Up-regulation of blood arachidonate (20:4) levels in patients with chronic obstructive pulmonary disease

Context and objective: Plasma arachidonate (20:4) levels in patients with chronic obstructive pulmonary disease (COPD) were investigated. Methods: Plasma was extracted and free fatty acids (FFAs) were separated using column chromatography and measured by fluorescence. Plasma 20:4 levels and its percentage relative to total FFA levels (%20:4) were measured in COPD (n = 18) and control (n = 20) subjects. Results and conclusions: FFA levels were lower in COPD compared with normals. However, there was a significant increase in %20:4 levels in COPD patients (GOLD stage I/II 0.9 ± 0.4%; GOLD stage III/IV 1.1 ± 0.1%) compared with control subjects (0.6 ± 0.1, p < 0.05). %20:4 is a potential biomarker for COPD.     

Basal and Stimulated Plasma Leptin in Diabetic Subjects

LIU, JIANMEI, HASAN ASKARI, AND SAMUEL DAGOGO-JACK. Basal and stimulated plasma leptin in diabetic subjects. Obes Res. Objective: To determine whether leptin secretion is impaired in diabetes, we compared basal and stimulated plasma leptin levels in diabetic subjects and healthy controls. Research Methods and Procedures: Blood samples for assay of leptin and other hormones were obtained at baseline in 54 diabetic patients and 65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined as “negative” if ≤0.1 ng/mL or “positive” if ≥0.3 ng/mL, in fasting plasma. Results: Basal plasma leptin levels were 19. 7±2. 2 ng/mL in nondiabetic subjects, 13. 4±1. 5 ng/ml in C-peptide negative (n = 28) and 26. 1±23. 7 ng/mL in C-peptide positive (n = 26, p = 0. 001) diabetic patients. Dexamethasone increased leptin levels of controls (n = 6) to 145±17% of baseline values at 8 hours (p = O. O3), 224±18% at 16 hours (p = 0. 01), and 134218% at 40 hours (p = 0. 05). The corresponding changes were 108±13%, 126±23%, and 98±16% in C-peptide negative (n = 6), and 121±10%, 144±16% (p = 0. 03), and 147±23% (p = 0. 11) in C-peptide positive (n = 6) diabetic patients, respectively. The peak stimulated leptin levels were lower in the diabetic patients, compared with controls. Plasma insulin increased (p = 0. 02) in controls, but not in the diabetic patients, following dexamethasone. Discussion: Although diabetic patients have normal plasma leptin levels under basal conditions, their leptin responses to glucocorticoid are impaired, probably because of the concomitant insulin secretory defect. A subnormal leptin secretory response could worsen obesity and insulin resistance in diabetes.     

Reduction of Plasma Leptin Concentrations by Arginine but Not Lipid Infusion in Humans

Objective: We examined short-term effects of arginine infusion on plasma leptin in diabetic and healthy subjects. Research Methods and Procedures: Arginine stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin A_1c; 7.3 ± 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 ± 0.7%), and nondiabetic subjects (CON; 5.4 ± 0.1%). Results: Fasting plasma leptin correlated linearly with body mass index among all groups (r = 0.61, p = 0.001). During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p < 0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by ∼11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in DM1 (0.6 ± 0.1 mM) and DM2 (0.6 ± 0.1 mM) than in CON (0.4 ± 0.1 mM, p < 0.05) and transiently declined by ∼50% (p < 0.05) at 45 minutes in all groups before rebounding toward baseline. To examine the direct effects of FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and glycerol during fasting, and somatostatin-insulin (∼35 pM) -glucagon (∼90 ng/mL) clamps were performed. In both protocols, plasma leptin continuously declined by ∼25% (p < 0.05) during 540 minutes without any difference between the high and low FFA conditions. Discussion: Arginine infusion transiently decreased plasma leptin concentrations both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a direct inhibitory effect of the amino acid but not of insulin or FFAs.     

