Combination treatment with statins and bezafibrate induces myotoxicity via inhibition of geranylgeranyl pyrophosphate biosynthesis and Rho activation in L6 myoblasts and myotube cells.

Statins and fibrates are frequently used to treat hyperlipidemia; however, these drugs may have adverse effects such as rhabdomyolysis. The incidence of rhabdomyolysis due to fibrates and statins is low (0.0028-0.0096%) when administered as monotherapy, however it increases to 0.015-0.021% when the drugs are used in combination. The mechanism underlying myotoxicity induced by the combination of statins and fibrates is yet unclear. Here, we investigated the mechanisms underlying induced myotoxicity in rat myoblasts L6 and differentiated L6 cells (myotubes) using a combination of statins and fibrates. We found that cell death induced by a combination of fluvastatin or simvastatin with bezafibrate or fenofibrate in L6 myoblasts and myotubes was mediated by inhibition of geranylgeranyl pyrophosphate (GGPP) production. Additionally, the drug combination inhibited Rho activation in L6 myoblasts and myotube cells. In L6 myoblasts, the combination of statins and bezafibrate enhanced p27 expression and induced G1 arrest and apoptosis. Furthermore, combined treatment suppressed Akt activation and enhanced Bim expression in L6 myotubes but did not affect extracellular regulated protein kinase 1/2 activation. These results suggested that combined administration of statins and fibrates induced death of L6 myoblasts and myotube cells by inhibiting GGPP biosynthesis and Rho pathway activation. Supplementation with GGPP may be therapeutically beneficial for preventing myotoxicity associated with combined statin and fibrates treatment.

[Late asthmatic response by recruitment of homocytotropic antibody from circulating blood to the airway wall in guinea pig].

Many reports have been published about the late asthmatic response (LAR) of animal model. But most of the animals used were sensitized actively and it is considered generally that it is impossible to generate LAR in passively sensitized animals, especially in guinea pig. About the mechanism of LAR, most discussion are focused on airway hyperreactivity, inflammation and chemical mediators. But little is known about the direct initiator of the late phase bronchoconstriction. Instead of the circulating antibody which is generated by antibody producing cells in actively sensitized animals, anti-serum was administered to guinea pigs intravenously as passive sensitization fifteen minutes prior to antigen inhalation. Four to eight hours after antigen inhalation, we investigated bronchoconstriction. Eight hours after antigen challenge, bronchoalveolar lavage (BAL) were performed. In the BAL fluid, macrophages decreased and neutrophils increased significantly. These results suggest that LAR can occur without airway inflammation and the inflammation might be the result of antigen-antibody reaction at the airway wall, and that the direct initiator of late phase bronchoconstriction might be the recruitment of homocytotropic antibody from circulating blood to the airway wall.

[Clinical experience of epididymovasostomy and vasovasostomy for obstructive azoospermia].

PIP: 14 patients with obstructive azoospermia were treated with microsurgical vasovasostomy or epididymovasostomy. A total of 11 patients underwent 2-layer vasovasostomy, 6 cases following bilateral vasectomy and 5 cases suffering from bilateral vasal disruption by inguinal herniorrhaphy. 3 patients underwent end-to-end epididymovasostomy with Silber's specific tubule technique following bilateral epididymitis. After the operation, fertility was restored in 6 of 14 cases. The recovered sperm density was greater than 20 x 10 6/ml and sperm motility exceeded 50%. Pregnancy was achieved in 1 case following inguinal herniorrhaphy. Preoperative testicular biopsies carried out in 11 cases disclosed slight deterioration of spermatogenesis. Johnsen's mean score was 8.20 +or- 0.38 (mean +or- S.D.). The mean scores of the biopsies obtained from the cases obstructed for more than 20 years were significantly lower than those with less than a 20-year time period. After inguinal herniorrhaphy, reanastomosis of the vas deferens was difficult in order to restore fertility. This was due to the presence of longterm obstruction, defects in the vas deferens, or the absence of sperm granuloma at the vasectomy site. Epididymovasostomy restored fertility in 67% of the cases. The specific tubule technique was the most effective in the management of such pathological conditions. (author's modified)^ieng

[Functional preservation in cancer surgery of the large intestine].

Distal Surgical margin, required in the sphincter preserving operation for rectal cancer was studied histologically on the 78 resected specimens. The extramural cancer spread, examined by clearing method, was found in 20.5%, and was more frequent and expansive compared to intramural spread of cancer. No distal spread was found in cancer limited to the rectal wall. Length of the spread by 3 cm in lower rectal cancer and 4 cm in the upper rectal cancer. Postoperative anal function showed a good or fair in patients with internal sphincteric function preserved. Postoperative dysuria and male sexual disturbance showed a close relation to the pelvic nodes dissection. Ro-dissection was followed by 20% of dysuria, while RI and R 2 46.7%, R 3 1.8%.