Proinflammatory endothelial activation detected by molecular imaging in obese nonhuman primates coincides with onset of insulin resistance and progressively increases with duration of insulin resistance.

BACKGROUND: Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates. METHODS AND RESULTS: Ten adult male rhesus macaques were studied at baseline and every 4 to 6 months on a high-fat diet for 2 years. Truncal fat, carotid intima-media thickness, plasma inflammatory biomarkers, and carotid P-selectin and vascular cell adhesion molecule-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test was performed at baseline and at 4 and 18 months. A high-fat diet produced a rapid increase (P<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area under the curve and glucose disappearance rate on intravenous glucose tolerance test, all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in endothelial cell adhesion molecule expression over time (5- to 7-fold greater than control agent signal at 2 years; P<0.01). Changes in intima-media thickness were not detected until 2 years and, although there was a trend toward an increase in plasma markers of inflammation (monocyte chemotactic protein-1, C-reactive protein), the pattern of increase varied considerably over time. CONCLUSIONS: In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change in carotid intima-media thickness. Endothelial activation is related more to the duration rather than to the severity of IR and is not mirrored by changes in plasma biomarkers.

Short-term variability in outpatient pain intensity scores in a national sample of older veterans with chronic pain.

OBJECTIVE: The Department of Veterans Affairs (VA) uses the 11-point pain numeric rating scale (NRS) to gather pain intensity information from veterans at outpatient appointments. Yet, little is known about how NRS scores may vary over time within individuals; NRS variability may have important ramifications for treatment planning. Our main objective was to describe variability in NRS scores within a 1-month timeframe, as obtained during routine outpatient care in older patients with chronic pain treated in VA hospitals. A secondary objective was to explore for patient characteristics associated with within-month NRS score variability. DESIGN: Retrospective cohort study. SUBJECTS: National sample of veterans 65 years or older seen in VA in 2010 who had multiple elevated NRS scores indicating chronic pain. METHODS: VA datasets were used to identify the sample and demographic and clinical variables including NRS scores. For the main analysis, we identified subjects with two or more NRS scores obtained in each of two or more months in a 12-month period; we examined ranges in NRS scores across the first two qualifying months. RESULTS: Among 4,336 individuals in the main analysis cohort, the mean and median of the average NRS score range across the 2 months were 2.7 and 2.5, respectively. In multivariable models, main significant predictors of within-month NRS score variability were baseline pain intensity, overall medical comorbidity, and being divorced/separated. CONCLUSIONS: The majority of patients in the sample had clinically meaningful variation in pain scores within a given month. This finding highlights the need for clinicians and their patients to consider multiple NRS scores when making chronic pain treatment decisions.

Predictors of Improvements in Pain Intensity in a National Cohort of Older Veterans With Chronic Pain.

UNLABELLED: Little is known about the factors associated with pain-related outcomes in older adults. In this observational study, we sought to identify patient factors associated with improvements in pain intensity in a national cohort of older veterans with chronic pain. We included 12,924 veterans receiving treatment from the Veterans Health Administration with persistently elevated numeric rating scale scores in 2010 who had not been prescribed opioids in the previous 12 months. We examined: 1) percentage decrease over 12 months in average pain intensity scores relative to average baseline pain intensity score; and 2) time to sustained improvement in average pain intensity scores, defined as a 30% reduction in 3-month scores compared with baseline. Average relative improvement in pain intensity scores from baseline ranged from 25% to 29%; almost two-thirds met criteria for sustained improvement during the 12-month follow-up period. In models, higher baseline pain intensity and older age were associated with greater likelihood of improvement in pain intensity, whereas Veterans Affairs service-connected disability, mental health, and certain pain-related diagnoses were associated with lower likelihood of improvement. Opioid prescription initiation during follow-up was associated with lower likelihood of sustained improvement. The findings call for further characterization of heterogeneity in pain outcomes in older adults as well as further analysis of the relationship between prescription opioids and treatment outcomes. PERSPECTIVE: This study identified factors associated with improvements in pain intensity in a national cohort of older veterans with chronic pain. We found that older veterans frequently show improvements in pain intensity over time, and that opioid prescriptions, mental health, and certain pain diagnoses are associated with lower likelihood of improvement.

Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance.

The inability of insulin to increase skeletal muscle capillary blood volume (CBV) reduces glucose uptake in insulin resistance (IR). We hypothesized that abnormalities in endothelial-derived vasodilator pathways are temporally associated with the development of IR and an impaired ability to increase skeletal muscle CBV. A comprehensive metabolic and vascular screening assessment was performed on 10 adult rhesus macaques at baseline and every 4-6 months for 2 years after starting a high-fat diet supplemented with fructose. Diet changes resulted in an 80% increase in truncal fat by 4 months. Hyperinsulinemia and decreased glucose utilization were observed from 4 to 18 months. At 24 months, pancreatic secretory function and the glucose utilization rate declined. CBV at rest and during an intravenous glucose tolerance test demonstrated a sustained increase from 4 to 18 months and then abruptly fell at 24 months. Nitric oxide bioavailability progressively decreased over 2 years. Conversely, endothelial-derived vasodilators progressively increased over 18 months and then abruptly decreased at 24 months in concert with the CBV. The increase in basal and glucose-mediated CBV early in IR may represent a compensatory response through endothelial-derived vasodilator pathways. The inability to sustain a vascular compensatory response limits glucose-mediated increases in CBV, which correlates with the severity of IR.

Orphanin FQ/nociceptin and mu-opioid receptor mRNA levels in human SH-SY5Y neuroblastoma cells: effects of activating the cAMP-PKA signal transduction pathway.

