Unscheduled changes in pre-clinical stroke model housing contributes to variance in physiological and behavioural data outcomes: A post hoc analysis.

Ischaemic stroke presents a significant problem worldwide with no neuroprotective drugs available. Many of the failures in the search for neuroprotectants are attributed to failure to translate from pre-clinical models to humans, which has been combatted with rigorous pre-clinical stroke research guidelines. Here, we present post hoc analysis of a pre-clinical stroke trial, conducted using intraluminal filament transient middle cerebral artery occlusion in the stroke-prone spontaneously hypertensive rat, whereby unscheduled changes were implemented in the animal housing facility.

A computable biomedical knowledge object for calculating in-hospital mortality for patients admitted with acute myocardial infarction.

Introduction: Quality indicators play an essential role in a learning health system. They help healthcare providers to monitor the quality and safety of care delivered and to identify areas for improvement. Clinical quality indicators, therefore, need to be based on real world data.

Ribonucleicacid interference or small molecule inhibition of Runx1 in the border zone prevents cardiac contractile dysfunction following myocardial infarction.

Aims: Myocardial infarction (MI) is a major cause of death worldwide. Effective treatments are required to improve recovery of cardiac function following MI, with the aim of improving patient outcomes and preventing progression to heart failure. The perfused but hypocontractile region bordering an infarct is functionally distinct from the remote surviving myocardium and is a determinant of adverse remodelling and cardiac contractility.

Agonist-induced phosphorylation of orthologues of the orphan receptor GPR35 functions as an activation sensor.

G protein-coupled receptor 35 (GPR35) is poorly characterized but nevertheless has been revealed to have diverse roles in areas including lower gut inflammation and pain. The development of novel reagents and tools will greatly enhance analysis of GPR35 functions in health and disease. Here, we used mass spectrometry, mutagenesis, and [P] orthophosphate labeling to identify that all five hydroxy-amino acids in the C-terminal tail of human GPR35a became phosphorylated in response to agonist occupancy of the receptor and that, apart from Ser, each of these contributed to interactions with arretin-3, which inhibits further G protein-coupled receptor signaling.

Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

Aims: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.

Methods And Results: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size.

Preclinical models of myocardial infarction: from mechanism to translation.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models.

Hand injuries during COVID-19: Lessons from lockdown.

The two-month nationwide lockdown implemented in Australia in response to COVID-19 involved restrictions on social gatherings and non-essential services, resulting in marked changes to the distribution of time spent at home and in the workplace. Given the likelihood of future lockdowns, this study aimed to investigate whether the lockdown was associated with an alteration in the pattern of acute hand injuries admitted to Sydney Hospital Hand Unit relative to the same period in 2019, and whether target areas for preventative strategies could be identified. During the lockdown period in 2020, 332 acute presentations were noted, and in the same period in 2019, 310 cases were noted.

The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential.

Stroke is the 2nd leading cause of death worldwide and the leading cause of physical disability and cognitive issues. Although we have made progress in certain aspects of stroke treatment, the consequences remain substantial and new treatments are needed. Hypertension has long been recognised as a major risk factor for stroke, both haemorrhagic and ischaemic.

The role of extracellular vesicles in neointima formation post vascular injury.

Pathological neointimal growth can develop in patients as a result of vascular injury following percutaneous coronary intervention and coronary artery bypass grafting using autologous saphenous vein, leading to arterial or vein graft occlusion. Neointima formation driven by intimal hyperplasia occurs as a result of a complex interplay between molecular and cellular processes involving different cell types including endothelial cells, vascular smooth muscle cells and various inflammatory cells. Therefore, understanding the intercellular communication mechanisms underlying this process remains of fundamental importance in order to develop therapeutic strategies to preserve endothelial integrity and vascular health post coronary interventions.

Signalling pathways linking cysteine cathepsins to adverse cardiac remodelling.

