Levent Demirtas

Platelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patients.

Neutrophil‐to‐lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in end‐stage renal disease (ESRD) patients. Recently, platelet‐to‐lymphocyte ratio (PLR) and NLR were found to positively correlated with inflammatory markers including tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐6 in cardiac and noncardiac patients. Data regarding PLR and its association with inflammation are lacking in hemodialysis (HD) and peritoneal dialysis (PD) patients. Hence, we aimed to determine the relationship between PLR, NLR, and inflammation in ESRD patients. This was a cross‐sectional study involving 62 ESRD patients (29 females, 33 males; mean age, 49.6 ± 14.6 years) receiving PD or HD for ≥6 months in the Dialysis Unit of Necmettin Erbakan University. PLR, NLR, C‐reactive protein, TNF‐α, IL‐6 levels were measured. PLR, NLR, serum high sensitive C‐reactive protein, IL‐6, and TNF‐α levels were significantly higher in PD patients when compared with HD patients. ESRD patients with PLR ≥ 140 had significantly higher NLR, IL‐6, and TNF‐α levels when compared to patients with PLR < 139. In the bivariate correlation analysis, PLR was positively correlated with NLR, IL‐6, and TNF‐α in this population. When we compared the association of PLR and NLR with IL‐6 (r = 0.371, P = 0.003 vs. r = 0.263, P = 0.04, respectively) and TNF‐α (r = 0.334, P = 0.008 vs. r = 0.273, P = 0.032, respectively), PLR was found to be superior to NLR in terms of inflammation in ESRD patients. Simple calculation of PLR can predict inflammation better than NLR in ESRD patients.

The possible role of interleukin-33 as a new player in the pathogenesis of contrast-induced nephropathy in diabetic rats.

Abstract Introduction: Patients with diabetic kidney disease (DKD) are more prone to contrast-induced nephropathy (CN). Apoptosis and autophagy were found to be essential in the pathogenesis of DKD. Interleukin-33 (IL-33) is a cytokine, but its role in DKD and CN is unknown. As IL-33 is modulated by apoptosis, we aimed to determine the relationship between IL-33 apoptosis and autophagy in DKD with CN. Materials and methods: Thirty male Sprague–Dawley rats were enrolled and randomly allocated into three groups. The first group was comprised of healthy rats (HRs), whereas the other two groups were made up of diabetic rats (DRs) and diabetic rats with CN (DRs + CN). All groups except the HRs received 50 mg/kg/day of streptozotocin (STZ). The DRs + CN group was induced by administering 1.5 mg/kg of intravenous radiocontrast dye on the 35th day. Results: We observed increased IL-33 in the kidney tissue following induction of CN in the DRs. The DRs showed moderate immunopositivity, and the DRs + CN showed severe immunopositivity for caspase-3, cleaved caspase-3, caspase-8, caspase-9, LC3B, and Beclin-1 in tubular cells and glomeruli. The DRs also showed moderate immunopositivity in tubular cells, and the DRs + CN group showed severe immunopositivity for IL-33 in tubular cells. Increased caspase-3 was found in both glomeruli and tubuli; however, we could not demonstrate IL-33 in glomeruli. This could be secondary to inactivation of IL-33 via increased caspase-3 activity. Conclusion: The release of IL-33 from necrotic cells might induce autophagy, which can further balance the effects of increased apoptosis secondary to CN in DKD.

Genotoxic evaluation of two oral antidiabetic agents in the Drosophila wing spot test

In this study, two sulfonylureas—glimepiride and glipizide—commonly used in type 2 diabetes mellitus were investigated for genotoxicity in the Drosophila wing spot test. For this purpose, three-day-old transheterozygous larvae were treated with three mutagenic compounds, and the results obtained were compared with the control group. Mutational or recombinogenic changes were recorded in two recessive genes—multiple wing hairs (mwh) and flare (flr 3). Two recessive markers were located on the left arm of chromosome 3, mwh in map position 0.3, and flare-3 (flr3) at 38.8, while the centromere was located in position 47.7. Wing spot tests are targeted on the loss of heterozygosity, which may be grounded in different genetic mechanisms such as mutation, mitotic recombination, deletion, half-translocation, chromosome loss, or nondisjunction. Genetic changes formatting in somatic cells of the imaginal discs cause nascence different mutant cloning in different body parts of adult flies. Our in vivo experiments demonstrated that glimepiride and glipizide show the genotoxicity, which is especially dependent on homologous somatic recombination.

