Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy

Background. Duchenne Muscular Dystrophy (DMD) is characterized by increased muscle damage and an abnormal blood flow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesis of DMD and functional ischemia was unclear. We examined (i) whether functional ischemia is necessary to cause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage. Methodology/Principal Findings. In vivo microscopy was used to document assays developed to measure intramuscular red blood cell flux, to quantify the amount of vasodilatory molecules produced from myofibers, and to determine the extent of myofiber damage. Reversal of functional ischemia via pharmacological manipulation prevented contraction-induced myofiber damage in mdx mice, the murine equivalent of DMD. This result indicates that functional ischemia is required for, and thus an essential cause of, muscle damage in mdx mice. Next, to determine whether functional ischemia alone is enough to explain the disease, the extent of ischemia and the amount of myofiber damage were compared both in control and mdx mice. In control mice, functional ischemia alone was found insufficient to cause a similar degree of myofiber damage observed in mdx mice. Additional mechanisms are likely contributing to cause more severe myofiber damage in mdx mice, suggestive of the existence of a ‘‘two-hit’ ’ mechanism in the pathogenesis of this disease. Conclusions/Significance. Evidence was provided supporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, the first quantitative evidence for the ‘‘two-hit’ ’ mechanism in this disease was documented. Significantly, the vasoactive dru

Risk factors for coronary heart disease in middle-aged men in Crete in 1982.

Risk factors for coronary heart disease were studied in healthy middle- aged Cretan men in order to compare them with the middle-aged men of a previous generation studied in 1960 as the Cretan cohort of the Seven Countries Study (1960). In the present cohort mean values for total cholesterol were 5.48 mmol/L, for HDL-cholesterol 1.26 mmol/L, for triglycerides 1.41 mmol/L, for systolic blood pressure 128 mmHg, and for diastolic blood pressure 77 mmHg. Serum cholesterol was higher and blood pressure slightly lower than the values observed in 1960. However, it is uncertain whether these changes were real or caused by changes in methodology. The mean body mass index has increased from 22.6 in 1960 to 26.9 kg/m2 in 1982, due to an increase in fatness. The percentage of smokers had increased from 57.4% to 74.1%. Upon multiple regression analysis the body mass index, the subscapular to triceps skinfold ratio and smoking were negatively and independently related with HDL-cholesterol. Body mass index correlated positively with serum triglycerides. Although the incidence of coronary heart disease is still low in Crete, it is concluded that there is nothing in the risk profile of these middle-aged men to suggest that they are at a low risk for coronary heart disease