Whole genome sequencing can provide detailed information in a clinically relevant time frame to aid management of outbreaks in critical patient management areas. The superior discriminatory power of this method makes it a powerful tool in infection control.
Cardiovascular diseases are the leading causes of mortality worldwide. Among them, hypertension and its pathological complications pose a major risk for the development of other cardiovascular diseases, including heart failure and stroke. Identifying novel and early stage biomarkers of hypertension and other cardiovascular diseases is of paramount importance in predicting and preventing the major morbidity and mortality associated with these diseases. Biomarkers of such diseases or predisposition to their development are identified by changes in a specific indicator’s expression between healthy individuals and patients. These include changes in protein and microRNA (miRNA) levels. Protein profiling using mass spectrometry and miRNA screening utilizing microarray and sequencing have facilitated the discovery of proteins and miRNA as biomarker candidates. In this review, we summarized some of the different, promising early stage protein and miRNA biomarker candidates as well as the currently used biomarkers for hypertension and other cardiovascular diseases. Although a number of promising markers have been identified, it is unlikely that a single biomarker will unambiguously aid in the classification of these diseases. A multi-marker panel-strategy appears useful and promising for classifying and refining risk stratification among patients with cardiovascular disease.
Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 μg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.
Hypertension induces vascular hypertrophy, which changes blood vessels structurally and functionally, leading to reduced tissue perfusion and further hypertension. It is also associated with dysregulated levels of the circulating adipokines leptin and adiponectin (APN). Leptin is an obesity-associated hormone that promotes vascular smooth muscle cell (VSMC) hypertrophy. APN is a cardioprotective hormone that has been shown to attenuate hypertrophic cardiomyopathy. In this study, we investigated the molecular mechanisms of hypertension-induced VSMC remodeling and the involvement of leptin and APN in this process. To mimic hypertension, the rat portal vein (RPV) was mechanically stretched, and the protective effects of APN on mechanical stretch-induced vascular remodeling and the molecular mechanisms involved were examined by using 10 μg/ml APN. Mechanically stretching the RPV significantly decreased APN protein expression after 24 hours and APN mRNA expression in a time-dependent manner in VSMCs. The mRNA expression of the APN receptors AdipoR1, AdipoR2, and T-cadherin significantly increased after 15 hours of stretch. The ratio of APN/leptin expression in VSMCs significantly decreased after 24 hours of mechanical stretch. Stretching the RPV for 3 days increased the weight and [3H]-leucine incorporation significantly, whereas APN significantly reduced hypertrophy in mechanically stretched vessels. Stretching the RPV for 10 minutes significantly decreased phosphorylation of LKB1, AMPK, and eNOS, while APN significantly increased p-LKB1, p-AMPK, and p-eNOS in stretched vessels. Mechanical stretch significantly increased p-ERK1/2 after 10 minutes, whereas APN significantly reduced stretch-induced ERK1/2 phosphorylation. Stretching the RPV also significantly increased ROS generation after 1 hour, whereas APN significantly decreased mechanical stretch-induced ROS production. Exogenous leptin (3.1 nM) markedly increased GATA-4 nuclear translocation in VSMCs, whereas APN significantly attenuated leptin-induced GATA-4 nuclear translocation. Our results decipher molecular mechanisms of APN-induced attenuation of mechanical stretch-mediated vascular hypertrophy, with the promising potential of ultimately translating this protective hormone into the clinic.
We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage.
Detection of HIV drug resistance is vital to successful anti-retroviral therapy (ART). HIV drug resistance (HIVDR) testing to determine drug resistance mutations (DRMs) is routinely performed in Australia to guide ART choice in either newly diagnosed people living with HIV or in cases of treatment failure. In 2022, our Australian clinical microbiology laboratory sought to validate a Next-generation sequencing (NGS)-based HIVDR assay to replace the previous Sanger sequencing (SS)-based ViroSeq assay. NGS solutions for HIVDR offer higher throughput, lower costs and higher sensitivity for variant detection. We sought to validate the previously described low-cost probe-based NGS method (veSEQ-HIV) for HIV-1 recovery and HIVDR testing in a diagnostic setting. The implemented veSEQ-HIV assay displayed 100% and 98% accuracy in major and minor mutation detection respectively and 100% accuracy of subtyping (provided >1000 mapped reads were obtained). Pairwise comparison exhibited low inter-and intra-run variability across the whole genome (Jaccard similarity coefficient [J] =0.993; J=0.972) and limited to the Pol gene only (J=0.999; J=0.999) respectively. The veSEQ-HIV assay met all our pre-set criteria based on the WHO ″Recommended methods for validating an in-house genotyping assay for surveillance of HIV drug resistance″ and has successfully replaced the ViroSeq assay in our laboratory.Scaling-down the veSEQ-HIV assay to a limited batch size and sequencing on the Illumina iSeq100, allowed easy implementation of the assay into the workflow of a small sequencing laboratory with minimal staff and equipment and the ability to meet clinically relevant test turn-around times.
Background and aimsThe mechanisms that contribute to the development of hypertension leading to cardiovascular diseases (CVD) have not been fully‐elucidated. Increased vascular pressure is associated with the formation of reactive oxygen species (ROS) in vascular smooth muscle cells. ROS has been related to the secretion of Cyclophlin A (CyPA). Moreover, studies have shown the incorporation of CyPA in CVD. Obesity is associated with decrease in adiponectin (APN) levels. Several studies have revealed that APN preserves the normal physiology of the heart. In this study, we aimed to investigate whether hypertension/mechanical stretch enhances the overexpression of CyPA protein and to explore the molecular mechanisms that mediates stretch‐induced CyPA expression. We will also assess the different possible pathways of CyPA induced vascular remodeling. We will focus on the protective effects of APN and its effects on CyPA protein expression.MethodsRat portal veins (RPV) organ culture with or without stretching along with aorta organ culture with or without angiotensin‐II (Ang‐II) were performed to study CyPA protein expression. CyPA treatment was also done on aorta and RPV. Western blot was used to study the expression of various proteins. Immunohistochemistry was performed to study ROS, CyPA, adiponectin and leptin expressions.ResultsThis study has shown that CyPA expression increases in response to stretch in RPV and Ang‐II in aorta. Moreover, CyPA was able to increase extracellular signal‐regulated kinases 1/2 (ERK1/2) activation and to decrease 5′‐AMP‐activated protein kinase (AMPK) and endothelial nitric oxide synthase (e‐NOS) phosphorylation. CyPA was also able to increase ROS and leptin expression and to attenuate APN expression. Furthermore, we have shown that APN decreases CyPA expression. This study also demonstrated that RhoA/ROCK inhibition with Y‐27632 and ROS inhibition with apocynin inhibits CyPA expression.ConclusionBased on the obtained results, we showed that mechanical stretch and Ang‐II upregulates CyPA protein expression via activation of ROS and RhoA/ROCK pathway. We also demonstrated that CyPA induces vascular remodeling by phosphorylation/activation of ERK 1/2, by inhibition of AMPK and e‐NOS phosphorylation, by activation of leptin and downregulation of adiponectin. Moreover, the protective effect of adiponectin was also studied and we demonstrated that APN anti‐hypertrophic effect was in part due to inhibition of CyPA activity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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