ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope

Using Immersive Technologies to Develop Medical Education Materials

Principles of modern surgical education for clerkship and residency were established by the novel approaches of Sir William Osler, MD, Flexner report, and Halsted's principles. The evaluation of surgical education has continued to benefit from the wisdom of the past by harnessing technologies. Rapidly changing and improving the nature of the surgery fostered that evaluation and enforced the institutions to find new solutions for surgical education

Treatment of mild-to-moderate hypertension with calcium channel blockers: A multicentre comparison of once-daily nifedipine gits with once-daily amlodipine

PubMed ID: 12803737Background: Hypertension is one of the most important causes of cardiovascular disease, and treatment of hypertension leads to a significant reduction in cardiovascular mortality and morbidity. Although calcium channel blockers are regarded as an important part of the therapeutic armamentarium against cardiovascular diseases, and are among the most frequently prescribed antihypertensive medications, concern has been aroused about these drugs, particularly the short-acting dihydropyridine derivatives. However, the value of nifedipine GITS (Adalat-Crono*), the long-acting dihydropyridine, is in need of being re-established. Objective: To compare the effectiveness, safety and tolerability of once-daily nifedipine and amlodipine treatment in patients with mild-to-moderate essential hypertension. Design: Randomised multicentre trial with an open comparison of treatments for 12 weeks, with a preceding placebo run-in period of 2 weeks (patients on beta-blockers at the time of enrolment entered a mandatory 2-week wash-out period before being allowed in the placebo run-in period; this wash-out period was one week for patients using any antihypertensive medication other than beta-blockers). Setting: Nine centres (all university hospitals) in Turkey. Patients: 155 patients with essential hypertension (diastolic blood pressure 95-109 mmHg). Interventions: Initial treatment (step 1) consisted of 30 mg nifedipine GITS (n = 76; (Adalat-Crono tablets), or 5 mg amlodipine (n = 79; Norvasc† 5-mg tablets), either administered once daily, as a morning dose, or if the blood pressure was not below 140/90 mmHg, or the reduction in diastolic blood pressure was lower than 10 mmHg after a treatment period of 6 weeks, the dose was increased (Step 2) to 60 mg once daily in the nifedipine group, or 10 mg once daily in the amlodipine group. Main efficacy parameter: Diastolic blood pressure at trough after 12 weeks of active compound therapy adjusted to baseline. Results: After 12 weeks of treatment, the mean diastolic blood pressure was 83.1 and 81.9 mmHg, in the nifedipine and amlodipine groups, respectively (p = 0.436). The mean decrease in systolic blood pressure (28.5 ± 11.9 and 28.2 ± 11.2 mmHg in the nifedipine and amlodipine groups, respectively) and the mean decrease in diastolic blood pressure (16.4 ± 7.0 and 17.5 ± 6.9 mmHg in the nifedipine and amlodipine groups, respectively), as well as the responder rates (88.1 % and 92.1%, in the nifedipine and amlodipine groups, respectively) were comparable at the end of the study. No significant differences between groups were detected in the efficacy parameters assessed in this study. Both drugs were well tolerated. The overall incidence of adverse events was 7.9% in the nifedipine group and 10.1% in the amlodipine group. However, more patients discontinued treatment prematurely in the amlodipine group (13 patients; 19.7%), than in the nifedipine group (four patients; 5.6%). Conclusions: The results of this study demonstrated that once-daily nifedipine in GITS formulation and amlodipine are comparably safe and effective treatment options in patients with mild-to-moderate essential hypertension.BayerThis study was funded by Bayer, Turkey. -

Treatment of mild-to-moderate hypertension with calcium channel blockers: a multicentre comparison of once-daily nifedipine GITS with once-daily amlodipine

