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Open access

Goran Koraćević, Vladan Ćosić and Ivana Stojanović

Summary

Cardiac troponins have a crucial role in diagnosing acute myocardial infarction, but have been considered by some authors to have a high false positive rate. Such opinions may decrease the confidence in troponin with important clinical consequences. The aim of the paper is to analyze three different meanings of the phrase »false positive troponin«: A) analytic (technical) false positive, with no real myocardial damage; B) false positive considering AMI: cardiac injury is present, but there is no AMI; C) false positive considering CAD: there is myocardial damage, but no CAD. The most frequent and the most important source of misunderstanding is the confusion between aspects A) and B). Namely, there has been a relatively small percentage of false positive troponin elevations due to analytic reasons. On the contrary, there has been a re - latively large percentage of »false positive« results in patients with myocardial necrosis due to causes other than AMI; for them - instead of »FP troponin elevation« - another phrase ought to be used, e.g., »non-AMI troponin elevation « until the etiopathogenesis in an individual patient is recognized. The phrase »false positive troponin« should be restricted to the artificial increase in troponin due to preanalytic and analytic reasons. By doing so, we may decrease the degree of confusion about troponin and increase the confidence in this highly specific marker of myocardial injury. The possibility of an analytic false positive result should always be kept in mind when one interprets elevated troponin.

Open access

Lilika Zvezdanović, Vidosava Đorđević, Vladan Ćosić, Tatjana Cvetković, Slavica Kundalić and Aleksandra Stanković

The Investigation of Cytokines and Oxidative Stress in Patients with Systemic Lupus Erythematosus

Numerous factors can influence the onset of SLE and development of some clinical disease manifestations with various organ involvements and occurrence of characteristic symptoms and disease signs. This paper studies the balance between proinflammatory and antiinflammatory cytokines, investigates the presence of oxidative stress measuring certain prooxidative factors and determines the activation of antioxidative protection pathways aiming to establish possible correlations between the studied parameters. ELISA, enzymatic spectrophotometry and colorimetric methods were used to determine the above-mentioned parameters. The results obtained indicate that disturbed pro/antioxidative status is associated with the change of antioxidative factors, with the fall od SOD activity and increase of GPx and CAT activity in the erythrocytes of all studied groups of patients. At the same time, the cytokine production was altered, not only compared to the healthy control samples, but also in various clinical disease manifestations. Altered relationships of pro and antiinflammatory cytokines and the consequential disorders of other studied systems provide us with useful strategic targets for diagnostic monitoring and possible therapeutic interventions in SLE patients.

Open access

Dušan Lazarević, Vladimir Đorđević, Vladan Ćosić, Predrag Vlahović, Suzana Tošić-Golubović, Tatjana Ristić and Vidosava Đorđević

Increased Lymphocyte Caspase-3 Activity in Patients with Schizophrenia

A growing body of evidence indicates that cortical brain cells of schizophrenic patients are vulnerable to apoptosis. As apoptosis is an important mechanism in organism modeling during development, active since the early phase of intrauterine life, it could be involved in the pathogenesis of schizophrenia. To test this hypothesis, caspase-3 activity was determined in peripheral blood mono nuclear cells from 30 patients with schizophrenia and from 30 age and gender matched healthy subjects by a colorimetric commercially available kit. Consistent with increased susceptibility to apoptosis, caspase-3 activity in lymphocytes of patients with schizophrenia was significantly increased (0.111±0.055 μmol/mg protein, p<0.05) in comparison with those in the matched control group (0.086±0.030 μmol/mg protein). The highest activity was obtained in the group showing almost equally positive and negative symptoms (0.159±0.096 μmol/mg protein) and it was significantly higher (p<0.05) compared to the group with a relative predomination of positive symptoms (0.100±0.029 μmol/mg protein). Caspase-3 activity in patients receiving typical antipsychotic drugs (0.124± 0.071 μmol/mg protein) was not significantly different from that in patients treated with atypical antipsychotics (0.104±0.039 μmol/mg protein). To our knowledge to date, this has been the first demonstration that there is a significant increase in caspase-3 activity, determined in native cells, in patients with schizophrenia, indicating a dysregulated apoptotic mechanism in this disease.

