Predisposing effect of anti-Beta cell autoimmune process in NOD mice on the induction of diabetes by environmental insults

Summary In NOD mice, 50–70% of females and 10–20% of males develop diabetes, although almost all the animals show insulitis. To see if environmental insults could induce diabetes in subjects with pre-clinical anti-Beta cell autoimmunity, non-diabetic NOD mice were selected and injected with a sub-diabetogenic dose of streptozotocin at 6 or 20 weeks of age. The streptozotocin failed to induce diabetes in 16 male and 16 female NOD mice within 4 weeks when they were injected at the age of 6 weeks. In contrast, 6 of 16 male and 10 of 16 female NOD mice developed diabetes within 4 weeks when they were injected at the age of 20 weeks. In untreated age-matched control NOD mice, none of the male and only 2 of 16 female mice became diabetic during the same 4 week period. On histologic examination, the degree of insulitis in streptozotocin-treated NOD mice (at the age of 24 weeks) was not significantly different from that of untreated control NOD mice. However, the streptozotocin-treated animals showed significantly lower pancreatic insulin content than the control mice. These results show that an anti-Beta cell autoimmune process in NOD mice has a predisposing effect on the induction of diabetes by a sub-diabetogenic dose of streptozotocin, and suggest that the precipitation of clinical diabetes by some environmental insults in subjects with pre-existing pre-clinical autoimmune Beta-cell destruction may be one mechanism of disease presentation in human Type 1 (insulin-dependent) diabetes.     

High-level expression of stem cell marker CD133 in clear cell renal cell carcinoma with favorable prognosis

The cancer stem cell (CSC) model suggests that high levels of CSCs within a tumor are associated with poor prognosis. The aim of this study was to investigate the expression of the stem cell marker CD133 in clear cell renal cell carcinoma (ccRCC), and its prognostic significance. The expression of CD133 was examined in 140 cases of ccRCC using immunohistochemistry. Ki-67 and Oct-4 were double-immunostained with CD133 to evaluate the proliferative activity and the stemness of CD133-expressing cells, respectively. CD133 expression was observed in 45 cases (32.1%) and high levels of expression were found to be associated with a macro-/microcystic pattern, non-sarcomatoid changes and non-metastatic disease. The Ki-67 labeling index tended to be lower in CD133-expressing ccRCCs compared to non-expressing tumors. CD133-expressing tumor cells rarely expressed Oct-4. A high degree of CD133 expression was observed in ccRCC with more differentiated morphology and non-metastatic disease, suggesting that CD133 is a favorable prognostic marker. These results also indicate that CD133 as a single marker may not be sufficient for CSC identification in ccRCC and, therefore, more specific CSC markers should be developed.     

Cerebral glucose metabolism abnormalities in patients with major depressive symptoms in pre-dialytic chronic kidney disease: statistical parametric mapping analysis of F-18-FDG PET, a preliminary study

Aims: The aim of the present study was to investigate the relationship between depressive symptoms and cerebral glucose metabolism in pre‐dialytic chronic kidney disease (PDCKD) patients. Methods: Twenty‐one patients with stage 5 CKD and 21 healthy volunteers underwent depressive mood assessment and statistical parametric mapping (SPM) using F‐18‐fluorodeoxyglucose (FDG) positron emission tomography (PET). Results: Several voxel clusters of significantly decreased cerebral glucose metabolism were found in PDCKD patients. The largest cluster was left prefrontal cortex (Brodmann area [BA] 9). The second largest cluster was also left prefrontal cortex (BA 9). The third largest clusters were right prefrontal cortex (BA 10) and right basolateral prefrontal cortex (BA 46). Other brain areas also showed decreased cerebral glucose metabolism including left anterior cingulate gyrus (BA 32), left premotor cortex (BA 6), left transverse temporal gyrus (BA 41), left superior temporal gyrus (BA 42), right basolateral prefrontal cortex (BA 44), right inferior parietal lobule (BA 39), left middle temporal gyrus (BA 19), and left angular gyrus (BA 39). Hypermetabolized brain areas, however, were not found in PDCKD patients compared to normal controls. For the right orbitofrontal cortex there was a negative correlation of cerebral glucose metabolism with Hamilton Depression Rating Scale (HDRS) in PDCKD patients (BA 11). Conclusion: PDCKD patients with depressive symptoms had decreased cerebral glucose metabolism in several brain areas. For the right orbitofrontal cortex there was a negative correlation with HDRS in PDCKD patients. The present findings provide functional neuroimaging support for abnormal cerebral glucose metabolism in PDCKD patients with depressive symptoms.     

