bluuebunny/crossref_metadata_2025 huggingface dataset:
Lung and thorax development during adolescence: relationship with pubertal status
Authors: Nève V. , Girard F. , Flahault A. , Boulé M.
Published: November 2002

The aim of the present study was to define reference values for lung volumes and the lung transfer factor for carbon monoxide (TL,CO) for an adolescent population using thoracic volume index (TVI) and an index of pubertal stage in order to account for the variation in growth pattern between adolescents.

TVI, pubertal stage by Tanner scale (PST), time since menarche, functional residual capacity measured using the helium­dilution technique, vital capacity, total lung capacity andTL,COmeasured using a steady­state method were determined in 51 males (aged 13–20 yrs; PST T3–T5) and 52 females (aged 13–18 yrs; PST T2–T4; all but three had already undergone menarche).

In male adolescents, height, weight, TVI, lung volumes andTL,COincreased with age. This was not the case in female adolescents. In males, the TVI was the independent variable that best correlated with pulmonary volumes. In females, height was the independent variable that best correlated with pulmonary volumes. In both sexes, the variable that best correlated withTL,COwas PST, associated with height in males.

This cross­sectional study provides prediction equations for lung volumes and the lung transfer factor for carbon monoxide taking into account thoracic volume index and pubertal stage. It shows that, in adolescent males, lung and thoracic development occurs during and until the end of puberty. Conversely, in adolescent females, lung development is almost finished following menarche.
Steroid treatment based on the findings of transbronchial biopsy in idiopathic interstitial pneumonia
Authors: Watanabe K. , Higuchi K. , Ninomiya K. , Ohshima T. , Aritomi T. , Kawabata Y. , Yoshida M.
Published: November 2002

This study was performed to find the rationale for administering steroids to patients with idiopathic interstitial pneumonia (IIP), which was unlikely to be usual interstitial pneumonia (UIP) but was not surgically biopsied.

Among IIP patients in the file of the departments, nine patients who met the following criteria were selected for this study (“non-UIP” group): 1) transbronchial lung biopsy showed dense mononuclear cell infiltration in thickened alveolar septa; 2) chest radiograph and computed tomography showed irregular linear, reticular or ground-glass opacities with alveolar consolidation without honeycombing in the lung base; and 3) spirometry was performed before and after steroid therapy. Ten patients with pathologically confirmed nonspecific interstitial pneumonia (“NSIP” group) were also selected for the comparison. Baseline values and percentage increase of vital capacity (VC) after steroid therapy were plotted.

Steroids improved VC in both groups of patients. After 1 yr of steroid therapy, percentage increase of VC in “non-UIP” was 28.8±7.7%, which was not significantly different from that in NSIP (30.0±11.7%). One “non-UIP” patient and one NSIP patient died after 6.4 and 4.3 yrs of follow-up, respectively.

Patients with idiopathic interstitial pneumonia presenting cellular interstitial pneumonia in transbronchial lung biopsy, in addition to radiographic findings not typical for usual interstitial pneumonia, could expect a beneficial effect of steroids without undergoing surgical biopsy.
Sex-related interactive effect of smoking and household pets on asthma incidence
Authors: Chen Y. , Dales R. , Tang M. , Krewski D.
Published: November 2002

The authors examined the interactive effect of smoking and pets at home on the incidence of asthma and the difference between sexes.

The longitudinal data from the first two cycles of the National Population Health Survey, conducted in Canada, were used. A total of 12,636 subjects who reported no asthma at baseline were included in the analysis.

The 2-yr cumulative incidence of asthma was higher in females than in males. Female sex and household pets demonstrated a significant interaction in the development of asthma. After adjustment for age, immigration and history of allergy, the odds ratio for smoking in relation to the asthma incidence was 2.50 (95% confidence interval: 1.24–5.05) for females who had pets at home and close to unity for those who had no pets. The incidence of asthma was not associated with smoking status and household pets in males.

These results indicate that smoking, having pets at home and other environmental factors can partly explain asthma morbidity among female Canadians.
Evidence for left ventricular dysfunction in patients with obstructive sleep apnoea syndrome
Authors: Alchanatis M. , Tourkohoriti G. , Kosmas E.N. , Panoutsopoulos G. , Kakouros S. , Papadima K. , Gaga M. , Jordanoglou J.B.
Published: November 2002

There is limited information on the development of left ventricular (LV) dysfunction in patients with obstructive sleep apnoea (OSA) in the absence of lung and cardiac comorbidity. This study aimed to investigate whether OSA patients without heart morbidity develop LV dysfunction, and to assess the effect of continuous positive airway pressure (CPAP) on LV function.

Twenty-nine OSA patients and 12 control subjects were studied using technetium-99m ventriculography to estimate LV ejection fraction (LVEF), LV peak emptying rate (LVPER), time to peak emptying rate (TPER), peak filling rate (LVPFR) and time to peak filling rate (TPFR) before and after 6 months of treatment with CPAP.