Open access

Vidosava Đorđević, Tatjana Ristić, Vladan Ćosić, Predrag Vlahović, Lilika Zvezdanović and Gordana Đorđević

Inflammatory and Apoptotic Markers in Ischemic Heart Disease Patients

Ischemic heart disease is the most frequent cause of cardiovascular morbidity and mortality. It is developed on the basis of atherosclerosis which is today considered a chronic inflammatory disease. It is documented by an increase in inflammatory and immune biomarkers, such as C-reactive protein, fibrinogen, neopterin, leukocytes, lymphocytes and others, that are significantly changed in patients with unstable angina or acute myocardial infarction. CRP is mostly studied. Increased concentrations of CRP are associated with a series of risk factors. CRP may predict recurrent events and mortality independently of cardiac troponin levels, and it is also an independent predictor of a cardiovascular event after adjustment for traditional risk factors. Although CRP currently appears to be the most promising biological marker, there is still controversy regarding its use in clinical practice. Both necrotic and apoptotic cell death are documented during atherogenesis, however, limited data are available about apoptotic markers in ischemic heart disease patients. Increasing evidence supports the existence of apoptotic death initiated by ligation of membrane-bound death receptors or by release of cytochrome c from mitochondria, as well as their regulators in the heart. The studies of serum markers show that the apoptotic process is disregulated in ischemic heart disease patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is present in stable atherosclerotic lesions, is increased in vulnerable plaques, but its serum levels are reduced significantly in patients with unstable angina. Serum Fas concentrations are increased and FasL are decreased in subjects at high cardiovascular risk. The results of our study show significant changes in serum Fas, FasL, and Bcl-2 concentrations, and lymphocyte caspase-3 activity in different stages of ischemic heart disease. For now, there is evidence that statins are effective in the regulation of some apoptotic markers. The better understanding of the pathways of apoptosis and their regulation is promissing in yielding novel therapeutic targets for cardiovascular disease.

Open access

Vidosava B. Đorđević, Ivana Stojanović, Slavica Kundalić, Tatjana Ristić, Radmila Pavlović, Vladan Ćosić and Tatjana Cvetković

Summary

Nitric oxide (NO) is produced by many cells in the body; however, its production by vascular endothelium is particularly important in the regulation of blood flow. Vascular actions of NO include the following: direct vasodilation, indirect vasodilation by inhibiting the vasoconstrictor influences, anti-thrombotic, anti-inflammatory and anti-proliferative effects. Due to its importance in vascular function, abnormal production of NO, occurring in different diseases can adversely affect blood flow and other vascular functions. It has been suggested that alterations in NO generation are a critical cause of injury in the ischemic heart. A biologic link between the endothelial damage and atherosclerotic coronary arterial disease has been presumably related to de - creased arterial bioavailability of NO through the increased leucocyte and platelet adhesions, vasoconstriction and smooth muscle cell proliferation. However, the precise me - chanism of the impaired NO generation is not known, and there is a considerable controversy regarding whether myo - cardial ischemia results in increased or decreased NO for - mation. Asymmetric dimethylarginine (ADMA) is a natural, com petitive inhibitor, and one of the primary factors controlling the nitric oxide production. ADMA was found to be elevated and closely correlated with the impaired vasodilator function in conditions associated with the endothelial dysfunction, such as hypercholesterolemia, hypertension, insulin resistance and type 2 diabetes, and renal failure. But ADMA also seems to be involved in myocardial ischemia, since its plasma levels predict future coronary events in patients with the elevated cardiovascular risk. It has been recently reported that the elevated plasma ADMA concentrations in the acute coronary events are an independent cardiovascular risk factor.

Open access

Tatjana Ristić, Vladan Ćosić, Predrag Vlahović, Marina Deljanin-Ilić and Vidosava Đorđević

Could Lymphocyte Caspase-3 Activity Predict Atherosclerotic Plaque Vulnerability?

