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2.  Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma 
Thorax  2006;62(4):314-319.
Subepithelial hypervascularity and angiogenesis in the airways are part of structural remodelling of the airway wall in asthma, but the effects of inhaled corticosteroids (ICS) on these have not been explored. Increased vascularity in asthma may contribute to a number of functional abnormalities. A study was undertaken to explore angiogenic modulation by ICS and its likely regulation via vascular endothelial growth factor (VEGF), its receptors and the angiopoietins.
A placebo‐controlled intervention study with ICS in asthma was performed, examining vascularity, VEGF, its receptors (VEGFR1 and VEGFR2), and angiopoietin‐1 (Ang1) to assess which of these factors were changed in the asthmatic airways after ICS treatment. Airway wall biopsy specimens, lavage fluid and cells were obtained from 35 patients with mild asthma randomised to receive ICS or placebo for 3 months, after which bronchoscopic examination and sample collection were repeated. Immunohistochemistry and image analysis were used to obtain quantitative measures of vessels, angiogenic sprouts, VEGF, VEGFR1, VEGFR2 and Ang1 staining in airway biopsy specimens. ELISA was used to assess VEGF concentrations in the lavage fluid.
Vessel, VEGF and sprout staining were decreased after 3 months of ICS treatment. VEGF levels remained unchanged. VEGF receptors and Ang1 staining were not reduced after treatment.
The findings of this study support an effect of ICS in downregulating angiogenic remodelling in the airways in asthma, associated with decreasing VEGF activity within the airway wall. The environment of the airways after treatment with ICS, with changes in the balance between VEGF, its receptors, Ang1 and sprouts, appears to be less angiogenic than in untreated asthma.
PMCID: PMC2092477  PMID: 17105777
3.  Differences in aerosol output and airways responsiveness between the DeVilbiss 40 and 45 hand held nebulisers. 
Thorax  1995;50(6):635-638.
BACKGROUND--The DeVilbiss 40 glass hand held nebulisers have been widely used for airways responsiveness testing in epidemiological surveys of asthma. These nebulisers have been superseded in some recent studies by the DeVilbiss 45 plastic hand held nebulisers with the assumption that they are interchangeable. This study compared the aerosol outputs of the DeVilbiss 40 and DeVilbiss 45 nebulisers and investigated whether there was any difference in the in vivo measurements of airways responsiveness when using the two nebuliser types. METHODS--The aerosol output of six DeVilbiss 40 and six DeVilbiss 45 nebulisers was calculated by weight loss per actuation, the usual method of calibrating nebuliser output, and compared with the true amount of aerosol obtained measured by a flouride tracer technique. Airways responsiveness was measured twice in 13 asthmatic patients under identical conditions by the Yan protocol using DeVilbiss 40 and 45 nebulisers in random order. RESULTS--Weight loss overestimated the true aerosol output of both types of nebulisers. Weight loss was similar for the DeVilbiss 40 and 45 nebulisers but the true aerosol output of the DeVilbiss 45 was nearly twice that of the DeVilbiss 40 nebuliser. The geometric mean PD20 values with the DeVilbiss 40 nebuliser was a mean 1.7 doubling doses of histamine higher than that obtained with the DeVilbiss 45 nebuliser. CONCLUSIONS--The DeVilbiss 40 and 45 nebulisers should not be used interchangeably for airways responsiveness testing merely because their outputs based on weight loss are similar. Artefactual differences in the prevalence rates of airways responsiveness could occur in longitudinal studies if a change was inadvertently made from using DeVilbiss 40 to DeVilbiss 45 nebulisers.
PMCID: PMC1021263  PMID: 7638805
4.  Evaluation of albumin as a reference marker of dilution in bronchoalveolar lavage fluid from asthmatic and control subjects. 
Thorax  1993;48(5):518-522.