Adverse cardiac remodelling clinically manifests as deleterious changes to heart architecture (size, mass and geometry) and function. These changes, which include alterations to ventricular wall thickness, chamber dilation and poor contractility, are important because they progressively drive patients with cardiac disease towards heart failure and are associated with poor prognosis. Cysteine cathepsins contribute to key signalling pathways involved in adverse cardiac remodelling including synthesis and degradation of the cardiac extracellular matrix (ECM), cardiomyocyte hypertrophy, impaired cardiomyocyte contractility and apoptosis.

Extracellular vesicle signalling in atherosclerosis.

Atherosclerosis is a major cardiovascular disease and in 2016, the World Health Organisation (WHO) estimated 17.5 million global deaths, corresponding to 31% of all global deaths, were driven by inflammation and deposition of lipids into the arterial wall. This leads to the development of plaques which narrow the vessel lumen, particularly in the coronary and carotid arteries.

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system.

RUNX1: an emerging therapeutic target for cardiovascular disease.

Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies.

Regulation of connexin 43 by interleukin 1β in adult rat cardiac fibroblasts and effects in an adult rat cardiac myocyte: fibroblast co-culture model.

Connexin 43 expression (Cx43) is increased in cardiac fibroblasts (CFs) following myocardial infarction. Here, potential mediators responsible for increasing Cx43 expression and effects of differential CF phenotype on cardiac myocyte (CM) function were investigated. Stimulating adult rat CFs with proinflammatory mediators revealed that interleukin 1β (IL-1β) significantly enhanced Cx43 levels through the IL-1β pathway.

Human Adenovirus Serotype 5 Is Sensitive to IgM-Independent Neutralization In Vitro and In Vivo.

Human adenovirus 5 (HAdV-5) is used as a vector in gene therapy clinical trials, hence its interactions with the host immune system have been widely studied. Previous studies have demonstrated that HAdV-5 binds specifically to murine coagulation factor X (mFX), inhibiting IgM and complement-mediated neutralization. Here, we examined the physical binding of immune components to HAdV-5 by nanoparticle tracking analysis, neutralization assays, mass spectrometry analysis and in vivo experiments.

Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment.

Although cardiovascular disease (CVD) is the leading cause of morbimortality worldwide, promising new drug candidates are lacking. We compared the arterial high-resolution proteome of patients with advanced versus early-stage CVD to predict, from a library of small bioactive molecules, drug candidates able to reverse this disease signature. Of the approximately 4000 identified proteins, 100 proteins were upregulated and 52 were downregulated in advanced-stage CVD.

Assessing the effects of Ang-(1-7) therapy following transient middle cerebral artery occlusion.

The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone.

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

Hypertension is a complex and multifactorial cardiovascular disorder. With different mechanisms contributing to a different extent to an individual's blood pressure, the discovery of novel pathogenetic principles of hypertension is challenging. However, there is an urgent and unmet clinical need to improve prevention, detection, and therapy of hypertension in order to reduce the global burden associated with hypertension-related cardiovascular diseases.

The Orphan Receptor GPR35 Contributes to Angiotensin II-Induced Hypertension and Cardiac Dysfunction in Mice.

Background: The orphan receptor G protein-coupled receptor 35 (GPR35) has been associated with a range of diseases, including cancer, inflammatory bowel disease, diabetes, hypertension, and heart failure. To assess the potential for GPR35 as a therapeutic target in cardiovascular disease, this study investigated the cardiovascular phenotype of a GPR35 knockout mouse under both basal conditions and following pathophysiological stimulation.

Methods: Blood pressure was monitored in male wild-type and GPR35 knockout mice over 7-14 days using implantable telemetry.

Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction.

Background: Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim.

Defining a Novel Role for the Coxsackievirus and Adenovirus Receptor in Human Adenovirus Serotype 5 Transduction in the Presence of Mouse Serum.

Human adenoviral serotype 5 (HAdV-5) vectors have predominantly hepatic tropism when delivered intravascularly, resulting in immune activation and toxicity. Coagulation factor X (FX) binding to HAdV-5 mediates liver transduction and provides protection from virion neutralization in mice. FX is dispensable for liver transduction in mice lacking IgM antibodies or complement, suggesting that alternative transduction pathways exist.

Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction.

Background: Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).

Objectives: The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.