Changes in liver mitochondrial plasticity induced by brain tumor

BACKGROUND: Accumulating data suggest that liver is a major target organ of systemic effects observed in the presence of a cancer. In this study, we investigated the consequences of the presence of chemically induced brain tumors in rats on biophysical parameters accounting for the dynamics of water in liver mitochondria. METHODS: Tumors of the central nervous system were induced by intraveinous administration of ethylnitrosourea (ENU) to pregnant females on the 19th day of gestation. The mitochondrial crude fraction was isolated from the liver of each animal and the dynamic parameters of total water and its macromolecule-associated fraction (structured water, H(2)Ost) were calculated from Nuclear Magnetic Resonance (NMR) measurements. RESULTS: The presence of a malignant brain tumor induced a loss of water structural order that implicated changes in the physical properties of the hydration shells of liver mitochondria macromolecules. This feature was linked to an increase in the membrane cholesterol content, a way to limit water penetration into the bilayer and then to reduce membrane permeability. As expected, these alterations in mitochondrial plasticity affected ionic exchanges and led to abnormal features of mitochondrial biogenesis and caspase activation. CONCLUSION: This study enlightens the sensitivity of the structured water phase in the liver mitochondria machinery to external conditions such as tumor development at a distant site. The profound metabolic and functional changes led to abnormal features of ion transport, mitochondrial biogenesis and caspase activation

Applying an immersive tutorial in virtual reality to learning a new technique

International audienc

Rev Med Interne

We aimed to evaluate the impact of an immersive simulation session on the experience of the beginning of residency. The interventional group consisted of newly recruited residents in 2019, who participated in the workshop presenting four emergency scenarios frequently encountered during night shifts; the control group comprised residents who had begun their internship in 2018, without having participated in the simulation workshop. The level of psychological stress and self-confidence were self-estimated in the simulation group before and immediately after the workshop. During the second semester of residency, stress, self-efficacy and anxiety were evaluated in both groups with the Perceived Stress Scale (PSS), General Self-efficacy Scale (GSES), and Generalized Anxiety Disorder-7 (GAD-7) scale. In the second semester 2020, the PSS, GSES and GAD-7 were 20.71±8.15 and 22.44±5.68 (P=0.40); 26.88±6.30 and 27.11±3.95 (P=0.87); 6.94±5.25 and 8.89±4.78 (P=0.22) for the simulation (n=17, 89.5% of participation) and control (n=9, 75%) groups, respectively. In the simulation group, the level of self-confidence had significantly improved from 1.82±0.95 before the session to 2.29±1.16 after the session (P=0.05). Interestingly, this improvement in self-confidence was significantly correlated with GAD-7 (P=0.014) and PSS (P=0.05), and tended to be correlated with GSES (P=0.09). Our study showed a significant improvement in self-confidence between before and after the simulation session. Residents who experienced an improvement in self-confidence saw their stress and anxiety levels decrease during the second semester reevaluation, in favor of a prolonged benefit from the session

Les directives anticipées en psychiatrie : revue de la littérature qualitative, état des lieux et perspectives

Les directives anticipées sont un ensemble d’instructions écrites, rédigées à l’avance par une personne consciente, pour le cas où elle serait dans l’incapacité d’exprimer sa volonté. Dans certains pays, les directives anticipées sont aussi utilisées en psychiatrie dans la prise en charge de pathologies chroniques sévères comme la schizophrénie ou les troubles bipolaires. L’objectif est alors de permettre à un patient d’exprimer à l’avance ses volontés concernant sa prise en charge future, s’il devait traverser une nouvelle décompensation et se trouver dans l’incapacité de donner son consentement. Les directives anticipées permettent de donner des informations concernant les traitements médicamenteux, des instructions non médicales et de désigner une personne de confiance. Elles ont pour principal objectif la réduction de la fréquence des réhospitalisations, notamment lorsqu’elles se font sous contrainte. La revue de la littérature présentée dans ce travail permet de dresser un état des lieux de l’utilisation actuelle des directives anticipées en psychiatrie (DAP). Les bénéfices en termes de perception par les patients et de diminution des soins sous contrainte sont prometteurs. De plus, cette forme d’intervention s’inscrit bien dans les nouvelles perspectives de soins actuelles qui mettent l’accent sur les actions d’éducation thérapeutique et de prévention. Au vu des résultats présentés, un modèle particulier de directives anticipées, le joint crisis plan (JCP), nous semble proposer l’approche la plus intéressante et la plus riche sur le plan clinique

Inhibitors of Leishmania GDP-Mannose Pyrophosphorylase Identified by High-Throughput Screening of Small-Molecule Chemical Library ▿

The current treatment for leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations, such as high cost, toxicity, and a lack of efficacy in regions of endemicity. Therefore, the development of new, effective, and affordable antileishmanial drugs is a global health priority. Leishmania synthesizes a range of mannose-rich glycoconjugates that are essential for parasite virulence and survival. A prerequisite for glycoconjugate biosynthesis is the conversion of monosaccharides to the activated mannose donor, GDP-mannose, the product of a reaction catalyzed by GDP-mannose pyrophosphorylase (GDP-MP). The deletion of the gene encoding GDP-MP in Leishmania led to a total loss of virulence, indicating that the enzyme is an ideal drug target. We developed a phosphate sensor-based high-throughput screening assay to quantify the activity of GDP-MP and screened a library containing ∼80,000 lead-like compounds for GDP-MP inhibitors. On the basis of their GDP-MP inhibitory properties and chemical structures, the activities of 20 compounds which were not toxic to mammalian cells were tested against ex vivo amastigotes and in macrophage amastigote assays. The most potent compound identified in the primary screen (compound 3), a quinoline derivative, demonstrated dose-dependent activity in both assays (50% inhibitory concentration = 21.9 μM in the macrophage assay) and was shown to be nontoxic to human fibroblasts. In order to elucidate signs of an early structure-activity relationship (SAR) for this class of compounds, we obtained and tested analogues of compound 3 and undertook limited medicinal chemistry optimization, which included the use of a number of SAR probes of the piperazinyl aryl substituent of compound 3. We have identified novel candidate compounds for the design and synthesis of antileishmanial therapeutics