Abnormal glutathione metabolism and increased cytotoxicity caused by H2O2 in human umbilical vein endothelial cells cultured in high glucose medium

Summary To determine whether increased oxidative stress in diabetes mellitus is due to an impaired freeradical scavenger function in endothelial cells, GSH-dependent H₂O₂ degradation in human umbilical vein endothelial cells was studied. The GSH-dependent, NaN₃-uninhibitable H₂O₂-degradation in endothelial cells was reduced by 48% (p <0.001) when the cells were exposed to 33 mmol/l d-glucose vs 5.5 mmol/l d-glucose. This impairment was dependent not only on the d-glucose concentration in the medium but also on d-glucose specific metabolism, since neither 27.5 mmol/l l-glucose nor 27.5 mmol/l d-raffinose had any effect on the peroxide degradation activity. Activation of the glutathione redox cycle by H₂O₂ in cells exposed to high glucose concentrations was attenuated as compared with 5.5 mmol/l d-glucose because of: 1) a 42% decrease (p <0.001) in intracellular NADPH content, and 2) a 34% reduction (p <0.01) in glutathione release into the media. This results in an accumulation of GSSG in the cells following exposure to H₂O₂. Both H₂O₂-evoked ⁵¹Cr-release and H₂O₂-induced endothelial cell damage were significantly (p <0.01) greater in the 33 mmol/l d-glucose group than in the 5.5 mmol/l d-glucose group. These results indicate that the abnormal glutathione redox cycle observed in endothelial cells is induced by high glucose concentrations in the medium, resulting in an impairment of reduced GSH-dependent H₂O₂-degradation. These abnormalities may associate with the increased cellular damage following an exogenous exposure to H₂O₂.Abbreviations GSH Reduced glutathione - GSSG oxidized glutathione - BSO L-buthionine-[S,R]-sulfoximine     

Safety,reliability, and operability of cochlear implant electrode arrays coated with biocompatible polymer

Conclusion: Polymer-coated electrodes can reduce surgically-induced trauma associated with the insertion of a cochlear implant (CI) electrode array. Objectives: To evaluate if insertion trauma in CI surgery can be reduced by using electrode arrays coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer. Methods: We analyzed characteristics of the Contour Advance® electrode arrays coated with MPC polymer. To assess surgical trauma during electrode insertion, polymer-coated or uncoated (n = 5 each) animal electrode arrays were implanted in guinea pig cochleae and operability and electrophysiological and histological changes were assessed. Results: Under light and scanning electron microscopy, polymer-coated electrodes did not appear different from uncoated electrodes, and no change was observed after mechanical stressing of the arrays. Electrode insertion was significantly easier when polymer-coated electrodes were used. Auditory brainstem response (ABR) thresholds did not differ between groups, but p1-n1 amplitudes of the coated group were larger compared with the uncoated group at 32 kHz at 28 days after surgery. The survival of outer hair cells and spiral ganglion cells was significantly greater in the polymer-coated group.     

Paraneoplastic Opsoclonus-myoclonus Syndrome with Anti-Hu and Anti-SOX-1 Antibodies after Immune-checkpoint Inhibitor Treatment Combined with Chemotherapy in a Patient with Small-cell Lung Cancer

A 69-year-old man with advanced small-cell lung cancer achieved partial remission after 3 courses of immunochemotherapy that included atezolizumab. Ten days after the last treatment, he developed paraneoplastic opsoclonus-myoclonus syndrome and required mechanical ventilation. Serology testing detected anti-Hu and anti-SOX-1 antibodies. Despite steroid pulse therapy, various anticonvulsants, continuous intravenous sedation, and a fourth course of chemotherapy without atezolizumab, his condition failed to improve. Paraneoplastic opsoclonus-myoclonus syndrome with autoantibodies after immune-checkpoint inhibitor treatment has not been reported previously. Although a causal relationship between immune-checkpoint inhibitors and paraneoplastic syndromes has been suggested, the mechanism remains unknown.     

Rapid hepatic fate specification of adipose-derived stem cells and their therapeutic potential for liver failure

Background and Aim:  Multipotential mesenchymal stem cells (MSC), present in many organs and tissues, represent an attractive tool for the establishment of a successful stem cell-based therapy in the field of regeneration medicine. Adipose tissue mesenchymal stem cells (AT-MSC), known as adipose-derived stem cells (ASC) are especially attractive in the context of future clinical applications because of their high accessibility and minimal invasiveness during the procedure to obtain them. The goal of the present study was to induce human ASC into functional hepatocytes in vitro within a very short period of time and to check their therapeutic potential in vivo .
Methods:  In vitro generated ASC-derived hepatocytes were checked for hepatocyte-specific markers and functions. Afterwards, they were transplanted into nude mice with liver injury. Twenty-four hours after transplantation, biochemical parameters were evaluated in blood serum.
Results:  We have shown here that ASC can be differentiated into hepatocytes within 13 days and can reach the functional properties of primary human hepatocytes. After transplantation into mice with acute liver failure, ASC-derived hepatocytes can restore such liver functions as ammonia and purine metabolism. Markers of liver injury, alanine aminotransferase, aspartate aminotransferase, as well as ammonia, were decreased after ASC-derived hepatocyte transplantation.
Conclusions:  Our data highlight the properties of ASC as having a special affinity for hepatocyte differentiation in vitro and liver regeneration in vivo . Thus, ASC may be a superior choice for the establishment of a therapy for injured liver.     

Amiodarone Decreases Plasma Brain Natriuretic Peptide Level in Patients with Heart Failure and Ventricular Tachyarrhythmia

Brain natriuretic peptide (BNP) is a powerful neurohormonal marker of left ventricular function and prognosis. Amiodarone either has no effect or improves the haemodynamics in patients with left ventricular dysfunction, but its effect on BNP is unknown. This study evaluated the effect of amiodarone on plasma BNP level in patients with heart failure and ventricular tachyarrhythmia.Plasma BNP level was studied in 46 patients with heart failure ventricular tachyarrhythmia, before (baseline) and at week 2 and months 1, 3 and 6 of amiodarone treatment. In addition, 21 patients with heart failure and ventricular tachyarrhythmia, who received an implantable cardioverter defibrillator, but not amiodarone, were studied on the same schedule. All patients had previously received potent vasodilator and beta-blocker therapy. Echocardiography and Holter monitoring were also performed.Amiodarone significantly decreased plasma BNP levels at week 2 to month 6 during therapy. Heart rates and frequencies of premature ventricular complexes were markedly reduced by amiodarone. Echocardiographic findings did not show a change in left ventricular end-diastolic dimensions, despite a slight increase in fraction shortening at month 6 during amiodarone therapy. The above parameters showed no change in patients without amiodarone. The effect of heart rate, premature ventricular complexes, fraction shortening, serum creatinine or thyroid stimulating hormone level was not significantly associated with decrease in BNP level during amiodarone therapy by a multivariate analysis. Among amiodarone-treated patients, mortality was higher in 24 with BNP levels 100 pg/ml at month 6 than in 22 with BNP levels <100 pg/ml during a mean follow-up period of 31 months.Amiodarone appears to have a decreasing effect on plasma BNP level, as well as an antiarrhythmic effect, in patients with heart failure and ventricular tachyarrhythmia.