Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Prevalence of Undescended Testis and its Associated Factors among under-fives seen at Reproductive and Child Health Clinic in Ifakara, Tanzania

Background: The diagnosis of undescended testis/cryptorchidism is missed and ignored by most clinicians following tendency of not performing genital examination in children unless asked by parents. The male sexual differentiation and development is important for the normal reproductive life span. Similarly, risk of carcinoma of testis will be prevented, if early diagnosis of undescended testis (UDT) is made. To aim of the study was to determine the prevalence of undescended testis, its characteristics and associated risk factors among children underfive.Methods: This was a hospital-based cross sectional study that was conducted at the Reproductive and Child Health Clinic (RCHC) of the St. Francis Referral Hospital (SFRH) from October 2011 to May 2012. The district hospital is located in Ifakara, southeast Tanzania, a city of 49,528 people. Among the estimated 4500 under-five male children in the district attending the RCHC for routine services, 616 children were physically examined their genitalia after consent from their caretakers. Results: The prevalence of the undescended testis (UDT) was 2.1% (13/616) with 12 children having unilateral UDT and one child with bilateral UDT. About 85% of families of recruited children own durable assets. A small proportion of children, 6.8% (49/616) were of low birth weight and 2.6% (16/616) were born prematurely. Among mothers who had preeclampsia, only 2.4% (1/41) of the children had UDT and none of eclamptic mothers‟ children had UDT. None of the children with UDT had exhibited evidence of birth asphyxia. In case of mothers who had been smoking or exposed to second hand smoking 5.4% (33/616) and those who have been binge drinking alcohol, 0.6% (4/616) of their children had UDT. Among mothers exposed to herbs during pregnancy only 3.2% (1/31) had UDT. None of the mothers had gestational diabetes or existing diabetes mellitus prior to conception.Conclusion: The prevalence of UDT in this rural setting has a pattern similar to that observed in previous studies in other areas. Efforts should be done to do genital examination by all clinicians. The associated factors exist but no statistically significant association was found and a long term follow up study is needed.Key words: Cryptorchidism/undescended testis, underfives, Reproductive Child Health Clinic, small for gestation age

Mesure continue de la fréquence cardiaque en entraînement spécifique de judo

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Activity and unexpected lung toxicity of the sequential administration of two alkylating agents--dacarbazine and fotemustine--in patients with melanoma

We report the results and discuss the toxicity of clinical trials based on a single concept: the decrease in O6alkyl DNA alkyltransferase (O6AT) resistance mechanism when a chloroethylating agent is used sequentially after a methylating agent. This decrease in O6AT being dose dependent, several increasing doses of dacarbazine (DTIC) have been tested (400 mg/m2 to 1000 mg/m2 every 4 weeks, 3-4 h before fotemustine (100 mg/m2 intravenously every 4 weeks). These results (mean overall response rate 27%) compared with reference regimes, demonstrate that DTIC is able to increase the alkylating power of fotemustine: same range of response rate with only half of the two drug doses compared to an alternated combination, high activity rate especially in lung metastases (10/42 complete responses + 13/42 partial responses), different pattern for haematotoxicity, and occurrence of a new side-effect: acute lung toxicity as adult respiratory distress syndrome (ARDS). This lung toxicity was totally unexpected since several hundreds of patients had been so far treated with fotemustine as single agent or in other combinations with DTIC without any case of acute or delayed lung toxicity. Prophylactic administration of corticoids was not effective and monitoring of the respiratory function was of no predictive value. Due to the additional depleting effects of DTIC on at least two main defence mechanisms--the O6AT system and cytosolic and/or nuclear glutathione--we suppose that the sequence is able to increase the alkylating power of fotemustine to an excessive extent and/or that the detoxication capacity of the cell against DTIC and/or fotemustine metabolites is overwhelmed. Other depletors of the O6AT activity which do not generate metabolites that compete for the same detoxication pathway as the chloroethylnitrosourea (CENU) metabolites should be tested