Heterogeneity in the processing of ClC-5 mutants related to Dent disease

International audienceMutations in the electrogenic Cl-/H+ exchanger ClC-5 gene CLCN5 are frequently associated with Dent disease, an X-linked recessive disorder affecting the proximal tubules. Here, we investigate the consequences in X. laevis oocytes and in HEK293 cells of 9 previously reported, pathogenic, missense mutations of ClC-5, most of them which are located in regions forming the subunit interface. Two mutants trafficked normally to the cell surface and to early endosomes, and displayed complex glycosylation at the cell surface like wild-type ClC 5, but exhibited reduced currents. Three mutants displayed improper N-glycosylation, and were non-functional due to being retained and degraded at the endoplasmic reticulum. Functional characterization of four mutants allowed us to identify a novel mechanism leading to ClC-5 dysfunction in Dent disease. We report that these mutant proteins were delayed in their processing and that the stability of their complex glycosylated form was reduced, causing lower cell surface expression. The early endosome distribution of these mutants was normal. Half of these mutants displayed reduced currents, whereas the other half showed abolished currents. Our study revealed distinct cellular mechanisms accounting for ClC-5 loss-of-function in Dent disease

Exploring a New Simulation Approach to Improve Clinical Reasoning Teaching and Assessment: Randomized Trial Protocol

Helping trainees develop appropriate clinical reasoning abilities is a challenging goal in an environment where clinical situations are marked by high levels of complexity and unpredictability. The benefit of simulation-based education to assess clinical reasoning skills has rarely been reported. More specifically, it is unclear if clinical reasoning is better acquired if the instructor's input occurs entirely after or is integrated during the scenario. Based on educational principles of the dual-process theory of clinical reasoning, a new simulation approach called simulation with iterative discussions (SID) is introduced. The instructor interrupts the flow of the scenario at three key moments of the reasoning process (data gathering, integration, and confirmation). After each stop, the scenario is continued where it was interrupted. Finally, a brief general debriefing ends the session. System-1 process of clinical reasoning is assessed by verbalization during management of the case, and System-2 during the iterative discussions without providing feedback

Hemodynamic effects of fluid restriction in preterm infants with significant patent ductus arteriosus

Objective: To determine the hemodynamic impact of fluid restriction in preterm newborns with significant patent ductus arteriosus. Study design: Newborns ≥24 and <32 weeks' gestational age with significant patent ductus arteriosus were eligible for this prospective multicenter observational study. We recorded hemodynamic and Doppler echocardiographic variables before and 24 hours after fluid restriction. Results: Eighteen newborns were included (gestational age 24.8 ± 1.1 weeks, birth weight 850 ± 180 g). Fluid intake was decreased from 145 ± 15 to 108 ± 10 mL/kg/d. Respiratory variables, fraction of inspired oxygen, blood gas values, ductus arteriosus diameter, blood flow-velocities in ductus arteriosus, in the left pulmonary artery and in the ascending aorta, and the left atrial/aortic root ratio were unchanged after fluid restriction. Although systemic blood pressure did not change, blood flow in the superior vena cava decreased from 105 ± 40 to 61 ± 25 mL/kg/min (P < .001). The mean blood flow-velocity in the superior mesenteric artery was lower 24 hours after starting fluid restriction. Conclusions: Our results do not support the hypothesis that fluid restriction has beneficial effects on pulmonary or systemic hemodynamics in preterm newborns. © 2012 Mosby, Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Novel CLCN5 mutations in patients with Dent’s disease result in altered ion currents or impaired exchanger processing

International audienc

Efficacy and Tolerance of Rituximab in IgG4-Related Disease: A retrospective Multicentric Study in 24 patients

info:eu-repo/semantics/publishe

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients

Objectives: To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. Methods: Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. Results: Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia 5 g/l in 3 patients. Conclusion: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Kaplan-Meier plots of the risk of disease relapse following rituximab for patients with IgG4-RD RI >9 and with IgG4-RD RI ≤9 at RTX treatment.

<p>IgG4-RD RI, IgG4-related disease Responder Index.</p

Clinical, biological and radiological efficacy of RTX in 33 patients with IgG4-RD.

<p>Clinical, biological and radiological efficacy of RTX in 33 patients with IgG4-RD.</p

Kaplan-Meier plots of the risk of disease relapse following rituximab in 31 IgG4-RD responding patients.

<p>Kaplan-Meier plots of the risk of disease relapse following rituximab in 31 IgG4-RD responding patients.</p