Fezan Mutlu

The association of MMP-9 enzyme activity, MMP-9 C1562T polymorphism, and MMP-2 and -9 and TIMP-1, -2, -3, and -4 gene expression in lung cancer.

AIM To investigate the association of gene expression of MMP-2 and -9, and TIMP-1, -2, -3, and -4 and polymorphism frequencies of MMP-9 C1562T and plasma MMP-9 enzyme activity in lung cancer patients. METHODS In this study, DNA and RNA samples were extracted from peripheral blood of 300 subjects (200 lung cancer patients and 100 controls). MMP-9 C1562T polymorphism was determined using restriction fragment length polymorphism (RFLP) method, and expression of MMP-2 and -9, TIMP-1, -2, -3, and -4 was determined using reverse transcriptase polymerase chain reaction. Plasma MMP-9 enzyme activity levels were measured using enzyme-linked immunosorbent assay. RESULTS AND CONCLUSION The frequencies of C1562T genotypes were found to be CC 67%, CT 30%, and TT 3% in the control group and CC 75%, CT 24%, and TT 1% in the patient group. It was determined that CC genotype frequency increases significantly in patients according to control group. Plasma MMP-9 enzyme activity levels increased in patients with lung cancer compared to the control group. The cut-off value of MMP-9 enzyme activity was determined as 7.76 ng/mL by receiver operating characteristics curve analysis. The sensitivity, specificity, positive predictive value, and negative predictive value were 77%, 51%, 75.9%, and 52.6%, respectively. The expression of MMP-2 and TIMP-1 was found to be higher in lung cancer patients. Finally, we claim that determination of MMP-9 enzyme levels and expression of MMP-2 and -9 and TIMP-1 can be used as a marker in lung cancer.

Ivabradine treatment prevents dobutamine-induced increase in heart rate in patients with acute decompensated heart failure.

Background Ivabradine is a heart rate (HR)-lowering agent acting by inhibiting the If-channel. Dobutamine does increase the HR and has some deleterious effects on myocardium. So, we aimed to evaluate whether ivabradine treatment blunts a dobutamine-induced increase in HR. Methods The main study population consisted of 58 acute decompensated heart failure patients requiring inotropic support with left-ventricular ejection fraction below 35%, who were randomized to ivabradine (n = 29) or control (n = 29). All patients underwent Holter recording for 6 h and then dobutamine was administered at incremental doses of 5, 10 and 15 &mgr;g/kg/min, with 6-h steps. Holter recording was continued during dobutamine infusion. Ivabradine 7.5 mg was given at the initiation of dobutamine and readministered at 12 h of infusion. Also, a nonrandomized beta-blocker group with 15 patients receiving beta-blocker was included in the analysis. Control and beta-blocker groups did not receive ivabradine. Results In the control group, mean HR gradually and significantly increased at each step of dobutamine infusion (81 ± 11, 90 ± 16, 97 ± 14 and 101 ± 16 b.p.m., respectively; P = 0.001), whereas no significant increase in HR was observed in the ivabradine group (82 ± 17, 82 ± 15, 85 ± 14 and 83 ± 12 b.p.m., respectively; P = 0.439). Mean HR was also found to significantly increase during dobutamine infusion in the beta-blocker group (75 ± 13, 82 ± 13, 86 ± 14 and 88 ± 13 b.p.m., respectively; P = 0.001). The median increase in HR from baseline was significantly higher in the control group compared to those in the ivabradine group (5 vs. 2 b.p.m.; P = 0.007 at first step, 13 vs. 5 b.p.m.; P = 0.001 at second step and 18 vs. 6 b.p.m.; P = 0.0001 at third step of dobutamine, respectively). Conclusions Ivabradine treatment prevents dobutamine-induced increase in HR and may be useful in reducing HR-related adverse effects of dobutamine.

Evaluation of Labral Pathology and Hip Articular Cartilage in Patients with Femoroacetabular Impingement (FAI): Comparison of Multidetector CT Arthrography and MR Arthrography.

