Bojko Bjelakovic

Glucocorticoids and oxidative stress.

Glucocorticoids (GC) are used widely for the treatment of patients with various disorders, including autoimmune diseases, allergies, and lymphoproliferative disorders. Glucocorticoid therapy is often limited by several adverse reactions associated with GC excess. Excess GC can elicit a variety of symptoms and signs, including growth retardation in children; immunosuppression; cardiovascular disorders like hypertension and atherosclerosis; osteoporosis; myopathy; and diabetes mellitus. Currently, attention is focused on oxidative stress as one of the major determinants of endothelial dysfunction and cardiovascular senescence. The main reason for all unwanted effects of GC is that dexamethasone induces the overproduction of reactive oxygen species, causing dysregulation of physiological processes. Humans and animals with GC-induced hypertension exhibit reduced nitric oxide levels; patients with excess GC levels also suffer from depression as a consequence of low levels of serotonin and melatonin. The common cofactor for the production of these vasoactive molecules is tetrahydrobiopterin (BH4), which is required for nitric oxide synthesis.

Artificial neural networks based prediction of cerebral palsy in infants with central coordination disturbance.

BACKGROUND In a previous study we demonstrated that heart variability parameters (HRV) could be helpful clinically as well as a prognostic tool in infants with central coordination disturbance (CCD). In recent years, outcome predictions using artificial neural networks (ANN) have been developed in many areas of health care research, but there are no published studies considered ANN models for prediction of cerebral palsy (CP) development. OBJECTIVE To compare the results of an ANN analysis with results of regression analysis, using the same data set and the same clinical and HRV parameters. METHODS The study included 35 infants with CCD and 37 healthy age and sex-matched controls. Time-domain HRV indices were analyzed from 24h electrocardiography recordings. Clinical parameters and selected time domain HRV parameters are used to predict CP by logistic regression, and then an ANN analysis was applied to the same data set. Input variables were age, gender, postural responses, heart rate parameters (minimum, maximum and average), and time domain parameters of HRV (SDNN, SDANN and RMSSD). For each of one the pairs of ANN and clinical predictors, the area under the receiver operating characteristic (ROC) curves with test accuracy parameters were calculated and compared. RESULTS In the observed dataset, ANN model overall correctly classified all infants, compared with 86.11% correct classification for the logistic regression model, and compared with 67.65% and 77.14% for SDANN and SDNN respectively. CONCLUSIONS ANN model, based on clinical and HRV data can predict development of CP in patients with CCD with accuracy greater than 90%. Our results strongly indicate that a well-validated ANN may have a role in the clinical prediction of CP in infants with CCD.

Heart rate variability in infants with central coordination disturbance.

Despite a remarkable medical progress in the field of Developmental Medicine and Child Neurology, early identification of infants at risk for permanent motor disabilities still presents challenge for both clinicians and researchers. As an indicator of cardiac autonomic control, it was shown that heart rate variability (HRV) might reflect not only sympathetic or parasympathetic activity but also functional integrity of the central nervous system (CNS). Furthermore a pattern of HRV was demonstrated to correlate with motor developmental outcome in high risk infants. The purpose of this study was to analyze the clinical usefulness as well as predictive value of time-domain HRV parameters in infants with central coordination disturbance. The study included 35 infants with central coordination disturbance and 37 healthy age and sex-matched controls. Time-domain HRV indices were analyzed from 24-h electrocardiography recordings. We found significantly lower values of SDNN, SDANN and RMSSD parameters in infants with central coordination disturbance compared to controls. Additionally, logistic regression analyses demonstrated independent predictive value of parameters SDNN and SDANN in infants who subsequently developed cerebral palsy (CP). By performing receiver operating characteristic (ROC) analyses, the optimal cut-off value of SDNN<=48ms predicted CP with a sensitivity of 68.7% (95% CI 41.4-88.9) and specificity of 84.2% (95 CI 60.4-96.4) while the optimal cut-off value of SDANN<=41ms predicted CP with a sensitivity of 87.5% (95% CI 61.6-98.1) and specificity of 57.9% (95 CI 33.5-79.7). We are in opinion that time domain HRV analysis could be helpful clinically as well as a prognostic tool in infants with central coordination disturbance.

