Recent brain imaging studies have provided new insight into how students are able to extend their previous problem solving skills to new but similar problems. It is still unclear, however, what the basis is of individual differences in their success at transfer. In this study, 75 subjects had been trained to solve a set of mathematical problems before they were put into the fMRI scanner, where they were challenged to solve modified versions of familiar problems. A hidden semi-Markov model identified the sequential structure of thought when solving the problems. Analyzing the patterns of brain activity over the sequence of states identified by the model, we observed that subjects who showed consistent brain patterns performed better. This consistency refers to both how consistently subjects respond to different problems (within-subject consistency), and how brain responses of a given subject deviate from the population average (between-subjects consistency). Early withinsubject consistency is particularly predictive of later performance in the experiment.

Rationale

The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine.

Objective

We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure.

Methods and results

We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na(+) channels in the setting of normal physiology, long-QT syndrome type 3-linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na(+) channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure-induced remodeling.

Conclusions

Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL.

BACKGROUND: The clinical benefits of the left internal thoracic artery-to-left anterior descending coronary artery graft are well established in coronary artery bypass graft surgery (CABG). However, limited data are available regarding the long-term outcome of the radial artery (RA) as a secondary conduit over the established standard of the saphenous venous graft. METHODS AND RESULTS: We compared the 12-year survival outcome in a set of propensity-matched CABG patients who received either the RA or the saphenous vein as a secondary conduit. A multivariable logistic regression that included 18 baseline characteristics was used to define the propensity of receiving an RA graft. The propensity model resulted in 260 matched pairs who underwent first-time isolated CABG from 1996 to 2001 with similar preoperative characteristics (C statistic=0.86). The cumulative 12-year survival estimated by use of the Kaplan-Meier method was higher for the RA graft patients (hazard ratio 0.76; P=0.03). This survival advantage was especially significant in diabetics (P=0.005), in women (P=0.02), and in the elderly (P=0.04.) The protective effect appeared beginning at year 5 post surgical intervention. CONCLUSION: The RA as a secondary conduit provided superior long-term survival after CABG, especially in diabetic patients, women, and the elderly. This effect was most pronounced >5 years after surgery.

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

In February 2014, a group of scientists convened as part of the University of California Davis Cardiovascular Symposium to bring together experimental and mathematical modelling perspectives and discuss points of consensus and controversy on the topic of sodium in the heart. This paper summarizes the topics of presentation and discussion from the symposium, with a focus on the role of aberrant sodium channels and abnormal sodium homeostasis in cardiac arrhythmias and pharmacotherapy from the subcellular scale to the whole heart. Two following papers focus on Na(+) channel structure, function and regulation, and Na(+)/Ca(2+) exchange and Na(+)/K(+) ATPase. The UC Davis Cardiovascular Symposium is a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The focus on Na(+) in the 2014 symposium stemmed from the multitude of recent studies that point to the importance of maintaining Na(+) homeostasis in the heart, as disruption of homeostatic processes are increasingly identified in cardiac disease states. Understanding how disruption in cardiac Na(+)-based processes leads to derangement in multiple cardiac components at the level of the cell and to then connect these perturbations to emergent behaviour in the heart to cause disease is a critical area of research. The ubiquity of disruption of Na(+) channels and Na(+) homeostasis in cardiac disorders of excitability and mechanics emphasizes the importance of a fundamental understanding of the associated mechanisms and disease processes to ultimately reveal new targets for human therapy.