Pyroptosis Tuning in Intestinal Cryptosporidiosis via the Natural Histone Deacetylase Inhibitor Romidepsin.

Cryptosporidium is an opportunistic protozoan, with many species of cross-human infectivity. It causes life-threatening diarrhoea in children and CD4-defective patients. Despite its limited efficacy, nitazoxanide remains the primary anti-cryptosporidial drug. Cryptosporidium infects the intestinal brush border (intracellular-extracytoplasmic) and down-regulates pyroptosis to prevent expulsion. Romidepsin is a natural histone deacetylase inhibitor that triggers pyroptosis. Romidepsin's effect on cryptosporidiosis was assessed in immunocompromised mice via gasdermin-D (GSDM-D) immunohistochemical expression, IFN-γ, IL-1ß and IL-18 blood levels by ELISA, and via parasite scanning by modified Ziehl-Neelsen staining and scanning electron microscopy (SEM). Oocyst deformity and local cytokines were also assessed in ex vivo ileal explants. Following intraperitoneal injection of romidepsin, oocyst shedding significantly reduced at the 9th, 12th and 15th d.p.i. compared with infected-control and drug-control (nitazoxanide-treated) mice. H&E staining of intestinal sections from romidepsin-treated mice showed significantly low intestinal scoring with marked reduction in epithelial hyperplasia, villous blunting and cellular infiltrate. SEM revealed marked oocyst blebbing and paucity (in vivo and ex vivo) after romidepsin compared with nitazoxanide. Regarding pyroptosis, romidepsin triggered significantly higher intestinal GSDM-D expression in vivo, and higher serum/culture IFN-γ, IL-1ß and IL-18 levels in romidepsin-treated mice than in the control groups. Collectively, in cryptosporidiosis, romidepsin succeeded in enhancing pyroptosis in the oocysts and infected epithelium, reducing infection and shifting the brush border towards normalisation.

Emergency Contraception Knowledge, Attitudes, and Barriers Among Men: A Cross-Sectional Study.

Background Emergency contraception (EC) plays a pivotal role in the prevention of unintended pregnancies following unprotected sexual intercourse. Men's awareness regarding emergency contraception is pivotal for informed decision-making and for enhancing reproductive health in this context. This study investigated Syrian men's awareness and perspectives on emergency contraception to inform diverse reproductive health initiatives. Methods We conducted a cross-sectional study in Syria, from June 2022 and April 2023. Our study included male participants aged 18 years or older who held Syrian nationality and volunteered to participate. The data collection involved administering a questionnaire comprising three sections (knowledge, attitude, and barrier assessment), encompassing a total of 30 questions. Data analysis was performed using the Statistical Package for Social Sciences (SPSS) (IBM SPSS Statistics, Armonk, NY). Results Most participants were aged 18-25 (65.7%) and single (75.4%) and held a university degree (79.3%). The knowledge of emergency contraception was low (36.1%), with the Internet and social media (77.5%) being the primary sources of information. While 89% held positive attitudes toward emergency contraception, only 37.3% supported nonprescription availability. Age, income, and desire for children were associated with knowledge, attitudes, and the use of emergency contraception. Men aged 26-35 exhibited the highest positive attitude (8.11±1.83). Those desiring no children showed higher attitude scores (7.42±2.04). Income was positively associated with knowledge (adjusted odds ratio {AOR}=1.75 and confidence interval {CI}=1.02-2.99) and emergency contraception use (AOR=2.87 and CI=1.27-6.48). Conclusion This study underscores the knowledge gap regarding emergency contraception in Syrian men. Despite positive attitudes, awareness remains limited, particularly among those of childbearing age. Targeted education and improved accessibility to emergency contraception can enhance its use among men, particularly in those with low socioeconomic status and younger age groups.

Targeting Two-Pore-Domain Potassium Channels by Mechanical Stretch Instantaneously Modulates Action Potential Transmission in Mouse Sciatic Nerves.

Recent reports indicate dominant roles of TRAAK and TREK-1 channels, i.e., mechanosensitive two-pore-domain potassium channels (K2P) at the nodes of Ranvier for action potential repolarization in mammalian peripheral nerves. Functional changes in mammalian peripheral nerve conduction by mechanical stretch studied by recording compound action potentials lack the necessary resolution to detect subtle neuromodulatory effects on conduction velocity. In this study, we developed a novel in vitro approach that enables single-fiber recordings from individual mouse sciatic nerve axons while delivering computer-controlled stepped stretch to the sciatic nerve trunk. Axial stretch instantaneously increased the conduction delay in both myelinated A-fibers and unmyelinated C-fibers. Increases in conduction delay linearly correlated with increases in axial stretch ratio for both A- and C-fibers. The slope of the increase in conduction delay versus stretch ratio was steeper in C-fibers than in A-fibers. Moderate axial stretch (14-19% of in vitro length) reversibly blocked 37.5% of unmyelinated C-fibers but none of the eight myelinated A-fibers tested. Application of arachidonic acid, an agonist to TRAAK and TREK-1 to sciatic nerve trunk, blocks axonal transmission in both A- and C-fibers with delayed onset and prolonged block. Also, the application of an antagonist ruthenium red showed a tendency of suppressing the stretch-evoked increase in conduction delay. These results could draw focused research on pharmacological and mechanical activation of K2P channels as a novel neuromodulatory strategy to achieve peripheral nerve block.

Simulating the effect of sodium channel blockage on cardiac electromechanics.

There is growing interest to better understand drug-induced cardiovascular complications and to predict undesirable side effects at as early a stage in the drug development process as possible. The purpose of this paper is to investigate computationally the influence of sodium ion channel blockage on cardiac electromechanics. To do so, we implement a myofiber orientation dependent passive stress model (Holzapfel-Ogden) in the multiphysics solver Chaste to simulate an imaged physiological model of the human ventricles. A dosage of a sodium channel blocker was then applied and its inhibitory effects on the electrical propagation across ventricles were modeled. We employ the Kerckhoffs active stress model to generate electrically excited contractile behavior of myofibers. Our predictions indicate that a delay in the electrical activation of ventricular tissue caused by the sodium channel blockage translates to a delay in the mechanical biomarkers that were investigated. Moreover, sodium channel blockage was found to increase left ventricular twist. A multiphysics computational framework from the cell level to the organ level was thus used to predict the effect of sodium channel blocking drugs on cardiac electromechanics.