Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

Background & Aims: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB.

Methods And Results: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects.

Background & Aims: Amino acids may interfere with insulin action, particularly in obese individuals. We hypothesized that increased circulating branched-chain and aromatic amino acids herald insulin resistance and ectopic fat storage, particularly hepatic fat accumulation.

Methods And Results: We measured fasting branched-chain and aromatic amino acids (tryptophan, tyrosine, and phenylalanine) by mass spectrometry in 111 overweight to obese subjects.

Vitamin D antagonizes negative effects of preeclampsia on fetal endothelial colony forming cell number and function.

Context: Endothelial dysfunction is a primary feature of preeclampsia, a pregnancy complication associated with an increased future cardiovascular risk for mother and offspring. Endothelial colony forming cells (ECFC) are endothelial progenitor cells that participate in vasculogenesis and endothelial repair.

Objective: We hypothesized that the number and functional properties of fetal cord blood-derived ECFCs are reduced in preeclampsia compared to uncomplicated pregnancy (controls), and asked if adverse effects of preeclampsia on ECFC function are reversed by 1,25 (OH)2 vitamin D3.

Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.

Acute atherosis (Aa) affects uteroplacental spiral arteries in 20-40% of cases of preeclampsia. Its hallmark is lipid-filled, CD68-positive foam cells. It usually develops in the decidua (the pregnancy endometrium) at the distal ends of arteries that are often unremodelled in their proximal segments.

Aldosterone abrogates nuclear factor kappaB-mediated tumor necrosis factor alpha production in human neutrophils via the mineralocorticoid receptor.

Mineralocorticoid receptor (MR) activation by aldosterone controls salt homeostasis and inflammation in several tissues and cell types. Whether or not a functional MR exists in polymorphonuclear neutrophils is unknown. We investigated the hypothesis that aldosterone modulates inflammatory neutrophil responses via the MR.

Circulating endocannabinoid concentrations during orthostatic stress.

Background: In animals, the endocannabinoid system is activated during hemodynamic insults and restrains blood pressure in part through sympathetic inhibition.

Materials And Methods: We tested the hypothesis that hemodynamic stress elicited by head-up tilt testing increases systemic endocannabinoid concentrations in humans and that excessive endocannabinoid availability predisposes to presyncope.

Results: With head-up tilt, 2-arachidonoylglycerol increased, whereas anandamide remained unchanged.

Heritability of left ventricular and papillary muscle heart size: a twin study with cardiac magnetic resonance imaging.

Aims: Earlier studies in monozygotic (MZ) and dizygotic (DZ) twins showed genetic variance on echocardiographically determined heart size. However, cardiovascular magnetic resonance (CMR) is more precise and reproducible. We performed a twin study relying on CMR, focusing on left ventricular (LV) mass and papillary muscle, since there are no genetic reports on this structure.

C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-induced necrotizing crescentic glomerulonephritis (NCGN) requires complement participation in its pathogenesis. We tested the hypothesis that the anaphylatoxin C5a is pivotal to disease induction via the neutrophil C5a receptor (C5aR). Supernatants from ANCA-activated neutrophils activated the complement cascade in normal serum, producing C5a.

The Valsalva maneuver: screening for drug-induced baroreflex dysfunction.

Objective: Many drugs can interfere with baroreflex mechanisms thereby impairing blood pressure control, but few have undergone sufficient testing. The state of affairs may be explained by the lack of simple and inexpensive screening tests.

Methods: In eleven healthy men, we tested the hypothesis that a simple Valsalva maneuver could detect drug-induced changes in baroreflex function that have previously been described using more elaborate and invasive methodologies.

Single- or dual-bolus approach for the assessment of myocardial perfusion reserve in quantitative MR perfusion imaging.

A dual-bolus protocol can overcome limitations due to T1-induced MR signal attenuation and hence enables more accurate quantification of myocardial blood flow (MBF) by contrast enhanced MR perfusion imaging. The study explores potential benefits of the dual-bolus technique for the assessment of myocardial perfusion reserve (MPR) over a standard single-bolus protocol. Nineteen patients without obstructive coronary artery disease as assessed by cardiac catheterization underwent a stress-rest MR perfusion study using a dual-bolus protocol.

