Cholesterol oxidation products are increasingly considered as much more bioactive than the parent compound in the multifactor and multistep process that characterizes atherosclerosis. In particular, 7-ketocholesterol has been reported to induce oxidative stress as well as a marked pro-apoptotic effect in vascular cells including macrophages. With the aim to investigate a possible pathogenic correlation between the two events, cultivated murine macrophages were challenged with a concentration of 7-ketocholesterol actually detectable in human vasculature. Conclusive proof was obtained of a primary role of NADPH-oxidase in the overproduction of reactive oxygen species within cells treated with the oxysterol. In addition, such oxidative burst occurred very early after cell intoxication and it was definitely demonstrated as able to lead cells to apoptotic death. In fact, two metabolic inhibitors of NADPH-oxidase and the antioxidant epicatechin very well counteracted 7-ketocholesterol-induced apoptosis by preventing the oxysterol pro-oxidant action.

Oxysterols are common components of oxidized low-density lipoprotein and accumulate in the core of fibrotic plaques as a mixture of cholesterol and cholesteryl ester oxidation products. The proapoptotic effects of a biologically representative mixture of oxysterols was compared with equimolar amounts of 7-ketocholesterol and unoxidized cholesterol. The oxysterol mixture in a concentration range actually detectable in hypercholesterolemic patients did not stimulate programmed cell death in cultivated murine macrophages. Unoxidized cholesterol also produced no effect. By contrast, when given alone, 7-ketocholesterol strongly stimulated the mitochondrial pathway of apoptosis with cytochrome c release, caspase-9 activation, and eventually caspase-3 activation. Subsequent experiments showed that when 7-ketocholesterol was administered to cells together with another oxysterol, namely 7betaOH-cholesterol, the strong proapoptotic effect of 7-ketocholesterol was markedly attenuated. As regards the mechanism underlying this quenching, we found that the combined oxysterol treatment counteracted the ability of 7-ketocholesterol, when administered alone, to strongly up-regulate the steady-state levels of reactive oxygen species (ROS) without interfering with sterol uptake. Furthermore, this increase in intracellular ROS appeared to be responsible for the up-regulation of proapoptotic factor, p21, after treatment with 7-ketocholesterol but not in cells challenged with the oxysterol mixture. Competition among oxysterols, apparently at the level of NADPH oxidase, diminishes the ROS induction and direct toxicity that is evoked by specific oxysterols. As a consequence, a more subtle gene modulation by oxysterols becomes facilitated in vascular cells.

developed a Markov analysis decision tree for Japanese patients with HCV-I b infection, and compared six strategies of IFN treatment using the Quality Adjusted Life Years (QALYs).Patients and Methods: The Markov simulation followed a cohort of Japanese patients with HCV-lb infection (age; 40 years old).Data were based on our clinical data for 397 patients and the Medline literature from 1966 to 1999.The utilities of the patients were surveyed prospectively using Japanese Health Utilities Index mark 2, 3 SU l5Q that had been translated in accordance with the IQOLA guidelines cooperated by the McMaster group.Strategy I was that patients with the mutant (more than 4 amino acid changes in ISDR) and intermediate (I to 3 amino acid changes) were treated with IFN but those with the wild (no amino acid changes) were not treated.Srategy 2 was that the mutant was treated, but the intermediate and wild were not treated if serum HCV-RNA levels were above 0.5 Meq/ml.Strategy 3 was that the mutant and intermediate were treated, but the wild was not treated if HCV-RNA levels were above 0.5 Meq/ml.Strategy 4 was that ISDR typing was not performed and all patients with serum HCV-RNA levels below 0.5 Meq/ml were treated.Strategy 5 was that all patients were treated and Strategy 6 was that all patients were not treated.Results: A baseline analysis showed that Strategy 3 was the most preferable; the QALYs were 34.63.Sensitivity analyses showed that there were four valuables having potential effects on the QALYs; the rate of complete response (CR) in patients with total HCV-I b infection, in patients with the mutant and intermediate ISDR, and in patients whose HCV-RNA levels were below 0.5 Meq/ml.For Strategy 3 to be most preferred, the threshold values of these four factors were 22.7%, 60%, 6%, and 84%, respectively.Conclusion: IFN may not be the first choice of treatment for patients with HCV-Ib infection earring the wild type ISDR if HCV-RNA levels are above 0.5 Meq/ml.6664