Summary Background To compare the multidetector computed tomography (MDCT) arthrography (CTa) and magnetic resonance (MR) arthrography (MRa) findings with surgical findings in patients with femoroacetabular impingement (FAI) and to evaluate the diagnostic performance of these methods. Material/Methods Labral pathology and articular cartilage were prospectively evaluated with MRa and CTa in 14 hips of 14 patients. The findings were evaluated by two musculoskeletal radiologists with 10 and 20 years of experience, respectively. Sensitivity, specificity, accuracy, and positive predictive value were determined using surgical findings as the standard of reference. Results While the disagreement between observers was recorded in two cases of labral tearing with MRa, there was a complete consensus with CTa. Disagreement between observers was found in four cases of femoral cartilage loss with both MRa and CTa. Disagreement was also recorded in only one case of acetabular cartilage loss with both methods. The percent sensitivity, specificity, and accuracy for correctly assessing the labral tearing were as follows for MRa/CTa, respectively: 100/100, 50/100, 86/100 (p<0.05). The same values for acetabular cartilage assessment were 89/56, 40/60, 71/71 (p>0.05) and for femoral cartilage assessment were 100/75, 90/70, 86/71 (p>0.05). Inter-observer reliability value showed excellent agreement for labral tearing with CTa (κ=1.0). Inter-observer agreement was substantial to excellent with regard to acetabular cartilage assessment with MRa and CTa (κ=0.76 for MRa and κ=0.86 for CTa) Conclusions Inter-observer reliability with CTa is excellent for labral tearing assessment. CTa seems to have an equal sensitivity and a higher specificity than MRa for the detection of labral pathology. MRa is better, but not statistically significantly, in demonstrating acetabular and femoral cartilage pathology.

Comparison of Semiparametric, Parametric, and Nonparametric ROC Analysis for Continuous Diagnostic Tests Using a Simulation Study and Acute Coronary Syndrome Data

We aimed to compare the performance of three different individual ROC methods (one from each of the broad categories of parametric, nonparametric and semiparametric analysis) for assessing continuous diagnostic tests: the binormal method as a parametric method, an empirical approach as a nonparametric method, and a semiparametric method using generalized linear models (GLM). We performed a simulation study with various sample sizes under normal, skewed, and monotone distributions. In the simulations, we used estimates of the ROC curve parameters a and b, estimates of the area under the curve (AUC), the standard errors and root mean square errors (RMSEs) of these estimates, and the 95% AUC confidence intervals for comparison. The three methodologies were also applied to an acute coronary syndrome dataset in which serum myoglobin levels were used as a biomarker for detecting acute coronary syndrome. The simulation and application studies suggest that the semiparametric ROC analysis using GLM is a reliable method when the distributions of the diagnostic test results are skewed and that it provides a smooth ROC curve for obtaining a unique cutoff value. A sample size of 50 is sufficient for applying the semiparametric ROC method.

BCL2, BCL6, IGH, TP53, and MYC protein expression and gene rearrangements as prognostic markers in diffuse large B-cell lymphoma: a study of 44 Turkish patients.

The purpose of this study was to determine the frequency of BCL2, BCL6, IGH, TP53, and MYC protein expression and rearrangements of the respective genes in diffuse large B-cell lymphoma (DLBCL) patients and to assess their prognostic values. Samples from 44 patients with DLBCL were evaluated using fluorescence in situ hybridization and immunohistochemical analyses. BCL6 was the most rearranged gene (63.6%), followed by MYC (31.8%), TP53 (22.7%), and BCL2 (18.2%). Multiple rearrangements were detected in 40.9% of the cases. BCL6 was the most expressed protein (78.6%), followed by TP53 (69.04%), BCL2 (59.5%) and MYC (14.3%). Expression of multiple proteins was detected in 67.4% of the cases. BCL2 (P = .003) expression had a significant negative influence on overall survival,whereas BCL6 (P = .014) expression had a significant positive influence. Our results with a different pattern of gene rearrangements and associated protein overexpression indicate the molecular genetic complexity of DLBCLs, which reflects the morphologic, biologic, and clinical heterogeneity of these lymphomas.

