Children and adolescents with congenital heart disease often do not have the opportunity, inclination, or education to participate in safe and effective exercise. The consequences of this behavioral ...pattern affect not only cardiopulmonary parameters, but also psychosocial factors, especially when lack of participation in peer activities or sports leads to isolation and further sedentary behaviors. Importantly, unlike cardiac rehabilitation programs for adults with atherosclerotic disease, the goal for congenital heart disease patients was less about “rehabilitation” and more about promotion of optimal fitness. We thus developed a comprehensive “Cardiac Fitness Program” at Boston Children’s Hospital to promote exercise training, enhanced self-confidence, and motivation for patients with congenital heart disease. Since much of sustained fitness relates to consistency and behavior change, we crafted a progressive, goal-oriented exercise curriculum and augmented it with a self-learning workbook of targeted positive mindset practices to develop self-efficacy, an app for motivation and data collection, and exercise videos to demonstrate mechanics and to reiterate a positive message. We now report our experience including program structure and framework, navigating insurance, curriculum development, and outcome measures. Methods employed and barriers encountered in the initial development and execution of this program are reviewed. Key take-aways and further considerations including virtual and home-based programs are discussed.
Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous ...daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG).
Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acute toxicity, and response was assessed via serial magnetic resonance imaging.
Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%.
Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.
To identify genes involved in cardiac arrhythmia, we investigated patients with long OT syndrome (LOT), an inherited disorder causing sudden death from a ventricular tachyarrhythmia, torsade de ...pointes. We previously mapped LOT loci on chromosomes 11 (
LQT1), 7 (
LQT2), and 3 (
LQT3). Here, linkage and physical mapping place
LQT2 and a putative potassium channel gene,
HERG, on chromosome 7835-36. Single strand conformation polymorphism and DNA sequence analyses reveal
HERG mutations in six LQT families, including two intragenic deletions, one splice-donor mutation, and three missense mutations. In one kindred, the mutation arose de novo. Northern blot analyses show that
HERG is strongly expressed in the heart. These data indicate that
HERG is
LQT2 and suggest a likely cellular mechanism for torsade de pointes.
The C57BL/6 (B6) mouse is the background strain most frequently used for genetically-modified mice. Previous studies have found significant behavioral and genetic differences between the B6J (The ...Jackson Laboratory) and B6N substrains (National Institutes of Health); however, most studies employed only male mice. We performed a comprehensive battery of motor function and learning and memory tests on male and female mice from both substrains. The B6N male mice had greater improvement in the rotarod test. In contrast, B6J female mice had longer latencies to falling from the rotarod. In the Morris water maze (MWM), B6J males had significantly shorter latencies to finding the hidden platform. However, B6N females had significantly shorter path lengths in the reversal and shifted-reduced phases. In open field locomotor activity, B6J males had higher activity levels, whereas B6N females took longer to habituate. In the fear conditioning test, B6N males had a significantly longer time freezing in the new context compared with B6J males, but no significant differences were found in contextual or cued tests. In summary, our findings demonstrate the importance of testing both males and females in neurobehavioral studies. Both factors (sex and substrain) must be taken into account when designing developmental neurotoxicology studies.
Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K(+) channels have been ...well characterized in the heart, much less is known about regulation and/or targeting of two-pore K(+) channel (K(2P)) family members, despite their potential importance in modulation of heart function.
Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K(2P) channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that β(IV)-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing β(IV)-spectrin lacking TREK-1 binding (qv(4J)) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal β(IV)-spectrin levels in human heart failure.
These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for β(IV)-spectrin in organizing functional membrane domains critical for normal heart function.
Cardiovascular disease is a leading cause of death worldwide. Arrhythmias are associated with significant morbidity and mortality related to cardiovascular disease. Recent work illustrates that many ...cardiac arrhythmias are initiated by a pathologic imbalance between kinase and phosphatase activities in excitable cardiomyocytes.
To test the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome.
By using a combination of biochemical, electrophysiological, and in vivo approaches, we tested the ability of calcium/calmodulin-dependent kinase (CaMKII) inhibition to rescue imbalance in kinase/phosphatase pathways associated with human ankyrin-B-associated cardiac arrhythmia.
The cardiac ryanodine receptor (RyR(2)), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B(+/-) heart. Notably, RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized by treatment with the CaMKII inhibitor KN-93. CaMKII inhibition is sufficient to rescue abnormalities in ankyrin-B(+/-) myocyte electrical dysfunction including cellular afterdepolarizations, and significantly blunts whole animal cardiac arrhythmias and sudden death in response to elevated sympathetic tone.
These findings illustrate the complexity of the molecular components involved in human arrhythmia and define regulatory elements of the ankyrin-B pathway in pathophysiology. Furthermore, the findings illustrate the potential impact of CaMKII inhibition in the treatment of a congenital form of human cardiac arrhythmia.
Next-generation sequencing (NGS) technologies have become much more efficient, allowing whole human genomes to be sequenced faster and cheaper than ever before. However, processing the raw sequence ...reads associated with NGS technologies requires care and sophistication in order to draw compelling inferences about phenotypic consequences of variation in human genomes. It has been shown that different approaches to variant calling from NGS data can lead to different conclusions. Ensuring appropriate accuracy and quality in variant calling can come at a computational cost.
We describe our experience implementing and evaluating a group-based approach to calling variants on large numbers of whole human genomes. We explore the influence of many factors that may impact the accuracy and efficiency of group-based variant calling, including group size, the biogeographical backgrounds of the individuals who have been sequenced, and the computing environment used. We make efficient use of the Gordon supercomputer cluster at the San Diego Supercomputer Center by incorporating job-packing and parallelization considerations into our workflow while calling variants on 437 whole human genomes generated as part of large association study.
We ultimately find that our workflow resulted in high-quality variant calls in a computationally efficient manner. We argue that studies like ours should motivate further investigations combining hardware-oriented advances in computing systems with algorithmic developments to tackle emerging 'big data' problems in biomedical research brought on by the expansion of NGS technologies.
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