A significantly lower LVEF was found in OSA patients, compared to control subjects, (53±7versus61±6%) along with a reduced LVPER (2.82±0.58versus3.82±0.77 end-diastolic volumes·s−1). Furthermore, OSA patients had significantly lower LVPFR (2.67±0.71versus3.93±0.58 end-diastolic volumes·s−1) and delayed TPFR (0.19±0.04versus0.15±0.03 s) in comparison with the control group. Six-months of CPAP treatment was effective in significantly improving LVEF, LVPER, LVPFR and TPFR.

In conclusion, obstructive sleep apnoea patients without any cardiovascular disease seem to develop left ventricular systolic and diastolic dysfunction, which may be reversed, either partially or completely, after 6 months of continuous positive airway pressure treatment.
Electroencephalographic spectral analysis: detection of cortical activity changes in sleep apnoea patients
Authors: Dingli K. , Assimakopoulos T. , Fietze I. , Witt C. , Wraith P.K. , Douglas N.J.
Published: November 2002

There are no visible electroencephalographic (EEG) changes at the termination of some apnoeas and hypopnoeas. This study tests the hypothesis that cortical activity fluctuates at apnoea/hypopnoea termination, despite the lack of visible changes.

To detect these changes, EEG spectral analysis was performed and centred around the end of apnoeas/hypopnoeas in 15 sleepy patients. Ten second windows were applied and comparisons were conducted between the normalised power of the same frequency bands before and after termination of each apnoea/hypopnoea. Comparisons were performed within patients between apnoeas/hypopnoeas and periods of undisturbed sleep as well as between patients and healthy subjects during sleep.

Normalised theta power (4–8 Hz) decreased significantly at apnoea/hypopnoea termination. No significant changes were found between consecutive periods of undisturbed sleep across the 15 patients. During nonrapid eye movement sleep, changes were detected irrespective of arousal visibility. During rapid eye movement sleep, nonarousal apnoeas/hypopnoeas were not accompanied by any significant spectral power changes. Theta power was significantly lower across patients compared to healthy subjects (p=0.03) and was correlated to the apnoea/hypopnoea index (rho=0.6, p=0.008).

The authors conclude that electroencephalographic spectral analysis improves detection of changes at apnoea/hypopnoea termination. Further validation is needed to determine whether it improves correlation between nocturnal measures and daytime symptoms.
CC and C chemokine expression in pulmonary sarcoidosis
Authors: Petrek M. , Kolek V. , Szotkowská J. , du Bois R.M.
Published: November 2002

The chemokines RANTES (regulated on activation, T-cell expressed and secreted; CC chemokine ligand (CCL)-5) and monocyte inflammatory protein (MIP)-1α (CCL-3) have been implicated in the development of alveolitis in pulmonary sarcoidosis. The novel C chemokine single cysteine motif (SCM)-1α (XCL-1) and the CC chemokine monocyte chemoattractant protein (MCP)-1 (CCL-2) are also mononuclear-cell attractants and represent alternative candidate mediators of alveolitis. Therefore, the expression of MCP-1 and SCM-1α was investigated together with the expression of RANTES and MIP-1α in bronchoalveolar lavage fluid (BALF) from control subjects and patients with sarcoidosis. The relationship between chemokine expression and sarcoidosis clinical course was also explored.

Messenger ribonucleic acid (mRNA) expression for all four chemokines was determined by semiquantitative reverse transcriptase-polymerase chain reaction of RNA extracted from unseparated bronchoalveolar cells (17 patients, 12 controls). RANTES, MIP-1α and MCP-1 proteins were measured by enzyme-linked immunosobent assay of unconcentrated BALF (60 patients, 17 controls).

MCP-1, and namely RANTES and SCM-1α mRNA expression was upregulated in sarcoidosis, particularly in patients with more advanced disease. RANTES, and namely MCP-1 concentrations were elevated in BALF samples obtained from patients; MCP-1 levels were most increased in patients with chest radiographic stage 2 disease and also in patients with persistent and recurrent disease.

In conclusion, chemokines monocyte chemotactive protein-1 and single cysteine motif-1α are, in addition to RANTES, associated with the development of alveolitis in sarcoidosis and their expression parallels the disease course.
Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study
Authors: Wadbo M. , Löfdahl C-G. , Larsson K. , Skoogh B.E. , Tornling G. , Arweström E. , Bengtsson T. , Ström K.
Published: November 2002

The aim of this study was to compare the effects of formoterol, ipratropium bromide and a placebo on walking distance, lung function, symptoms and quality of life (QoL) in chronic obstructive pulmonary disease (COPD) patients.

A total of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe nonreversible COPD participated in this randomised, double-blind, parallel-group study. After a 2-week placebo run-in, patients were randomised to formoterol Turbuhaler® 18 μgb.i.d.(delivered dose), ipratropium bromide 80 μgt.i.d.viaa pressurised metered dose inhaler, or placebo for 12 weeks. Inhaled short-acting β2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose. The primary variable was walking distance in the shuttle walking test (SWT). Baseline mean SWT distance was 325 m, mean forced expiratory volume in one second (FEV1) was 40% predicted.

Clinically significant improvements in SWT (>30 m) were seen in 41, 38 and 30% of formoterol, ipratropium and placebo patients, respectively (not significant). Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium and placebo groups, respectively. Both active treatments significantly improved FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea score compared with placebo. Formoterol reduced relief medication use compared with placebo. Neither active treatment improved QoL.

