ABSTRACT
In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.
Subject(s)
Diet, High-Fat/adverse effects , Enzyme Inhibitors/pharmacology , Glucose Intolerance/drug therapy , NADPH Oxidases/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hyperglycemia/drug therapy , Hyperglycemia/etiology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Mice , Mice, Inbred C57BL , NADPH Oxidase 4 , NADPH Oxidases/metabolism , Piperazines/pharmacology , Reactive Oxygen Species/metabolism , Thiophenes/pharmacologyABSTRACT
BACKGROUND: Living donor liver transplantation (LDLT) has been accepted as a valuable treatment for patients with end-stage liver disease seeking to overcome the shortage of organs and the waiting list mortality. The aim of this study was to report our experience with LDLT. METHODS: We retrospectively analyzed 50 LDLTs performed in our organ transplant center from January 1997 to March 2008. We reviewed the demographic data, family history, operative and hospital stay durations as well as postoperation complications among donors and recipients. We also performed a retrospective analysis of recipient chemical and biochemical data. RESULTS: Among 50 patients (30 males and 20 females) of overall mean age of 7.21 +/- 5.35 who underwent LDLT (10 right lobe, 38 left lobe, and 2 left lateral segments), 47 received a liver graft from their parent, two from a brother, and one from an uncle. The most common indications for LDLT were end-stage liver disease due to Wilson's disease (16%), cryptogenic cirrhosis (16%), tyrosinemia (14%), biliary atresia (12%), autoimmune hepatitis (12%), and progressive familial intrahepatic cholestasis (12%). The mean follow-up was 16.91 +/- 23.74 months. There were 13 (26%) recipient mortalities including vascular complications; three to sepsis after bowel perforation, two from liver dysfunction, two from chronic rejection due to noncompliance, and one from diffuse aspergillosis. The morbidity rate was 50%, including 19 reexplorations during the hospital course and five biliary complications. CONCLUSION: This study demonstrated that LDLT can decrease the number of patients awaiting liver transplantation especially in the pediatric group. However, because of relatively high mortality and morbidity, we must improve our treatment outcomes.
Subject(s)
Liver Transplantation/physiology , Living Donors/statistics & numerical data , Adult , Child , Child, Preschool , Family , Female , Hepatectomy/methods , Humans , Iran , Length of Stay , Liver Diseases/classification , Liver Diseases/surgery , Male , Nuclear Family , Retrospective Studies , Tissue Donors/statistics & numerical dataABSTRACT
Event-related potentials (ERPs) were recorded from 16 native speakers of Turkish while they watched Turkish sentences flashed upon the screen of a videomonitor. The sentences were three words long and contained a verb at the terminal position that was manipulated (1) to have either the correct or the incorrect number with regard to the subject of the sentence, and (2) to be semantically appropriate, inappropriate or to be a pseudoverb. The ERPs from 19 scalp channels revealed a more positive waveform at the left-fronto-temporal site with an onset latency of about 200 ms for the verbs having the wrong number regardless of the semantic appropriateness of the word, while at right fronto-temporal sites a more negative waveform was observed for plural words only. This number incongruency ERP-effect in Turkish is clearly at odds with findings from other languages.
