Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis.

Objective: Changes in cardiac function due to sepsis have been widely reported. However, the underlying mechanisms remain poorly understood. In the mammalian heart, myocyte function and intracellular calcium homeostasis are closely coupled.

Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1.

Abnormal calcium cycling, characteristic of experimental and human heart failure, is associated with impaired sarcoplasmic reticulum calcium uptake activity. This reflects decreases in the cAMP-pathway signaling and increases in type 1 phosphatase activity. The increased protein phosphatase 1 activity is partially due to dephosphorylation and inactivation of its inhibitor-1, promoting dephosphorylation of phospholamban and inhibition of the sarcoplasmic reticulum calcium-pump.

Mesenchymal stem cells in the infarcted heart.

A loss of functional cardiomyocytes forms the cellular basis of cardiac dysfunction and heart failure. Stem cell based repletion of scarred myocardial tissue and regeneration of cardiomyocytes have been proposed as a potential treatment of ventricular dysfunction. In this review, we provide an overview of recent studies utilizing mesenchymal stem cells in cardiac regeneration and post-myocardial infarct therapy.

Genetic maneuvers to ameliorate ventricular function in heart failure: therapeutic potential and future implications.

Gene therapy to treat heart failure has evolved into a growing field of investigation yielding remarkable results in preclinical models. Whether these results will persist in clinical trials remains to be seen. However, researchers still face a number of obstacles that need to be overcome before this treatment can be employed effectively.

Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy.

Objectives: We investigated the effects of erbB2 inhibition by anti-erbB2 antibody on cardiomyocyte survival and mitochondrial function.

Background: ErbB2 is an important signal integrator for the epidermal growth factor family of receptor tyrosine kinases. Herceptin, an inhibitory antibody to the erbB2 receptor, is a potent chemotherapeutic but causes cardiac toxicity.

In vivo tracking of stem cells for clinical trials in cardiovascular disease.

Various stem cells hold promise for the treatment of human cardiovascular disease. Regardless of stem cell origin, future clinical trials will require that the location and number of such cells be tracked in vivo, over long periods of time. The problem of tracking small numbers of cells in the body is a difficult one, and an optimal solution does not yet exist.

In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis.

Background: Prolongation of the action potential duration (APD) and decreased transient outward K+ current (I(to)) have been consistently observed in cardiac hypertrophy. The relation between electrical remodeling and cardiac hypertrophy in vivo is unknown.

Methods And Results: We studied rat hearts subjected to pressure overload by surgical ascending aortic stenosis (AS) and simultaneously infected these hearts with an adenovirus carrying either the Kv4.

Targeted gene transfer in heart failure: implications for novel gene identification.

Heart failure remains an intractable disease with epidemic proportions in the Western World. While progress in conventional treatment modalities for congestive heart failure is making steady and incremental gains to reduce this disease burden, there remains a need to explore new potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders.

Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts.

In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. In this study, we analyzed titin expression in left ventricles of 19 control human donors and 9 severely diseased (nonischemic) dilated cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, and quantitative RT-PCR. Both human-heart groups coexpressed smaller (approximately 3 MDa) N2B-isoform and longer (3.

Cardiac-specific gene expression facilitated by an enhanced myosin light chain promoter.

Background: Adenoviral gene transfer has been shown to be effective in cardiac myocytes in vitro and in vivo. A major limitation of myocardial gene therapy is the extracardiac transgene expression.

Methods: To minimize extracardiac gene expression, we have constructed a tissue-specific promoter for cardiac gene transfer, namely, the 250-bp fragment of the myosin light chain-2v (MLC-2v) gene, which is known to be expressed in a tissue-specific manner in ventricular myocardium followed by a luciferase (luc) reporter gene (Ad.

Transcriptional changes following restoration of SERCA2a levels in failing rat hearts.

Heart failure is characterized at the cellular level by impaired contractility and abnormal Ca2+ homeostasis. We have previously shown that restoration of a key enzyme that controls intracellular Ca(2+) handling, the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), induces functional improvement in heart failure. We used high-density oligonucleotide arrays to explore the effects of gene transfer of SERCA2a on genetic reprogramming in a model of heart failure.

Cancer in the elderly: is it preventable?