Do supervised weekly exercise programs maintain functional exercise capacity and quality of life, twelve months after pulmonary rehabilitation in COPD?

Background

Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency.

Methods

Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7). Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis.

Results

No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively).

Conclusion

Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT.     

Serum selenium versus lymphocyte subsets and markers of disease progression and inflammatory response in human immunodeficiency virus-1 infection

Serum selenium levels were determined cross-sectionally in 57 HIV-infected patients who were classified according to the Centers for Disease Control (CDC) 1993 classification system. Mean serum selenium levels were lower in CDC stage II (58.7±12.2 μg/L;p<0.01;n=18) and stage III (47.6±11.3 μg/L;p<0.01;n=19) HIV-infected patients, than in healthy subjects (80.6±9.6 μg/L;n=48) and stage I patients (73.6±16.5 μg/L;n=20). Serum selenium levels were positively correlated with CD4 count, CD4/8 ratio, hematocrit, and serum albumin (r=0.42;r=0.39;r=0.48; andr=0.45;p<0.01, respectively) and inversely with serum levels of thymidine kinase (r=−0.49;p<0.01;n=49) and β2-microglobulin (r=−0.46;p<0.001;n=49). In addition, serum selenium levels in 20 randomly selected AIDS-free individuals (CDC I:n=10; CDC II:n=10) were inversely correlated with serum concentrations of interleukin-8 (IL-8) and soluble tumor necrosis factor receptors (sTNFR) types I and II. There was no correlation with serum immuneglobulin A and total serum protein levels. The results show that the progressive deprivation of serum selenium in HIV-infection is associated with loss of CD4⁺-cells and with increased levels of markers of disease progression and inflammatory response.     

Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised,placebo-controlled TORCH study

Background

The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease.

Methods

TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV₁ < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV₁, 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV₁ to segment patients into three groups: moderate COPD (GOLD stage II and above: ≥ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937).

Results

Compared with placebo, SFC improved post-bronchodilator FEV₁: 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.

Conclusion

In the TORCH study, SFC reduced moderate-to-severe exacerbations and improved health status and FEV₁ across GOLD stages. Treatment with SFC may be associated with reduced mortality compared with placebo in patients with GOLD stage II disease. The effects were similar to those reported for the study as a whole. Thus, SFC is an effective treatment option for patients with GOLD stage II COPD.

Trial registration

Clinicaltrial.gov registration {"type":"clinical-trial","attrs":{"text":"NCT00268216","term_id":"NCT00268216"}}NCT00268216; Study number: {"type":"entrez-protein","attrs":{"text":"SCO30003","term_id":"1252146891","term_text":"SCO30003"}}SCO30003     

Plasma Levels of Adiponectin,a Novel Adipocyte‐Derived Hormone,in Sleep Apnea**

Objective: Obstructive sleep apnea (OSA) is associated with obesity, sympathetic activation, systemic inflammation, and cardiovascular morbidity. Obesity, β‐adrenergic agonists, and inflammation are linked to decreased expression and/or secretion of an adipose tissue‐derived antiatherogenic hormone, adiponectin. The purpose of the study was to investigate whether OSA affected plasma levels of adiponectin, which might help explain OSA‐associated cardiovascular morbidity. Research Methods and Procedures: We randomly selected 68 otherwise healthy male subjects, either with moderate/severe OSA [apnea‐hypopnea index (AHI) ≥ 20; n = 35] or without OSA (AHI ≤ 5; n = 33). The diagnosis of OSA was made based on prospective full polysomnography. Adiponectin was measured before polysomnography between 8 and 10 PM . Results: AHI was higher in the OSA group (49.5 ± 4.4 vs. 2.9 ± 0.4 events/h; p < 0.001). OSA subjects were also more obese, with greater BMI (33 ± 1 vs. 30 ± 1; p = 0.016) and percentage body fat (29 ± 1% vs. 26 ± 1%; p = 0.030). Adiponectin levels were 7.67 ± 0.73 and 6.33 ± 0.51 μg/mL in the OSA and non‐OSA groups, respectively, and this difference was significant in covariate analysis (taking into account age, hemodynamic characteristics, measures of body fat, and OSA severity) (p = 0.009). After excluding from both groups the subjects with extreme BMI, such that the OSA and non‐OSA study cohorts had similar BMI and percentage body fat, subjects with OSA had significantly higher plasma adiponectin (8.49 ± 0.92 vs. 6.32 ± 0.55 μg/mL; p = 0.042), differences also evident in covariate analysis (p = 0.017). Discussion: Plasma adiponectin levels are elevated in otherwise healthy subjects with OSA. Therefore, low adiponectin is unlikely to explain the association between OSA and cardiovascular disease.     

