The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-␣ induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1

We previously reported that depletion of glutathione in murine hepatocytes by diethylmaleate (DEM) or acetaminophen (APAP) leads to oxidative stress-dependent necrosis and sensitizes to tumor necrosis factor (TNF)-induced apoptosis in an oxidative stress-independent fashion, which could not be explained by interference with nuclear factor B (NF-B) nuclear translocation. The present report explores the mechanisms of these effects. We observed that DEM led to necrosis when both mitochondrial and cytosol glutathione were depleted profoundly but sensitized to TNF-induced apoptosis when cytosol glutathione was depleted selectively. DEM and APAP lead to a significant decrease in reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Glutathione depletion by DEM or APAP was associated with inhibition of TNF-induced NF-B transactivation of anti-apoptotic genes, including inducible nitric oxide synthase (i-NOS). Provision of exogenous NO partially abrogated the sensitization to TNF in response to glutathione depletion. Glutathione depletion alone led to sustained increase in phospho-jun levels and c-Jun-N-terminal kinase (JNK) activity. JNK inhibitor partially blocked the sensitization to TNF-induced apoptosis accompanying glutathione depletion. In conclusion, these findings suggest that extramitochondrial glutathione depletion alters the thiol-disulfide redox state, leading to inhibition of NF-B transactivation of survival genes and to sustained activation of JNK, both of which contribute to the sensitization to TNF-induced apoptosis.

AIM:To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC). METHODS:Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m 2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m 2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir. RESULTS:The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P < 0.05). CONCLUSION:Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

In a 68-year-old Japanese man, a gastric polyp 24mm in diameter with a stalk 15 mm in diameter was diagnosed as well differentiated adenocarcinoma and treated by endoscopic polypectomy. Histologically, most of the resected tissue was adenoma, and atypical cells were papillarily proliferating to form adenocarcinoma in adenoma, a Nakamura type IV gastric polyp. Infiltration of carcinoma was limited to within the mucosal layer. Immunohistochemical study with anti-CA19-9 antibody revealed positive staining in carcinoma cells. Serum CA19-9 level, which showed slight elevation, returned to the normal range 1 month after the polypectomy. The proliferating cell nuclear antigen (PCNA) labeling index and DNA ploidy pattern were analyzed in the resected tissue. The PCNA labeling index was 30% in carcinoma, 17% in adenoma, and 0.1% in the normal tissue. The DNA ploidy pattern was diploid in adenoma and aneuploid in adenocarcinoma. These findings suggest that gastric adenoma, as well as colonic adenoma, may have the potential for malignant transformation.

Introduction:In daily practice, it is common to experience difficulty in treating decubitus ulcers (pressure ulcers, also known as decubitus ulcers) and stasis dermatitis of the lower limbs. We hereby report that omega-3-acid ethyl esters were remarkably effective when administered to cases of refractory pressure ulcers and stasis dermatitis for the purpose of improving the blood flow and promoting blood circulation.Case Presentation:Case 1: A 21-year-old Japanese female with lower-body paralysis. Pressure ulcers appeared on the heel and first toe of her left lower extremity. Although the patient had been treated with various ointments such as dimethyl isopropylazulene and 0.9% iodine-containing ointment, the course showed no improvement, so omega-3-acid ethyl esters was administered orally, completely healing the ulcer of the first toe in 10 weeks. Case 2: A 76-year-old Japanese male. The patient had been treated on an outpatient basis for 15 years due to hypertension, heart failure, type 2 diabetes mellitus, and hyperlipidemia. Two years prior to this presentation, stasis dermatitis occurred in the lower limbs and at the end of last year, erosive ulcers appeared on the front part of the lower-right thigh and shin. Although treatment with various topical ointment and dressings was performed, the course showed no improvement. Oral administration of omega-3-acid ethyl esters was initiated. At 12 weeks, his condition entered the white phase and healed almost completely.Conclusions:This report is the first to document other treatment possibilities for pressure ulcer and/or stasis dermatitis in cases where the use of topical applied ointments and medications is difficult. This new therapy may therefore help physicians to treat pressure ulcers and stasis dermatitis.