Phenolic profile, antioxidant capacity and oxidoreductase enzyme activity in autochthonous grape varieties from Bosnia and Herzegovina.

The variability of phenolic compounds among grape varieties has an important role in selecting winemaking techniques, but the use of phenolic profiles for quality control is still fragmented and incomplete. Given the recent climate change and global warming, biochemical characterisation of secondary metabolites in autochthonous grape varieties is a very important factor for their preservation and sustainable agriculture. Two autochthonous grape varieties from the western Herzegovina region in Bosnia and Herzegovina have been selected for the research targeting at the evaluation of their phenolic profiles, antioxidant activities, and the correlation with oxidoreductase enzymes polyphenol oxidase and Class III peroxidase, in different berry tissues. The obtained results indicate a similar qualitative profile of phenolic compounds in exocarp and mesocarp in both varieties, but their concentrations and antioxidant activity vary significantly. The correlation between phenolic compounds and oxidoreductase enzyme activities in different grape berry tissues is discussed in this article.

Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis.

Introduction: IL-6 and IL-10 may affect the activity of cytochrome P450 (CYP) 3A enzymes involved in tacrolimus (Tac) metabolism. Moreover, the effect of IL-6 and IL-10 on Tac pharmacokinetics may differ with respect to the genetic variations in their genes.Aim: To examine the influence of IL-6 and IL-10 gene polymorphisms on Tac dose requirements and exposure over a 5-year period following kidney transplantation. Univariate and standard multivariate linear regression and Monte Carlo analysis were performed to investigate potential covariates influencing Tac dose-adjusted trough concentration (C0/D) in various post-transplantation periods.Materials & methods: IL-6 (-174G > C), IL-10 (-1082G > A, -819C > T and -592C > A) genotype, Tac daily dose, C0, C0/D and intrapatient variability data were collected from 113 patients.Results: Multivariate regression analysis and accompanied Monte Carlo simulation underscore the importance of considering IL-6 -174G > C and IL-10 -1082G > A gene polymorphisms, alongside Tac metabolic phenotype and post-transplantation period, when tailoring Tac dosage regimen.Conclusion: This study provides valuable insights regarding the individualized adjustment of Tac treatment in various post-transplantation periods.

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Depression, anxiety, and quality of life as predictors of rehospitalization in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is a severe condition, often co-occurring with depression and anxiety, that strongly affects the quality of life (QoL) in some patients. Conversely, depressive and anxiety symptoms are associated with a 2-3 fold increase in mortality risk and were shown to act independently of typical risk factors in CHF progression. The aim of this study was to examine the impact of depression, anxiety, and QoL on the occurrence of rehospitalization within one year after discharge in CHF patients. METHODS: 148 CHF patients were enrolled in a 10-center, prospective, observational study. All patients completed two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Questionnaire Short Form Health Survey 36 (SF-36) at discharge timepoint. RESULTS: It was found that demographic and clinical characteristics are not associated with rehospitalization. Still, the levels of depression correlated with gender (p ≤ 0.027) and marital status (p ≤ 0.001), while the anxiety values ​​were dependent on the occurrence of chronic obstructive pulmonary disease (COPD). However, levels of depression (HADS-Depression) and anxiety (HADS-Anxiety) did not correlate with the risk of rehospitalization. Univariate logistic regression analysis results showed that rehospitalized patients had significantly lower levels of Bodily pain (BP, p = 0.014), Vitality (VT, p = 0.005), Social Functioning (SF, p = 0.007), and General Health (GH, p = 0.002). In the multivariate model, poor GH (OR 0.966, p = 0.005) remained a significant risk factor for rehospitalization, and poor General Health is singled out as the most reliable prognostic parameter for rehospitalization (AUC = 0.665, P = 0.002). CONCLUSION: Taken together, our results suggest that QoL assessment complements clinical prognostic markers to identify CHF patients at high risk for adverse events. CLINICAL TRIAL REGISTRATION: The study is registered under http://clinicaltrials.gov (NCT01501981, first posted on 30/12/2011), sponsored by Charité - Universitätsmedizin Berlin.

Exploration and Comparison of the Behavior of Some Indigenous and International Varieties (Vitis vinifera L.) Grown in Climatic Conditions of Herzegovina: The Influence of Variety and Vintage on Physico-Chemical Characteristics of Grapes.