Changes of Body Weight and Plasma Ghrelin Levels after Gastric Banding and Gastric Bypass

Objective: Ghrelin is an enteric peptide with strong orexigenic and adipogenic effects. Plasma ghrelin levels are decreased in obese subjects but increase after weight loss; this increase is not observed after Roux‐en‐Y gastric bypass (RYGB). Prospective and comparative data after adjustable silicone gastric banding (ASGB) have not been reported previously. Research Methods and Procedures: Overnight fasting plasma ghrelin concentration was measured in morbidly obese subjects at baseline and 3, 6, 12, and 24 months after ASGB (n = 8) or RYGB (n = 5) and in nonoperated controls (n = 7). Results: After RYGB, body weight (BW) decreased by 29.5 ± 5.5 kg (mean ± SE, p < 0.001), whereas plasma ghrelin failed to increase significantly (+167 ± 119 pg/mL, not significant). In contrast, after ASGB, BW decreased less (by 22.8 ± 5.9 kg; p < 0.001), and plasma ghrelin significantly increased by 377 ± 201 pg/mL (p = 0.025). Neither BW nor plasma ghrelin changed in nonoperated controls. Plasma leptin decreased in both operated groups (similarly p < 0.05) but not in nonoperated controls. Plasma growth hormone and insulin‐like growth factor 1 were not correlated with changes in plasma ghrelin concentrations. Discussion: Plasma ghrelin levels failed to increase during substantial weight loss after RYGB, but did increase in response to lesser weight loss after ASGB. These findings suggest that the plasma ghrelin response after weight loss is impaired after exclusion of major parts of the stomach and the duodenum (RYGB), and the smaller long‐term weight loss after ASGB compared with RYGB may be due, at least in part, to an absent increase in plasma ghrelin after RYGB.     

Deconvolution as a novel approach to analyze moment-to-moment free fatty acid release

Objective: Recent studies have shown that free fatty acid (FFA) release is pulsatile and that this pattern is controlled by the sympathetic nervous system. It is, then, necessary to understand and characterize adipose tissue lipolysis to elucidate its effect on metabolism. In this study, we introduce deconvolution as a method to detect and quantify pulsatile FFA release. Research Methods and Procedures: Octanoate, a medium‐chain fatty acid, was infused in male mongrel dogs (n = 7) to mimic the pulsatile appearance of plasma FFAs. Deconvolution analysis was used to reconstruct the number and timing of infused octanoate pulses from plasma FFA concentrations. Results: Deconvolution analysis was able to reconstruct the exogenously infused pulses of octanoate used to mimic pulsatile appearance of FFAs (pulse frequency, 8 per hour; interpulse interval, 7 minutes). However, determination of pulse mass was less accurate (1.0 ± 0.0 vs. 0.54 ± 0.1 mM). The addition of varying levels of Gaussian noise to non‐oscillatory FFA time series did not lead to detection of extraneous FFA pulses. However, goodness of fit declined with increasing variability. Discussion: These results support the use of deconvolution as an accurate approach to determine the temporal sequence of endogenous FFA release.     

Plasma sE-cadherin and the plasma sE-cadherin/sVE-cadherin ratio are potential biomarkers for chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with endothelial dysfunction. Cadherins are adhesion molecules on epithelial (E-) and vascular endothelial (VE-) cells. Soluble (s) cadherin is released from the cell surface by the effects of proteases including matrix metalloproteinases (MMPs).