BACKGROUND--Standardised expression of results of bronchoalveolar lavage (BAL) is problematical in the absence of a validated "denominator" of epithelial lining fluid dilution. The suitability of albumin in BAL fluid has been investigated in groups of clinically stable asthmatic and control subjects. METHODS--Absolute levels of albumin in BAL fluid were measured in a preliminary study of 21 asthmatic and 10 control subjects. In a more complex study designed to investigate the origin of albumin sampled at BAL in nine asthmatic and seven control subjects, radiolabelled albumin was injected intravenously five minutes before BAL. RESULTS--In the preliminary study levels of albumin in BAL fluid were very similar, with a geometric mean value of 44 (95% CI 35-54) micrograms/ml BAL supernatant for the asthmatic subjects and 41 (95% CI 33-52) micrograms/ml for the controls. The majority of control and asthmatic subjects in the radiolabel study exhibited minimal flux of albumin from the circulation into the BAL aspirate. This finding was not uniform, however, and in a third of the asthmatic subjects an albumin flux equivalent to > 20% of the measurable albumin was found in two or more aliquots of a 3 x 60 ml lavage. CONCLUSIONS--The results of this investigation into the source of albumin sampled at BAL suggest that, in general, albumin would be a reasonable reference solute for normalising the degree of dilution of BAL fluid in the groups studied. The origin of albumin was not always restricted to the bronchopulmonary segment under investigation, however, with significant leakage from the blood compartment in some individuals despite the consistency of absolute levels observed in the preliminary study.
PMCID: PMC464506  PMID: 8322239
5.  Effects of diurnal variation and prolonged refractoriness on repeated measurements of airways responsiveness to methacholine. 
Thorax  1995;50(3):235-239.
BACKGROUND--A number of studies have suggested that diurnal variation in airways responsiveness underlies the circadian rhythm of ventilatory function in asthma. Measurements of airways responsiveness are therefore often performed at standardised times in order to avoid this possible effect, but this is not practical for epidemiological studies. Refractoriness to methacholine has also been reported and this, too, could confound the results of methacholine tests repeated over short intervals. This investigation was carried out to evaluate the possible magnitude of diurnal variation and refractoriness in repeated measures of airways responsiveness to methacholine. METHODS--To investigate diurnal variation in airways responsiveness, 24 asthmatic subjects aged 18-45 underwent five methacholine tests over three days which were not necessarily consecutive: day 1 at 08:00 hours; day 2 at 08:00 hours, 14:00 hours, 20:00 hours; day 3 at 20:00 hours. To investigate refractoriness a retrospective analysis was undertaken of all paired methacholine tests performed in individuals within our unit between 1984 and 1990 where there had been no intervention likely to affect the results. RESULTS--The first investigation revealed no diurnal change in airways responsiveness although there was a change in FEV1. Mean PD20 did, however, increase 1.57 fold from 08:00 hours on day 1 to 08:00 hours on day 2 for subjects studied on consecutive days. The second investigation confirmed that a test interval of up to 24 hours (but not of 48 or more hours) was associated with a refractory index (PD20 test 2/PD20 test 1) of > 1. CONCLUSIONS--No diurnal variation in airways responsiveness was detected for measurements made between 08:00 hours and 20:00 hours, but an interval between successive tests of up to 24 hours was associated with refractoriness. Diurnal variation is not likely to exert an important confounding effect on methacholine tests carried out between 08:00 hours and 20:00 hours, but confounding could result from refractoriness if tests are repeated at intervals up to 24 hours.
PMCID: PMC1021184  PMID: 7660334
6.  Measurement of airway responsiveness to methacholine: relative importance of the precision of drug delivery and the method of assessing response. 
Thorax  1993;48(3):239-243.
