Indicators of stress hematopoiesis in the blood predict COVID-19 progression in patients over 65 years old.

OBJECTIVES: Advanced age is a well-established risk factor for severe coronavirus disease 2019 (COVID-19). Exacerbated inflammation affects multiple organs, among which hematopoiesis responds by increased output of various cells. We aimed to determine the association between COVID-19 progression and large immature cell (LIC) counts, changes in erythrocyte and platelet distribution widths (RDW, PDW) with reference to patients' age. METHODS: A total of 755 patients with complete blood cell (CBC) analysis in the first 24 h of hospitalization were enrolled. Patients were divided into two groups: under and above 65 years of age. RESULTS: The LIC counts were different in both groups (p < 0.003). However, only the senior patients had markedly different values of RDW and PDW (p < 0.001). The receiver operating characteristic (ROC) curve analysis provided increased LIC (AUC = 0.600), RDW (AUC = 0.609), PDW (AUC = 0.556), and platelet to LIC ratio (AUC = 0.634) as significant in discriminating outcome in the older group. Importantly, these results were not repeated in the younger patients. In the elderly, the progression was predicted with LIC cut-off at ≥ 0.305 × 109/L (OR = 3.166) and RDW over 12.15% (OR = 2.081). DISCUSSION: Aging is characterized by a decline in immunological competence with a compromised control of inflammation leading to a proinflammatory state. This background together with the actions of pathogens may lead to emergency myelopoiesis. CONCLUSION: Our results point to the important differences between age groups regarding CBC-related parameters of stress hematopoiesis during severe infection. Higher LIC, RDW and PDW levels were reliable in the early identification of COVID-19 progression only in the elderly.

Biomarker Phenotypes in Heart Failure with Preserved Ejection Fraction Using Hierarchical Clustering-A Pilot Study.

OBJECTIVES: We hypothesized the existence of distinct phenotype-based groups within the very heterogeneous population of patients of heart failure with preserved ejection fraction (HFpEF) and using an unsupervised hierarchical clustering applied to plasma concentration of various biomarkers. We sought to characterize them as "biomarker phenotypes" and to conclude differences in their overall characteristics. SUBJECTS AND METHODS: A cross-sectional study was conducted on 75 patients with HFpEF. An agglomerative hierarchical clustering was performed using the concentrations of cardiac remodeling biomarkers, BNP and cystatin C. RESULTS: According to the obtained heat map of this analysis, we concluded two distinctive biomarker phenotypes within the HFpEF. The "remodeled phenotype" presented with significantly higher concentrations of cardiac remodeling biomarkers and cystatin C (p < 0.001), higher prevalence of myocardial infarction (p = 0.047), STEMI (p = 0.045), atrial fibrillation (p = 0.047) and anemia: lower erythrocytes count (p=0.037), hemoglobin concentration (p = 0.034) and hematocrit (p = 0.046), compared to "non-remodeled phenotype". Echocardiography showed that patients within "remodeled phenotype" had significantly increased parameters of left ventricular remodeling: left ventricular mass index (p < 0.001), left ventricular mass (p = 0.001), diameters of the interventricular septum (p = 0.027) and posterior wall (p = 0.003) and function alterations, intermediate pauses duration >2.0 seconds (p < 0.006). CONCLUSION: Unsupervised hierarchical clustering applied to plasma concentration of various biomarkers in patients with HFpEF enables the identification of two biomarker phenotypes, significantly different in clinical characteristics and cardiac structure and function, whereas one phenotype particularly relates to patients with reduced ejection fraction. These findings imply distinct underlying pathophysiology within a unique cohort of HFpEF.

The Multi-Faceted Nature of Renalase for Mitochondrial Dysfunction Improvement in Cardiac Disease.

The cellular mechanisms and signaling network that guide the cardiac disease pathophysiology are inextricably intertwined, which explains the current scarcity of effective therapy and to date remains the greatest challenge in state-of-the-art cardiovascular medicine. Accordingly, a novel concept has emerged in which cardiomyocytes are the centerpiece of therapeutic targeting, with dysregulated mitochondria as a critical point of intervention. Mitochondrial dysfunction pluralism seeks a multi-faceted molecule, such as renalase, to simultaneously combat the pathophysiologic heterogeneity of mitochondria-induced cardiomyocyte injury. This review provides some original perspectives and, for the first time, discusses the functionality spectrum of renalase for mitochondrial dysfunction improvement within cardiac disease, including its ability to preserve mitochondrial integrity and dynamics by suppressing mitochondrial ΔΨm collapse; overall ATP content amelioration; a rise of mtDNA copy numbers; upregulation of mitochondrial genes involved in oxidative phosphorylation and cellular vitality promotion; mitochondrial fission inhibition; NAD+ supplementation; sirtuin upregulation; and anti-oxidant, anti-apoptotic, and anti-inflammatory traits. If verified that renalase, due to its multi-faceted nature, behaves like the "guardian of mitochondria" by thwarting pernicious mitochondrial dysfunction effects and exerting therapeutic potential to target mitochondrial abnormalities in failing hearts, it may provide large-scale benefits for cardiac disease patients, regardless of the underlying causes.

