemia and its maximal amplitude over the first 48 h following ICU admission in an analysis of outcome predictors., Methods: We conducted a database study in a cardiac arrest center in Paris, France. Between 2006 and 2010, we included 381 patients who were all resuscitated from an OHCA. A moderate glycemic control was applied in all patients. The median glycemia and the largest change over the first 48 h were included in a multivariate analysis that was performed to determine parameters associated with a favorable outcome., Results: Of the 381 patients, 136 (36 %) had a favorable outcome (CPC 1-2). Median BG level was 7.6 mmol/L (6.3-9.8) in patients with a favorable outcome compared to 9.0 mmol/L (IQR 7.1-10.6) for patients with an unfavorable outcome (p < 0.01). Median BG level variation was 7.1 (4.2-11) and 9.6 (5.9-13.6) mmol/L in patients with and without a favorable outcome, respectively (p < 0.01). In multivariate analysis, an increased median BG level over the first 48 h was found to be an independent predictor of poor issue [OR = 0.43; 95 % CI (0.24-0.78), p = 0.006]. Finally a progressive increase in median BG level was associated with a progressive increase in the proportion of patients with a poor outcome., Conclusion: We observed a relationship between high blood glucose level and outcome after cardiac arrest. These results suggest the need to test a strategy combining both control of glycemia and minimization of glycemic variations for its ability to improve post-resuscitation care.

Purpose of Review: Percutaneous coronary revascularization is the cornerstone treatment of acute coronary syndromes. Out-of-hospital cardiac arrest (OHCA) is in most cases related to a culprit coronary occlusion and should be treated as soon as possible., Recent Findings: To date, no biomarker has been evidenced to correctly predict culprit coronary occlusion in OHCA patients in order to select the best candidates for coronary angiography after OHCA. Moreover, successful percutaneous coronary intervention has been associated with better ICU and long-term survival in such patients. Although all these data are provided by retrospective studies, results can be considered strong enough to support systematic coronary angiography after OHCA. Taken together, these findings strongly suggest the necessity to systematically perform coronary angiography after no obvious noncardiac cause of OHCA., Summary: Systematic percutaneous coronary intervention after no obvious noncardiac cause of OHCA appears to be the most secure and the best adapted in these patients.

Ethylene glycol poisoning is rare, but prompt diagnosis is crucial, in order to initiate specific treatments. Herein, we report the case of a patient who was admitted to ICU for coma and extreme metabolic acidosis with unexpected hyperlactatemia on initial ICU blood gas analyzer. Ethylene glycol poisoning was diagnosed, and hyperlactatemia was ruled out on a blood sample sent to the biochemistry department. Interference of blood gas analyzers lactate electrodes with metabolites of ethylene glycol were the source of this apparent hyperlactatemia. Symptoms gradually improved and false hyperlactatemia resolved after renal replacement therapy and fomepizole administration. Time course of ethylene glycol concentration showed similar evolution. After initial confirmation of ethylene glycol presence, this biological interference could thus be used as a surrogate of costly and highly specialised dosages., (Copyright © 2014 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Background: Hepatitis C virus (HCV) is associated with B-cell disorders, including mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). We hypothesized that combination of serum biomarkers could be used to identify B-NHL in HCV patients., Methods: We measured in 155 HCV infected patients, with and without MC and/or B-NHL, serum levels of eight markers previously described to be increased in patients with B-NHL, i.e. sCD22, sCD27, sIL-2Rα, sCD137, free-light chains of Ig (ratio κ/λ), heavy chains of Ig (ratio IgMκ/IgMλ), gammaglobulins and C4. We used a multiparametric analysis to determine a signature that identifies patients with overt B-NHL., Results: Serum levels were significantly different between patients without MC, patients with asymptomatic MC, patients with MC vasculitis and those with MC vasculitis and B-NHL for all biomarkers except for sCD137. Using multiparametric analysis, we identified a signature involving sCD27, sIL-2Rα, gammaglobulins and C4 levels associated with the presence of overt B-NHL in HCV-infected patients. This signature had a sensitivity of 100%, a specificity of 90%, and positive and negative predictive values of 97 and 100%, respectively for discriminating patients with overt B-NHL and those without B-NHL., Conclusion: Our data indicate that serum biomarker signature allows identifying HCV-infected patients presenting with overt B-NHL., (Copyright © 2013. Published by Elsevier B.V.)

