Upregulation of the Adhesin Gene EPA1 Mediated by PDR1 in Candida glabrata Leads to Enhanced Host Colonization.

Candida glabrata is the second most common Candida species causing disseminated infection, after C. albicans. C. glabrata is intrinsically less susceptible to the widely used azole antifungal drugs and quickly develops secondary resistance. Resistance typically relies on drug efflux with transporters regulated by the transcription factor Pdr1. Gain-of-function (GOF) mutations in PDR1 lead to a hyperactive state and thus efflux transporter upregulation. Our laboratory has characterized a collection of C. glabrata clinical isolates in which azole resistance was found to correlate with increased virulence in vivo. Contributing phenotypes were the evasion of adhesion and phagocytosis by macrophages and an increased adhesion to epithelial cells. These phenotypes were found to be dependent on PDR1 GOF mutation and/or C. glabrata strain background. In the search for the molecular effectors, we found that PDR1 hyperactivity leads to overexpression of specific cell wall adhesins of C. glabrata. Further study revealed that EPA1 regulation, in particular, explained the increase in adherence to epithelial cells. Deleting EPA1 eliminates the increase in adherence in an in vitro model of interaction with epithelial cells. In a murine model of urinary tract infection, PDR1 hyperactivity conferred increased ability to colonize the bladder and kidneys in an EPA1-dependent way. In conclusion, this study establishes a relationship between PDR1 and the regulation of cell wall adhesins, an important virulence attribute of C. glabrata. Furthermore, our data show that PDR1 hyperactivity mediates increased adherence to host epithelial tissues both in vitro and in vivo through upregulation of the adhesin gene EPA1. IMPORTANCE Candida glabrata is an important fungal pathogen in human diseases and is also rapidly acquiring drug resistance. Drug resistance can be mediated by the transcriptional activator PDR1, and this results in the upregulation of multidrug transporters. Intriguingly, this resistance mechanism is associated in C. glabrata with increased virulence in animal models and also with increased adherence to specific host cell types. The C. glabrata adhesin gene EPA1 is a major contributor of virulence and adherence to host cells. Here, we show that EPA1 expression is controlled by PDR1 independently of subtelomeric silencing, a known EPA1 regulation mechanism. Thus, a relationship exists between PDR1, EPA1 expression, and adherence to host cells, which is critical for efficient virulence. Our results demonstrate that acquisition of drug resistance is beneficial for C. glabrata in fungus-host relationships. These findings further highlight the challenges of the therapeutic management of C. glabrata infections in human patients

Évaluation des greffons rénaux avant la transplantation; une mise au point sur la situation actuelle et les méthodes émergentes

Le manque de greffons rénaux adéquats amène à une augmentation du nombre de patients sur liste d’attente de transplantation. A ce jour, aucun processus d’évaluation universel ne permet de prédire avec une fiabilité suffisante l’issue favorable de ces transplants. Les méthodes établies comme l’évaluation histologique, les scores cliniques et les techniques de perfusion offrent une prédiction relativement fiable du retard du fonctionnement du greffon, mais ne sont pas systématiquement capables de prédire la survie d’un greffon. Les techniques émergentes comme les marqueurs moléculaires, les nouvelles techniques d’imagerie et la perfusion des organes normothermique offrent des approches innovatrices tout en permettant d’identifier des cibles d’interventions thérapeutiques. Cependant, les études rigoureuses sur le sujet font défauts et ces nouvelles méthodes nécessitent d’être validées. Le but ultime étant que ces nouvelles approches permettent de diminuer le taux d’organes non-utilisés tout en améliorant la finesse dans l’établissement d’un pronostic pour les greffons rénaux

Impact of maternal obesity on the gut microbiome, chronic liver disease and hepatocellular carcinoma in the offspring

L’épidémie d’obésité représente un enjeu de santé majeur. Les femmes en âge de procréer sont particulièrement touchées. L’objectif de cette thèse est de comprendre l’impact de l’obésité maternelle sur le risque de développer une maladie hépatique. Nous avons démontré que l’obésité maternelle entraînait de profonds changements de l’expression des gènes hépatiques. Nous avons constaté une association entre l’obésité maternelle et des taux plus élevés de stéatose, fibrose et d’inflammation. La descendance des mères obèses présente également un risque plus élevé de développer des tumeurs hépatiques. Les modifications du microbiome intestinal de la progéniture des souris obèses sont conservées à l’âge adulte. En restaurant un microbiome normal, nous avons pu réduire le risque de développer un cancer du foie. Ces observations mettent en évidence le rôle clé du microbiome intestinal dans la transmission des maladies du foie de la mère à l’enfant, et ouvrent la voie vers le développement de thérapies.The obesity epidemic represents a major challenge to our health systems. Women of childbearing age are particularly affected. Overweight and obesity have a multitude of adverse health effects and can lead to chronic liver disease and liver cancer. In addition, maternal obesity is associated with metabolic disorders in children, and an increased rate of childhood cancers. Obesity alters the composition of the gut microbiome, which contributes to the progression of chronic liver disease and is passed on to the next generation. The objective of this thesis is to understand the impact of maternal obesity on the risk of developing chronic liver disease and liver cancer in children, and the role of the microbiome in this context. We have demonstrated, in a mouse model, that maternal obesity leads to profound changes in gene expression in their offspring. We observed that signaling pathways of the innate immune system and the cell cycle are altered, and that genes important for the development of chronic liver diseases are dysregulated. In addition, we found that maternal obesity leads to higher rates of steatosis, fibrosis and inflammation in adult offspring of obese mothers. The offspring of obese mothers also have a significantly higher risk of developing liver tumors. The gut microbiome of offspring of obese mouse mothers is altered and these alterations are retained into adulthood. By restoring a normal microbiome, we were able to normalize the next generation's risk of developing liver cancer. This highlights the key role of the gut microbiome and its alterations in the transmission of liver disease from mother to child, and paves the way for the development of a future therapy

