Factors contributing to variability in metformin concentration in polycystic ovary syndrome.

AIM: To investigate the factors affecting metformin concentrations after chronic administration in patients with polycystic ovary syndrome (PCOS), focusing on the pharmacokinetic variability and its implications for personalized therapy. METHODS: This study enrolled 53 PCOS patients undergoing long-term metformin treatment at the Clinic for Gynecology and Obstetrics in Nis, Serbia, from February to December 2019. Pharmacokinetic parameters were measured from blood samples, and metformin concentrations were determined with validated analytical techniques. RESULTS: There was a significant variability in metformin concentrations among PCOS patients, with body mass index (BMI) identified as a major influencing factor. Higher BMI was associated with lower plasma metformin levels, a finding suggesting an altered pharmacokinetic profile in obese patients. CONCLUSIONS: This study highlights the critical role of BMI in influencing metformin pharmacokinetics in PCOS patients and underscores the need for personalized treatment strategies in patients with PCOS.

Spontaneous coronary artery dissection in women in the generative period: clinical characteristics, treatment, and outcome-a systematic review and meta-analysis.

Introduction: Spontaneous coronary artery dissection (SCAD) is a non-traumatic and non-iatrogenic separation of the coronary arterial wall. Materials and methods: This systematic review and meta-analysis is reported following the PRISMA guidelines and is registered in the PROSPERO database. A literature search was focused on female patients in generative period (16-55 of age) with acute coronary syndrome (ACS) caused by SCAD, and comparison from that database NP-SCAD (spontaneous coronary artery dissection in non pregnant women) and P-SCAD (spontaneous coronary artery dissection in pregnant women). Results: 14 studies with 2,145 females in the generative period with ACS caused by SCAD were analyzed. The median age was 41 years (33.4-52.3 years). The most common risk factor was previous smoking history in 24.9% cases. The most common clinical presentation of ACS was STEMI in 47.4%. Conservative treatment was reported in 41.1%. PCI was performed in 32.7%, and 3.8% of patients had CABG surgery. LAD was the most frequently affected (50.5%). The prevalence of composite clinical outcomes including mortality, non-fatal MI and recurrent SCAD was 3.3% (95% CI: 1.4-5.1), 37.7% (95% CI: 1.9-73.4) and 15.2% (95% CI: 9.1-21.3) of patients. P-SCAD compared to NP-SCAD patients more frequently had STEMI (OR = 3.16; 95% CI: 2.30-4.34; I2 = 64%); with the left main and LAD more frequently affected [(OR = 14.34; 95% CI: 7.71-26.67; I2 = 54%) and (OR = 1.57; 95% CI: 1.06-2.32; I2 = 23%)]; P-SCAD patients more frequently underwent CABG surgery (OR = 6.29; 95% CI: 4.08-9.70; I2 = 0%). NP-SCAD compared to P-SCAD patients were more frequently treated conservatevly (OR = 0.61; 95% CI: 0.37-0.98; I2 = 0%). In P-SCAD compared to NP-SCAD mortality rates (OR = 1.13; 95% CI: 0.06-21.16; I2 = not applicable) and reccurence of coronary artery dissection (OR = 2.54; 95% CI: 0.97-6.61; I2 = 0%) were not more prevalent. Conclusion: The results of this meta-analysis indicated that patients with P-SCAD more frequently had STEMI, and events more frequently involved left main and LAD compared to NP-SCAD patients. Women with NP-SCAD were significantly more often treated conservatively compared to P-SCAD patients. P-SCAD compared to NP-SCAD patients did not have significantly higher mortality rates or recurrent coronary dissection.

Is Antihelminthics Necessary in Postoperative Treatment of Intraventricular Neurocysticercosis? A Systematic Review.

