Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury

Background

Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation.

Methods

Serum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay.

Results

Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile.

Conclusions

A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.

Trial Registration

ClinicalTrials.gov, No.: NCT00056264.     

Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD

Background

Cigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age.

Methods

All participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non-susceptible individuals, and by multiple regression analysis.

Results

Young susceptible individuals showed significantly higher increases in the expression of FcγRII (CD32) in its active forms (A17 and A27) on neutrophils after smoking (p = 0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients.

Conclusions

We show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00807469","term_id":"NCT00807469"}}NCT00807469

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0121-2) contains supplementary material, which is available to authorized users.     

Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial

Background

Data examining the characteristics of patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD) and associated hospitalisations and mortality are scarce.

Methods

Post-hoc analysis of the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, targeting exacerbations as the primary endpoint. Patients were classified as non-, infrequent, and frequent exacerbators (0, 1, or ≥ 2 exacerbations during study treatment), irrespective of study treatment. A multivariate Cox regression model assessed the effect of covariates on time to first exacerbation.

Results

In total, 7376 patients were included in the analysis: 63.5% non-exacerbators, 22.9% infrequent, 13.6% frequent exacerbators. Factors significantly associated with exacerbation risk were age, sex, body mass index, COPD duration and severity, smoking history, baseline inhaled corticosteroid use, and preceding antibiotic or systemic corticosteroid courses. Frequent exacerbators had greater severity and duration of COPD, received more pulmonary medication, and ≥ 2 systemic corticosteroid or antibiotic courses in the preceding year, and were more likely to be female and ex-smokers. The small proportion of frequent exacerbators (13.6%) accounted for 56.6% of exacerbation-related hospitalisations, which, overall, were associated with a three-fold increase in mortality.

Conclusion

The frequent exacerbator phenotype was closely associated with exacerbation-related hospitalisations, and exacerbation-related hospitalisations were associated with poorer survival.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00563381","term_id":"NCT00563381"}}NCT00563381; Study identifier: BI 205.389.     

Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease

Background

Past studies have shown that mean values of Interleukin-6 (IL-6) and C-reactive protein (CRP) do not change significantly in COPD patients over a one-year period. However, longer period follow-up studies are still lacking. Thus, the aim of this study is to evaluate plasma CRP and IL-6 concentration over three years in COPD patients and to test the association between these inflammatory mediators and disease outcome markers.

Methods

A cohort of 77 outpatients with stable COPD was evaluated at baseline, and 53 (mean FEV₁, 56% predicted) were included in the prospective study. We evaluated Interleukin-6 (IL-6), C-reactive protein (CRP), six-minute walking distance (6MWD), and body mass index (BMI) at baseline and after three years. Plasma concentration of IL-6 was measured by high sensitivity ELISA, and CRP was obtained by high sensitivity particle-enhanced immunonephelometry.

Results

IL-6 increased significantly after 3 years compared to baseline measurements [0.8 (0.5-1.3) vs 2.4 (1.3-4.4) pg/ml; p < 0.001] and was associated with worse 6MWD performance. In the Cox regression, increased IL-6 at baseline was associated with mortality [Hazard Ratio (95% CI) = 2.68 (0.13, 1.84); p = 0.02]. CRP mean values did not change [5 (1.6-7.9) vs 4.7 (1.7-10) pg/L; p = 0.84], although eleven patients (21%) presented with changes >3 mg/L in CRP after 3 years.

Conclusions

The systemic inflammatory process, evaluated by IL-6, seems to be persistent, progressive and associated with mortality and worse physical performance in COPD patients.

Trial registration

No.:{"type":"clinical-trial","attrs":{"text":"NCT00605540","term_id":"NCT00605540"}}NCT00605540     

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Background

The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Methods

In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity ratio of ≤70% and FEV₁ <80% of the predicted value. The primary endpoint was trough FEV₁ at 12 and 28 weeks. Secondary endpoints were health status measured by St George''s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.

Results

At 12 and 28 weeks, aclidinium improved trough FEV₁ versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.

Conclusion

Aclidinium is effective and well tolerated in patients with moderate to severe COPD.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00363896","term_id":"NCT00363896"}}NCT00363896 (ACCLAIM/COPD I) and {"type":"clinical-trial","attrs":{"text":"NCT00358436","term_id":"NCT00358436"}}NCT00358436 (ACCLAIM/COPD II).     

The clinical features of the overlap between COPD and asthma

Background

The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.

Methods

We performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.

Results

119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.

Conclusion

Subjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.

Trial registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00608764","term_id":"NCT00608764"}}NCT00608764     

COPD association and repeatability of blood biomarkers in the ECLIPSE cohort

Background

There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE) cohort.

