The "parallel-cohort RCT": Novel design aspects and application in the Kids-DOTT trial of pediatric venous thromboembolism.

In traditional randomized controlled trial (RCT) designs, patients who are ineligible for randomization are excluded from study participation. However, these patients often constitute an important subgroup of the disease population. By extending existing RCT infrastructure, efforts to evaluate such patients in parallel cohort arms would provide an efficient means of generating multi-center prospective data on natural history, which would facilitate the development of future RCTs involving these subgroups of interest.

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults.

The prevalence of cardiovascular disease is lower in middle-aged and older women than men. Increased endothelin-1-mediated vasoconstriction has been linked to the etiology of a number of cardiovascular diseases, including atherosclerosis, heart failure, and hypertension. It is unknown whether a sex difference in endothelin-1-mediated vasoconstrictor tone exists in middle-aged and older adults.

Seasonal proteomic changes reveal molecular adaptations to preserve and replenish liver proteins during ground squirrel hibernation.

Hibernators are unique among mammals in their ability to survive extended periods of time with core body temperatures near freezing and with dramatically reduced heart, respiratory, and metabolic rates in a state known as torpor. To gain insight into the molecular events underlying this remarkable physiological phenotype, we applied a proteomic screening approach to identify liver proteins that differ between the summer active (SA) and the entrance (Ent) phase of winter hibernation in 13-lined ground squirrels. The relative abundance of 1,600 protein spots separated on two-dimensional gels was quantitatively determined using fluorescence difference gel electrophoresis, and 74 unique proteins exhibiting significant differences between the two states were identified using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS).

Calcineurin activates interleukin-6 transcription in mouse skeletal muscle in vivo and in C2C12 myotubes in vitro.

Expression of the cytokine interleukin-6 (IL-6) by skeletal muscle is hugely increased in response to a single bout of endurance exercise, and this appears to be mediated by increases in intracellular calcium. We examined the effects of endurance exercise on IL-6 mRNA levels and promoter activity in skeletal muscle in vivo, and the role of the calcium-activated calcineurin signaling pathway on muscle IL-6 expression in vivo and in vitro. IL-6 mRNA levels in the mouse tibialis anterior (TA) were increased 2-10-fold by a single bout of treadmill exercise or by 3 days of voluntary wheel running.

Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure.

At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological, and prognostic features in common. PAH is a particularly severe and progressive form of PH that frequently leads to right heart failure and premature death.

Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants.

Exposure of preterm infants to hyperoxia impairs vascular growth, contributing to the development of bronchopulmonary dysplasia and retinopathy of prematurity. Disruption of vascular endothelial growth factor (VEGF)-nitric oxide (NO) signaling impairs vascular growth. Endothelial progenitor cells (EPCs) may play an important role in vascular growth.

Acute hypoxia impairs dynamic cerebral autoregulation: results from two independent techniques.

We investigated the effect of acute hypoxia (AH) on dynamic cerebral autoregulation (CA) using two independent assessment techniques to clarify previous, conflicting reports. Twelve healthy volunteers (6 men, 6 women) performed six classic leg cuff tests, three breathing normoxic (Fi(O2) = 0.21) and three breathing hypoxic (Fi(O2) = 0.

Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences.

Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release.

Ghrelin protects mice against endotoxemia-induced acute kidney injury.

Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50-80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI.

Role of purinergic P2Y1 receptors in regulation of vasopressin and oxytocin secretion.

Pharmacological studies demonstrated that ATP elevates intracellular calcium ([Ca(2+)](i)) in supraoptic nucleus (SON) neurons primarily by activation of P2X2 and P2Y1 purinergic receptors [P2Y1R]. The current studies provide evidence for the presence of P2Y1R protein in SON neurons, evidence that activation of these P2Y1Rs induces an increase in [Ca(2+)](i) from both intracellular stores and Ca(2+) influx, and functional evidence that activation of P2Y1Rs induces vasopressin (VP) and oxytocin (OT) hormone release. Pretreatment of Fura-2 AM-loaded explants of the hypothalamo-neurohypophyseal system (HNS) with thapsigargin (TG) significantly (approximately 80%) reduced the increase in [Ca(2+)](i) induced by the P2Y1R-specific agonist, 2-methylthio-ADP (2-MeSADP).

Greater systemic lipolysis in women compared with men during moderate-dose infusion of epinephrine and/or norepinephrine.

Women have lower circulating catecholamine levels during metabolic perturbations, such as exercise or hypoglycemia, but similar rates of systemic lipolysis. This suggests women may be more sensitive to the lipolytic action of catecholamines, while maintaining similar glucoregulatory effects. The aim of the present study, therefore, was to determine whether women have higher rates of systemic lipolysis compared with men in response to matched peripheral infusion of catecholamines, but similar rates of glucose turnover.

Myocardial FFA metabolism during rest and atrial pacing in humans.

There is limited in vivo data in humans evaluating myocardial fat utilization during increased heart work. This study was done to determine myocardial free fatty acid (FFA) metabolism during rest and atrial pacing, which increases cardiac work without changing arterial substrate concentration. We studied seven healthy men and women (age = 49.

Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse.

