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Purinergic signalling is involved in physiological processes, particularly during ischemia-reperfusion injuries for which it has a protective effect. The purpose of this work was to develop a method for simultaneous quantification of eight nucleotides and adenosine in biological matrices by liquid chromatography coupled with high-resolution mass spectrometry. A method was developed that was sufficiently robust to quantify the targeted analytes in 20 min with good sensitivity. Analysis of extracellular media from cultured endothelial cells detected the release of nucleotides and adenosine during 2 h of hypoxia. The quantification of cylic adenosine monophosphate (cAMP) allowed to establish a dose-response curve after receptor stimulation. Therefore, our method allows us to study the involvement of nucleotides in various processes in both the intracellular and extracellular compartment.Commercial benzamide fungicides are applied to crops to control damage caused by oomycete fungi and are used as veterinary pharmaceuticals in aquaculture. The mechanism of action of these fungicides is to induce mitotic arrest via binding to beta-tubulin, thus inhibiting tubulin polymerization. However, there are little toxicity data available for benzimidazole fungicides in fish. To address this knowledge gap, we conducted zebrafish embryo toxicity tests to assess deformities, survival, and sub-lethal responses following exposure to zoxamide (0, 0.5, 1.0, 2.5, 5.0 and 10 μM zoxamide). We hypothesized that skeletal deformities would be prevalent in zebrafish due to its mechanism of inhibiting beta-tubulin polymerization. Zoxamide was relatively toxic to zebrafish embryos and larvae, and survival was reduced ∼50 % at 2 days post fertilization (dpf) with 10 μM exposure and over time at 6 dpf, 2.5 μM exposure reduced survival by ∼20 %. Frequency of hatch was also reduced/delayed in zebrafish at 3 dpf with >2.5 μM zoxamide. Pericardial edema, body length shortening, and spine curvature were observed in larvae exposed to >5 μM. Mitochondrial bioenergetics were assessed in ∼30 hpf embryos (24-hour exposure) using an XFe24 Flux Analyzer and regression analysis revealed a negative relationship between basal respiration and zoxamide concentration. Superoxide dismutase 1 and caspase 3 mRNA levels were both decreased in 6 dpf larvae exposed to 2.5 μM zoxamide, but were not changed in expression at 0.5 nor 1 μM zoxamide. Continuous 6-day exposure to zoxamide reduced larval activity at 2.5 μM; conversely a 24-hour exposure (at 5-6 dpf) induced hyperactivity at 5 μM suggesting dose and time dependent effects on fish behavior. Based on sub-lethal endpoints, we conceptualize an adverse outcome pathway for chemicals that inhibit tubulin polymerization.Objective Infection is the most critical cause of early death after liver transplantation (LT). However, the effect of preoperative body composition on bacteremia after LT is unclear. The aim of this study was to examine the effects of preoperative body composition on bacteremia after living donor LT (LDLT). Methods The study comprised 277 patients who underwent LDLT at Kyoto University, Kyoto, Japan, between January 2008 and June 2016. We evaluated body composition parameters including skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using preoperative plain computed tomography at the L3 level. We compared the incidence of bacteremia, species, period of antibiotic administration, mortality due to bacteremia, and survival rates according to the number of abnormal body composition factors (low SMI, high IMAC, and high VSR). Moreover, risk factors for post-transplant bacteremia were examined. Results Incidence of bacteremia was significantly higher in patients with three abnormal factors (47.1%), two factors (42%), or a single factor (37%) than in patients with no factors (22.5%; P = 0.027). Species of bacteremia did not differ significantly among the four groups. G6PDi-1 mw The period of antibiotic administration was significantly shorter (P = 0.039) and mortality of patients with bacteremia and survival rates were significantly better (P less then 0.001, each) in patients with no factors. Multivariate analysis identified ABO incompatibility (P = 0.002) and low SMI (P = 0.045) as independent risk factors for bacteremia after LT. Conclusion Preoperative abnormal body composition was closely related to bacteremia after LDLT.North America is experiencing an unprecedented overdose crisis driven by the proliferation of fentanyl and its analogues in the illicit drug supply. In 2018 there were 67,367 drug overdose deaths in the United States, and since 2016, there have been more than 14,700 overdose deaths in Canada, with most related to fentanyl. Despite concerted efforts and some positive progress, current public health, substance use treatment, and harm reduction interventions (such as widespread naloxone distribution and implementation of supervised consumption sites) have not been able to rapidly decrease overdose fatalities. In view of the persistent gaps in services and the limitations of available options, immediate scale-up of low-barrier opioid distribution programs are urgently needed. This includes "off-label" prescription of pharmaceutical grade opioids (e.g., hydromorphone) to disrupt the toxic drug supply and make safer opioids widely available to people at high risk of fatal overdose.Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) quickly subverted the standard of treatment in Non-Small Cell Lung Cancer (NSCLC), where they were first introduced in all comers previously treated advanced/metastatic NSCLC patients and subsequently in the first line of PD-L1 selected cases of metastatic and locally advanced disease. Treatment algorithm is an evolving landscape, where the introduction of front-line ICIs, with or without chemotherapy, unavoidably influences the following treatment lines. In this context, medical oncologists are currently facing many unclear issues, which have been not clarified so far by available data. Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients - are only a part of the unexplored side of ICIs in the real world. Indeed, pivotal randomized clinical trials (RCTs) often lack of external validity because eligibility criteria exclude some patient subgroups commonly treated in real-world clinical practice.