Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated ...inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
Abstract Objective Recent data show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity-induced ER stress and Unfolded Protein Response ...(UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress-associated insulin resistance. Methods For this purpose, we used the intraperitoneal glucose tolerance test (GTT), euglycemic-hyperinsulinemic clamp, western blotting and qPCR in liver, muscle, and adipose tissue of iNOS KO and control mice on HFD. Results The results of the present study demonstrated that, in HFD fed mice, iNOS-induced alteration in insulin signaling is an essential mechanism of insulin resistance in muscle, suggesting that iNOS may represent an important target that could be blocked in order to improve insulin sensitivity in this tissue. However, in liver and adipose tissue, the insulin resistance induced by HFD was only partially dependent on iNOS, and, even in the presence of genetic or pharmacological blockade of iNOS, a clear ER stress associated with altered insulin signaling remained evident in these tissues. When this ER stress was blocked pharmacologically, insulin signaling was improved, and a complete recovery of glucose tolerance was achieved. Conclusions Taken together, these results reinforce the tissue-specific regulation of insulin signaling in obesity, with iNOS being sufficient to account for insulin resistance in muscle, but in liver and adipose tissue ER stress and insulin resistance can be induced by both iNOS-dependent and iNOS-independent mechanisms.
Objective
Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with ...polyangiitis (Wegener's) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.
Methods
Long‐term outcomes in patients enrolled in the WEGENT trial were analyzed according to their randomized treatment group (AZA or MTX). Parameters at trial entry were evaluated as potential prognostic factors for death, relapse, or damage in multivariate models.
Results
Data from 10 years of followup were available for 112 (88.8%) of the 126 original trial participants. The median followup time was 11.9 years (95% confidence interval 95% CI 11.3–12.5 years). In patients receiving AZA and those receiving MTX, the 10‐year overall survival rates were 75.1% (95% CI 64.8–86.9%) and 79.9% (95% CI 70.3–90.8%) (P = 0.56), respectively, and relapse‐free survival rates were 26.3% (95% CI 17.3–40.1%) and 33.5% (95% CI 23.5–47.7%) (P = 0.29), respectively. No between‐treatment differences were observed with regard to rates of relapse, adverse events, damage, survival without severe side effects, and survival without relapse and severe side effects. In analyses limited to the 97 patients with GPA, no between‐treatment differences in survival rates were observed. The 10‐year relapse‐free survival rate was lower in patients with GPA than in patients with MPA. However, in the multivariate analysis, anti–proteinase 3 antineutrophil cytoplasmic antibody (ANCA) positivity, and not GPA, was retained as being independently associated with the relapse rate.
Conclusion
The results of this long‐term analysis confirm that AZA and MTX are comparable treatment options for maintaining remission of GPA or MPA. Despite achieving good overall survival with these treatments, relapse rates, adverse events, and damage remain matters of concern and further studies are needed to reduce their frequency in these ANCA‐associated vasculitides.
Ecstasy is the popular name of the abuse drug 3,4-methylenedioxymethamphetamine (MDMA) that decreases immunity in animals. The mechanisms that generate such alterations are still controversial. Seven ...independent pharmacological approaches were performed in mice to identify the possible mechanisms underlying the decrease of neutrophil activity induced by MDMA and the possible effects of MDMA on host resistance to
Listeria monocytogenes
. Our data showed that MDMA (10 mg kg
−1
) administration decreases NFκB expression in circulating neutrophils. Metyrapone or RU-486 administration prior to MDMA treatment abrogated MDMA effects on neutrophil activity and NFκB expression, while 6-OHDA or ICI-118,551 administration did not. As MDMA treatment increased the plasmatic levels of adrenaline and noradrenaline, propranolol pre-treatment effects were also evaluated. Propranolol suppressed both MDMA-induced increase in corticosterone serum levels and its effects on neutrophil activity. In a L. monocytogenes experimental infection context, we showed that MDMA: induced myelosuppression by decreasing granulocyte-macrophage hematopoietic progenitors (CFU-GM) in the bone marrow but increased CFU-GM in the spleen; decreased circulating leukocytes and bone marrow cellularity and increased spleen cellularity; decreased pro-inflammatory cytokine (IL-12p70, TNF, IFN-γ, IL-6) and chemokine (MCP-1) production 24 h after the infection; increased the production of pro-inflammatory cytokines and chemokines 72 h after infection and decreased IL-10 levels at all time points analyzed. It was proposed that MDMA immunosuppressive effects on neutrophil activity and host resistance to
L monocytogenes
rely on NFκB signaling, being mediated by HPA axis activity and corticosterone.
Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Due to the incidence of symptomatic atherosclerosis in uremic patients, ...hemostasis-derived cardiovascular risk factors, basal plasma concentrations of some endothelial-derived glycoproteins and desmopressin-induced variations of endothelial-derived proteins were studied in 22 uremic patients on prolonged maintenance hemodialysis with no cardiovascular antecedent. Compared to control subjects, patients had increased predialysis hemostasis-related cardiovascular risk factors: high fibrinogen, proconvertin, and type 1 plasminogen activator inhibitor plasma concentrations; low albumin values; generally low antithrombin III values but sometimes high. They had high predialysis plasma concentrations of endothelium-derived glycoproteins: von Willebrand factor, tissue-type plasminogen activator and urokinase-type plasminogen activator, which are secreted by endothelial cells, but also soluble thrombomodulin, a marker of endothelial cell injury. The desmopressin-induced release of tissue-type plasminogen activator and of von Willebrand factor were lower than in controls. High fibrinogen, type 1 plasminogen activator inhibitor and low albumin plasma concentrations may be linked to repeated acute phase reactions associated with hemodialysis. Data concerning endothelium-related proteins are concordant with the co-existence of a chronic in vivo endothelial activation and endothelial injury in uremia. This could be linked to the initiation and progression of atherosclerosis.
La cryptosporidiose (Cs) a une prévalence réelle sous-estimée, car sous-diagnostiquée. Il s’agit du deuxième agent pathogène responsable de diarrhée dans le monde, après les rotavirus. En France, a ...été responsable d’épidémies, mais aussi dans le monde. Soixante pour cent des cas surviennent chez des immunodéprimés, principalement VIH et transplantés rénaux. Vingt-cinq pour cent des cas surviennent chez des immunocompétents. La transmission est féco-orale, par contacts avec animaux ou hommes contaminés, par ingestion d’eau (principalement de piscine, mer) ou d’aliments souillés. Les oocystes excrétés dans le milieu sont très résistants, survivent jusqu’à 1 an. Le risque de contamination nosocomiale est élevé.
Un patient âgé de 72 ans, ayant reçu une greffe de rein en 2012 sur Wegener, est hospitalisé 4 fois de 03/16 à 01/17 pour AEG, diarrhées profuses, dégradation de fonction rénale. Les coproparasitologies des selles, les PCR CMV, EBV, recherche de toxines de Clostridum difficile restent négatives. TEP-TDM exclut un lymphome du grêle. La coloscopie montre une diverticulose, sans biopsie en zone saine. Lors de la dernière hospitalisation, une recherche spécifique de cryptosporidiose et microsporidiose sur échantillon de selles, avec examen direct et coloration Ziehl Nielsen est réalisée (PCR non réalisée) : une Cs est diagnostiquée.
Devant une diarrhée aiguë ou chronique non étiquetée chez le patient ayant reçu une greffe de rein, une Cs doit être systématiquement recherchée. Le diagnostic s’effectue par recherche de l’ADN de Cs par PCR sur les selles, et non sur parasitologie des selles standard. L’examen direct avec ou sans coloration est moins sensible et moins spécifique, opérateur dépendant, mais moins coûteux. Une biopsie colique en zone saine est conseillée. Le traitement associe nitazoxandine (N) et paramomycine (P) ou macrolide pour plusieurs semaines, jusqu’à négativation des contrôles hebdomadaires des selles. Nécessité de diminuer l’immunodépression, isolement contact et traitement du sol par eau de javel non diluée.
Les patients ayant eu une greffe de rein sont une population à risque pour la Cs. Chez un patient greffé, une diarrhée inexpliquée ne doit pas être attribuée trop rapidement au traitement immunosuppresseur (MMF), mais doit faire rechercher systématiquement une Cs.
