Impact of DNA ligase IV on the fidelity of end joining in human cells

A DNA ligase IV (LIG4)‐null human pre‐B cell line and human cell lines with hypomorphic mutations in LIG4 are significantly impaired in the frequency and fidelity of end joining using an in vivo plasmid assay. Analysis of the null line demonstrates the existence of an error‐prone DNA ligase IV‐independent rejoining mechanism in mammalian cells. Analysis of lines with hypomorphic mutations demonstrates that residual DNA ligase IV activity, which is sufficient to promote efficient end joining, nevertheless can result in decreased fidelity of rejoining. Thus, DNA ligase IV is an important factor influencing the fidelity of end joining in vivo. The LIG4‐defective cell lines also showed impaired end joining in an in vitro assay using cell‐free extracts. Elevated degradation of the terminal nucleotide was observed in a LIG4‐defective line, and addition of the DNA ligase IV–XRCC4 complex restored end protection. End protection by DNA ligase IV was not dependent upon ligation. Finally, using purified proteins, we demonstrate that DNA ligase IV–XRCC4 is able to protect DNA ends from degradation by T7 exonuclease. Thus, the ability of DNA ligase IV–XRCC4 to protect DNA ends may contribute to the ability of DNA ligase IV to promote accurate rejoining in vivo

Cardiology News /Recent Literature Review / First Quarter 2014

Athens Cardiology Update 2014: Athens (Crown Plaza Hotel), 10-12/4/2014HRS Meeting: San Francisco, 7-10/5/2014EuroPCR: Paris, 20-23/5/2014CardioStim: Nice, 18-21/6/2014ESC Congress: Barcelona, 30/8-3/9/14TCT: Washington, 12-17/9/14HCS Annual Meeting: Athens, 23-25/10/2014AHA: Chicago, 15-19/11/14Cutting Inappropriate ICD Shocks: Long Arrhythmia-Detection Time Strategy Confirmed            Programming implantable cardioverter defibrillators (ICDs) to delay the time they take to treat ventricular arrhythmias cuts mortality by 23% and inappropriate shocks by more than one-half in a meta-analysis encompassing ~4900 patients. The included studies were prospective and multicenter and covered both primary and secondary prevention and patients with either ischemic or nonischemic cardiomyopathy. The risk of syncope did not rise significantly with longer detection times, despite traditional concerns that lots of patients would not tolerate prolonged arrhythmia exposure before their ICD is allowed to deliver therapy, either shocks or antitachycardia pacing (ATP). Instead, the extra time frequently gave devices a better chance to exclude non–life-threatening arrhythmias like atrial fibrillation and to let otherwise self-terminating ventricular arrhythmias play out on their own. Current nominal settings used by some ICD manufacturers are likely to be too aggressive, with arrhythmia detection times that in some cases may be as short as 1-3 s. These results highlight the importance of setting longer default ICD detection times. The analysis included 4896 patients from the MADIT-RIT, ADVANCE 3, and PROVIDE randomized trials and the RELEVANT nonrandomized study. Overall, 264 patients received appropriate shocks and 253 experienced inappropriate shocks at follow-up (12 - 17 months). The relative risk (RR) of death from any cause was 0.77 (p=0.02) in the prolonged-detection-time groups compared with controls; the risks of inappropriate shocks and appropriate and inappropriate ATP also fell significantly. Why there were fewer deaths with longer detection times is unclear but it may derive from less exposure to potential hazards of shocks and ATP; inappropriate shocks may up mortality, and ATP poses a small risk of inducing ventricular fibrillation; or it may be due to some other factor, e.g. avoidance of treatment for multiple ICD therapies (e.g., prescription of antiarrhythmic drugs) (Scott PA et al, Heart Rhythm 2014; DOI:10.1016/j.hrthm.2014.02.009. Epub 2014 Feb 12)... (excerpt

Early Repolarization: Not Benign Any More- the J-Wave Syndromes

An early repolarization (ER) pattern characterized by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has been traditionally considered to be totally benign over the past decades. A flurry of data derived from recently published studies demonstrates that an ER pattern in inferior or inferolateral leads, named early repolarization syndrome (ERS), is associated with increased risk for sudden cardiac arrest (SCA), being responsible for some cases of idiopathic ventricular fibrillation (IVF). Current evidence support the notion that although ERS and Brugada syndrome (BrS) show discrete differences, they also share similar clinical, electrocardiographic and pathophysiological features, especially concerning the presence of amplified J-waves; thus, they can be considered to represent a continuous spectrum of phenotypic expression, termed J-wave syndromes. Research has provided us with fascinating insights into the underlying mechanisms responsible for repolarization abnormalities and we presently have more evidence to implement reliable risk stratification methods to patients with ER. However, many unanswered questions remain and still need to be addressed in future studie

Novel Technology for Ablation of Atrial Fibrillation Using Multi- Electrode Catheters and Duty-Cycled Radiofrequency Energy

These are fluoroscopic views of the heart demonstrating the use of novel technology for catheter ablation of atrial fibrillation (AF) in a patient who has had frequent episodes of paroxysmal AF and had failed antiarrhythmic drug therapy. In the upper panels, a steerable guiding catheter has been introduced via a transseptal approach into the left atrium and inserted into the right upper (left upper panel) and left upper (right upper panel) pulmonary veins (PVs), which are visualized with hand injection of contrast material. Subsequently, through the same guiding catheter, another deflectable circular multi-electrode (decapolar) 9-F catheter is inserted over a guide-wire and stabilized at the antrum of each PV (lower panels). Via this catheter, simultaneous mapping and ablation is performed by delivering duty-cycled unipolar and bipolar radiofrequency (RF) energy at 4-10 Watts with use of a multichannel RF generator. Thus, electrical isolation of the PVs is effected by delivering RF energy simultaneously to multiple points in the perimetry of the PV antrum, rather than employing extensive point-by-point or stepwise ablation with use of conventional single electrode catheters. With this novel technology, the procedure appears potentially safer and more efficiently performed with a shorter procedural time in a simplified approach compared with the conventional single-electrode catheter technique

Does a Short QT Interval Presage a Short Life Span?

A case of a 16-year old adolescent is presented who was referred for investigation of a syncopal episode. The ECG displayed a very short QT interval of 280 ms, compatible with the newly described short QT syndrome, which is genetic primary electrical disease of abnormal potassium currents responsible for the repolarization process of the cardiac muscle. The prognosis is similar to the other well known familial cardiac channelopathies, such as the long QT or the Brugada syndromes which are associated with a high risk of sudden cardiac death, requiring an implantable cardioverter defibrillator device for life-long protection

Video-Based Depression Detection Using Local Curvelet Binary Patterns in Pairwise Orthogonal Planes

International audienceDepression is an increasingly prevalent mood disorder. This is the reason why the field of computer-based depression assessment has been gaining the attention of the research community during the past couple of years. The present work proposes two algorithms for depression detection, one Frame-based and the second Video-based, both employing Curvelet transform and Local Binary Patterns. The main advantage of these methods is that they have significantly lower computational requirements, as the extracted features are of very low dimensionality. This is achieved by modifying the previously proposed algorithm which considers Three-Orthogonal-Planes, to only Pairwise-Orthogonal-Planes. Performance of the algorithms was tested on the benchmark dataset provided by the Audio/Visual Emotion Challenge 2014, with the person-specific system achieving 97.6% classification accuracy, and the person-independed one yielding promising preliminary results of 74.5% accuracy. The paper concludes with open issues, proposed solutions, and future plans