Guldal Yilmaz

Sevoflurane and isoflurane preconditioning provides neuroprotection by inhibition of apoptosis-related mRNA expression in a rat model of focal cerebral ischemia.

Background: This study aimed to examine the effects of sevoflurane or isoflurane preconditioning on cerebral ischemia/reperfusion–induced inflammation, oxidative stress, and lipid peroxidation and test the hypothesis that the underlining mechanism of the protective effect of preconditioning involves changes in the apoptotic gene expression profiles in an experimental model of middle cerebral artery occlusion in rats. Methods: Twenty-four adult male rats were randomly divided into 3 groups: control (n=8), sevoflurane (n=8), and isoflurane (n=8). For preconditioning, these 3 groups were exposed to 40% O2, 2% sevoflurane, and 1.5% isoflurane, respectively, for 60 minutes, followed immediately by 1 hour of middle cerebral artery occlusion and then 6 hours of reperfusion. Blood and brain tissue samples were collected for determination of blood gas tension, tumor necrosis factor-&agr;, interleukin-6, and interleukin-1&bgr;. Brain tissue samples were collected for determination of the wet/dry ratio, myeloperoxidase, malondialdehyde, and total RNA and also for histologic examinations. Results: Tumor necrosis factor-&agr;, interleukin-1&bgr;, and myeloperoxidase levels decreased and antioxidant enzyme levels increased in the sevoflurane group compared with the control and isoflurane groups. Proapoptotic genes (Tnf, Tnfrsf10b, and Tp53) downregulated and antiapoptotic genes (Aven, Bcl2, Bcl2l2, and Prok2) upregulated with sevoflurane treatment compared with the isoflurane and control groups. Both isoflurane and sevoflurane pretreatment decreased malondialdehyde, Dffb, the wet/dry ratio, and injury score and upregulated Bax and Apaf 1 compared with the control group. Conclusions: Sevoflurane and isoflurane preconditioning ameliorates inflammation, cerebral lipid peroxidation, and histologic injury. Downregulation of proapoptotic molecules and upregulation of antiapoptotic molecules may be associated with this effect.

Is increased red cell distribution width an indicating marker of nonalcoholic steatohepatitis and fibrotic stage

AIM To evaluate the red cell distribution width (RDW) as an indicator of the presence of non-alcoholic steatohepatitis (NASH) and its association with fibrotic scores. METHODS A retrospective study was carried out that included sixty-two biopsy proven NASH, 32 simple steatosis patients and 30 healthy controls. The correlation between the clinical and histopathological features of NASH patients and RDW values was evaluated. Liver fibrosis scores were measured using a 0 to 4 point scale and were divided in to two groups; fibrosis scores 0-1 were termed mild and fibrosis scores 2-4 were termed advanced fibrosis. RDW values were compared between NASH, simple steatosis and healthy controls. Univariate and multivariate analyses were performed to evaluate the independent predicting factors for the presence of liver fibrosis caused by NASH. RESULTS Patients with NASH had higher RDW values compared with simple steatosis and healthy control groups [14.28% ± 0.25% vs 13.37% ± 0.12%, 12.96% ± 0.14% (P < 0.01), respectively]. Patients with advanced fibrosis had higher RDW values than the mild fibrosis group (15.86% ± 0.4% vs 13.63% ± 0.67%, P < 0.01, respectively). RDW also correlated with fibrotic scores (r = 0.579 and P < 0.01). The variables that were significant in the univariate analysis were evaluated in multivariate logistic regression analysis, and RDW was an independent predicting factor of NASH (OR = 1.75, 95%CI: 1.129-2.711, P < 0.05). CONCLUSION RDW a new non-invasive marker that can be used to demonstrate the presence of NASH and indicate advanced fibrotic scores.

Spheroid formation and invasion capacity are differentially influenced by co-cultures of fibroblast and macrophage cells in breast cancer