The vascular endothelium expresses endothelial nitric oxide synthase (eNOS) that generates nitric oxide (NO) to help maintain vascular integrity due to its anti-inflammatory, antiproliferative, and antithrombogenic effects. Pharmacological blockade of NO production has been shown to exacerbate renal injury in chronic renal disease and induces endothelial cell loss. However, pharmacological inhibition of NO nonspecifically blocks other types of NOS and therefore does not define the specific role of eNOS in kidney disease.

Electrogenic NBCe1 (SLC4A4), but not electroneutral NBCn1 (SLC4A7), cotransporter undergoes cholinergic-stimulated endocytosis in salivary ParC5 cells.

Cholinergic agonists are major stimuli for fluid secretion in parotid acinar cells. Saliva bicarbonate is essential for maintaining oral health. Electrogenic and electroneutral Na(+)-HCO(3)(-) cotransporters (NBCe1 and NBCn1) are abundant in parotid glands.

Endothelial EphA receptor stimulation increases lung vascular permeability.

Mediators of angiogenesis such as VEGFs and angiopoietins may regulate pulmonary vascular permeability under normal and pathological conditions. Ephrin family receptor tyrosine kinases are expressed in the vasculature and also regulate angiogenesis under some circumstances, but whether they also modulate lung vascular permeability is unknown. We hypothesized that stimulation of lung endothelial EphA receptors with ephrin-a1 ligand would alter pulmonary vascular permeability and tested this idea in vivo and in vitro.

Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling.

Although production of reactive oxygen species (ROS) such as superoxide (O(2)(.-)) has been implicated in chronic hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling, the transcription factors and gene targets through which ROS exert their effects have not been completely identified. We used mice overexpressing the extracellular antioxidant enzyme extracellular superoxide dismutase (EC-SOD TG) to test the hypothesis that O(2)(.

Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude.

Reduced uteroplacental blood flow is hypothesized to play a key role in altitude-associated fetal growth restriction. It is unknown whether reduced blood flow is a cause or consequence of reduced fetal size. We asked whether determinants of uteroplacental blood flow were altered prior to reduced fetal growth and whether vasoactive and/or angiogenic factors were involved.

Role of AQP1 in endotoxemia-induced acute kidney injury.

The effect of endotoxemia (lipopolysaccharide, 2.5 mg/kg ip) was investigated in aquaporin (AQP) 1 knockout (KO) compared with wild-type (WT) mice. At baseline, KO mice exhibited higher water intake (WI) and urine output (UO).

Electromyographic measures of muscle activation and changes in muscle architecture of human elbow flexors during fatiguing contractions.

The study compared changes in intramuscular and surface recordings of EMG amplitude with ultrasound measures of muscle architecture of the elbow flexors during a submaximal isometric contraction. Ten subjects performed a fatiguing contraction to task failure at 20% of maximal voluntary contraction force. EMG activity was recorded in biceps brachii, brachialis, and brachioradialis muscles using intramuscular and surface electrodes.

Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists.

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults.

Adaptive inverse control of linear and nonlinear systems using dynamic neural networks.

In this paper, we see adaptive control as a three-part adaptive-filtering problem. First, the dynamical system we wish to control is modeled using adaptive system-identification techniques. Second, the dynamic response of the system is controlled using an adaptive feedforward controller.

Impaired VEGF and nitric oxide signaling after nitrofen exposure in rat fetal lung explants.

We hypothesized that abnormal fetal lung growth in experimental congenital diaphragmatic hernia after maternal nitrofen exposure alters lung structure due to impaired VEGF signaling, which can be reversed with VEGF or nitric oxide (NO) treatment. Timed-pregnant Sprague-Dawley rats were treated with nitrofen on embryonic day 9 (E9), and fetal lungs were harvested for explant culture on E15. Explants were maintained in 3% O2 for 3 days and were treated with NO gas or recombinant human VEGF protein for 3 days.

High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men.

Resting whole leg blood flow and vascular conductance decrease linearly with advancing age in healthy adult men. The potential role of age-related increases in oxidative stress in these changes is unknown. Resting leg blood flow during saline and ascorbic acid infusion was studied in 10 young (25 +/- 1 yr) and 11 older (63 +/- 2 yr) healthy normotensive men.

Early inhaled nitric oxide treatment decreases apoptosis of endothelial cells in neonatal rat lungs after vascular endothelial growth factor inhibition.

Vascular endothelial growth factor (VEGF) receptor blockade impairs lung growth and decreases nitric oxide (NO) production in neonatal rat lungs. Inhaled NO (iNO) treatment after VEGF inhibition preserves lung growth in infant rats by unknown mechanisms. We hypothesized that neonatal VEGF inhibition disrupts lung growth by causing apoptosis in endothelial cells, which is attenuated by early iNO treatment.

Physiological genetics of dietary restriction: uncoupling the body temperature and body weight responses.

Numerous physiological and molecular changes accompany dietary restriction (DR), which has been a major impediment to elucidating the causal basis underlying DR's many health benefits. Two major metabolic responses to DR that potentially underlie many of these changes are the body temperature (T(b)) and body weight (BW) responses. These responses also represent an especially difficult challenge to uncouple during DR.