Objective: The aim of this study was to examine the associations of sE-/sVE-cadherin levels in plasma with the development of COPD.

Methods: Plasma sE-/VE-cadherin levels were measured by an enzyme-linked immunosorbent assay in 115 patients with COPD, 36 symptomatic smokers (SS), 63 healthy smokers (HS) and 78 healthy non-smokers (HN). sE-cadherin and MMP-7 levels in epithelial lining fluid (ELF) were measured in 24 patients (12 COPD and 12 control).

Results: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios were significantly higher in COPD and SS than in HS and HN groups, while plasma sVE-cadherin levels were lower in COPD than in HS and HN groups (p?p?p?p?Conclusions: Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios are potential biomarkers for COPD.     

DNA adducts of ortho-toluidine in human bladder

Background: 4-Aminobiphenyl (4-ABP) and o-toluidine are known human bladder carcinogens, but only 4-ABP-releasing DNA adducts are known.

Methods: Determination of 4-ABP and o-toluidine-releasing DNA adducts in epithelial and submucosal bladder tissues of sudden death victims (SDV: n?=?46), and bladder tumours (n?=?12) by gas chromatography/mass spectrometry.

Results: Above background, 4 and 11 of 12 tumour samples contained adducts of 4-ABP (0.057?±?0.125?fmol/µg DNA) and o-toluidine (8.72?±?4.49?fmol/µg DNA), respectively. Lower adduct levels were present in both epithelial and submucosal bladder tissues of SDV (4-ABP: 0.011?±?0.022 and 0.019?±?0.047?fmol/µg DNA; o-toluidine: 0.24?±?0.63 and 0.27?±?0.70?fmol/µg DNA).

Conclusion: Detection of o-toluidine-releasing DNA adducts support the carcinogenicity of o-toluidine in the human bladder.     

Relationships of Plasma Leptin Levels to Changes in Plasma Free Fatty Acids in Women Who Are Lean and Women Who Are Abdominally Obese

HENNES, MAGDA MI, ARNAVAZ DUA, DIANA L MAAS, GABRIELE E SONNENBERG, GLENN R KRAKOWER, AHMED H KISSEBAH. Relationships of plasma leptin levels to changes in plasma free fatty acids in women who are lean and women who are abdominally obese. Regulation of leptin production by the hormonal and metabolic milieu is poorly understood. Because abdominal obesity is commonly associated with elevated plasma free fatty acid (FFA) flux, we examined the effects of augmenting FFA on plasma leptin levels in women who were lean and of suppressing FFA in women with abdominal obesity. In study 1, nine subjects who were lean, after a 12-hour overnight fast, received either intravenous saline or Intralipid plus heparin to increase the plasma FFA concentration to approximately 1000 μmol/ L. After 3 hours of additional fasting, subjects underwent 3-hour hyperglycemic clamps. In study 2, seven subjects with abdominal obesity were evaluated by a similar protocol, but lipolysis and plasma FFA flux were instead maximally suppressed by acipimox. In the individuals who were lean, leptin levels were unchanged during clamping. Increasing plasma FFA reduced plasma leptin from 7.66 ± 0.66 to 7.05 ±0 0.66 (p=0.03), but 3 hours of hyperglycemia plus hyperinsulinemia had no additional effect on leptin levels (7.15 ± 0.71). Basal leptin levels, 4-fold higher in the subjects with obesity, were reduced from 34.6 ± 2.4 μg/L to 32.3 ± 1.1 μg/L (p=0.004) during the clamp period. When plasma FFA flux was suppressed, however, plasma leptin levels after clamped hyperglycemia/hyperinsulinemia were increased to 38.9 ± 1.2 μg/L (p=0.014 vs. time 0 and 0.001 vs. saline protocol). Changes in leptin concentrations are not correlated with changes in FFA. These results suggest that plasma FFA concentration does not regulate plasma leptin levels in basal, extended fasting, or hyperglycemic/hyperinsulinemic states.     

