Current epigenetic aspects the clinical kidney researcher should embrace

Chronic kidney disease (CKD), affecting 10-12% of the world's adult population, is associated with a considerably elevated risk of serious comorbidities, in particular, premature vascular disease and death. Although a wide spectrum of causative factors has been identified and/or suggested, there is still a large gap of knowledge regarding the underlying mechanisms and the complexity of the CKD phenotype. Epigenetic factors, which calibrate the genetic code, are emerging as important players in the CKD-associated pathophysiology. In this article, we review some of the current knowledge on epigenetic modifications and aspects on their role in the perturbed uraemic milieu, as well as the prospect of applying epigenotype-based diagnostics and preventive and therapeutic tools of clinical relevance to CKD patients. The practical realization of such a paradigm will require that researchers apply a holistic approach, including the full spectrum of the epigenetic landscape as well as the variability between and within tissues in the uraemic milieu

On the Interaction between Verb Movement and Ellipsis: New Evidence from Hungarian

Theoretical and Experimental Linguistic

What sluicing can do, what it can’t and in which language : on the cross-linguistic syntax of ellipsis

Theoretical and Experimental Linguistic

MicroRNAs in AKI and kidney transplantation

MicroRNAs are epigenetic regulators of gene expression at the posttranscriptional level. They are involved in intercellular communication and crosstalk between different organs. As key regulators of homeostasis, their dysregulation underlies several morbidities including kidney disease. Moreover, their remarkable stability in plasma and urine makes them attractive biomarkers. Beyond biomarker studies, clinical microRNA research in nephrology in recent decades has focused on the discovery of specific microRNA signatures and the identification of novel targets for therapy and/or disease prevention. However, much of this research has produced equivocal results and there is a need for standardization and confirmation in prospective trials. This review aims to provide an overview of general concepts and available clinical evidence in both the pathophysiology and biomarker fields for the role of microRNA in AKI and kidney transplantation

Oxidative stress and endothelial function in normal pregnancy versus pre-eclampsia, a combined longitudinal and case control study

Background: Pre-eclampsia (PE) is related to an impaired endothelial function. Endothelial dysfunction accounts for altered vascular reactivity, activation of the coagulation cascade and loss of vascular integrity. Impaired endothelial function originates from production of inflammatory and cytotoxic factors by the ischemic placenta and results in systemic oxidative stress (OS) and an altered bioavailability of nitric oxide (·NO). The free radical ·NO, is an endogenous endothelium-derived relaxing factor influencing endothelial function. In placental circulation, endothelial release of ·NO dilates the fetal placental vascular bed, ensuring feto-maternal exchange. The Endopreg study was designed to evaluate in vivo endothelial function and to quantify in vitro OS in normal and pre-eclamptic pregnancies. Methods/design: The study is divided into two arms, a prospective longitudinal study and a matched case control study. In the longitudinal study, pregnant patients ≥18 years old with a singleton pregnancy will be followed throughout pregnancy and until 6 months post-partum. In the case control study, cases with PE will be compared to matched normotensive pregnant women. Maternal blood concentration of superoxide (O2·) and placental concentration of ·NO will be determined using EPR (electron paramagnetic resonance). Endothelial function and arterial stiffness will be evaluated using respectively Peripheral Arterial Tonometry (PAT), Flow-Mediated Dilatation (FMD) and applanation tonometry. Placental expression of eNOS (endothelial NOS) will be determined using immune-histochemical staining. Target recruitment will be 110 patients for the longitudinal study and 90 patients in the case-control study. Discussion: The results of Endopreg will provide longitudinal information on in vivo endothelial function and in vitro OS during normal pregnancy and PE. Adoption of these vascular tests in clinical practice potentially predicts patients at risk to develop cardiovascular events later in life after PE pregnancies. ·NO, O2·- and eNOS measurements provide further inside in the pathophysiology of PE

Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF

Oxidative stress and endothelial function in normal pregnancy versus pre-eclampsia, a combined longitudinal and case control study