Formoterol and ipratropium improved airway function and symptoms, without significant improvements in the shuttle walking test.
Health status measured with the CRQ does not predict mortality in COPD
Authors: Oga T. , Nishimura K. , Tsukino M. , Sato S. , Hajiro T. , Ikeda A. , Mishima M.
Published: November 2002

One purpose of measuring health status is to predict future outcomes. The aim of this study was to investigate the ability of health status derived from the Chronic Respiratory Disease Questionnaire (CRQ) to predict mortality in chronic obstructive pulmonary disease (COPD).

One-hundred and forty-three patients with COPD were recruited. Health status, using the CRQ, and pulmonary function were measured at entry. Mortality after 7 yrs was then assessed. Univariate and multivariate Cox proportional hazards analyses were performed to predict those factors related to mortality.

Of all the patients, 13 could not be followed up and 40 had died. The survival rate was 69% at 7 yrs. Univariate regression analyses revealed that the dyspnoea and emotional function domains and the total score of the CRQ were weakly but significantly correlated with mortality from all causes. However, multivariate regression analyses revealed that age and forced expiratory volume in one second were the strongest predictors of mortality, and health status was not a significant factor.

Although there was a weak but significant relationship between health status and subsequent mortality in chronic obstructive pulmonary disease, it was not significant after an adjustment for age and pulmonary function. Mortality cannot be predicted from Chronic Respiratory Disease Questionnaire scores.
Alveolar epithelial fluid transport in acute lung injury: new insights
Authors: Sartori C. , Matthay M.A.
Published: November 2002

Pulmonary oedema is a life-threatening condition that frequently leads to acute respiratory failure. From a physiological perspective, pulmonary oedema develops either because of an increase in lung vascular hydrostatic pressure or an increase in lung vascular permeability. Resolution of alveolar oedema depends on the active removal of salt and water from the distal air spaces of the lung across the distal lung epithelial barrier.

Much has been learned about the molecular and cellular basis for oedema fluid reabsorption, including the role of apical ion transporters for sodium (epithelial sodium channel) and chloride (cystic fibrosis transmembrane conductance regulator), as well as the central importance of the sodium pump. The rate of fluid clearance can be upregulated by both catecholamine-dependent and -independent mechanisms.

Injury to the alveolar epithelium can disrupt the integrity of the alveolar barrier or downregulate ion transport pathways, thus, reducing net alveolar fluid reabsorption and enhancing the extent of alveolar oedema. Endogenous catecholamines upregulate alveolar fluid clearance in several experimental models of acute lung injury, but this upregulation may be short term and insufficient to counterbalance alveolar flooding. There is new evidence, however, that pharmacological treatment with β2-adrenergic agonists and/or epithelial growth factors may influence a more sustained stimulation of alveolar fluid reabsorption and in turn facilitate recovery from experimental pulmonary oedema. Similar results have been achieved experimentally by gene transfer to enhance the abundance of sodium transporters in the alveolar epithelium.

Clinical studies show that impaired alveolar fluid transport mechanisms contribute to the development, severity and outcome of pulmonary oedema in humans. Very recent data suggest that mechanisms that augment transepithelial sodium transport and enhance the clearance of alveolar oedema may lead to more effective prevention or treatment for some types of pulmonary oedema.
Noninvasive ventilation in children
Authors: Nørregaard O.
Published: November 2002

The use of noninvasive ventilation (NIV)/ventilatory assistance has in its modern form experienced a resurgence during the last two decades, primarily in the adult population.

During the last few years, NIV, predominantly in the form of positive-pressure ventilation/ventilatory assistance, has also become an option in the paediatric population. Although the technique is increasingly being applied, data in this often very heterogeneous group of patients are still very limited, and are usually derived from case series and not randomised controlled studies.

Available experience indicates that the technique is useful for children with a wide spectrum of hypercapnic and/or hypoxaemic respiratory disorders, in the acute as well as in the chronic setting. Results have shown improvements in survival and arterial blood gases, and have indicated better quality of life. Adverse effects are generally minor, although the impact on facial bony structures should be monitored closely during long-term ventilation.

Considering the paucity of data, the area badly needs research, which preferentially should include: 1) short- and long-term effects and adverse effects in various conditions and age groups; 2) techniques, in particular interfaces and triggering mechanisms; 3) comprehensive plans for training of attendants, discharge and follow-up; and 4) quality of life measurements. As many of the conditions suited for noninvasive ventilation are very rare, much of the research would probably benefit from multicentre studies, or even studies on a European level.
Complications of flexible bronchoscopy in children: prospective study of 1,328 procedures
Authors: de Blic J. , Marchac V. , Scheinmann P.
Published: November 2002

Complications of flexible bronchoscopy (FB) were prospectively evaluated during 1,328 diagnostic procedures in children, not in intensive care units. A total 92.8% of the procedures were performed in conscious patients under sedation and 7.2% under deep sedation. Supplementary oxygen was provided in ∼80% of casesviaendoscopic face mask (n=783) or nasal prongs (n=290).

