Seizure termination

A better understanding of the mechanisms by which most focal epileptic seizures stop spontaneously within a few minutes would be of highest importance, because they could potentially help to improve existing and develop novel therapeutic measures for seizure control. Studies devoted to unraveling mechanisms of seizure termination often take one of the two following approaches. The first approach focuses on metabolic mechanisms such as ionic concentrations, acidity, or neuromodulator release, studying how they are dependent on, and in turn affect changes of neuronal activity. The second approach uses quantitative tools to derive functional networks from electrophysiological recordings and analyzes these networks with mathematical methods, without focusing on actual details of cell biology. In this chapter, we summarize key results obtained by both of these approaches and attempt to show that they are complementary and equally necessary in our aim to gain a better understanding of seizure termination.

Investigation of premature termination codon recognition in nonsense-mediated mRNA decay

Nonsense-mediated mRNA decay (NMD) is best known for its role in quality control of mRNAs, where it recognizes premature translation termination codons (PTCs) and rapidly degrades the corresponding mRNA. The basic mechanism of NMD appears to be conserved among eukaryotes: aberrant translation termination triggers NMD. According to the current working model, correct termination requires the interaction of the ribosome with the poly(A)-binding protein (PABPC1) mediated through the eukaryotic release factors 1 (eRF1) and 3 (eRF3). The model predicts that in the absence of this interaction, the NMD core factor UPF1 binds to eRF3 instead and initiates the events ultimately leading to mRNA degradation. However, the exact mechanism of how the decision between proper and aberrant (i.e. NMD-inducing) translation termination occurs is not yet well understood. We address this question using a tethering approach in which proteins of interest are bound to a reporter transcript into the vicinity of a PTC. Subsequently, the ability of the tethered proteins to inhibit NMD and thus stabilize the reporter transcript is assessed. Our results revealed that the C-terminal domain interacting with eRF3 seems not to be necessary for tethered PABPC1 to suppress NMD. In contrast, the N-terminal part of PABPC1, consisting of 4 RNA recognition motifs (RRMs) and interacting with eukaryotic initiation factor 4G (eIF4G), retains the ability to inhibit NMD. We find that eIF4G is able to inhibit NMD in a similar manner as PABPC1 when tethered to the reporter mRNA. This stabilization by eIF4G depends on two key interactions. One of these interactions is to PABPC1, the other is to eukaryotic initiation factor 3 (eIF3). These results confirm the importance of PABPC1 in inhibiting NMD but additionally reveal a role of translation initiation factors in the distinction between bona fide termination codons and PTCs.

Five-Year Outcome of Catheter Ablation of Persistent Atrial Fibrillation Using Termination of Atrial Fibrillation as a Procedural Endpoint.

BACKGROUND -This study aimed to determine five-year efficacy of catheter ablation for persistent atrial fibrillation (PsAF) using AF termination as a procedural endpoint. METHODS AND RESULTS -150 patients (57±10 years) underwent PsAF ablation using a stepwise ablation approach (pulmonary vein isolation, electrogram-guided and linear ablation) with the desired procedural endpoint being AF termination. Repeat ablation was performed for recurrent AF or atrial tachycardia (AT). AF was terminated by ablation in 120 patients (80%). Arrhythmia-free survival rates after a single procedure were 35.3±3.9%, 28.0±3.7%, and 16.8±3.2% at 1, 2, and 5 years, respectively. Arrhythmia-free survival rates after the last procedure (mean 2.1±1.0 procedures) were 89.7±2.5%, 79.8±3.4%, and 62.9±4.5%, at 1, 2, and 5 years, respectively. During a median follow-up of 58 (IQR 43-73) months following the last ablation procedure, 97 of 150 (64.7%) patients remained in sinus rhythm without antiarrhythmic drugs (AADs). Another 14 (9.3%) patients maintained sinus rhythm after re-initiation of AADs, and an additional 15 (10.0%) patients regressed to paroxysmal recurrences only. Failure to terminate AF during the index procedure (HR 3.831; 95%CI: 2.070-7.143; p<0.001), left atrial diameter ≥50mm (HR 2.083; 95%CI: 1.078-4.016; p=0.03), continuous AF duration ≥18 months (HR 1.984; 95%CI: 1.024-3.846; p<0.04) and structural heart disease (HR 1.874; 95% CI: 1.037-3.388; p=0.04) predicted arrhythmia recurrence. CONCLUSIONS -In patients with PsAF, an ablation strategy aiming at AF termination is associated with freedom from arrhythmia recurrence in the majority of patients over a 5-year follow up period.Procedural AF non-termination and specific baseline factors predict long-term outcome after ablation.

