Necat Yilmaz

Serum IL-1β, sIL-2R, IL-6, IL-8 and TNF-α in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment

Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation. The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1beta, soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)-alpha in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy. Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays. According to our results, serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-alpha concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients. The present study demonstrates that plasma levels of IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-alpha may contribute to symptomatology in schizophrenia

High Density Lipoprotein and it's Dysfunction

Plasma high-density lipoprotein cholesterol(HDL-C) levels do not predict functionality and composition of high-density lipoprotein(HDL). Traditionally, keeping levels of low-density lipoprotein cholesterol(LDL-C) down and HDL-C up have been the goal of patients to prevent atherosclerosis that can lead to coronary vascular disease(CVD). People think about the HDL present in their cholesterol test, but not about its functional capability. Up to 65% of cardiovascular death cannot be prevented by putative LDL-C lowering agents. It well explains the strong interest in HDL increasing strategies. However, recent studies have questioned the good in using drugs to increase level of HDL. While raising HDL is a theoretically attractive target, the optimal approach remains uncertain. The attention has turned to the quality, rather than the quantity, of HDL-C. An alternative to elevations in HDL involves strategies to enhance HDL functionality. The situation poses an opportunity for clinical chemists to take the lead in the development and validation of such biomarkers. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport (RCT). The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High antioxidant and anti-inflammatory activities of HDL are associated with protection from CVD. This review addresses the current state of knowledge regarding assays of HDL functions and their relationship to CVD. HDL as a therapeutic target is the new frontier with huge potential for positive public health implications.

Increased Levels of Nitric Oxide, Cortisol and Adrenomedullin in Patients with Chronic Schizophrenia

Objective: To investigate the levels of serum cortisol, dehydroepiandrosterone sulfate (DHEA-S), nitric oxide (NO) and adrenomedullin (AM) in schizophrenic patients. Subjects and Methods: Sixty-six male patients with chronic schizophrenia and 28 normal male subjects participated in this study. The duration of disease was 145 ± 120 (mean ± SD) months. Serum levels of cortisol and DHEA-S were measured by electrochemiluminescence; plasma nitrite levels as an index of NO were measured with the Griess reaction, while plasma AM concentration was measured by using high-performance liquid chromatography. Results: Patients (12.48 ± 3.2 µg/dl), as compared to controls (10.31 ± 3.1 µg/dl), had higher levels of baseline cortisol (p < 0.05). DHEA-S levels were lower in patients though this did not reach statistical significance (302 ± 156 µg/dl compared to control, 322 ± 96 µg/dl, p > 0.05). The mean levels of plasma AM and NO in the schizophrenic group (44.33 ± 5.07 pmol/l and 36.27 ± 17.6 µmol/l) were significantly higher than the levels in the control group (14.56 ± 4.03 pmol/l and 32.54 ± 7.14 µmol/l; p < 0.001, p < 0.03, respectively). There was a positive association between duration of disease and cortisol/DHEA-S ratio and cortisol level. Conclusion: The data show that schizophrenia is associated with abnormal levels of cortisol, DHEA-S, NO and AM.

Angiotensin-converting enzyme gene polymorphism and microvascular complications in Turkish type 2 diabetic patients

The aim of this study was to investigate whether an association exists between the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and microvascular complications of type 2 diabetes mellitus in Turkish patients. A total of 239 type 2 diabetic patients and 138 sex and age matched control subjects were included into the study. The I/D polymorphism was determined by polymerase chain reaction (PCR). Nephropathy status was determined according to urinary albumin/creatinine ratio (microg/mg) (<30 normoalbuminuria, 30-300 microalbuminuria, >300 macroalbuminuria) and retinopathy was evaluated by fundoscopic examination and by flourescein fundus angiography. The distribution of ACE I/D polymorphism and allele frequencies in diabetic patients were not significantly different from controls, DD genotype 32.2 versus 37.2%; ID genotype 50.6 versus 47.1%; and II 17.2 versus 15.2%; D allele 57.5 versus 61.2%; I allele 42.5 versus 38.8%. Genotype distribution between normo-, micro- and macroalbuminuric patients did not differ significantly (DD:ID:II (%), normoalbuminuria, 35:46:19; microalbuminuria, 28:55:17; macroalbuminuria, 31:55:14). There was also no difference in genotype distribution between patients with and without retinopathy (DD:ID:II (%), retinopathy positive, 32:51:17; retinopathy negative, 33:49:18). In conclusion, the ACE I/D polymorphism does not seem to be associated with diabetic nephropathy and retinopathy in Turkish type 2 diabetic patients.