At least one complication was recorded in 91 cases (6.9%). Minor complications (n=69; 5.2%) included moderate and transient episodes of desaturation (n=15), isolated excessive coughing (n=22), excessive nausea reflex with coughing (n=20), transient laryngospasm (n=6) and epistaxis (n=6). Major complications (n=22; 1.7%) included oxygen desaturation to <90%, either isolated (n=10) or associated with laryngospasm (n=6), coughing (n=4), bronchospasm (n=1), and pneumothorax (n=1).

Major complications involving oxygen desaturation were associated with age <2 yrs (13 of 529versus8 of 778) and laryngotracheal abnormalities (7 of 85versus14 of 1,222). The overall frequency of complications was similar in conscious (6.7%) but sedated patients and patients under deep (7.3%) sedation. However, the frequency of transient desaturation was significantly higher in children undergoing FB under deep sedation. Transient fever after bronchoalveolar lavage was observed in 52 of 277 cases (18.8%).

Flexible bronchoscopy is a safe procedure with <2% major complications. Careful analysis of indications and clinical status for each patient, and proper anaesthesia and monitoring during the examination ensure that the procedure is successful, with a minimum of complications.
HLA-DP-unrestricted TNF-α release in beryllium-stimulated peripheral blood mononuclear cells
Authors: Amicosante M. , Berretta F. , Franchi A. , Rogliani P. , Dotti C. , Losi M. , Dweik R. , Saltini C.
Published: November 2002

Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the β-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-γ releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-α which has been shown to increase berylliosis risk independent of HLA-DPGlu69.

In order to determine whether TNF-α release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO4-stimulated blood mononuclear cells and the release of IFN-γ, TNF-α, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO4-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation.

While proliferation and IFN-γ release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88±16 and 77±16%, respectively; anti-HLA-DR: 29±38 and 14±10%, respectively), the release of TNF-α was not (inhibition with anti-HLA-DP mAb: 8.9±7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF-α production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-γ production.

In conclusion, these data suggest that the tumour necrosis factor-α response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.
Variability and lack of predictive ability of asthma end-points in clinical trials
Authors: Zhang J. , Yu C. , Holgate S.T. , Reiss T.F.
Published: November 2002

While a consensus definition of the clinical parameters important in asthma control exists, an adequate objective definition of a response to asthma treatment and parameters for prediction of that response remain undefined. Given that asthma is a complex biological disease and that different parameters may measure dissimilar aspects of the disease status, this study assessed the relationship among several end-points of asthma control, and attempted to select a combination of variables measured before (baseline characteristics) or early in asthma therapy which would be predictive of a long-term clinical response.

Data from two previously reported clinical studies which included montelukast, inhaled beclomethasone, and placebo in mild-to-moderate asthmatics (n=1,576) were analysed. The forced expiratory volume in one second (FEV1), daily symptoms score (DSS), β-agonist use, and morning peak expiratory flow (PEFAM) were recorded during the baseline period and throughout the 12-week treatment period.

For the long-term response, as measured during the last 9 weeks of treatment, there was a large within-patient variability and no more than a moderate correlation between the changes in FEV1and PEFAM; DSS and FEV1; and DSS and β-agonist use. The overall predictive values for FEV1and DSS were 70–80%.

The results showed that multiple measurements over a length of time are needed to establish a more complete profile of response, and that demographic and early treatment responses had a small but inadequate ability to predict future response. This study demonstrates the complex relationship among asthma end-points and the difficulty of reliably estimating long-term response using common, surrogate clinical markers of asthma control.
Negative pressure ventilation versus conventional mechanical ventilation in the treatment of acute respiratory failure in COPD patients
Authors: Corrado A , Gorini M , Ginanni R , Pelagatti C , Villella G , Buoncristiano U , Guidi F , Pagni E , Peris A , De Paola E
Published: November 2002

This case-control study was aimed to evaluate the effectiveness of negative pressure ventilation (NPV) versus conventional mechanical ventilation (CMV) for the treatment of acute respiratory failure (ARF) in patients with chronic obstructive pulmonary disease (COPD) admitted to a respiratory intermediate intensive care unit (RIICU) and four general intensive care units (ICU). Twenty-six COPD patients in ARF admitted in 1994-95 to RIICU and treated with NPV (cases) were matched according to age (+/-5 yrs), sex, causes triggering ARF, Acute Physiology and Chronic Health Evaluation (APACHE) II score (+/- 5 points), pH (+/-0.05) and arterial carbon dioxide tension (Pa,CO2) on admission with 26 patients admitted to ICU and treated with CMV (controls). The primary end points of the study were inhospital death for both groups and the need for endotracheal intubation for cases. The secondary endpoints were length and complications of mechanical ventilation and length of hospital stay. The effectiveness of matching was 91%. Mortality rate was 23% for cases and 27% for controls (NS), five cases needed endotracheal intubation, four of whom subsequently died. The duration of ventilation in survivors was significantly lower in cases than in controls, with a median of 16 h (range 2-111) versus 96 h (range 12-336) (P<0.02), whereas the length of hospital stay was similar in the two groups, with a median of 12 days (range 2-47) for cases vs 12 days (range 3-43) (NS) for controls. No complications were observed in cases, whereas three controls developed infective complications. These results suggest that negative pressure ventilation is as efficacious as conventional mechanical ventilation for the treatment of acute respiratory failure in patients with chronic obstructive pulmonary disease and that it is associated with a shorter duration of ventilation and a similar length of hospital stay compared with conventional mechanical ventilation.
Increased peak expiratory flow variation in asthma: severe persistent increase but not nocturnal worsening of airway inflammation
Authors: ten Hacken NH , Timens W , Smith M , Drok G , Kraan J , Postma DS
Published: November 2002

Asthma at night is characterized by a nocturnal increase in airway obstruction. It has been hypothesized that nocturnal asthma results from an increase in airway wall inflammation at night. However, studies on inflammatory cells in bronchoalveolar lavage (BAL) fluid and bronchial biopsies have produced conflicting data. This study assessed inflammatory cell numbers at 16:00 h and 04:00 h in bronchial biopsies of 13 healthy controls, 15 asthmatic patients with peak expiratory flow (PEF) variation < or =15% and 10 asthmatic patients with PEF variation >15%. There was no significant increase at night in the number of CD3, CD4, CD8, CD25, AAI (tryptase) and EG2-immunopositive cells in the submucosa in both groups. Numbers of EG2-positive cells in the two asthmatic groups were significantly higher than in healthy controls, both at 16:00 h (p<0.05) and 04:00 h (p<0.01). The number of EG2, CD4 and CD25-positive cells at 04:00 and 16:00 h tended to be higher in asthmatics with a PEF variation >15% than in asthmatics with PEF variation < or =15%. At 04:00 h the median numbers of EG2-positive cells (per mm basement membrane) in subjects with PEF variation >15% and < or =15% were 6 and 3 cells, respectively, and at 16:00 h 4 and 25 cells respectively. Increased nocturnal airway obstruction is not associated with increased numbers of inflammatory cells in the bronchial submucosa at night. Apparently, asthmatic patients with a peak expiratory flow variation >15% suffer from a higher overall severity of bronchial inflammation at night and during the day.
Individual use of antiasthmatic drugs in the European Community Respiratory Health Survey
Authors: Janson C , Chinn S , Jarvis D , Burney P
Published: November 2002

A previous analysis of drug utilization in the European Community Respiratory Health Survey found that only between 8 and 29% of subjects with asthma-related symptoms were using antiasthmatic medication in the different areas studied. The aim of this analysis was to investigate which variables were related to individual use of antiasthmatic medication in different geographical areas. Thirty-three centres in 14 countries were analysed, in which a total of 16,854 people (52.1% females, mean age 33.8 yrs, range 20-48) underwent a structured interview, measurement of specific immunoglobin E, spirometry and methacholine challenge test. The use of antiasthmatic drugs in individuals was, in most countries, independently related to asthma-related respiratory symptoms, bronchial hyperresponsiveness (BHR) and atopy. In all countries smokers with respiratory symptoms were less likely to be using antiasthmatic drugs than nonsmokers and exsmokers. In four of 14 countries females were significantly more likely to use antiasthmatic medication than males, while age and socioeconomic status were unrelated to medication. The use of inhaled anti-inflammatory drugs was positively related to symptoms, BHR and atopy and negatively related to current smoking. In conclusion, in many countries smokers were less likely to be using antiasthmatic drugs than were nonsmokers with comparable levels of symptoms and bronchial hyperresponsiveness. Age and socioeconomic status were unrelated to medication, while in some countries females were more likely than males to use antiasthmatic medication.
Protective effect of respiratory devices in farmers with occupational asthma
Authors: Muller-Wening D , Neuhauss M
Published: November 2002

To the authors' knowledge there have been no previous reports on the protection afforded by powered filtering respirators in farmers with occupational asthma attributed to the inhalation of organic dust. In order to investigate this question, 26 farmers with occupational asthma were challenged with an exposure to work-related dusts for up to 60 min. This resulted in highly significant increases in airway resistance (Raw), thoracic gas volume (TGV) and specific airway resistance (sRaw) compared to baseline values. After a mean period of 21 weeks the farmers were subjected to a second challenge, this time wearing a protective respiratory device (RD) with a P2 filter. Significant increases in Raw, TGV and sRaw were again observed, but on average these were 50-80% smaller than the increases seen when RDs were not worn. These differences were found to be statistically significant. This shows that the use of a respiratory device in farmers suffering from occupational asthma reduces the development of bronchial obstruction but does not prevent it. The use of this kind of respiratory device cannot substitute for the proper management of asthma since the devices do not offer complete protection.
Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients
Authors: Totterman KJ , Huhti L , Sutinen E , Backman R , Pietinalho A , Falck M , Larsson P , Selroos O
Published: November 2002

This randomized, double-blind, crossover study in two parts compared tolerability to high doses of formoterol (Oxis Turbuhaler) with that of high doses of terbutaline (Bricanyl Turbuhaler). After Holter monitoring at home, 12 patients were treated with 4+4+4 doses of formoterol Turbuhaler, 6 microg x dose(-1), (total daily metered dose 72 microg) or 4+4+4 doses of terbutaline Turbuhaler, 0.5 mg x dose(-1) (daily dose 6 mg) given in the morning, after lunch and in the evening, for 3 consecutive days. After a one week washout period at home, patients received the alternative treatment. Thereafter, 15 other patients received 8+6+6 doses of formoterol Turbuhaler (total daily metered dose 120 microg) or 8+6+6 doses of terbutaline Turbuhaler (daily dose 10 mg). Pulse, cardiac frequency, blood pressure, serum potassium, electrocardiogram and forced expiratory volume in one second (FEV1) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days. Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse, blood pressure, cardiac frequency and QTc (QT interval corrected for heart rate). Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels, pulse, cardiac frequency and QTc. No differences in FEV1 levels were found. Both drugs were safe and generally well tolerated on both dose levels. In conclusion, high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated. Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol, respectively. The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use.
Subsensitivity to bronchoprotection against adenosine monophosphate challenge following regular once-daily formoterol
Authors: Aziz I , Tan KS , Hall IP , Devlin MM , Lipworth BJ
Published: November 2002

Regular treatment with inhaled long-acting beta2-agonists leads to subsensitivity to their bronchoprotective effects, although the effect of dosing frequency on this subsensitivity is not known. The aim of this study was to assess whether a once-daily dosing regimen with formoterol might be associated with a lesser degree of subsensitivity. In a randomized placebo-controlled double-blind, double-dummy crossover study 10 asthmatics treated with inhaled steroids (mean age 31 yrs, forced expiratory volume in one second (FEV1) 82% predicted) received 1 week of treatment with: formoterol dry powder 24 microg twice daily (08:00 and 20:00 h); formoterol 24 microg once daily (20:00 h); or identical placebo. Adenosine monophosphate (AMP) bronchial challenge was performed 12 h after the first and the last dose of each treatment. There was significant loss of protection with formoterol twice daily between the first and last dose (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20)): 475 versus 129 mg x mL(-1) (a 3.7-fold loss, p=0.006) and with formoterol once daily: 367 versus 127 mg x mL(-1) (a 2.9-fold loss, p=0.005), compared with placebo: 71 versus 75 mg x ml(-1) (nonsignificant). There was no significant difference in the degree of loss of protection between formoterol once and twice daily. For first-dose protection there was a significant difference between active treatments and placebo, but after the last dose the residual protection between active treatments and placebo was not significant. Thus, in patients taking inhaled corticosteroids, regular formoterol 24 micreog once daily induces a similar degree of subsensitivity to adenosine monophosphate bronchial challenge as with formoterol 24 microg twice daily. This in turn suggests that even with a 24-h dosing interval there is the development of tolerance to formoterol by prolonged occupancy of airway beta2-adrenoceptors.
Effect of theophylline on CD11b and L-selectin expression and density of eosinophils and neutrophils in vitro
Authors: Spoelstra FM , Berends C , Dijkhuizen B , de Monchy JG , Kauffman HF
Published: November 2002

The nonspecific phosphodiesterase inhibitor theophylline, widely used in asthma therapy, may cause a decrease in inflammatory responses of airways. In asthma, eosinophils migrate to the airway wall and become activated. Activated eosinophils are characterized by low cell density, as well as increased expression of CD11b and reduced expression of L-selectin, two adhesion molecules involved in transendothelial migration. To study the anti-inflammatory effect of theophylline on granulocyte adhesion molecules in vitro, the platelet-activating factor (PAF)-induced density shift was determined by density centrifugation and the modulation of CD11b and L-selectin expression by flow cytometry on eosinophils and neutrophils in human whole blood. A relatively high concentration of theophylline (10(-3) M) inhibited the increase in the percentage of hypodense eosinophils and neutrophils in whole-blood samples after PAF stimulation in vitro. A more pharmacological concentration (10(-4) M) inhibited the CD11b upregulation and L-selectin shedding induced by PAF (10(-7) M) on both eosinophils and neutrophils. The effect of isoproterenol on the inhibitory effect of theophylline was mainly additive, but a small synergistic effect could not be excluded. In conclusion theophylline can attenuate eosinophil and neutrophil activation in vitro at the level of adhesion molecule expression and changes in cell density. This may have implications for transendothelial migration of these cells in asthma.
Expression of leukocyte integrins and tissue factor in mononuclear phagocytes
Authors: Nakstad B , Haugen T , Skjonsberg OH , Lyberg T
Published: November 2002

Coagulation is intimately involved in the pathology of inflammation. The leukocyte beta2-integrins have several functions, including serving as receptors for coagulation factor X and fibrinogen. Tissue factor (TF) is a receptor for factor VII and a very potent trigger of coagulation. The intention of this study was to examine a possible coexpression of beta2-integrins (CD11b/CD18 and CD11c/CD18) and the procoagulant TF in alveolar macrophages (AM) and blood monocytes, i.e. cells of the same differentiation lineage. The expression of beta2-integrins in human AM isolated by bronchoalveolar lavage and in blood monocytes was analysed by flow cytometry, whereas TF activity was analysed in a one-stage clotting assay. In monocytes, TF activity, CD11b and CD11c expression were highly inducible by lipopolysaccharide (LPS), with a 13-, 19- and four-fold increase, respectively. In AM, TF and beta2-integrins were all constitutively expressed, but the expression could not be further enhanced by LPS stimulation. CD11b and CD11c expression varied inversely with the cell size of AM, in contrast to TF activity which is known to be proportional to AM cell size. In vitro expression of beta2-integrins and tissue factor in lipopolysaccharide-stimulated blood monocytes seems to be intimately coregulated, whereas the expression of these receptors in alveolar macrophages seems to be unresponsive to lipopolysaccharide. These results indicate that blood monocytes and alveolar macrophages have different roles and use different mechanisms in cell-induced fibrin formation.
Neutrophils induce damage to respiratory epithelial cells infected with respiratory syncytial virus
Authors: Wang SZ , Xu H , Wraith A , Bowden JJ , Alpers JH , Forsyth KD
Published: November 2002

The mechanisms by which respiratory syncytial virus (RSV) infection induces bronchiolitis and airway disease are unclear. The presence of large numbers of polymorphonuclear leukocytes (PMN) in the airways of infants with RSV infection suggests a potential role of PMN in airway injury associated with RSV infection. To investigate the potential role of neutrophils in RSV bronchiolitis, human alveolar type II cells (A549 cells) were infected with different doses of RSV for 6-48 h. A 51Cr-releasing assay was used to measure PMN-induced damage and image analysis was used to determine PMN adhesion and detachment of epithelial cells. The results showed that RSV infection of epithelial cells enhanced PMN adherence in a dose- and time-dependent pattern, RSV infection alone could damage and detach epithelial cells to a limited extent and PMN significantly augmented RSV infection-induced damage and detachment of epithelial cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances neutrophil adhesion to the epithelium and that activated neutrophils augment the damage and detachment of epithelium infected with the virus. Polymorphonuclear leukocytes may contribute to the pathogenesis of respiratory syncytial virus airway disease by inducing epithelial damage and cell loss.
Th2 cytokines exert a dominant influence on epithelial cell expression of the major group human rhinovirus receptor, ICAM-1
Authors: Bianco A , Sethi SK , Allen JT , Knight RA , Spiteri MA
Published: November 2002

Intercellular adhesion molecule (ICAM)-1 is a cell receptor important in both human rhinovirus (HRV) attachment and immune effector cell mobilization. The level of expression of ICAM-1 by epithelial cells (EC) therefore plays a crucial role in the intricate biological phenomena underlying viral binding, host infection and consequent inflammatory events. As T-helper (Th)2 lymphocytes predominate within the asthmatic airway, the influence was evaluated of Th2-associated mediators in the modulation of ICAM-1 expression on uninfected and HRV-infected EC. H292 EC were cultured in vitro, with varying concentrations of interleukin (IL)-4, IL-5, IL-10 and IL-13 for 24 h and then infected with live HRV-14. Surface ICAM-1 expression was assessed by immunocytochemistry. Infection with HRV-14 resulted in a twofold increase in ICAM-1 expression. IL-4, IL-5, IL-10 and IL-13 produced a 2.7-5.1-fold enhancement of ICAM-1 expression of uninfected cells and caused approximately a further twofold increase in infected cells over the expression induced by HRV infection itself. Interferon-gamma in combination with each Th2-associated cytokine only slightly reduced, but did not override, the Th2-induced level of ICAM-1 expression on both uninfected and virus-infected EC. These data suggest that the effects of Th2-associated cytokines on intercellular adhesion molecule-1 expression and recovery of infectious virus are dominant over the effects of the Th1-associated cytokines such as interferon-gamma. Since the airway mucosa in atopic asthma is predominantly infiltrated by Th2 lymphocytes, these results could explain both the increased susceptibility to human rhinovirus infection in asthmatic patients and the associated exacerbation of asthma symptoms.
Tracking of lung function parameters and the longitudinal relationship with lifestyle
Authors: Twisk JW , Staal BJ , Brinkman MN , Kemper HC , van Mechelen W
Published: November 2002

The purpose of this study was to analyse tracking (i.e. relative stability over time/predictability of future values by early measurements) of lung function parameters and their longitudinal relationship with lifestyle (smoking, alcohol consumption, daily physical activity, neuromotor and cardiopulmonary fitness, and dietary intake of retinol and polyunsaturated fatty acids (PUFA)). Data were obtained from the observational Amsterdam Growth and Health Study, a longitudinal study with six repeated measurements between ages 13-27 yrs (n=167). The statistical analyses were carried out with generalized estimating equations. The following "stability" coefficients were found: for forced vital capacity (FVC) in males 0.66 (95% confidence interval (CI): 0.54-0.77) and in females 0.51 (95% CI: 0.43-0.60); for forced expiratory volume in one second (FEV1) in males 0.65 (95% CI: 0.50-0.80), in females 0.53 (95% CI 0.46-0.60); for peak expiratory flow (PEF) in both males and females 0.41 (95% CI: 0.31-0.51). Positive relationships were found between alcohol consumption and FVC and FEV1 and between neuromotor fitness and PEF and (only for males) with FVC and FEV1. Physical activity was inversely related to PEF and the intake of PUFA positively related to FVC and FEV1. Smoking was related to a decrease in FVC and FEV1; changes in physical activity positively correlated to changes in FVC. In conclusion, high to moderate stability/tracking was observed for forced vital capacity and forced expiratory volume in one second; for peak expiratory flow it was slightly lower. Preventive strategies regarding improvements of lung function should focus on smoking cessation and improving daily physical activity.
Impaired ventilatory function and elevated insulin levels in nondiabetic males: the Normative Aging Study
Authors: Lazarus R , Sparrow D , Weiss ST
Published: November 2002

Lower levels of baseline ventilatory function have consistently been associated with increased risk of cardiovascular mortality in prospective studies, but the underlying mechanisms are not known. Increased risk of coronary heart disease is associated with higher serum insulin levels. This report examines the relationship between ventilatory function and indirect measures of insulin resistance. Cross-sectional data from 922 nondiabetic participants in the Normative Aging Study were analysed using multiple linear regression models with adjustment for potential confounders. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined in relation to indicators of insulin resistance, i.e. fasting insulin and the fasting insulin resistance index (FIRI). Diabetics were excluded because impaired insulin secretion interferes with the validity of these as measures of insulin resistance. Fasting insulin and FIRI were negatively correlated with FVC and FEV1 (all p< 0.001). These associations persisted after adjusting for potential confounders including age, height, body mass index, waist to hip circumference ratio, physical activity, alcohol intake and smoking in separate multiple linear regression models, for both insulin (all p< or =0.0008) and FIRI (all p< or =0.0001). Negative cross-sectional associations between ventilatory function and indirect measures of insulin resistance were found in nondiabetic males. Insulin resistance may contribute to the previously unexplained association between ventilatory function impairment and cardiovascular mortality. Mechanisms underlying the relationship between insulin resistance and decreased ventilatory function remain to be elucidated.
Time to peak tidal expiratory flow and the neuromuscular control of expiration
Authors: van der Ent CK , van der Grinten CP , Meessen NE , Luijendijk SC , Mulder PG , Bogaard JM
Published: November 2002

The ratio of the time needed to reach peak tidal expiratory flow (tPTEF) and the duration of expiration (tE) is used to detect airflow obstruction in young children. tPTEF is decreased in patients with asthma, but knowledge about the physiological determinants of this parameter is scarce. This study examined the relationship between tPTEF and postinspiratory activities of inspiratory muscles and evaluated the effects of changing sensory information from the lung. Airflow patterns and electromyographic (EMG) activity of inspiratory muscles were recorded in seven spontaneously breathing, anaesthetized cats. The trachea was cannulated and, as a result, the larynx and upper airways were bypassed. Changes in postinspiratory muscle activity were induced by changing afferent sensory nerve information (by cooling the vagus nerves, by administration of histamine and by additional application of continuous positive airway pressure (CPAP)). Durations of postinspiratory activities of the diaphragm and intercostal muscles (characterized by their time constants tau diaphr and tau interc) correlated strongly with tPTEF (r=0.85 and 0.77, respectively). Tau diaphr, tau interc and tPTEF were significantly increased during cooling of the vagus nerves (4-8 degrees C) compared with values at 22 and 37 degrees C (p<0.05). Conversely, administration of histamine and CPAP caused significant decreases in tau diaphr, tau interc and tPTEF, which were absent during cooling of the vagus nerves. In conclusion, the time needed to reach peak tidal expiratory flow is highly influenced by the activities of inspiratory muscles during the early phase of expiration which, in turn, depend on the activities of vagal receptors in the lung.
Acute effects of hypoxaemia, hyperoxaemia and hypercapnia on renal blood flow in normal and renal transplant subjects
Authors: Sharkey RA , Mulloy EM , O'Neill SJ
Published: November 2002

The aim of this investigation was to study noninvasively the effects of hypoxaemia, hyperoxaemia and hypercapnia on renal blood flow in normal subjects and renal allograft recipients, i.e. with denervated kidneys. By comparing these two groups, the influence of renal innervation on any resulting changes in renal blood flow could be ascertained. Nine normal and eight renal allograft recipients were studied. Each subject inhaled the following gas mixtures in order: room air, 10% O2 (hypoxaemia), 10% O2 + baseline CO2 (isocapnic hypoxaemia), 10% O2 + high CO2 (hypercapnic hypoxaemia), 100% O2 (hyperoxaemia), 100% O2 + baseline CO2 (isocapnic hyperoxaemia) and 100% O2 + high CO2 (hypercapnia hyperoxaemia). Using Doppler ultrasonography, the pulsatility index (PI), an index of renovascular resistance, was measured at the various gas inhalation levels. In normal subjects, the renovascular resistance increased in response to hypoxaemia, with a greater increase in response to hypercapnic hypoxaemia. Hyperoxaemia caused a decrease in renovascular resistance but this was abolished with the addition of CO2. There was a similar pattern in the PI response to the different gas inhalations in the renal transplant subjects, but these responses were attenuated in comparison with those of the normals. In conclusion, renal denervation does not completely abolish the renovascular responses to inhaled oxygen and carbon dioxide.