The outcomes of methicillin-resistant Staphylococcus aureus infection after living donor liver transplantation in a Japanese center

Objective: The objective of this study is to present results from our review of methicillin-resistant Staphylococcus aureus (MRSA) infection in living-donor liver transplant (LDLT) recipients. Methods: Seventy patients with primary LDLT between August 1997 and May 2007 were retrospectively reviewed. Results: Overall, 9 patients (12.9%) encountered various kinds of MRSA infection after transplantation [peritonitis (6), bacteremia (6), pneumonia (3), wound infection (3), cholangitis (1)]; 4 of these 9 patients died. Of these 4 expired patients, 3 were highly urgent cases with very poor pretransplant status under ventilator support. In one patient, linezolid was effective after teicoplanin failure for severe systemic MRSA infections (bacteremia, peritonitis, cholangitis, pneumonia, and enteritis). Of the 4 patients in whom MRSA was isolated only in a nasal swab before transplantation, none developed MRSA infection after transplantation with a 3-day course of mupirocin prophylaxis. Conclusions: MRSA infection was a contributing factor in death after transplantation in cases with poor pretransplant status. Linezolid was effective even for treating systemic MRSA infection after LDLT. A short course of mupirocin prophylaxis seemed to be effective and did not have any adverse effects.Journal of Hepato-Biliary-Pancreatic Sciences, 17(6), pp.839-843; 2010journal articl

Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata.

Abstract The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings

Functional characterization of the regulators of calcineurin in Candida glabrata

The serine-threonine-specific protein phosphatase calcineurin is a key mediator of various stress responses in fungi. Herein, we characterized functions of the endogenous regulators of calcineurin (RCNs), Rcn1 and Rcn2, in the pathogenic fungus Candida glabrata. Rcn1 exerted both inhibitory and stimulatory effects on calcineurin signaling, but Rcn2 displayed only inhibitory activity. Phenotypic analyses of C. glabrata strains lacking either RCNs, calcineurin, or both revealed that calcineurin requires Rcn1, but not Rcn2, for antifungal tolerance in C. glabrata

Two-surgeon technique using saline-linked electric cautery and ultrasonic surgical aspirator in living donor hepatectomy: its safety and efficacy

Background: Saline-linked electric cautery (SLC) is introduced as an effective device to reduce blood loss in liver surgery. The aim of this study is to evaluate the safety and efficacy of two-surgeon technique using SLC and Cavitron Ultrasonic Surgical Aspirator (CUSA) in living donor hepatectomy. Methods: Forty-three living donor right hepatectomies were enrolled in this study. The first 28 cases underwent liver transection with CUSA alone (CUSA group), while additional SLC was applied in the current 15 cases (two-surgeon technique, TS group). Results: Blood loss was significantly reduced by two-surgeon technique (1115.2±652.9g in CUSA group vs 732.3±363.6g in TS group, p<0.05). In the TS group, there was no bile leakage from the cut surface. The early graft function and postoperative recipient survival were not significantly different between the groups. Conclusions: According to our single center experience, blood loss and donor complications were significantly reduced by two-surgeon technique using CUSA and SLC, with maintaining the graft viability

The glycosylphosphatidylinositol-linked aspartyl protease Yps1 is transcriptionally regulated by the calcineurin-Crz1 and Slt2 MAPK pathways in Candida glabrata.

In the pathogenic fungus Candida glabrata, the YPS1 gene, which encodes a glycosylphosphatidylinositol-linked aspartyl protease, is required for cell wall integrity and virulence. Although the expression of YPS1 has been studied in Saccharomyces cerevisiae, the transcriptional regulation of this gene in C. glabrata is not well understood. Here, we report that C. glabrata Yps1 is required for cell growth at elevated temperatures, and that the heat-induced expression of YPS1 is regulated predominantly by the calcineurin-Crz1 pathway and partially by the Slt2 MAPK pathway. Although a total of 11 YPS genes are present in the C. glabrata genome, the loss of transcriptional induction in a calcineurin mutant was observed only for YPS1. The results of a YPS1 promoter-lacZ reporter assay using a series of constructs with mutated promoter elements indicated that the transcription factor Crz1 binds to multiple sites in the promoter region of YPS1. To date, as none of the putative Crz1 targets in C. glabrata have been characterized using a Δcrz1 mutant, monitoring the expression of YPS1 represents an effective method for measuring the activity of the calcineurin-Crz1 signaling pathway in this fungus

A multicenter randomized controlled trial to evaluate the efficacy and safety of nelfinavir in patients with mild COVID-19

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms