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1.  Validity, reliability, and responsiveness of a new shortVisual Simplified Respiratory Questionnaire (VSRQ©) for health-related quality of life assessment in chronic obstructive pulmonary disease 
The Visual Simplified Respiratory Questionnaire (VSRQ) was designed to assess health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD). It contains eight items: dyspnea, anxiety, depressed mood, sleep, energy, daily activities, social activities and sexual life. Psychometric properties were assessed during a clinical trial that evaluated the impact of tiotropium on HRQoL of COPD patients. These included the determination of structure, internal consistency reliability, concurrent validity with the St George’s Respiratory Questionnaire (SGRQ), test – retest reliability, clinical validity and responsiveness to change over two weeks. Minimal important difference (MID) was calculated; cumulative response curves (CRC) were based on the dyspnea item. Psychometric analyses showed that VSRQ structure was unidimensional. The questionnaire demonstrated good internal consistency reliability (Cronbach’s alpha = 0.84), good concurrent validity with SGRQ (Spearman = −0.70) and clinical validity, good test-retest reproducibility (ICC = 0.77), and satisfactory responsiveness (standardized response mean = 0.57; Guyatt’s statistic = 0.63). MID was 3.4; CRC median value of the ‘minimally improved’ patients was 3.5. In conclusion, VSRQ brevity and satisfactory psychometric properties make it a good candidate for large studies to assess HRQoL in COPD patients. Further validation is needed to extend its use in clinical practice.
PMCID: PMC2672786  PMID: 19436682
chronic obstructive pulmonary disease; VSRQ; SGRQ; health-related quality of life; minimal important difference
2.  Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS 
Vascular endothelial growth factor (VEGF) is implicated in motor neurone degeneration. In normal individuals, hypoxia is known to induce an overexpression of VEGF, as measured in CSF. We show that patients with ALS do not manifest this VEGF overexpression in the presence of hypoxia. Although VEGF gene expression is mainly stimulated by hypoxia, we have measured lower VEGF levels in cerebrospinal fluid (CSF) from hypoxaemic patients with amyotrophic lateral sclerosis (ALS) than in CSF from normoxaemic patients with ALS. In contrast, hypoxaemic neurological controls displayed higher levels than normoxaemic neurological controls. There was a negative correlation between VEGF levels and the severity of hypoxaemia in patients with ALS, suggesting deregulation of VEGF in ALS.
PMCID: PMC2077591  PMID: 16421133
amyotrophic lateral sclerosis; VEGF; hypoxia; motor neurone degeneration
3.  Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD 
Clinical manifestations of chronic obstructive pulmonary disease (COPD), including airflow limitation, dyspnea, and activity limitation, ultimately lead to impaired health-related quality of life (HRQoL). This 9-month, randomized, double-blind, multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL, spirometric parameters, and exacerbations in 554 patients with moderate-to-severe COPD. HRQoL was assessed using the St. George’s Respiratory Questionnaire (SGRQ) and the new 8-item Visual Simplified Respiratory Questionnaire (VSRQ), which is currently being validated. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end (Month 9). Mean ± SD baseline SGRQ total score was 47.4 ± 18.1. Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end (59.1% vs 48.2%, respectively; p = 0.029). Tiotropium significantly improved spirometric parameters (forced expiratory volume in 1 second [FEV1]: 0.11 ± 0.02 L vs 0.01 ± 0.02 L; between-group difference: 0.10 ± 0.03 L, p = 0.0001) and reduced exacerbations vs placebo. Maintenance treatment with tiotropium provided significant and clinically relevant improvements in HRQoL, as measured by the SGRQ.
PMCID: PMC2629970  PMID: 18686739
chronic obstructive pulmonary disease; long-acting anticholinergic; health-related quality of life; tiotropium
4.  IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG 
Whilst BCG inhibits allergic airway responses in murine models, IL-18 has adversary effects depending on its environment. We therefore constructed a BCG strain producing murine IL-18 (BCG-IL-18) and evaluated its efficiency to prevent an asthma-like reaction in mice. BALB/cByJ mice were sensitized (day (D) 1 and D10) by intraperitoneal injection of ovalbumin (OVA)-alum and primary (D20–22) and secondary (D62, 63) challenged with OVA aerosols. BCG or BCG-IL-18 were intraperitonealy administered 1 hour before each immunization (D1 and D10). BCG-IL-18 and BCG were shown to similarly inhibit the development of AHR, mucus production, eosinophil influx, and local Th2 cytokine production in BAL, both after the primary and secondary challenge. These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation.
PMCID: PMC2235931  PMID: 18299704
5.  Segregation of eosinophil proteins in alveolar macrophage compartments in chronic eosinophilic pneumonia. 
Thorax  1993;48(1):57-62.
BACKGROUND: The objective was to characterise the process and consequences of eosinophil activation and lysis in patients with chronic eosinophilic pneumonia and to compare them with those in patients with eosinophil pulmonary infiltrates from other causes. METHODS: Cells from bronchoalveolar lavage fluid of four patients with chronic eosinophilic pneumonia and four patients with eosinophilic infiltrates associated with Sjögren's syndrome, drug hypersensitivity pneumonia, postradiotherapy fibrosis, and pulmonary disease associated with graft versus host disease were studied ultrastructurally and with immunogold labelled antibodies directed against eosinophil proteins: major basic protein, eosinophil cationic protein, and Charcot-Leyden crystal protein. The concentration of eosinophil cationic protein was also measured in bronchoalveolar fluid. RESULTS: In the four patients with chronic eosinophilic pneumonia, ultrastructural studies demonstrated numerous lysed eosinophils. Further, three released eosinophil proteins were detected in distinct cytoplasmic structures in alveolar macrophages. These features were not found in the four patients with eosinophilic pulmonary infiltrates from other causes. CONCLUSION: Eosinophils in chronic eosinophilic pneumonia show signs of activation with release of eosinophil proteins. The appearance of three of these eosinophil proteins in different macrophage compartments suggests that macrophage uptake, with or without intracellular transport of released eosinophil proteins, involves separate mechanisms. This interaction does not lead to macrophage lysis, however, and one or more of these eosinophil proteins might directly affect macrophage function.