Total Bilirubin Levels Predict Subclinical Atherosclerosis in Patients With Prediabetes

Bilirubin may have important antiatherosclerotic effects. Prediabetes (PD), the intermediate stage before diabetes mellitus, is associated with increased cardiovascular morbidity and mortality. We evaluated the relationship between serum bilirubin levels and carotid intima–media thickness (cIMT), as a surrogate marker of subclinical atherosclerosis, in patients with PD. We enrolled 170 consecutive patients with PD. The patients underwent ultrasonography to evaluate cIMT. The patients were divided into groups according to cIMT values (<0.9 vs ≥0.9 mm). The patients with cIMT ≥ 0.9 mm had significantly higher diastolic blood pressure, neutrophil–lymphocyte ratio (NLR), and glycated hemoglobin values compared with patients having cIMT < 0.9 mm, whereas total and direct bilirubin values were significantly lower in this group. Multivariate regression analyses revealed NLR and total bilirubin as the independent predictors of subclinical atherosclerosis. The present study demonstrated that NLR and lower total bilirubin levels were independent predictors of subclinical atherosclerosis in patients with PD. Simple measures such as NRL and total bilirubin may provide predictive information regarding the risk of cardiovascular disease in patients with PD.

Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus

The prevalence of diabetes mellitus (DM) is increasing secondary to increased consumption of food and decreased physical activity worldwide. Hyperglycaemia, insulin resistance and hypertrophy of pancreatic beta cells occur in the early phase of diabetes. However, with the progression of diabetes, dysfunction and loss of beta cells occur in both types 1 and 2 DM. Programmed cell death also named apoptosis is found to be associated with diabetes, and apoptosis of beta cells might be the main mechanism of relative insulin deficiency in DM. Autophagic cell death and apoptosis are not entirely distinct programmed cell death mechanisms and share many of the regulator proteins. These processes can occur in both physiologic and pathologic conditions including DM. Besides these two important pathways, endoplasmic reticulum (ER) also acts as a cell sensor to monitor and maintain cellular homeostasis. ER stress has been found to be associated with autophagy and apoptosis. This review was aimed to describe the interactions between apoptosis, autophagy and ER stress pathways in DM.

Neutrophil-to-lymphocyte ratio as a possible indicator of epicardial adipose tissue in patients undergoing hemodialysis

Introduction Chronic inflammation is a major risk factor in the pathogenesis of cardiovascular disease in end-stage renal disease (ESRD) patients. Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between coronary artery disease and EAT was shown in healthy subjects and ESRD patients. In the present study we aimed to investigate the relationship between EAT and inflammation parameters including neutrophil-to-lymphocyte ratio (NLR) in hemodialysis (HD) patients. Material and methods Forty-three HD patients (25 females, 18 males; mean age: 64.1 ±11.9 years) receiving HD and 30 healthy subjects (15 females, 15 males; mean age: 59.1 ±10.8 years) were enrolled in the study. Epicardial adipose tissue measurements were performed by echocardiography. Results Neutrophil-to-lymphocyte ratio levels were significantly higher in HD patients than in the healthy control group. Hemodialysis patients were separated into two groups according to their median value of NLR (group 1, NLR < 3.07 (n = 21) and group 2, NLR ≥ 3.07 (n = 22)). Group 2 patients had significantly higher EAT, C-reactive protein and ferritin levels, while albumin levels were significantly lower in this group. In the bivariate correlation analysis, EAT was positively correlated with NLR (r = 0.600, p < 0.001) and ferritin (r = 0.485, p = 0.001) levels. Conclusions Neutrophil-to-lymphocyte ratio was found to be an independent predictor of EAT in HD patients (odds ratio = 3.178; p = 0.008). We concluded that this relationship might be attributed to increased inflammation in uremic patients.