Orexitropic Signaling Proteins in Obese Children

Adipose tissue is not only the main organ for energy storage, but it also has endocrine properties, producing “adipokines” responsible for energy homeostasis, insulin sensitivity, and inflammation. Leptin, produced by adipocytes, is the key hormone in appetite regulation and suppression of orexigenic, hypothalamic neuropeptide Y (NPY). We wanted to establish and compare levels of leptin and NPY in different obesity types in childhood, and to investigate their correlations with auxological parameters. Twenty-one obese children (seven girls and 14 boys), divided into two groups, were compared with 14 controls. The mean age of the study group was 10.81 ± 3.69 years and the mean puberty stage was 2.21. The mean body mass index (BMI) was 32.80 kg/m (range 23.30– 47.02) and the mean overweight 30.73 kg (range 8.00–74.00). The mean leptin level was higher in boys and in the group with central obesity, but was not significant. Leptin/NPY ratio and leptin/BMI ratio was also higher in the central obesity group and there was a more significant difference compared with controls. We found significant correlation of the leptin level with body mass (BM), body mass excess (BME), and BMI (p < 0.05). The mean leptin level in obese children was very high (36.39 ng/ml). Leptin and NPY levels showed inverse values in two different obesity types. Results are suggestive for leptin resistance rather than leptin deficiency in our group of obese children. Orexitropic signaling proteins correlated significantly with auxological parameters. Determination of the leptin and NPY concentrations provided evidence that obesity represents disease with neuroendocrine dysfunction and high leptin/NPY ratio, which could be a useful marker for central obesity.

Assessment of general movements and heart rate variability in prediction of neurodevelopmental outcome in preterm infants

BACKGROUND Adverse neurologic outcome in preterm infants could be associated with abnormal heart rate (HR) characteristics as well as with abnormal general movements (GMs) in the 1st month of life. AIMS To demonstrate to what extent GMs assessment can predict neurological outcome in preterm infants in our clinical setting; and to assess the clinical usefulness of time-domain indices of heart rate variability (HRV) in improving predictive value of poor repertoire (PR) GMs in writhing period. STUDY DESIGN Qualitative assessment of GMs at 1 and 3 months corrected age; 24h electrocardiography (ECG) recordings and analyzing HRV at 1 month corrected age. SUBJECTS Seventy nine premature infants at risk of neurodevelopmental impairments were included prospectively. OUTCOME MEASURES Neurodevelopmental outcome was assessed at the age of 2 years corrected. Children were classified as having normal neurodevelopmental status, minor neurologic dysfunction (MND), or cerebral palsy (CP). RESULTS We found that GMs in writhing period (1 month corrected age) predicted CP at 2 years with sensitivity of 100%, and specificity of 72.1%. Our results demonstrated the excellent predictive value of cramped synchronized (CS) GMs, but not of PR pattern. Analyzing separately a group of infants with PR GMs we found significantly lower values of HRV parameters in infants who later developed CP or MND vs. infants with PR GMs who had normal outcome. CONCLUSIONS The quality of GMs was predictive for neurodevelopmental outcome at 2 years. Prediction of PR GMs was significantly enhanced with analyzing HRV parameters.

Blood Pressure Variability and Left Ventricular Mass Index in Children

Clinical implications of blood pressure variability (BPV) on subclinical organ damage in children are unknown. The authors sought to explore the potential utility of two newly derived BPV indices: weighted standard deviation (wBPSD) and real average variability (ARV), as well as two standard ambulatory blood pressure indices: average 24‐hour systolic blood pressure (SBP) and 24‐hour SBP load, to identify children at high risk for left ventricular (LV) hypertrophy (LVH). The study group consisted of 67 consecutive children who were referred to our institution for evaluation of suspected hypertension. LV mass was estimated by M‐mode echocardiography using Devereuxs formula according to the Penn convention and indexed for height2.7. We found a statistically significant, positive correlation between 24‐hour wBPSD and LV mass index (LVMI) (ρ=0.389; P=.002) and no correlation between 24‐hour ARV and LVMI (P>.05). However, partial correlation analysis of 24‐hour wBPSD adjusted for body mass index (BMI) and LVMI showed only a weak correlation (ρ=0.3; P=.022). By using multiple linear regression analysis in a model with LVMI as a dependent variable and 24‐hour wBPSD, 24‐hour ARV, and BMI as independent variables, only BMI showed statistically significant independent positive associations with LVMI (P=.028). Results of our study showed that currently used BPV indices (24‐hour wBPSD and 24‐hour ARV) are not clinically reliable parameters to identify children at risk for LVH. Apparent contribution of the 24‐hour wBPSD parameter to LVMI is negligible and is secondary to its close correlation with BMI (ρ=0.335 P=.009).

The therapeutic efficacy of propranolol in children with recurrent primary epistaxis

We hypothesized that some characteristics of beta-blockers, including negative inotropic, peripheral vasoconstrictor, and antiangiogenic effects, might be potentially useful in treating children with epistaxis. From June 2010 to March 2012, a total of seven children with recurrent primary epistaxis resistant to conventional management were observed at our institution. An overall effectiveness of propranolol was noted in all seven children when given a dose of 1.5–2 mg/kg/day (divided into three doses) as a second line therapy for terminating epistaxis. Based on our first experience, we believe that propranolol could be a favorable treatment option for patients with primary epistaxis.