BACKGROUND: The value of measuring airway responsiveness in asthma research is currently limited by the number of different methods used by different investigators, by the lack of a standardised method of expressing precision, and by an inability to equate the results of one method with those of another. METHODS: Two pairs of measurements of airway responsiveness to methacholine were performed in 20 asthmatic subjects, one pair using a dosimeter method (AR-D) and one pair using the conventional Wright nebuliser tidal breathing method (AR-W). The two methods normally use different techniques for quantifying changing levels in forced expiratory volume in one second (FEV1) after each dose of methacholine (the mean of the highest three of six measurements for AR-D, the lower of two measurements for AR-W), and different techniques for expressing measurements of airway responsiveness (the provoking dose (PD20) and the provoking concentration (PC20) respectively responsible for a 20% decrement in FEV1). RESULTS: The coefficient of repeatability (and hence precision) for the measurement of airway responsiveness was significantly better for AR-D (3.0) than for AR-W (10.9), but the technique for quantifying FEV1 contributed more to this than the technique for delivering methacholine. A PC20 of 1 mg/ml with AR-W was equivalent to a PD20 of 103 micrograms with AR-D. CONCLUSIONS: It is practical as well as desirable to compare the precision of different techniques for the measurement of airway responsiveness and to derive conversion factors so that results may be equated.
PMCID: PMC464360  PMID: 8497822
7.  Jet and ultrasonic nebuliser output: use of a new method for direct measurement of aerosol output. 
Thorax  1990;45(10):728-732.
Output from jet nebulisers is calibrated traditionally by weighing them before and after nebulisation, but the assumption that the weight difference is a close measure of aerosol generation could be invalidated by the concomitant process of evaporation. A method has been developed for measuring aerosol output directly by using a solute (fluoride) tracer and aerosol impaction, and this has been compared with the traditional weight loss method for two Wright, six Turbo, and four Micro-Cirrus jet nebulisers and two Microinhaler ultrasonic nebulisers. The weight loss method overestimated true aerosol output for all jet nebulisers. The mean aerosol content, expressed as a percentage of the total weight loss, varied from as little as 15% for the Wright jet nebulisers to 54% (range 45-61%) for the Turbo and Micro-Cirrus jet nebulisers under the operating conditions used. In contrast, there was no discrepancy between weight loss and aerosol output for the ultrasonic nebulisers. These findings, along with evidence of both concentrating and cooling effects from jet nebulisation, confirm that total output from jet nebulisers contains two distinct fractions, vapour and aerosol. The vapour fraction, but not the aerosol fraction, was greatly influenced by reservoir temperature within the nebuliser; so the ratio of aerosol output to total weight loss varied considerably with temperature. It is concluded that weight loss is an inappropriate method of calibrating jet nebuliser aerosol output, and that this should be measured directly.
PMCID: PMC462714  PMID: 2247862
8.  Absence of genetic linkage of chromosome 5q31 with asthma and atopy in the general population 
Thorax  1997;52(9):816-817.
BACKGROUND: Clinical asthma is associated with increased serum total immunoglobulin E (IgE), atopy (skin prick test positivity to common aeroallergens), and bronchial hyperreactivity (BHR) to non-specific stimuli (positive methacholine challenge test). A region on chromosome 5q31-33 has been linked with increased total serum IgE and BHR. A study of the genetic linkage of this region with clinical asthma and atopy was therefore undertaken. METHODS: A polymorphic microsatellite marker in chromosome 5q31 (D5S399) was studied in 119 sibling pairs recruited from the general population who shared asthma, atopy, and/or BHR. Based on our population distribution of 13 different alleles, it was expected that by chance alone sibling pairs would share on average 1.24 alleles and that a significant excess would indicate genetic linkage. RESULTS: No evidence of linkage was found in 45 siblings concordant for asthma (shared alleles = 1.09, p = 0.95), in 103 sibling pairs with atopy (shared alleles = 1.18, p = 0.82), in 51 sibling pairs with BHR (shared alleles = 1.22, p = 0.62), or in 68 sibling pairs who shared atopy in the absence of BHR (shared alleles = 1.22, p = 0.61). A slight non- significant excess of shared alleles (1.44, p = 0.11) was observed in siblings who shared BHR without atopy. CONCLUSIONS: No evidence of genetic linkage of chromosome 5q31 with either clinical asthma or atopy was therefore detected in the population studied. Linkage between chromosome 5q and BHR needs further investigation. 