Viticulture is of great economic importance in the southern part of Bosnia and Herzegovina, thanks to favorable climatic conditions and a long-standing tradition of growing vines. The assortment is dominated by international varieties, as well as some autochthonous and domesticated varieties. The subject of the research is the analysis of the quality of Cabernet Sauvignon, Merlot, Vranac, and Blatina varieties at two localities in Herzegovina during the period 2020-2021. The paper examined the most important economic and technological characteristics, grape quality, and berry phenolic profile. A particularly pronounced variation of the tested characteristics during the research period was observed in the Merlot and Blatina varieties, while the Cabernet Sauvignon and Vranac varieties showed a slightly higher stability of the tested characteristics. Poorer grape quality during the research period was registered with the Blatina variety, which can be considered a varietal characteristic to some extent. The analyzed grape varieties were rich in polyphenols, and the impact of grape variety on the berry phenolic profiles was confirmed. The most abundant polyphenols in the analyzed grape samples were quercetin 3-O-glucoside and catechin gallate, followed by kaempferol 3-O-glucoside. The highest values of polyphenols were found mainly in the samples originating from Trebinje. Indigenous Balkan grape varieties (Vranac and Blatina) stood out with particularly high contents of some phenolics. Research has shown that climatic conditions have a significant influence on the most important characteristics of grapes, which are conditioned by genotypic specificities. The conditions for growing vines in the conditions of Herzegovina enable high quality in the production of grapes, especially the Cabernet Sauvignon and Vranac varieties. The autochthonous variety Blatina shows significant variations in grape quality during the test period, which was confirmed by the results of a larger number of studies in the previous period.

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.

Platelet thrombus formation in patients with end-stage renal disease before and after hemodialysis as measured by the total thrombus-formation analysis system.

BACKGROUND: Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) often experience bleeding. However, mechanisms behind this bleeding tendency are incompletely understood but may involve platelet dysfunction. We, therefore, studied platelet-dependent thrombus formation in flowing whole blood inside a microchip coated with collagen, and its association with circulating von Willebrand factor (VWF). METHODS: Blood samples were obtained in 22 patients before and after HD. The area under the 10 min flow pressure curve in a microchip (AUC10) reflecting total platelet thrombogenicity was measured, using the Total Thrombus-formation Analysis System (T-TAS01). AUC10 < 260 indicates platelet dysfunction. VWF activity and antigen in plasma were also assayed. RESULTS: VWF levels were moderately elevated and increased further after HD (P < 0.01 or lower). In contrast, AUC10 before and after HD was < 260 in 17/22 patients and < 130 in 15/22 patients, with no statistically significant difference in pre- vs post-HD measurements, indicating reduced platelet thrombogenicity, but with some variability as 5/22 patients showed normal platelet responsiveness. AUC10 and VWF activity or antigen levels in plasma were not correlated, either before or after HD. CONCLUSIONS: Most ESRD patients display moderate-to-severe platelet dysfunction as assessed by shear-induced platelet-dependent thrombus formation with T-TAS01. HD does not influence platelet function despite HD-induced elevations in VWF. T-TAS01 should be further evaluated as a tool in the assessment of bleeding risk in patients on HD.

Influence of Interaction Effects of the Different Pollenizers on the Blatina Variety (Vitis vinifera L.) Grape Cluster and Seed Characteristics.

Indigenous grape varieties represent a significant potential for viticultural diversification. Due to fertilization problems, certain varieties from this group require suitable pollenizers for successful fertilization and in order to achieve high-quality grapes. The study was conducted during the years 2016 and 2017 in the vineyard in Herzegovina (southern part of Bosnia and Herzegovina). The aim of this research is to define a suitable pollenizer for the 'Blatina' variety, which has a functionally female flower. Manual pollination was performed with five different pollenizers during the flowering period by applying pollen to the 'Blatina' variety inflorescence during the full bloom stage in the early morning hours. Pollinated inflorescences were isolated, marked, and monitored until the end of the vegetation, while open-pollinated clusters were the control group. The most important characteristics of grape clusters and seeds were analyzed. The best results during the research were obtained by open pollination. The significant effect of the pollenizers was registered in parameters: cluster mass, mass of grape berries in the cluster, number of grape berries per cluster, and average seed mass. Varieties 'Zilavka' and 'Vranac' had better characteristics compared to other pollenizer varieties. The results show that the Blatina variety production with a greater number of pollenizers ensures stable yields.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach.

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6-12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6-12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

A Comparative Study of Antioxidative Activity of Saliva in Children and Young Teenagers with and without Gingivitis.

