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.     

Removal of Antimony and Bismuth from Copper Electrorefining Electrolyte: Part II—An Investigation of Two Proprietary Solvent Extraction Extractants

Antimony and bismuth recovery from copper electrorefining electrolyte could reduce the impacts of these problem elements and produce a new primary source for them. Two proprietary phosphonic acid ester extractants were examined (REX-1 and REX-2) for the removal of antimony and bismuth from copper electrorefining electrolytes. Experimentation included shakeout and break tests to determine the basic parameters for the extractants in terms of maximum loading, break times, and extraction and stripping efficiency. Five permutations of extractant mixtures (100 wt.% REX-1 and 25 wt.%, 50 wt.%, 75 wt.% and 100 wt.% REX-2) were studied. It was determined that REX-2 was able to extract Sb and Bi from the electrolyte, but required some mixture with REX-1 to better facilitate stripping with 400 g/L sulfuric acid. The laboratory electrorefining electrolyte containing glue had faster disengagement times than a synthetic solution without glue.     

Self Assembly–Assisted Additive Manufacturing: Direct Ink Write 3D Printing of Epoxy–Amine Thermosets

The use of self‐assembling, pre‐polymer materials in 3D printing is rare, due to difficulties of facilitating printing with low molecular weight species and preserving their reactivity and/or functions on the macroscale. Akin to 3D printing of small molecules, examples of extrusion‐based printing of pre‐polymer thermosets are uncommon, arising from their limited rheological tuneability and slow reactions kinetics. The direct ink write (DIW) 3D printing of a two‐part resin, Epon 828 and Jeffamine D230, using a self‐assembly approach is reported. Through the addition of self‐assembling, ureidopyrimidinone‐modified Jeffamine D230 and nanoclay filler, suitable viscoelastic properties are obtained, enabling 3D printing of the epoxy–amine pre‐polymer resin. A significant increase in viscosity is observed, with an infinite shear rate viscosity of approximately two orders of magnitude higher than control resins, in addition to, an increase in yield strength and thixotropic behavior. Printing of simple geometries is demonstrated with parts showing excellent interlayer adhesion, unachievable using control resins.     

Investigation of the Sharkskin melt instability using optical Fourier analysis

An optical method allowing the characterization of melt flow instabilities typically occurring during an extrusion process of polymers and polymer compounds is presented. It is based on a camera-acquired image of the extruded compound with a reference length scale. Application of image processing and transformation of the calibrated image to the frequency domain yields the magnitude spectrum of the instability. The effectiveness of the before mentioned approach is shown on Styrene-butadiene rubber (SBR) compounds, covering a wide range of silica filler content, extruded through a Göttfert capillary rheometer. The results of the image-based analysis are compared with the results from the sharkskin option, a series of highly sensitive pressure transducers installed inside the rheometer. A simplified version of the code used to produce the optical analysis results is included as supplementary material. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48806.     

Modelling the combined effect of surface roughness and topography on bacterial attachment

Bacterial attachment is a complex process affected by flow conditions,imparted stresses,and the sur-face properties and structure of both the supporting material and the cell.Experiments on the initial attachment of cells of the bacterium Streptococcus gordonii (S.gordonii),an important early coloniser of dental plaque,to samples of stainless steel (SS) have been reported in this work.The primary aim motivating this study was to establish what affect,if any,the surface roughness and topology of sam-ples of SS would have on the initial attachment of cells of the bacterium S.gordonii.This material and bacterium were chosen by virtue of their relevance to dental implants and dental implant infections.Prior to bacterial attachment,surfaces become conditioned by the interfacing environment (salivary pellicle from the oral cavity for instance).For this reason,cell attachment to samples of SS pre-coated with saliva was also studied.By implementing the Extended Derjaguin Landau Verwey and Overbeek(XDLVO) theory coupled with convection-diffusion-reaction equations and the surface roughness infor-mation,a computational model was developed to help better understand the physics of cell adhesion.Surface roughness was modelled by reconstructing the surface topography using statistical parame-ters derived from atomic force microscopy (AFM) measurements.Using this computational model,the effects of roughness and surface patterns on bacterial attachment were examined quantitatively in both static and flowing fluid environments.The results have shown that rougher surfaces (within the sub-microscale) generally increase bacterial attachment in static fluid conditions which quantitatively agrees with experimental measurements.Under flow conditions,computational fluid dynamics (CFD) simula-tions predicted reduced convection-diffusion inside the channel which would act to decrease bacterial attachment.When combined with surface roughness effects,the computational model also predicted that the surface topographies discussed within this work produced a slight decrease in overall bacterial attachment.This would suggest that the attachment-preventing effects of surface patterns dominate over the adhesion-favourable sub-microscale surface roughness;hence,producing a net reduction in adhered cells.This qualitatively agreed with experimental observations reported here and quantitatively matched experimental observations for low flow rates within measurement error.     

Dynamics and control of a thermally self-sustaining energy storage system using integrated solid oxide cells for an islanded building

A solid oxide cell-based energy system is proposed for a solar-powered stand-alone building. The system is comprised of a 5 kW_el solid oxide fuel cell (SOFC), a 9.5 kW_el solid oxide electrolysis cell (SOEC), and the required balance of plant. The SOFC supplies: 1- building demand in the absence of sufficient solar power, 2- heat for SOEC in endothermic and standby modes. Thermal integration of SOFC and SOEC is implemented through a network of heat exchangers, combined with set of control algorithms. Two control strategies were implemented to actuate the SOFC in response to endothermic heat demands of SOEC by manipulating: 1- electric power, 2- fuel utilization. The results of dynamic simulation of system for two scenarios (sunny day and cloudy day) showed successful compliance of temperature constraints with both methods. Manipulation of fuel utilization, however, resulted in better system performance in terms of efficiency and H₂ balance.