Svetlana Ignjatovic

Cortisol response to ACTH stimulation correlates with blood interleukin 6 concentration in healthy humans

OBJECTIVE Interleukin 6 (IL6) has the ability to influence each level of the hypothalamo-pituitary-adrenocortical (HPA) axis. The aim of the study was to test whether IL6 concentration correlates with the adrenal cortex response to ACTH in healthy humans. We postulated that higher basal IL6 concentration would be associated with the higher cortisol response to the stimulation. DESIGN AND METHODS Basal IL6 concentration was measured and a low dose (1 microg) ACTH test was performed to assess cortisol response. Twenty-seven apparently healthy subjects (11 male, 16 female, mean age 31.1 years, age range 22-47 years) were included in the study. RESULTS Data are presented as mean+/-S.E.M. Basal IL6 level was 0.84+/-0.10 pg/ml. Basal cortisol was 351.9+/-18.3 nmol/l. Maximal cortisol during synacthen test was 653.0+/-20.6 nmol/l. Maximal cortisol increment was 301.1+/-20.0 nmol/l. IL6 concentration was not correlated with basal or maximal cortisol concentration, but correlated significantly with cortisol increment (r=0.63, 95% confidence interval) 0.42-0.83). CONCLUSIONS In our study, we found that higher basal IL6 concentration is associated with the higher cortisol response to ACTH stimulation. Based on previous research and our data, IL6, even in low concentrations and under physiologic conditions, modulates adrenal cortex responsivity to ACTH. Therefore, it seems that immune modulation of HPA axis is also present under physiologic and not only pathologic conditions.

New insights into the pathogenesis of perinatal hypoxic-ischemic brain injury.

Background:  Pathogenesis of perinatal hypoxic‐ischemic brain injury (HIE) is complex. In this study, we examined the role of neuroinflammation, oxidative stress and growth factors in perinatal hypoxic‐ischemic brain damage.

Changes of behavioral parameters during long-term food restriction in middle-aged Wistar rats

Food restriction (FR) has a beneficial effect on aging process and exerts a significant effect on the responses of rodents to standard behavioral tasks. The aim of this study was to assess the cumulative influence of FR on the behavioral and biochemical parameters in Wistar rats. Six-month-old rats were subjected to restrictive feeding (50% of the daily food intake, every-other-day feeding regimen) for one month or for six months until ages of 7 and 12months, respectively. We examined the habituation of exploratory movement, amphetamine (AMPH)-induced motor activity, as well as changes in serum corticosterone (CORT) and glucose levels. The results obtained from FR animals were compared with ad libitum (AL)-fed age-matched control rats. Habituation of motor activity was only affected by six months of restrictive feeding. The sensitization of the motor response to AMPH that was observed in animals exposed to FR for one month was not observed in animals that were exposed to the same feeding regimen for six months. Serum CORT was increased and serum glucose was decreased in both FR groups. These results clearly show that despite the similarity of the biochemical changes that were induced by one and six months of FR, the nature of the changes in motor activities in these two groups of animals during habituation and after AMPH treatment was different. Our findings indicate that long-term FR has complex behavioral consequences that need to be carefully evaluated with respect to animal age, duration of FR and severity of the diet.

Biochemical Evaluation of Patients with Acute Pancreatitis

Abstract In this study we determined the clinical accuracy of α2- macroglobulin, α-amylase, C-reactive protein, lipase, non-esterified fatty acids, pancreatic α-amylase and phospholipase A in the diagnosis and prognosis of acute pancreatitis in a group of patients with acute abdominal pain using receiver operator characteristic curve analysis. We investigated 59 patients with acute pancreatitis and 72 patients with extrapancreatic diseases of gastrointestinal origin. On the basis of initial enzyme activities, at cut-offs of 245 U/l for amylase, 656 U/l for lipase, and 182 U/l for pancreatic α-amylase, the diagnostic efficiencies were 0.993, 0.980, and 0.975, respectively. Receiver operator characteristic curve analysis showed the same diagnostic accuracies. We evaluated the accuracy of serum α2-macroglobulin, C-reactive protein, non-esterified fatty acids and phospholipase A for differentiation between acute necrotizing pancreatitis and acute oedematous pancreatitis. C-reactive protein had the highest prognostic accuracy of the parameters studied (the area under curve = 0.9082) and at a cut-off value of 126 mg/l, sensitivity and specificity were 0.759 and 0.912, respectively. The role of the clinical laboratory in the investigation of patients with acute pancreatitis continues to evolve and biochemical parameters are a good diagnostic and prognostic option.