Reproducibility and Respiratory Function Correlates of Exhaled Breath Fingerprint in Chronic Obstructive Pulmonary Disease

Background

The electronic nose (e nose) provides distinctive breath fingerprints for selected respiratory diseases. Both reproducibility and respiratory function correlates of breath fingerprint are poorly known.

Objectives

To measure reproducibility of breath fingerprints and to assess their correlates among respiratory function indexes in elderly healthy and COPD subjects.

Method

25 subjects (5 COPD patients for each GOLD stage and 5 healthy controls) over 65 years underwent e-nose study through a seven sensor system and respiratory function tests at times 0, 7, and 15 days. Reproducibility of the e nose pattern was computed. The correlation between volatile organic compound (VOC) pattern and respiratory function/clinical parameters was assessed by the Spearman''s rho.

Measurements and Main Results

VOC patterns were highly reproducible within healthy and GOLD 4 COPD subjects, less among GOLD 1–3 patients.VOC patterns significantly correlated with expiratory flows (Spearman''s rho ranging from 0.36 for MEF25% and sensor Co-Buti-TPP, to 0.81 for FEV1% and sensor Cu-Buti-TPP p<0.001)), but not with residual volume and total lung capacity.

Conclusions

VOC patterns strictly correlated with expiratory flows. Thus, e nose might conveniently be used to assess COPD severity and, likely, to study phenotypic variability. However, the suboptimal reproducibility within GOLD 1–3 patients should stimulate further research to identify more reproducible breath print patterns.     

Characterisation of COPD heterogeneity in the ECLIPSE cohort

Background

Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).

Methods

We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.

Results

COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.

Conclusions

The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.     

Chromium status of full-term and preterm newborns

In order to obtain reference values from normal babies, Cr status of full-term newborns has been studied. Plasma and urine values were (mean±SEM) 0.7±0.1 μg/L and 0.9±0.3 μg/L, respectively, for the first month of life (n=19), and 0.6±0.1 μg/L and 0.8±0.2 μg/L for the second-to-third-month period (n=31). Premature newborns (gestational age 28–36 wk) were compared to these control values; concentrations were 0.9±0.1 μg/L and 1.1±0.2 μg/L for the first month (n=47), and 1.0±0.2 μg/L and 1.5±0.3 μg/L for the second to third months (n=27). For the whole group, there was a positive correlation between plasma and urine concentrations (p=0.0001); multiple regression analysis was performed between plasma levels and gestational age at birth (p=?0.002) and postnatal age (NS). Plasma levels of prematures and full terms were statistically different (p=0.03) only for the second- to third-month period. It is suggested that these high Cr levels result from high dietary intakes and/or high absorption rates.     

Biomarker-specific differences between transpulmonary and peripheral arterial–venous blood sampling in patients with pulmonary hypertension

Abstract

Purpose: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial–venous ratio (PR) could substitute for the transpulmonary ratio (TPR).

Materials and methods: Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH (n?=?18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH; n?=?7) and isolated post-capillary PH (Ipc-PH; n?=?9). Bland–Altman comparisons were made between peripheral venous and PA samples and between peripheral arterial and PAW samples. TPR was defined as [PAW]/[PA].

Results: For ET-1, Bland–Altman analysis indicated negative bias (?24%) in peripheral arterial compared to PAW concentration and positive bias (23%) in peripheral venous compared to PA concentration. There was <10% absolute bias for NT-pro-BNP and cAMP. For ET-1, there was no difference in PR between Cpc-PH and Ipc-PH (0.87?±?0.4 vs. 0.94?±?0.6, p?=?0.8), whereas there was a difference in TPR (2.2?±?1.1 vs. 1.1?±?0.2, p?<?0.05).

Conclusions: In PH-LHD, peripheral samples may be inadequate surrogates for transpulmonary samples, particularly when measuring mediators with prominent pulmonary secretion or clearance, such as ET-1.     

