No abstract

Communicated by Maria Rita Passos-BuenoMalignant hyperthermia (MH) is a dominantly inherited pharmacogenetic condition that manifests as a life-threatening hypermetabolic reaction when a susceptible individual is exposed to common volatile anesthetics and depolarizing muscle relaxants. Although MH appears to be genetically heterogeneous, RYR1 is the main candidate for MH susceptibility. However, since molecular analysis is generally limited to exons where mutations are more frequently detected, these are routinely found only in 30-50% of susceptible subjects. In this study the entire RYR1 coding region was analyzed in a cohort of 50 Italian MH susceptible (MHS) subjects. Thirty-one mutations, 16 of which were novel, were found in 43 individuals with a mutation detection rate of 86%, the highest reported for RYR1 in MH so far. These data provide clear evidence that mutations in the RYR1 gene are the predominant cause of MH.

Aims: In atrial fibrillation (AF) patients, age z75 years is one of the major risk factors for stroke. However, it is not clear if an upper limit for the indication to OAT exists. Methods and results: For this reason, we performed a prospective study on 290 AF patients on OAT aged z75 years (median age 82 years, total follow-up period 814 pt/ years) followed by our Anticoagulation Clinic. Seventeen major bleeding events were recorded (rate 2.1 × 100 pt/years), 11 of which cerebral (1.35 × 100 pt/years). The occurrence of major bleedings was associated with history of previous TIA or stroke [OR 3.4 (1.1-12.5), p = 0.01] and with diabetes .7) p = 0.01]. We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS 2 score: patients with score 4-6 showed a rate of 3.4 × 100 pt/years with respect to 1.5 × 100 pt/years of patients with lower score. Number Needed to Harm (NNH) was calculated in relation to different classes of age (75-89, 80-84, z85 years) and to CHADS 2 score. For patients in CHADS 2 score 1-3 NNH remained stable across the different age classes. Instead for patients in CHADS 2 score 4-6, NNH varied among the 3 groups of ages, reaching a value of 10 in patients ≥ 85 years. Conclusion: Our data suggest that: 1) in AF patients older than 75 years with CHADS 2 score 1-3 the risk of bleeding is low, 2) in AF patients N85 years with CHADS 2 4-6 the risk of bleeding is high so that the use of OAT should be highly individualised.

The present study showed that the eNOS G894T polymorphism is a mild modulator of the predisposition to AAA apart from traditional risk factors, suggesting a genetic influence on the molecular mechanisms responsible for this complex disease.