PMCID: PMC1758647  PMID: 9371215
9.  Bronchial hyperresponsiveness in lung transplant recipients: lack of correlation with airway inflammation 
Thorax  1997;52(6):551-556.
BACKGROUND: Bronchial hyperresponsiveness (BHR) to methacholine has been reported to occur in most lung transplant recipients. BHR to physical stimuli such as exercise and non-isotonic aerosols has not been as extensively studied in this subject population. This report aims to assess the presence and degree of BHR to methacholine and hypertonic saline in stable lung transplant recipients and to relate it to the presence of airway inflammation. METHODS: Ten patients undergoing bilateral sequential lung transplantation and six heart-lung transplant recipients, all with stable lung function, were recruited 66- 1167 days following transplantation. Subjects underwent a methacholine challenge and bronchoscopy for sampling of bronchoalveolar lavage fluid, transbronchial and endobronchial biopsy tissues. Hypertonic saline challenge was performed six days later. RESULTS: Nine of the 16 transplant recipients had positive methacholine challenges (geometric mean PD20 0.18 mg, interquartile range 0.058-0.509) and three of these subjects also had positive hypertonic saline challenges (PD15 = 2.3, 33.0, and 51.5 ml). No clear relationship was found between BHR to either methacholine or hypertonic saline and levels of mast cells, eosinophils or lymphocytes in samples of biopsy tissue or lavage fluid. CONCLUSIONS: Most of the lung transplant recipients studied were responsive to methacholine and unresponsive to hypertonic saline. BHR was not clearly related to airway inflammation, suggesting an alternative mechanism for BHR following lung transplantation from that usually assumed in asthma. 

PMCID: PMC1758572  PMID: 9227723
10.  Immunopathological changes in the airways of stable lung transplant recipients 
Thorax  1997;52(4):322-328.
BACKGROUND: Pathological obliterative bronchiolitis, characterised by inflammation and occlusion of airways, is a serious complication of lung transplantation. Endobronchial biopsy (EBB) provides a means of examining transplanted airways. This study aimed to investigate the role of EBB samples in revealing early signals of airway injury. METHODS: In 18 stable lung transplant recipients with close to maximal lung function (median FEV1, best after transplantation 100%, interquartile range 98-100%) EBB samples were taken simultaneously with transbronchial biopsy samples and bronchoalveolar lavage (BAL) fluid (median 195 days after transplantation). OCT embedded specimens were snap frozen on an isopentane slurry made with liquid nitrogen and 7 microns sections were stained with monoclonal antibodies using a three stage immunoperoxidase method. RESULTS: Compared with nine non- transplanted control subjects, EBB specimens from the stable transplant group had significantly increased CD8 positivity (median 53 versus 27 cells/mm basement membrane, p = 0.04; 95% CI for the difference 1 to 46)) and increased HLA-DR positivity (median 84 versus 26 cells/mm basement membrane, 95% CI for the difference 6 to 115). There was an increase in CD68 positive cells in the EBB specimens from transplant recipients of borderline significance (median 92 versus 68, p = 0.08, 95% CI for the difference 1 to 84). CD3, CD4, and CD25 counts were similar in the two groups. EBB findings were not influenced by age, sex, indication for transplant, immunosuppression doses or levels, nor the presence of airway commensals in the BAL fluid. CONCLUSIONS: EBB is practicable in a transplant setting and provides information about bronchial inflammatory changes. It is likely that there is ongoing inflammation, possibly rejection mediated, even in healthy lung transplant recipients despite triple immunosuppression. 

PMCID: PMC1758532  PMID: 9196513
11.  Salmeterol tachyphylaxis in steroid treated asthmatic subjects. 
Thorax  1996;51(11):1100-1104.