With increasing public education in basic life support and with the widespread use of automated defibrillators, post-cardiac arrest comatose patients represent a growing part of ICU admissions. However the prognosis remains very poor and only a very low proportion of these resuscitated patients will recover and will leave the hospital without major neurological impairments. Neurological dysfunction predominantly includes disorders of consciousness, and may also include other manifestations such as seizures, myoclonus status epilepticus and other forms of movement disorders including post-anoxic myoclonus. In the most severe cases, coma may be irreversible or evolve towards a minimally conscious state, a vegetative state or even brain death. These severe conditions represent by far the leading cause of mortality and disability in such patients. Currently, early use of mild therapeutic hypothermia is the only treatment that demonstrated its ability to decrease neurological consequences and to improve the prognosis. Prognostication outcome is still mainly based on a rigorous clinical evaluation coupled with neuro-physiological investigations, but brain functional imaging could become a valuable tool in the near future. Clinical research focusing on survivors should be strongly encouraged in order to assess the mid- and long-terms outcome of survivors and to evaluate the impact of new treatments or strategies., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Central nervous system (CNS) angiitis is a rare inflammatory disorder. To date, clinical data are lacking and treatment remains a matter of debate. The aim of this study is to analyse the main characteristics, response to therapy and outcome of 32 patients with CNS angiitis. Single-centre retrospective study in a tertiary centre was made. Diagnosis of CNS angiitis was made by cerebral angiography and/or magnetic resonance angiography and/or CNS biopsy. The main features and outcomes of primary and secondary CNS angiitis were compared and predictive factors of a favourable outcome were searched. Thirty-one patients (median age 45 Q1-Q3 37-54) sex ratio F/M 2.1) were included. Main clinical features were hemiparesis (35.5 %) and headache (29 %). The median CSF protein level was 0.64(0.52-0.81) g/L and was superior to 1 g/L in six cases. CNS magnetic resonance (MR) imaging findings were most frequently ischemic (96.8 %), bilateral (83.9 %), multiple (87.1 %) and supratentorial (96.8 %). The MR angiography was abnormal in all cases. Among the 31 patients in the study, 19 (61.3 %) were diagnosed with primary CNS angiitis. Systemic lupus erythematosus (n = 6) and vasculitis (n = 4) were the most frequent aetiologies of secondary CNS angiitis. No difference was evidenced between primary and secondary CNS angiitis. Steroids were administered in 79.2 % of treated patients and combined with immunosuppressants in 79.2 % of cases. Eight cases of CNS angiitis relapse were noted. CNS angiitis remains a severe illness. Treatment often associated steroids and immunosuppressants, and diagnosis delay is significantly associated with a poorer prognosis.

Purpose: Early identification of the cause of out-of-hospital cardiac arrest (OHCA) remains a challenge. Our aim was to determine whether high-sensitivity cardiac troponin T (HsTnT) was useful to diagnose a recent coronary artery occlusion as the cause of OHCA., Methods: Retrospective study including OHCA patients evaluated by systematic coronary angiogram at hospital admission. HsTnT was assessed at ICU admission. Predictive factors of a recent coronary occlusion were identified by logistic regression. Net reclassification improvement (NRI) was calculated to estimate the potential enhancement of prediction with HsTnT., Results: During the 5 year study period, 272 patients (median age 60 y, 76.5% men) were included, and a culprit coronary occlusion was found in 133 (48.9%). The optimum HsTnT cut-off to predict a recent coronary occlusion was 575 ng/l (sensitivity 65.4%, specificity 65.5%). In multivariate analysis, current smoking (OR 3.2 95%, 95%CI 1.62-6.33), time from collapse to BLS<3 min (OR 2.11, 95%CI 1.10-4.05), initial shockable rhythm (OR 5.29, 95%CI 2.06-13.62), ST-segment elevation (OR 2.44, 95%CI 1.18-5.03), post-resuscitation shock onset (OR 2.03, 95%CI 1.01-4.07) and HsTnT≥575 ng/l (OR 2.22, 95%CI 1.16-4.27) were associated with the presence of a recent coronary occlusion. Nevertheless, adding HsTnT to established risk factors of recent coronary occlusion identified above provided a non-significant NRI of -0.43%., Conclusions: Admission HsTnT is increased after OHCA and is an independent factor of a recent coronary occlusion. However, HsTnT does not seem to be a strong enough diagnostic tool to select candidates for emergent coronary angiogram in OHCA survivors., (© 2013.)

Objective: This review aims at providing an update on post-cardiac arrest syndrome, from pathophysiology to treatment., Data Sources: Medline database., Data Extraction: All data on pathophysiology, clinical manifestations and therapeutic management, with focus on the publications of the 5 last years., Data Synthesis: Care of the patients after cardiac arrest is a medical challenge, in face of "post-cardiac arrest syndrome", which culminates into multi-organ failure. This syndrome mimics sepsis-related dysfunctions, with all clinical and biological manifestations related to the phenomenon of global ischemia-reperfusion. Acute cardiocirculatory dysfunction is usually controlled through pharmacological and mechanical support. Meanwhile, as a majority of cardiac arrest is related to myocardial infarction, early angiographic exploration should then be discussed when there is no obvious extracardiac cause, percutaneous coronary revascularization being associated with improved short and long-term prognosis. Therapeutic hypothermia is the cornerstone of neuroprotective armamentarium, beyond hemodynamic stabilization and metabolic maintenance., Conclusion: If ongoing evaluations should shed light on potential efficiency of new therapeutic drugs, a multidisciplinary approach of the post-cardiac arrest syndrome in expertise centre is essential., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Pittl U, Schratter A, Desch S et al. Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial. Clin. Res. Cardiol. 102(8), 607-614 (2013). Therapeutic hypothermia is the cornerstone of the postcardiac arrest period management. Several methods may be used as external or internal cooling. Pittl et al. reported a randomized, prospective, single-center study evaluating an invasive (Coolgard(®)) versus a non-invasive (Arctic Sun(®)) cooling method after cardiac arrest in 80 patients in Germany. The neurological outcome and neuron-specific enolase level were not different in the two groups at 72 h after cardiac arrest. The efficacy of the two cooling methods were similar. This study underlines the fact that the type of cooling method is not the most important thing to consider in therapeutic hypothermia, but the need of a progressive and soft rewarming may make the difference in the future between different devices.