Methods

Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients.

Results

Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201) of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201) reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved.

Conclusions

Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD). Further analysis of more promising biomarkers may reveal utility in subsets of patients. Fibrinogen in particular has emerged as a potentially useful biomarker from this cohort and requires further investigation.

Trial Registration

SCO104960, clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00292552","term_id":"NCT00292552"}}NCT00292552     

Dietary Patterns Differently Associate with Inflammation and Gut Microbiota in Overweight and Obese Subjects

Background

Associations between dietary patterns, metabolic and inflammatory markers and gut microbiota are yet to be elucidated.

Objectives

We aimed to characterize dietary patterns in overweight and obese subjects and evaluate the different dietary patterns in relation to metabolic and inflammatory variables as well as gut microbiota.

Design

Dietary patterns, plasma and adipose tissue markers, and gut microbiota were evaluated in a group of 45 overweight and obese subjects (6 men and 39 women). A group of 14 lean subjects were also evaluated as a reference group.

Results

Three clusters of dietary patterns were identified in overweight/obese subjects. Cluster 1 had the least healthy eating behavior (highest consumption of potatoes, confectionary and sugary drinks, and the lowest consumption of fruits that was associated also with low consumption of yogurt, and water). This dietary pattern was associated with the highest LDL cholesterol, plasma soluble CD14 (p = 0.01) a marker of systemic inflammation but the lowest accumulation of CD163+ macrophages with anti-inflammatory profile in adipose tissue (p = 0.05). Cluster 3 had the healthiest eating behavior (lower consumption of confectionary and sugary drinks, and highest consumption of fruits but also yogurts and soups). Subjects in this Cluster had the lowest inflammatory markers (sCD14) and the highest anti-inflammatory adipose tissue CD163+ macrophages. Dietary intakes, insulin sensitivity and some inflammatory markers (plasma IL6) in Cluster 3 were close to those of lean subjects. Cluster 2 was in-between clusters 1 and 3 in terms of healthfulness. The 7 gut microbiota groups measured by qPCR were similar across the clusters. However, the healthiest dietary cluster had the highest microbial gene richness, as evaluated by quantitative metagenomics.

Conclusion

A healthier dietary pattern was associated with lower inflammatory markers as well as greater gut microbiota richness in overweight and obese subjects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01314690","term_id":"NCT01314690"}}NCT01314690     

Blood levels of macrophage migration inhibitory factor after successful resuscitation from cardiac arrest

Introduction

Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post-resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patients undergoing cardiac surgery with the use of extracorporeal circulation.

Methods

Blood samples of 17 patients with return of spontaneous circulation (ROSC) after OHCA were obtained upon admission to the intensive care unit, and 6, 12, 24, 72 and 96 h later. Arrest and treatment related data were documented according to the Utstein style.

Results

In patients after ROSC, MIF levels at admission (475.2±157.8 ng/ml) were significantly higher than in healthy volunteers (12.5±16.9 ng/ml, p<0.007) and in patients after cardiac surgery (78.2±41.6 ng/ml, p<0.007). Six hours after admission, MIF levels were decreased by more than 50% (150.5±127.2 ng/ml, p<0.007), but were not further reduced in the subsequent time course and remained significantly higher than the values observed during the ICU stay of cardiac surgical patients. In this small group of patients, MIF levels could not discriminate between survivors and non-survivors and were not affected by treatment with mild therapeutic hypothermia.

Conclusion

MIF shows a rapid and pronounced increase following CPR, hence allowing a very early assessment of the inflammatory response. Further studies are warranted in larger patient groups to determine the prognostic significance of MIF.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01412619","term_id":"NCT01412619"}}NCT01412619     

The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: Patient Characterization Phase of a Randomized Clinical Trial

Background

To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls.

Methods

Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests.

Results

Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001).

Conclusions

Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01072396","term_id":"NCT01072396"}}NCT01072396     

Hesperidin displays relevant role in the nutrigenomic effect of orange juice on blood leukocytes in human volunteers: a randomized controlled cross-over study

Background

We previously showed, in healthy, middle-aged, moderately overweight men, that orange juice decreases diastolic blood pressure and significantly improves postprandial microvascular endothelial reactivity and that hesperidin could be causally linked to the observed beneficial effect of orange juice. The objective was to determine the effect of chronic consumption of orange juice on the gene expression profile of leukocytes in healthy volunteers and to assess to what extent hesperidin is involved in the effect of orange juice.

