Functional Biomarkers: an Approach to Bridge Pharmacokinetics and Pharmacodynamics in Pediatric Clinical Trials.

Over the past 30 years, much has been learned about the impact of development on drug disposition (i.e., pharmacokinetics).

scaRNAs regulate splicing and vertebrate heart development.

Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs.

Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.

Monogenic diseases are frequent causes of neonatal morbidity and mortality, and disease presentations are often undifferentiated at birth. More than 3500 monogenic diseases have been characterized, but clinical testing is available for only some of them and many feature clinical and genetic heterogeneity. Hence, an immense unmet need exists for improved molecular diagnosis in infants.

Noncoding RNA expression in myocardium from infants with tetralogy of Fallot.

Background: The importance of noncoding RNAs (ncRNA), especially microRNAs (miRNAs), for maintaining stability in the developing vertebrate heart has recently become apparent; however, there is little known about the expression pattern of ncRNA in the human heart with developmental anomalies.

Methods And Results: We examined the expression of miRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, 3 fetal heart samples, and 8 normally developing infants.

Modulation of human cardiovascular outward rectifying chloride channel by intra- and extracellular ATP.

The macroscopic volume-regulated anion current (VRAC) is regulated by both intracellular and extracellular ATP, which has important implications in signaling and regulation of cellular excitability. The outwardly rectifying Cl(-) channel (ORCC) is a major contributor to the VRAC. This study investigated the effects of intracellular and extracellular ATP on the ORCCs expressed in the human cardiovascular system.

beta2-Adrenergic receptor agonists stimulate L-type calcium current independent of PKA in newborn rabbit ventricular myocytes.

Selective stimulation of beta(2)-adrenergic receptors (ARs) in newborn rabbit ventricular myocardium invokes a positive inotropic effect that is lost during postnatal maturation. The underlying mechanisms for this age-related stimulatory response remain unresolved. We examined the effects of beta(2)-AR stimulation on L-type Ca(2+) current (I(Ca,L)) during postnatal development.

Phospholemman expression is high in the newborn rabbit heart and declines with postnatal maturation.

Phospholemman (PLM) is a small sarcolemmal protein that modulates the activities of Na(+)/K(+)-ATPase and the Na(+)/Ca(2+) exchanger (NCX), thus contributing to the maintenance of intracellular Na(+) and Ca(2+) homeostasis. We characterized the expression and subcellular localization of PLM, NCX, and the Na(+)/K(+)-ATPase alpha1-subunit during perinatal development. Western blotting demonstrates that PLM (15kDa), NCX (120kDa), and Na(+)/K(+)-ATPase alpha-1 (approximately 100kDa) proteins are all more than 2-fold higher in ventricular membrane fractions from newborn rabbit hearts (1-4-day old) compared to adult hearts.

Consequences of cardiac myocyte-specific ablation of KATP channels in transgenic mice expressing dominant negative Kir6 subunits.

Cardiac ATP-sensitive K+ (K(ATP)) channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice that express dominant negative Kir6.

Expression of ATP-sensitive K+ channel subunits during perinatal maturation in the mouse heart.

Prevailing data suggest that sarcolemmal ATP-sensitive (K(ATP)) channels in the adult heart consist of Kir6.2 and SUR2A subunits, but the expression of other K(ATP) channel subunits (including SUR1, SUR2B, and Kir6.1) is poorly defined.

Paradoxical effect of dofetilide on action potential duration and calcium transient amplitude in newborn rabbit ventricular myocytes.

The Na+-Ca2+ exchanger (NCX) is up-regulated in the neonatal rabbit heart. Because the duration of membrane depolarization is an important determinant of calcium entry via NCX, pharmacological agents that lengthen the action potential (AP) may significantly increase the amount of activator calcium in newborns. We tested this potentially novel therapeutic strategy by using action potential voltage clamp steps or using dofetilide, a blocker of IKr, to prolong the action potential duration (APD).

Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature.

Background: Electrophysiological data suggest that cardiac KATP channels consist of Kir6.2 and SUR2A subunits, but the distribution of these (and other KATP channel subunits) is poorly defined. We examined the localization of each of the KATP channel subunits in the mouse and rat heart.

Negative inotropic effect of nifedipine in the immature rabbit heart is due to shortening of the action potential.

Contractions in neonatal rabbit ventricular myocytes seem to depend predominantly on Ca2+ influx through the Na+-Ca2+ exchanger (NCX). Unexpectedly, neonates are sensitive to the negative inotropic effect of L-type Ca2+ channel blockers. L-type Ca2+ channel blockers depress contractile function indirectly in neonatal myocytes by shortening the action potential duration (APD), thereby decreasing the influx of activator Ca2+ through the NCX.

K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits.

Functional ATP-sensitive potassium (K(ATP)) channels can be reconstituted by expression of various combinations of different pore-forming subunits (Kir6.1 and Kir6.2) and sulfonylurea receptor (SUR) subunits.

Posttraumatic stress disorder in children after cardiac surgery.

Objective: Children undergoing cardiac surgery often experience traumatic situations related to their care and may be at risk for developing posttraumatic stress disorder (PTSD). The purpose of this study was to examine children's responses to cardiac surgery and the factors that mediate responses.

Study Design: Forty-three 5- to 12-year-old children undergoing cardiac surgery were evaluated pre- and postoperatively for PTSD.

Developmental expression of NCS-1 (frequenin), a regulator of Kv4 K+ channels, in mouse heart.

The channel proteins responsible for the cardiac transient outward K+ current (Ito) of human and rodent heart are composed, in part, of pore-forming Kv4.3 or Kv4.2 principal subunits.

Impact of a clinical pathway on the postoperative care of children undergoing surgical closure of atrial septal defects.

The purpose of this study was to impact of a clinical pathway on the postoperative management of children undergoing surgical closure of atrial septal defects (ASDs). Three groups of children were studied: group 1 (14 patients), before introduction of an intensive care team, minimally invasive surgery, and the clinical pathway; group 2 (17 patients), after the introduction of the intensive care team and minimally invasive surgical techniques but before the pathway; and group 3 (30 patients), after implementation of the clinical pathway. Average hospital length of stay fell from 118.

Measuring health-related quality of life in children with heart disease.

This study tested an instrument for measuring health-related quality of life (HRQL) in children with heart disease. HRQL was measured using the New York University Children's Heart Health Survey in a sample of 0- to 20-year-old subjects with heart disease compared with a control group. Heart disease was associated with impairment on all subscales except psychological function.