Coordinated Management of Academic Health Centers.

Academic health centers (AHCs) are the nation's primary resource for healthcare discovery, innovation, and training. US healthcare revenue growth has declined sharply since 2009, and is forecast to remain well below historic levels for the foreseeable future. As the cost of education and research at nearly all AHCs is heavily subsidized through large transfers from clinical care margins, our institutions face a mounting crisis.

Research in academic medical centers: two threats to sustainable support.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias.

The human Ether-à-go-go-related gene (hERG)-encoded K(+) current, I(Kr) is essential for cardiac repolarization but is also a source of cardiotoxicity because unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes I(Kr) block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC(70) of dofetilide, a well characterized hERG blocker.

Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases.

Beyond Flexner: a new model for continuous learning in the health professions.

One hundred years after Flexner wrote his report for the Carnegie Foundation, calls are heard for another "Flexnerian revolution," a reform movement that would overhaul an approach to medical education that is criticized for its expense and inefficiency, its failure to respond to the health needs of our communities, and the high cost and inefficiency of the health care system it supports. To address these concerns, a group of Vanderbilt educators, national experts, administrators, residents, and students attended a retreat in November 2008. The goal of this meeting was to craft a new vision of physician learning based on the continuous development and assessment of competencies needed for effective and compassionate care under challenging circumstances.

Novel molecular determinants in the pore region of sodium channels regulate local anesthetic binding.

The pore of the Na+ channel is lined by asymmetric loops formed by the linkers between the fifth and sixth transmembrane segments (S5-S6). We investigated the role of the N-terminal portion (SS1) of the S5-S6 linkers in channel gating and local anesthetic (LA) block using site-directed cysteine mutagenesis of the rat skeletal muscle (Na(V)1.4) channel.

The evolutionarily conserved residue A653 plays a key role in HERG channel closing.

Human ether-a-go-go-related gene (HERG) encodes the rapid, outwardly rectifying K(+) current I(Kr) that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of I(Kr) can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K(+) channels.

Functional Interactions between Distinct Sodium Channel Cytoplasmic Domains through the Action of Calmodulin.

Sodium channels are fundamental signaling molecules in excitable cells, and are molecular targets for local anesthetic agents and intracellular free Ca(2+) ([Ca(2+)](i)). Two regions of Na(V)1.5 have been identified previously as [Ca(2+)](i)-sensitive modulators of channel inactivation.

Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5.

The voltage-gated sodium channel NaV1.5 is responsible for the initial upstroke of the action potential in cardiac tissue. Levels of intracellular calcium modulate inactivation gating of NaV1.

Genetic screening in C. elegans identifies rho-GTPase activating protein 6 as novel HERG regulator.

The human ether-a-go-go related gene (HERG) constitutes the pore forming subunit of I(Kr), a K(+) current involved in repolarization of the cardiac action potential. While mutations in HERG predispose patients to cardiac arrhythmias (Long QT syndrome; LQTS), altered function of HERG regulators are undoubtedly LQTS risk factors. We have combined RNA interference with behavioral screening in Caenorhabditis elegans to detect genes that influence function of the HERG homolog, UNC-103.

Centralized oversight of physician-scientist faculty development at Vanderbilt: early outcomes.

Purpose: In 2000, faced with a national concern over the decreasing number of physician-scientists, Vanderbilt School of Medicine established the institutionally funded Vanderbilt Physician-Scientist Development (VPSD) program to provide centralized oversight and financial support for physician-scientist career development. In 2002, Vanderbilt developed the National Institutes of Health (NIH)-funded Vanderbilt Clinical Research Scholars (VCRS) program using a similar model of centralized oversight. The authors evaluate the impact of the VPSD and VCRS programs on early career outcomes of physician-scientists.

Science at the interstices: an evolution in the academy.

Biomedical science is at an evolutionary turning point. Many of the rate-limiting steps to realizing the next generation of personalized, highly targeted diagnostics and therapeutics rest at the interstices between biomedical science and the classic, university-based disciplines, such as physics, mathematics, computational science, engineering, social sciences, business, and law. Institutes, centers, or other entities created to foster interdisciplinary science are rapidly forming to tackle these formidable challenges, but they are plagued with substantive barriers, born of traditions, processes, and culture, which impede scientific progress and endanger success.

Potential role of isoketals formed via the isoprostane pathway of lipid peroxidation in ischemic arrhythmias.

Unabated reactive oxygen species (ROS) are potentiated by an ischemia-induced shift in anaerobic metabolism, which generates superoxide anion upon reperfusion and reintroduction of oxygen. ROS can modify protein structure and function in fundamental ways, one of which is by forming reactive lipid species from the oxidation of lipids. In this review, we discuss these pathways and discuss the literature that shows that these species can produce dramatic effects on cardiac ion channel function (eg, Na+ channel function).

HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function.

The HERG (human ether-à-go-go-related gene) protein, which underlies the cardiac repolarizing current I(Kr), is the unintended target for many pharmaceutical agents. Inadvertent block of I(Kr), known as the acquired long QT syndrome (aLQTS), is a leading cause for drug withdrawal by the United States Food and Drug Administration. Hence, an improved understanding of the regulatory factors that protect most individuals from aLQTS is essential for advancing clinical therapeutics in broad areas, from cancer chemotherapy to antipsychotics and antidepressants.

