Informed consent in clinical research: Consensus recommendations for reform identified by an expert interview panel.

Background: Informed consent is the cornerstone for protection of human subjects in clinical trials. However, a growing body of evidence suggests that reform of the informed consent process in the United States is needed.

Methods: The Clinical Trials Transformation Initiative conducted interviews with 25 experienced observers of the informed consent process to identify limitations and actionable recommendations for change.

Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes.

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS).

Development, validation, and application of a microsimulation model to predict stroke and mortality in medically managed asymptomatic patients with significant carotid artery stenosis.

Objective: To develop a model to predict stroke-free survival and mortality over a multiyear time frame for a trial-excluded population of medically managed asymptomatic patients with significant carotid artery stenosis.

Methods: We calibrated, validated, and applied a Monte Carlo microsimulation model. For calibration we adjusted general-population mortality and stroke risks to capture these risks specific to asymptomatic carotid stenosis patients.

Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart.

Background: Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the "dose" of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers.

An outline for public registration of clinical trials evaluating medical devices.

Public registration of clinical trials is fundamentally important to the integrity of the medical device development process. In addition to fulfilling obligations to those study volunteers, a complete record of trial results provides the general public, clinical community, and medical device manufacturers with a more accurate understanding as to how a specific therapeutic should be used. Although the issues associated with public disclosure of clinical trials are similar to the pharmaceutical industries, the iterative nature of device development introduces differences in what type of information needs to be disclosed during development and commercialization.

Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure.

Neuregulins and their erbB receptors are essential for cardiac development and postulated to be cardioprotective in the presence of injury in the postnatal heart. We tested the hypothesis that the development of doxorubicin-induced cardiotoxicity in vivo is more severe in mice with heterozygous knockout of the neuregulin-1 gene (NRG-1(+/-)) compared with wild-type mice (WT). Three-month old NRG-1(+/-) and WT mice were injected with a single dose of doxorubicin (20 mg/kg ip).

Aldosterone directly stimulates cardiac myocyte hypertrophy.

Background: Clinical and experimental studies suggest that aldosterone modulates myocardial hypertrophy. From in vivo studies, it is not possible to distinguish between direct actions on myocyte growth and effects of mechanical load. In this study we tested the hypothesis that aldosterone induces myocyte hypertrophy in low-density, serum-free cultures of neonatal rat ventricular myocytes.

Mechanisms for increased glycolysis in the hypertrophied rat heart.

Glycolysis increases in hypertrophied hearts but the mechanisms are unknown. We studied the regulation of glycolysis in hearts with pressure-overload LV hypertrophy (LVH), a model that showed marked increases in the rates of glycolysis (by 2-fold) and insulin-independent glucose uptake (by 3-fold). Although the V(max) of the key glycolytic enzymes was unchanged in this model, concentrations of free ADP, free AMP, inorganic phosphate (P(i)), and fructose-2,6-bisphosphate (F-2,6-P2), all activators of the rate-limiting enzyme phosphofructokinase (PFK), were increased (up to 10-fold).

Effects of tai chi mind-body movement therapy on functional status and exercise capacity in patients with chronic heart failure: a randomized controlled trial.

Purpose: To examine the effects of a 12-week tai chi program on quality of life and exercise capacity in patients with heart failure.

Methods: Thirty patients with chronic stable heart failure and left ventricular ejection fraction < or =40% (mean [+/- SD] age, 64 +/- 13 years; mean baseline ejection fraction, 23% +/- 7%; median New York Heart Association class, 2 [range, 1 to 4]) were randomly assigned to receive usual care (n = 15), which included pharmacologic therapy and dietary and exercise counseling, or 12 weeks of tai chi training (n = 15) in addition to usual care. Tai chi training consisted of a 1-hour class held twice weekly.

Chronic ventricular myocyte-specific overexpression of angiotensin II type 2 receptor results in intrinsic myocyte contractile dysfunction.

ANG II type 2 receptor (AT(2)) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca(2+) concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT(2) was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT(2) in the ventricular myocytes and partial colocalization of AT(2) with AT(1).

Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion.

Background: Neuregulins are required for maintenance of acetylcholine receptor-inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances beta-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1+/-) and examined the effects of beta-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol.

Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice.

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/dt were depressed while LV diastolic pressure was elevated (P < 0.