BACKGROUND: Tachyphylaxis to the protection afforded by salmeterol to broncho-constrictor stimuli after regular use has been described in patients with mild asthma not receiving inhaled corticosteroids. The present study was performed to investigate whether airway tachyphylaxis occurs in symptomatic asthmatic subjects receiving inhaled corticosteroids, the group for whom salmeterol is recommended in clinical practice. METHODS: Thirty one adult patients with symptomatic chronic asthma who were receiving inhaled corticosteroids were randomised in a double blind manner and on a 2:1 basis to receive salmeterol 50 micrograms (n = 22) or placebo (n = 9) twice daily. Baseline forced expiratory volume in one second (FEV1) was measured during the run-in period, on day 0, and after four and eight weeks of regular treatment (following a 36 hour test drug washout period). Airway responsiveness to methacholine was measured one hour after administration of the test drug on these occasions. Diary cards were kept throughout the study and for a two week follow up period. RESULTS: Baseline FEV1 was not significantly different between the treatment groups or between visits. There was significant bronchodilatation one hour after salmeterol administration at 0, four, and eight weeks. No significant tachyphylaxis of the bronchodilator action of salmeterol was seen. Protection against methacholine induced bronchoconstriction reduced from 3.3 doubling dilutions after the first dose of salmeterol to two doubling dilutions after four and eight weeks of regular treatment. Symptom scores and "rescue" salbutamol use were significantly reduced during salmeterol treatment and daytime improvements were maintained into the follow up period. CONCLUSIONS: Inhaled corticosteroids did not prevent tachyphylaxis to the protection afforded by salmeterol to methacholine induced bronchoconstriction. The clinical significance, if any, of these findings remains to be defined.
PMCID: PMC1090520  PMID: 8958892
12.  Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients. 
Thorax  1993;48(11):1121-1124.
BACKGROUND--Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine, but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment. METHODS--The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients, 19 of whom were receiving maintenance inhaled corticosteroids. The study was of a randomised, placebo controlled, double blind design. Airway responsiveness to methacholine was measured as PD20 by a standardised dosimeter technique 12 hours after the first dose, at four weeks and eight weeks during treatment (12 hours after the last dose of test medication), and at 60 hours, one week and two weeks after stopping treatment. RESULTS--There were no significant differences between the baseline characteristics of the two groups. A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group, with no significant fall off with time. PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group. CONCLUSIONS--Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration. This protection was of small magnitude, but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients, the majority of whom were receiving inhaled corticosteroids.
PMCID: PMC464894  PMID: 8296255
13.  Bronchus associated lymphoid tissue (BALT) in human lung: its distribution in smokers and non-smokers. 
Thorax  1993;48(11):1130-1134.
BACKGROUND--Bronchus associated lymphoid tissue (BALT) is a normal component of the lung's immune system in many animals and may be analogous to gut associated lymphoid tissue (GALT). This study aimed at assessing the nature and extent of BALT in human lung and determining whether its expression is induced within the human airway in response to smoking. METHODS--Paraffin embedded, formalin fixed full thickness bronchial wall sections were examined from 31 whole lung specimens derived from both smokers and non-smokers. Samples were taken from throughout the bronchial tree to include main stem bronchi, lobar bronchi and segmental bronchi, as well as first to third generation carinae. Standard 4 microns step sections were stained by haematoxylin and eosin and immunocytochemical methods to show foci of BALT. RESULTS--Examination of 256 airway sites detected 46 foci of BALT. These differed from those described in other mammals in being distributed throughout the bronchial tree, in being found in relation to bronchial glandular epithelium as well as luminal bronchial epithelium, and in lacking any accompanying M cells. Analysis by smoking status showed that the expression of BALT was significantly more common in smokers than non-smokers (82% (14/17) v 14% (2/14) respectively). CONCLUSIONS--The findings support the view that BALT in humans is an integral feature in a comparatively small proportion of lungs from non-smokers while being significantly more prominent in lungs from smokers. The tissue shows several important differences from that described in other mammals.
