AimsHypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction between NO and ROS increases VMH sGC S-nitrosylation levels and impairs the CRR to subsequent episodes of hypoglycemia. VMH ROS production and S-nitrosylation were quantified following three consecutive daily episodes of insulin-hypoglycemia (RH model). The CRR was evaluated in rats in response to acute insulin-induced hypoglycemia or via hypoglycemic-hyperinsulinemic clamps. Pretreatment with the anti-oxidant N-acetyl-cysteine (NAC) was used to prevent increased VMH S-nitrosylation.ResultsAcute insulin-hypoglycemia increased VMH ROS levels by 49±6.3%. RH increased VMH sGC S-nitrosylation. Increasing VMH S-nitrosylation with intracerebroventricular injection of the nitrosylating agent S-nitroso-L-cysteine (CSNO) was associated with decreased glucagon secretion during hypoglycemic clamp. Finally, in RH rats pre-treated with NAC (0.5% in drinking water for 9 days) hypoglycemia-induced VMH ROS production was prevented and glucagon and epinephrine production was not blunted in response to subsequent insulin-hypoglycemia.ConclusionThese data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.

Our results suggest that genetic instabilities of the E-cadherin gene have a role in meningioma development and progression. Detected microsatellite instability indicates that mismatch repair may also be targeted in meningioma.

Adenosine, a key extracellular signaling mediator, regulates several aspects of metabolism by activating 4 G-protein-coupled receptors, the A, A, A, and A adenosine receptors (ARs). The role of AARs in regulating high-fat-diet (HFD)-induced metabolic derangements is unknown. To evaluate the role of AARs in regulating glucose and insulin homeostasis in obesity, we fed AAR-knockout (KO) and control mice an HFD for 16 wk to initiate HFD-induced metabolic disorder. We found that genetic deletion of AARs caused impaired glucose tolerance in mice fed an HFD. This impaired glucose tolerance was caused by a decrease in insulin secretion but not in insulin sensitivity. Islet size and insulin content in pancreata of AAR-deficient mice were decreased compared with control mice after consuming an HFD. AAR-KO mice had decreased expression of the β-cell-specific markers pdx1, glut2, mafA, and nkx6.1 and increased expression of the dedifferentiation markers sox2 and hes1. islet experiments confirmed the role of AARs in protecting against decreased insulin content and release caused by HFD. Other experiments with bone marrow chimeras revealed that inflammation was not the primary cause of decreased insulin secretion in AAR-KO mice. Altogether, our data showed that AARs control pancreatic dysfunction in HFD-induced obesity.-Csóka, B., Törő, G., Vindeirinho, J., Varga, Z. V., Koscsó, B., Németh, Z. H., Kókai, E., Antonioli, L., Suleiman, M., Marchetti, P., Cseri, K., Deák, Á., Virág, L., Pacher, P., Bai, P., Haskó, G. A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity.

In surgical pathophysiology ischemia-reperfusion, inflammatory processes, sepsis, vascular interventions, tissue trauma, shock, all mean conditions in which hemorheological parameters show alterations. Despite of numerous clinical and experimental studies, the in vivo hemorheology is not completely understood yet, and several fundamental questions still need to be answered. Investigating these issues, experimental surgical models are important, in point of view of the translational research as well. In this paper we aimed to make an attempt on summarizing the possible factors and conditions that might have an effect on hemorheological results in experimental surgical studies. Hemorheological parameters show alterations in surgical pathophysiological processes in a complex way. However, the changes are dominantly non-specific. Standardized experimental conditions, related to the experimental animal (species, animal welfare) anesthesia-medications, operation, sampling and, if applicable, conditions of the postoperative period, are inevitable for a safe assessment of valuable (hemorheological) results. Parallel investigations - such as microcirculatory monitoring, imaging techniques, other laboratory methods, histomorphology- have great importance, together with individual analysis of changes, for a better understanding of the changes and for comparability with clinical results.

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