We investigated the significance of endogenous reactive oxygen species (ROS) produced by fungi treated with miconazole. ROS production in Candida albicans was measured by a real-time fluorogenic assay. The level of ROS production was increased by miconazole at the MIC (0.125 g/ml) and was enhanced further in a dose-dependent manner, with a fourfold increase detected when miconazole was used at 12.5 g/ml. This increase in the level of ROS production was completely inhibited by pyrrolidinedithiocarbamate (PDTC), an antioxidant, at 10 M. In a colony formation assay, the decrease in cell viability associated with miconazole treatment was significantly prevented by addition of PDTC. Moreover, the level of ROS production by 10 clinical isolates of Candida species was inversely correlated with the miconazole MIC (r ‫؍‬ ؊0.8818; P < 0.01). These results indicate that ROS production is important to the antifungal activity of miconazole.Candidiasis is a life-threatening disease in patients with immune suppression. Azoles are used widely for the treatment of candidiasis, but some clinical isolates show resistance (11,28). Further investigation of the mechanisms underlying the antifungal effects of azoles may aid in the development of new treatment strategies.Azoles exert a cytostatic or cytotoxic effect via inhibition of synthesis reactions in the metabolic pathways of essential fungal cell membrane components including ergosterol (29,30). Their primary target is the cytochrome P450-catalyzed 14␣-demethylation of ergosterol precursors. Mutations or overexpression of 14␣-demethylase, encoded by the ERG11 gene, as well as changes in the ergosterol synthesis pathway reportedly participates in the induction of resistance (14,19,20,25).Since it was found that miconazole, ketoconazole, and deacetylated ketoconazole were inserted in a lipid layer (6) and miconazole induced the release of K ϩ and intracellular ATP from Candida species (3, 4, 7), these agents may cause direct membrane damage.Recent studies clarified that a decrease in drug concentration brought about by energy-dependent efflux pumps is usually involved in multidrug resistance including azole resistance (1,2,16,26). This pumping system closely resembles a system in cancer cells based on the P-glycoprotein encoded by the MDR-1 gene. Thus, common biologic mechanisms shared with other eukaryotic cells are involved in the antifungal effects of azoles.In eukaryotic cells, mitochondria are common organelles that represent an important source of reactive oxygen species (ROS). Many cellular stresses such as irradiation and cytotoxic drugs cause growth inhibition and the death of mammalian cells via endogenous ROS production (5, 15, 27). ROS produced by granulocytes or monocytes are known to exert activity against fungi (9, 31). Furthermore, recent studies demonstrated that Candida albicans possesses an ROS scavenger, superoxide dismutase; this suggests that fungi may require a cytoprotective mechanism against not only exogenous ROS but also endogenous, fungus-derived ROS (1...

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Background-Stent fracture (SF) after drug-eluting stent implantation has recently become an important concern because of its potential association with in-stent restenosis and stent thrombosis. However, the incidence and clinical impact of SF after everolimus-eluting stent implantation remain unclear. Methods and Results-A total of 1035 patients with 1339 lesions undergoing everolimus-eluting stent implantation and follow-up angiography 6 to 9 months after index procedure were analyzed. SF was defined as complete or partial separation of the stent, as assessed by plain fluoroscopy or intravascular ultrasound during follow-up. We assessed the rates of SF and major adverse cardiac events, defined as cardiac death, myocardial infarction, stent thrombosis, and clinically driven target lesion revascularization within 9 months. SF was observed in 39 of 1339 lesions (2.9%) and in 39 of 1035 patients (3.8%). Ostial stent location and lesions with hinge motion, tortuosity, or calcification were independent predictors of SF. The rate of myocardial infarction and target lesion revascularization were significantly higher in the SF group than in the non-SF group (5.1% versus 0.4%; P=0.018 and 25.6% versus 2.0%; P<0.001, respectively). Stent thrombosis was more frequently observed in the SF group than in the non-SF group (5.1% versus 0.4%; P=0.018). Major adverse cardiac events within 9 months were significantly higher in the SF group than in the non-SF group (25.6% versus 2.3%; P<0.001). Conclusions-SF after everolimus-eluting stent implantation occurs in 2.9% of lesions and is associated with higher rate of major adverse cardiac events, driven by higher target lesion revascularization and stent thrombosis. (Circ Cardiovasc Interv. 2012;5:663-671.)

Luminal renarrowing of the stented segment beyond 4 years was a progressive process extending beyond 10 years. The angiographic observation of late in-stent restenosis was clinically relevant because a corresponding progressive increase in the incidence of late target lesion revascularization was observed beyond 4 years and up to 15 to 20 years after bare metal stent implantation.

We investigate the finiteness structure of a complete non-compact n-dimensional Riemannian manifold M whose radial curvature at a base point of M is bounded from below by that of a non-compact von Mangoldt surface of revolution with its total curvature greater than π . We show, as our main theorem, that all Busemann functions on M are exhaustions, and that there exists a compact subset of M such that the compact set contains all critical points for any Busemann function on M. As corollaries by the main theorem, M has finite topological type, and the isometry group of M is compact.

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TSL per lesion and patient had significantly impacts on TLR rates. Longer TSL per patient was associated with increased incidence of stent thrombosis through 3 years.