OBJECTIVE: Patients with intraventricular neurocysticercosis (IVNCC) may require cerebrospinal fluid diversion surgery for late-onset hydrocephalus in the postsurgical period. Controversy exists regarding cysticidal treatment. Our main objective was to compare surgically treated cases of IVNCC that received postoperative anthelmintics with those that did not regard the incidence and treatment of late-onset hydrocephalus. METHODS: We searched the Medline database and extracted the following data: age, gender, stage of development of cysticercosis, type of operation, frequency of delayed hydrocephalus, cerebrospinal fluid diversion surgery, outcome, and follow-up. RESULTS: We analyzed 130 articles on intraventricular cysticercosis and identified 117 cases of isolated IVNCC and 314 patients in the case-control series who met inclusion criteria. There was no significant difference in postoperative delayed hydrocephalus between isolated IVNCC and case-control study groups. Children under the age of 16 received anthelmintic drugs more frequently during the postoperative period. Statistical relevance was observed in all patient groups regarding the application of steroids in favor of cysticidal therapy Endoscopy was a better option than craniotomy for cases of isolated IVNCC and case-control studies. Other variables were not relevant. CONCLUSIONS: Patients who received antihelminths did not show a statistically significant reduction in delayed hydrocephalus compared to individuals who did not receive after surgical resection of the parasite. Corticosteroid therapy prevailed in people who have been treated with anthelmintics. Children under the age of 16 were administered anthelmintic drugs more frequently during the postoperative period. Endoscopy was the preferred method for all groups, but some patients with cysts in the fourth ventricle required a craniotomy.

Antifungal Activity and Type of Interaction of Melissa officinalis Essential Oil with Antimycotics against Biofilms of Multidrug-Resistant Candida Isolates from Vulvovaginal Mucosa.

(1) Background: Vulvovaginal candidosis (VVC) is a major therapy issue due to its high resistance rate and virulence factors such as the ability to form biofilms. The possibility of combining commonly used antifungals with natural products might greatly improve therapeutic success. (2) Methods: A total of 49 vulvovaginal isolates, causative agents of recurrent VVC, were tested for their susceptibility to fluconazole, nystatin, and Melissa officinalis essential oil (MOEO). This examination included testing the antibiofilm potential of antifungals and MOEO and the determination of their types of interaction with mature biofilms. (3) Results: Antimicrobial testing showed that 94.4% of the Candida albicans isolates and all the Candida krusei isolates were resistant to fluconazole, while all strains showed resistance to nystatin. The same strains were susceptible to MOEO in 0.156-2.5 mg/mL concentrations. Additionally, the results revealed very limited action of fluconazole, while nystatin and MOEO reduced the amount of biofilm formed by as much as 17.7% and 4.6%, respectively. Testing of the combined effect showed strain-specific synergistic action. Furthermore, the lower concentrations exhibited antagonistic effects even in cases where synergism was detected. (4) Conclusions: This study showed that MOEO had a very good antibiofilm effect. However, combining MOEO with antimycotics demonstrated that the type of action depended on the choice of antifungal drugs as well as the applied concentration.

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.

Intraventricular Neurocysticercosis: Comparative Analysis of Different Localizations. Clinical Course and Treatment. A Systematic Review.