Purpose: Tuberculous paradoxical reactions (PR) have been seldom studied in non-immunocompromised patients. We conducted a study to describe the incidence, clinical and biological features, treatment and outcome of PR in human immunodeficiency virus (HIV)-negative patients treated for extrapulmonary tuberculosis (TB) and to identify predictive factors of PR., Methods: A single-center retrospective study was conducted in consecutive HIV-negative patients presenting with TB with at least one extrapulmonary manifestation who were hospitalized in an internal medicine department between 2000 and 2010., Results: Seventy-six patients were enrolled in the study. Lymphadenitis was the most common extrapulmonary manifestation of tuberculosis among this patient population (72 %). PR occurred in 19 (25 %) patients, mostly involving the lymph nodes (68 %) and lung (16 %), but also the pericardium, pleura, bone, muscle and brain. Median time to PR onset after initiation of anti-TB regimen was 86 days (interquartile range 36-125). Treatment of PR consisted mainly of corticosteroids (47 % of patients) and needle aspiration of PR lymph nodes (31 %). Peripheral lymph node involvement (p = 0.009), lymphopenia (p = 0.03) and anemia (p = 0.002) at presentation were associated with PR occurrence. Outcome was favorable in all patients with PR but one; the latter suffered residual paraplegia., Conclusions: Paradoxical reactions are frequent in the course of extrapulmonary TB treatment in HIV-negative patients but their outcome is excellent, except in some cases with central nervous system involvement.

The acute appendicitis (AA) is an infection of the vermiform appendix and conservative antibiotic treatment is regularly mentioned since 50 years. Its success depends on the susceptibility of bacteria to empiric antibiotic therapy. The main bias of the studies comparing conservative antibiotic treatment versus appendectomy is that AA can not be proven histologically during medical treatment. However, after antibiotic conservative, 12-23% of patients are operated early after revaluation, and 11 to 15% in the first year for a total of 25% to 40% failure of conservative antibiotic treatment when proposed in first intention. In case of complicated appendicitis, severe infection and peritonitis, surgical treatment should be carried out urgently and remains the gold standard.

Objective: Chronic HCV infection is associated with extra-hepatic manifestations. Recent studies have suggested an immunomodulatory role for vitamin D during HCV infection. We investigated the association between serum vitamin D status and the presence of HCV extra-hepatic manifestations., Methods: 25(OH)D serum levels were assessed in 94 HCV(+)RNA(+) patients [including 48 patients with mixed cryoglobulinaemia (MC) vasculitis]. Correlations between serum 25(OH)D levels and the presence of extra-hepatic manifestations of HCV infection were analysed., Results: Overall, 84 of 94 patients (89%) had hypovitaminosis D (≤30 ng/ml). Patients with vitamin D deficiency vs insufficiency vs sufficiency more frequently had systemic vasculitis (P = 0.02), in particular purpura (P = 0.006), detectable MC (P = 0.008) and low C4 serum levels (P = 0.006). Serum levels of 25(OH)D were also correlated with cryoglobulin and C4 levels and with marginal zone B cells and regulatory T cells. In multivariate analysis, the presence of MC and systemic vasculitis remained independently associated with low 25(OH)D levels., Conclusion: In chronic HCV infection, low 25(OH)D levels correlate with the presence of mixed cryoglobulinaemia and systemic vasculitis in chronic HCV infection. These findings suggest the potential multifaceted benefits of vitamin D supplementation in HCV-infected patients with extra-hepatic manifestations, but interventional studies are needed to confirm these data.