PMCID: PMC464898  PMID: 8296257
14.  Distribution of gamma delta T-cells in the bronchial tree of smokers and non-smokers. 
Journal of Clinical Pathology  1993;46(10):926-930.
AIMS--To assess the distribution of gamma delta T-cells in the human bronchial tree; and to compare quantitatively the differences between gamma delta T-cell numbers in different parts of the airway wall in smokers and non-smokers. METHODS--Full thickness bronchial wall sections were taken from 10 whole lung specimens from both smokers and non-smokers. Serial cryostat sections stained with the monoclonal antibodies CD3 and TCR delta-1 were examined with the aid of interactive image analysis to assess gamma delta T-cell numbers both in absolute terms and as a proportion of total T lymphocyte numbers. RESULTS--In all cases gamma delta T-cells were demonstrable throughout the airway wall. Although in absolute terms they tend to occur predominantly in the bronchial epithelium, this seems to reflect higher numbers of T lymphocytes in the epithelium in general compared with the submucosa. No genuine epitheliotropism is evident. Comparison by smoking status shows a significant increase in gamma delta T-cell numbers in the bronchial glands of smokers compared with non-smokers. CONCLUSIONS--gamma delta T-cells form an integral though variable component of the immunocompetent cell population of the human airway in both smokers and non-smokers. Although epitheliotropism does not exist in the bronchial tree, gamma delta T-cells seem to form a significant part of the bronchial gland inflammation associated with smoking.
PMCID: PMC501620  PMID: 8227410
15.  Bronchoalveolar lavage as a research tool. 
Thorax  1991;46(9):613-618.
PMCID: PMC463336  PMID: 1948787
16.  Refractory period following bronchoconstriction provoked by histamine in asthmatic subjects. 
Thorax  1989;44(2):146-150.
To determine whether refractoriness to histamine induced bronchoconstriction occurs, 20 asthmatic subjects aged 19-50 years were tested. Subjects underwent two histamine challenge tests (1 and 2) on the same day, the second one being given 45-60 minutes after the first, once the FEV1 after test 1 had returned spontaneously to within 90% of baseline. A further "control" histamine challenge test was carried out on a different day at the same time (+/- 2 hours) as test 1. Bronchial responsiveness was recorded as the cumulative dose (microgram) of histamine provoking a 20% fall in FEV1 (PD20), and the ratio PD20 test 2:PD20 test 1 was used to assess refractoriness. The median value of this ratio (2.20) was significantly greater than 1 (p = 0.003), indicating refractoriness at the time of test 2. By contrast the median ratio PD20 control:PD20 test 1 of 1.03 was not significantly different from 1. Refractoriness could not be accounted for by failure to regain the initial baseline FEV1, though such failure may have exaggerated the effect. An increase in PD20 with the second test was observed uniformly in subjects with moderate or high initial PD20 values but not in those with low values. This suggests that there may be a PD20 threshold of the order 25-100 micrograms for refractoriness to occur. Refractoriness could exert an important confounding effect in investigations in which repeated histamine tests are carried out at short intervals.
PMCID: PMC461723  PMID: 2929000
17.  Number and activity of inflammatory cells in bronchoalveolar lavage fluid in asthma and their relation to airway responsiveness. 
Thorax  1988;43(9):684-692.