Interactions with stromal components influence the growth, survival, spread, and colonization capacities of tumor cells. Fibroblasts and macrophages which are responsible for the stroma production and maintenance are of the basic elements found in tumor microenvironment. Cellular density and ratio of stromal cells to tumor cells can also have modulatory effects in cancer. Here, the contribution of fibroblast and/or macrophage cells on the malignant behavior of breast cancer cells was modeled in co-culture systems. Co-cultures were established at different cell densities and ratios with 4T1 breast cancer, NIH/3T3 or 3T3-L1 fibroblast, and J774A.1 monocyte/macrophage cell lines. Flow cytometry-based proliferation, 3D growth on alginate matrix, and matrigel invasion assays were performed to determine the change in the malignant assets of tumor cells. The data were also supported by immunocytochemical and morphological analyses. Co-culturing with fibroblasts (especially, NIH/3T3 cells) significantly supported the proliferation, scattering, and invasiveness of 4T1 cells whereas inclusion of macrophages disrupted this positive influence. On the other hand, the invasion capacity of 4T1 cells was not enhanced in the co-cultures with fibroblasts whose motility were inhibited with pertussis toxin pretreatment. Particularly at low-density seeding in 3D cultures, 4T1 cells could form substantially more spheroids than that of in the co-cultures with fibroblasts. Only, increasing the amount of fibroblasts could restore the 3D-growth. Intriguingly, co-existence of macrophage, fibroblast, and tumor cells in 3D cultures provided a convenient stroma sustaining the spheroid formation and growth. In conclusion, fibroblasts can form a favorable environment for tumor cells’ spread and motility whereas restricting their 3D-growth capacity. On the other hand, presence of macrophages may disrupt the influence of fibroblasts and enhance the spheroid formation by the tumor cells.

Diagnostic potential of serum direct markers and non-invasive fibrosis models in patients with chronic hepatitis B

Aim:  Liver biopsy is recommended in the majority of patients with chronic viral hepatitis for fibrosis evaluation. Because of the disadvantages of liver biopsy, many studies related to non‐invasive biomarkers and scores have been performed. In this study, we aimed to assess the diagnostic value of serum direct markers and non‐invasive fibrosis models to predict liver fibrosis in the treatment‐naive chronic hepatitis B (CHB) patients and to compare their diagnostic performance.

Effects of Sitagliptin on Nonalcoholic Fatty Liver Disease in Diet-Induced Obese Rats

BACKGROUND Studies investigating the effects of dipeptidyl peptidase-4 inhibitors on hepatic steatosis are lacking. We aimed to determine the effects of sitagliptin on nonalcoholic fatty liver disease (NAFLD) in rats with diet-induced obesity. METHODS A total of 24 adult female Sprague-Dawley rats, which were 24 weeks old and weighed 199-240 grams, were used. The rats were randomly separated into two groups. The control group (n=6) was fed with standard rat diet; the remaining rats (n=18) were fed with a high-fat diet (HFD) to induce NAFLD. After 12 weeks, rats that were fed with a HFD were randomly separated into two groups: (1) HFD-only group (n=8) was fed with a HFD for an additional 4 weeks, (2) HFD-sitagliptin group (n=10) received sitagliptin (3 mg/kg) for 4 weeks in addition to HFD. At the end of the study (16(th) week), blood samples were drawn from all rats to determine serum glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), and plasma insulin levels. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. Histopathologic evaluation of liver samples was undertaken. RESULTS The HFD-sitagliptin group had significantly lower serum glucose (140.8±18.8 vs. 224.7±20.6 mg/dL, P<0.001), plasma insulin (15.8±4.4 vs. 28.0±5.9 μIU/L, P<0.001), HOMA-IR index (4.9±1.8 vs. 15.9±2.3, P<0.001), serum triglycerides (199.0±108.7 vs. 468.0±370.7 mg/dL, P<0.001), and cholesterol (82.0±26.7 vs. 90.5±7.0, P<0.001) values compared to the HFD-only group. Hepatic steatosis was significantly less (mean score, 1 vs. 2; P<0.001) in the HFD-sitagliptin group compared to the HFD-only group, whereas there was no difference in hepatic inflammation (P=0.057), liver weight (P=0.068), and ALT levels (P=0.232). CONCLUSION Sitagliptin may improve hepatic steatosis by increasing insulin sensitivity and improving lipid profiles in rats.

Visceral Leishmaniasis Mimicking Autoimmune Hepatitis, Primary Biliary Cirrhosis, and Systemic Lupus Erythematosus Overlap

Visceral leishmaniasis (VL) is a life-threatening infection caused by Leishmania species. In addition to typical clinical findings as fever, hepatosplenomegaly, and cachexia, VL is associated with autoimmune phenomena. To date, VL mimicking or exacerbating various autoimmune diseases have been described, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and autoimmune hepatitis (AIH). Herein, we presented a patient with VL who had overlapping clinical features with SLE, AIH, as well as antimitochondrial antibody (AMA-M2) positive primary biliary cirrhosis.