Introduction: Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in Th17 cells. Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells. A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels [25(OH)D] was also shown., Methods: In this prospective study, we evaluated the safety and the immunological effects of vitamin D supplementation (100,000 IU of cholecalciferol per week for 4 weeks, followed by 100,000 IU of cholecalciferol per month for 6 months.) in 20 SLE patients with hypovitaminosis D., Results: Serum 25(OH)D levels dramatically increased under vitamin D supplementation from 18.7±6.7 at day 0 to 51.4±14.1 (p<0.001) at 2 months and 41.5±10.1 ng/mL (p<0.001) at 6 months. Vitamin D was well tolerated and induced a preferential increase of naïve CD4+ T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells. Vitamin D also induced a decrease of memory B cells and anti-DNA antibodies. No modification of the prednisone dosage or initiation of new immunosuppressant agents was needed in all patients. We did not observe SLE flare during the 6 months follow-up period., Conclusions: This preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by alterations of the B cell subset, global regulatory T cell (Treg) depletion, and an increase in Th17 cells. Interleukin 21 (IL-21) plays a critical role in T cell and B cell homeostasis. Our objective was to determine the implication of IL-21 and IL-21-producing CD4+ T cells in the pathogenesis of SLE., Methods: Twenty-five patients with SLE and 25 healthy donor controls were included. Analysis of CD4+ T cells producing IL-21, Th1, Th2, Th17, Treg, follicular helper T (TFH) cells, and B cells was performed in peripheral blood, and levels of cytokines were measured in culture supernatants., Results: Circulating CD4+ T cells producing IL-21 were markedly expanded in patients with SLE compared to controls and were correlated with increased Th17, decreased Treg, and increased memory B cells. CD4+ T cells producing IL-21 were composed of CXCR5+ and CXCR5-CD4+ T cell subsets. Both IL-21-producing CXCR5+CD4+ T cells and CXCR5-CD4+ T cells were increased in patients with SLE, the CXCR5-CD4+ subset correlating with Th17 cells and Treg, while the CXCR5+CD4+ subset was correlated with alterations of the B cell subset. The CXCR5+CD4+ subset comprised mainly circulating Bcl6+CXCR5+CD4+ TFH cells that were markedly expanded in patients with SLE and were correlated with increased circulating Bcl6+CXCR5+ germinal center B cells., Conclusion: These findings suggest that IL-21, produced by distinct cellular CD4+ T cells, correlates with alterations of T cell and B cell subsets in SLE, and that targeting IL-21 could provide beneficial effects on both T cell and B cell alterations.

Behçet's disease (BD) is a recurrent systemic inflammatory disorder of unknown origin characterized by oral and genital mucous ulcer, uveitis, and skin lesions. Involvement of large vessels, central nervous system (CNS), gastrointestinal tract and thrombotic events are less frequent but can be life threatening. The aim of this review is to provide new insights into the pathogenesis of BD. Over the past year substantial advances have been done in the understanding of the genetic [1,2] and immunology [3] of BD. BD is at the crossroad between autoimmune and autoinflammatory syndromes. In common with autoimmune diseases BD shares class I MHC association. However, in contrast to autoimmune disorders, BD has clinical features that seem to be mostly autoinflammatory. The pathogenesis of BD is still unknown, but major determinants of the genetic and immune system abnormalities have been reported recently. Triggering infectious factors are supposed to participate in the outbreak of BD in genetically predisposed patients. Two recent large genome-wide association study (GWAS) conducted in Turkey and Japan reported association between single nucleotide polymorphism (SNP) of interleukin (IL)-10 and IL-23R/IL-12RB2 genes and BD. New insights into the perturbations of T cell homeostasis of BD recently emerged. We have recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells (Tregs) that were driven by interleukin (IL)-21 production and that correlates with BD activity. Inflammatory cells within BD inflammatory lesions included mostly neutrophils, Th1 and Th17 cells, and cytotoxic CD8+ and γδ T cells. Altogether, the recent progresses in the knowledge of BD pathogenesis pave the way for innovative therapy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Therapeutic options in hepatitis C virus (HCV)-related vasculitis may target the viral trigger using antiviral therapy [pegylated interferon plus ribavirin (PEG-IFN/RBV)], and/or the downstream B-cell arm of autoimmunity with rituximab (RTX). To date, no study has compared the efficacy of RTX combined with PEG-IFN/RBV on biomarkers of liver insufficiency in patients with severe liver fibrosis. Twenty-eight untreated HCV-related vasculitis patients with severe liver fibrosis (Metavir F3-F4) were included: 14 patients received RTX plus PEG-IFN/RBV and 14 patients PEG-IFN/RBV. The main clinical and biological data were recorded and compared at baseline, month 3 (M3), M12 and M24 of follow-up. Baseline epidemiological, clinical, virological and immunological features were similar between the groups. The virological response did not differ between cases and controls. The alanine aminotransferase (ALT) level and HCV viral load did not increase in patients treated with RTX. Serum albumin levels increased in patients treated with RTX at M3 and M6 (108% and 111% of baseline value; P = 0.06 and P = 0.13), whereas it was stable in patients treated without RTX. FibroTest values decreased from 0.70 at baseline to 0.59 at M3 (P = 0.5) and returned to 0.69 at M24 in the RTX-PEG-IFN/RBV group, whereas they were stable in the PEG-IFN/RBV group. RTX is safe in patients with severe HCV liver fibrosis and vasculitis. No beneficial effects of RTX were evidenced on liver fibrosis progression, but we found interesting correlations with the serum albumin level, FibroTest values and B-cell count., (© 2012 Blackwell Publishing Ltd.)