Cardiovascular involvement in patients with pseudoexfoliation syndrome.

Aim Pseudoexfoliation (PEX) syndrome, diagnosed by ocular examination, is a common disorder of the extracellular matrix. Previous studies have demonstrated accumulation of PEX material in the walls of blood vessels and myocardium. We aimed to investigate whether PEX is associated with cardiovascular involvement using carotid ultrasound measurements and myocardial tissue Doppler imaging (TDI). Methods Thirty-six PEX patients and 34 age-matched and sex-matched healthy controls who had no PEX material were included. Fasting blood samples were taken and the following data were obtained from all cases: myocardial TDI measurements, the mean carotid intima-media thickness (IMT), total carotid plaque area and number. Results There were no significant differences between the groups regarding clinical and biochemical data. The peak systolic TDI velocities at the septal (septal S) and lateral annuli (lateral S), and the isovolumic contraction velocity at the lateral annulus [lateral isovolumic contraction velocity (IVC)] were significantly lower in patients with PEX, than in controls (P = 0.001, <0.001 and 0.016, respectively) whereas IMT, total carotid plaque area and number were significantly higher (P = 0.002, 0.035 and 0.033, respectively). In a logistic regression analysis including age, septal S, lateral S, lateral IVC, IMT, total carotid plaque area and number, septal S, lateral S and IMT were significantly associated with PEX, (P = 0.035, 0.011 and 0.035, respectively). Conclusion Peak systolic TDI velocities were significantly lower and IMT was significantly increased in patients with PEX. However, PEX was weakly associated with carotid plaque measurements.

Dopamine D2 receptor gene −141C Insertion/Deletion polymorphism in Turkish schizophrenic patients

Schizophrenia is a chronic and neuropsychiatric disease that affects about 0.5–1% of the world’s population. An increase in dopamine and dopamine D2 receptor (DRD2) gene products has been well described in schizophrenic patients. Several groups have studied the relationship between dopaminergic hyperactivity and cellular communications have obtained discordant results. Studies searching for the relationship between the schizophrenia and DRD2 gene have gained more interest. Our objective was to determine the relationships among schizophrenic symptoms in schizophrenia subtypes and severity of symptoms in terms of DRD2 gene −141C Insertion/Deletion [Ins/Del; I/D] polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) assay method. Genomic DNA was prepared from peripheral blood by using salt extraction method. After amplification of genomic DNA, PCR products were digested with BstNI restriction enzyme for the detection of DRD2 gene −141C Ins/Del polymorphism in 73 schizophrenic patients and 60 healthy control subjects. The allelic frequencies of the DRD2 gene −141C Ins/Del polymorphism in case and control groups were 79.5 and 77.5% for I allele; 20.5 and 22.5% for D allele respectively. There was no significant difference in frequencies of genotypes and alleles between the two groups. In schizophrenic and control subjects, there were no significant relationship in severity of the disease and schizophrenia types among the −141C Ins/Del genotypes and alleles.

Effect of Iron Therapy on Platelet Function among Iron-Deficient Women with Unexplained Menorrhagia.

This study was performed to evaluate the effect of iron therapy on platelet function among women with unexplained menorrhagia in order to better understand possible interactions between iron deficiency anemia and platelet behavior and menorrhagia. Platelet aggregation and adenosine triphosphate (ATP) release induced by 5.0 mM adenosine diphosphate (ADP), 0.5 mM arachidonic acid (AA), 1.0 mg/ml ristocetin and 2 μg/ml collagen were studied by whole-blood platelet lumi-aggregometer in 50 menorrhagic women before and after oral iron therapy and in 22 women of the control group. There was a significant increase in AA- induced platelet aggregation (p < 0.05) and a decrease in ristocetin-induced platelet aggregation (p < 0.01) after treatment. Pre- and posttreatment platelet aggregation responses to ADP and collagen were not significantly different (p > 0.05). Pre- and posttreatment platelet secretion responses to all agonists disclosed no significant difference (p > 0.05). There was no significant difference between the study group after treatment and the control group in respect to platelet aggregation and ATP secretion values induced by all agonists (p > 0.05). We conclude that iron deficiency anemia in women causes AA-induced platelet dysfunction, which may give rise to increased menstrual blood loss and can be reversed by iron repletion.

