The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy.
The prognostic factors for amputation following envenoming by snakes of the Bothrops genus were identified from the medical records of 3139 patients. Each of these patients had been bitten by Bothrops sp. and treated in the Hospital Vital Brazil, in São Paulo, Brazil, between 1981 and 1990. The 21 (0.67%) of the patients who had undergone amputation were compared with the 3118 who had not, with respect to the characteristics of the accident, the snake, the victim, the local and systemic manifestations of the envenoming and the treatment. There was an association between amputation and the month of the accident, the time of day when the accident happened, the length of the attacking snake, the anatomical region bitten, systemic bleeding and renal failure. Patients bitten in the fingers, during the cooler months, between 00.00 and 12.00 hours and/or by snakes > 60 cm in length, who developed blisters and abscesses at the site of the bite, systemic bleeding and/or renal failure underwent amputation more frequently than the others (P < 0.05 for each).
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