It is the goal of the American Cancer Society to decrease the mortality from cancer by 50% and the incidence of cancer by 25% by the year 2015 in the United States. Achieving this goal requires intervention at the primary (incidence) and secondary (mortality) prevention stages, and will involve a concerted effort of the individual practitioner, governmental agencies, local, state, and national interest groups, and the population at large. Primary care practitioners must increase their level of enthusiasm for cancer prevention, and actively counsel patients about cancer risks and preventive measures.

Gene transfer of parvalbumin improves diastolic dysfunction in senescent myocytes.

Background: Impaired relaxation is a cardinal feature of senescent myocardial dysfunction. Recently, adenoviral gene transfer of parvalbumin, a small calcium-buffering protein found exclusively in skeletal muscle and neurons, has been shown to improve cardiomyocyte relaxation in disease models of diastolic dysfunction. The goal of this study was to investigate whether parvalbumin gene transfer could reverse diastolic dysfunction in senescent cardiomyocytes.

Osteoporosis for the home care physician. Part 1: etiology and current diagnostic strategies.

Osteoporosis affects over 20 million individuals in North America and is responsible for over 1.5 million fractures in the US. Although most cases of osteoporosis are primary, in 20% of older women and 40% of older men presenting with vertebral fractures, a secondary cause can be identified.

Gene transfer in cardiac myocytes.

Congestive heart failure (CHF) represents an enormous clinical problem and remains a leading cause of death despite advances in treatment. New treatments significantly impact mortality and disease course; they do not cure the underlying pathology. Gene transfer, the ability to genetically reprogram the heart in relevant cardiovascular disease models, allows testing the role of specific molecular pathways in disease pathogenesis.

Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling.

Abnormal intracellular Ca(2+) cycling plays an important role in cardiac dysfunction and ventricular arrhythmias in the setting of heart failure and transient cardiac ischemia followed by reperfusion (I/R). We hypothesized that overexpression of the sarcoplasmic reticulum Ca(2+) ATPase pump (SERCA2a) may improve both contractile dysfunction and ventricular arrhythmias. Continuous ECG recordings were obtained in 46 conscious rats after adenoviral gene transfer of either SERCA2a or the reporter gene beta-galactosidase (beta gal) or parvalbumin (PV), as early as 48 h before and 48 h after 30 min ligation of the left anterior descending artery by using an implantable telemetry system.

Sexuality in the nursing home, part 2: managing abnormal behavior--legal and ethical issues.

Everyone, regardless of age, needs love, touch, companionship, and intimacy. The 1.6 million elderly in the 20,000 U.

Sexuality in the nursing home, part 1: attitudes and barriers to sexual expression.

Sexuality is a basic human need that begins at birth and continues throughout life. The sexual needs of the elderly are similar to those of the young, but with variations in frequency, intensity, and mode of expression. Regardless of age, every individual has a need for love, intimacy, and companionship.

Titin--springing back to youth?

Mutations in the muscle protein titin have been linked to dilated cardiomyopathy, a condition in which the heart chambers are enlarged and blood is ineffectively pumped, in humans and in animal models. This protein, which is a component of sarcomeres, provides essential scaffolding for other muscle proteins and acts as a spring to confer passive elasticity on the cardiomyocyte. Several titin isoforms exist, and they display varying size and degrees of elasticity.

Contractile effects of adenovirally-mediated increases in SERCA2a activity: a comparison between adult rat and rabbit ventricular myocytes.

Adenoviral vectors have been successfully used to increase the activity of the sarcoplasmic reticulum Ca(2+)-ATPase in adult ventricular myocytes and to produce functional improvements in contractility in vivo and in vitro. While in vivo experiments are often performed in rat, in vitro manipulation of myocytes has been confined to rabbit and human cells. In the present study we make quantitative comparisons between cultured adult rat and rabbit myocytes in their responses to SERCA2a overexpression using adenoviral vectors.

Sex and the nursing home.

Despite the known benefits of continued sexual activity on physical, mental, and emotional health, the nursing home resident continues to be sexually invisible. There are so few opportunities where the quality of life can be enhanced so greatly by so basic interventions. Sexuality in the nursing home is one of them.

Damped elastic recoil of the titin spring in myofibrils of human myocardium.

The giant protein titin functions as a molecular spring in muscle and is responsible for most of the passive tension of myocardium. Because the titin spring is extended during diastolic stretch, it will recoil elastically during systole and potentially may influence the overall shortening behavior of cardiac muscle. Here, titin elastic recoil was quantified in single human heart myofibrils by using a high-speed charge-coupled device-line camera and a nanonewtonrange force sensor.