Objective: Giant cell arteritis (GCA) is a large-vessel vasculitis of unknown origin. Recent findings indicate that at least 2 separate lineages of CD4+ T cells, Th1 and Th17 cells, participate in vascular inflammation. The pathways driving these T cell differentiations are incompletely understood, but may provide novel therapeutic targets. This study was undertaken to identify cytokines involved in the pathogenesis of GCA., Methods: Thirty GCA patients fulfilling the American College of Rheumatology criteria, with active disease or disease in remission, and 30 age-matched controls were included. Levels of 27 cytokines were determined in culture supernatants, and flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of temporal artery samples were performed., Results: Multiparametric analysis of cytokines produced by PBMCs associated with GCA disease activity identified a signature involving interleukin-2 receptor (IL-2R), IL-12, interferon-γ (IFNγ), IL-17A, IL-21, and granulocyte-macrophage colony-stimulating factor (GM-CSF). An expansion of Th1 and Th17 cells and a decrease in Treg cells were observed in the peripheral blood of patients with active GCA. An expansion of IL-21-producing CD4+ T cells was also observed in patients with active GCA and correlated positively with Th17 and Th1 cell expansion. Immunohistochemical analysis revealed IFNγ, IL-17A, and IL-21 expression within inflammatory infiltrates. Stimulation of purified CD4+ T cells with IL-21 increased Th1 and Th17 cell frequencies and decreased FoxP3 expression. In contrast, blockade of IL-21 using IL-21R-Fc markedly decreased the production of IL-17A and IFNγ and increased FoxP3 expression., Conclusion: Our findings indicate that IL-21 plays a critical role in modulating Th1 and Th17 responses and Treg cells in GCA, and might represent a potential target for novel therapy., (Copyright © 2012 by the American College of Rheumatology.)

The vasculitis of Behçet disease (BD) is distinctive because of involvement of both arteries and veins of all sizes. The concept of vasculo-Behçet disease has been adopted for cases in which vascular manifestations are present and often dominate the clinical features. While venous manifestations are frequent and have been reported in many publications, data regarding arterial lesions in patients with BD are rare and often isolated. In this study, we report the main characteristics, treatment, and long-term outcome of 101 patients with arterial lesions among a cohort of 820 (12.3%) BD patients. Factors that affect prognosis were assessed by multivariate analysis. There were 93 (91.2%) male patients; the median (Q1-Q3) age at diagnosis of BD was 33 (27-41) years. Arterial lesions included aneurysms (47.3%), occlusions (36.5%), stenosis (13.5%), and aortitis (2.7%). Lesions mainly involved the aorta (n = 25) and femoral (n = 23) and pulmonary (n = 21) arteries. Patients with arterial lesions were more frequently male (91.2% vs. 62.4%, respectively; p = 0.017) and had higher rates of venous involvement (80.4% vs. 29.8%, respectively; p < 0.001) compared to patients without arterial manifestations. Thirty-nine (38.6%) patients achieved complete remission. In multivariate analysis, the presence of venous involvement (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.08-1.11) and arterial occlusive lesions (OR, 0.13; 95% CI, 0.01-1.25) were negatively associated with complete remission. The use of immunosuppressants (OR, 3.38; 95% CI, 0.87-13.23) was associated with the occurrence of complete remission. The 20-year survival rate was significantly lower in BD patients with arterial involvement than in those without arterial lesions (73% vs. 89%, respectively; p < 0.0001). In conclusion, the long-term outcome of arterial lesions in BD is poor, especially in the case of occlusive lesions and associated venous involvement. The use of immunosuppressants improved the prognosis.

Cardiac abnormalities in patients with Behçet disease (BD) include pericarditis, myocarditis, endocarditis with valvular regurgitation, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with or without myocardial infarction, and aneurysms of the coronary arteries or sinus of Valsalva. Data regarding the clinical spectrum, prevalence, and outcome of cardiac lesions in BD are lacking. In this study, we report the main characteristics, treatment, and long-term outcomes of 52 patients with cardiac lesions from a cohort of 807 (6%) BD patients. Forty-five (86.5%) patients were male, with a mean (±SD) age at BD diagnosis of 29.3 ± 10.3 years.Cardiac involvement was the first feature of BD in 17 (32.7%) patients. Cardiac lesions included pericarditis (n = 20; 38.5%), endocarditis (mostly aortic insufficiency) (n = 14; 26.9%), intracardiac thrombosis (n = 10; 19.2%), myocardial infarction (n = 9; 17.3%), endomyocardial fibrosis (n = 4; 7.7%) and myocardial aneurysm (n = 1; 1.9%). Patients with cardiac involvement were more frequently male (86.5% vs. 64.9%; p < 0.01) and had more arterial (42.3% vs. 11.1%; p < 0.01) and venous lesions (59.6% vs. 35.8%; p < 0.01) compared to those without cardiac manifestations. Factors associated with complete remission of cardiac involvement were treatment regimens with oral anticoagulants, immunosuppressants, and colchicine. The 5-year survival rate was 83.6% and 95.8% (p = 0.03) in BD patients with and without cardiac involvement, respectively. After a median (Q1-Q3) follow-up of 3.0 (1.75-4.2) years, 8 patients had died, in 3 cases directly related to cardiac involvement.In conclusion, cardiac lesions affected 6% of our large cohort of BD patients. The prognosis of cardiac involvement in BD is poor and improves with oral anticoagulation, immunosuppressive therapy, and colchicine.

