Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases ...documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
Background
Limited prospective data exist about the clinical relevance of frailty in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) receiving direct oral anticoagulants ...(DOACs). The aim of this study was to evaluate whether frailty phenotype identifies DOAC‐treated patients at higher risk of adverse clinical outcomes.
Methods
Consecutive, adult outpatients treated with DOACs for AF or VTE were prospectively enrolled. Patients were classified as frail, pre‐frail, or non‐frail according to frailty phenotype. Study outcomes were clinically relevant bleeding, including major and clinically relevant non‐major bleeding, arterial and venous thromboembolism, and all‐cause mortality.
Results
236 patients (median age 78 years, 44% females) were included, of whom 156 (66%) had AF and 80 (34%) VTE. Ninety‐eight (41%) patients were frail, 115 (49%) pre‐frail, and 23 (10%) non‐frail. Inappropriately high or low dose DOAC was used in 33% of frail and in 20% of non‐frail or pre‐frail patients. Over a median follow‐up of 304 days, the incidence of clinically relevant bleeding, thromboembolism, and mortality were 20%, 4%, 9% in frail, and 10%, 3%, and 2% in pre‐frail, respectively, while no study outcome occurred among non‐frail patients. Risk ratios (95% confidence intervals) for these outcomes in frail versus pre‐frail and non‐frail patients were respectively 2.5 (1.8, 3.7), 1.9 (0.9, 4.0), and 6.3 (2.9, 13.6).
Conclusion
In a prospective cohort of ambulatory patients receiving DOAC treatment for AF or VTE, frailty phenotype identified patients at higher risk of bleeding and all‐cause mortality. Frailty assessment could be valuable to guide targeted interventions potentially improving patient prognosis.
The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial ...Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.
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