Background Neurocysticercosis is significant due to its high prevalence and considerable morbidity and mortality. The intraventricular form of NCC is less common than parenchymal, may have a rapidly progressive course and it requires a corresponding therapeutic response. Despite the extensive literature dealing with NCC and intraventricular cystic lesions, no systematic reviews have addressed similar work related to the clinical course and treatment of the infestation. Our main objective was to analyze the clinical type of the disease and the management for each ventricle separately on the basis of case reports or series of patients with individual data on the course of the disease and its treatment. As a control group, we used data on signs&symptoms and treatment of patients from published series on intraventricular neurocysticercosis. Method We performed a search in the Medline database. Google Scholar was also randomly searched. We extracted the following data from the eligible case/series: age and gender, symptoms, clinical signs, diagnostic examinations and findings, localization, treatment, follow-up period, outcome, and publication year. All data are presented in the form of absolute and relative numbers. The frequency of signs and symptoms, treatment and outcomes of the observed groups were checked by the Chi-square test and Fisher's test. The hypothesis was tested with p <0.05 as statistical significance. Results We selected 160 cases of intraventricular neurocysticercosis (IVNCC) and divided them according to their localization into five categories. Hydrocephalus was recognized in 134 cases (83.4%). Patients with isolated IVNCCare are younger (P=.0264) and have a higher percentage of vesicular cysts (p <.00001). In mixed IVNCC, degenerative and multiple confluent cysts predominate (p = 0.00068). Individuals carrying fourth + third ventricular cysts (potentially obstructive form) are younger than individuals with lateral ventricles (potentially less obstructive forme) (p = .0083). The majority of patients had individual symptoms for a longer period before the acute onset of the disease (p <.00001). The predominant clinical manifestation is headache (88.7%); the proportion within the groups ranged from 100% to 75% without statistical significance (p.074214). The same was true for patients with symptoms of vomiting or nausea, who had a lower and roughly balanced percentage of 67.7% to 44.4% (p.34702). Altered level of consciousness (ranging from 21% to 60%) and focal neurological deficit (from 51.2% to 15%) are the only clinical category with statistical significance (p <0.001 and p.023948 ). Other signs and symptoms were less frequent and statistically irrelevant. Surgical resection of the parasite was the predominant type of treatment, varying from 55.5% to 87.5% (p- .02395); endoscopy (48.2%) and craniotomy (24.4%), each individually, showed statistical significance (.00001 and .000073, respectively). The difference was also relevant among patients who had CSF diversion performance with/without medical treatment (p-.002312. Postoperatively, 31.8% of patients received anthelmintics with/without anti-inflammatory or other drugs. Endoscopy, open surgery, and postoperative antiparasitic therapy showed statistical differences (p < 0.001). Favorable outcomes or regression of symptoms were recorded in 83.7%, mortality 7.5%. In the case series, the clinical signs&symptoms were as follows: headache-64%, nausea and vomiting 48.4%, focal neurological deficit 33.6% and altered level of consciousness 25%. Open surgery was the predominant form of intervention (craniotomy (57.6% or endoscopy 31.8%); with statistical significance between them (p< .00001). Conclusion. Ventricular neurocysticercosis is an alarming clinical condition. Hydrocephalus is the dominant diagnostic sign. Isolated IVNCC patients were recognized at a younger age than Mix.IVNCC individuals; poeple with cysts in the fourth and third ventricles (as a potentially more occlusive type of disease), presented their symptoms at a younger age than individuals with LVNCC. The majority of patients had long-term signs and symptoms before the acute onset of the disease. Headache, nausea& vomiting are the most common symptoms of infestation accompanied by altered sensorium and focal neurological deficits. Surgery is the best treatment option. A sudden increase in ICP due to cerebrospinal fluid obstruction with a successive cerebral hernia is the leading cause of fatal outcomes.

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.

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.

Trends of Stomach Cancer in Central Serbia.

Somach cancer is the third most common cause of cancer-related deaths worldwide. The objective of the paper was to analyze the incidence and mortality trends of stomach cancer in Central Serbia in the period between 1999-2017. Materials and Methods: trends and annual percentage change (APC) of the incidence and mortality rate with corresponding 95% confidence intervals (CI) were calculated by joinpoint regression analyses. The optimal number of Joinpoints was identified using the Monte Carlo permutation method. 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 new cases was 16,914 (10,873 males and 6041 females) and the total number of mortality cases was 14,790 (9348 in and 5442 in females). Almost one third (30.8%) of new cases were registered in the 60-69-year age group, and new cases were significantly more frequent in males than in females (30.8% vs. 29.02%, p < 0.001). Joinpoint regression analysis showed a significant decrease of incidence trend in females during the 2000-2015 period with APC of -2.13% (95% CI: -3.8 to -0.5, p < 0.001). An insignificant decrease in incidence trend was in males with APC of -0.72% (95% CI: -2.3 to 0.9, p = 0.30). According to the joinpoint analysis, a significant decrease of mortality trends both in males during 2000-2015 with APC of -2.21% (95% CI: -1.6 to -7.5, p ≤ 0.001 and in females, during the same period, with APC of -1.75% (95% CI: -2.9 to -0.6, p < 0.001) was registered. From 2015 to 2017, a significant increase of mortality was registered with APC of 44.5% (95% CI: from 24.2 to -68.1, p ≤ 0.001) in females and in males with APC of 53.15% (95% CI: 13.5 to -106.6, p ≤ 0.001). Conclusion: a significant decrease of stomach cancer incidence trend in females and insignificant decrease of incidence trend in males were determined in Central Serbia. Based on presented results, the mortality trend decreased significantly both in males and in females during 2000-2015, and from 2015 to 2017 we recorded a significant increase in mortality in both sexes. We found significantly more new cases in women than in men in the age group of 40-49, and the mortality of stomach cancer was significantly more frequent among females compared to males in the age groups 30-39, as well as in the 50-59 age group. There is a need for improving recording and registration of new cases of stomach cancer, especially in females. Urgent primary and secondary preventive measures are needed-introducing stomach cancer screening and early detection of premalignant changes. Urgent primary and secondary preventive measures are needed.

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.

