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This study presents the results of probabilistic seismic hazard (PSH) deaggregation for 5 %-damped 0.2 and 1.0 s spectral accelerations, corresponding to mean return periods (MRPs) of 50, and 475 yr for Tehran city. The aim of this paper is to quantify the dominant events that have the most contribution on ground-motion exceedance from the above mentioned hazard levels. The scenario earthquakes are characterized by bins of magnitude (M), source-to-site distance (R), and epsilon (ε). The results reveal that for Tehran city, the hazard is mainly controlled by local seismicity. Generally, as the spectral acceleration period increase, the contribution of larger and more distant scenario earthquakes to the overall seismic hazard increase. [ABSTRACT FROM AUTHOR]

Purpose: The development of multidrug resistance (MDR) is one of the major limitations in the treatment of cancer. Induction of P-glycoprotein (Pgp) has been regarded as one of the main mechanisms underlying anticancer drug-induced MDR. Since the induction of Pgp is (in part) regulated by the pregnane X receptor (PXR), the ability of several widely used anticancer drugs to activate PXR-mediated Pgp induction was investigated.Methods: A Pgp-reporter gene assay was employed to determine the ability of a panel of widely used anticancer drugs to induce Pgp. To further assess whether PXR could be involved in the induction of Pgp by anticancer drugs, Pgp protein expression after treatment with the anticancer drugs was determined in both wild-type and PXR-knocked down LS180 cells. Furthermore, the effect of the anticancer drugs on the intracellular accumulation of the Pgp-probes rhodamine 123 and doxorubicin was determined.Results: Our study showed that vincristine, tamoxifen, vinblastine, docetaxel, cyclophosphamide, flutamide, ifosfamide and paclitaxel activate PXR-mediated Pgp induction, and were additionally shown to affect the intracellular accumulation of the Pgp probe rhodamine 123. Moreover, PXR activation was also shown to reduce the cytotoxic activity of the Pgp substrate doxorubicin in colon cancer cells.Conclusion: Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates. [ABSTRACT FROM AUTHOR]

Induction of cytochrome P450 (CYP) 3A4, an enzyme that is involved in the biotransformation of more than 50% of all drugs, by xenobiotics is an important cause of pharmacokinetic drug–drug interactions in oncology. In addition to rifampicin and hyperforin, the anticancer drug paclitaxel has also been shown to be an inducer of CYP3A4 via activation of the pregnane X receptor (PXR). We therefore screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1’-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. Paclitaxel, erlotinib, tamoxifen, ifosfamide, flutamide and docetaxel are able to activate PXR, while only strong PXR activation leads to significant induction of CYP3A4 activity. The identified PXR agonists may have the propensity to cause clinically relevant drug–drug interactions as a result of CYP3A4 induction. [ABSTRACT FROM AUTHOR]

Background. Debridement and retention of the prosthesis represents an attractive surgical modality for treatment of prosthetic joint infection, but risk factors for treatment failure require clarification. Methods. We conducted a retrospective cohort analysis of all patients with a prosthetic joint infection who were treated with debridement and retention of the prosthesis at the Mayo Clinic (Rochester, Minnesota) between 1995 and 1999. Results. Debridement and retention of the prosthesis was the initial treatment modality for 99 episodes of prosthetic joint infection that occurred in 91 patients who presented to the Mayo Clinic during 1995-1999. A total of 32% and 23% of all episodes were due to Staphylococcus aureus and coagulase-negative staphylococci, respectively. The median duration of intravenous antimicrobial therapy was 28 days (range, 1-90 days). Oral antimicrobial suppression was used in 89% of the episodes, for a median duration of 541 days (range, 5-2673 days). Treatment failure occurred in 53 episodes during a median follow-up period of 700 days (range, 1-2779 days). The 2-year survival rate free of treatment failure was 60% (95% confidence interval [CI], 50%-71%). Variables associated with an increased risk of treatment failure in multivariable analysis included the presence of a sinus tract (hazard ratio, 2.84; 95% CI, 1.48-5.44; P = .002) and a duration of symptoms prior to debridement of ⩾8 days (hazard ratio, 1.77; 95% CI, 1.02-3.07; P = .04). Conclusions. Debridement and retention of the prosthesis is a common surgical modality at our institution to treat prosthetic joint infection. Risk factors independently associated with treatment failure include the presence of a sinus tract and duration of symptoms prior to debridement of ⩾8 days. [ABSTRACT FROM AUTHOR]