Atrial septal defect-associated pulmonary hypertension with decompensated heart failure: outcomes after fenestrated device closure.

BACKGROUND: Up to 90% of adults with untreated atrial septal defect will be symptomatic by 4th decade, and 30-49% will develop heart failure. 8-10% of these patients have pulmonary arterial hypertension with a female predominance regardless of age. We aimed to demonstrate that fenestrated closure can be safely performed in patients with decompensated heart failure and atrial septal defect-associated pulmonary arterial hypertension with improved outcome. METHODS: Transcatheter fenestrated atrial septal defect closures (Occlutech GmbH, Jena, Germany) were performed on a compassionate-use basis in 5 consecutive adult patients with atrial septal defect-associated pulmonary arterial hypertension and severe heart failure with prohibitive surgical mortality risks. Change in systemic oxygen saturation, 6-minute walk test, NYHA class, echocardiographic and haemodynamic parameters were used as parameters of outcome. RESULTS: All patients were female, mean age 48.8 ± 13.5 years, followed up for a median of 29 months (max 64 months). Significant improvements observed in the 6-minute walk test, and oxygen saturation comparing day 0 time point to all other follow-up time points data (B = 1.32, SE = 0.28, t (22.7) = -4.77, p = 0.0001); and in the haemodynamic data (including pulmonary vascular resistance and pulmonary pressure) (B = -0.60, SE = 0.22, t (40.2) = 2.74, p = .009). All patients showed improved right ventricular size and function along with NYHA class. There were no procedure-related complications. CONCLUSION: Fenestrated atrial septal defect closure is feasible in adults with decompensated heart failure and atrial septal defect-associated pulmonary arterial hypertension. It results in sustained haemodynamic and functional improvement.

The Assessment of Affective Responses within Exercise Prescription: A Narrative Review.

The assessment of affective responses (pleasure-displeasure) to exercise, is a useful tool for tailoring exercise prescription. Ideally, the proper prescription is a balance between minimizing risks, such as negative affect and dropout, and maximizing gains, such as improvements in health and fitness. Measuring affective responses to exercise facilitates the process of self-regulation. When individuals have the autonomy to select the exercise intensity, they are more likely to have a positive exercise experience and adhere to the program. The American College of Sports Medicine (ACSM) has put forth guidelines on how to incorporate affective responses within exercise prescription. The primary purpose of this review is to expand upon the techniques and recommendations provided by the ACSM on the topic of affective responses. Topics include an overview of the existing research of affective responses to exercise intensity, the impact of affective responses on motivation and exercise behaviors, and recommendations of specific techniques for measuring, monitoring, and evaluating affective responses within an exercise prescription.

Surge of neurophysiological coherence and connectivity in the dying brain.

The brain is assumed to be hypoactive during cardiac arrest. However, the neurophysiological state of the brain immediately following cardiac arrest has not been systematically investigated. In this study, we performed continuous electroencephalography in rats undergoing experimental cardiac arrest and analyzed changes in power density, coherence, directed connectivity, and cross-frequency coupling. We identified a transient surge of synchronous gamma oscillations that occurred within the first 30 s after cardiac arrest and preceded isoelectric electroencephalogram. Gamma oscillations during cardiac arrest were global and highly coherent; moreover, this frequency band exhibited a striking increase in anterior-posterior-directed connectivity and tight phase-coupling to both theta and alpha waves. High-frequency neurophysiological activity in the near-death state exceeded levels found during the conscious waking state. These data demonstrate that the mammalian brain can, albeit paradoxically, generate neural correlates of heightened conscious processing at near-death.

A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.

De novo designed Hsp70 activator dissolves intracellular condensates.

Protein quality control (PQC) is carried out in part by the chaperone Hsp70, in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of a set of Hsp70 binding proteins that either inhibited or stimulated Hsp70's ATPase activity; a stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to condensates and other cellular targets.

Controlling the Evolution of Resistance.

Evolution has long been understood as the driving force for many problems of medical interest. The evolution of drug resistance in HIV and bacterial infections is recognized as one of the most significant emerging problems in medicine. In cancer therapy, the evolution of resistance to chemotherapeutic agents is often the differentiating factor between effective therapy and disease progression or death. Interventions to manage the evolution of resistance have, up to this point, been based on steady-state analysis of mutation and selection models. In this paper, we review the mathematical methods applied to studying evolution of resistance in disease. We present a broad review of several classical applications of mathematical modeling of evolution, and review in depth two recent problems which demonstrate the potential for interventions which exploit the dynamic behavior of resistance evolution models. The first problem addresses the problem of sequential treatment failures in HIV; we present a review of our recent publications addressing this problem. The second problem addresses a novel approach to gene therapy for pancreatic cancer treatment, where selection is used to encourage optimal spread of susceptibility genes through a target tumor, which is then eradicated during a second treatment phase. We review the recent in Vitro laboratory work on this topic, present a new mathematical model to describe the treatment process, and show why model-based approaches will be necessary to successfully implement this novel and promising approach.

Improving Family Communication.

INTRODUCTION: TeenSmart International harnesses the power and flexibility of technology to empower youth to take personal responsibility for their health and lifestyle choices. Access to the Internet via mobile phones is often cheaper than paying to connect to a wired broadband service, and in rural areas, mobile networks may be the only means of accessing the Internet. This study assessed the feasibility, acceptability, and impact of "cues to action" or brief motivating cell phone text messages to improve adolescent family communication and relationships. METHOD: A quasi-experimental design using a voluntary sample of 100 Nicaraguan youth at high risk for poor family communication participated. Pre- and posttest quantitative measures using Student t statistical analysis, a focus group, and a participant testimony provided the evaluation evidence. RESULTS: Findings suggest that there are economic and motivational barriers to the use of text messages, but when barriers are eliminated, the behavioral results are positive. Youth who received two weekly text messages over a 6-month period demonstrated statistically significant improvements in family communication perceptions, attitudes, and behaviors, strengthening their family communications and relationships. CONCLUSION: Brief and personalized text messaging "cues to action" may be a cost-effective intervention to improve adolescent healthy lifestyle behaviors.