Role of Insulin and Free Fatty Acids in the Regulation of ob Gene Expression and Plasma Leptin in Normal Rats

Objective: It is under debate whether free fatty acids (FFAs) play an independent role in the regulation of adipose cell functions. In this study, we evaluated whether leptin secretion induced by FFA is due directly to an increased FFA availability or whether it is mediated by insulin levels. Research Methods and Procedures: To test this hypothesis, we compared the effects of six different experimental designs, with different FFA and insulin levels, on plasma leptin: euglycemic clamp, euglycemic clamp + FFA infusion, FFA infusion alone, FFA + somatostatin infusion, somatostatin infusion alone, and saline infusion. Results: Our results showed that euglycemic clamp, FFA infusion, or both in combination induced a similar increment of circulating leptin (3.31 ± 0.30, 3.40 ± 0.90, and 3.35 ± 0.80 ng/mL, respectively). Moreover, the inhibition of FFA‐induced insulin increase by means of somatostatin infusion completely abolished the rise of leptin in response to FFA (1.05 ± 0.30 vs. 3.40 ± 0.90 ng/mL, p < 0.001). Discussion: In conclusion, our data showed that the effects of high FFA levels on plasma leptin were mediated by the rise of insulin concentration. These data confirm a major role for insulin in the regulation of leptin secretion from rat adipose tissue and support the hypothesis that leptin secretion is coupled to net triglyceride synthesis in adipose tissue.     

Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis

Background

Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).

Methods

We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.

Results

COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.

Conclusions

The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.     

Anti‐lipolytic Effects of Insulin in African American and White Prepubertal Boys

Objective: Relative to whites, African Americans have lower circulating triglycerides (TG) and greater highdensity lipoprotein cholesterol. The metabolic basis for this difference is not known. This study was conducted to test the hypothesis that insulin‐induced suppression of free fatty acids (FFA) results in lower serum TG in African American versus white prepubertal children. Research Methods and Procedures: Insulin, FFA, and TG were determined at baseline and during a frequently sampled, intravenous glucose tolerance test in eight African American and eight white prepubertal males pair‐matched for whole‐body insulin sensitivity. Results: Baseline TG was lower in African Americans (0.43 ± 0.10 vs. 0.79 ± 0.37 mM/L; mean ± SD; p < 0.01). African Americans had higher peak insulin (218 ± 102 vs. 100 ± 30 pM/L; mean ± SD; p < 0.01) and a greater acute insulin response (9282 ± 4272 vs. 4230 ± 1326 pM/L × 10 minutes; mean ± SD; p < 0.05). FFA and TG values determined at the FFA nadir were lower in African Americans (0.26 ± 0.02 vs. 0.30 ± 0.03 mEq/L; mean ± SD; p < 0.01 for FFA nadir and 0.49 ± 0.07 vs. 0.77 ± 0.33 mM/L; mean ± SD; p < 0.05 for TG). Among all subjects, FFA nadir was correlated with peak insulin (r = ?0.54; p < 0.05). After adjusting for FFA nadir, neither baseline nor postchallenge TG differed with ethnicity (p = 0.073 and 0.192, respectively). The ethnic difference in FFA nadir disappeared after adjusting for peak insulin (p = 0.073). Discussion: These data suggest that hyperinsulinemiainduced suppression of FFA among African Americans is a determinant of lower TG in this group.     

Vitamin E attenuates acute lung injury in sheep with burn and smoke inhalation injury

Abstract

Introduction: A decrease in α-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (α-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury.

Materials and Methods: Under deep anesthesia, sheep (33 ± 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40°C). Half of the injured group received α-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH₂O; tidal volume = 15 ml/kg) for 48 h.

Results: Plasma α-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 ± 6.2 ml/min, compared with 27.3 ± 6.0 ml/min, respectively), increased the PaO₂/FiO₂ ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine.

Conclusions: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.