Heart Rate Variability in Children with Exercise-Induced Idiopathic Ventricular Arrhythmias

Ventricular arrhythmias (VAs) are common pediatric rhythm disorders requiring comprehensive laboratory evaluation. Although usually idiopathic, implying a benign character and favorable prognosis, the initial clinical approach is still not established in all cases. Considering their prognostic significance, exercise-induced (precipitated or aggravated) VAs usually require additional diagnostics, treatment, and follow-up. A number of reports have presented experimental and clinical evidence that increased sympathetic activity can initiate, or at least facilitate, VAs. Recent data highlight the relationship between exercise-induced idiopathic VAs (IVAs) and the long-term risk of cardiovascular death. The aim of this study was to assess the utility of heart rate variability (HRV) analysis as a noninvasive method for estimating autonomic nervous activity in children with exercise-induced IVAs. The study included 42 children with IVAs, who were divided into two groups: children with exercise-induced (precipitated or aggravated) IVAs and children with exercised-suppressed IVAs. Time-domain HRV parameters were analyzed from 24-h ambulatory electrocardiography recordings, and the majority of children underwent an exercise stress test using the McMaster protocol. The results of this study showed no significant changes in parasympathetic index, i.e., the square root of the mean of the sum of the squares of the differences between adjacent NN intervals (the length between two successive heartbeats) between the groups examined. On the other hand, we observed diminished time-domain values for the standard deviation of all adjacent NN intervals, as well as diminished time-domain values for standard deviation of the averages of NN intervals in all 5-min segments in the group of children with exercise-induced IVAs, implicating increased sympathetic activity in such individuals. HRV analysis could be a helpful diagnostic method, giving useful information regarding cardiac autonomic control in some children with exercise-induced IVAs.

Morphometric and biochemical characteristics of short-term effects of ethanol on rat cardiac muscle

Alcoholism is a very important cause of congestive cardiomyopathy in man. The aim of this study was to examine a short-term effect of ethanol in rat cardiac muscle, using histologic, morphometric and biochemical methods. Experiments were carried out in Wistar male albino rats, divided into two groups: the control group consisting of eight animals receiving tap water, and the experimental group comprising eight animals received ethyl alcohol for ten days, in a single daily dose of 3 g ethanol/kg body weight, per os, using esophageal intubation. The mean volume weighted nuclear volume of cardiac myocytes was estimated by point sampled intercept method, by objective x 100. The mean cubed nuclear intercept length was multiplied by pi and divided by 3. For biochemical analysis, a 10% water tissue homogenate from the left ventricle was made. In the experimental group, the mean volume-weighted nuclear volume (15.08 +/- 5.20 microm3) was significantly lower than in the control group (51.32 +/- 7.83 microm3) (p < 0.001). The treatment of experimental animals with ethanol caused significant increase of aldolase (p < 0.0001) and aspartate transaminase (p < 0.05) activity in the rat cardiac tissue; at the same time, the enzyme activity of creatine phosphokinase, alanine transaminase and alkaline phosphatase were not changed in the experimental group compared to the control values. The amount of the glucose in the cardiac muscle was greater in the experimental group compared to the control animals. Our results suggest that there is depression of cardiomyocyte nuclei in experimental animals treated with ethanol. Alcohol intake results in the loss of Krebs cycle enzymes and as a consequence there is greater utilization of fatty acids for energy production.

Beta-Blockers (Carvedilol) in Children with Systemic Ventricle Systolic Dysfunction - Systematic Review and Meta-Analysis

BACKGROUND Numerous prospective randomized clinical trials demonstrated favorable effect of beta-blockers in adults with chronic heart failure. However, effectiveness of beta blockers in pediatric patients with systemic ventricle systolic dysfunction was not recognized sufficiently. Limited number of pediatric patients might be the course of unrecognized carvediolol treatment benefit. Currently, no meta-analysis has examined the impact of carvedilol and conventional therapy on the clinical outcome in children with chronic heart failure due to impaired systemic ventricle systolic function. MATERIALS AND METHODS We have systematically searched the Medline/PubMed and Cochrane Library for the controlled clinical trials that examine carvedilol and standard treatment efficacy in pediatric patients with systemic ventricle systolic dysfunction. Mean differences for continuous variables, odds ratios for dichotomous outcomes, heterogeneity between studies and publication bias were calculated using Cochrane Review Manager (Rev Man 5.2). RESULTS Total of 8 prospective/observational studies met established criteria. Odds ratio for chronic heart failure related mortality/heart transplantation secondary to carvedilol was 0.52 (95% CI: 0.28-0.97, I(2) = 0%). Our analysis showed that carvedilol could prevent 1 death/ heart transplantation by treating 14 pediatric patients with impaired systemic ventricle systolic function. CONCLUSION Meta-analysis demonstrated clinical outcome benefit of carvedilol in children with chronic heart failure.