Methodology/Principal Findings

Volunteers were included in a randomized, controlled, crossover study. Throughout three 4-week periods, volunteers consumed daily: 500 ml orange juice, 500 ml control drink plus hesperidin or 500 ml control drink and placebo. Blood samplings were performed on 10 overnight-fasted subjects after the 4-week treatment period. Global gene expression profiles were determined using human whole genome cDNA microarrays. Both orange juice and hesperidin consumption significantly affected leukocyte gene expression. Orange juice consumption induced changes in expression of, 3,422 genes, while hesperidin intake modulated the expression of 1,819 genes. Between the orange juice and hesperidin consumption groups, 1,582 regulated genes were in common. Many of these genes are implicated in chemotaxis, adhesion, infiltration and lipid transport, which is suggestive of lower recruitment and infiltration of circulating cells to vascular wall and lower lipid accumulation.

Conclusions

This study shows that regular consumption of orange juice for 4 weeks alters leukocyte gene expression to an anti-inflammatory and anti-atherogenic profile, and hesperidin displays a relevant role in the genomic effect of this beverage.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT 00983086","term_id":"NCT00983086"}}NCT 00983086     

Nocturnal CPAP improves walking capacity in COPD patients with obstructive sleep apnoea

Background

Exercise limitation is an important issue in patients with chronic obstructive pulmonary disease (COPD), and it often co-exists with obstructive sleep apnoea (overlap syndrome). This study examined the effects of nocturnal continuous positive airway pressure (CPAP) treatment on walking capacity in COPD patients with or without obstructive sleep apnoea.

Methods

Forty-four stable moderate-to-severe COPD patients were recruited and completed this study. They all underwent polysomnography, CPAP titration, accommodation, and treatment with adequate pressure. The incremental shuttle walking test was used to measure walking capacity at baseline and after two nights of CPAP treatment. Urinary catecholamine and heart rate variability were measured before and after CPAP treatment.

Results

After two nights of CPAP treatment, the apnoea-hypopnoea index and oxygen desaturation index significantly improved in both overlap syndrome and COPD patients, however these changes were significantly greater in the overlap syndrome than in the COPD group. Sleep architecture and autonomic dysfunction significantly improved in the overlap syndrome group but not in the COPD group. CPAP treatment was associated with an increased walking capacity from baseline from 226.4 ± 95.3 m to 288.6 ± 94.6 m (P < 0.05), and decreased urinary catecholamine levels, pre-exercise heart rate, oxygenation, and Borg scale in the overlap syndrome group. An improvement in the apnoea-hypopnoea index was an independent factor associated with the increase in walking distance (r = 0.564).

Conclusion

Nocturnal CPAP may improve walking capacity in COPD patients with overlap syndrome.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00914264","term_id":"NCT00914264"}}NCT00914264     

Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health--a randomized controlled clinical pilot study

Background

Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man''s deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded.

Methods

In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets.

Results

In the MOF group serum total cholesterol and LDL decreased significantly (P≤0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05) in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P≤0.05).

Conclusion

Our integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 weeks supplementation with 200 mg/d MOF in humans.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00742287","term_id":"NCT00742287"}}NCT00742287     

Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial

Background and Aims

The association between hygiene and prevalence of autoimmune disease has been attributed in part to enteric helminth infection. A pilot study of experimental infection with the hookworm Necator americanus was undertaken among a group of otherwise healthy people with celiac disease to test the potential of the helminth to suppress the immunopathology induced by gluten.

Methods

In a 21-week, double-blinded, placebo-controlled study, we explored the effects of N. americanus infection in 20 healthy, helminth-naïve adults with celiac disease well controlled by diet. Staged cutaneous inoculations with 10 and 5 infective 3^rd stage hookworm larvae or placebo were performed at week-0 and -12 respectively. At week-20, a five day oral wheat challenge equivalent to 16 grams of gluten per day was undertaken. Primary outcomes included duodenal Marsh score and quantification of the immunodominant α-gliadin peptide (QE65)-specific systemic interferon-γ-producing cells by ELISpot pre- and post-wheat challenge.

Results

Enteric colonisation with hookworm established in all 10 cases, resulting in transiently painful enteritis in 5. Chronic infection was asymptomatic, with no effect on hemoglobin levels. Although some duodenal eosinophilia was apparent, hookworm-infected mucosa retained a healthy appearance. In both groups, wheat challenge caused deterioration in both primary and several secondary outcomes.

Conclusions

Experimental N. americanus infection proved to be safe and enabled testing its effect on a range of measures of the human autoimmune response. Infection imposed no obvious benefit on pathology.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00671138","term_id":"NCT00671138"}}NCT00671138     

Short and long-term safety of the 2009 AS03-adjuvanted pandemic vaccine

Background

This study assessed the short and the long term safety of the 2009 AS03 adjuvanted monovalent pandemic vaccine through an active web-based electronic surveillance. We compared its safety profile to that of the seasonal trivalent inactivated influenza vaccine (TIV) for 2010–2011.

