Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.     

Flora Crockett Stephenson (1914–1979): A life and professional partnership in planning

This article contributes to the growing literature on women's contributions to planning, especially in the UK, the USA, and Australia, and to research into the phenomenon of life partners who work together professionally. The subject is Flora Crockett Stephenson (1914–1979), the first woman to complete the Master in City Planning degree at the Massachusetts Institute of Technology. Presented as a biographical exposé, the discussion introduces Flora's background and reveals her largely unrecorded contributions as the life and professional partner of British architect-planner Gordon Stephenson (1908–1997), already the subject of several academic studies.     

Thermodynamic and Experimental Investigations of High-Temperature Refractory Corrosion by Molten Slags

Corrosion mechanisms between MgO refractory substrates and FeNi slags were investigated. The FeNi slags taken into consideration represent a simple synthetically mixed slag with specific oxides and a real slag from a ferroalloy producer. The MgO refractory substrates with the specimens of FeNi slag were heated in a hot-stage microscope at 10 K/min from room temperature to three different temperatures 1573 K, 1723 K, and 1923 K (1300 °C, 1450 °C, and 1650 °C). The experiments were carried out under a controlled gas atmosphere that simulates the relevant process conditions. The corrosion mechanisms of each system were followed by scanning electron microscope analyses. The results obtained showed that slag corrosion dominates, with a pronounced partial dissolution of refractory fines forming Mg-silicates of type forsterite. It was also observed that iron oxide present in the slag diffused into the coarse refractory grains forming magnesiowustite. Finally, the results obtained were compared with those predicted by FACTSAGE software to understand the corrosion mechanisms and draw implications for improving the refractory performance and lifetime.     

Open Augmented Reality Standards： Current Activities in Standards- Development Organizations

Augmented reality (AR) has emerged from research laboratories and is now being accepted in other domains as an attractive way of visualizing information.Before AR can be used in the mass market,there are a number of obstacles that need to be overcome.Several of these can be overcome by adopting open standards.A global grassroots community seeking open,interoperable AR content and experiences began to take shape in early 2010.This community is working collaboratively to reduce the barriers to the flow of data from content provider to AR end user.Standards development organizations and industry groups that provide open interfaces for AR meet regularly to provide updates,identify complementary work,and seek harmonization.The community also identifies deployer and implementer needs,communicates requirements,and discusses emerging challenges that could be resolved with standards.In this article,we describe current activities in international standards-development organizations.We summarize the AR standards gap analysis and shed light on special considerations for using standards in mobile AR.     

Development of a questionnaire to assay recalled liking for salt,sweet and fat

Liking for a sweet, salty or fatty diet may induce overconsumption of simple carbohydrates, sodium or lipids. Measuring overall liking of the corresponding sensory sensations contributes to understanding the determinants of dietary behaviours. However, no standardized validated questionnaire assaying these sensations is currently available. In the present study, we developed a web-based questionnaire, “PrefQuest”, which measures recalled liking for the following four sensations: salt, fat and salt, sweet, fat and sweet. PrefQuest included four types of items: (1) liking for sweet, fatty-sweet and fatty-salty foods, (2) preferences in the level of seasoning by adding salt, sweeteners, or fat, (3) preferences for types of dishes in a restaurant menu and (4) overall questions about sweet-, salt- and fat-related behaviours. A development study (n = 198) demonstrated that PrefQuest was feasible, well-perceived, only lasted about 20 min and that items were repeatable (overall mean intra-class correlation coefficient: 0.77, SD 0.08). Construct validity was then evaluated on a larger population sample (n = 47 803). The underlying structure within each of the four sensations was determined by exploratory factor analysis and then internally validated by confirmatory factor analysis. After a selection of the most relevant items, the salt, fat-and-salt, sweet, and fat-and-sweet scales exhibited a theoretically meaningful factor structure, unidimensional for the salt scale and with interrelated sub-dimensions for the sweet, fat-and-salt, and fat-and-sweet scales. Based on the fat-and-sweet and fat-and-salt scales, a fat model was also unveiled. For each factor, internal consistency as well as convergent and divergent validities were demonstrated. Overall, PrefQuest is an internally valid and original tool that can be used to assay recalled liking for sweet, salt, and fat considered altogether or separately as fat and salt or fat and sweet, and can be applied to large population surveys.     

