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Open access

Tatjana Jevtović-Stoimenov, Danica Marković, Milena Despotović, Dušica Pavlović and Gordana Kocić


TNF-alpha and LT-alpha are involved in the pathogenesis of established lymphoproliferative diseases. Both molecules bind to TNFRI and TNFRII. TNFRI is the major mediator of the TNF pro-apoptotic and proliferative effects and TNFRII might enhance these effects. TNF receptors I and II are normally present on hematopoetic cells. TNFR II is characteristic only on immune cells, especially on peripheral leukocytes. Neoplastic B cells and activated B lymphocytes have increased expression of surface TNFR I. In this study, we have analyzed polymorphisms in the TNFRI gene (TNFRI+36A/G SNP) and polymorphism in the TNFRII gene (TNFRII + 676 T/G). All these polymorphisms were studied in patients with chronic lymphocytic leukemia (CLL), patients with non-Hodkin’s lymphoma (NHL) and in healthy controls. The present study was undertaken to investigate the genetic association of these polymorphisms with lymproproliferative disease development.

A total of 68 patients (49-CLL, 19-HNL) were diagnosed at the Clinic of Hematology, Clinical centre Niš, Serbia, using clinical findings and conventional morphological, cytochemical and immunological tests. Genomic DNA was isolated from isolated lymphocytes by proteinase K/phenol/chloroform method, and genotyped for TNFR I (A36G) and TNFR II (T676G) using the PCR-RFLP method.

No significant differences in allele frequencies of TNFR1 polymorphism were found between the patients with lymphoproliferative disease and healthy individuals. In a group of healthy individuals, the study has revealed for the first time significantly higher TNFRI G/G genotype compared to the patients with lymphoproliferative disease (χ22 = 5.66; p = 0.017). Also, we reported the implication of TNFRII T allele in NHL pathogenesis, respectively (χ22 = 10.77; p = 0.001; Mantel-Haenszel: χ22 = 10.64; p = 0.0011).

Our data showed that TNFRII T676G polymorphisms have an important role in NHL pathogenesis but not in CLL patients. A/A polymorphism in TNFRI was not associated with CLL and NHL patients in the Serbian population. Investigated polymorphisms on TNFR genes in leukemic cells of CLL and NHL patients have not showed a correlation with increased proliferation of B lymphocytes and increased expression of TNF R II on B CLL lymphocytes.

Open access

Sonja Stojanović, Bojana Stamenković, Jovan Nedović, Tatjana Jevtović-Stoimenov and Dušica Pavlović


To examine whether the presence of the rare A allele of the TNF-Alpha-308 G/A gene polymorphism is associated with erosive arthritis and rapid radiological progression of the disease.

The examined group included 131 patients with early RA. Using the PCR-RFLP method, the TNF-Alpha-308 G/A gene polymorphism was determined for all patients. In relation to the presence of the A allele of the examined polymorphism, the patients were divided into two subgroups: subgroup A (G/A and A/A genotypes) and subgroup G (G/G genotype). Based on the presence of the destructive changes in joints found in the initial radiographs, the findings were classified as erosive and non-erosive RA. Radiological progression was assessed on the basis of the annual change in the Larsen score – LS (0-200).

Group A comprised 62 (47.33%) patients, while group G comprised 69 (52.67%) patients. The presence of cysts and erosions in subgroups A and G was compared before the start of the methotrexate therapy. It was determined that erosions (erosive RA) were statistically significantly more frequent in group A (83.87% of patients) in comparison with group G (44.93% of patients), p < 0,001. Group A patients had a higher value of the Larsen score in relation to the group G both before and after methotrexate was administered for a year (before therapy, LS in group A: 48.58 ± 20.54; in group G 20.73 ± 12.31; p < 0.01; after MTX therapy, LS in group A: 58.32 ± 22.25; in group G 25.35 ± 14.57; p < 0.001). The average value of the annual LS change in group A was statistically significantly greater than the change in group G patients (9.98 ± 4.95 to 5.23 ± 2.72) (p < 0.05).

The presence of the A allele of the TNF-Alpha-308 G/A gene polymorphism is associated with the occurrence of early erosive joint changes and more rapid radiological progression of the disease.

Open access

Milena Despotović, Tatjana Jevtović Stoimenov, Ivana Stanković, Jelena Bašić, Branka Đorđević and Dušica Pavlović


Bronchial asthma (BA) is a chronic inflammatory disease of the airways in the pathogenesis of which oxidative stress has a very important role. Single nucleotide polymorphisms (SNPs) in catalase gene may result in decreased antioxidative defense capacity, and thus a higher risk for BA development. Since oxidative stress has an important role in the pathogenesis of BA and catalase has a key role in antioxidant defense, the aim of this study was to examine the association of CAT C-262T polymorphism with BA in Serbian patients with BA.

A total of 170 subjects (79 patients with BA and 91 controls) were screened for CAT C-262T SNP using PCR-RFLP method.

The analysis of genotype distribution did not show statistically significant differences between BA patients and controls (p > 0.05). Moreover, no differences were detected when comparison was performed based on dominant or recessive model. The distribution of CAT-262C and CAT-262T alleles did not show differences between patients and healthy controls (p = 0.715; OR = 1.091; 95% CI = 0.684–1.741). Further analysis of genotype and allele distributions, based on stratification by sex, did not show significant differences between BA patients and controls (p > 0.05).

This is the first study that examined CAT C-262T (rs1001179) SNP in Serbian patients with BA. The results obtained in this study showed that biallelic SNP at the position-262 in the catalase gene is not associated with BA in the Serbian population.