Plasma advanced oxidation products as an additional tool in assessment of post-infarction heart failure.

OBJECTIVE: To define which oxidative stress markers could be used as diagnostic tools in the assessment of post-infarction heart failure (HF). METHODS: This observational study enrolled patients with HF that were divided into three subgroups (ejection fraction [EF] ≥ 50%; EF 40-49%; EF < 40%) and age- and sex-matched healthy control subjects. The plasma concentrations of advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances, catalase activity and free thiols were determined in all participants. RESULTS: The study enrolled 81 patients with HF and 68 healthy control subjects. There were significant differences in the values ​​of oxidative stress markers between patients and controls. Oxidative stress parameters did not differ between the subgroups of patients, except for AOPP, which was significantly higher in the EF < 40% group. Univariate and multivariate logistic regression analyses showed an association between AOPP and HF in the EF ≥ 50% group, while receiver operating characteristic (ROC) curve analysis identified a cut-off value of 60.89 µmol/l for AOPP. CONCLUSIONS: Based on the ROC curve analysis of AOPP and the higher significance in the multivariate analyses for patients with EF ≥ 50%, these current results suggest that AOPP could be a useful additional tool in the assessment of post-infarction HF.

Renalase Challenges the Oxidative Stress and Fibroproliferative Response in COVID-19.

The hallmark of the coronavirus disease 2019 (COVID-19) pathophysiology was reported to be an inappropriate and uncontrolled immune response, evidenced by activated macrophages, and a robust surge of proinflammatory cytokines, followed by the release of reactive oxygen species, that synergistically result in acute respiratory distress syndrome, fibroproliferative lung response, and possibly even death. For these reasons, all identified risk factors and pathophysiological processes of COVID-19, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated. Experimental evidence indicates that renalase, a novel amino-oxidase, derived from the kidneys, exhibits remarkable organ protection, robustly addressing the most powerful pathways of cell trauma: inflammation and oxidative stress, necrosis, and apoptosis. As demonstrated, systemic renalase administration also significantly alleviates experimentally induced organ fibrosis and prevents adverse remodeling. The recognition that renalase exerts cytoprotection via sirtuins activation, by raising their NAD+ levels, provides a "proof of principle" for renalase being a biologically impressive molecule that favors cell protection and survival and maybe involved in the pathogenesis of COVID-19. This premise supports the rationale that renalase's timely supplementation may prove valuable for pathologic conditions, such as cytokine storm and related acute respiratory distress syndrome. Therefore, the aim for this review is to acknowledge the scientific rationale for renalase employment in the experimental model of COVID-19, targeting the acute phase mechanisms and halting fibrosis progression, based on its proposed molecular pathways. Novel therapies for COVID-19 seek to exploit renalase's multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase's employment in the experimental models of COVID-19.

Platelet-derived immuno-inflammatory indices show best performance in early prediction of COVID-19 progression.

BACKGROUND: Coronavirus disease 2019 (COVID-19) profoundly affects the immune and hematopoietic systems with various degrees of reactive changes in the blood cell counts. Immuno-inflammatory indices are considered a simple and effective tool in the prediction of COVID-19 outcomes. We aimed to evaluate and compare the usefulness of leukocyte and platelet counts-based immuno-inflammatory indices on admission to hospital in predicting COVID-19 progression and mortality. METHODS: A total of 945 patients were enrolled. In addition to blood cell counts, we assessed hemogram-derived immuno-inflammatory indices in relation to COVID-19 progression and death. The indices were tested by analysis of variance, receiver operating characteristic curve analysis, and binomial logistic regressions. RESULTS: Patients with severe COVID-19 had significantly higher counts of neutrophils, eosinophils, and large immature cells (LIC), while decreased counts of platelets and monocytes. Lymphopenia was found in all of the patients, but without significant association with the outcomes. Patients with a LIC count ≥0.265 x 09 /L had 54.7% more odds of having COVID-19 progression. In multivariable analyses, platelets/neutrophil-to-lymphocyte ratio (P/NLR) and platelets-to-neutrophil radio (P/N) were significant independent predictors of COVID-19 progression and mortality. The odds of a poor outcome were two times higher in cases with P/NLR < 43 x 109 /L and P/N < 29 x 109 /L. CONCLUSION: Indices that include platelet count in combination with neutrophil and/or lymphocyte counts displayed the best discriminatory ability and prognostic value of COVID-19 outcomes. Additionally, LIC showed promising results in the early identification of severe COVID-19.