Parameters Related to Lumbar Puncture Do not Affect Occurrence of Postdural Puncture Headache but Might Influence Its Clinical Phenotype.

BACKGROUND: Post-dural puncture headache (PDPH) has been the most common complication of diagnostic and therapeutic lumbar puncture (LP). The occurrence and clinical features of PDPH in relationship to different demographic, clinical, and paraclinical parameters and parameters related to LP were assessed. METHODS: We conducted a cohort, prospective, single-center study of 252 consecutive patients (105 men and 147 women; average age, 47.3 ± 15.0 years), who had undergone LP for different medical reasons from February 2018 to June 2018 at the Clinic for Neurology Clinical Center of Serbia (Belgrade, Serbia). RESULTS: Of the 252 patients, PDPH was reported in 133 (52.8%). The incidence of PDPH was more frequent in women (64.7%; P = 0.043). Univariate analyses identified the following significant risk factors for PDPH: female gender (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.05-2.89), age (OR, 0.95; 95% CI, 0.94-0.97), smoking duration (OR, 0.91; 95% CI, 0.88-0.95), preexisting headaches (OR, 2.40; 95% CI, 1.39-4.17), circulatory system disease (OR, 0.52; 95% CI, 0.29-0.92), and musculoskeletal system and connective tissue disease (OR, 0.31; 95% CI, 0.12-0.81). In the multivariable model, duration of smoking and preexisting headaches remained independent risk factors for PDPH (OR, 0.93; 95% CI, 0.88-0.97; P = 0.002; and OR, 4.23; 95% CI, 1.27-14.08; P = 0.019, respectively). For various PDPH characteristics, significant risk factors were identified, including age, female gender, body mass index, circular or endocrine system diseases, and the use of caffeinated drinks before LP. In addition, the caliber of the traumatic needle, direction and number of needle stitches during LP, occurrence, intensity, and radiation of pain during LP, volume of sampled cerebrospinal fluid, rest and hydration after LP, preexisting headache, and earlier PDPH were significant. All these models were well-calibrated (Hosmer-Lemeshow test, P > 0.05). CONCLUSION: The results of the present study are important for the prediction of the occurrence of PDPH and the differential diagnosis of headaches after LP.

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.

Age, gender, and topography influence the clinical and dermoscopic appearance of lentigo maligna.

BACKGROUND: Little is known about the frequency of clinical and dermoscopic patterns of lentigo maligna (LM) in relation to specific anatomic subsites and patients characteristics. OBJECTIVE: We sought to assess the frequency of clinical and dermoscopic features of LM and to correlate them to specific anatomic subsites, and patients' age and gender. METHODS: This was a retrospective analysis of clinical and dermoscopic images of a series of consecutive, histopathologically diagnosed, facial and extrafacial LM. RESULTS: A total of 201 cases from 200 patients (mean age 69.51 ± 12.26 years) including 120 women were collected. Most cases were located on the face (n = 192, 95.5%). In 102 cases, LM presented as clinically solitary facial macule (s/LM), whereas it was associated with multiple surrounding freckles in the remaining cases. s/LM were significantly smaller (<10 vs >10 mm; P = .020) and associated with younger age compared with LM associated with multiple surrounding freckles (mean age 67.73 ± 12.68 years vs 71.34 ± 11.59 years, respectively; P = .036). Dermoscopically, gray color irrespective of a specific pattern was the most prevalent finding seen in 178 (88.6%) cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: The knowledge about patient age, patient gender, and site-related clinical features of LM associated with gray color upon dermoscopy may enhance the clinical recognition of LM.

Oxidative and Nitrosative Stress in Stable Renal Transplant Recipients with Respect to the Immunosuppression Protocol - Differences or Similarities?

BACKGROUND: The aim of the study was to evaluate parameters of oxidative and nitrosative stress as well as antioxidative parameters in a group of renal transplant recipients with stable graft function and no clinical signs of cardiovascular disease. We also aimed to determine the correlations among these parameters and to evaluate potential differences in all the biomarkers with regard to the immunosuppression protocol. METHODS: We enrolled 57 renal transplant recipients and 31 controls who were age and sex matched with the renal transplant recipients. All of the patients included in this study had post-renal transplant surgery at least 12 months earlier and were on standard immunosuppressive therapy. In this study, we determined thiobarbituric acid-reactive substances in plasma and red blood cells and advanced oxidation protein products, nitrosative stress parameters (asymmetric and symmetric dimethylarginine - ADMA and SDMA), and antioxidative parameters (total SH groups and catalase activity). RESULTS: The results of our study demonstrated that the levels of oxidative and nitrosative stress were significantly increased compared to the healthy population (p<0.01 except for plasma catalase activity p<0.05). Correlation analysis showed significant positive correlations between: ADMA and SDMA (p<0.01); ADMA and nitrates (p<0.05); SDMA and nitrates (p<0.05); between OS parameters in the experimental group; AOPP and SH groups (p<0.05) and TBARS in plasma and SH groups (p<0.01), SDMA and AOPP (p< 0.05); SDMA and TBARS in plasma (p<0.05); SDMA and SH groups (p<0.01); nitrates and SH groups (p<0.05). CONCLUSION: There was no significant difference in oxidative and nitrosative stress parameters with respect to the immunosuppressive protocol.

Seroreactivity to Dirofilaria antigens in people from different areas of Serbia.

BACKGROUND: The Northern part of Serbia is hyperendemic-endemic for canine dirofilarioses. Considering this fact, many human dirofilarial infections could be expected, however only about 30 cases in Serbia have been described until today. Aims of this survey were to assess the people reactivity to the antigens of D. repens and D. immitis and to identify risk factors for the contact exposure. METHODS: Investigation included sera taken from 297 people (179 women and 118 men) living in different areas of Serbia (Pancevo, Novi Sad, Zajecar, Leskovac, Vranje, Nis, Pirot). Sera were analysed by means of two indirect enzyme-linked immunosorbent (ELISA) home-designed that use as antigens adult somatic/metabolic polyproteins of D. repens (DR) and D. immitis (DI), respectively. The results were elaborated using the statistical method of descriptive and quantitative analysis. RESULTS: Significant differences by area in the reactivity of human sera to dirofilarial antigens were not observed (p = 0.056). A high seroreactivity was demonstrated in people from the towns of northern Serbia (Pancevo = 27,1%; Novi Sad = 16,3%), as well as in people from Zajecar (eastern Serbia = 15,8%) and Vranje (southern Serbia = 15,1%). No differences were evidenced between people reactivity to polyproteins of the two dirofilarial species, nor differences related to the gender of examinees. Factor risks evidenced were: i) place of residence; ii) spending work time outdoors during the mosquito season; iii) spending time outdoors and nearby rivers, lakes, swamps or canals; unespectedly, iv) cat owning. CONCLUSION: The findings emerging from this investigation indicate that clinicians and public health authorities should pay greater attention to this zoonosis. Continuing education and training of physicians will greatly contribute to the knowledge of the actual impact of filarial worms on animal and public health, and allow for the planning of suitable measures to prevent the infections.

Canine Dirofilaria infections in two uninvestigated areas of Serbia: epidemiological and genetic aspects.

In 2009 canine filarial infections were investigated in two northern areas of Serbia (Pancevo and Veliko Gradiste), applying morphometry, biochemical staining, and immunological kit to detect Dirofilaria immitis antigens, and two home-made ELISAs to detect antibodies to D. repens and D. immitis somatic/metabolic polyproteins. Moreover, molecular tools were applied to analyze the phylogenetic relationships of the isolates. The microfilariae detected in 21/122 dogs (17.2%) were identified as D. repens (n=21) and D. immitis (n=2). D. immitis antigens were found in another 13 animals with occult infection. All of the 15 heartworm-positive dogs also had antibodies to this parasite, which were detected in another 13 subjects, indicating an overall D. immitis seroprevalence rate of 22.9%. Serology for D. repens revealed evidence of antibodies in 42.6% of the dogs, but was negative for 4 microfilaremic dogs. As for the two different areas, the prevalence of microfilariae and/or D. immitis antigens, mainly due to D. repens microfilaremic animals, was not significantly higher in Veliko Gradiste (33.3%) than in Pancevo (22%). However, serology showed a different epidemiological picture. Heartworm infection occurred more often in both areas, and antibodies to dirofilarial nematodes were detected in 72.9% of dogs living in Pancevo, a rate higher than in those living in Veliko Gradiste (57.1%). No risk factors for infection were found, confirming the uselessness of prophylactic drugs against D. repens, and suggesting the presence in these areas of sunrise- or sunset-biting mosquitoes as important vectors. The results indicate the need for both appropriate entomological studies and further research on the intra-species variability shown by D. repens.