WOS: 000183228900011PubMed ID: 12803737Background: Hypertension is one of the most important causes of cardiovascular disease, and treatment of hypertension leads to a significant reduction in cardiovascular mortality and morbidity. Although calcium channel blockers are regarded as an important part of the therapeutic armamentarium against cardiovascular diseases, and are among the most frequently prescribed anti hypertensive medications, concern has been aroused about these drugs, particularly the short-acting dihydropyridine derivatives. However, the value of nifedipine GITS (Adalat-Crono*), the long-acting dihydropyridine, is in need of being re-established. Objective: To compare the effectiveness, safety and tolerability of once-daily nifedipine and amlodipine treatment in patients with mild-to-moderate essential hypertension. Design: Randomised multicentre trial with an open comparison of treatments for 12 weeks, with a preceding placebo run-in period of 2 weeks (patients on beta-blockers at the time of enrolment entered a mandatory 2-week wash-out period before being allowed in the placebo run-in period; this wash-out period was one week for patients using any antihypertensive medication other than beta-blockers)

Detection Of Patients With Hypertrophic Cardiomyopathy At Risk For Paroxysmal Atrial Fibrillation During Sinus Rhythm By P-Wave Dispersion

Background: Paroxysmal atrial fibrillation (PAF) in hypertrophic cardiomyopathy (HCM) is associated with poor prognosis. Previous studies have shown good correlation between P-wave dispersion (Pd) and occurrence of PAR However, Pd in patients with HCM for predicting PAF has not been studied. Hypothesis: The aim of the study was to determine whether Pd could identify patients with HCM who are likely to suffer from PAF. Methods: Twenty-two patients with HCM with a history of PAF (Group 1) and 26 patients with HCM without a history of PAF (Group 2) were studied. Maximum (Pmax) and minimum (Pmin) P-wave durations, as well as P-wave dispersion (Pd = Pmax-Pmin) were calculated from 12-lead surface electrocardiograms (ECG). Results: P-wave dispersion was significantly different between the groups (Group 1: 55+/-6 ms vs. Group 2: 37+/-8 ms; p < 0.001), while Pmax (Group 1: 134+/-11 ms vs. Group 2: 128+/-13 ms; p = 0.06) and Pmin (Group 1: 78+/-9 ms vs. Group 2: 81+/-7 ms; p = 0.07) was not significantly different. Patients with a history of PAF had higher left atrial diameter than the patients without PAF (Group 1: 52+/-8 mm vs. Group 2:48+/-10 mm; p = 0.02). A cut-off value of 46 ms for Pd had a sensitivity of 76% and a specificity of 82% in discriminating between patients with and without PAF. Conclusion: This study suggests that P-wave dispersion could identify patients with HCM who are likely to develop PAF.Wo

Supplementary Material for: Mutation Analysis of NPHS1 in a Worldwide Cohort of Congenital Nephrotic Syndrome Patients

<p><b><i>Background:</i></b> Congenital nephrotic syndrome (CNS) is defined as nephrotic syndrome that manifests within the first 3 months of life. Mutations in the <i>NPHS1</i> gene encoding nephrin, are a major cause for CNS. Currently, more than 173 different mutations of <i>NPHS1</i> have been published as causing CNS, affecting most exons. <b><i>Methods:</i></b> We performed mutation analysis of NPHS1 in a worldwide cohort of 20 families (23 children) with CNS. All 29 exons of the NPHS1 gene were examined using direct sequencing. New mutations were confirmed by demonstrating their absence in 96 healthy control individuals. <b><i>Results:</i></b> We detected disease-causing mutations in 9 of 20 families (45%). Seven of the families showed a homozygous mutation, while two were compound heterozygous. In another 2 families, single heterozygous <i>NPHS1</i> mutations were detected. Out of 10 different mutations discovered, 3 were novel, consisting of 1 splice site mutation and 2 missense mutations. <b><i>Conclusion:</i></b> Our data demonstrate that the spectrum of <i>NPHS1</i> mutations is still expanding, involving new exons, in patients from a diverse ethnic background.</p