Bronchial responsiveness to inhaled methacholine was measured four to six days before fibreoptic bronchoscopy in 22 asthmatic patients (10 smokers) and 20 control subjects (12 smokers). The asthmatic patients had a baseline FEV1 greater than 60% predicted and a PD20FEV1 (provocative dose of methacholine causing a 20% fall in FEV1) of 0.006-3.7 mg. The 20 control subjects had normal pulmonary function and a PD20FEV1 above the maximum cumulative dose of methacholine of 6.4 mg. Bronchoalveolar lavage of a middle lobe segment (lingula in four subjects) was performed with three sequential 60 ml aliquots of sterile saline. Cellular metabolic activity was stimulated with latex in aliquots of resuspended cells, and measured by means of luminol enhanced chemiluminescence to assess neutrophil activity and lucigenin enhanced chemiluminescence to assess macrophage activity. Mean absolute total cell counts were similar in the asthmatic and control groups but there were differences in differential cell counts, with a significant increase in eosinophil (p less than 0.05) and lymphocyte (p less than 0.005) counts in asthma. PD20FEV1 was negatively correlated with percentage neutrophil counts (p less than 0.005). Luminol enhanced chemiluminescence/1000 neutrophils was increased about twofold in asthmatic subjects (p less than 0.001), but was not correlated with PD20FEV1 Lucigenin enhanced chemiluminescence/1000 macrophages was increased nearly fourfold in asthmatic patients (p less than 0.001) and showed a negative correlation with PD20FEV1 (p less than 0.01). The macrophage count was increased twofold in current smokers in both groups, but other cell numbers were not altered significantly. Smoking did not affect cellular metabolic activity in either group. This study supports the idea that an inflammatory process is present in the airways of those with asthma, and suggests a relation between bronchial responsiveness and both neutrophil numbers and macrophage activity.
PMCID: PMC461456  PMID: 3194874
18.  Anatomical distribution of bronchoalveolar lavage fluid as assessed by digital subtraction radiography. 
Thorax  1987;42(8):624-628.
A digital subtraction imaging technique was used to visualise directly the anatomical distribution of 3 X 60 ml aliquots of saline containing a low concentration of radio-opaque dye, introduced sequentially into a segment of the middle lobe. It was possible to estimate the relative movement of fluid within the segment during the sequential aspiration of each of these aliquots. The first 60 ml aliquot introduced stayed close to the bronchoscope and probably sampled only the proximal airways. With the introduction of cumulative volumes of 120 ml or more, the fluid filled the segment more evenly. Aspiration then moved fluid back from the periphery, implying that the aspirate had also lavaged both distal airways and alveoli.
PMCID: PMC460864  PMID: 3310313
19.  Asthmagenic properties of a newly developed detergent ingredient: sodium iso-nonanoyl oxybenzene sulphonate. 
The suspicion that a newly developed detergent ingredient, sodium iso-nonanoyl oxybenzene sulphonate (SINOS), was inducing asthma among a workforce led to a series of inhalation challenge tests to determine the specificity and dose response characteristics of its asthma provoking properties. Three previously exposed workers, three non-exposed non-asthmatic controls, and three non-exposed asthmatic controls were challenged with SINOS 0.01-100 micrograms and another chemically similar surface active detergent ingredient, linear alkyl benzene sulphonate (LAS) 0.01-100 micrograms. Asthmatic symptoms, late falls in FEV1, and increases in non-specific bronchial responsiveness were seen after the inhalation of SINOS in all three workers, confirming SINOS as a cause of occupational asthma. No changes were seen after the inhalation of SINOS in either group of control subjects nor after LAS in any subject. These findings suggest that SINOS causes asthma through a specific hypersensitivity mechanism unrelated to its surface active properties.
PMCID: PMC1035191  PMID: 2165800
20.  Assessment of pulmonary macrophage and neutrophil function in sequential bronchoalveolar lavage aspirates in sarcoidosis. 
Thorax  1988;43(10):787-791.
Bronchoalveolar lavage was performed in eight patients with biopsy proved sarcoidosis and eight control subjects matched for age and smoking habit, three sequential 60 ml aliquots of sterile saline being used. Each aliquot was aspirated and analysed separately to determine total and differential cell counts. Cellular metabolic activity was stimulated with latex and measured by means of luminol enhanced chemiluminescence to assess neutrophil activity and lucigenin enhanced chemiluminescence to assess macrophage activity. In control subjects mean total cell counts were significantly greater in the second aspirate than in the first, but fell slightly in the third. Similarly, in the patients with sarcoidosis mean total cell counts increased from aspirate 1 to a maximum in aspirate 2, before falling again marginally in aspirate 3. The only significant difference in cell counts between patients with sarcoidosis and controls was an approximately threefold increase in total lymphocyte counts in the former in each of the three aspirates. Luminol chemiluminescence was similar in patients with sarcoidosis to that in controls in the first aspirate, but was significantly greater in the second and third aspirates. Lucigenin chemiluminescence was also significantly greater in the second and third aspirates only. Thus in patients with sarcoidosis lymphocyte numbers are increased in all three aspirates whereas cellular metabolic activity is increased to a greater extent in later aspirates, which may reflect events occurring in the periphery of the lung segment.