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis.

Cardiac fibrosis represents a redundant accumulation of extracellular matrix proteins, resulting from a cascade of pathophysiological events involved in an ineffective healing response, that eventually leads to heart failure. The pathophysiology of cardiac fibrosis involves various cellular effectors (neutrophils, macrophages, cardiomyocytes, fibroblasts), up-regulation of profibrotic mediators (cytokines, chemokines, and growth factors), and processes where epithelial and endothelial cells undergo mesenchymal transition. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. The most effective anti-fibrotic strategy will have to incorporate the specific targeting of the diverse cells, pathways, and their cross-talk in the pathogenesis of cardiac fibroproliferation. Additionally, renalase, a novel protein secreted by the kidneys, is identified. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase's compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-α, IL-6, MCP-1, MIP-2, ROS, TGF-ß1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins (1 and 3) activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression ('α-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. This review provides the scientific rationale for renalase's scrutiny regarding cardiac fibrosis, and there is great anticipation that these newly identified pathways are set to progress one step further. Although substantial progress has been made, indicating renalase's therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase, concerning cardiac fibrosis, before any potential translation to clinical investigation.

Temporal Changes in Incidence Rates of the Most Common Gynecological Cancers in the Female Population in Central Serbia.

Background and Objectives: There were 1,335,503 newly diagnosed cases of the most common gynecological cancers in women (cervical, uterine and ovarian cancer) worldwide in 2020. The main objective of this paper was to assess temporal changes in incidence rates of the most common gynecological cancers and to determine the age group with the greatest increase in incidence in the Serbian female population in the period 2003-2018. Material and Methods: Trends and annual percentage change (APC) of the incidence rate with corresponding 95% confidence intervals (CI) were calculated by Joinpoint regression analysis. The trend was considered to be significantly increasing (positive change) or decreasing (negative change) when the p-value was below 0.05 (p < 0.05). Results: The total number of newly registered cancer cases from 2003 to 2018 was 35,799. There was a significant increase of age standardized rate (ASR) for all cancer incidences in women from 2012 to 2018 with APC 6.9% (95% CI from 0.9 to 13.3, p = 0.028) and for uterine cancer during the 2014-2018 period with APC of 16.8% (95% CI: from 4.0 to 31.1, p = 0.014), as well as for ovarian cancer incidence in the 2012-2018 period with APC of 12.1% (95% CI: from 6.7 to 17.8, p < 0.001). A non-significant decrease of ASRs of incidence for cervical cancer was determined from 2003 to 2015 with APC of -0.22% (95% CI: from -3.4 to 3.1, p = 0.887) and a non-significant increase of ASRs incidence from 2015 to 2018 with APC of 14.21% (95% CI: from -13.3 to 50.5, p = 0.311). The most common gynecological cancers were present in all age groups and only ovarian cancer was registered in the youngest age group (0-4 years). Cervical cancer showed a typical increase after the age of 30, with peak incidence in women aged 40-44 and 65-69 years. The increased incidence trend regarding age for cervical cancer (y = 1.3966x + 0.3765, R2 = 0.3395), uterine cancer (y = 1.7963x - 5.4688, R2 = 0.5063) and ovarian cancer (y = 1.0791x - 0.8245, R2 = 0.5317) is statistically significant. Conclusion: Based on our presented results, a significant increase of incidence trend for the most common gynecological cancers in the Serbian female population from 2012 to 2018 was determined. There has been a significant increase in the incidence of uterine cancer from 2014 up to 2018, as well as for ovarian cancer from 2012 up to 2018, while cervical cancer showed a non-significant decrease of incidence trend from 2003 until 2015 and then a non-significant increase. In women below 20 years of age, ovarian cancer was significantly more prevalent, while cervical cancer was significantly more prevalent in the age groups 20-39 and 40-59 years. In the age group of 60-79, uterine cancer had a significantly higher incidence than the other two cancers. Measures of primary prevention, such as vaccination of children against Human Papilloma Virus and screening measures of secondary prevention, for the female population aged 25 to 64 years of age are needed, as well as educating females about healthy lifestyles via media and social networks to help prevent the most common gynecological cancers.

Vitamins, microelements and the immune system: current standpoint in the fight against coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) is an acute respiratory disease associated with severe systemic inflammation. The optimal status of vitamins and microelements is considered crucial for the proper functioning of the immune system and necessary for successful recovery. Most patients with respiratory distress in COVID-19 are vitamin and microelement deficient, with vitamin D and Se deficiency being the most common. Anyway, various micronutrient supplements are widely and arbitrarily used for prevention or in the treatment of COVID-19. We aimed to summarise current knowledge about molecular and physiological mechanisms of vitamins (D, A, C, B6, B9 and B12) and microelements (Se, Zn, Cu and Fe) involved in the immune system regulation in consideration with COVID-19 pathogenesis, as well as recent findings related to their usage and effects in the prevention and treatment of COVID-19. In the early course of the pandemic, several, mainly observational, studies reported an association of some micronutrients, such as vitamin C, D and Zn, with severity reduction and survival improvement. Still, emerging randomised controlled trials showed no effect of vitamin D on hospitalisation length and no effect of vitamin C and Zn on symptom reduction. Up to date, there is evidence neither for nor against the use of micronutrients in the treatment of COVID-19. The doses that exceed the recommended for the general population and age group should not be used, except in clinical trials. Benefits of supplementation are primarily expected in populations prone to micronutrient deficiencies, who are, as well, at a higher risk of worse outcomes in COVID-19.

Cancer of unknown primary - incidence, mortality trend, and mortality-to-incidence ratio is associated with human development index in Central Serbia, 1999-2018: Evidence from the national cancer registry.

OBJECTIVES: The aim was to estimate the trend of incidence, mortality and mortality-to-incidence ratio (MIR) in Central Serbia in 1999-2018 and its possible association with the human development index (HDI). METHODS: In this study, cancer of unknown primary (CUP) was included as C77-C80 codes. Trend analysis was performed in the Joinpoint Regression Programme version 4.8.0.1. HDI combines life expectancy, educational attainment and gross national income. HDI values for Serbia are extracted from the global bank site. RESULTS: Joinpoint regression analysis of the age-standardised incidence rate of CUP showed a significantly increasing trend with annual percent change (APC) of 8.5% (95% confidence interval [CI] 3.0-14.3%) in males and 7.8% (95%CI 2.7-13.2) in females. The age-standardised mortality rate of CUP showed a significantly decreasing trend with APC of -1.7% (95%CI -2.8 to -0.5%) in males and -1.4% (95%CI -2.7 to -0.1%) in females. MIR showed a significantly decreasing trend with APC of -9.3% (95%CI -14.6 - -3.6%) in males and -7.1% (95%CI -10.5% to -4.2%) in females. The linear regression showed significant inverse association among HDI and the MIR of CUP in males (r2 = 0.464, p = 0.002) and in females (r2 = 0.612, p < 0.001). CONCLUSIONS: Decline of MIR was associated with HDI, suggesting that CUP prognosis follows socio-economic status.

The Discriminatory Ability of Renalase and Biomarkers of Cardiac Remodeling for the Prediction of Ischemia in Chronic Heart Failure Patients With the Regard to the Ejection Fraction.

Background: Renalase has been implicated in chronic heart failure (CHF); however, nothing is known about renalase discriminatory ability and prognostic evaluation. The aims of the study were to assess whether plasma renalase may be validated as a predictor of ischemia in CHF patients stratified to the left ventricular ejection fraction (LVEF) and to determine its discriminatory ability coupled with biomarkers representing a range of heart failure (HF) pathophysiology: brain natriuretic peptide (BNP), soluble suppressor of tumorigenicity (sST2), galectin-3, growth differentiation factor 15 (GDF-15), syndecan-1, and cystatin C. Methods: A total of 77 CHF patients were stratified according to the LVEF and were subjected to exercise stress testing. Receiver operating characteristic curves were constructed, and the areas under curves (AUC) were determined, whereas the calibration was evaluated using the Hosmer-Lemeshow statistic. A DeLong test was performed to compare the AUCs of biomarkers. Results: Independent predictors for ischemia in the total HF cohort were increased plasma concentrations: BNP (p = 0.008), renalase (p = 0.012), sST2 (p = 0.020), galectin-3 (p = 0.018), GDF-15 (p = 0.034), and syndecan-1 (p = 0.024), whereas after adjustments, only BNP (p = 0.010) demonstrated predictive power. In patients with LVEF <45% (HFrEF), independent predictors of ischemia were BNP (p = 0.001), renalase (p < 0.001), sST2 (p = 0.004), galectin-3 (p = 0.003), GDF-15 (p = 0.001), and syndecan-1 (p < 0.001). The AUC of BNP (0.837) was statistically higher compared to those of sST2 (DeLong test: p = 0.042), syndecan-1 (DeLong: p = 0.022), and cystatin C (DeLong: p = 0.022). The AUCs of renalase (0.753), galectin-3 (0.726), and GDF-15 (0.735) were similar and were non-inferior compared to BNP, regarding ischemia prediction. In HFrEF patients, the AUC of BNP (0.980) was statistically higher compared to those of renalase (DeLong: p < 0.001), sST2 (DeLong: p < 0.004), galectin-3 (DeLong: p < 0.001), GDF-15 (DeLong: p = 0.001), syndecan-1 (DeLong: p = 0.009), and cystatin C (DeLong: p = 0.001). The AUC of renalase (0.814) was statistically higher compared to those of galectin-3 (DeLong: p = 0.014) and GDF-15 (DeLong: p = 0.046) and similar to that of sST2. No significant results were obtained in the patients with LVEF >45%. Conclusion: Plasma renalase concentration provided significant discrimination for the prediction of ischemia in patients with CHF and appeared to have similar discriminatory potential to that of BNP. Although further confirmatory studies are warranted, renalase seems to be a relevant biomarker for ischemia prediction, implying its potential contribution to ischemia-risk stratification.

Interaction of thrombophilic SNPs in patients with unexplained infertility-multifactor dimensionality reduction (MDR) model analysis.

PURPOSE: Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis. METHODS: A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed. RESULTS: There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02). CONCLUSION: The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

Cardiac Remodeling Biomarkers as Potential Circulating Markers of Left Ventricular Hypertrophy in Heart Failure with Preserved Ejection Fraction.

Soluble suppressor of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor (GDF)-15 and syndecan-1 represent biomarkers of cardiac remodeling, involved in heart failure (HF) progression. We hypothesize that their plasma concentrations, together with brain natriuretic peptide (BNP), are different in HF stratified by ejection fraction (EF), demonstrating correlations with echocardiographic parameters that indicate left ventricular (LV) hypertrophy; LV mass index (LVMI) and posterior wall and septum diameters. HF patients (n = 77) were classified according to EF: reduced EF < 40% (HFrEF), mid-range EF = 40-49% (HFmrEF), preserved EF > 50% (HFpEF). We found that plasma concentrations of four cardiac remodeling biomarkers were highest in HFrEF and lowest in HFpEF, p < 0.001. In HFpEF, remodeling biomarkers independently correlated with LVMI: sST2 (p = 0. 002), galectin-3 (p < 0.001), GDF-15 (p = 0.011), and syndecan-1 (p = 0.006), whereas galectin-3 correlated after multivariable adjustments (p = 0.001). Independent correlates of septum and posterior wall diameters, in HFpEF, were sST2 (p = 0.019; p = 0.026), galectin-3 (p = 0.011; p = 0.009), GDF-15 (p = 0.007; p = 0.001), and syndecan-1 (p = 0.005; p = 0.002). In HFrEF, only sST2, adjusted, correlated with LVMI (p = 0.010), whereas BNP correlated with LVMI (p = 0.002) and EF (p = 0.001). GDF-15 correlated with diastolic dysfunction in HFpEF (p = 0.046) and HFrEF (p = 0.024). Cardiac remodeling biomarkers are potential circulating indicators of LV hypertrophy in HFpEF, which may ensure timely recognition of disease progression among high-risk patients.

The partnership between renalase and ejection fraction as a risk factor for increased cardiac remodeling biomarkers in chronic heart failure patients.

Objective: Heart failure (HF) represents a huge socio-economic burden. It has been demonstrated, experimentally, that renalase, a newly discovered protein, prevents cardiac hypertrophy and adverse remodeling, which is seen in HF. We postulated the following aims: to investigate associations of renalase with biomarkers of cardiac remodeling: galectin-3, soluble suppression of tumorigenicity, (sST2), growth differentiation factor 15 (GDF-15) and syndecan-1, myocardial stretch (BNP) and cardio-renal axis (cystatin C) in HF patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) to determine whether renalase, in combination with left ventricular ejection fraction (LVEF), represents a risk factor for plasma elevation in biomarkers.Methods: We classified HF patients (n = 76) according to LVEF (preserved/reduced), applied a median plasma renalase (113 ng/mL) as a cut-off value (low/high) and created four subgroups of HF patients: HFpEF/low renalase (n = 19), HFrEF/low renalase (n = 19), HFrEF/high renalase (n = 32) and HFpEF/high renalase (n = 6). A control group (n = 35) consisted of healthy volunteers.Results: Plasma concentrations of evaluated biomarkers were determined using an ELISA technique and were highest in HF patients with reduced EF (p < .001, respectively), and renalase's positive correlations were obtained relating to all biomarkers: galectin-3 (r = 0.913; p < .001), sST2 (r = 0.965; p < .001), GDF-15 (r = 0.887; p < .001), syndecan-1 (r = 0.922; p < .001), BNP (r = 0.527; p < .001) and cystatin C (r = 0.844; p < .001) and strong and negative correlation with LVEF (r = -0.456, p < .001). Increased renalase, regardless of the EF (preserved/reduced), was shown to be an independent risk factor for an increase in all evaluated cardiac remodeling biomarkers, p < .001, respectively. However, increased renalase and reduced EF was the only independent risk factor for BNP and cystatin C elevation, p < .001, respectively. Results after multivariable adjustments (age/gender) were identical.Conclusion: When elevated plasma renalase and HF are present, regardless of EF being reduced or preserved, that represents a significant risk factor for increase in cardiac remodeling biomarker plasma concentrations. However, only elevated renalase and reduced EF demonstrated significance as a risk factor for BNP and cystatin C plasma elevation. Renalase may be considered a promising molecule for the improved predictive abilities of conventional biomarkers and is worthy of further investigation.

Association of Plasma Renalase and Left Ventricle Mass Index in Heart Failure Patients Stratified to the Category of the Ejection Fraction: A Pilot Study.

Heart failure represents a growing health problem, with increasing morbidity and mortality globally. According to the mechanisms involved in the pathogenesis of heart failure, many biomarkers have been proposed for the timely diagnosis and prognostication of patients with heart failure, but other than natriuretic peptides, none of them has gained enough clinical significance. Renalase, a new protein derived from kidneys was demonstrated to metabolize catecholamines and to have a cardioprotective role. The aim of the study was to determine whether renalase and brain natriuretic peptide (BNP) concentration could be used to differentiate heart failure patients stratified to the category of the ejection fraction and whether plasma renalase could be used as a biomarker for left ventricle hypertrophy in all subgroups of heart failure patients. We included patients diagnosed with heart failure and stratified them to the three subgroups according to the ejection fraction. Regarding echocardiographic parameters, HFmrEF had an intermediate profile in between HFrEF and HFpEF, with statistical significance in most evaluated parameters. BNP concentration was significantly different in all three subgroups (p < 0.001), and renalase was statistically higher in HFrEF (p = 0.007) compared to the HFmrEF and HFpEF, where its results were similar, without statistical significance. Renalase plasma concentration was demonstrated to be highly and positively associated with left ventricle mass index in HFrEF (p = 0.029), as well as increased plasma concentration of BNP (p = 0.006). In the HFmrEF group of patients, body mass index was positively associated with LVMI (p = 0.05), while in the patients with HFpEF, diabetes mellitus was demonstrated to have a positive association with LVMI (p = 0.043). These findings suggest that renalase concentration may be measured in order to differentiate patients with reduced ejection fraction. Plasma renalase concentrations positively correlated with left ventricle hypertrophy in patients with reduced ejection fraction, being strongly associated with increased left ventricular mass index.

Impact of socio-demographic characteristics and long-term complications on quality of life in patients with diabetes mellitus.

OBJECTIVE: Diabetes mellitus (DM) has been one of the leading chronic diseases worldwide over past decades. The objective of the study was to identify predictors associated with health-related quality of life (HRQOL) in diabetic patients. METHODS: A cross-sectional questionnaire-based study was conducted at the General Hospital of the city of Leskovac, between June and November 2015. The Short Form-36 (SF-36) questionnaire, EuroQol-5D (EQ-5D) and EuroQol-VAS (EQ-VAS) questionnaires were used. Univariate and multivariate linear regression analyses were performed. RESULTS: The total number of patients was 285, 112 men (39.3%) and 173 women (60.7%), average age 63.92 ± 1.07 years. The results of multiple linear regression of socio-demographic characteristics in relation to dimensions of the quality of life measured by SF-36 and EQ-VAS showed that age, country (rural) life, low level of education, retirement, and poor economic status are predictors of lower quality of life. Our results showed that employment has a significant association with higher Physical Component Score (PCS), Mental Component Score (MCS) and EQ-VAS score, which can be explained with higher incomes, improved economic status and less possibility for the occurrence of depressive mood. Patients without formal education have lower QOL. Univariate multiple regression analysis of the presence of micro- and macrovascular complications of DM showed that angina pectoris, heart failure, diabetic retinopathy, and diabetic nephropathy are the most important factors affecting the quality of life in our population. After including the multivariate model, all tested complications remained statistically significant. CONCLUSION: Our results showed that both socioeconomic and chronic complications are relevant factors of HRQOL in type 1 and 2 diabetes mellitus patients. Age, rural lifestyle, retirement, lower level of education and low socioeconomic status, as well as DM complications (angina pectoris, hearth failure, diabetes nephropathy, and diabetes retinopathy) were found to be independent risk factors for the component scores of SF-36 and EQ-VAS score. Taking into consideration the results obtained, health practitioners should be aware not only of the clinical parameters of patients with DM, but also of their educational level and working status.

Renalase Assessment With Regard to Kidney Function, Lipid Disturbances, and Endothelial Dysfunction Parameters in Stable Renal Transplant Recipients.

BACKGROUND: Renal transplant dysfunction has been shown to be independent predictor for premature cardiovascular disease and mortality. Renalase, a flavoprotein secreted by several tissues, including the kidney, has been found to regulate sympathetic tone and blood pressure. The purpose of this secondary analysis was to explore relationships among parameters of endothelial dysfunction, lipids, glomerular filtration rate, and renalase in 2 groups: renal transplant patients with controlled hypertension and healthy volunteers. METHODS: In the parent study, 73 renal transplant recipients and 32 age- and gender-matched controls were enrolled. A fasting sample for endothelial, lipid, and renalase values, along with other clinical parameters, was obtained. RESULTS: We found statistically significant inverse correlation between renalase and estimated glomerular filtration rate ( r = -0.552, P < .001), positive correlation between renalase and creatinine ( r = 0.364, P = .003), total cholesterol ( r = 0.578, P < .001), low-density lipoprotein cholesterol ( r = 0.261, P = .046), and non-high-density lipoprotein cholesterol ( r = 0.327, P = .01). Renalase inversely correlated with hemoglobin ( r = -0.232, P = .032) and positively with white blood cells ( r = 0.233, P = .032). There was a significant difference in plasma renalase with regard to chronic kidney disease stages ( F = 13.346, P < .001) but did not correlate with C-reactive protein. Renalase did not correlate with any of parameters of endothelial dysfunction, C-reactive protein, neither with some demographic data (gender, age, time or type of transplantation, risk factors). There were no differences in renalase concentration with regard to antihypertensive therapy. CONCLUSION: Renalase strongly and inversely correlated with kidney function, positively with creatinine and lipid disturbances. Due to that it is very likely that renalase levels are determined mostly by renal function.

Trends in thyroid cancer incidence and mortality in Central Serbia, 1999-2014.

INTRODUCTION: Thyroid cancer (TC) is the most common malignant disease of the endocrine system. The incidence of the TC has been increasing worldwide, especially in female population. However, mortality from TC is low in both males and females. The objective of the paper was to determine and to analyze incidence and mortality trends of TC in males and females in the central Serbia in the period 1999-2014. METHOD: In this descriptive study data from the Serbian Cancer Registry were used. Crude and age-standardized rates (ASRs) of incidence and mortality were calculated. Trend and annual percentage change (APC) of the incidence and mortality rate with corresponding 95% confidence intervals (CI) were calculated by performing Joinpoint regression analyses. RESULTS: A total number of new cases of TC was 3113. TC was diagnosed in 2343 females and 770 males (female-to-male ratio, 3:1). A total number of fatal cases was 770 (while 504 female and 266 male died from TC, female-to-male ratio, 1.9:1). TC was not common before 30 years of age. The highest incidence was recorded both in males and females aged 50-59. Joinpoint regression analysis showed the statistically significant increase of ASRs of TC incidence in males in 1999-2014 period with APC 6.2% (95% CI: 4.2-8.3, p < 0.001) and there was also significant increase of ASRs of TC incidence in females in the same study period with a APC 6.1% (95% CI: 4.2-8.0, p < 0.001). Joinpoint regression analysis showed an insignificant increase of ASRs of TC mortality in males with APC 2.4% (95% CI: -0.5-5.5, p = 0.1). There was an insignificant decrease of ASRs of TC mortality in females with APC -1.3% (95% CI: -4.4-1.9, p = 0.4). CONCLUSION: The increasing trend of age-standardized incidence rates of TC both in males and females and decreasing trend of age-standardized mortality rates during the observed period were registered. Females had higher age-standardized incidence and mortality rates than males. Female to male ratio of incidence was 3:1 and for mortality 1.9:1. Measures of primary and secondary prevention are needed.

