Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases.

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model "Mitomouse" (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

Attention deficit hyperactivty disorder in Korean juvenile delinquents.

This study was conducted to identify attention deficit hyperactivity disorder (ADHD) in Korean juvenile delinquents. Intelligence tests (KEDI-WISC, K-WAIS), the Test of Variables of Attention (TOVA), the Teacher Report Form (TRF), the Youth Self-Report (YSR), and the Rosenberg Self-Esteem Scale were administered to 98 incarcerated Korean adolescents (the delinquent group) and 84 adolescent nondelinquents (the control group). The groups were compared, and significant differences were found for ADHD; 42.4% of the adolescents in the delinquent group were identified as having ADHD, in comparison to 11.9% of the adolescents in the control group. Delinquent adolescents and adolescents with ADHD were found to have lower IQ scores, poorer TOVA performance, more severe problem behaviors, and lower self-esteem than nondelinquent adolescents and adolescents without ADHD. Delinquent adolescents with ADHD consistently fared the worst on assessments of intelligence, TOVA performance, problem behaviors, and self-esteem.

A clinical consideration of systemic embolism complicated to infective endocarditis in Korea.

OBJECTIVES: Infective endocarditis is still one of the important fatal diseases in Korea, especially when systemic embolisms are supervene. So, identification of patients who are in the high risk of embolism and who can be helped by early surgical intervention is very important. Considering these, we tried to elaborate the risk factors for the systemic embolism in patients with an infective endocarditis and the influence of systemic embolism on the mortality and morbidity in patients with an infective endocarditis. METHODS: We retrospectively reviewed the clinical records of 97 patients who were admitted with the infective endocarditis between January 1983 and October 1993. RESULTS: Among 97 patients, 80 patients met our diagnostic criteria. The mean age of patients was 38 years old. There were 43 males and 37 females. The mean duration of fever since the fever developed by history was 38 days. Valvular heart disease was the most frequent underlying heart disease. Mitral regurgitation and aortic regurgitation were the most common among valvular heart diseases. Pneumonia and acute pharyngotonsillitis were the most frequent predisposing factors of infective endocarditis. Blood cultures were positive in 51 patients (63.8%). Streptococcus viridans was the organism isolated most frequently, and Staphylococcus aureus was the second most frequently isolated one. Vegetations were detected in 58 patients (76.3%) by an echocardiography. Mitral valve and aortic valve were the most frequently involved incidence rate of embolism was 50% and the most frequent embolism site was the central nervous system and extremities were the next. Embolism occurred at the mean of 37 days after onset of fever. Overall in-hospital mortality rate was 26.3% and a cardiac-origin was the major cause of death. The only statistically significant risk factor for mortality was systemic embolism. The analysis of the relation between an incidence of embolism and the multivariables (age, presence of vegetation, location of vegetation, size of vegetation, causative organisms) showed that only the growth of Staphylococcus aureus had a significant trend toward a risk of subsequent systemic embolism. CONCLUSION: This study suggests that systemic emboli increases the mortality rate in patients with infective endocarditis. Age of patients, presence of vegetation, size and location of vegetation are not the risk factors for embolism, while certain organism, especially Staphylococcus aureus, could be a risk factor for the systemic embolism.

Increased alpha 1- and decreased alpha 2-adrenoceptor sensitivities upon chronic treatment with imipramine in mediating cardiovascular responses in pithed rats.

After chronic treatment with imipramine (20 mg/kg, i.p., twice daily for 14 days) the pressor dose-response curves to phenylephrine, methoxamine and cirazoline (alpha 1-adrenoceptor agonists) significantly shifted to the left with decreased PD50 values in pithed rats; however, the dose-response curve to Sgd 101/75, a selective alpha 1-adrenoceptor agonist was not affected. On the other hand, the alpha 2-adrenoceptor agonists such as B-HT 920, xylazine and clonidine produced a rightward shift for both the pressor (increased PD50) and cardioinhibition (increased ID50) dose-response curves in these rats. These results required treatment with imipramine over 2 weeks. Chronic treatment with imipramine has reduced the antagonism by prazosin of the pressor effect of phenylephrine when compared with the dose-ratios between the 2 groups. On the contrary, the antagonism by piperoxan of the cardioinhibitory effect of B-HT 920 was rather enhanced by the treatment, but that of the pressor effect of B-HT 920 was little changed. In cerebrocortical membrane fractions obtained from rats pretreated with imipramine, Ki of phenylephrine to displace [3H]prazosin was decreased, whereas that of clonidine and yohimbine to displace [3H]yohimbine was increased. In conclusion, it is demonstrated that after chronic imipramine treatment the peripheral alpha 2-adrenoceptors (both presynaptic and postsynaptic sites) as well as central alpha 2-adrenoceptors respond with a decreased sensitivity to the alpha 2-adrenoceptor agonists, and moreover, this treatment produces an increased sensitivity of the central and peripheral alpha 1-adrenoceptors to the alpha 1-adrenoceptor full agonists.