Objectives: The aim of this study was to compare the values of total antioxidant capacity (TAC), catalase (CAT) and glutathione peroxidase (GPX) in the saliva of children and young teenagers with and without gingivitis. Materials and Methods: A total of 120 children and young teenagers of the mean age of 12.2 participated in the research. Gingival condition was assessed using the Löe and Silness Gingival Index. The subjects were divided into groups of those without gingivitis and those with gingivitis. Samples of unstimulated saliva were collected, and TAC, CAT and GPX were determined spectrophotometrically. Results: By comparing the values of TAC, CAT and GPX in subjects with and without gingivitis, significantly lower values of TAC (p < 0.001) and CAT (p < 0.001) were observed in the group of subjects with gingivitis. The correlation analysis of these values showed a positive correlation in groups of subjects not suffering from gingival inflammation and those with gingival inflammation. Conclusions: The study showed significantly lower values of TAC and CAT in the saliva of subjects with gingivitis. This indicates their possible role as a potential biomarker in the early diagnosis and expression of periodontal disease in children and young teenagers.

The significant role of dietary intake of vitamin D in non-menopausal women health.

Optimal vitamin D status is very important for reflecting not only bone but overall woman's health. The aim of the study was to determine pharmacokinetic variability of 25-hydroxy vitamin D, to reveal and quantify the most significant factors that affect its variability in the population of healthy non-menopausal women using the population pharmacokinetic (PopPK) approach. The study population consisted of 74 healthy reproductive women aged from 35 to 50 years, without the use of any supplement. A population pharmacokinetics analysis was conducted using a nonlinear mixed-effects model software. A total of 35 factors were assessed: demographic, clinical, biochemical data and lifestyle factors. The average age and bodyweight of our participants were 40.11 ± 4.35 years 65.30 ± 6.80 kg, respectively. The observed mean serum concentration of 25-hydroxy vitamin D was 26.51 ± 13.49 ng/mL with a wide range of 6.97 to 59.89 ng/mL. Development final PopPK model of the clearance of 25-hydroxy vitamin D showed that only the average daily dose of vitamin D intake from food had a significant influence, with a magnitude of its effects of 0.00401. These results could help when individualizing vitamin D intake in the form of supplements, especially during the wintertime, in healthy reproductive women.

Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience.

BACKGROUND AND OBJECTIVE: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

Can phytoplankton blooming be harmful to benthic organisms? The toxic influence of Anabaena sp. and Chlorella sp. on Chironomus riparius larvae.

Cyanobacteria and microalgae are abundant biota groups in eutrophic freshwater ecosystems, serving as a food source for many aquatic organisms, including the larvae of non-biting midges (Chironomidae). Many species of cyanobacteria are toxin producers, which can act as stressors to other organisms. The present study aimed to analyze and compare the effects of dietary exposure to the common toxic cyanobacteria Anabaena sp. and non-toxic microalgae Chlorella sp. in Chironomus riparius larvae. Microcystin was detected and quantified in the methanolic extract of Anabaena sp. using the HPLC-DAD technique, and it was identified as microcystin-LR. Both Anabaena sp. and Chlorella sp. were suitable food sources to enable the survival of C. riparius larvae in laboratory conditions, causing negligible mortality and significant differences in the larval mass (ANOVA and Post hoc LSD test; p < 0.05) and hemoglobin concentration (Student's t-test; p < 0.05). Oxidative stress parameters such as advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS), catalase (CAT) and superoxide dismutase (SOD) activity, and DNA damage, were also investigated. One-way ANOVA, followed by the Post hoc LSD test, showed a significant increase in AOPP and CAT for the group of larvae fed with Chlorella sp. The same test showed moderate DNA damage in both groups of larvae, with greater damage in the group fed with Anabaena sp. Thus, Chlorella sp. and microcystin-LR producing Anabaena sp. are food sources that did not result in any drastic acute effect on the population level of C. riparius larvae. However, sub-individual-level endpoints revealed significant effects of the treatments, since they caused oxidative stress and DNA damage that may pose a danger to successive generations of test organisms.

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.

Metronidazole- and levofloxacin-induced psychotic disorders in chronic kidney patient.