Diagnostic value of NT-proBNP in identifying impaired coronary flow reserve in asymptomatic moderate or severe aortic stenosis

AIM NT-proBNP has been shown to be a reliable biochemical marker for left ventricular wall stress. The relationship between NT-proBNP and coronary flow reserve (CFR) was evaluated in patients with significant asymptomatic aortic stenosis (AS). METHODS A total of 74 patients with moderate or severe AS, mean age 66.68 ± 10.02 years (56.75% males), were enrolled in this prospective study. All patients underwent coronary angiography and had no obstructive coronary disease (defined as having no stenosis >50% in diameter). They had all undergone standard transthoracic Doppler-echo study and adenosine stress transthoracic-echo for CFR measurement and laboratory analysis for NT-proBNP measurement. RESULTS The median NT-proBNP value was significantly increased (417.0 pg/ml; interquartile range [IQR]: 176.8-962.2 pg/ml). NT-proBNP was significantly higher in the group with CFR ≤2.5 (median: 549.0 pg/ml; IQR: 311.5-1131.0 pg/ml; as opposed to median: 291.5 pg/ml; IQR: 123.0-636.2 pg/ml; W = 452; p = 0.012). NT-proBNP showed significant negative correlation with CFR (ρ = -0.377, p = 0.001). There was also significant correlation between NT-proBNP and E/E´, S´ and aortic valve resistance. The NT-proBNP value of 334.00 pg/ml was determined as the best cut-off value for the diagnosis of CFR ≤2.5 (area under the curve: 0.67; 95%CI: 0.54-0.79; p < 0.01) and the sensitivity and specificity were 74 and 64%, respectively. CONCLUSION Elevated NT-proBNP can indicate patients with impaired CFR in asymptomatic moderate or severe AS patients with preserved ejection fraction and nonobstructive coronary arteries.

Biomarkers in Serbian patients with Gaucher disease

OBJECTIVES The aim of the study was to evaluate the efficiency of the biomarkers chitotriosidase (Chito), total acid phosphatase (TACP), angiotensin converting enzyme (ACE) and ferritin in the diagnosis of Gaucher disease (GD) and to assess the utility of biomarkers for monitoring the effects of enzyme replacement therapy (ERT). DESIGN AND METHODS Forty treatment-naive Gaucher patients were studied. 27/40 GP were put on ERT and monitored every 6 months. RESULTS The baseline median values of Chito, TACP, ACE and ferritin were highly elevated in GP: 10216 nmol/mL/h, 26.1 U/L, 253 U/L, 515 μg/L, and 555 μg/L, respectively. The only significant difference between mild and moderate GP subgroups is observed for Chito activity (p=0.0116). During ERT, Chito showed the steepest decrease in regard to TACP and ACE, mainly within the first year (71.4%). CONCLUSIONS Among these biomarkers, Chito proved to be the most useful biomarker for diagnosing GD and monitoring the ERT.

Evaluation of Criteria for the Diagnosis of Balkan Endemic Nephropathy

Background. The diagnosis of Balkan endemic nephropathy (BEN) is often made using Danilovics criteria. The aim of this study was to determine the prevalence, sensitivity, specificity, and predictive value of Danilovics criteria and several additional indices. Methods. The study included 19 BEN patients, 23 BEN-suspected patients, 34 patients with other kidney diseases, and 23 healthy controls. The sensitivity and specificity of Danilovics criteria was calculated, and these criteria, in addition to age, sex, blood pressure, creatinine clearance, glucosuria, urine osmolality, alkaline phosphatase, alpha 1-microglobulin, fractional sodium excretion, tubular phosphate reabsorption, kidney length, and volume, were combined in a logistic regression. Results. All examined persons were from a BEN-affected village (criterion 1), and all BEN, BEN-suspected patients, and 12/23 healthy controls were from BEN families (criterion 2). None of the remaining Danilovics criteria was found in the healthy controls. The prevalence of proteinuria, low specific gravity, and anemia (criteria 3–5) differed insignificantly among the patient groups. Azotemia and shrunken kidney (criteria 6 and 7) were significantly more frequent in BEN than in other patients. Only proteinuria showed high sensitivity and specificity in differentiating BEN and BEN-suspected patients from healthy persons, but no criteria differentiated BEN or BEN-suspected from other kidney diseases. Proteinuria is a significant predictor of both BEN and BEN-suspected vs. healthy persons, and alpha 1-microglobulinuria is a significant predictor of BEN vs. other kidney diseases. Conclusion. Danilovics criteria enabled a diagnosis of BEN only in chronic renal failure and differential diagnosis between BEN and healthy persons but not between BEN and other kidney diseases. Out of the examined indices of proximal tubular disorders, only alpha 1-microglobulinuria significantly discriminated BEN from other kidney diseases.