The relationship between advanced oxidation protein products (AOPP) and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis

To investigate the correlation between advanced oxidation protein products (AOPP) levels and biochemical and histopathological findings in patients with nonalcoholic steatohepatitis (NASH).

CXCL7-induced macrophage infiltration in lung tumor is independent of CXCR2 expression: CXCL7-induced macrophage chemotaxis in LLC tumors

Chemokines play diverse roles in modulating the immune response during tumor development. Levels of CXC chemokine ligand 7 (CXCL7) protein vary during tumorigenesis, and the evidence suggests that this chemokine serves as a novel biomarker of early-stage lung cancer. We investigated the effect of CXCL7 gene expression on the infiltration of myeloid cells into the tumor microenvironment in Lewis lung carcinoma (LLC). Tumors established from LLC cells overexpressing CXCL7 (CXCL7-LLC tumors) increased the infiltration of CD206(+) M2 macrophages at the early stages of tumorigenesis. This infiltration was independent of CXCR2 expression on either tumor cells or macrophages. CXCL7-LLC tumors developed faster than control-LLC tumors (IRES-LLC tumor) did. The extent of CD4(+) T cell, CD8(+) T cell, and natural killer T cell infiltration was similar between the two tumor groups. Our findings suggest that CXCL7 attracts macrophages especially at the tumor site and may accelerate lung tumor development in the early stages.

Investigation of diagnostic utility and expression profiles of stem cell markers (CD133 and CD90) in hepatocellular carcinoma, small cell dysplasia, and cirrhosis

The aim of this study was to investigate the expression rates of CD133 and CD90 in cirrhosis-dysplastic nodule-HCC (Crh-DN-HCC) sequence related to the etiologic background. Thirty-five HCC, 8 small cell dysplasia (SCD), and 63 cases of cirrhosis having different etiologies were collected. Immunohistochemical expressions of CD133 and CD90 were evaluated. CD133 positivity was higher in HCC cases with chronic hepatitis B and CD90 with chronic hepatitis C. The highest staining rate was seen in poorly differentiated HCC cases. Only one SCD case and almost half of the cirrhotic cases which were stained for CD133 were associated with hepatitis B; none was stained for CD90. Increased CD133 expression indicated a significantly shorter overall survival rate. No significant relationship was detected between the expression rates of CD133 or CD90 and other parameters. In this study, which investigates the immunohistochemical expression profiles of CD133 and CD90 through Crh-DN-HCC sequence, the highest staining rate was detected in HCC. It is rational to try to elucidate the earliest events in hepatocarcinogenesis by studying SCD. It is important to be aware of this issue in daily practice, which will provide a deeper insight into the understanding of the effects of CSCs in the progression and management of HCC.

Hepatoportal Sclerosis in Childhood: Some Presenting With Cholestatic Features (A Re-evaluation of 12 Children)

Hepatoportal sclerosis (HPS) is a syndrome of obscure etiology, and is one of the causes of noncirrhotic portal hypertension (PH). We aimed to investigate this heterogeneous group of patients whose presentation showed cholestatic features, histopathologically. Between 1999 and 2009, 12 children diagnosed with HPS were retrospectively evaluated. HPS was diagnosed with evidence of PH, noncirrhotic liver biopsy with typical histopathologic findings, and exclusion of other possible causes of PH. The data was obtained from pathology reports and microscopic slides. In histopathological re-evaluation fibrosis state, aberrant portal vessels, portal tract dilation and inflammation, ductular reaction, regenerative nodular hyperplasia, acinar transformation, presence of bile pigment, and cholangitis were noted. Serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl, alkaline phosphatase, bilirubin, and albumin levels, presentation patterns, and radiologic findings were assessed. Familial relationship degrees were also investigated. Twelve patients (9 boys, 3 girls; 3–180 months) were re-evaluated. Two pairs of the patients were siblings. Parents of 7 patients were consanguine. The most common presenting symptom was abdominal distension. Histopathologically, all patients had hepatoportal sclerosis/intimal fibrous thickening of portal vein and periportal fibrosis, acinar transformation, and regenerative nodules not surrounded by fibrous septae. Eight patients had vascular aberrations, 7 had ductular reaction, 1 showed mild cholangitis, and 1 had canalicular bile pigment. We conclude that genetic predisposition might be a possible factor for HPS development in Turkish patients and it should be kept in mind that cholestatic features noticed in histopathological evaluation may represent a variant group in the spectrum of HPS.