We present a case which reports the occurrence of psychotic disorders after metronidazole and levofloxacin therapy in a chronic kidney patient while being treated for enterocolitis and urinary infection. A 48-year-old female was admitted to a hospital for the placement of a peritoneal dialysis catheter due to indicated peritoneal dialysis. During admission, symptoms of enterocolitis and urinary infection had occurred, so metronidazole and levofloxacin were introduced into therapy, respectively. After 4 days of metronidazole and 3 days of levofloxacin therapy, the patient became confused, disoriented, with signs of delirium. Since the diagnosis of psychoorganic disorder was made, the therapy with lorazepam and haloperidol was initiated, while metronidazole and levofloxacin were discontinued. Complete recovery 4 days after discontinuation indicates that the patient has experienced antibiotics-induced neurotoxicity. This is the first report of expressed neurotoxicity after the combination of metronidazole and levofloxacin in chronic kidney patients.

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.

Protein Carbonyl Content Is a Predictive Biomarker of Eccentric Left Ventricular Hypertrophy in Hemodialysis Patients.

High prevalence of left ventricular hypertrophy (LVH) and elevated oxidative stress are associated with poor outcomes in chronic hemodialysis patients. Abnormal left ventriculаr geomеtry and different geometric patterns play an important role as well. Our study analyzed the role of oxidative stress on myocardial remodeling in these patients. Plasma malondialdehyde (MDA), protein carbonyl (PC) content, and total antioxidative capacity (TAC) were investigated in 104 hemodialysis patients together with transthoracic echocardiography. Compared to patients with normal ventricular geometry, patients with LVH had increased MDA and PC plasma concentration. Multivariate analysis demonstrated that protein carbonyls, as biomarkers of oxidative protein modification, were an independent predictor of eccentric hypertrophy (eLVH), including higher LV end-diastolic diameter and LV end-diastolic volume, (ß = 0.32 and ß = 0.28, p < 0.001 for both). The incidence of eLVH increased progressively from the lowest to the highest baseline PC tertile (p < 0.001 for the trend) and the subjects in the former group showed a 76% greater risk of developing eLVH compared to their counterparts. After further adjustment for the potential mediators, PCs carried eLVH odds (95% confidence interval (CI)) of 1.256 (0.998-1.514), per standard deviation increase. High plasma protein carbonyls levels are a significant independent predictor of eccentric LVH in chronic hemodialysis patients.

The predictive value of Klotho polymorphism, in addition to classical markers of CKD-MBD, for left ventricular hypertrophy in haemodialysis patients.

PURPOSE: Cardiovascular events are the major reasons for mortality in haemodialysis patients. Fibroblast growth factor 23 (FGF23), Klotho protein and G-395A Klotho gene polymorphism have been associated with effects on the cardiovascular system. Our study investigates the interrelationship between Klotho protein gene variations, mineral-bone metabolism and left ventricular hypertrophy in patients undergoing chronic haemodialysis programme. MATERIALS AND METHODS: Patients (n = 142) were genotyped for G-395A Klotho gene. Components of mineral-bone metabolism, classical and non-classical (FGF23, Klotho and vitamin D) as well as echocardiographic examination were determined. Predictive models were designed to determine the significance of Klotho gene variations and mineral-bone metabolism components for left ventricle hypertrophy (LVH). RESULTS: A-allele carriers were longer on haemodialysis (p = 0.033), and had higher phosphorus levels (p = 0.016) while the level of Klotho protein was significantly lower (p = 0.001) compared to non-A-allele carriers. The best gains were achieved upon addition of allele A, and all three new markers; the AUC made significant improvement from 0.596 to 0.806 (p < 0.001), and improved net reclassification for 82.1% (95% CI 42.9-121.3%). CONCLUSIONS: The genetic background of A-allele carriers of the G-395A Klotho gene polymorphism increases the susceptibility patients to haemodialysis. A-allele carriers are at a higher risk for the development of cardiovascular complications. The addition of non-classical to classical mineral metabolism components improves prediction power to LVH.

Adverse effects of mycophenolic acid in renal transplant recipients: gender differences.