Atherosclerotic cardiovascular disease is the leading cause of the increased morbidity and mortality observed in uremic patients. Thrombosis is an important contributor to the evolution of ...atherosclerotic lesions. The physiologically-relevant blood clotting depends on binding of activated factor VII (FVIIa) to exposed tissue factor (TF) on activated/damaged cells.
A cross-sectional study was performed on three age- and sex-matched groups of individuals: one group of 50 patients on maintenance hemodialysis (D group), one of 50 patients with a non-dialysed renal insufficiency (ND group) and one of 50 healthy controls (HC group). We studied basal plasma concentrations of FVIIa, factor VII-related antigen (FVIIAg), soluble TF, tissue factor pathway inhibitor (TFPI), TF-dependent circulating monocytes procoagulant activity (TF-dMPA), tissue factor-dependent plasma reactivity to activated protein C (TF-aPC), D-dimers (D-Di), and circulating markers of cellular activation/injury: soluble thrombomodulin (sTM), circulating microparticles (microP), soluble leukocyte, endothelial and platelet selectins (sL-selectin, sE-selectin, sP-selectin), soluble intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 (sICAM-1 and sVCAM-1). Their variations induced, in hemodialysis patients, by a dialysis run were thereafter studied
Values of FVIIa, FVIIa/FVIIAg ratio, sTF, TFPI, TF-dMPA, D-Di, sTM, microP, sL, sE and sP selectins, sICAM-1 and sVCAM-1 increased all along the hierarchy HC group/ND group/D group. Microparticles were mainly of platelet origin, to a lesser extent of monocyte origin. Dialysis induced an increase of FVIIa, sTF, TF-dMPA and circulating markers of cellular activation/injury. Strong correlations were observed between FVIIa/FVIIAg ratio and serum creatinine levels, sTF, TF-dMPA, sTM, sE-selectin, sVCAM-1. The TF-aPC was impaired in the ND and the D group, and the lower values were, in the D group, associated with antecedents of vascular access thrombosis.
Renal insufficiency is associated to an activation of the tissue factor coagulation pathway, to a platelet, monocyte and endothelial activation/injury and to a deficient tissue-factor induced response to activated protein C which culminate in end-stage disease and are increased by hemodialysis runs. This contributes to linked coagulation and cellular conditions for an enhanced atherosclerosis progression. Due to the TF pathway activation, the therapeutic use of recombinant TFPI should be evaluated.
Since 1991 we have used subcutaneous administration of recombinant human erythropoietin (rHuEpo) in predialysis patients selected on the basis of chronic anaemia haemoglobin (Hb) < 7.5 g% without any ...extrarenal cause and chronic renal failure with a creatinine clearance of less than 10 ml/min. rHuEpo was given to 16 predialysis patients with nephropathy, due to chronic glomerulonephritis in all 12 of the cases. The sex ratio was 1:1 and mean age was 65 +/- 9 years (range 43-87). Hb was 7 +/- 0.4 g%. rHuEpo was injected subcutaneously thrice weekly while iron was given orally systematically before rHuEpo administration. Follow-up was performed monthly until dialysis (mean 9 months). Anaemia was corrected in all cases (Hb 11 +/- 0.5 g%). Mean Epo dose was 53 +/- 26 IU/kg/week in males and 47 +/- 11 IU/kg/week in females. Iron was systematically added (Fe2+ 8.2 mg/kg/week). Every patient had improved physical and intellectual ability after rHuEpo within the first month. No adverse side effects were noted but all patients were under antihypertensive therapy (one to three drugs). Serum potassium was unchanged. Mean creatinine before treatment was 507 mumol/l, and was 820 mumol/l after the treatment. Progression of renal failure was only affected by rHuEpo in one patient. In this case renal failure progression decreased. There was no significant alteration in the slope of the creatinine curve from 12 months before to after rHuEpo. Ten patients underwent dialysis (five CAPD, five haemodialysis), while six remained dialysis free. From January 1991 to December 1993 rHuEpo was given to 12.3% of the end-stage renal failure patients on dialysis.
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