Apoptotic cell death may play a critical role in a variety of cardiovascular diseases, especially in those developing on the basis of atherosclerosis. The goal of this study was to compare the activity of caspase-3 in different forms of ischemic heart disease and to correlate caspase-3 activity with inflammatory and lipid markers as well as risk factors. This enzyme activity was determined in peripheral blood mononuclear cells (PBMC) of 30 patients with stable angina pectoris (SAP), 27 with unstable angina (USAP), 39 with acute ST-elevation myocardial infarction (STEMI) and 27 healthy volunteers by a colorimetric commercially available ELISA method. In the SAP group caspase-3 activity was 0.093±0.036 μmol/mg protein, in patients with STEMI it was 0.110±0.062 μmol/mg protein, and both values were insignificantly higher in comparison with controls (0.092±0.022 μmol/mg protein). In PBMC of USAP patients caspase-3 activity (0.122±0.062 μmol/mg protein) was significantly higher (p<0.05) compared to the control group. In SAP patients caspase-3 activity showed a significant positive correlation with triglicerydes (p<0.05). Caspase-3 activity may be a valid parameter for assessing the atherosclerotic plaque activity, and a new target for therapeutic intervention.

Open access

Tatjana Stanković, Vidosava Đorđević, Borislav Kamenov, Hristina Stamenković, Vladan Ćosić, Radovan Milićević and Vjeroslava Slavić

Antioxidative Enzyme Activities and Lipid Peroxidation in Children with Inflammatory Endothelial Injury

During the inflammatory process endothelial cells are activated and a proadherent ability is assumed. The synthesis of reactive oxygen metabolites, which follows the immunological processes, can cause oxidative damage to endothelial cells leading to the clinical expression of disease including a variety of skin manifestations. In this study the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and the malondialdehyde concentration were examined in 36 children with inflammation-mediated damage to microvascular endothelial cells. On the basis of clinical manifestations the studied children were divided into 4 groups (1st group-macular skin manifestations, 2nd group-maculo-papular skin manifestations, 3rd group-papular skin manifestations, 4th group- erythematous skin manifestations). All the examined children showed symptoms of inflammation (mainly respiratory tract infections) with leukocytosis and monocytosis before actual skin manifestations took place. Superoxide dismutase activity was significantly decreased in three groups of patients, except in the group with erythematous skin manifestations. Catalase activity was significantly increased in all the groups compared to the control group. The values of malondialdehyde were significantly increased in the groups of children with maculo-papular and erythematous skin manifestations. The results have confirmed the presence of a changed antioxidant enzyme pattern indicating oxidative stress during inflammatory endothelial cells injury. Malondialdehyde was not an adequate parameter in its evaluation.

Open access

Vidosava Đorđević, Lilika Zvezdanović, Vladan Ćosić, Predrag Vlahović, Slavica Kundalić, Tatjana Jevtović-Stoimenov, Bojana Stamenković and Dragoslav Mitrović

Serum Levels and in Vitro Production of Th1- and Th2-Type Cytokines by Peripheral Blood Mononuclear Cells in Patients Suffering from Systemic Lupus Erythematosus

Th1-type and Th2-type cytokine profiles and adhesion molecules in the serum of patients suffering from systemic lupus erythematosus and the cytokine production by peripheral blood mononuclear cells (PBMC) were studied. Tumor necrosis factor-alpha (TNF-α), interferongamma (IFN-γ), interleukin-1β (IL-1β), IL-4, IL-10, IL-13, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured using ELISA technique in the sera of 16 systemic lupus erythematosus patients without vasculitis (SLE), 30 SLE patients with vasculitis (LV), and in 18 healthy controls. The cytokines were also measured in the culture media of unstimulated, concana valin-A (Con-A) and phorbol-12-myristate-13-acetate (PMA) stimulated PBMC. TNF-α serum levels were significantly elevated in both SLE and LV patients and those of IL-1β in SLE patients. TNF-α was also significantly increased in SLE compared to LV patients. Serum levels of all three Th-2 cytokines were significantly elevated in both SLE and LV patients compared to healthy controls. Serum IFN-γ and Th2 cytokine levels were significantly increased in patients with more active disease. Both ICAM-1 and VCAM-1 were significantly increased in SLE patients and only VCAM-1 in LV patients. ICAM-1 showed a significant correlation with IL-1β, IFN-γ, IL-4 and IL-10 in both patient groups. In the SLE group VCAM-1 correlated significantly only with ICAM-1, but in the LV group only with IL-1β and IFN-γ. Compared to healthy controls, basal TNF-α and IL-4 production by unstimulated PBMC derived from SLE patients were significantly increased. Con-A-stimulated PBMC of both SLE groups produced significantly more IFN-γ, IL-4 and IL-13 than Con-A-stimulated control cells. Con-A-stimulated cells derived from LV patients produced much more INF-γ than cells from SLE patients. PMA strongly stimulated INFγ, TNFα and IL-13 production by cells derived from both SLE groups but had no effect on IL-4 production. In addition, it had little if any effect on the production of INFγ and IL-13 by PBMC derived from healthy donors. These findings suggest that the altered pattern of cytokine production by PBMC may play an important role in the SLE pathophysiology, accounting for differences in the clinical expression of the disease. The differences in adhesion molecules production and their correlation with cytokines suggest ICAM-1 and VCAM-1 as useful markers in SLE patients stratification.