Oxytocin in corticosterone-induced chronic stress model: Focus on adrenal gland function

Chronic stress conditions can lead to considerable and extensible changes in physiological and psychological performances, and in emergence of risk for various somatic diseases. On the other hand, the neuropeptide oxytocin is reported to increase the resistance of the organism to stress and modulate activity of autonomic nervous system. Chronic corticosterone administration is used as a rat model for a state observed in terms of chronic stress exposure, when negative feedback mechanism of hypothalamus-pituitary-adrenal axis activity is disrupted. In our study, we aimed to investigate whether chronic administration of oxytocin (10 IU/400μL/day for 14days, s.c.) influenced adrenal gland morphology and activity in adult male Wistar rats during long-term corticosterone administration via drinking water (100mg/L for 21days). We examined the influence of treatments on the levels of adrenal gland hormones, corticosterone, adrenaline and noradrenaline, as well as their response to an acute stress challenge evoked by 15-min forced swimming. In addition, the expression of two main monoamine transporters, the noradrenaline transporter (NAT) and vesicular monoamine transporter 2 (VMAT2) in adrenal medulla was measured in the rats exposed to acute stress. Our results showed that oxytocin treatment prevented corticosterone-induced decrease in body weight gain, attenuated adrenal gland atrophy by increasing glandular weight, and the area of the zona fasciculate and reticularis. Chronic corticosterone intake blunted the response of all measured hormones to acute stress, whereas concomitant oxytocin treatment reversed adrenaline and noradrenaline response to acute stress. Furthermore, in adrenal medulla, oxytocin produced significant vasodilatation and stimulated expression of both catecholamine transporters detected both on mRNA and protein level. Our data suggest that oxytocin, by reducing atrophy of adrenal gland, and by increasing catecholamine storage capacity, may be beneficial in conditions accompanied with high glucocorticoid levels, such as chronic stress exposure.

Beta-Trace Protein as a Marker of Renal Dysfunction in Patients with Chronic Kidney Disease: Comparison with Other Renal Markers