The comparison of cystatin C and creatinine as an accurate serum marker in the prediction of type 2 diabetic nephropathy

In a clinic-based, cross-sectional study of 320 type 2 diabetic patients, we staged the level of diabetic nephropathy (normoalbuminuric, microalbuminuric and macroalbuminuric stage) and estimated GFR based on serum creatinine and cystatin C (CysC). Serum creatinine and CysC levels were 0.91+/-0.21 mg/dL and 0.87+/-0.26 mg/L, respectively. Correlation coefficients between CysC-GFR and each of the creatinine-based GFR measurements (MDRD-GFR, Cockcroft-Gault-GFR, and CLcr) were 0.589, 0.569, and 0.479 (p<0.001). Serum CysC was significantly lower in normoalbuminurics (0.83+/-0.22) than in microalbuminurics and macroalbuminurics (0.94+/-0.33 and 1.05+/-0.28; p=0.004 and p<0.001). Of the estimations of GFR, significant differences among the groups were found on CysC-GFR and CLcr. CysC-GFR (mL/min) was statistically lower in macroalbuminurics (79.5+/-30.5) than in normoalbuminurics (104.3+/-30.9, p=0.01). The logistic regression analyses showed that retinopathy, A1C, CysC, diabetic duration, and CysC-GFR were indicators to predict the development of microalbuminuria. Serum CysC seems to be more accurate serum marker than serum creatinine in evaluating a prognostic stage of type 2 diabetic nephropathy. Our study suggests that, in Korean type 2 diabetic patients, CysC-based GFR might be more valuable than creatinine-based GFR in the prediction of the microalbuminuric stage.     

RAGE ligands induce apoptotic cell death of pancreatic β-cells via oxidative stress

Activation of the receptor for advanced glycation endproducts (RAGE) by its ligands leads to cellular damage contributing to diabetic complications. It is not clearly known whether RAGE ligands influence pancreatic β-cells. In this study, we investigated the expression of RAGE in islet cells and the effect of RAGE ligands, S100b and HMG-1, on islet cells. RAGE was expressed in INS-1 cells and isolated rat and human islets at mRNA and protein levels. RAGE and its ligand, S100b, were detected on islet cells in 28-week-old diabetic OLETF rats. Both S100b and HMG-1 induced apoptotic cell death of INS-1 and islet cells. This INS-1 cell apoptosis was accompanied by increased intracellular oxidative stress and inhibited by antioxidants or a NADPH oxidase inhibitor. Our results showing S100b/RAGE expression on islets of diabetic rat model and RAGE ligands-induced islet cell apoptosis via NADPH oxidase-mediated ROS generation suggest that RAGE ligands-RAGE interaction may contribute not only to the development of diabetic complications but also to the progressive β-cell loss in type 2 diabetes by inducing oxidative stress.     

Relationship between Resting Electrocardiographic Parameters and Estimated 10‐Year Risk for Coronary Heart Disease in Healthy Adults in the USA

Background: Little is known about the relationship between resting electrocardiogram (ECG) parameters and the incidence of coronary heart disease (CHD). We sought to establish the association between ECG parameters and estimated 10‐year risk for CHD. Methods: We applied the risk prediction algorithm used by the National Cholesterol Education Program Adult Treatment Panel III guidelines to data from 6399 individuals in the Third National Health and Nutrition Examination Survey (aged 40–79 years) who had sinus rhythm, no previous heart disease, and no evidence of prior myocardial infarction according to the 12‐lead Minnesota Code. We used multiple linear and logistic regression models to determine the relationship between 10‐year risk for CHD and levels of resting ECG parameters. Results: After adjusting for age, gender, race, and body mass index, individuals with high risk had higher heart rate (HR), left ventricular mass index (LVMI), and cardiac infarction injury score (CIIS), and longer HR‐corrected QT (QTc) interval than those with low risk. In models fully adjusted for coronary risk factors, individuals in the highest quintile of HR, PR, and QTc interval were 2.2, 0.7, and 1.8 times, respectively, more likely to have a high 10‐year risk as those in the lowest quintiles. There are dose‐dependent associations between HR, LVMI, CIIS, and QTc interval and the 10‐year risk group. Conclusions: These findings indicate that high HR, LVMI, and CIIS and prolonged QTc interval are positively and prolonged PR interval is negatively associated with high 10‐year risk for CHD in a general population. Ann Noninvasive Electrocardiol 2010;15(4):315‐320