Calcium-dependent regulation of the voltage-gated sodium channel hH1: intrinsic and extrinsic sensors use a common molecular switch.

The function of the human cardiac voltage-gated sodium channel Na(V)1.5 (hH1) is regulated in part by binding of calcium to an EF hand in the C-terminal cytoplasmic domain. hH1 is also regulated via an extrinsic calcium-sensing pathway mediated by calmodulin (CaM) via binding to an IQ motif immediately adjacent to the EF-hand domain.

Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels.

Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na+) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na+ channel dysfunction and ventricular arrhythmias.

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families.

Background: Mutations in the gene encoding the human cardiac sodium channel (SCN5A) have been associated with three distinct cardiac arrhythmia disorders: the long QT syndrome, the Brugada syndrome and cardiac conduction disease. Here we report the biophysical features of a novel sodium channel mutation, E161K, which we identified in individuals of two non-related families with symptoms of bradycardia, sinus node dysfunction, generalized conduction disease and Brugada syndrome, or combinations thereof.

Methods And Results: Wild-type (WT) or E161K sodium channel alpha-subunit and beta-subunit were cotransfected into tsA201 cells to study the functional consequences of mutant sodium channels.

Compound-specific Na+ channel pore conformational changes induced by local anaesthetics.

Upon prolonged depolarizations, voltage-dependent Na+ channels open and subsequently inactivate, occupying fast and slow inactivated conformational states. Like C-type inactivation in K+ channels, slow inactivation is thought to be accompanied by rearrangement of the channel pore. Cysteine-labelling studies have shown that lidocaine, a local anaesthetic (LA) that elicits depolarization-dependent ('use-dependent') Na+ channel block, does not slow recovery from fast inactivation, but modulates the kinetics of slow inactivated states.

In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia.

Human ether-a-go-go-related gene (HERG) encodes the pore-forming subunit of I(Kr), a cardiac K(+) channel. Although many commonly used drugs block I(Kr), in certain individuals, this action evokes a paradoxical life-threatening cardiac rhythm disturbance, known as the acquired long QT syndrome (aLQTS). Although aLQTS has become the leading cause of drug withdrawal by the U.

Functional interaction between extracellular sodium, potassium and inactivation gating in HERG channels.

We have studied the interaction between extracellular K(+) (K(+)(o)) and extracellular Na(+) (Na(+)(o)) in human ether-à-go-go related gene (HERG)-encoded K(+) channels expressed in Chinese hamster ovary (CHO-K1) cells, using the whole-cell voltage clamp technique. Prior studies indicate that Na(+)(o) potently inhibits HERG current (IC(50) 3 mm) by binding to an outer pore site, and also speeds recovery from inactivation. In this study, we sought to explore the relationship between the Na(+)(o) effect on recovery and Na(+)(o) inhibition of HERG current, and to determine whether inactivation gating plays a critical role in Na(+)(o) inhibition of HERG current.

An EF-hand in the sodium channel couples intracellular calcium to cardiac excitability.

Sodium channels initiate the electrical cascade responsible for cardiac rhythm, and certain life-threatening arrhythmias arise from Na(+) channel dysfunction. We propose a novel mechanism for modulation of Na(+) channel function whereby calcium ions bind directly to the human cardiac Na(+) channel (hH1) via an EF-hand motif in the C-terminal domain. A functional role for Ca(2+) binding was identified electrophysiologically, by measuring Ca(2+)-induced modulation of hH1.

Inherited sodium channelopathies: a continuum of channel dysfunction.

Voltage-gated sodium channels are transmembrane proteins that produce the ionic current responsible for the rising phase of the cardiac action potential and play a fundamental role in the initiation, propagation, and maintenance of normal cardiac rhythm. Inherited mutations in SCN5A, the gene encoding the pore-forming subunit of the cardiac Na+ channel, have been associated with distinct cardiac rhythm syndromes: the congenital long QT syndrome, Brugada syndrome, and isolated conduction disease. Electrophysiologic characterization of heterologously expressed mutant Na+ channels have revealed gating defects that, in many cases, can explain the distinct phenotype associated with the rhythm disorder.

New treatments for perioperative cardiac arrhythmias.

Cardiac arrhythmias remain a major source of morbidity, mortality, and prolonged postoperative hospital stay in surgical patients. Recent studies in patients experiencing out-of-hospital cardiac arrest have expanded our knowledge in the management of cardiac arrhythmias. Future advances require additional studies focused on the unique proarrhythmic substrates in surgical patients, to provide a clear rationale for antiarrhythmic drug therapy in the perioperative period.

The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines.

The cardiac potassium channel encoded by the human ether-à-go-go related gene (HERG) is blocked by a diverse array of common therapeutic compounds. Even transient exposure to such agents may provoke the life-threatening cardiac arrhythmia torsades de pointes in some, but not all, individuals. Although the molecular and genetic factors predicting such wide variability in drug response remain unclear, known sequence variations within the coding region of HERG do not explain the adverse drug response in many cases.