Recurrent pericarditis are common and their management remains a matter of debate. Their precise pathophysiology is unclear, and both innate and adaptative immunity seem involved. An extensive work-up seeking for etiology seems to be unnecessary during the first episode of acute pericarditis, whereas it is mandatory in recurrent pericarditis. Despite extensive investigations, up to 80 % of recurrent pericarditis remains of unknown origin. Colchicin associated to non steroidal antiinflammatory drugs is the first line treatment whereas immunosuppressive drugs are exceptionally required., (Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Background: Bronchiectasis is frequently associated (up to 30%) with chronic inflammatory rheumatic diseases and leads to lower respiratory tract infections. Data are lacking on the risk of lower respiratory tract infections in patients treated with biologic agents., Methods: Monocenter, retrospective systematic study of all patients with a chronic inflammatory rheumatic disease and concomitant bronchiectasis, seen between 2000 and 2009. Univariate and multivariate analyses were performed to evidence predictive factors of the number of infectious respiratory events., Results: 47 patients were included (mean age 64.1±9.1 years, 33 (70.2%) women), with a mean follow-up per patient of 4.3±3.1 years. Rheumatoid arthritis was the main rheumatic disease (90.1%). The mean number of infectious events was 0.8±1.0 event per patient-year. The factors predicting infections were the type of treatment (biologic vs. non biologic disease-modifying treatments), with an odds ratio of 8.7 (95% confidence interval: 1.7-43.4) and sputum colonization by any bacteria (odds ratio 7.4, 2.0-26.8). In multivariate analysis, both factors were independently predictive of infections., Conclusion: Lower respiratory tract infectious events are frequent among patients receiving biologics for chronic inflammatory rheumatic disease associated with bronchiectasis. Biologic treatment and pre-existing sputum colonization are independent risk factors of infection occurrence.

Objectives: To assess the frequency and effectiveness of switching TNF blockers in spondyloarthritis, and the predisposing factors of this effectiveness., Methods: This was a retrospective systematic monocentre study; inclusion criteria were definite spondyloarthritis (Amor's criteria) and introduction of a first TNF blocker after January 2004. The retention rate of the first and second TNF blocker (if applicable) was evaluated (Kaplan-Meier technique). Patients' characteristics were compared with regard to requirement for switching. Predisposing factors of retention of the second TNF blocker were analysed (log-rank, Cox)., Results: A total of 222 patients started a first TNF blocker; 79% fulfilled the New York modified criteria, with increased CRP (75%) and median BASDAI of 50 (35-61). Mean follow up was 29±20 months (i.e. a total of 538 patient-years). By the end of follow-up, 72 patients (32%) had switched to a second TNF blocker. Patients who switched had more peripheral enthesitic symptoms (p=0.01) and a tendency for more peripheral involvement (p=0.06). Retention of the first and second TNF blocker was similar (p=0.32). No predictive factors were found for retention of the second TNF blocker; including no difference between TNF blockers and between reasons for stopping the first., Conclusions: The effectiveness of switching TNF blocker in spondyloarthritis appears clinically relevant; no predictive factors of this effectiveness were evidenced.

