Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations

Effet de la supplémentation en vitamine D native sur le blocage du système rénine-angiotensine-aldostérone

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Eculizumab Use in Scleroderma Renal Crisis With Thrombotic Microangiopathy: A Case Report

A Black woman in her 40s with past medical history significant for obesity treated with Roux-en-Y bypass surgery and a history of Raynaud’s phenomenon, presented with acute pulmonary edema secondary to severe malignant hypertension and critically accelerated acute kidney injury, with evidence of systemic microangiopathic hemolytic anemia in the setting of clinical suspicion of systemic sclerosis sine scleroderma. Renin-angiotensin system blockade (angiotensin-converting enzyme inhibitor) was immediately started at the maximum possible dose in the setting of scleroderma renal crisis. Despite better control of blood pressure and volume status, kidney function continued to rapidly decline, thus a decision was made to go ahead with a kidney biopsy on day 3 of admission, which revealed severe features of scleroderma renal crisis with active thrombotic microangiopathy. The multidisciplinary team elected to treat the patient with terminal complement blockade using eculizumab in addition to high dose lisinopril and blood pressure control. Her serum creatinine peaked at 9.3 mg/dL shortly after eculizumab initiation, but improved soon after, dropping to 2.8 mg/dL after completion of the final eculizumab dose and 1.8 mg/dL 3 years later

Detection of Drug–Drug Interactions Inducing Acute Kidney Injury by Electronic Health Records Mining

International audienceBackground and Objective : While risk of acute kidney injury (AKI) is a well documented adverse effect of some drugs, few studies have assessed the relationship between drug–drug interactions (DDIs) and AKI. Our objective was to develop an algorithm capable of detecting potential signals on this relationship by retrospectively mining data from electronic health records.Material and methods : Data were extracted from the clinical data warehouse (CDW) of the Hôpital Européen Georges Pompidou (HEGP). AKI was defined as the first level of the RIFLE criteria, that is, an increase ≥50 % of creatinine basis. Algorithm accuracy was tested on 20 single drugs, 10 nephrotoxic and 10 non-nephrotoxic. We then tested 45 pairs of non-nephrotoxic drugs, among the most prescribed at our hospital and representing distinct pharmacological classes for DDIs.Results : Sensitivity and specificity were 50 % [95 % confidence interval (CI) 23.66–76.34] and 90 % (95 % CI 59.58–98.21), respectively, for single drugs. Our algorithm confirmed a previously identified signal concerning clarithromycin and calcium-channel blockers (unadjusted odds ratio (ORu) 2.92; 95 % CI 1.11–7.69, p = 0.04). Among the 45 drug pairs investigated, we identified a signal concerning 55 patients in association with bromazepam and hydroxyzine (ORu 1.66; 95 % CI 1.23–2.23). This signal was not confirmed after a chart review. Even so, AKI and co-prescription were confirmed for 96 % (95 % CI 88–99) and 88 % (95 % CI 76–94) of these patients, respectively.Conclusion : Data mining techniques on CDW can foster the detection of adverse drug reactions when drugs are used alone or in combination

Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease

International audienceBackground - Recent years have seen increasing use of rituximab (RTX) for various types of primary and secondary glomerulopathies. However, there are no studies that specifically address the risk of infection related to this agent in patients with these conditions. Methods - We reviewed the outcomes of all patients who received RTX therapy for glomerular disease between June 2000 and October 2011 in eight French nephrology departments. Each case was analysed for survival, cause of death if a non-survivor and/or the presence of infectious complications, including severe or opportunistic infection occurring within the 12 months following RTX infusion. Results - Among 98 patients treated with RTX, 25 presented with at least one infection. We report an infection rate of 21.6 per 100 patient-years. Five patients died within 12 months following an RTX infusion, of whom four also presented with an infection. The median interval between the last RTX infusion and the first infectious episode was 2.1 months (interquartile range 0.5-5.1). Most infections were bacterial (79%) and pneumonia was the most frequent infection reported (27%). The presence of diabetes mellitus (P = 0.006), the cumulative RTX dose (P = 0.01) and the concomitant use of azathioprine (P = 0.03) were identified as independent risk factors. Renal failure was significantly associated with an increased infection risk by bivariate analysis (P = 0.03) and was almost significant by multivariate analysis (P = 0.05). Nephrotic syndrome did not further increase the risk of infection and/or death. Conclusion - The risk of infection after RTX-based immunosuppression among patients with glomerulopathy must be considered and patients should receive close monitoring and appropriate infection prophylaxis, especially in those with diabetes and high-dose RTX regimens

Far Western blot analysis of the interaction between <i>in-vitro</i> translated wild type GATA4 and wild-type NR5A1, NR5A1p.Arg39Pro and p.Arg313Cys.

<p>Blots containing wild-type NR5A1, NR5A1p.Arg39Pro and NR5A1p.Arg313Cys proteins were incubated with GATA4 protein and probed by anti-GATA4 antibody. Both the wild-type and mutant NR5A1 proteins can bind to GATA4 protein.</p

Plasma AMH and inhibin B concentrations in each patient group.

<p>In each AMH graph the broken lines correspond to the upper and lower limits of the normal range <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024117#pone.0024117-Flatau1" target="_blank">[22]</a>. For inhibin B, the solid line corresponds to the median and the broken lines to the 5^th and 95^th percentiles <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024117#pone.0024117-Rey1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024117#pone.0024117-Andersson1" target="_blank">[24]</a>. The red asterisk indicates individuals carrying an <i>NR5A1</i> heterozygote mutation and the numbers indicate the patients described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024117#pone-0024117-t001" target="_blank">table 1</a>.</p