The effects of benefit finding on athletes’ quality of adjustment to career termination

Retirement from elite sports requires athletes to cope with adjustments on an occupational, financial, physical, social or emotional level. Research on critical life events (e.g., Filipp & Aymanns, 2010) suggests that benefit finding, defined as “the process of deriving positive growth from adversity” (Cassidy et al., 2014), may have a positive impact on this transition. The present study examined the effects of benefit finding on the quality of adjustment to career termination in the short, middle and long term. Former Swiss elite athletes (N = 290) completed a written survey collecting information on a) their emotional reaction to career termination, b) the amount of adjustment in various respects, c) situational characteristics of their career termination, d) the duration and quality of the transition, and e) their subjective well-being. Using Latent Variable Modelling, finding benefit in career termination was found to have both a direct and an indirect effect on long-term well-being (γ=.18). It predicts favorable emotional reactions to career termination (γ = .53) and less adjustment (γ = -.38) which in turn shortens the transition duration (β = -.15 and β = .55, respectively) and quality (β = -.15), and finally augments well-being (β = .41). The data suggest that a focus on benefit finding in both crisis-prevention and crisis-coping interventions may prove useful to prevent crisis transitions.

Multiple strategies to prevent premature termination in psychotherapy

A Review of Premature Termination in Psychotherapy: Strategies for Engaging Clients and Improving Outcomes by Joshua K. Swift and Roger P. Greenberg Washington, DC: American Psychological Association. 2015. 212 pp, ISBN 978-1-4338-1801- 1. $69.95 http://dx.doi.org/10.1037/a0038612 Premature Termination in Psychotherapy: Strategies for Engaging Clients and Improving Outcomes is one of the very best examples of the new generation of psychotherapy development. Based on rigorous research findings and a deep look into the preexisting literature, this book presents practical guidelines to understand premature termination and provides evidence-based strategies for how to engage patients in treatment. It will especially be a highlight for practitioners who are interested in a broad insight of the overall empirical literature. For graduate students in clinical and counseling psychology, this book might be an excellent prototype for how to bring rigorous quantitative research and convenient practice examples together.

Termination and cost analysis: Complexity and precision issues

The research in this thesis is related to static cost and termination analysis. Cost analysis aims at estimating the amount of resources that a given program consumes during the execution, and termination analysis aims at proving that the execution of a given program will eventually terminate. These analyses are strongly related, indeed cost analysis techniques heavily rely on techniques developed for termination analysis. Precision, scalability, and applicability are essential in static analysis in general. Precision is related to the quality of the inferred results, scalability to the size of programs that can be analyzed, and applicability to the class of programs that can be handled by the analysis (independently from precision and scalability issues). This thesis addresses these aspects in the context of cost and termination analysis, from both practical and theoretical perspectives. For cost analysis, we concentrate on the problem of solving cost relations (a form of recurrence relations) into closed-form upper and lower bounds, which is the heart of most modern cost analyzers, and also where most of the precision and applicability limitations can be found. We develop tools, and their underlying theoretical foundations, for solving cost relations that overcome the limitations of existing approaches, and demonstrate superiority in both precision and applicability. A unique feature of our techniques is the ability to smoothly handle both lower and upper bounds, by reversing the corresponding notions in the underlying theory. For termination analysis, we study the hardness of the problem of deciding termination for a speci�c form of simple loops that arise in the context of cost analysis. This study gives a better understanding of the (theoretical) limits of scalability and applicability for both termination and cost analysis.