Methodology/Principal Findings

Health care workers (HCW) vaccinated in 2009 with the pandemic vaccine (Arepanrix ® from GSK) or HCW vaccinated in 2010 with the 2010–2011 TIV were invited to participate in a web-based active surveillance of vaccine safety. They completed two surveys the day-8 survey covered the first 7 days post-vaccination and the day-29 survey covered events occurring 8 to 28 days after vaccination. Those who reported a problem were called by a nurse to obtain details. The main outcome was the occurrence of a new health problem or the worsening of an existing health condition that resulted in a medical consultation or work absenteeism. For the pandemic vaccine, a six-month follow-up for the occurrence of serious adverse events (SAE) was conducted. Among the 6242 HCW who received the pandemic vaccine, 440 (7%) reported 468 events compared to 328 of the 7645 HCW (4.3%) who reported 339 events after the seasonal vaccine. The 2009 pandemic vaccine was associated with significantly more local reactions than the 2010–2011 seasonal vaccine (1% vs. 0.03%, p<0.001). Paresthesia was reported by 7 HCW (0.1%) after the pandemic vaccine but by none after the seasonal vaccine. For the pandemic vaccine, no clustering of SAE was found in the 6 month follow-up.

Conclusion

The 2009 pandemic vaccine seems to have a good safety profile, similar to the 2010–2011 TIV, with the exception of local reactions. This surveillance was adequately powered to identify AE associated with an excess risk ≥1 per 1000 vaccinations but is insufficient to detect rare AE.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01289418","term_id":"NCT01289418"}}NCT01289418, {"type":"clinical-trial","attrs":{"text":"NCT01318876","term_id":"NCT01318876"}}NCT01318876     

FEV1 inversely correlates with metalloproteinases 1, 7, 9 and CRP in COPD by biomass smoke exposure

Background

Matrix metalloproteinases (MMPs) and C-reactive protein (CRP) are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. The aim of the present work was to determine plasma concentrations of MMPs and CRP in COPD associated to biomass combustion exposure (BE) and tobacco smoking (TS).

Methods

Pulmonary function tests, plasma levels of MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP were measured in COPD associated to BE (n = 40) and TS (n =40) patients, and healthy non-smoking (NS) healthy women (controls, n = 40).

Results

Plasma levels of MMP-1, MMP-7, MMP-9, and MMP-9/TIMP-1 and CRP were higher in BE and TS than in the NS healthy women (p <0.01). An inverse correlation between MMP-1, MMP-7, MMP-9, MMP-9/TIMP-1 and CRP plasma concentrations and FEV₁ was observed.

Conclusions

Increase of MMPs and CRP plasma concentrations in BE suggests a systemic inflammatory phenomenon similar to that observed in COPD associated to tobacco smoking, which may also play a role in COPD pathogenesis.     

Vaccination with Ad5 vectors expands Ad5-specific CD8 T cells without altering memory phenotype or functionality

Background

Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8⁺ T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8⁺ T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.

Methodology/Principal Findings

Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8⁺ T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8⁺ T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8⁺ T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8⁺ T-cells.

Conclusions

These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8⁺ T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680 [{"type":"clinical-trial","attrs":{"text":"NCT00849680","term_id":"NCT00849680"}}NCT00849680]     

Beneficial effects on arterial stiffness and pulse-wave reflection of combined enalapril and candesartan in chronic kidney disease - a randomized trial

Background

Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD.

Methods

Sixty-seven CKD patients (mean GFR 30, range 13–59 ml/min/1.73 m²) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device.

Results

Significant additive BP independent reductions were found after dual blockade in aortic PWV (−0.3 m/s, P<0.05) and in augmentation index (−2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (−6 mmHg, P<0.01).

Conclusions

Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients.

Trial Registration

Clinical trial.gov {"type":"clinical-trial","attrs":{"text":"NCT00235287","term_id":"NCT00235287"}}NCT00235287 http://www.clinicaltrials.gov/ct2/show/NCT00235287?term=ras+block&rank=1     

Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer

Background

Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy.

Methods and Findings

14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease.

Conclusions

These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00954525","term_id":"NCT00954525"}}NCT00954525     

Leptin replacement improves cognitive development

Background

Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown.

Objective

To evaluate the effect of leptin on neurocognitive development.

Methodology

A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children.

Principal Findings

Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia.

Conclusions

We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00659828","term_id":"NCT00659828"}}NCT00659828