PMCID: PMC461513  PMID: 3206387
21.  Occupational asthma due to sodium iso-nonanoyl oxybenzene sulphonate, a newly developed detergent ingredient. 
Thorax  1988;43(6):501-502.
Research with sodium iso-nonanoyl oxybenzene sulphonate (SINOS) for use in a detergent product was complicated by the development of asthma in an atopic 38 year old laboratory technician. Inhalation challenge tests with nebulised SINOS solutions over a dose range of 0.01-32 micrograms gave reproducible late asthmatic reactions after the higher doses and an increase in bronchial responsiveness to methacholine. The magnitude of the late reaction was related to the challenge dose.
PMCID: PMC461327  PMID: 3420567
22.  Demeclocycline in the treatment of the syndrome of inappropriate secretion of antidiuretic hormone. 
Thorax  1979;34(3):324-327.
Fourteen patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been treated with demethylchlortetracycline (demeclocycline) 1200 mg daily. In 12 patients the underlying lesion was malignant. The serum sodium returned to normal (greater than 135 mmol/l) in all patients after a mean of 8.6 days (SD +/- 5.3 days). Blood urea rose significantly from the pretreatment level of 4.2 +/- 2.3 mmol/l to 10.1 +/- 5.1 mmol/l at ten days (P less than 0.001). The average maximum blood urea was 13.4 +/- 6.8 mmol/l. In four patients the urea rose above 20 mmol/l, and in two of these demecyocycline was discontinued because of thie rise. The azotaemia could be attributed to a combination of increased urea producation and a mild specific drug-induced nephrotoxicity. Discontinuation of demeclocycline in six patients led to a fall in serum sodium, in one case precipitously, and return of the urea towards normal levels. Demeclocycline appears therefore to be an effective maintenance treatment of SIADH, and the azotaemia that occurs is reversible and probably dose dependent.
PMCID: PMC471068  PMID: 113900
Thorax  1992;47(3):207.
PMCID: PMC1021018
24.  Effects of calcium channel blockade on histamine induced bronchoconstriction in mild asthma. 
Thorax  1984;39(8):572-575.
Inhalation histamine dose-response curves were constructed 15 minutes after inhalation of saline placebo or verapamil (4 mg) for eight patients with mild atopic asthma in a double blind, random manner. No significant change in baseline specific airways conductance occurred after inhalation of verapamil, though there was a significant decrease in sensitivity to histamine (increase in threshold of response) (p less than 0.01). There was, however, an associated significant increase (p less than 0.01) in the slopes of the subsequent histamine dose-response curves.
PMCID: PMC1020506  PMID: 6474383
25.  Effect of inhibition of prostaglandin synthesis on induced bronchial hyperresponsiveness. 
Thorax  1983;38(3):195-199.
Two groups of normal subjects were immunised with live attenuated influenza virus given by the intranasal route. One group was then treated with placebo capsules for 48 hours. At the end of this time an increase in sensitivity to inhaled histamine was found but with a coincident decrease in reactivity. The other group was treated with indomethacin (50 mg four times daily). The increase in sensitivity associated with influenza vaccination was prevented but there was a significant increase in reactivity. It is proposed that prostaglandins released as part of the inflammatory response in the airways after viral infection may be concerned in induction of the changes in response to histamine observed under these conditions.
PMCID: PMC459518  PMID: 6857584

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