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Background: Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD). We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD., Methods: In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF), and salbutamol use and assessed their course during exacerbations., Results: There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively), whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70., Conclusions: Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice.

In patients with chronic obstructive pulmonary disease (COPD) classified as moderate onwards, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines recommend regular treatment with one or more long-acting bronchodilators, such as beta(2)-agonists or anticholinergics. In contrast to currently available long-acting beta(2)-agonists, which have a duration of action of 12 h, indacaterol has demonstrated effective 24-h bronchodilation on once-daily dosing. A double-blind, randomised, placebo-controlled study was conducted to compare the safety, tolerability and efficacy of indacaterol with that of placebo, over a 28-day period, in patients with moderate COPD (as defined by GOLD 2001 criteria; equivalent to moderate-to-severe COPD in the GOLD 2005 criteria). Patients were randomised 2:2:1 to receive indacaterol 400 microg or 800 microg or placebo once-daily (between 07:00 and 11:00 h) via a single-dose dry-powder inhaler for 28 days. Assessments included monitoring of adverse events (AEs), blood chemistry (including serum potassium and blood glucose), vital signs (blood pressure and heart rate), electrocardiograms and spirometry. One hundred and sixty-three patients were randomised, with 155 (95%) completing the study. There were no statistically significant differences between treatment groups in the overall incidence of AEs, with AEs reported by 35%, 51% and 25% of patients in the indacaterol 400 microg, 800 microg and placebo groups, respectively. The majority of AEs were mild or moderate in severity, and there were no study-drug related serious AEs. There were no statistically significant differences between indacaterol groups and placebo in mean pulse rate and QTc interval, and isolated statistically significant (p<0.05) treatment-placebo differences in mean blood pressure, blood glucose and serum potassium. There was a statistically significant improvement in FEV(1) vs placebo at all post-baseline timepoints for both indacaterol treatment groups; 30 min post-dose, adjusted mean+/-SE FEV(1) indacaterol-placebo differences were: Day 1, 220+/-36 ml and 210+/-36 ml; Day 14, 320+/-50 ml and 270+/-50 ml; Day 28, 260+/-61 ml and 200+/-61 ml for 400 and 800 microg, respectively (all p<0.01 vs placebo). Bronchodilation was still apparent after 24h, with pre-dose (i.e. trough) adjusted mean+/-SE FEV(1) indacaterol-placebo differences of: Day 14, 230+/-44 ml and 210+/-44 ml; Day 28, 220+/-49 ml and 210+/-49 ml for indacaterol 400 and 800 microg, respectively (all p<0.0001 vs placebo). Once-daily indacaterol was well tolerated at doses up to 800 microg with a good overall safety profile. There was no statistical difference at any dose between the safety of indacaterol and placebo. Furthermore, this study supports the previously demonstrated 24-h bronchodilator efficacy of indacaterol.

A 48 year old patient with active Crohn's disease presented with bilateral nodules over his lungs resembling malignant metastasis. Bronchoscopic and pathological examination of the airways and sputum did not show any malignancy. After 6 weeks Mycobacterium xenopi was cultured from his bronchial washings while all other cultures remained negative. Treatment was started with rifampicin, ethambutol, and clarithromycin and, after 9 months of treatment, there was an almost complete resolution of his chest radiograph.

