Introduction: Focal epilepsy is the most common type of epilepsy with approximately 30 million patients affected worldwide. There is a major challenge to develop new antiepileptic treatments as currently approximately one third of patients remain uncontrolled under our best standards of care.
Areas covered: An overview is given on first- and second generation antiepileptic drugs and their mechanisms of action, and on recent new strategies for antiepileptic targets, including drugs aiming at disease modification.
Expert opinion: Newer antiepileptic drugs have enabled a better tolerated and individualized treatment for many patients. Despite the successful history of antiepileptic drug development programs, second and third generation antiepileptic drugs targeting synaptic transmission have, however, failed to solve the problem of pharmacoresistance. New directions in pharmacological development include chronic models of epilepsy in drug screening and address primary and secondary epileptogenesis rather than focusing on the suppression of the symptoms, acute seizures. There is hope that the new approaches will allow for patient stratification for targeted therapy and will prove efficacy particularly in the patient group so far drug resistant. 相似文献
Background Substrate modification guided by CARTO system has been introduced to facilitate linear ablation of ventricular tachycardia (VT) after myocardial infarction (MI). However, there is no commonly accepted standard approach available for drawing these ablation lines. Therefore, the aim of the present study was to practically refine this time consuming procedure. Methods Substrate modification was performed in 23 consecutive patients with frequent VTs after MI using the CARTO system. The initial target site (ITS) for ablation was identified by pace mapping (PM) during sinus rhythm and/or entrainment pacing (EM) during VT. According to the initial target site, two approaches were used. The initial target site in approach one has a similar QRS morphology as VT and an interval from the stimulus to the onset of QRS cmplex (S-QRS) of ≥50 ms during PM in sinus rhythm or a difference of the post pacing interval and VT cycle length ≤30 ms during concealed entrainment pacing of VT; The initial target site in approach two has an similar QRS morphology as VT and an S-QRS of 〈50 ms during PM in sinus rhythm. Results Overall, 50 lines were performed with a length of (35±11) mm. Procedure time averaged (232±56) minutes, fluoroscopy time (10±8) minutes. Sixteen patients were initially involved into approach one. After completion of 3±1 ablation lines, no further VT was inducible in 13 patients. The remaining 3 patients were switched to use the alternative approach. However, in none of them the alternative approaches were successful. Approach two was initially used in 7 patients. After completion of 3±1 ablation lines, no further VT was inducible in only 2 patients. The remaining 5 patients were switched to approach one, which resulted in noninducibility of VT in 4 of them. The initial successful rate was significantly higher in the group of approach one compared to that in the group of approach two (13/16 patients vs 2/7 patients, P=-0.026). Conclusions The approach for 相似文献
Histone variants play an important role in numerous biological processes through changes in nucleosome structure and stability and possibly through mechanisms influenced by posttranslational modifications unique to a histone variant. The family of histone H2A variants includes members such as H2A.Z, the DNA damage-associated H2A.X, macroH2A (mH2A), and H2ABbd (Barr body-deficient). Here, we have undertaken the challenge to decipher the posttranslational modification-mediated "histone code" of mH2A, a variant generally associated with certain forms of condensed chromatin such as the inactive X chromosome in female mammals. By using female human cells as a source of mH2A, endogenous mH2A was purified and analyzed by mass spectrometry. Although mH2A is in low abundance compared with conventional histones, we identified a phosphorylation site, S137ph, which resides within the "hinge" region of mH2A. This lysine-rich hinge is an approximately 30-aa stretch between the H2A and macro domains, proposed to bind nucleic acids. A specific antibody to S137ph was raised; by using this reagent, S137 phosphorylation was found to be present in both male and female cells and on both splice variants of the mH2A1 gene. Although mH2A is generally enriched on the inactive X chromosome in female cells, mH2AS137ph is excluded from this heterochromatic structure. Thus, a phosphorylated subpopulation of mH2A appears to play a unique role in chromatin regulation beyond X inactivation. We provide evidence that S137ph is enriched in mitosis, suggestive of a role in the regulation of mH2A posttranslational modifications throughout the cell cycle. 相似文献