Dehydrated hereditary stomatocytosis (DHS) is a genetic condition with defective red blood cell (RBC) membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations inthe mechanically activated PIEZO1(FAM38A) ion channel were associated with DHS. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated DHS cases, we identifythree novel missense mutations and one recurrent duplication in PIEZO1, demonstrating that it is the major gene for DHS. All the DHS-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in RBCs of DHS patients. Our findings also suggest a new role for mechanotransduction in RBC biology and pathophysiology.
Objective. Management of nonviral cryoglobulinemia vasculitis has yet to be defined. Rituximab has emerged as a novel and promising therapeutic alternative, but data are scarce. Our objective was to evaluate the safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis in off-trial real-life patients. Methods. Prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with rituximab in off-label conditions, were analyzed. Results. Twenty-three patients received treatment with rituximab for cryoglobulinemia vasculitis. Tolerance was marked by the occurrence of side effects in almost half of the patients, including severe infections in 6 (26%) of 23, with a rate of 14.1 per 100 patient-years. These infections occurred in a particular subset of patients ages >70 years, with essential type II mixed cryoglobulinemia and renal failure with a glomerular filtration rate of <60 ml/minute, and receiving high-dose corticosteroids. Three of these patients died. In contrast, clinical and immunologic efficacy was noted in all evaluable patients. Clinical relapses occurred in half of the patients after a median time of 13.5 months following rituximab administration, and were more frequent in patients refractory to previous immunosuppressive therapy than in previously untreated patients. Conclusion. Data from the AIR registry show a dramatic efficacy and a steroid-sparing effect of rituximab, but also show the occurrence of severe infections in elderly patients with renal failure and high-dose steroids. The role of rituximab in nonviral cryoglobulinemia vasculitis remains to be defined in well-designed randomized controlled trials.
The prevalence of occult hepatitis B infection in HIV infected patients is controversial, varying from less than 1% to 62% in different studies. Blood samples of 111 HIV-infected patients, HCV-positive, HBs antigen negative, followed in the APROCO-ANRS EP11 cohort, were used to detect HBV DNA by using 2 different validated assays (Cobas Amplicor HBV Monitor Test and INSERM U271 qualitative ultra-sensitive PCR), completed when positive by HBV real-time PCR. HBV DNA was found in 6 (5.4%, 95% CI 1.2%-9.6%) patients by at least 1 of these assays, but none tested positive in all 3 assays. All 6 patients had anti-HBc without anti-HBs antibodies; 5 were not on lamivudine. Their median CD4 and CD8 counts were significantly lower and their HIV viral load higher than in the other 105 patients. In conclusion, the prevalence of occult hepatitis B may vary significantly according to the molecular assay used, even though these assays are validated with high specificity and quite high sensitivity. Occult hepatitis B may be encountered in HIV-HCV coinfected patients without anti-HBV treatment, with anti-HBc but without anti-HBs antibodies, and relatively low immunity, suggesting a potential risk of further reactivation, as already sporadically reported.
In the first paragraph of the Methods section in this Article, case 8 (K8 in Table 1) was incorrectly referred to as case 4. The following is the correct sentence: 'Case 8 (ref. 3) and family 3 (refs 32, 33) were case reports, these patients expressed a moderate form of anaemia and haemolysis without initial evidence of perinatal oedema or pseudohyperkalaemia.'
HIV-1 DNA impacted the virological response in our cohort. Further research is warranted to study the impact of HIV-1 DNA with currently recommended first-line cART.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.