The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study.

Background/Aims: Fabry disease is a treatable cause of chronic kidney disease (CKD) characterized by a genetic deficiency of α-galactosidase A. European Renal Best Practice (ERBP) recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. Methods: This prospective study assessed α-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. Results: Three (all males) of 313 CKD patients (0.95%) were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. Conclusions: The prevalence of Fabry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin.

Bone Marrow Metaplasia in Multinodular Goiter With Primary Hyperparathyroidism

M ultinodular goiter (MNG) constitutes a mixed group of nodular entities. Structural and functional heterogeneity is the most characteristic feature of MNG and may exhibit degenerative alterations such as hemorrhagic and cystic changes, fibrosis, squamous metaplasia and calcification. Rarely, osseous metaplasia, mature bone formation and bone marrow metaplasia have been reported in thyroid tissue. However, according to our literature search, mature bone formation and bone marrow metaplasia in thyroid tissue with primary hyperparathyroidism (PHPT) have not been reported previously. We report a patient with bone marrow metaplasia in the thyroid tissue and PHPT. A 57-year-old white female patient was admitted to the general surgery department for swelling in the neck (over 5 years) and constipation lasting 3 months. On physical examination, a grade 2 goiter was palpated; there was no other pathology in the physical examination. The patient had a history of hyperparathyroidism (parathyroid hormone: 199; normal range: 11–54 pg/mL) and hypercalcemia (Ca: 11.7; normal range: 8.5–10.5 mg/dL). The common blood count and peripheral blood smear were within the normal ranges. The thyroid stimulating hormone and thyroid hormones were also within the normal ranges. On thyroid ultrasonography, a 21 3 14 mm solid nodule in the left lobe of the thyroid in an inferior location, with a peripheral hypoechoic area, was detected. In the middle of the same lobe, there was a calcified nodule (7 mm in diameter), and near the right thyroid lobe in the posteroinferior area, a 15 3 5-mm hypoechogenic lobulated solid nodule, similar to parathyroid adenoma in the sonographic view, was seen. In parathyroid scintigraphy, minimally focused activity retention in the right inferior lobe of the thyroid was detected, which could be a parathyroid adenoma. Because of a prediagnosis of MNG and parathyroid adenoma, a left thyroidectomy and parathyroid adenoma resection of the right inferior location of the right thyroid lobe, by frozen section, was performed. Based on the results of the frozen section, which were similar to the parathyroid adenoma, the operation was ended. On the 1st postoperative day, the patient had a PTH of 18 and Ca of 9.9. In the macroscopic view, a 4 3 3.5 3 2 cm-sized, 12-g weight, claret red–colored, localized, elastic-hard stiffness thyroid tissue was detected. In the cross-sectional view, a 1.5-cm-diameter claret red nodule and, near it, a 0.8-cm-diameter hard calcified region were seen. After decalcification of the tissue, localized degenerated hyalinizing areas and, near them, hypocellular bone marrow and lamellar bone trabeculae were seen (Figures 1 and 2). This was reported as an MNG consisting of bone marrow metaplasia. The frozen section material included parathyroid tissue of 13 0.53 0.4 cm in size, 0.7 g in weight, encapsulated and pink beige color. Using the light microscope, chief cells that compressed the normal parathyroid tissue were seen and described as an adenoma. There was no complaint from the patient during the postoperative follow-up time. Thyroid nodules are a common occurrence in clinical practice. The incidence of thyroid nodules has been on the rise in recent decades, mainly because of the wider use of imaging instruments. The incidence of nodular goiter in the general adult population is 3% to 5% clinically, about 50% discovered at autopsy, whereas it is nearly 100% in the endemic areas. Clinically, most patients are euthyroid and their clinical importance is primarily to exclude a malignancy. Thyroid nodules may undergo a broad spectrum of degenerative changes, such as infarction, hemorrhage or fibrosis, which are associated with calcification or even ossification. Osseous metaplasia, in contrast to calcification, is a rare event in any organ or tissue, and the detection of mature bone formation in a thyroid nodule is extremely rare. Osseous metaplasia could be seen secondary to ischemia, necrosis or inflammation in the tumor or surrounding tissue. Some studies have shown that bone formation might occur as a result of local or systemic inflammation. Additionally, there are studies reporting that hypercalcemia levels are closely associated with bone formation. PHPT is characterized by the autonomous production of PTH, in which there is hypercalcemia or normal to high serum FIGURE 1. Histopathologic view.