Commentary: Insulin-Producing Organoids Engineered From Islet and Amniotic Epithelial Cells to Treat Diabetes

A Commentary on : "Insulin-Producing Organoids Engineered from Islet and Amniotic Epithelial Cells to Treat Diabetes" By Lebreton F, Lavallard V, Bellofatto K, Bonnet R, Wassmer CH, Perez L, Kalandadze V, Follenzi A, Boulvain M, Kerr-Conte J, Goodman DJ, Bosco D, Berney T, Berishvili E. Nat Commun. (2019). 10(1):4491. doi: 10.1038/s41467-019-12472-3

FGF21 negatively affects long-term female fertility in mice

AbstractIn this project we studied the impact of subcutaneously administered recombinant FGF21 on the female fertility in a murine model. DOI:https://doi.org/10.1016/j.heliyon.2022.e1149

Impact of Maternal Obesity on Liver Disease in the Offspring - Biomedicines - 2022

AbstractSources data of the publication doi: 10.3390/biomedicines10020294 A Comprehensive Transcriptomic Analysis and Confirmation of Results in a Murine Mode

Evolution of the Surgical Residency System in Switzerland: An In-Depth Analysis Over 15 Years

Background: The landscape of surgical training has been subject to many changes over the past 15 years. This study examines resident satisfaction, determinants of satisfaction, demographics, working hours and the teaching rate of common operations in a longitudinal fashion with the aim to identify trends, shortcomings and possible ways to improve the current training system. Methods: The Swiss Medical Association administers an annual survey to all Swiss residents to evaluate the quality of postgraduate medical training (yearly respondents: 687-825, response rate: 68-72%). Teaching rates for general surgical procedures were obtained from the Swiss association for quality management in surgery. Results: During the study period (2003-2018), the number of surgical residents (408-655 (+61%)) and graduates in general surgery per year (42-63 (+50%)) increased disproportionately to the Swiss population. While the 52 working hour restriction was introduced in 2005 reported average weekly working hours did not decline (59.9-58.4 h (-3%)). Workplace satisfaction (6 being highest) rose from 4.3 to 4.6 (+7%). Working climate and leadership culture were the main determinants for resident satisfaction. The proportion of taught basic surgical procedures fell from 24.6 to 18.9% (-23%). Conclusions: The number of residents and graduates in general surgery has risen markedly. At the same time, the proportion of taught operations is diminishing. Despite the introduction of working hour restrictions, the self-reported hours never reached the limit. The low teaching rate combined with the increasing resident number represents a major challenge to the maintenance of the current training quality

Timing of surgical repair of bile duct injuries after laparoscopic cholecystectomy: A systematic review

Background: The surgical management of bile duct injuries (BDIs) after laparoscopic cholecystectomy (LC) is challenging and the optimal timing of surgery remains unclear. The primary aim of this study was to systematically evaluate the evidence behind the timing of BDI repair after LC in the literature. Aim: To assess timing of surgical repair of BDI and postoperative complications. Methods: The MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to August 2021. Risk of bias was assessed via the Newcastle Ottawa scale. The primary outcomes of this review included the timing of BDI repair and postoperative complications. Results: A total of 439 abstracts were screened, and 24 studies were included with 15609 patients included in this review. Of the 5229 BDIs reported, 4934 (94%) were classified as major injury. Timing of bile duct repair was immediate (14%, n = 705), early (28%, n = 1367), delayed (28%, n = 1367), or late (26%, n = 1286). Standardization of definition for timing of repair was remarkably poor among studies. Definitions for immediate repair ranged from < 24 h to 6 wk after LC while early repair ranged from < 24 h to 12 wk. Likewise, delayed (> 24 h to > 12 wk after LC) and late repair (> 6 wk after LC) showed a broad overlap. Conclusion: The lack of standardization among studies precludes any conclusive recommendation on optimal timing of BDI repair after LC. This finding indicates an urgent need for a standardized reporting system of BDI repair

Parastomal gallbladder herniation: A case report and review of the literature

Introduction: Parastomal hernia is a common complication of patients living with an enterostomy. However, a parastomal hernia involving the gallbladder is a rare condition with only eight cases documented in the literature.Presentation of case: We report the case of a 69-year old female who underwent an open right hemicolectomy with creation of a colostomy and terminal ileostomy. She presented with parastomal swelling and pain 16 months later. A computed tomography scan revealed a parastomal herniation of the gallbladder. We elected to proceed with a cholecystectomy and hernia repair, the patient was asymptomatic at her last follow-up.Discussion: A systematic search of the literature found eight previously published cases. This condition primarily affects elderly females. Five patients were treated surgically and three conservatively, all with a favorable outcome. In frail patients without complicating factors, a conservative treatment approach with surveillance may be safe. We chose a surgical approach due to the symptomatic nature of the presentation and the gallstone containing hernia. This is the first case of a parastomal gallbladder herniation containing a large gallstone.Conclusion: This report should help broadening the physician's differential diagnosis in dealing with patients with symptomatic parastomal hernias and provide an example for diagnosis and management of this complication.</p