Background Mycophenolic acid is widely used immunosuppressive drug, associated with adverse effects which increase patient morbidity and decrease medication adherence. Objective To evaluate the adverse effects in renal transplant recipients under mycophenolate treatment with respect to gender. Setting University Clinical Centre of Nis, Clinic of Nephrology, Serbia. Method This research included 96 renal transplant recipients, who received immunosuppressive regimen, based on tacrolimus or cyclosporin A, prednisone and mycophenolic acid. The high-performance liquid chromatography method combined with protein precipitation was used for the analysis of mycophelate concentration in human plasma. Drug concentration and dose-adjusted concentration were determined with respect to the patients' gender. An adverse effect scoring system developed by nephrologists within the University of Buffalo Nephrology/Transplant Program was used to monitor adverse effects of therapy. Main outcome measure Individual and scores of adverse effects in relation to the dosing regimen and gender. Results Results showed statistically lower dose and concentrations in men compared to the women in our investigation group. Also, female patients demonstrated higher mean scores (cumulative and subscores) within the same dosing regimens of mycophenolic acid. The gastrointestinal score was significantly higher in women who received a dose greater than 720 mg compared to men (0.20 ± 0.12 vs 0.12 ± 0.12). Women demonstrated higher individual adverse effects such as diarrhea and skin changes (41.7 vs 17.0; p = 0.038 and 62.5 vs 30.2; p = 0.037, respectively). Conclusions The results of our research showed that recipients' gender may play an important role in pharmacokinetic profile of mycophenolic acid, suggesting that women had higher concentration of mycophenolic acid and more serious side effects.

The association of CAT-262C/T polymorphism with catalase activity and treatment response in juvenile idiopathic arthritis.

Oxidative stress is believed to be of great importance for both the etiology and the persistence of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the association of -262C/T polymorphism of the catalase (CAT) gene with JIA, as well as to evaluate whether this polymorphism can influence plasma CAT activity and outcome in JIA patients treated with etanercept. A total of 154 subjects (60 JIA patients and 94 healthy volunteers) were screened for CAT-262C/T gene polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Plasma CAT activity was determined using the spectrophotometric method according to Goth, prior to and 12 months after anti-TNF (etanercept) therapy. Clinical outcome was assessed using the JIA ACR (American College of Rheumatology) response criteria. The genotype and allele frequency distributions of CAT-262C/T polymorphism in the patients were significantly different from those of the controls (p = 0.014, p = 0.006). The TT genotype (polymorphic homozygous) was associated with a 4.36-fold higher likelihood of having JIA (95% CI 1.545-12.323, p = 0.005) as compared to the CC genotype (wild-type). At month 12 of treatment, JIA patients, carriers of the CC genotype, showed significantly higher plasma CAT activity (p = 0.004) and achieved the JIA ACR 70 response more often (p = 0.003) than the patients, carriers of the CT/TT genotype. This is the first study implying the possible association of CAT-262C/T polymorphism with JIA. The results suggest the potential protective effect of the CC genotype, with regard to CAT activity and treatment outcome.

Oral supplementation with melatonin reduces oxidative damage and concentrations of inducible nitric oxide synthase, VEGF and matrix metalloproteinase 9 in the retina of rats with streptozotocin/nicotinamide induced pre-diabetes.

Hyperglycemia mediated oxidative stress and pro-angiogenic molecules such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9) are considered important for diabetic retinopathy onset and progression. Melatonin is a pineal hormone that regulates circadian and seasonal rhythms and most likely is involved in regulating glucose metabolism. We aimed to evaluate the potential benefit of melatonin supplementation to the pre-diabetic retina by assessing melatonin effects on lipid peroxidation (thiobarbituric acid reactive substances, TBARS), protein oxidation (advanced oxidation protein products, AOPP) and concentrations of inducible nitric oxide synthase (iNOS), VEGF and MMP9 in the retina of rats with pre-diabetes. Pre-diabetes was induced by streptozotocin (45 mg/kg, i.p.) following nicotinamide injection (110 mg/kg, i.p.). Beside mild hyperglycemia, lower serum insulin, increased fructosamine and lower HDL cholesterol, the present study demonstrated decreased serum melatonin in pre-diabetic rats, as well as, increased concentration of retinal TBARS, AOPP, iNOS, VEGF, and MMP9. Oral supplementation with melatonin (85 µg/animal/day) caused melatonin and HDL cholesterol levels to rise in treated rats and reduced levels of fasting serum glucose and fructosamine. It also affected serum insulin and quantitative insulin sensitivity check index (QUICKI) in treated groups but had no significant effect on non-fasting glucose. Finally, supplementation with melatonin reduced concentrations of TBARS, AOPP, iNOS, VEGF, and MMP9 in significant level, thereby exerting an overall positive effect on oxidative stress and pro-angiogenic signaling in the pre-diabetic retina. Thus, oral melatonin might be considered in an early treatment or in the prevention of retinal changes associated with pre-diabetes.