Rimonabant improves cardiometabolic risk factors in overweight/obese patients irrespective of treatment with statins: Pooled data from the RIO program

peer reviewe

Recombinant expression of Aryl Hydrocarbon Receptor for quantitative ligand-binding analysis

Recombinant expression of the Aryl Hydrocarbon Receptor (AhR) yields small amounts of ligand-binding competent AhR. Therefore, Spodoptera frugiperda (Sf9) cells and baculovirushave been evaluated for high level and functional expression of AhR. Rat and human AhR wereexpressed as soluble protein in significant amounts. Expression of ligand-binding competentAhR was sensitive to the protein concentration of Sf9 extract, and co-expression of the chaperonep23 failed to affect the yield of functional ligand-binding AhR. The expression systemyielded high levels of functional protein, with the ligand-binding capacity (Bmax) typically 20-fold higher than that obtained with rat liver cytosol. Quantitative estimates of the ligand-bindingaffinity of human and rat AhR were obtained; the Kd for recombinant rat AhR was indistinguishablefrom that of native rat AhR, thereby validating the expression system as a faithfulmodel for native AhR. The human AhR bound TCDD with significantly lower affinity than therat AhR. These findings demonstrate high-level expression of ligand-binding competent AhR,and sufficient AhR for quantitative analysis of ligand-binding

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment. Objectives Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Retrograde Synovial Biopsy of the Knee Joint Using a Novel Biopsy Forceps

Synovial biopsies of the knee joint are commonly performed arthroscopically with the patient under full or regional anesthesia. To overcome the effort, costs, and potential risks of surgery, we developed an office-based technique for retrograde synovial biopsy using a designated novel biopsy forceps. Using this technique, no arthroscopic or radiologic control is needed to perform rapid synovial biopsies of the knee joint. Concomitant aspiration of synovial fluid can be performed. A technical description of the procedure is given