Currently, up to 50% of the operations in early-stage non-small cell lung cancer (NSCLC) are futile owing to the presence of locally advanced tumour or distant metastases. More accurate pre-operative staging is required in order to reduce the number of futile operations. The cost-effectiveness of fluorine-18 fluorodeoxyglucose positron emission tomography ((18)FDG-PET) added to the conventional diagnostic work-up was studied in the PLUS study. Prior to invasive staging and/or thoracotomy, 188 patients with (suspected) NSCLC were randomly assigned to conventional work-up (CWU) and whole-body PET or to CWU alone. CWU was based on prevailing guidelines. Pre-operative staging was followed by 1 year of follow-up. Outcomes are expressed in the percentage of correctly staged patients and the associated costs. The cost price of PET varied between 736 and 1,588 depending on the (hospital) setting and the procurement of (18)FDG commercially or from on-site production. In the CWU group, 41% of the patients underwent a futile thoracotomy, whereas in the PET group 21% of the thoracotomies were considered futile ( P=0.003). The average costs per patient in the CWU group were 9,573 and in the PET group, 8,284. The major cost driver was the number of hospital days related to recovery from surgery. Sensitivity analysis on the cost and accuracy of PET showed that the results were robust, i.e. in favour of the PET group. The addition of PET to CWU prevented futile surgery in one out of five patients with suspected NSCLC. Despite the additional PET costs, the total costs were lower in the PET group, mainly due to a reduction in the number of futile operations. The additional use of PET in the staging of patients with NSCLC is feasible, safe and cost saving from a clinical and from an economic perspective.

Antimicrobial therapy can have a significant impact in the treatment of acute infectious exacerbations in patients with chronic bronchitis, in whom repeated episodes are common. The aim of this randomised, double-blind, double-dummy, parallel group study was to compare the efficacy and safety of oral gatifloxacin (200 and 400 mg once daily) administered for 5 days with co-amoxiclav (500 mg amoxicillin/125 mg clavulanic acid t.i.d.) administered for 10 days in 414 adult patients with acute exacerbation of chronic bronchitis. Overall clinical response rates (cure plus improvement) were 86.2%, 79.4% and 81.7% in the gatifloxacin 200 mg, gatifloxacin 400 mg and co-amoxiclav groups, respectively, and the equivalence hypothesis used for statistical analysis showed equivalent efficacy for both gatifloxacin 200 and 400 mg compared to co-amoxiclav. The same was true for rates of bacterial response, with eradication or presumed eradication of causative pathogens achieved in 87.5%, 87.3% and 79.1% of cases in the gatifloxacin 200 mg, gatifloxacin 400 mg and co-amoxiclav groups, respectively. All treatments were well tolerated, with the nature and frequency of treatment-related adverse events similar in all groups. The results of the study show that gatifloxacin is a safe and effective agent for the treatment of patients with chronic bronchitis experiencing an acute infectious exacerbation.

Background: Up to 50% of curative surgery for suspected non-small-cell lung cancer is unsuccessful. Accuracy of positron emission tomography (PET) with 18-fluorodeoxyglucose (18FDG) is thought to be better than conventional staging for diagnosis of this malignancy. Up to now however, there has been no evidence that PET leads to improved management of patients in routine clinical practice. We did a randomised controlled trial in patients with suspected non-small-cell lung cancer, who were scheduled for surgery after conventional workup, to test whether PET with 18FDG reduces number of futile thoracotomies., Methods: Before surgery (mediastinoscopy or thoracotomy), 188 patients from nine hospitals were randomly assigned to either conventional workup (CWU) or conventional workup and PET (CWU+PET). Patients were followed up for 1 year. Thoracotomy was regarded as futile if the patient had benign disease, explorative thoracotomy, pathological stage IIIA-N2/IIIB, or postoperative relapse or death within 12 months of randomisation. The primary outcome measure was futile thoracotomy. Analysis was by intention to treat., Findings: 96 patients were randomly assigned CWU and 92 CWU+PET. Two patients in the CWU+PET group did not undergo PET. 18 patients in the CWU group and 32 in the CWU+PET group did not have thoracotomy. In the CWU group, 39 (41%) patients had a futile thoracotomy, compared with 19 (21%) in the CWU+PET group (relative reduction 51%, 95% CI 32-80%; p=0.003)., Interpretation: Addition of PET to conventional workup prevented unnecessary surgery in one out of five patients with suspected non-small-cell lung cancer.