Background & Aims: Recent findings in hepatitis C virus (HCV)-monoinfected patients have shown a correlation between low serum levels of 25-OH vitamin D3 [25(OH)D3] and severe liver fibrosis and low sustained virologic response to therapy. Data are lacking in HIV-HCV coinfected patients., Methods: One hundred and eighty nine HIV-HCV coinfected patients, who received ≥80% of interferon (IFN) plus ribavirin therapy, were analyzed for baseline serum 25(OH)D3 levels. Correlations between serum 25(OH)D3 levels, chronic hepatitis C features, HCV virologic response to antiviral therapy, and HIV infection characteristics were analyzed., Results: Mean serum 25(OH)D3 level was 18.5 ± 9.8 ng/ml, including 162 (85%) patients with level ≤30 ng/ml. Serum 25(OH)D3 levels were significantly correlated with the histological Metavir fibrosis score (r = -0.16; p = 0.027). Patients with severe fibrosis (Metavir F3/F4) had lower serum 25(OH)D3 levels compared to F2 and F1 patients (16.2 ± 10.0 vs. 18.9 ± 8.5 and 20.9 ± 11.1 ng/ml, respectively; p = 0.06). In multivariate analysis, low serum 25(OH)D levels were independently associated with severe liver fibrosis (p = 0.04) and cold season (p = 0.0002). Serum levels of 25(OH)D3 were also significantly correlated with liver fibrosis as assessed by FibroTest® (r = -0.22; p = 0.008) and serum α2-macroglobulin levels (r = -0.23; p = 0.006). In contrast, no correlation was found between 25(OH)D3 levels and HCV sustained virologic response to IFN-based therapy [OR 0.98 (0.95-1.01); p = 0.22]. No association was found between 25(OH)D3 levels and markers of HIV-related immunodeficiency., Conclusions: In HIV-HCV coinfected patients, low serum 25(OH)D3 levels correlate with severe liver fibrosis. In contrast, serum 25(OH)D3 levels are not linked to HCV virologic response to therapy or severity of immunodeficiency., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown etiology., Objective: To determine the nature of T cells driving inflammatory lesions in BD., Methods: T cell homeostasis and cytokines production were analyzed in peripheral blood and brain inflammatory lesions from 45 adult patients with BD (active and untreated BD [n = 25] and patients in remission [n = 20]) and 20 healthy donors, using Luminex, flow cytometry, immunohistochemistry, and immunofluorescence analysis., Results: We found a marked increase in T(H)17 cells and a decrease in the frequency of CD4(+) forkhead box P3(+) regulatory T cells (Tregs) in peripheral blood that were induced by IL-21 production and that correlate with BD activity. The addition of serum from patients with active BD in a sorted CD4(+) T cells culture of healthy donors induced a significant and dose-dependent production of IL-17A and a decrease in forkhead box P3 expression. We demonstrated the presence of IL-21- and IL-17A-producing T cells within the cerebrospinal fluid, brain parenchyma inflammatory infiltrates, and intracerebral blood vessels from patients with active BD and central nervous system involvement. The stimulation of CD4(+) T cells with IL-21 increased T(H)17 and T(H)1 differentiation and decreased the frequency of Treg cells. Conversely, IL-21 blockade with an IL-21R-Fc restored the T(H)17 and Treg homeostasis in patients with BD., Conclusion: We provided here the first evidence of the critical role of IL-21 in driving inflammatory lesions in BD by promoting T(H)17 effectors and suppressing Treg cells. IL-21 represents a promising target for novel therapy in BD., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Liver granulomas are histopathologically defined and associated with various liver and non-livers disorders. There are five main causes of liver granulomatosis: primary biliary cirrhosis, tuberculosis, sarcoidosis, B and C viral hepatitis, and drug related. In the other cases, not associated with an underlying systemic granulomatous disease, a systematic diagnostic approach should be used to identify less common etiologies. After a careful diagnostic work-up, a long-term follow-up of patients with undetermined liver granulomatosis is mandatory as it may be a presenting feature of liver lymphoma., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Liver involvement is common in connective tissue disorders and usually asymptomatic. However, it may be symptomatic and cases of fulminant hepatitis have been reported. A diagnosis of specific hepatic involvement needs to rule out drug toxicity, viral hepatitis, or auto-immune liver disease. The large panel of auto-antibodies that is now available to the clinician is helpful to differentiate auto-immune hepatitis and specific liver involvement associated with connective tissue disease. In the latter, the outcome is generally favourable with immunosuppressive treatment., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Cardiac involvement is unfrequent in antiphospholipid syndrome (APS) but its prognosis is poor. It may involve all the cardiac structures. Endocardial involvement is the most frequent feature. Prognosis of coronary arteries involvement is poor. Catastrophic APS may be revealed by cardiac symptoms. Except for the catastrophic APS, there is no specific treatment as anticoagulation remains the gold standard., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate clinical and biological surrogate markers associated with the presence of B cell non-Hodgkin's lymphoma (B-NHL) in patients with hepatitis C virus (HCV) with mixed cryoglobulinaemia (MC) vasculitis., Methods: A total of 104 patients with HCV-MC vasculitis (including 20 with B-NHL) were included. The main clinical and biological markers associated with the presence of B-NHL were evaluated., Results: Patients with B-NHL compared to those without showed higher rates of poor general status (40% vs 16.7%; p = 0.032), purpura (90% vs 66.7%; p = 0.05), renal (50% vs 28.6%; p = 0.11) and cardiac involvement (15% vs 0%; p = 0.0006), higher cryoglobulin levels (1.44 g/litre vs 0.67 g/litre; p = 0.0004), and lower C4 (0.025 g/litre vs 0.06 g/litre; p=0.001) and γ-globulin levels (5.3 g/litre vs 13.3 g/litre; p < 0.0001). The free light chain κ/λ ratio was more frequently abnormal in patients with than without B-NHL (64.3% vs 33.3%, p = 0.10). On multivariate analysis, only γ-globulin level was associated with the presence of B-NHL (OR 0.77 (95% CI -0.44 to -0.13), p = 0.0006). The optimal cut-off value for γ-globulin level was 9 g/litre, with sensitivity, specificity, positive and negative predictive values for the presence of B-NHL of 75%, 82%, 50% and 93%, respectively., Conclusions: In patients with HCV-MC, a low γ-globulin level (< 9 g/litre) is strongly associated with the presence of B-NHL.