Crosstalk of Various Biomarkers That Might Provide Prompt Identification of Acute or Chronic Cardiorenal Syndromes.

INTRODUCTION: Pathophysiological interaction between the heart and kidneys represents the basis for clinical entities called cardiorenal syndromes. The purpose of the study was to assess the relations between acute and chronic cardiorenal syndromes and biomarkers [advanced oxidation protein products, brain natriuretic peptide, malondialdehyde, xanthine oxidoreductase (XOD), xanthine oxidase, xanthine dehydrogenase, interleukin 8, cystatin C, plasminogen activator inhibitor-1, high-sensitive troponin T, C-reactive protein and glomerular filtration rate, measured by the Modification of Diet in Renal Disease (MDRD) formula], to hypothesize biomarkers that might provide a prompt identification of acute or chronic cardiorenal syndromes, and to distinguish acute versus chronic types of these syndromes. METHODS: A total of 114 participants were enrolled in this study, i.e. 79 patients divided into subgroups of acute and chronic cardiorenal syndromes and 35 volunteers. RESULTS: Nonadjusted odds ratio (OR) showed that there was a significant risk for acute cardiorenal syndrome with increased XOD activity (p = 0.037), elevated cystatin C concentration (p = 0.038) and MDRD (p = 0.028). Multivariable adjusted OR, on the other hand, revealed that only glomerular filtration rate measured by the MDRD formula had a significance for acute cardiorenal syndrome (p = 0.046). Nonadjusted OR showed a significant risk for chronic cardiorenal syndrome only in elderly (p = 0.002). Multivariable adjusted OR exhibited that age was the only risk factor for chronic cardiorenal syndrome (p = 0.012). CONCLUSION: Cystatin C, glomerular filtration rate measured by the MDRD equation and XOD were independent risk factors for acute cardiorenal syndrome, while age remained an independent risk factor for chronic cardiorenal syndrome. When comparing ORs of evaluated parameters, the highest significance for acute cardiorenal syndrome was plasma concentration of cystatin C.

The influence of type 2 diabetes mellitus on the frequency and complexity of ventricular arrhythmias and heart rate variability in patients after myocardial infarction.

Background/Aim: After myocardial infarction arrhythmic cardiac deaths are significantly more frequent compared to non-arrhythmic ones. The aim of the study was to investigate the influence of type 2 diabetes mellitus (T2DM) on the frequency and complexity of ventricular arrhythmias after myocardial infarction. Methods: The study included 293 patients, mean age 59.5 ± 9.21 years, who were at least six months after acute myocardial infarction with the sinus rhythm, without atrioventricular blocks and branch blocks. In the clinical group 95 (32.42%) patients were with T2DM, while 198 (67.57%) patients were without diabetes. All of the patients were subjected to the following procedures: standard ECG according to which the corrected QT dispersion (QTdc) was calculated, exercise stress test, and 24-hour holter monitoring according to which, the four parameters of time domain of heart rate variability (HRV) were analyzed: standard deviation of all normal RR intervals during 24 hours (SDNN), standard deviation of the averages of normal RR intervals in all five-minute segments during 24 hours (SDANN), the square root of the mean of the sum of the squares of differences between adjacent normal (RMS-SD), and percentage of consequtive RR intervals which differed for more than 50 ms during 24 hours (NN > 50 ms). Results: In patients after myocardial infarction, patients with T2DM had significantly higher percentage of frequent and complex ventricular arrhythmias compared to the patients without diabetes (p < 0.001). The patients with T2DM had significantly higher percentage of residual ischemia (p < 0.001), and arterial hypertension (p < 0.001), compared to patients without diabetes. The patients with T2DM had significantly lower values of HRV parameters: SDNN (p < 0.001); SDANN (p < 0.001); RMS-SD (p < 0.001), and NN > 50 ms (p < 0.001), and significantly higher values of QTdc (p < 0.001) compared to the patients without diabetes. Conclusion: The study showed that type 2 diabetes mellitus has significant influence on ventricular arrhythmias, HRV parameters and QT dispersion in patients after myocardial infarction.