Open access

Vidosava B. Djordjević, Dušan Lazarević, Vladan Ćosić, Marinela Z. Knežević, Vidosava B. Djordjević, Ivana Stojanović and Vladimir Djorgevič

Summary

Background: Brain-derived neurotrophic factor (BDNF) and nitric oxide (NO) play multiple roles in the developing and adult CNS. Since BDNF and NO metabolisms are dysregulated in schizophrenia, we measured these markers simultaneously in the blood of schizophrenics and assessed their diagnostic accuracy.

Methods: Thirty-eight patients with schizophrenia classified according to demographic characteristics, symptomatology and therapy and 39 age- and gender-matched healthy controls were enrolled. BDNF was determined by the ELISA technique while the concentration of nitrite/nitrate (NO- 2 /NO- 3) was measured by the colorimetric method.

Results: Serum BDNF levels were significantly lower (20.38±3.73 ng/mL, P=1.339E-05), whilst plasma NO- 2/NO- 3concentrations were significantly higher (84.3 (72-121) mmol/L, P=4.357E-08) in patients with schizophrenia than in healthy controls (25.65±4.32 ng/mL; 60.9 (50-76) mmol/L, respectively). The lowest value of BDNF (18.14±3.26 ng/mL) and the highest NO- 2/NO- 3 concentration (115.3 (80-138) mmol/L) were found in patients treated with second-generation antipsychotics (SGA). The patients diseased before the age of 24 and the patients suffering for up to one year had significantly lower serum BDNF levels than those diseased after the age of 24 and the patients who were ill longer than one year. Both BDNF and NO- 2 /NO- 3 showed good diagnostic accuracy, but BDNF had better ROC curve characteristics, especially in patients with negative symptomatology.

Conclusions: BDNF and nitrite/nitrate showed inverse changes in schizophrenic patients. The most pronounced changes were found in patients treated with second-gene - ration antipsychotics. Although BDNF is not specific of schizophrenia, it may be a clinically useful biomarker for the diagnosis of patients expressing predominantly negative symptoms.

Open access

Danica Marković, Tatjana Jevtović-Stoimenov, Vladan Ćosić, Biljana Stošić, Vesna Dinić, Bojana Marković-Živković and Radmilo J. Janković

Summary

Background: Recent studies indicate that survivin (BIRC5) is sensitive to the existence of previous ischemic heart disease, since it is activated in the process of tissue repair and angiogenesis. The aim of this study was to determine the potential of survivin (BIRC5) as a new cardiac biomarker in the preoperative assessment of cardiovascular risk in comparison with clinically accepted cardiac biomarkers and one of the relevant clinical risk scores.

Methods: We included 79 patients, female (41) and male (38), with the mean age of 71.35±6.89. Inclusion criteria: extensive non-cardiac surgery, general anesthesia, age >55 and at least one of the selected cardiovascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking and positive family history). Exclusion criteria: emergency surgical procedures and inability to understand and sign an informed consent. Blood sampling was performed 7 days prior surgery and levels of survivin (BIRC5), hsCRP and H-FABP were measured.

Results: Revised Lee score was assessed based on data found in patients’ history. Levels of survivin (BIRC5) were higher in deceased patients (P<0.05). It showed AUC=0.807 (95% CI, P<0.0005, 0.698–0.917), greater than both H-FABP and revised Lee index, and it increases the mortality prediction when used together with both biomarkers and revised Lee score. The determined cut-off value was 4 pg/mL and 92.86% of deceased patients had an increased level of survivin (BIRC5), (P=0.005).

Conclusions: Survivin (BIRC5) is a potential cardiac biomarker even in elderly patients without tumor, but it cannot be used independently. Further studies with a greater number of patients are needed.