Background: Pre-eclampsia (PE) is related to an impaired endothelial function. Endothelial dysfunction accounts for altered vascular reactivity, activation of the coagulation cascade and loss of vascular integrity. Impaired endothelial function originates from production of inflammatory and cytotoxic factors by the ischemic placenta and results in systemic oxidative stress (OS) and an altered bioavailability of nitric oxide (·NO). The free radical ·NO, is an endogenous endothelium-derived relaxing factor influencing endothelial function. In placental circulation, endothelial release of ·NO dilates the fetal placental vascular bed, ensuring feto-maternal exchange. The Endopreg study was designed to evaluate in vivo endothelial function and to quantify in vitro OS in normal and pre-eclamptic pregnancies. Methods/design: The study is divided into two arms, a prospective longitudinal study and a matched case control study. In the longitudinal study, pregnant patients ≥18 years old with a singleton pregnancy will be followed throughout pregnancy and until 6 months post-partum. In the case control study, cases with PE will be compared to matched normotensive pregnant women. Maternal blood concentration of superoxide (O2·) and placental concentration of ·NO will be determined using EPR (electron paramagnetic resonance). Endothelial function and arterial stiffness will be evaluated using respectively Peripheral Arterial Tonometry (PAT), Flow-Mediated Dilatation (FMD) and applanation tonometry. Placental expression of eNOS (endothelial NOS) will be determined using immune-histochemical staining. Target recruitment will be 110 patients for the longitudinal study and 90 patients in the case-control study. Discussion: The results of Endopreg will provide longitudinal information on in vivo endothelial function and in vitro OS during normal pregnancy and PE. Adoption of these vascular tests in clinical practice potentially predicts patients at risk to develop cardiovascular events later in life after PE pregnancies. ·NO, O2·- and eNOS measurements provide further inside in the pathophysiology of PE

Acute Exercise-Induced Response of Monocyte Subtypes in Chronic Heart and Renal Failure

Purpose. Monocytes (Mon1-2-3) play a substantial role in low-grade inflammation associated with high cardiovascular morbidity and mortality of patients with chronic kidney disease (CKD) and chronic heart failure (CHF). The effect of an acute exercise bout on monocyte subsets in the setting of systemic inflammation is currently unknown. This study aims (1) to evaluate baseline distribution of monocyte subsets in CHF and CKD versus healthy subjects (HS) and (2) to evaluate the effect of an acute exercise bout. Exercise-induced IL-6 and MCP-1 release are related to the Mon1-2-3 response. Methods. Twenty CHF patients, 20 CKD patients, and 15 HS were included. Before and after a maximal cardiopulmonary exercise test, monocyte subsets were quantified by flow cytometry: CD14++CD16−CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2− (Mon3). Serum levels of IL-6 and MCP-1 were determined by ELISA. Results. Baseline distribution of Mon1-2-3 was comparable between the 3 groups. Following acute exercise, %Mon2 and %Mon3 increased significantly at the expense of a decrease in %Mon1 in HS and in CKD. This response was significantly attenuated in CHF (P<0.05). In HS only, MCP-1 levels increased following exercise; IL-6 levels were unchanged. Circulatory power was a strong and independent predictor of the changes in Mon1 (β=-0.461, P<0.001) and Mon3 (β=0.449, P<0.001); and baseline LVEF of the change in Mon2 (β=0.441, P<0.001). Conclusion. The response of monocytes to acute exercise is characterized by an increase in proangiogenic and proinflammatory Mon2 and Mon3 at the expense of phagocytic Mon1. This exercise-induced monocyte subset response is mainly driven by hemodynamic changes and not by preexistent low-grade inflammation

A comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequences versus full sequences

<p>Abstract</p> <p>Background</p> <p>As second-line antiretroviral treatment (ART) becomes more accessible in resource-limited settings (RLS), the need for more affordable monitoring tools such as point-of-care viral load assays and simplified genotypic HIV drug resistance (HIVDR) tests increases substantially. The prohibitive expenses of genotypic HIVDR assays could partly be addressed by focusing on a smaller region of the HIV reverse transcriptase gene (RT) that encompasses the majority of HIVDR mutations for people on ART in RLS. In this study, an <it>in silico </it>analysis of 125,329 RT sequences was performed to investigate the effect of submitting short RT sequences (codon 41 to 238) to the commonly used virco^®TYPE and Stanford genotype interpretation tools.</p> <p>Results</p> <p>Pair-wise comparisons between full-length and short RT sequences were performed. Additionally, a non-inferiority approach with a concordance limit of 95% and two-sided 95% confidence intervals was used to demonstrate concordance between HIVDR calls based on full-length and short RT sequences.</p> <p>The results of this analysis showed that HIVDR interpretations based on full-length versus short RT sequences, using the Stanford algorithms, had concordance significantly above 95%. When using the virco^®TYPE algorithm, similar concordance was demonstrated (>95%), but some differences were observed for d4T, AZT and TDF, where predictions were affected in more than 5% of the sequences. Most differences in interpretation, however, were due to shifts from fully susceptible to reduced susceptibility (d4T) or from reduced response to minimal response (AZT, TDF) or vice versa, as compared to the predicted full RT sequence. The virco^®TYPE prediction uses many more mutations outside the RT 41-238 amino acid domain, which significantly contribute to the HIVDR prediction for these 3 antiretroviral agents.</p> <p>Conclusions</p> <p>This study illustrates the acceptability of using a shortened RT sequences (codon 41-238) to obtain reliable genotype interpretations by virco^®TYPE and Stanford algorithms. Implementation of this simplified protocol could significantly reduce the cost of both resistance testing and ARV treatment monitoring in RLS.</p