Different ratios of carbon sources in the fermentation of cheese whey and glucose as substrates for hydrogen and ethanol production in continuous reactors

The fermentation of glucose, cheese whey and the mixture of glucose and cheese whey were evaluated in this study from two inocula sources (sludge from a UASB reactor for swine wastewater treatment and poultry slaughterhouse) for hydrogen production in continuous anaerobic fluidized bed reactors (AFBR). For all fermentations, a hydraulic retention time (HRT) of 6 h and a substrate concentration of 5 g COD L⁻¹ were used. In glucose fermentation, the maximum hydrogen yield (HY) was 1.37 mmol H₂ g⁻¹ COD. The co-fermentation of the cheese whey and glucose mixture was favorable for the concomitant production of hydrogen and ethanol, with yields of up to 1.7 mmol H₂ g⁻¹ COD and 3.45 mol EtOH g⁻¹ COD in AFBR2. The utilization of cheese whey as a sole substrate resulted in an HY of 1.9 mmol H₂ g⁻¹ COD. Throughout the study, ethanol fermentation was evident.     

Direct Determination of Energy Band Alignments of Ni/Al2O3/GaN MOS Structures Using Internal Photoemission Spectroscopy

The energy band alignments of Ni/Al₂O₃/GaN heterostructures have been explored by internal photoemission (IPE) and capacitance–voltage (CV) measurements. By performing IPE measurements at both reverse- and forward-bias conditions, the Ni/Al₂O₃ Schottky barrier is found to be 2.9 ± 0.1 eV with the presence of a strong image force lowering effect, while the Al₂O₃/GaN conduction-band offset is determined to be 2.2 ± 0.1 eV and is insensitive to oxide electrical field. CV-based flat-band voltage analysis has further been performed on samples with different oxide thicknesses, not only confirming the IPE-measured band alignment but also revealing the presence of 3.0 × 10¹² cm^-2 net positive charge at the Al₂O₃/GaN interface.     

PhosphoTyrosyl Phosphatase Activator of Plasmodium falciparum: Identification of Its Residues Involved in Binding to and Activation of PP2A

In Plasmodium falciparum (Pf), the causative agent of the deadliest form of malaria, a tight regulation of phosphatase activity is crucial for the development of the parasite. In this study, we have identified and characterized PfPTPA homologous to PhosphoTyrosyl Phosphatase Activator, an activator of protein phosphatase 2A which is a major phosphatase involved in many biological processes in eukaryotic cells. The PfPTPA sequence analysis revealed that five out of six amino acids involved in interaction with PP2A in human are conserved in P. falciparum. Localization studies showed that PfPTPA and PfPP2A are present in the same compartment of blood stage parasites, suggesting a possible interaction of both proteins. In vitro binding and functional studies revealed that PfPTPA binds to and activates PP2A. Mutation studies showed that three residues (V²⁸³, G²⁹² and M²⁹⁶) of PfPTPA are indispensable for the interaction and that the G²⁹² residue is essential for its activity. In P. falciparum, genetic studies suggested the essentiality of PfPTPA for the completion of intraerythrocytic parasite lifecycle. Using Xenopus oocytes, we showed that PfPTPA blocked the G2/M transition. Taken together, our data suggest that PfPTPA could play a role in the regulation of the P. falciparum cell cycle through its PfPP2A regulatory activity.     

A Posteriori Analysis of a Positive Streamwise Invariant Discretization of a Convection-Diffusion Equation

We consider the finite element discretization of a convection-diffusion equation, where the convection term is handled via a fluctuation splitting algorithm. We prove a posteriori error estimates which allow us to perform mesh adaptivity in order to optimize the discretization of these equations. Numerical results confirm the interest of such an approach.