Herein we describe the development of a focused series of functionalized pyridazin-3(2 H)-one-based formyl peptide receptor (FPR) agonists that demonstrate high potency and biased agonism. The compounds described demonstrated biased activation of prosurvival signaling, ERK1/2 phosphorylation, through diminution of the detrimental FPR1/2-mediated intracellular calcium (Ca) mobilization. Compound...

Background Recent studies have revealed sexually dimorphic associations between the carbamoyl-phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease ( CAD ) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl-phosphate synthase 1 could be mediated by the strong genetic effe...

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising resul...

Non-insulin-dependent diabetes mellitus (NIDDM) is reported to increase the risk of cognitive impairment and dementia. However, the underlying mechanisms are not fully understood. While the brain homeostasis of metals and lipids is pivotal to maintaining energy metabolism and redox homeostasis for healthy brain function, no studies have reported hippocampal metal and biochemical changes in NIDD...

Mitochondrial dysfunction is associated with a diverse array of diseases ranging from dystrophy and heart failure to obesity and hepatosteatosis. One of the major biochemical consequences of impaired mitochondrial function is an accumulation of mitochondrial superoxide, or reactive oxygen species (ROS). Excessive ROS can be detrimental to cellular health and is proposed to underpin many mitocho...

. Comparability of accelerometers in epidemiological studies is important for public health researchers. This study aimed to compare physical activity (light, LPA; moderate, MPA; and moderate-to-vigorous, MVPA) and sedentary behavior (SB) data collected using two Omron triaxial accelerometer generations (Active style Pro, ASP) among a sample of Japanese workers in a free-living environment. . T...

Background Patients with a Fontan circulation achieve lower peak heart rates ( HR ) during exercise. Whether this impaired chronotropic response reflects pathology of the sinoatrial node or is a consequence of altered cardiac hemodynamics is uncertain. We evaluated the adequacy of HR acceleration throughout exercise relative to metabolic demand and cardiac output in patients with a Fontan circu...

To develop a cost-effectiveness model to address the outcome and economic implications of different thresholds for surgery in the management of aortopathy associated with bicuspid aortic valve disease (ABAV).A model was created from the perspective of an Australian healthcare funding agency. The index case was a 65-year-old with BAV and ascending aorta diameter of 5.0 cm. Health states were def...

The primary care setting is the ideal location for identifying the condition of frailty in older adults.The aim of this pragmatic study was twofold: (1) to identify data items to extract the data required for an electronic Frailty Index (eFI) from electronic health records (EHRs); and (2) test the ability of an eFI to accurately and feasibly identify frailty in older adults.In a rural South Aus...

Atrial fibrillation and heart failure (HF) frequently coexist and are associated with a significant increase in morbidity and mortality. Despite the shared common risk factors atrial fibrillation and HF subtypes exacerbate each other. This review provides an overview of the pathophysiologic relationship between atrial fibrillation and the two most common types of heart failure syndromes: HF wit...

Sepsis is associated with a systemic inflammatory reaction, which can result in a life-endangering organ dysfunction. Pro-inflammatory responses during sepsis are characterized by increased activation of leukocytes and platelets, formation of platelet-neutrophil aggregates, and cytokine production. Sequestration of platelet-neutrophil aggregates in the microvasculature contributes to tissue dam...

There is conflicting evidence about the obesity paradox-the counterintuitive survival advantage of obesity among certain subpopulations of individuals with chronic conditions. It is believed that results supporting the obesity paradox are due to methodological flaws, such as collider bias. The aim of this study was to examine the association between obesity and mortality in Australian men and w...

We examined associations of neighborhood population density with 12-year changes in diabetes risk (post-challenge plasma glucose), and potential moderation by neighborhood socio-economic status (SES) among 4,816 Australians. In lower SES neighborhoods, post-challenge plasma glucose increased by 6% in low-density, remained stable in medium-density and decreased by 3% in high-density neighborhood...

Traditionally, opioids have been the analgesia of choice for patients with ST-Elevation Myocardial Infarction (STEMI). Recent studies, however, have raised the possibility of harmful effects of opioid administration through delayed onset of antiplatelet agents.To perform a systematic review of the effects of parenteral opioids in patients presenting with STEMI.Medical databases were systematica...

The authors used cluster analysis of data from cardiovascular domains associated with exercise intolerance to help define prognostic phenotypes of patients with heart failure with preserved ejection fraction (HFpEF).Resting and postexercise echocardiography was performed in 177 patients with HFpEF and 51 asymptomatic control subjects sharing a common clinical profile. Patterns of features that ...

Disease management programs (DMPs) may reduce short-term readmission or death after heart failure (HF) hospitalization. We sought to determine if targeting of DMP to the highest-risk patients could improve efficiency.Patients (n = 412) admitted with HF were randomized to usual care or an intensive DMP including optimizing intravascular volume status at discharge, increased self-care education, ...

Glomerular hyperfiltration is not able to be detected in clinical practice. We assessed whether hyperfiltration is associated with albuminuria progression among Indigenous Australians at high risk of diabetes and kidney disease to determine its role in kidney disease progression.Longitudinal observational study of Indigenous Australians aged ≥18 years recruited from >20 sites, across diabetes a...

Histone deacetylases (HDACs) regulate gene transcription by catalyzing the removal of acetyl groups from key lysine residues in nucleosomal histones and via the recruitment of other epigenetic regulators to DNA promoter/enhancer regions. Over the past two decades, HDACs have been implicated in multiple processes pertinent to cardiovascular and metabolic diseases, including cardiac hypertrophy a...

We have previously shown that the increase in muscle sympathetic nerve activity (MSNA) to contracting muscle during sustained isometric exercise is due primarily to central command and that contracting muscle does not express a metaboreceptor-driven increase in MSNA. Here we tested the hypothesis that MSNA increases to the contracting muscle also during rhythmic isotonic exercise, in which musc...