PMCID: PMC464245  PMID: 8434356
6.  The abnormal in vitro response to aspirin of platelets from aspirin-sensitive asthmatics is inhibited after inhalation of nedocromil sodium but not of sodium cromoglycate. 
1. Blood platelets from patients with aspirin-sensitive asthma (ASA) generated cytotoxic mediators in the presence of aspirin. This abnormal in vitro response to aspirin was abolished within 1 h after nedocromil sodium inhalation but not after sodium cromoglycate inhalation. 2. Platelets recovered this reactivity to aspirin by 12 hours after nedocromil sodium treatment of ASA-patients. 3. The in vitro reactivity to aspirin of ASA platelets isolated before inhalation was inhibited in the presence of serum isolated 15 and 60 min after nedocromil sodium inhalation.
PMCID: PMC1380151  PMID: 2161678
7.  Activated alveolar macrophages in subclinical pulmonary inflammation in collagen vascular diseases. 
Thorax  1988;43(1):24-30.
A study was initiated to determine whether alveolar macrophages from patients with collagen vascular diseases but free of pulmonary symptoms were spontaneously activated and whether they released various mediators related to the pathogenesis of pulmonary fibrosis. Alveolar macrophages obtained by bronchoalveolar lavage from 32 patients with proved collagen vascular disease but no evidence of lung disease were compared with those from 10 patients with collagen vascular disease with interstitial lung disease (CVD-ILD) and from 10 healthy controls. The total number of alveolar macrophages did not differ between patients with collagen vascular disease and controls but were substantially increased in the CVD-ILD group. Alveolar macrophages from 31 of the 32 patients with collagen vascular disease and from all 10 in the CVD-ILD group had at least one criterion of activation. Neutrophil chemotactic activity was detected in supernatants from alveolar macrophage culture in 23 of the 32 patients with collagen vascular disease and from nine of the 10 in the CVD-ILD group; fibronectin secretion by alveolar macrophages was increased in 12 of the 32 patients with collagen vascular disease and in nine of the 10 in the CVD-ILD group. Furthermore, alveolar macrophages from 20 of the 32 patients with collagen vascular disease and four of the 10 CVD-ILD patients spontaneously released increased amounts of superoxide anion. Thus alveolar macrophages were spontaneously activated in a high proportion of patients with collagen vascular disease.
PMCID: PMC461084  PMID: 2832961
8.  Latent pulmonary involvement in Crohn's disease: biological, functional, bronchoalveolar lavage and scintigraphic studies. 
Gut  1986;27(8):919-925.
We have investigated the following pulmonary related parameters in 22 patients with Crohn's disease who were free of clinical pulmonary symptoms and had normal chest roentgenograms and in 25 controls: serum angiotensin converting enzyme, pulmonary function tests, bronchoalveolar lavage (lymphocyte count and subpopulations, macrophage viability and superoxide anion release by macrophages) and pulmonary scannings. Serum angiotensin converting enzyme was lower in Crohn's disease (14.1 +/- 5.1) than in controls (25.2 +/- 4.7) (p less than 0.001). Twelve of 22 Crohn's disease (54%) had a bronchoalveolar lavage lymphocytosis (greater than 18% alveolar lymphocytes). Bronchoalveolar lavage lymphocytes subpopulations were quite variable. Twelve of 17 Crohn's disease (71%) had an increase spontaneous and/or stimulated superoxide anion production by alveolar macrophages. Six of 12 Crohn's disease (50%) had an increase physiologic dead space in the upper part of their lung against one of 11 controls (9%). These data suggest that most patients with Crohn's disease have a latent pulmonary involvement.
PMCID: PMC1433358  PMID: 3015749
9.  Involvement of immunoglobulin E in the secretory processes of alveolar macrophages from asthmatic patients. 
Journal of Clinical Investigation  1983;71(2):221-230.
Alveolar macrophages from nonatopic donors were passively sensitized with allergen-specific IgE antibody from the serum of asthmatic patients. A selective release of 4-8% of the lysosomal beta-glucuronidase of these cells occurred within 30 min of contact with the related allergen or with anti-human IgE antibody, in the absence of any mast or basophil cells. The cell reactivity was dependent on the interaction of macrophages with IgE, as shown by the disappearance of the allergen-induced enzyme release after heating or IgE-immune adsorption of the sensitizing serum, but not after IgG-adsorption. Alveolar macrophages from asthmatic patients behaved similarly to passively sensitized normal macrophages. Contact with the related allergen or with anti-IgE antibody induced the same percentage of enzyme release, demonstrating that these cells possess allergen-specific IgE bound on their surface. 18% of them formed rosettes with anti-IgE-coated sheep erythrocytes, and 15-22% with allergen-coated erythrocytes, but lost this property after preincubation with the specific allergen. The presence of IgE-specific receptors on the macrophage surface was demonstrated both at the ultrastructural level with immunoperoxidase labeling, and at low magnification by the formation of 15-18% rosettes with human IgE-coated erythrocytes. The formation of such rosettes was inhibited after incubation of alveolar phagocytes with aggregated myeloma IgE. On the basis of these observations, the participation of the alveolar macrophages in IgE-mediated pulmonary hypersensitivity must be considered. Its precise involvement requires, however, further investigations.
PMCID: PMC436860  PMID: 6185540

Results 1-9 (9)