Hormonal influences on cardiovascular norepinephrine transporter responses in healthy women.

Gender differences in human cardiovascular norepinephrine transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25+/-1 years) during the early follicular phase (day 5+/-0) and midluteal phase (day 22+/-0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective norepinephrine transporter inhibitor reboxetine or placebo.

(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats.

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats.

Direct renin inhibition with aliskiren in hypertension and target organ damage.

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage.

Contrast-dose relation in first-pass myocardial MR perfusion imaging.

Purpose: To determine the regime of linear contrast enhancement in human first-pass perfusion cardiovascular magnetic resonance (CMR) imaging to improve accuracy in myocardial perfusion quantification.

Materials And Methods: A total of 10 healthy subjects were studied on a clinical 1.5T MR scanner.

Major histocompatibility complex HLA region largely explains the genetic variance exercised on neutrophil membrane proteinase 3 expression.

ANCA-associated vasculitides, a common cause of rapidly progressive glomerulonephritis, are influenced by genetic variance. Neutrophil membrane expression of the ANCA antigen proteinase 3 (PR3) is pathogenically important. A subset of membrane PR3-positive neutrophils can be distinguished from a membrane-negative subset in any given subject.

Fever-like temperatures affect neutrophil NF-kappaB signaling, apoptosis, and ANCA-antigen expression.

The neutrophil is pivotal to ANCA vasculitis pathogenesis. Fever frequently complicates ANCA diseases. This study investigated the effects of short-term heat exposure on apoptosis in neutrophils that were treated with LPS, GM-CSF, IL-8, and dexamethasone.

Membrane proteinase 3 and Wegener's granulomatosis.

Proteinase 3 (PR3) is found in neutrophil and monocyte lysosomal granules. Anti-neutrophil cytoplasmatic antibodies (ANCA) with specificity for PR3 are characteristic for patients with Wegener's granulomatosis. The interaction of ANCA with neutrophilic ANCA antigens is necessary for the development of ANCA-associated diseases.

Renalase, a catecholamine-metabolizing hormone from the kidney.

A novel flavin adenine dinucleotide-dependent amine oxidase that is secreted by the kidney, circulates in the blood, and modulates cardiac function and systemic blood pressure has recently been discovered. Renalase appears to be a hormone that metabolizes catecholamines, and its discovery will facilitate our understanding of sympathetic regulation.

The mineralocorticoid receptor and oxidative stress.

Reactive oxygen species are profoundly important for many physiologic functions and are also pivotal to numerous disease processes, particularly those involving inflammation. Much evidence has accrued demonstrating that aldosterone acts locally in many cells aside from those in the cortical collecting duct. Peripheral blood monocytes and vascular smooth muscle cells are both influenced by aldosterone to produce reactive oxygen species.

Mendelian forms of human hypertension and mechanisms of disease.

Mendelian forms of hypertension have ushered in a revolution in our knowledge of blood pressure and volume regulation. If we include information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension.

Membrane proteinase 3 expression in patients with Wegener's granulomatosis and in human hematopoietic stem cell-derived neutrophils.

A large membrane proteinase 3 (mPR3)-positive neutrophil subset (mPR3high) is a risk for Wegener's granulomatosis (WG). The relationship between mPR3 expression and clinical manifestations was investigated in 81 WG patients and mPR3 expression was studied in CD34+ stem cell-derived human neutrophils. The mPR3high neutrophil percentage correlated with renal function, anemia, and albumin at the time of presentation.

Blood oxygen level-dependent MRI of tissue oxygenation: relation to endothelium-dependent and endothelium-independent blood flow changes.

Objectives: The contribution of endothelial function to tissue oxygenation is not well understood. Muscle blood oxygen level-dependent MRI (BOLD MRI) provides data largely dependent on hemoglobin (Hb) oxygenation. We used BOLD MRI to assess endothelium-dependent signal intensity (SI) changes.

Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1)-mediated pathway and vascular oxidative injury in older-age rat renal transplants.

Background: Older-age renal allografts are associated with inferior survival; however, the mechanisms are unclear. Reactive oxygen species participate in aging and in chronic vascular disease. We investigated how mediators of oxidative stress may increase allograft susceptibility to vascular injury.