Beta-Trace Protein as a Marker of Renal Dysfunction in Patients with Chronic Kidney Disease: Comparison with Other Renal Markers Beta-trace protein (BTP), also known as prostaglandin D synthase, is a low-molecular-mass protein which belongs to the lipocalin protein family. It was found to be increased in the serum of patients with renal diseases. The aim of this study was to compare the clinical usefulness of serum levels of beta-trace protein for the detection of renal dysfunction in patients with chronic kidney disease (CKD) with levels of other renal markers: creatinine, cystatin C and β2-microglobulin (B2M). The study included 134 patients with a wide range of renal dysfunction that encompassed all five CKD stages. Obtained data showed that beta-trace protein highly correlated (Spearman test) with creatinine (r = 0.890), cystatin C (r = 0.904) and B2M (r = 0.933) and its levels in serum significantly increased from CKD stage 1 to 5. Furthermore, the values of glomerular filtration rate (GFR) estimated from a BTP-based formula significantly correlated with GFR calculated from creatinine-based and cystatin C-based formulas. ROC analyses showed that BTP had similar diagnostic accuracy for detection of reduced renal function in CKD stages as other renal markers, for estimated GFRs of < 30, < 60 and < 90 mL/min/1.73 m2. The areas under the ROC curves (AUC) for BTP, for these GFR limits, were from 0.983 to 0.917 and they were not significantly different from AUCs for other renal markers. The results of this study showed that BTP may be a useful and reliable serum marker for identifying the magnitude of renal dysfunction in patients with CKD and may have its place beside serum cystatin C and creatinine as an alternative endogenous GFR marker. Beta-Trace Protein kao Marker Renalne Disfunkcije kod Pacijenata sa Hroničnom Bubrežnom Bolešću: Poređenje sa Drugim Renalnim Markerima Beta-trace protein (BTP), takođe poznat kao prostaglandin D sintaza, je protein male molekulske mase koji pripada familiji lipokalinskih proteina. Pronađeno je da je povećan u serumu pacijenata sa renalnim bolestima. Cilj ovog rada je bio da se uporedi klinička korisnost serumskih nivoa beta-trace proteina u detekciji renalne disfunkcije kod pacijenata sa hroničnom bolešću bubrega (CKD) sa nivoima drugih renalnih markera: kreatinina, cistatina C i β2-mikroglobulina (B2M). Studija je uključila 134 pacijenta sa širokim opsegom renalne disfunkcije koji obuhvata svih 5 CKD stadijuma. Dobijeni podaci su pokazali da beta-trace protein veoma dobro koreliše (Spearmanov test) sa kreatininom (r = 0,890), cistatinom C (r = 0,904) i B2M (r = 0,933) i da se njegovi nivoi u serumu značajno povećavaju od (1. do 5.) CKD stadijuma. Osim toga, vrednosti jačine glomerulske filtracije (GFR) procenjene iz formule bazirane na BTP značajno korelišu sa GFR izračunatom iz formula baziranih na kreatininu i cistatinu C. ROC analiza je pokazala da BTP ima sličnu dijagnostičku tačnost za detekciju redukovane renalne funkcije u CKD stadijumima kao drugi renalni markeri, pri procenjenim GFR od < 30, < 60 i < 90 mL/min/1,73 m2. Površine ispod ROC krivih (AUC) za BTP, za ove nivoe GFR, bile su od 0,983 do 0,917 i one se nisu značajno razlikovale od AUC za druge renalne markere. Rezultati ove studije su pokazali da BTP može biti koristan i pouzdan serumski marker za identifikaciju obima renalne disfunkcije kod pacijenata sa CKD i može se koristiti uz serumski cistatin C i kreatinin kao alternativni endogeni GFR marker.

Adiponectin, Non-Esterified Fatty Acids and Antiphospholipid Antibodies in Type II Diabetes Mellitus

Adiponectin, Non-Esterified Fatty Acids and Antiphospholipid Antibodies in Type II Diabetes Mellitus The importance of the association of antiphospholipid antibodies (aPL Abs) with the features of type II diabetes mellitus has not yet been elucidated. The aim of this work was to investigate the association of aPL Abs with adiponectin and non-esterified fatty acids (NEFA) in type II diabetes mellitus patients without micro and/or macrovascular complications, and to analyze the differences between the male and female patients with regard to the abovementioned parameters. Male patients with type II diabetes mellitus showed a positive correlation between NEFA concentrations and anti-oxLDL antibodies (r=0.334, p=0.019). A weak, but statistically significant correlation between adiponectin concentrations and the IgM isotype of anti-annexin A5 antibodies was found in type II diabetes mellitus patients (r=0.285, p=0.011). The presence of a positive correlation between NEFA and anti-oxLDL antibodies might be useful in the detection of patients with premature atherosclerosis in type II diabetes mellitus patients without any micro and/or macrovascular complications among type II diabetes mellitus patients. Adiponektin, Neesterifikovane Masne Kiseline i Antifosfolipidna Antitela u Dijabetesu Tip II Značaj povezanosti antifosfolipidnih antitela (aPL Abs) sa odlikama dijabetesa tip II još nije razjašnjen. Cilj rada bilo je ispitivanje povezanosti aPL Abs sa adiponektinom i neesterifikovanim masnim kiselinama (NEFA) kod pacijenata sa dijabetesom tip II bez mikro i/ili makrovaskularnih komplikacija i analiziranje razlika u navedenim parametrima između muškaraca i žena sa dijabetesom. Kod muškaraca sa dijabetesom tip II pokazana je pozitivna korelacija između koncentracija NEFA i anti-oxLDL antitela (r=0,334, p=0,019). Slaba ali statistički značajna korelacija između koncentracija adiponektina i IgM izotipa anti-aneksin A5 antitela pronađena je kod pacijenata sa dijabetesom tip II (r=0,285, p=0,011). Pozitivna korelacija između NEFA i anti-oxLDL antitela mogla bi da bude korisna u detekciji pacijenata sa prevremenom aterosklerozom u dijabetesu tip II bez mikro i/ili makrovaskularnih komplikacija.