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

Nikola Z. Stefanović, Tatjana P. Cvetković, Radmila M. Veličković-Radovanović, Tatjana M. Jevtović-Stoimenov, Predrag M. Vlahović, Ivana R. Stojanović and Dušica D. Pavlović


Background: The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.

Methods: The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.

Results: The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities.

Conclusions: Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.

Open access

Olivera Andrejić, Rada Vučić, Svetlana Apostolović, Milan Pavlović, Dragana Stokanović, Valentina Nikolić, Tatjana Jevtović-Stoimenov and Stefan Momčilović


The aim of our study was to determine the factors influencing galectin-3 levels in patients with acute coronary syndrome and decreased left ventricular ejection fraction. We collected material from 37 successive patients with acute coronary syndrome and decreased left ventricular ejection fraction, of which 19 patients had atrial fibrillation, and 18 patients who were without atrial fibrillation constituted a control group. Blood samples used for the biochemical measurements were obtained on the third day from acute coronary syndrome. We used Statistical Package for Social Sciences for data analysis. A p-value less than 0.05 was considered to be a measure of statistical significance. Galectin-3 concentration is directly correlated with age and B-type natriuretic peptide level. Also, our results showed an inverse correlation between galectin-3 and total body weight, body mass index, body surface area and creatinine clearance. The following variables were found to be significant predictors of galectin-3 level: decreased left ventricular ejection fraction, total body weight, LDL concentration and body mass index. We identified factors that can predict a decrease in the left ventricular ejection fraction below 45% after acute coronary syndrome: atrial fibrillation increases the risk by almost six times, and urea concentration increases the risk by 1.2 times for each unit. Left ventricular ejection fraction below 45%, TBW, body mass index and LDL level are good predictors of galectin-3 concentration in patients with ACS and decreased left ventricular ejection fraction. Atrial fibrillation could be a predictive marker of decreased left ventricular ejection fraction.

Open access

Vladimir V. Đorđević, Tatjana Jevtović-Stoimenov, Dušan Lazarević, Ivana Stojanović, Ljiljana Trajanović, Olivera Žikić and Vidosava Đorđević


Background: Single nucleotide polymorphisms (SNP) of many genes, including the gene for neuronal nitric oxide syn-thase (NOS1), were found significantly associated with schizo-phrenia. According to our previously published results of increased plasma nitric oxide concentration in patients with schizophrenia, we hypothesized that the NOS1 gene polymorphism might be a cause of increased nitric oxide production in patients with schizophrenia and tested the interdependence between plasma nitrite/nitrate concentrations and SNP (a CT transition located in exon 29) of the human NOS1 gene.

Methods: Nitrite/nitrate concentration was measured in blood plasma of 38 patients with schizophrenia and of 39 age and gender matched healthy persons by the colorimet-ric test. The NOS1 gene polymorphism was determined by polymerase chain reaction analysis.

Results: A significantly higher plasma nitrite/nitrate concentration was found in patients with schizophrenia (97.5±33.3 μmol/L, p<0.001) in comparison with controls (61.4±18.9 μmol/L). No T/T genotype was found in healthy individuals and there was a significant difference in the genotype distribution between patients and controls (χ2=24.54, p=0.0000047). Furthermore, a significant difference in the allele frequencies between patients and controls (χ2=19.00, p<0.000013, OR=4.45, 95% CI=2.12–9.39) was noted. Also, a significant difference in plasma nitrite/nitrate concentration was observed between patients having the C/T genotype (99.97±33.83 μmol/L) and the corresponding control (C/T) subgroup (63.88±10.26 μmol/L, p<0.01). However, there were no significant differences in nitrite/nitrate concentration between the patient subgroups with different genotypes (C/C, C/T, T/T).

Conclusions: CT transition located in exon 29 of the human NOS1 gene may be responsible for the increased plasma nitrite/nitrate levels.

Open access

Jelena Radović, Jelena Vojinović, Vladmila Bojanić, Tatjana Jevtović-Stoimenov, Gordana Kocićs, Maja Milojković, Andrej Veljković, Ivana Marković, Svetlana Stojanovic and Dušica Pavlović


Background: Episodic fever syndromes are commonly seen in pediatric practice. Episodic fever of unknown origin (FUO) lasts for a few days or weeks and is followed by a fever-free period with a sense of well-being. In this condition, activated neutrophils and monocytes intensively generate reactive oxidative species that may further damage various mole- cules. The aim of the study was to evaluate oxidative stress biomarkers, lipid peroxidation in erythrocytes and plasma, and advanced oxidation protein products (AOPP) in children with episodic FUO.

Methods: The study enrolled 25 children with episodic FUO in afebrile phase and 25 healthy children as controls. Lipid peroxidation was evaluated by measuring malondialdehyde (MDA) production with the thiobarbituric-acid-reactive sub- stances (TBARS) assay in erythrocytes and plasma. Oxidative modification of proteins was measured spectrophotometri- cally by the determination of AOPP in plasma.

Results: Mean duration of episodic fevers was 3.96±2.8 years. Erythrocyte MDA levels were higher in children with FUO than in controls (86.26± 10.75 vs. 78.0±3.21 nmol/g hemoglobin), although not significantly (p=0.202). The MDA plasma concentrations were similar (2.42±0.35 vs. 2.41 ±0.39 (xmol/L) between the groups (p=0.732). Unexpectedly, levels of AOPP were significantly lower in chil- dren with FUO than in healthy controls (18.8±5.04 vs. 25.1 ±3.35 nmol/L, p=0.047).

Conclusions: Episodic fevers of unknown origin with an aver- age duration of 3.96±2.8 years do not cause significant oxidative modifications of lipids and proteins in children.

Open access

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


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.