Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans

Avant-propos

Andlauer Philippe, Le Cacheux Jacques, Schmitt Bertrand. Avant-propos. In: Économie rurale. N°225, 1995. pp. 2-3

Acute and chronic nephropathy induced by fluindione must be addressed.

International audienceBACKGROUND: Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis. METHODS: Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA. RESULTS: The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 μmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 μmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione. CONCLUSION: In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed