Ictal and interictal MEG in pediatric patients with tuberous sclerosis and drug resistant epilepsy

Purpose: Drug resistant epilepsy (DRE) is common in patients with tuberous sclerosis (TS). Interictal MEG has been shown as a valuable instrument in the presurgical workup. The goal of our study was to evaluate the role of ictal MEG in epileptogenic tuber selection, especially in patients with multiple irritative zones. Methods: The clinical and MEG data of 23 patients with TS and DRE from two medical/research centers were reviewed. Seven pediatric patients, who had seizures during MEG recording and underwent resection or disconnection surgery, were included into the study. Cortical sources of ictal and interictal epileptiform MEG discharges were compared with epileptogenic zone location in six patients with favorable surgery outcome. Results: In patients who improved substantially after surgery all resected and several other tubers demonstrated epileptiform activity on interictal MEG. Ictal MEG provided crucial information about lobar location of the seizure onset zone (SOZ) in two cases, and in the other four it confirmed the SOZ location derived from the interictal data. In one case, ictal MEG findings were unreliable. In one patient, who did not benefit from surgical treatment, the resected tubers did not overlap with interictal and ictal MEG sources. Conclusion: The combination of interictal and ictal MEG is a valuable tool for identification of the epileptogenic tuber/tubers in presurgical work-up in patients with TS.Peer reviewe

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

The first stepwise crushing data on C, N and Ar isotopic and elemental ratios in Guli carbonatites fluid inclusions

To get insight into the fluid regime evolution during formation of Guli massif (Maymecha-Kotuy magmatic complex, Syberia) carbonatites we have studied C, N and Ar isotopic and elemental ratios in foure carbonatite samples by stepwise crushing method. Mineral separates representing different formation stages of the massif have been selected for the investigation: two early calcites (Cal) and a late stage dolomite (Dol) and siderite (Sid). The early calcites are carachterized by significantly lower CO2content and lower δ13C values than the late Dol and Sid (-14.1, -13.6‰ and -9.0, -10.5‰ in average respectively). Fractionation during melt degassing (when system is closing) could lead to a higher CO2content with higher d 13 C values in the late minerals. But the results on C, N and Ar elemental compositions in the fluid inclusions have shown that C/N and C/Ar ratios also dramatically increase from the early to the late samples (C/N: from 7 in Cal to 210 in Sid and 2100 in Dol; C/Ar ; from 870 in Cal to 12300 in Sid and 159000 in Dol), which could not be caused by a simple magmatic fractionation. An additional source of CO2could appear at the late stages of the fluid-magmatic evolution of the massif. The data on C, N and Ar concentration variations in crushing steps support this assumption: well-defined correlations between concentrations of these elements in fluid inclusions are observed in the early Cal (i.e. all gases in the inclusions have the same elemental composition and concequently the same source). For the late Sid and Dol the situation is different: when N and Ar concentrations decrease with crushing steps, the C concentration is increasing, suggesting different sources for (N+Ar) and for most of CO2. Moreover, 40Ar/36Ar ratios in early and late samples are quite different: 3680 in Cal and 657 and 549 in Sid and Dol, respectively. This suggests the air-like argon component to be domineted in fluids during formation of the late minerals. Thus, relationships between C, N and Ar concentrations as well as differences in C and Ar isotopic compositions in fluid inclusions of the early and late carbonitites suggest that at the late stages of Guli massif carbonatites formation an additional CO2source with havier carbon and atmosphere-like Ar have contributed to the system