Oxidation of mitochondrial fatty acids (FA) results in the generation of reactive oxygen species (ROS) which have been postulated to play a key role in the initiation and progression of prostate cancer (PC). We previously reported that androgens increase FA uptake into PC cells. We thus examined if androgens that are known to induce ROS generation regulate FA oxidation in PC cells. The effects of the androgen-depleted medium, R1881 (synthetic androgen) and/or androgen receptor blocker, bicalutamide were examined in the human androgen-responsive but not dependent 22rv1 cells. R1881 supplementation significantly increased mitochondrial FA oxidation ((14)C-radiolabeled FA degradation studies), resulting in increased ROS production. Androgens increased the mRNA levels of carnitine palmitoyltransferase (CPT1), the rate limiting enzyme in the process of mitochondrial FA oxidation. Treatment with R1881 and bicalutamide inhibited these androgen regulated effects. Inhibition of mitochondrial ROS generation by two different inhibitors, rotenone and thenoyltrifluoroacetone, eliminated the androgen-induced ROS generation, to the same level as in cells deprived of androgens or treated with R1881 and bicalutamide. Taken together, androgens increase the mitochondrial oxidation of FA, leading to increased production of ROS that is associated with prostate cell proliferation and mutagenesis. These results therefore support the rationale for PC prevention using 5-alpha reductase inhibitors, dietary restrictions or anti-oxidants, each of which has different inhibitory but complementary effects.
The Del Pozo and Patel (DPP) algorithm permits to identify suitable candidates for debridement and implant retention (DR) in prosthetic joint infections (PJI), but does not include gram-negative bacilli (GNB) as a risk factor of worst outcome. We conducted a retrospective study to validate the DPP algorithm and propose a simplified algorithm including GNB PJI. From 2002 to 2009, 73 PJI underwent surgery; 55% were chosen according to PDD algorithm. Non-adherence increased the risk of treatment failure (HR = 4.2). Performing DR in the presence of GNB PJI and performing DR in a joint prosthesis implanted for >3 months without hematogenous infection were independent risk factors. Our simplified algorithm, based on these 2 criteria, showed comparable performance to the DPP algorithm but increased eligibility for DR by a 2.4 fold.
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