Functionally Defective High-Density Lipoprotein and Paraoxonase: A Couple for Endothelial Dysfunction in Atherosclerosis

The endothelium is the primary target for biochemical or mechanical injuries caused by the putative risk factors of atherosclerosis. Endothelial dysfunction represents the ultimate link between atherosclerotic risk factors that promote atherosclerosis. HDL-C is thought to exert at least some parts of its antiatherogenic facilities via stimulating endothelial NO production, nearby inhibiting oxidative stress and inflammation. HDL-C is capable of opposing LDLs inductive effects and avoiding the ox-LDLs inhibition of eNOS. Paraoxonase 1 (PON1) is an HDL-associated enzyme esterase which appears to contribute to the antioxidant and antiatherosclerotic capabilities of HDL-C. “Healthy HDL,” namely the particle that contains the active Paraoxonase 1, has the power to suppress the formation of oxidized lipids. “Dysfunctional HDL,” on the contrary, has reduced Paraoxonase 1 enzyme activity and not only fails in its mission but also potentially leads to greater formation of oxidized lipids/lipoproteins to cause endothelial dysfunction. The association of HDL-C PON1 and endothelial dysfunction depends largely on the molecules with exact damaging effect on NO synthase coupling. Loss of nitric oxide bioavailability has a pivotal role in endothelial dysfunction preceding the appearance of atherosclerosis. Analyses of HDL-C and Paraoxonase1 would be more important in the diagnosis and treatment of atherosclerosis in the very near future.

Homocysteine oxidative stress and relation to bone mineral density in post-menopausal osteoporosis

Background and aims: Mildly elevated homocysteine (Hcy) and oxidative stress are novel and potentially modifiable risk factors for post-menopausal osteoporosis. We hypothesized that imbalance of oxidant/antioxidant status and increased Hcy concentration stimulates osteoporotic activity, leading to increased collagen I breakdown in post-menopausal women. Methods: Patients were divided into 2 groups (NOP and OP). Group NOP had normal bone mineral density (BMD) and group OP low BMD. Thirty-four (69%) were in group OP and 15 (31%) in group NOP. Serum Total Antioxidant Status (TAS) and Total Peroxide (TPx) levels were determined with new automated methods. The study included measurement of Deoxypyridinoline (DPD). Results: In OP patients plasma t-Hcy, urine deoxypyridinoline and plasma TPx were significantly higher than those in NOP controls. In addition, OP patients also had lower TAS levels than controls, which represent the oxidative imbalance. Pearson’s correlation analysis revealed a negative correlation between t-Hcy and TAS (p<0.038). A significant negative correlation was also found between TAS level and BMD values for the spine in OP patients (p<0.035). In contrast, a positive correlation between t-Hcy and TPx in OP patients was demonstrated significantly, r=0.52, p<0.029. Conclusions: We show that the OP group had reduced TAS, whereas the elevated TPx was different from that in the NOP group. Slightly elevated homocysteinemia may contribute to increasing TPx and reducing TAS in the OP group. However, our results suggest a weak but negative relationship between TAS and BMD. Further investigations are needed to examine the relationship of oxidative stress as an endogenous bioactive agent to bone loss in post-menopausal women. Since oxidative stress is the imbalance between total oxidants and antioxidants in the body, any single oxidant/antioxidant parameter may not reflect overall oxidative stress. Further studies are needed to understand the underlying mechanisms of these findings.

Biochemical markers of bone turnover and bone mineral density in patients with β‐thalassaemia major

In this study, bone formation markers (bone‐specific alkaline phosphatase and osteocalcin) and bone resorption markers (pyridinoline and deoxypyridinoline) were analysed. Bone formation, as evidenced by the levels of serum alkaline phosphatase and osteocalcin, did not appear to be impaired, while bone resorption was grossly increased in all patient groups. The decrease of bone mineral density values was more prominent in the lumbar spine, thus making this site particularly interesting for such studies. The patients had significantly lower femoral neck and lumbar spine bone mineral density when compared with control (all p < 0.001). Our conclusion is that, in spite of the severe bone destruction that occurs in thalassaemia major, the fact that bone formation remains intact calls for a more intensive treatment.

Increased levels of total oxidant status and decreased activity of arylesterase in migraineurs.