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

BACKGROUND Indirect evidences suggest that the If blocker ivabradine may exert an antiarrhythmic effect in ventricular myocardium in heart failure (HF) patients by inhibiting spontaneous depolarisations, but the clinical relevance of this mechanism is not known. Dobutamine (DOB) has been known to increase heart rate and the incidence of cardiac arrhythmias. AIM In this study, we evaluated the effects of ivabradine on DOB-induced ventricular arrhythmias and compared them with those of beta-blocker (BB) therapy. METHODS Patients with decompensated HF requiring inotropic support, left ventricular ejection fraction < 35%, and in sinus rhythm were included in the study (ivabradine group - 29 patients, control group - 29 patients, BB group - 15 patients). All patients underwent Holter recording for 6 h before the initiation of DOB infusion. Following baseline recording, DOB was administered at incremental doses of 5, 10, and 15 μg/kg/min, with 6-h steps. Holter monitoring was continued during 18 h of DOB infusion and analysed for the median number of ventricular premature contractions (VPC), ventricular couplets, episodes of non-sustained ventricular tachycardia, and total ventricular arrhythmias in each step of the study protocol. RESULTS The positive chronotropic effect of incremental DOB doses was blunted by beta-blockade and was totally abolished by ivabradine. The median number of VPCs, ventricular couplets, and total ventricular arrhythmias significantly increased with incremental doses of DOB in the control group (p = 0.018) and, to a lesser extent, in the ivabradine group (p = 0.015). In the BB group the absolute VPCs numbers were smaller than in the control or the ivabradine group, with the on-ivabradine VPCs numbers falling between those seen in control and BB groups. A numeric increase in VPCs with incremental DOB doses occurred in the BB group but did not reach statistical significance (p > 0.05), consistent with a protective effect of beta-blockade. Ivabradine reduced VPCs by 43% at 5 μg/kg/min DOB and by 38% at 10 μg/kg/min DOB against the control group (VPCs median 256 vs. 147 and 251 vs. 158) in the absence of significant differences at 15 μg/kg/min DOB between the control and ivabradine groups (overall p > 0.05). Thus, ivabradine administered without background beta-blockade attenuated the arrhythmogenic effect of increasing doses of DOB in the low and moderate DOB dose but not in the high DOB dose. CONCLUSIONS In patients with decompensated HF, ivabradine appears to reduce the incidence of VPCs in response to low and medium DOB dose. Whether the anti-arrhythmic effect of ivabradine is additive to the anti-arrhythmic effect of beta-blockade requires further investigation; this should also determine the clinical significance of ventricular arrhythmia attenuation with ivabradine.

Plasminogen activator inhibitor type-1 gene 4G/5G polymorphism and polycystic ovary syndrome.

AIM This study was conducted in Turkish patients with polycystic ovary syndrome (PCOS) to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene and to examine the role of this polymorphism in PCOS development. MATERIALS AND METHODS Genomic DNA obtained from 200 persons (100 patients with PCOS and 100 healthy controls) was used in the study. DNA was amplified by polymerase chain reaction using 4G and 5G allele-specific primers. Polymerase chain reaction products were assessed with charged-couple device camera after exposing to 2% agarose gel electrophoresis. RESULTS No statistically significant difference between the groups with respect to genotype distribution was found (p>0.05) in the study. The 4G and 5G allele frequencies were indicated as 51.5% and 48.5% in patients, respectively, whereas this was 51%-49% in the control group. CONCLUSION Consequently, it has been established by this study that the 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene do not play a role in the development of PCOS in the Turkish population.