New Paradigms in the Histopathology of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing global health problem. It can be separated histologically into two broad groups: steatosis, which usually follows a benign clinical course and non-alcoholic steatohepatitis (NASH) that typically has hepatocyte ballooning, necroinflammatory activity and can progress to fibrosis and cirrhosis. More recently the histological spectrum has expanded with the recognition of a paediatric pattern of NASH that has portal-based inflammation and fibrosis without ballooning. An overlap pattern is also described. There is increasing interest in the portal changes of NASH as these correlate with the progression of fibrosis. Disease-associated hepatocyte senescence appears to trigger an alternative regenerative pathway and the development of a periportal ductular reaction (DR), which in turn may have a role in progressive fibrogenesis. Portal inflammation, particularly in association with the DR, is an area of recent study.     

Community-associated methicillin-resistant Staphylococcus aureus in Indigenous communities in Canada

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have emerged as a significant issue in some Indigenous communities (including First Nations, Inuit and Métis) in Canada. Primarily associated with skin and soft-tissue infections, this organism can also result in significant morbidity and mortality. Canadian and American guidelines for managing CA-MRSA infections have been published. The specific epidemiology, microbiology and susceptibility patterns, and the social/environmental circumstances of CA-MRSA infections in Indigenous communities need to be considered for strategies to reduce transmission. While reducing household crowding and improving in-home potable water supply are optimal strategies to reduce the impact of this illness, implementing Canadian guidelines along with increased prevention strategies are recommended as interim measures.     

Implementation of a Practice Development Model to Reduce the Wait for Autism Spectrum Diagnosis in Adults

This study examined waiting times for diagnostic assessment of Autism Spectrum Disorder in 11 adult services, prior to and following the implementation of a 12 month change program. Methods to support change are reported and a multi-level modelling approach determined the effect of the change program on overall wait times. Results were statistically significant (b?=???0.25, t(136)?=???2.88, p?=?0.005). The average time individuals waited for diagnosis across all services reduced from 149.4 days prior to the change program and 119.5 days after it, with an average reduction of 29.9 days overall. This innovative intervention provides a promising framework for service improvement to reduce the wait for diagnostic assessment of ASD in adults across the range of spectrum presentations.     

Echocardiographic diagnosis of permanent pacemaker lead malposition in the left ventricle: A case study

Inadvertent endocardial lead malposition is recognized as a rare incident which is usually underreported and if recognized during implantation can be easily corrected. This phenomenon is caused by the ventricular lead unintentionally crossing a pre-existing patent foremen ovale, septal defects (atrial or ventricular) or directly from the aorta via an accidental subclavian puncture resulting in the lead implanting into the left ventricle. While this is a rare occurrence we report, the incidental finding of pacemaker lead malposition during a routine follow-up transthoracic echocardiogram and the benefits of three-dimensional transesophageal echocardiography in this patient prior to lead extraction.     

Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti‐thrombotic drugs

Background and Aim: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti‐thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. Methods: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti‐thrombotic therapy. VCE studies were re‐evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti‐thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti‐thrombotic therapy was resumed before the VCE study. Results: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty‐two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti‐thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20–60.42, P = 0.032). Conclusions: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti‐thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.     

SVEP1 plays a crucial role in epidermal differentiation

SVEP1 is a recently identified multidomain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell‐cell adhesion in an integrin‐dependent manner in osteogenic cells. In this study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT‐PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Downregulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 downregulation was associated with disturbed differentiation and marked epidermal acanthosis in three‐dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homoeostasis in vivo, we downregulated SVEP1 in zebrafish embryos with a Svep1‐specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the centre of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell‐cell adhesion with disadhesion between cells in Svep1‐deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.     

Restriction of cell lysis by homologous complement: II. Protection of erythrocytes against lysis by newly activated complement

Our previous work revealed that homologous complement (C) was ineffective in lysing antibody-sensitized erythrocytes (EA) even at high concentrations. It was also shown that activation of complement on homologous EA resulted in the binding of C9 and the formation of EA bearing complement proteins C1 through C9 (EAC1-9), yet few hemolytic sites were formed. Instead, as shown here, the formation of homologous EAC1-9 caused the cells to become resistant to lysis even by heterologous complement during a second incubation. In contrast, when homologous EAC1-8 were produced by incubating EA with C9-depleted serum, such intermediates were not protected against lysis by heterologous complement during a second incubation. Furthermore, homologous C9 on EAC1-9 was able to reduce the hemolytic efficiency of heterologous complement without blocking C activation and the formation of new C5b-9 complexes. Protection was not modified when homologous EAC1-9 were produced in one step, by incubation of EA with serum, or sequentially by adding C9 to EAC1-8. The minimum number of 9-sites required to confer a protective effect on EAC1-9 was less than 200 per cell. Thus, in addition to its known effect in heterologous cell killing, homologous C9 is capable of protecting homologous cells against inadvertent complement lysis.