Miconazole induces aneuploidy-mediated tolerance in Candida albicans that is dependent on Hsp90 and calcineurin.

Antifungal resistance and antifungal tolerance are two distinct terms that describe different cellular responses to drugs. Antifungal resistance describes the ability of a fungus to grow above the minimal inhibitory concentration (MIC) of a drug. Antifungal tolerance describes the ability of drug susceptible strains to grow slowly at inhibitory drug concentrations. Recent studies indicate antifungal resistance and tolerance have distinct evolutionary trajectories. Superficial candidiasis bothers millions of people yearly. Miconazole has been used for topical treatment of yeast infections for over 40 years. Yet, fungal resistance to miconazole remains relatively low. Here we found different clinical isolates of Candida albicans had different profile of tolerance to miconazole, and the tolerance was modulated by physiological factors including temperature and medium composition. Exposure of non-tolerant strains with different genetic backgrounds to miconazole mainly induced development of tolerance, not resistance, and the tolerance was mainly due to whole chromosomal or segmental amplification of chromosome R. The efflux gene CDR1 was required for maintenance of tolerance in wild type strains but not required for gain of aneuploidy-mediated tolerance. Heat shock protein Hsp90 and calcineurin were essential for maintenance as well as gain of tolerance. Our study indicates development of aneuploidy-mediated tolerance, not resistance, is the predominant mechanism of rapid adaptation to miconazole in C. albicans, and the clinical relevance of tolerance deserves further investigations.

Application of B-ultrasound for localization and its impact on first-attempt success rates of nasogastric tube insertion in critically ill patients.

The objective of this study is to explore the application effect of B-ultrasound positioning in assisting nasointestinal tube implantation in critically ill patients. This study is a retrospective study. In this study, 90 cases of severe patients with nasointestinal tube implantation were included. According to the different ways of nasointestinal tube insertion received by patients, 61 patients with conventional blind insertion methods were included in the blind insertion group, and 29 patients with conventional methods and B-ultrasound assisted positioning were included in the B-ultrasound positioning group. The general clinical data, success rate of catheterization, catheterization time, pyloric passage rate, and target nutritional value time of the 2 groups were compared. The changes of the 2 groups after catheterization were compared by SOFA and APACHE II. The contents of albumin and lymphocyte count were compared between the 2 groups before and after catheterization. The time of target nutritional value of the patients of the B-ultrasound positioning group was markedly decreased comparing with the patients of the blind insertion group. The index of catheterization time of the patients between the blind insertion group and B-ultrasound positioning group had no obvious contrast. The APACHE II score and SOFA score of the patients of the B-ultrasound positioning group were obviously lower than the blind insertion group. The contents of lymphocyte count of the patients of the B-ultrasound positioning group were markedly increased comparing with the patients of the blind insertion group after catheterization, but the contents of albumin content had no obvious change. The scores of respiratory system, circulatory system, nervous system, and urinary system in the B-ultrasound positioning group were significantly higher than those in the blind insertion group, while the COPT scores were significantly lower than those in the blind insertion group. B-ultrasound assisted nasointestinal tube implantation is well tolerated in critically ill patients, and can effectively ameliorate the nutritional status and of the ill patients.