Insulin receptor signalling in PDGFRβ-expressing cells influences systemic metabolism and negatively impacts lipid storage.

Pericytes are vascular mural cells that support the microvasculature; their dysfunction contributes to diabetic retinopathy and has been linked to obesity in humans. To explore the role of pericyte insulin signalling on systemic metabolism we utilised male mice from our previously described PIR (PIRKO) mouse line which has insulin receptor (Insr) knockout in PDGFRβ-expressing cells. These animals exhibit systemic insulin resistance from as early as 8-weeks of age, despite no change in body weight or activity level, and show altered body composition and hepatosteatosis.

The diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure.

Aims: Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers.

Methods And Results: RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with vs.

Relationship Among Diabetes, Obesity, and Cardiovascular Disease Phenotypes: A UK Biobank Cohort Study.

Objective: Obesity and diabetes frequently coexist, yet their individual contributions to cardiovascular risk remain debated. We explored cardiovascular disease biomarkers, events, and mortality in the UK Biobank stratified by BMI and diabetes.

Research Design And Methods: A total of 451,355 participants were stratified by ethnicity-specific BMI categories (normal, overweight, obese) and diabetes status.

Histopathology reporting of temporal artery biopsy specimens for giant cell arteritis: results of a modified Delphi study.

Unlabelled: The temporal artery biopsy (TAB) is regarded as the gold-standard test in the diagnosis of giant cell arteritis (GCA). There is a lack of agreement among experienced pathologists regarding the diagnostic features and classification of inflammation observed in TAB sections in the diagnosis of GCA.

Aims: The aim of this research study was to establish consensus on the key parameters which should be included in a standardised reporting proforma for TAB specimens.

Comparison of magnetic bead and rapid swab RNA extraction methods for detecting rabbit hemorrhagic disease virus 2 in rabbit liver samples.

We compared a bead RNA extraction method with a one-tube method that required only a heat block and ice. RNA was first extracted from liver samples from nine rabbits dying from rabbit hemorrhagic disease virus 2 (RHDV2) using magnetic beads, and RT-PCR was used to detect RHDV2 sequence. Following freezing, RNA was extracted a second time using the SwiftX™ Swabs Viral RNA Extraction Reagent.

Preservation of Smooth Muscle Cell Integrity and Function: A Target for Limiting Abdominal Aortic Aneurysm Expansion?

(1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression.

Developing consensus in Histopathology: the role of the Delphi method.

The Delphi method is a well-established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in Histopathology. This literature review seeks to critique the Delphi methodology and explore its potential applications to histopathology-based clinical and research questions.

Transglutaminase 2 moderates the expansion of mouse abdominal aortic aneurysms.

Objective: Previously published work has indicated that transcripts encoding transglutaminase 2 (TG2) increase markedly in a rat model of abdominal aortic aneurysm. This study determines whether TG2 and the related TG, factor XIII-A (FXIII-A), protect against aortic aneurysm development in mice.

Methods: C57BL/6J wild-type, knockout, knockout, and / double knockout mice were subjected to laparotomy and periaortic application of CaCl.

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling.

Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRβ-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers.

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency.

Autopsy in the time of COVID.

Whilst much literature has been published since the start of the COVID-19 pandemic, there remains limited knowledge of the autopsy findings following death from SARS-CoV-2 infection. The practicalities of triaging and examining bodies with suspected COVID-19 are complex and the need for full post-mortem must be balanced with the potential risks to mortuary staff. This brief case report describes the features of a COVID-19 autopsy performed at the start of the first phase of the pandemic and highlights some important learning points for trainees engaged in autopsy practice.

The role of endocarditis in sudden cardiac death: highlighting the value of the autopsy, pathological features and cardiac complications.

Objective: Endocarditis is increasing in incidence due to growing numbers of cardiac interventions, valve replacements and immunosuppressants. It can be difficult to diagnose clinically, has high mortality and can present as sudden cardiac death (SCD) with few/subtle preceding symptoms. True incidence of SCD related to endocarditis is unknown.

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction.

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased β-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and β-amyloid (Aβ) are linked with vascular disease development and increased BACE1 and Aβ accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Aβ, and vascular dysfunction is unclear.

Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage.

Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on superoxide generation in saphenous vein ECs (SVECs) from patients with advanced atherosclerosis and type 2 diabetes and on vascular function, vascular damage, and lipid deposition in apolipoprotein E-deficient (ApoE) mice with EC-specific insulin resistance (ESMIRO).

Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency.

Background And Aims: Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect.

Methods: Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases.

Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.

Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2 was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls.

Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A.

Objective: To establish the cellular source of plasma factor (F)XIII-A.

Approach And Results: A novel mouse floxed for the gene, FXIII-A (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.

Objective: To identify additional AAA risk loci using data from all available genome-wide association studies.

Pericytes in diabetes-associated vascular disease.

Pericytes are mural cells that support and stabilise the microvasculature, and are present in all vascular beds. Pericyte-endothelial cell crosstalk is essential in both remodelling and quiescent vasculature, and this complex interaction is often disrupted in disease states. Pericyte loss is believed to be an early hallmark of diabetes-associated microvascular disease, including retinopathy and nephropathy.

First Detection of Bat White-Nose Syndrome in Western North America.

White-nose syndrome (WNS) is an emerging fungal disease of bats caused by Pseudogymnoascus destructans. Since it was first detected near Albany, NY, in 2006, the fungus has spread across eastern North America, killing unprecedented numbers of hibernating bats. The devastating impacts of WNS on Nearctic bat species are attributed to the likely introduction of P.

Use of a novel floxed mouse to characterise the cellular source of plasma coagulation FXIII-A.

Background: Coagulation factor XIII-A has a crucial role in thrombus stabilisation and tissue repair. Factor XIII-A deficiency causes a severe bleeding phenotype and impaired wound healing, but the cellular origin of Factor XIII-A is unknown. To identify the cells that maintain the plasma pool, we generated a mouse floxed in coding exon7 of the factor XIII-A gene (F13A1).

TaqMan real-time polymerase chain reaction for detection of Ophidiomyces ophiodiicola, the fungus associated with snake fungal disease.

Background: Fungal skin infections associated with Ophidiomyces ophiodiicola, a member of the Chrysosporium anamorph of Nannizziopsis vriesii (CANV) complex, have been linked to an increasing number of cases of snake fungal disease (SFD) in captive snakes around the world and in wild snake populations in eastern North America. The emergence of SFD in both captive and wild situations has led to an increased need for tools to better diagnose and study the disease.

Results: We developed two TaqMan real-time polymerase chain reaction (PCR) assays to rapidly detect O.