Introduction: Purulent pneumoccocal pericarditis are extremely rare since the introduction of antibiotics., Exegesis: A 59-year-old woman presented to the emergency room with a seven-day history of dyspnea and fever. No signs of heart failure or cardiac friction rub were evidenced. Laboratory tests disclosed elevated acute phase reactants and elevated white blood cells with a high neutrophil count. Chest radiograph showed cardiomegaly and a bilateral pleural effusion. Chest-computed tomography confirmed the pleural effusion and evidenced a large pericardial effusion. Streptoccocus pneumoniae grew up form pericardial fluid and blood cultures. In addition to the pericardial drainage, the patient received intravenous amoxicillin therapy. Outcome was favourable. There was no evidence of immunodeficiency., Conclusion: Although exceptional, diagnosis of purulent pneumococcal pericarditis should not be missed as it may compromise vital prognosis. Therapy should combine pericardial drainage and antibiotics.

Genetic and phenotypic relationships between adipose tissue characteristics of 253 piglets aged 8 d and qualitative characteristics of their backfat at 95 and 145 kg live weight were studied. Heritability of these qualitative aspects was estimated as well. Backfat samples were tested for cellularity, moisture, lipid content and fatty acid composition of the outer and inner layers. Adipose cellularity at birth proved to be correlated with cell volume, moisture and total unsaturated fatty acid, C18:0 and C18:2 contents present in backfat at slaughter. Estimates of heritability calculated for the outer layer of backfat indicated that progress can be made by selecting for water content and fatty acid composition. Neonatal cellularity furnishes a useful indicator not only of the backfat cell size at slaughter but also of the chemical factors important in determining the physical and organoleptic characteristics of porcine fat.

Backfat thickness, carcass length, area of M. longissimus and carcass composition were determined for 253 Large White barrows and gilts to examine the genetic influence on the main characteristics of the carcass and the correlation of these traits with body measurements and fat characteristics at 8 d of age. Pigs were born to 32 sows mated to the same boar. At the age of 8 d, weight, body length and backfat thickness and cellularity were measured. Pigs were slaughtered at 95 and 145 kg live weight. Heritability and genetic correlations were estimated with dam component of variance. Higher adiposity of carcasses was noted for barrows than for gilts and for those animals slaughtered at the heavier vs at the lighter weight. High h2 values were observed for carcass length (.89 +/- .29), area of the M. longissimus (.67 +/- .26) and backfat thickness at the gluteus medius (.77 +/- .28). Percentage of commercial cuts also had high heritabilities. Phenotypic and genetic correlations between the characteristics at 8 d and backfat thickness, carcass length and M. longissimus area at slaughter were not statistically significant. However, significant phenotypic correlations were found between cellularity of the outer and inner layers at 8 d and percentage of major cuts (e.g., rp = .27 with total fat cuts); cellularity of the outer layer at 8 d also was correlated genetically with carcass composition (e.g., rg = .50 +/- .19 with total fat cuts). Genetic predisposition toward intensive fat deposition was more clearly predicted by cellularity than by thickness of adipose tissue in newborn pigs.

The genetic influence on body and adipose tissue characteristics of newborn pigs and their correlations to growth rate, BW, body length, backfat thickness and adipocyte size in the outer and inner layers of backfat in 8-d-old Large White piglets were determined. Samples of adipose tissue were obtained by biopsy. Pigs were born to 32 sows mated with the same boar. Heritability and genetic correlations were estimated with dam component of variance; therefore, bias due to common environmental effects cannot be excluded. The heritability estimate for adipocyte volume (.89 +/- .28) was higher than that for backfat thickness at the first and last thoracic vertebrae (.50 +/- .22; .63 +/- .24) and for body weight (.59 +/- .23) at 8 d. Backfat thickness was more closely related genetically and phenotypically to body weight and length than to adipose tissue cellularity. Heritability estimates were .75 +/- .28 for gain from 8 d to weaning and from weaning to 95 d (probably because of common environmental effects) but were .31 +/- .20 for ADG from 95 d to slaughter. Characteristics at 8 d were closely correlated phenotypically with growth rate until weaning. These correlations became lower in the two subsequent periods (to 95 d and to slaughter). Corresponding genetic correlations were nonsignificant.

We describe the computerized tomography findings in 85 patients affected with degenerative ataxias. Cerebellar atrophy was moderate in patients with Friedreich's disease (no. 28) and early onset cerebellar ataxia with retained reflexes (no. 10) and, in Friedreich's disease, it was mostly a late feature. On the contrary, in symptomatic patients with adult onset dominant cerebellar ataxia (no. 24), cerebellar atrophy was always present and often marked. However, it was absent in 3 asymptomatic affected relatives. Infratentorial and supratentorial atrophy were frequent findings in idiopathic late onset cerebellar ataxia (no. 16).