Drug-induced liver injury

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paractamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature, since affected individuals represent only a small proportion of those treated with such drugs. In many cases the mechanism for idiosyncrasy is immune mediation and is often identified by genetic risk determined by HLA variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, though recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued especially in the presence of elevated transaminases (AST/ALT ≥5ULN) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefit of N-acetylcysteine in early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory

The illusion of artificial inclusion

Human participants play a central role in the development of modern artificial intelligence (AI) technology, in psychological science, and in user research. Recent advances in generative AI have attracted growing interest to the possibility of replacing human participants in these domains with AI surrogates. We survey several such "substitution proposals" to better understand the arguments for and against substituting human participants with modern generative AI. Our scoping review indicates that the recent wave of these proposals is motivated by goals such as reducing the costs of research and development work and increasing the diversity of collected data. However, these proposals ignore and ultimately conflict with foundational values of work with human participants: representation, inclusion, and understanding. This paper critically examines the principles and goals underlying human participation to help chart out paths for future work that truly centers and empowers participants.Comment: Proceedings of the CHI Conference on Human Factors in Computing Systems (CHI 2024

The role of calcium ions in toxic cell injury.

Calcium ions have been increasingly implicated as a mediator of the mechanisms generating lethal cell injury under a variety of pathologic circumstances. An overview of the various roles suggested for such alterations in cellular calcium homeostasis is presented. The central role of plasma membrane damage in the genesis of irreversible cell injury is used to divide the postulated roles for calcium ions into two major mechanisms. On the one hand, calcium ions have been proposed as mediators of the functional consequences of plasma membrane injury. An influx of extracellular calcium ions across a damaged permeability barrier and down a steep concentration gradient may convert potentially reversible injury into irreversible injury. On the other hand, alterations in intracellular calcium homeostasis are postulated to participate in the mechanisms generating potentially lethal plasma membrane injury. The release of calcium stores sequestered within intracellular organelles raises the cytosolic concentration of free calcium, a process that may activate, in turn, a number of membrane-disruptive processes. The data supporting these two distinct actions of calcium are reviewed and discussed

Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: Mechanisms insights and efficiencies

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

A Novel G Protein-Coupled Receptor of Schistosoma mansoni (SmGPR-3) Is Activated by Dopamine and Is Widely Expressed in the Nervous System

Schistosomes have a well developed nervous system that coordinates virtually every activity of the parasite and therefore is considered to be a promising target for chemotherapeutic intervention. Neurotransmitter receptors, in particular those involved in neuromuscular control, are proven drug targets in other helminths but very few of these receptors have been identified in schistosomes and little is known about their roles in the biology of the worm. Here we describe a novel Schistosoma mansoni G protein-coupled receptor (named SmGPR-3) that was cloned, expressed heterologously and shown to be activated by dopamine, a well established neurotransmitter of the schistosome nervous system. SmGPR-3 belongs to a new clade of “orphan” amine-like receptors that exist in schistosomes but not the mammalian host. Further analysis of the recombinant protein showed that SmGPR-3 can also be activated by other catecholamines, including the dopamine metabolite, epinine, and it has an unusual antagonist profile when compared to mammalian receptors. Confocal immunofluorescence experiments using a specific peptide antibody showed that SmGPR-3 is abundantly expressed in the nervous system of schistosomes, particularly in the main nerve cords and the peripheral innervation of the body wall muscles. In addition, we show that dopamine, epinine and other dopaminergic agents have strong effects on the motility of larval schistosomes in culture. Together, the results suggest that SmGPR-3 is an important neuronal receptor and is probably involved in the control of motor activity in schistosomes. We have conducted a first analysis of the structure of SmGPR-3 by means of homology modeling and virtual ligand-docking simulations. This investigation has identified potentially important differences between SmGPR-3 and host dopamine receptors that could be exploited to develop new, parasite-selective anti-schistosomal drugs

The magnetic, electrical and structural properties of copper-permalloy alloys

Copper-permalloy [Cu1–x(Ni80Fe20)x] alloy films were deposited by co-sputtering and their chemical, structural, magnetic, and electrical properties were characterized. These films are found to have favorable weak ferromagnetic properties for low temperature magnetoelectronic applications. Our results show that by varying the composition, the saturation magnetization (Ms) can be tuned from 700 emu/cm3 to 0 and the Curie temperature (Tc), can be adjusted from 900 K to 0 K. The Ms and Tc are found to scale linearly between x = 25% and 100%. Electronic structure calculations are used to provide a strong fundamental understanding of the mechanisms responsible for establishing the observed electrical and magnetic properties. The theoretical results also show that the introduction of Cu into the permalloy lattice results in very strong spin scattering in the minority spin channel, with only moderate interactions in the majority channel

Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study

<p>Abstract</p> <p>Background</p> <p>Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of <it>Helicobacter pylori </it>(<it>H. pylori</it>) was found to play a protective role in development of ESCC. The interaction of COX-2 and <it>H. pylori </it>in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), <it>H. pylori </it>infection and the risk of developing ESCC.</p> <p>Methods</p> <p>One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. <it>H. pylori </it>seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression.</p> <p>Results</p> <p>In analysis adjusting for the covariates and confounders, <it>H. pylori </it>seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 – 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with <it>H. pylori </it>seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 – 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 – 22.5). Besides, <it>H. pylori </it>seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 – 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 – 0.47, <it>p </it>for multiplicative interaction 0.008)</p> <p>Conclusion</p> <p><it>H. pylori </it>seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between <it>H. pylori </it>and ESCC, especially in lower third esophagus.</p

Effects of interactions between the constituents of chitosan-edible films on their physical properties

The main objective of this work was to evaluate the effect of chitosan and plasticizer concentrations and oil presence on the physical and mechanical properties of edible films. The effect of the film constituents and their in-between interactions were studied through the evaluation of permeability, opacity and mechanical properties. The effects of the studied variables (concentrations of chitosan, plasticizer and oil) were analysed according to a 2 3 factorial design. Pareto charts were used to identify the most significant factors in the studied properties (water vapour, oxygen and carbon dioxide permeability; opacity; tensile strength; elongation at break and Young's modulus). When addressing the influence of the interactions between the films' constituents on the properties above, results show that chitosan and plasticizer concentrations are the most significant factors affecting most of the studied properties, while oil incorporation has shown to be of a great importance in the particular case of transport properties (gas permeability), essentially due to its hydrophobicity. Water vapour permeability values (ranging from 1. 62 × 10 -11 to 4. 24 × 10 -11 g m -1 s -1 Pa -1) were half of those reported for cellophane films. Also the mechanical properties (tensile strength values from 0. 43 to 13. 72 MPa and elongation-at-break values from 58. 62% to 166. 70%) were in the range of those reported for LDPE and HDPE. Based on these results, we recommend the use of 1. 5% (w/w) chitosan concentration to produce films, where the oil and plasticizer proportions will have to be adjusted in a case-by-case basis according to the use intended for the material. This work provides a useful guide to the formulation of chitosan-based film-forming solutions for food packaging applications.The author MA Cerqueira is a recipient of a fellowship from Fundacao para a Ciencia e Tecnologia (FCT, SFRH/BD/23897/2005) and BWS Souza is a recipient of a fellowship from the Coordenacao Aperfeicoamento de Pessoal de Nivel Superior, Brazil (Capes, Brazil)