OBJECTIVES There is strong evidence associating migraine with a variety of comorbid disorders, including cardiovascular disease and stroke, in which oxidative stress seems to be an important underlying mechanism. The aim of the study was to investigate in migraineurs the body oxidant/antioxidant balance and paraoxonase enzyme activities as a measure of HDL functionality. DESIGN AND METHODS Oxidative stress index, total oxidant status and antioxidant status were examined in addition to the paraoxonase and arylesterase enzyme activities in sixty-two migraineurs and fifty healthy control subjects. RESULTS Serum arylesterase activities were significantly lower in migraineurs (p=0.0065), whereas total oxidant status was higher in patients compared to the controls (p=0.0035). CONCLUSIONS This preliminary study showed that oxidative/antioxidative balance shifted towards the oxidative status in migraine. Moreover, the results also suggested that decreased arylesterase activities might be associated with HDL-related disfunction.

Evaluation of circulating betatrophin levels in gestational diabetes mellitus

Abstract Experimental data indicate that betatrophin plays a significant role in the regulation of lipid metabolism and glucose homeostasis. In recent years, considerable attention has focused on the relationship between betatrophin and diabetes mellitus in humans. This case-control study included 45 women diagnosed with gestational diabetes mellitus (GDM) and 45 pregnant healthy controls. The groups were matched for maternal and gestational age and body mass index. Serum betatrophin levels were significantly higher in women with GDM (median = 635.8 ng/L; range: 290–1841.6 ng/L) compared to control subjects (median = 320.1 ng/L; range: 94.6–936.8 ng/L; p = 0.001). No significant correlations were observed between serum betatrophin levels and clinical or biochemical parameters in the control group. However, in the GDM group, serum betatrophin levels were positively correlated with weight gain during pregnancy (r = 0.304, p = 0.042), systolic blood pressure (r = 0.394, p = 0.007), fasting insulin level (r = 0.348, p = 0.019), and homeostatic model assessment insulin resistance (HOMA-IR; r = 0.311, p = 0.038). Multivariate stepwise linear regression analysis revealed that fasting insulin levels (β = 0.342, p = 0.022) and HOMA-IR (β = 0.312, p = 0.037) were independently associated with serum betatrophin levels. Chinese abstract 实验数据表明，促胰岛生成素在脂质的代谢及糖类的稳态的调节方面起很重要的作用。近年来大量的注意力集中在促胰岛生成素和人类糖尿病的关系上。本病例对照研究包括45例诊断为妊娠期糖尿病的孕妇，以45例健康的孕妇作为对照组。以孕妇、胎龄、体重指数作为匹配项目。妊娠期糖尿病组(中位数=635.8ng/L；范围: 290–1841.6 ng/L)的血清促胰岛生成素水平显著高于对照组(中位数=320.1 ng/L；范围: 94.6–936.8 ng/L; p=0.001)。对照组的血清促胰岛生成素水平和临床、生物化学参数并没有发现有明显相关性。然而，妊娠期糖尿病组血清促胰岛生成素水平和妊娠期间体重增长(r=0.304, p=0.042)、收缩压(r=0.394, p=0.007)、空腹血糖(r=0.348, p=0.019)、与胰岛素抵抗相关的稳态模型(HOMA-IR;r=0.311, p=0.038)均有明显相关性。多元线性回归分析显示空腹血糖(β=0.342, p=0.022)及HOMA-IR (β =0.312, p=0.037)均与血清促胰岛生成素水平有独立相关性。

Heart valve disease: The role of calcidiol deficiency, elevated parathyroid hormone levels and oxidative stress in mitral and aortic valve insufficiency

Abstract Objectives Endothelia, intima, and connective tissues comprise the heart valves, but the relationship between heart valve damage, the pathogenesis of valve degeneration, and vitamin D, oxidative stress remains unclear. Here, we assessed serum 25(OH) vitamin D (calcidiol), parathormone (PTH), and redox balance in patients with mitral valve regurgitation (MR) and aortic valve regurgitation (AR). Methods This study includes 56 chronic heart valve disease (HVD) patients. Patients were diagnosed with MR or AR depending on the echocardiographic findings. Also, 40 sex-matched healthy control participants were enrolled for comparison. Serum calcidiol, PTH, total oxidative status (TOS), and total antioxidative capacity were measured, and the oxidative stress index (OSI) was calculated. Results Patients with HVD demonstrated significantly higher PTH, increased TOS and OSI, and a higher frequency of calcidiol deficiency than the control participants. Calcidiol and TOS were negatively correlated (r = −0.29; P <0.005), as were calcidiol and OSI (r = −0.413; P = 0.001). PTH and OSI were positively correlated (r = 0.22; P = 0.02). Discussion We demonstrate that vitamin D deficiency and secondary increases in PTH are highly prevalent. Heart valve regurgitation (AR and MR) is correlated to oxidative stress and hypovitaminosis D.