Responses to opioid agonists vary, depending on past opioid exposure and the physiological state. The intracellular signaling pathway mediated by cAMP and protein kinase A (PKA) has been linked to regulation of opioid receptor responsiveness. The role of the cAMP-PKA pathway in regulating opioid receptor gene expression is incompletely defined. Mu-opioid receptor (MuOR) and orphanin FQ/nociceptin receptor (ORL(1)) transcripts were measured after activating this pathway in human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were maintained in continuous monolayer culture. Cells were incubated with combinations of agents which activate the cAMP-PKA signal transduction pathway, including forskolin and choleratoxin (CTX). MuOR and ORL(1) transcript levels were measured by hybridization to specific probes. Activation of the cAMP-PKA signal transduction pathway with forskolin in the presence of phosphodiesterase inhibitors was associated with a time-dependent decrease in the level of MuOR mRNA; partial recovery was observed with prolonged incubations. Forskolin effects were mimicked by CTX, but not by dideoxyforskolin. The PKA inhibitor H89 blunted the actions of forskolin. However, forskolin responses persisted despite coincubation with protein synthesis inhibitors. ORL(1) transcript levels did not significantly change, but vasoactive intestinal polypeptide (VIP) transcripts exhibited substantial increases, in the presence of forskolin or CTX. These observations support a role for cAMP in regulating MuOR responsiveness through actions at the level of receptor gene expression. ORL(1) transcript levels are not effected, suggesting that the cAMP-PKA pathway has differential effects on the expression of mRNA for different, but biochemically closely related, opioid receptor subtypes.

Dual-energy X-ray absorptiometry for quantification of visceral fat.

Obesity is the major risk factor for metabolic syndrome and through it diabetes as well as cardiovascular disease. Visceral fat (VF) rather than subcutaneous fat (SF) is the major predictor of adverse events. Currently, the reference standard for measuring VF is abdominal X-ray computed tomography (CT) or magnetic resonance imaging (MRI), requiring highly used clinical equipment. Dual-energy X-ray absorptiometry (DXA) can accurately measure body composition with high-precision, low X-ray exposure, and short-scanning time. The purpose of this study was to validate a new fully automated method whereby abdominal VF can be measured by DXA. Furthermore, we explored the association between DXA-derived abdominal VF and several other indices for obesity: BMI, waist circumference, waist-to-hip ratio, and DXA-derived total abdominal fat (AF), and SF. We studied 124 adult men and women, aged 18-90 years, representing a wide range of BMI values (18.5-40 kg/m(2)) measured with both DXA and CT in a fasting state within a one hour interval. The coefficient of determination (r(2)) for regression of CT on DXA values was 0.959 for females, 0.949 for males, and 0.957 combined. The 95% confidence interval for r was 0.968 to 0.985 for the combined data. The 95% confidence interval for the mean of the differences between CT and DXA VF volume was -96.0 to -16.3 cm(3). Bland-Altman bias was +67 cm(3) for females and +43 cm(3) for males. The 95% limits of agreement were -339 to +472 cm(3) for females and -379 to +465 cm(3) for males. Combined, the bias was +56 cm(3) with 95% limits of agreement of -355 to +468 cm(3). The correlations between DXA-derived VF and BMI, waist circumference, waist-to-hip ratio, and DXA-derived AF and SF ranged from poor to modest. We conclude that DXA can measure abdominal VF precisely in both men and women. This simple noninvasive method with virtually no radiation can therefore be used to measure VF in individual patients and help define diabetes and cardiovascular risk.

N-acetylcysteine for patients with prolonged hypotension as prophylaxis for acute renal failure (NEPHRON).

BACKGROUND: Acute renal failure is a common complication in critically ill patients and carries an increased morbidity and mortality. N-acetylcysteine is an antioxidant and anti-inflammatory agent that may counteract some of the pathophysiologic derangements in shock states. OBJECTIVE: To test whether the administration of N-acetylcysteine, compared with placebo, reduces the incidence of acute renal failure in hypotensive patients. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study. SETTING: Intensive care units of a university tertiary care hospital. PATIENTS: One hundred forty-two patients with new onset (within 12 hrs) of at least>or=30 consecutive minutes of hypotension and/or vasopressor requirement. INTERVENTIONS: Patients were randomized to receive either N-acetylcysteine or placebo for 7 days, in addition to standard supportive therapy. MEASUREMENTS AND MAIN RESULTS: Patients who received N-acetylcysteine had an incidence of acute renal failure (>or=0.5 mg/dL increase in creatinine) of 15.5%, compared with 16.9% in those receiving placebo (p=.82, not significant). There were no significant differences between treatment arms in any of the secondary outcomes examined, including incidence of a 50% increase in creatinine, maximal rise in creatinine, recovery of renal function, length of intensive care unit and hospital stay, requirement for renal replacement therapy, and mortality. Among patients receiving N-acetylcysteine, there were trends toward reduced incidence of acute renal failure in patients with baseline Sequential Organ Failure Assessment (SOFA) score>8 (p=.12), lower SOFA scores during the first 4 days of treatment (p=.28), and reduced mortality in patients<65 yrs of age (p=.20). CONCLUSIONS: There were no significant differences in any of our primary or secondary end points between patients treated with N-acetylcysteine or placebo. Trends toward reduced incidence of acute renal failure in patients with baseline SOFA score >8, reduced SOFA scores during the first 4 days, and reduced mortality in patients<65 yrs of age are provocative but require further study to determine their clinical significance.