The preventive role of levosimendan against bleomycin-induced pulmonary fibrosis in rats

BACKGROUND In this study, the effects of levosimendan used in the treatment of acute congestive heart failure upon pulmonary fibrosis in rats induced with bleomycin (BL) were analyzed. METHODS A total of 33 male Sprague-Dawley type rats were categorized into five groups randomly. About 2.5U/kg BL was intratracheally administered to the rats in the BL, BL+L1, BL+L2, and BL+L3 groups, and 0.9% saline was intratracheally administered at the same rate to the control group. 0.3, 1, and 3mg/kg levosimendan was intraperitoneally administered to the BL+L1, BL+L2, and BL+L3 groups, respectively. Blood and tissue samples were taken from the rats euthanized to determine the changes in erythrocyte enzyme activities and to conduct histopathological evaluations after 14 days. With values between 0 and 3, histopathological scoring damage was assessed by the presence of inflammation and fibrosis in a semiquantitative manner. RESULTS Compared with those in the C group, glutathione reductase (GR) and Catalase (CAT) enzymes decreased in the BL group; compared with that in the BL group, GR increased in the BL+L1 and BL+L3 groups, 6-phosphogluconate dehydrogenase (6PGD) increased in the BL+L3 group, and CAT increased in the BL+L2 and BL+L3 groups (p<0.05). In the histopathological evaluation, fibrosis occurred in all rats in the BL group, and tissue damage was noticed to be generally less in the BL+L1, BL+L2, and BL+L3 groups (p<0.001). CONCLUSIONS The results obtained from biochemical and histopathological evaluations indicate that levosimendan had an anti-fibrotic effect without a dose-dependent response on pulmonary fibrosis.

Relationship of the total atrial conduction time to subclinical atherosclerosis, inflammation and echocardiographic parameters in patients with type 2 diabetes mellitus

OBJECTIVES: The aim of our study was to evaluate the total atrial conduction time and its relationship to subclinical atherosclerosis, inflammation and echocardiographic parameters in patients with type 2 diabetes mellitus. METHODS: A total of 132 patients with type 2 diabetes mellitus (mean age 54.5±9.6 years; 57.6% male) and 80 age- and gender-matched controls were evaluated. The total atrial conduction time was measured by tissue-Doppler imaging and the carotid intima-media thickness was measured by B-mode ultrasonography. RESULTS: The total atrial conduction time was significantly longer in the patients with type 2 diabetes mellitus than in the control group (131.7±23.6 vs. 113.1±21.3, p<0.001). The patients with type 2 diabetes mellitus had significantly increased carotid intima-media thicknesses, neutrophil to lymphocyte ratios and high-sensitivity C-reactive protein levels than those of the controls. The total atrial conduction time was positively correlated with the high-sensitivity C-reactive protein level, neutrophil to lymphocyte ratio, carotid intima-media thickness and left atrial volume index and negatively correlated with the early diastolic velocity (Em), Em/late diastolic velocity (Am) ratio and global peak left atrial longitudinal strain. A multiple logistic regression analysis demonstrated that the neutrophil to lymphocyte ratio, carotid intima-media thickness and global peak left atrial longitudinal strain were independent predictors of the total atrial conduction time. CONCLUSIONS: We suggest that subclinical atherosclerosis and inflammation may represent a mechanism related to prolonged total atrial conduction time and that prolonged total atrial conduction time and impaired left atrial myocardial deformation may be represent early subclinical cardiac involvement in patients with type 2 diabetes mellitus.