bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased asthma medication use in association with ambient fine and ultrafine particles
Authors: Klot S. von , Wölke G. , Tuch T. , Heinrich J. , Dockery D.W. , Schwartz J. , Kreyling W.G. , Wichmann H.E. , Peters A.
Published: September 2002

The association between particulate air pollution and asthma medication use and symptoms was assessed in a panel study of 53 adult asthmatics in Erfurt, Germany in winter 1996/1997.

Number concentrations of ultrafine particles, 0.01–0.1 µm in diameter (NC0.01–0.1), mean 17,300·cm−3, and mass concentrations of fine particles 0.01–2.5 µm in diameter (MC0.01–2.5), mean 30.3 µg·m−3, were measured concurrently. They were not highly correlated (r=0.45). The associations between ambient particle concentrations and the prevalence of inhaled β2-agonist, corticosteroid use and asthma symptoms, were analysed separately with logistic regression models, adjusting for trend, temperature, weekend, holidays, and first order autocorrelation of the error.

Cumulative exposures over 14 days of ultrafine and fine particles were associated with corticosteroid use. β2-agonist use was associated with 5-day mean NC0.01–0.1and MC0.01–2.5. The prevalence of asthma symptoms was associated with ambient particle concentrations. The results suggest that reported asthma medication use and symptoms increase in association with particulate air pollution and gaseous pollutants such as nitrogen dioxide.
Effect of montelukast added to inhaled corticosteroids on fractional exhaled nitric oxide in asthmatic children
Authors: Ghiro L. , Zanconato S. , Rampon O. , Piovan V. , Pasquale M.F. , Baraldi E.
Published: September 2002

The aim of this prospective, self-controlled, single-blind study was to assess the effect of montelukast added to maintenance therapy with inhaled corticosteroids (ICS) on fractional exhaled nitric oxide (FENO) in asthmatic children.

Thirty-five children (age 11.2±0.4 yrs (mean±sem)) with mild-to-moderate persistent asthma treated with low to medium doses of ICS and FENO>20 parts per billion (ppb) were included. The patients were randomly assigned to two groups: 17 patients continued ICS (group C) and 18 had montelukast added to ICS for 3 weeks (group M). FENOmeasurements were performed in both groups at baseline (T1) and after 3 weeks (T2), and in group M also after 2 weeks of washout. FENOwas measured by a chemiluminescence analyser using an on-line method (50 mL·s−1) with nitric oxide-free air.

The overall mean daily dose of ICS was equivalent to 530±58 µg·day−1of beclomethasone in group M and to 564±55 µg·day−1of beclomethasone in group C. There were no significant differences in baseline FENOand forced expiratory volume in one second (FEV1) between the two groups. After 3 weeks there was a significant reduction of FENOvalues in patients of group M (T152.2±7.8 ppb, T236.1±4.6 ppb) but no significant changes in group C (T143.5±6.0 ppb, T247.8±9.4 ppb). In group M after 2 weeks of montelukast withdrawal, FENOrose to baseline values (55.6±8.7 ppb).

In conclusion, after montelukast treatment there is a fractional exhaled nitric oxide reduction in asthmatic children receiving maintenance therapy with inhaled corticosteroids. This suggests an anti-inflammatory effect of montelukast additive to that of inhaled corticosteroids.
BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives
Authors: Humbert M. , Deng Z. , Simonneau G. , Barst R.J. , Sitbon O. , Wolf M. , Cuervo N. , Moore K.J. , Hodge S.E. , Knowles J.A. , Morse J.H.
Published: September 2002

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension.

BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations.

Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis.

In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.
Organic dust-induced interleukin-12 production activates T- and natural killer cells
Authors: Müller-Suur C. , Larsson K. , Grunewald J.
Published: September 2002

Exposure in swine confinement buildings causes intense airway inflammation and lymphocyte activation, as assessed by bronchoalveolar lavage. To further clarify the T-cell activation, the presentin vitrostudy focused on intracellular cytokine production following exposure to organic dust from swine houses.

Whole blood from healthy donors was incubated with swine dust, phytohaemagglutinin (positive control) or Roswell Park Memorial Institute 1640 medium (negative control), and the production of intracellular interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4 and IL-12 was analysed by flow cytometry. Cells were double stained for specific cell surface markers on T-cells (CD3+, CD4+, CD8+), natural killer (NK) cells (CD56+CD16+) and monocytes (defined as CD14+ cells).

Following 1 h of incubation of whole blood with swine dust, CD14+ cells produced high levels of TNF-α and IL-12, whereas CD3+, CD4+ and CD8+ T-cells and CD56+CD16+ NK cells required a longer incubation time (22 h) to produce IFN-γ and TNF-α. When antibodies that block the IL-12 receptor were added to whole blood incubated with swine dust, NK cell production of IFN-γ was attenuated and CD69 expression on CD3+ cells decreased.

In conclusion, this study indicates that swine dust can, at least in part, stimulate phagocytic cells to activate natural killer cells and T-lymphocytes through the production of interleukin-12.
Physiological responses to the 6-min walk test in patients with chronic obstructive pulmonary disease
Authors: Troosters T. , Vilaro J. , Rabinovich R. , Casas A. , Barberà J.A. , Rodriguez-Roisin R. , Roca J.
Published: September 2002

The 6-min walking test (6MWT) is frequently used to assess functional capacity in chronic cardiopulmonary disorders because of its simplicity. The study examines the physiological responses during encouraged 6MWT in patients with chronic obstructive pulmonary disease.

Pulmonary oxygen (O2) uptake (V′O2) was measured in 20 male patients (age 66±6 yrs, forced expiratory volume in one second 45±14% predicted) during 6MWT and incremental cycling, in random order. O2tension in arterial blood, carbon dioxide tension in arterial blood and arterial lactate concentration ([La]art) were obtained in the last 10 patients. During the 6MWT,V′O2showed a plateau after the 3rd min (1.39±0.28, 1.42±0.31, and 1.40±0.30 L·min−1, 4th, 5th and 6th min, respectively), and minute ventilation (V′E) (42±8 L·min−1) was 91% maximal voluntary ventilation.

No differences were shown between 6MWT (6th min) and peak cycling exercise inV′O2(1.40±0.30versus1.41±0.28 L·min−1, respectively), cardiac frequency (126±13versus130±12 beats·min−1), or arterial respiratory blood gases. The two tests were significantly different inV′E(42±8versus47±8 L·min−1, 6MWTversuscycling, respectively), carbon dioxide production (1.30±0.31versus1.45±0.18 L·min−1) and [La]art(2.9±1.99versus5.9±1.51 M).

The study demonstrates that an encouraged 6-min walking test generates a high but sustainable oxygen uptake. Since the oxygen uptake plateau reflects the integrated response of the system, it may explain the high prognostic value of the 6-min walking test.
The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients
Authors: Clini E. , Sturani C. , Rossi A. , Viaggi S. , Corrado A. , Donner C.F. , Ambrosino N.
Published: September 2002

Chronic obstructive pulmonary disease (COPD) patients with chronic ventilatory failure (CVF) are more likely to develop exacerbations, which are an important determinant of health-related quality of life (HRQL). Long-term noninvasive positive-pressure ventilation (NPPV) has been proposed in addition to long-term oxygen therapy (LTOT) to treat CVF but little information is available on its effects on HRQL and resource consumption. Therefore, the current authors undertook a 2-yr multicentric, prospective, randomised, controlled trial to assess the effect of NPPV+LTOT on: 1) severity of hypercapnia; 2) use of healthcare resources, and 3) HRQL, in comparison with LTOT alone.

One hundred and twenty-two stable hypercapnic COPD patients on LTOT for ≥6 months were consecutively enrolled. After inclusion and 1-month run-in, 90 patients were randomly assigned to NPPV+LTOT (n=43) or to LTOT alone (n=47). Arterial blood gases, hospital and intensive care unit (ICU) admissions, total hospital and ICU length of stay and HRQL were primary outcome measures; survival and drop-out rates, symptoms (dyspnoea and sleep quality) and exercise tolerance were secondary outcome measures. Follow-up was performed at 3-month intervals up to 2 yrs.

Lung function, inspiratory muscle function, exercise tolerance and sleep quality score did not change over time in either group. By contrast the carbon dioxide tension in arterial blood on usual oxygen, resting dyspnoea and HRQL, as assessed by the Maugeri Foundation Respiratory Failure Questionnaire, changed differently over time in the two groups in favour of NPPV+LTOT. Hospital admissions were not different between groups during the follow-up. Nevertheless, overall hospital admissions showed a different trend to change in the NPPV+LTOT (decreasing by 45%) as compared with the LTOT group (increasing by 27%) when comparing the follow-up with the follow-back periods. ICU stay decreased over time by 75% and 20% in the NPPV+LTOT and LTOT groups, respectively. Survival was similar.

Compared with long-term oxygen therapy alone, the addition of noninvasive positive-pressure ventilation to long-term oxygen therapy in stable chronic obstructive pulmonary disease patients with chronic ventilatory failure: 1) slightly decreased the trend to carbon dioxide retention in patients receiving oxygen at home and 2) improved dyspnoea and health-related quality of life. The results of this study show some significant benefits with the use of nocturnal, home noninvasive positive-pressure ventilation in patients with chronic ventilatory failure due to advanced chronic obstructive pulmonary disease patients. Further work is required to evaluate the effect of noninvasive positive-pressure ventilation on reducing the frequency and severity of chronic obstructive pulmonary disease exacerbation.
Does negative expiratory pressure influence performances of spirometry in older patients?
Authors: Vanpee D. , Swine Ch. , Delwiche J.P. , Jamart J. , Delaunois L.
Published: September 2002

The aim of this study is to assess the influence of the negative expiratory pressure (NEP) technique on the performance of maximal expiratory manoeuvre in elderly patients.

Firstly, the authors studied how NEP (at 5 and 10 cmH2O, NEP5 and NEP10) influences forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in 60 young healthy volunteers, in order to assess the fluctuations of the method. In the second part of the study, 65 successive elderly inpatients (>70 yrs old) were examined. In this group, 15 elderly patients were unable to perform the manoeuvre, 27 had a normal function, 14 had a lung function with obstructive pattern and nine with restrictive pattern.

In young subjects, FVC during NEP5 and NEP10 compared to baseline values was 101±5% and 103±5%, respectively, and FEV1was 100±4% and 101±5%, respectively. In elderly patients with normal function, FVC during NEP5 and NEP10 compared to baseline values was 99±14% and 109±23%, respectively, and FEV1was 97±9% and 104±13%, respectively. There were no relevant effects of the NEP application on FVC or FEV1values in elderly patients with an obstructive or restrictive pattern.

In elderly patients, the use of the negative expiratory pressure technique during maximal expiratory manoeuvres provides little complementary information compared to a classical manoeuvre. The negative expiratory pressure technique did not modify the initial diagnosis when compared with the classical manoeuvre.
Allergens and endotoxin on mothers' mattresses and total immunoglobulin E in cord blood of neonates
Authors: Heinrich J. , Bolte G. , Hölscher B. , Douwes J. , Lehmann I. , Fahlbusch B. , Bischof W. , Weiss M. , Borte M. , Wichmann H-E.
Published: September 2002

The current authors examined whether mite and cat allergen and bacterial endotoxin levels in dust of the mothers' mattresses were associated with cord blood immunoglobulin (Ig)E (CB-IgE) levels in newborns.

Data from 1,332 term and normal weight neonates, from an ongoing birth cohort study, Influences of life-style related factors on the immune system and the development of allergies in childhood (LISA), with complete information on exposure to biocontaminants in mattress dust and CB-IgE were analysed.

Two thirds of CB-IgE were undetectable (<0.35 kU·L−1). Thus, 0.35 and 0.45 kU·L−1(4th quartile) were chosen as cut-offs. Nonparametric smoothing (generalised additive models) showed statistically significant confounder-adjusted associations between elevated CB-IgE levels (≥0.45 kU·L−1) and log-transformed exposures to cat (linear), mite (inverse u-shaped), and endotoxin (u-shaped).

After adjustment for covariables, elevated CB-IgE levels (logistic regression using the 1st–4th quartiles of exposure) were positively associated with high cat-allergen exposure and medium exposure to mite allergen, but were inversely associated with exposure to endotoxin. The associations were similar, but somewhat weaker, when 0.35 kU·L−1was used as cut-off.

These results, showing an association between prenatal allergen and endotoxin exposures and immunoglobulin E production, suggest that the development of foetal immune responses may be affected.
Effects of inhaled salbutamol in primary pulmonary hypertension
Authors: Spiekerkoetter E. , Fabel H. , Hoeper M.M.
Published: September 2002

Although lung function is grossly normal in patients with primary pulmonary hypertension (PPH), mild-to-moderate peripheral airflow obstruction can be found in the majority of patients with this disease. Therefore, β2-agonists may affect pulmonary function, blood gases and haemodynamics in patients with PPH.

Pulmonary function testing, blood gas measurements and right heart catheterisation was performed in 22 patients with PPH and the acute effects of inhaled salbutamol (0.2 mg) were measured.

Salbutamol caused an increase in the forced expiratory volume in one second (FEV1) from 2446±704 to 2550±776 mL. The mean expiratory flow at 50% of the vital capacity (MEF50) rose from 58±17 to 66±21% pred. The pulmonary artery pressures remained unchanged after inhalation of salbutamol, but the cardiac output increased significantly from 3.9±1.4 to 4.2±1.4 L·min−1accompanied by significant increases in stroke volume and mixed venous oxygen saturation as well as a significant decrease in pulmonary vascular resistance. The arterial oxygen tension rose from 9±2.4 kPa (68±18 mmHg) at baseline to 9.7±2.8 kPa (73±21 mmHg) after inhalation of salbutamol, the alveolo-arterial oxygen gradient values improved from 6±2.5 kPa (45±19 mmHg) to 5.1±2.9 kPa (38±22 mmHg), respectively.

Inhaled salbutamol has beneficial acute effects on pulmonary function, blood gases and haemodynamics in patients with primary pulmonary hypertension.
Treatment of asthma with lipid extract of New Zealand green-lipped mussel: a randomised clinical trial
Authors: Emelyanov A. , Fedoseev G. , Krasnoschekova O. , Abulimity A. , Trendeleva T. , Barnes P.J.
Published: September 2002

Asthma is a chronic inflammatory disease of the airways mediated, at least in part, by leukotrienes and other lipid mediators. Experimental studies have shown that lipid extract of New Zealand green-lipped mussel,Perna canaliculus, is effective in inhibiting 5′-lipoxygenase and cyclo-oxygenase pathways responsible for production of eicosanoids, including leukotrienes and prostaglandins. The aim of this study was to assess its effect on symptoms, peak expiratory flow (PEF) and hydrogen peroxide (H2O2) in expired breath condensate as a marker of airway inflammation in patients with steroid-naïve atopic asthma in a double-blind randomised, placebo-controlled clinical trial.

Forty six patients with atopic asthma received two capsules of lipid extract (Lyprinol®) or placebob.i.d.for 8 weeks. Each capsule of lipid extract contained 50 mg ω-3 polyunsaturated fatty acids and 100 mg olive oil, whereas placebo capsules contained only 150 mg olive oil.

There was a significant decrease in daytime wheeze, the concentration of exhaled H2O2and an increase in morning PEF in the lipid extract group compared to the placebo group. There were no significant side-effects.

The authors conclude that lipid extract of New Zealand green-lipped mussel may have some beneficial effect in patients with atopic asthma.
Genetics of pulmonary hypertension: from bench to bedside
Authors: Humbert M. , Trembath R.C.
Published: September 2002

Primary pulmonary hypertension has been described as either sporadic or clustered in families. Familial primary pulmonary hypertension segregates as an autosomal dominant trait with markedly reduced disease gene penetrance. Defects within bone morphogenetic protein receptor type II gene, coding for a receptor member of the transforming growth factor-β family, underlie familial primary pulmonary hypertension. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of so-called sporadic primary pulmonary hypertension turns out to have an inherited basis, as demonstrated by germline bone morphogenetic protein receptor type II gene mutations. Analysis of cases in association with hereditary haemorrhagic telangiectasia led to the demonstration that pulmonary arterial hypertension can involve activin-receptor-like kinase 1 mutations, a type I transforming growth factor-β receptor. These findings emphasise the critical role of the transforming growth factor-β signalling pathway in pulmonary arterial hypertension. While this achievement has generated extreme interest, the pathobiology of severe pulmonary arterial hypertension remains unclear and genomic approaches to pulmonary hypertension research may identify additional molecular determinants for this disorder. Finally, there is an urgent need to develop relevant guidelines for genetic counselling to assist patients, their relatives and pulmonary vascular specialists to utilise these recent observations.
Diagnosing occupational asthma: use of induced sputum
Authors: Lemiere C , Pizzichini MM , Balkissoon R , Clelland L , Efthimiadis A , O'Shaughnessy D , Dolovich J , Hargreave FE
Published: September 2002

The diagnosis of occupational asthma (OA) needs to be made with as much objective evidence as possible. If there is airway inflammation, measurement of this should be an asset. The objective of this study was to investigate whether there is an increase in induced sputum and blood eosinophils and eosinophil cationic protein (ECP) in OA after work exposure. Patients were assessed after a 2-4 week period at work and away from work with cell counts and ECP assays performed blind to the clinical data. They were considered to have OA if symptoms were worse at work and there was a fall in forced expiratory volume in one second (FEV1) > or =20% or in the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of four-fold or more compared with away from work. Patients whose symptoms were worse at work but had a change in FEV1 of <20% and in methacholine PC20 of less than four-fold were considered as controls. Sixteen patients were studied. Ten had OA and six were controls. Patients with OA had a significant increase in median (interquartile range) sputum eosinophils and ECP when at work compared with the periods out of work, 10.0 (17.05) versus 0.8 (1.6)% (p=0.007) and 3,840 (6,076) versus 116 (180) microg x L(-1) (p=0.01). They also had a higher blood eosinophil count, 0.3 (0.5) x 10(9) versus 0.2 (0.1) x 10(9) x L(-1) (p=0.013), and a trend towards higher serum ECP levels, 44.0 (20.0) versus 32.0 (18.5) microg x L(-1) (p=0.07). In conclusion, the proportion of eosinophils and levels of eosinophil cationic protein in sputum are particularly high at work in patients with occupational asthma, suggesting that the measurement of these factors can supplement other physiological outcomes in establishing the diagnosis of occupational asthma.
Sputum eosinophils and exhaled nitric oxide during late asthmatic reaction in patients with western red cedar asthma
Authors: Obata H , Dittrick M , Chan H , Chan-Yeung M
Published: September 2002

Examination of sputum for eosinophils and measurement of exhaled nitric oxide have been proposed as noninvasive methods of assessing airway inflammation in asthma. The use of these tests in the evaluation of patients with occupational asthma has not been reported. This study investigated the changes in sputum eosinophils and exhaled NO before and at intervals after inhalation challenge with plicatic acid in patients with suspected western red cedar asthma. Of 17 subjects who underwent challenge, nine had a positive bronchoconstrictor reaction (responders) and eight had a negative reaction (nonresponders). At 6 and 24 h after plicatic acid challenge, there was a significant increase in sputum eosinophils among responders, which was inversely related to the fall in forced expiratory volume in one second (FEV1) at 6 h. An increase in sputum eosinophils was also found in three nonresponders. Levels of exhaled NO increased at 24 h after challenge with plicatic acid in both responders and nonresponders, being significant only in nonresponders. No correlation was found between the increase in nitric oxide and the magnitude of the functional changes in the airways. There were significant correlations between the degree of sputum eosinophilia and the level of exhaled NO before and after methacholine and plicatic acid challenge. In conclusion, the late asthmatic reaction induced by plicatic acid in patients with western red cedar asthma is associated with an increase in sputum eosinophils. The usefulness of measuring sputum eosinophils and exhaled nitric oxide in the clinical evaluation of patients with suspected occupational asthma caused by low molecular weight compounds has yet to be determined.
The risk of asthma in relation to occupational exposures: a case-control study from a Swedish city
Authors: Toren K , Balder B , Brisman J , Lindholm N , Lowhagen O , Palmqvist M , Tunsater A
Published: September 2002

The purpose of this study was to estimate the risk of adult asthma in relation to certain occupational exposures. The study was designed as a case-control study in Goteborg, including 321 subjects with asthma, born between 1926 and 1970. Controls (n=1,459) were randomly selected from the same area from registers of the 1986 population. Questionnaire information was collected in 1996, and included occupational exposures and smoking habits. Odds ratios were calculated for exposure before asthma onset, stratified by sex and age-class. The highest risks for asthma were associated with exposure to grain dust (odds ratio (OR) 4.2, 95% confidence interval (CI) 1.6-10.7) and flour dust (OR 2.8, 95% CI 1.1-7.2). Among males, significantly increased risks were observed after exposure to flour dust, welding fumes, man-made mineral fibres, and solvents. Among females, increased risks for asthma were associated with exposures to paper dust and textile dust. In logistic regression models controlling for age, smoking, sex and interacting exposures, increased risks were seen for welding fumes (OR 2.0, 95% CI 15-3.4), man-made mineral fibres (OR 2.6, 95% CI 1.4-7.3) and solvents (OR 2.2, 95% CI 1.2-3.2). The fraction of asthma attributed to occupational exposures after adjusting for sex, smoking and age was 11% (95% CI 7-14%). In conclusion, exposure to welding fumes, man-made mineral fibres, solvents and textile dust is associated with increased risk for asthma.
Bakery work, atopy and the incidence of self-reported hay fever and rhinitis
Authors: Brisman J , Jarvholm B
Published: September 2002

The aims of this study were to estimate the risk to bakers of developing hay fever and rhinitis, to assess the modifying effect of atopy and to estimate the occurrence of job change due to nasal symptoms. A retrospective cohort study was performed among bakers trained in Swedish trade schools from 1961 to 1989 (n=2,923). School control subjects (n=1,258) comprised students in other programmes in the trade schools and population controls (n=1,258) were randomly selected from the general population. A questionnaire on hay fever, rhinitis, the year of onset of these diseases, change of work due to nasal symptoms and work history was mailed to all participants. The atopic state of the responders was assessed by questions on allergic diseases in childhood and among next of kin. Incidence rates for hay fever and other rhinitis were calculated. The relative risk (RR) for hay fever when working as a baker compared with all control subjects combined was increased in males (RR=1.9, 95% confidence interval (CI) 1.2-2.9). The RR for rhinitis in male bakers compared with combined control subjects was 2.8 (95% CI 2.3-3.4) and for female bakers 2.0 (1.6-2.7). Of the bakers, 6.1% had changed job due to nasal symptoms, significantly more than the controls. A history of respiratory atopy increased the incidence rates of hay fever and rhinitis, with a synergistic effect between atopy and bakery work in males. In conclusion, Swedish bakers, mainly working in the 1970s and 1980s, had an approximately doubled risk of developing rhinitis. Male bakers also had an increased risk for hay fever. There was a synergistic effect of bakery work and atopy such as a family history of hay fever. Bakers also changed job due to nasal symptoms more often than control subjects.
Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude
Authors: Mason NP , Barry PW , Despiau G , Gardette B , Richalet JP
Published: September 2002

The aim of this study was to determine the frequency of cough and the citric acid cough threshold during hypobaric hypoxia under controlled environmental conditions. Subjects were studied during Operation Everest 3. Eight subjects ascended to a simulated altitude of 8,848 m over 31 days in a hypobaric chamber. Frequency of nocturnal cough was measured using voice-activated tape recorders, and cough threshold by inhalation of increasing concentrations of citric acid aerosol. Spirometry was performed before and after each test. Subjects recorded symptoms of acute mountain sickness and arterial oxygen saturation daily. Air temperature and humidity were controlled during the operation. Cough frequency increased with increasing altitude, from a median of 0 coughs (range 0-4) at sea level to 15 coughs (range 3-32) at a simulated altitude of 8,000 m. Cough threshold was unchanged on arrival at 5,000 m compared to sea level (geometric mean difference (GMD) 1.0, 95% confidence intervals (CI) 0.5-2.1, p=0.5), but fell on arrival at 8,000 m compared to sea level (GMD 3.3, 95% CI 1.1-10.3, p=0.043). There was no relationship between cough threshold and symptoms of acute mountain sickness, oxygen saturation or forced expiratory volume in one second. Temperature and humidity in the chamber were controlled between 18-24 degrees C and 30-60%, respectively. These results confirm an increase in cough frequency and cough receptor sensitivity associated with hypobaric hypoxia, and refute the hypothesis that high altitude cough is due to the inhalation of cold, dry air. The small sample size makes further conclusions difficult, and the cause of altitude-related cough remains unclear.
Empirical treatment with fibrinolysis and early surgery reduces the duration of hospitalization in pleural sepsis
Authors: Lim TK , Chin NK
Published: September 2002

The efficacy of three different treatment protocols was compared: 1) simple chest tube drainage (Drain); 2) adjunctive intrapleural streptokinase (IP-SK); and 3) an aggressive empirical approach incorporating SK and early surgical drainage (SK+early OP) in patients with pleural empyema and high-risk parapneumonic effusions. This was a nonrandomized, prospective, controlled time series study of 82 consecutive patients with community-acquired empyema (n=68) and high-risk parapneumonic effusions (n=14). The following three treatment protocols were administered in sequence over 6 years: 1) Drain (n=29, chest catheter drainage); 2) IP-SK (n=23, adjunctive intrapleural fibrinolysis with 250,000 U x day(-1) SK); and 3) SK+early OP (n=30, early surgical drainage was offered to patients who failed to respond promptly following initial drainage plus SK). The average duration of hospital stay in the SK+early OP group was significantly shorter than in the Drain and IP-SK groups. The mortality rate was also significantly lower in the SK+early OP than the Drain groups (3 versus 24%). It was concluded that an empirical treatment strategy which combines adjunctive intrapleural fibrinolysis with early surgical intervention results in shorter hospital stays and may reduce mortality in patients with pleural sepsis.
High pleural fluid hyaluronan concentrations in rheumatoid arthritis
Authors: Soderblom T , Pettersson T , Nyberg P , Teppo AM , Linko L , Riska H
Published: September 2002

Previous studies have shown that high pleural fluid (Pf) hyaluronan (HYA) concentrations may be due not only to malignant mesothelioma but also to inflammatory diseases. The objective of this study was to evaluate Pf-HYA in various nonmalignant inflammatory pleural disorders. A radiometric assay was used to determine HYA in Pf and serum (S) of 126 patients, 12 of whom had rheumatoid arthritis (RA), 22 tuberculosis, 22 pneumonia, 41 lung cancer, 10 malignant mesothelioma and 19 congestive heart failure. Pf-HYA values were correlated with values for Pf-tumour necrosis factor (TNF)-alpha and Pf-interleukin (IL)-1beta, as determined by radioimmunoassay. The highest median Pf-HYA (125.6 mg x L(-1), range 0.04-386.5 mg x L(-1)) occurred in patients with malignant mesothelioma. Among patients with nonmalignant inflammatory diseases, significantly higher median Pf-HYA were observed in those with rheumatoid arthritis (64.2 mg x L(-1), range 25.8-106.9 mg x L(-1)) than in those with tuberculosis (25.5 mg x L(-1), range 14.9-57.1 mg x L(-1), p<0.0005) or pneumonia (20.9 mg x L(-1), range 9.5-129.4 mg x L(-1), p<0.005). There was no correlation between Pf-HYA and S-HYA. Pf-HYA correlated positively with Pf-TNF-alpha (r=0.62) and Pf-IL-1beta (r=0.52). High pleural fluid hyaluronan occurs not only in malignant mesothelioma, but also in certain nonmalignant inflammatory diseases, especially rheumatoid arthritis. One explanation for the increase in pleural fluid hyaluronan may be local production of proinflammatory cytokines, such as tumour necrosis factor-alpha and interleukin-1beta.
Malignant mesothelioma due to environmental exposure to erionite: follow-up of a Turkish emigrant cohort
Authors: Metintas M , Hillerdal G , Metintas S
Published: September 2002

The incidence of malignant mesothelioma is extremely high in some Turkish villages where there is a low-level environmental exposure to erionite, a fibrous zeolite. The best known example is the village of Karain. However, since epidemiological studies are difficult to perform in Turkey, the incidence and the dose-response curve have not been thoroughly examined. A small cohort of immigrants from Karain who have lived in Sweden for many years were studied. Exposure data, i.e. the time residing in Karain, and hospital records including pathological diagnosis, were recorded. The cohort consisted of 162 people. During the observation time, 18 deaths occurred, 14 (78%) of which were due to malignant pleural mesothelioma. In addition, there were five patients with mesothelioma who were still alive, one of whom had a peritoneal mesothelioma. Thus, the risk of mesothelioma is 135-times and 1,336-times greater in males and females, respectively, than for the same sex and age groups in Sweden. The risk increased with duration of residence.
Establishment of four new mesothelioma cell lines: characterization by ultrastructural and immunophenotypic analysis
Authors: Orengo AM , Spoletini L , Procopio A , Favoni RE , De Cupis A , Ardizzoni A , Castagneto B , Ribotta M , Betta PG , Ferrini S , Mutti L
Published: September 2002

The aim of this study was to assess the biological characteristics of four new malignant mesothelioma (MM) cell lines. Since simian virus (SV)40 sequences have been recently detected in MM, SV40 large T antigen (Tag) expression was also analysed. MM cell lines were characterized by morphological, ultrastructural and cytogenetic analysis. Expression of Tag and of relevant MM markers was studied by immunocytochemistry, surface antigens by indirect immunofluorescence and immunomodulating cytokines by enzyme-linked immunosorbent assay (ELISA). The four MM cell lines, established from pleural effusions, showed a slow proliferation rate and pleomorphic changes during culture. Cell lines expressed vimentin, cytokeratins 8 and 18, and the mesothelial antigen recognized by HBME-1 monoclonal antibody, but not carcinoembryonic antigen. Surface human leukocyte antigen (HLA)-class I and intercellular adhesion molecule (ICAM)-1 molecules were present on all the cell lines. While HLA class II and CD86 were constitutively undetectable, HLA-class II was present after interferon (IFN)-gamma stimulation. All cell lines displayed abnormal karyotypes with chromosome 6 abnormalities. Transforming growth factor (TGF)-beta2 and interleukin (IL)-6 were constitutively secreted, while tumour necrosis factor (TNF)-alpha was secreted only in response to lipopolysaccharide. Intranuclear Tag was expressed in two cell lines. The persistence of large T antigen with human leukocyte antigen class I and intercellular adhesion molecule-1 positivity may point to large T antigen as a target for cytotoxic T-lymphocyte-based immunotherapy in some malignant mesothelioma patients.
Pathological and radiological changes in resected lung specimens in Mycobacterium avium intracellulare complex disease
Authors: Fujita J , Ohtsuki Y , Suemitsu I , Shigeto E , Yamadori I , Obayashi Y , Miyawaki H , Dobashi N , Matsushima T , Takahara J
Published: September 2002

The present study was designed to evaluate the pathological and immunohistochemical findings of Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed in five cases with positive cultures for MAC in whom lung resections were performed between January 1989 and December 1996. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria defined by the American Thoracic Society. In addition, MAC was cultured from all of the five lung specimens. Pathological and immunohistochemical findings as well as chest computed tomography (CT) findings were evaluated in these five patients. Pathological findings of bronchiectasis, bronchiolitis, centrilobular lesion, consolidation, cavity wall and nodules were demonstrated, respectively, in relation to chest CT findings. Extensive granuloma formation throughout the airways was clearly demonstrated. Immunohistochemical staining demonstrated: 1) epithelioid cells and giant cells; 2) myofibroblasts extensively infiltrating the cavity wall; and 3) B-cells detected in aggregates in the vicinity of the epithelioid granulomas. This study identified pathological and immunohistochemical characteristics of Mycobacterium avium complex infection relative to chest computed tomography findings and allowed the conclusion that bronchiectasis and bronchiolitis were definitely caused by Mycobacterium avium complex infection.
Social factors associated with increases in tuberculosis notifications
Authors: Tocque K , Regan M , Remmington T , Beeching NJ , Jamieson I , Syed Q , Davies PD
Published: September 2002

This study assessed the contribution of immigration and deprivation to the changes in tuberculosis notifications in Liverpool over the last 20 yrs. Ethnic origin was retrospectively assigned to all named cases from 1974 to 1995. Average tuberculosis rates were calculated for the 33 council wards in Liverpool for 1981-1985 and 1991-1995. Multiple regression was used to determine the independent effects of socioeconomic and population measures from the 1981 and 1991 censuses in explaining these ward-based rates. Since 1974, there has been a steady increase in the percentage of non-Caucasian cases of tuberculosis, from 8.7% in 1975-1977, 15.1% in 1981-1983, 17.5% in 1987-1989 to 28.0% in 1993-1995. Multiple regression analysis showed that in 1981 only unemployment had a significant independent relationship with tuberculosis rates, but in 1991 two indices of deprivation and ethnicity had a significant influence. The increasing proportion of non-Caucasian tuberculosis cases, both while the number of notifications was declining before 1987 and increasing afterwards, is not necessarily consistent with the concept that immigration has influenced the recent increase. However, the fact that ethnicity now independently explains some of the council ward variations but did not in the early 1980s suggests that immigration does influence the distribution of disease within the city.
The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation
Authors: Feldman C , Kassel M , Cantrell J , Kaka S , Morar R , Goolam Mahomed A , Philips JI
Published: September 2002

Endotracheal tube colonization in patients undergoing mechanical ventilation was investigated. In the first part of this prospective study, the airway access tube was examined for the presence of secretions, airway obstruction and bacterial colonization, in cases undergoing extubation or tube change. In the second part of the study, the sequence of oropharyngeal, gastric, respiratory tract and endotracheal tube colonization was investigated by sequential swabbing at each site twice daily for 5 days in consecutive noninfected patients. In the first part, it was noted that all airway access tubes of cases undergoing extubation had secretions lining the interior of the distal third of the tube which were shown on scanning electron microscopy to be a biofilm. Gram-negative micro-organisms were isolated from these secretions in all but three cases. In the second part, it was noted that the sequence of colonization in patients undergoing mechanical ventilation was the oropharynx (36 h), the stomach (3660 h), the lower respiratory tract (60-84 h), and thereafter the endotracheal tube (60-96 h). Nosocomial pneumonia occurred in 13 patients and in eight cases identical organisms were noted in lower respiratory tract secretions and in secretions lining the interior of the endotracheal tube. The endotracheal tube of patients undergoing mechanical ventilation becomes colonized rapidly with micro-organisms commonly associated with nosocomial pneumonia, and which may represent a persistent source of organisms causing such infections.
Construct and longitudinal validity of a modified Huang clinical scoring system in adult cystic fibrosis patients
Authors: Matouk E , Ghezzo RH , Gruber J , Hidvegi R , Gray-Donald K
Published: September 2002

This study reports on the evaluation of a modified Huang scoring system in adult cystic fibrosis patients for construct and longitudinal validity. Two studies were performed. In the first study, the scoring system was applied to 59 adult cystic fibrosis patients prospectively followed at the Montreal Chest Institute. The total score and all the subscores distinguished between patients with the expected mild degree of disease severity seen in patients colonized with only Staphylococcus aureus, compared to the more advanced disease severity seen in patients colonized with Pseudomonas aeruginosa or multiple resistant pseudomonads. The relationship between disease severity assessed by forced expiratory volume in one second per cent predicted and the nonpulmonary function subscores was significant and linear (for the radiological subscore, r2=0.694, p<0.0001) and curvilinear (for the clinical and complications subscores, r2=0.622, p=0.0192 and r2=0.508, p=0.0009 respectively). In the second study, 20 patients retrospectively recorded were added to the prospective group. There was a good association between changes in nonpulmonary function subscores and changes in spirometry over a mean follow-up period of 779+/-204 days, at all levels of disease severity. The contribution of changes in clinical and complications subscores to the changes in total score became progressively more significant with more advanced disease severity. In conclusion, significant evidence for the construct validity of the scoring system as a discriminative instrument and for the longitudinal validity as an evaluative instrument was demonstrated. It may prove of value in assessing outcome of therapeutic interventions in clinical trials in patients with cystic fibrosis.
Treatment of pulmonary exacerbations of cystic fibrosis leads to improved antioxidant status
Authors: Range SP , Dunster C , Knox AJ , Kelly FJ
Published: September 2002

Many cystic fibrosis (CF) patients have increased circulating levels of oxidation products and/or decreased antioxidant status. This study investigated whether treatment of pulmonary exacerbations decreased oxidative stress in CF patients. Seventeen adult patients were studied at the beginning and end of treatment with intravenous antibiotics. Plasma concentrations of the antioxidants ascorbic acid, alpha-tocopherol, uric acid and total reduced thiols, together with plasma retinol, lipid hydroperoxides, malondialdehyde and protein carbonyl levels were determined. Median (interquartile range) pretreatment and post-treatment levels were compared using the Wilcoxon signed rank test. Clinical resolution was reflected by improved spirometry. Significant increases were observed in plasma ascorbic acid (pre 30.4 (15.7-38.6) microM, post 35.2 (27.3-49.6) microM), alpha-tocopherol (pre 19.7 (13.6-25.2) microM, post 25.2 (19.3-31.6) microM) and retinol (pre 1.9 (1.5-2.5) microM, post 2.7 (1.7-3.5) microM). No change in plasma total reduced thiols occurred following treatment (pre 409 (366-420) microM, post 392 (366-423) microM), whereas uric acid fell with treatment (pre 307 (274-394) microM, post 260 (216-317) microM). Neither plasma protein carbonyls or malondialdehyde levels altered with treatment (protein carbonyls pre 0.47 (0.28-1.27), post 0.67 (0.42-0.83) nM x mg protein(-1); malondialdehyde pre 0.75 (0.53-1.18), post 0.84 (0.65-1.15) microM). Lipid hydroperoxides levels did decrease following treatment (53 (18-85) versus 17 (10-55) nM). This study demonstrated that treatment of infective exacerbations resulted in increased plasma levels of some antioxidant vitamins. No immediate change in plasma protein oxidation was observed, but lipid oxidation was decreased.
Reduction in the adherence of Pseudomonas aeruginosa to native cystic fibrosis epithelium with anti-asialoGM1 antibody and neuraminidase inhibition
Authors: Davies J , Dewar A , Bush A , Pitt T , Gruenert D , Geddes DM , Alton EW
Published: September 2002

The high incidence of colonization of the cystic fibrosis (CF) airway with Pseudomonas aeruginosa has been attributed to several mechanisms including increased numbers of asialoglycolipid receptors, which may be further increased by exposure to the bacterial exoproduct, neuraminidase. This study examined whether the adherence of P. aeruginosa to fresh CF respiratory epithelial cells can be reduced in vitro by anti-asialoGM1 (anti-aGM1) antibody, neuraminidase inhibition, or the use of asialoGM1 tetrasaccharide as a competitive inhibitor. CF nasal epithelial cells were incubated with a nonmucoid strain of P. aeruginosa, in the presence or absence of a polyclonal anti-aGM1 antibody, the neuraminidase inhibitor 2,3-dehydro-2-deoxy-N-acetyl-neuraminic acid (DANA), or the tetrasaccharide moiety of aGM1. Adherence of bacteria to the apical surface of ciliated epithelial cells was quantified using scanning electron microscopy. Incubation of the cells with bacteria in the presence of either anti-aGM1 antibody or DANA significantly reduced bacterial adherence by 51(7)%, (p<0.01), and 34(9)%, (p<0.01), respectively. In contrast, no significant effect on P. aeruginosa binding was seen in the presence of aGM1 tetrasaccharide. The data are consistent with previous studies on cultured cells, and suggest that the in vivo effects of such interventions should be explored as potential mechanisms to reduce Pseudomonas aeruginosa colonization in cystic fibrosis.
Multiple intracellular pathways for regulation of chloride secretion in cultured pig tracheal submucosal gland cells
Authors: Zhang AL , Roomans GM
Published: September 2002

Tracheal submucosal glands are of great relative importance in the secretion of chloride and water to the airway lumen. This study aimed to examine whether the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in cyclic adenosine monophosphate (cAMP) or Ca2+-activated Cl- secretion. Regulation of Cl- secretion in cell cultures derived from pig tracheal submucosal gland acini was investigated by X-ray microanalysis. With or without preincubation with CFTR antisense oligodeoxynucleotide (5 microM). A significant decrease in cellular Cl and K concentration was induced by 5 mM 8-bromo-adenosine 3': 5'-cyclic monophosphate (8-bromo-cAMP), 3 microM calcium ionophore ionomycin, 200 microM 5'-uridine triphosphate (UTP) and 200 microM 5'-adenosine triphosphate (ATP), respectively. The decrease in cellular Cl content was significantly inhibited by the Cl- channel blocker 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid (NPPB; 50 microm). Preincubation of the cells with CFTR antisense oligodeoxynucleotide significantly inhibited the 8-bromo-cAMP-induced decrease in Cl, whereas CFTR sense oligodeoxynucleotide had no effect. The effects of ionomycin, ATP or UTP were not blocked by either CFTR antisense oligodeoxynucleotide or CFTR sense oligodeoxynueleotide. To measure the cytosolic free calcium concentration ([Ca2+]i) the cells grown on glass coverslips were loaded with fura-2 tetraoxymethylester (fura-2 AM; 5 microM). The [Ca2+]i was measured as the fluorescence ratio of emission (340/380 nm). Ionomycin (3 microM) caused a rapid increase in [Ca2+]i followed by a sustained plateau, but 8-bromo-cAMP had a more complex effect on [Ca2+]i. Exposure to ATP or UTP caused a rapid increase in [Ca2+]i followed by a decrease. In conclusion, cystic adenosine monophosphate and ionomycin induced Cl- secretion through different intracellular pathways. Adenosine triphosphate and uridine triphosphate also induced Cl- secretion probably with Ca as an intracellular messenger. The cystic fibrosis transmembrane conductance regulator is not involved in Cl- secretion activated by extracellular adenosine triphosphate and uridine triphosphate.