A relationship between idiopathic spontaneous pneumothorax (ISP) and visible parenchymal bullae and blebs has been reported. The causal relationship between blebs and bullae and ISP is questionable. Consequently, resection of the involved area is only indicated if it predisposes to recurrence of the pneumothorax. CT studies on 101 cases of ISP were analysed. The presence of bullae and their distribution was then related to the first and recurrent pneumothorax. CT demonstrated bullae in 56% of first ISP and in 64% of recurrent ISP, mostly among older patients. Only eight patients had bullae larger than 2 cm on the side of the pneumothorax. The location of the bullae was not a factor in predicting recurrent pneumothorax.

In this multinational, randomized, double-blind study, the efficacy and safety of a 5 day course of moxifloxacin 400 mg orally od was compared with that of a 7 day course of clarithromycin 500 mg orally bd. in 750 patients with acute exacerbations of chronic bronchitis, characterized by at least two of the symptoms: sputum purulence, increased sputum volume or increased dyspnoea. Seven days after the end of therapy, clinical cure was achieved for 89% (287 of 322) of efficacy-evaluable patients in the moxifloxacin group and 88% (289 of 327) of patients in the clarithromycin group (95% CI, -3.9%, 5.8%). At follow-up (21-28 days post-treatment), the continued clinical cure rates were 89% (256 of 287) for moxifloxacin and 89% (257 of 289) for clarithromycin. A total of 342 pathogenic bacteria were isolated from the sputum of 287 patients. The most common pathogens were Haemophilus influenzae (37%), Streptococcus pneumoniae (31%) and Moraxella catarrhalis (18%). Seven days post-treatment, a successful bacteriological response was obtained for 77% (89 of 115) of patients in the moxifloxacin group and 62% (71 of 114) of patients in the clarithromycin group, indicating superiority of moxifloxacin (95% CI, 3.6%, 26.9%). Both treatments were well tolerated with few adverse events. This study demonstrated that for the treatment of acute exacerbations of chronic bronchitis a 5 day course of moxifloxacin 400 mg od was clinically equivalent and bacteriologically superior to a 7 day course of clarithromycin 500 mg bd.

Background: The objective of this multicentre, randomised, double blind, parallel group study was to compare the efficacy and safety of the addition of salmeterol with that of doubling the dose of fluticasone propionate in asthmatic patients not controlled by a low or intermediate dose of inhaled corticosteroids., Methods: After a four week run in period of treatment with fluticasone propionate (100 micrograms twice daily if pre-trial dose was 400-600 micrograms inhaled corticosteroids or 250 micrograms twice daily if pre-trial dose was 800-1200 micrograms inhaled corticosteroids), 274 patients were randomised to treatment for 12 weeks with either salmeterol 50 micrograms twice daily plus the run in dose of fluticasone propionate or twice the run in dose of fluticasone propionate (200 or 500 micrograms twice daily). Outcome measures were daily records of peak expiratory flow (PEF), symptom scores, and clinic lung function., Results: The improvements in both the morning and evening PEF were better in the salmeterol than in the fluticasone propionate group, the mean increase in morning PEF being 19 l/min higher (95% CI 11.0 to 26.1) and in evening PEF being 16 l/min (95% CI 18.4 to 24.0) higher in the salmeterol group. The increase in forced expiratory volume in one second (FEV1) was 0.09 1 greater in the salmeterol group than in the fluticasone propionate group after four weeks of treatment (95% CI 0.01 to 0.18), but not after 12 weeks. Both regimens showed an increase in symptom free days and a reduction in the need for rescue salbutamol both during the day and the night, but these improvements were greater in the salmeterol group. There were no significant differences between the groups in adverse effects or in the number of rescue course of oral corticosteroids., Conclusions: In this group of patients still symptomatic despite 100 or 250 micrograms fluticasone propionate twice daily, the addition of salmetterol caused a greater improvement in lung function and symptom control than doubling the dose of fluticasone propionate.

Objective: To evaluate the contribution of bronchoalveolar lavage (BAL) and bronchial brushing (BB) and the use of different tinctorial stains in the detection of Pneumocystis carinii (PC) in human immunodeficiency virus (HIV)-positive patients., Study Design: In a retrospective study, 195 HIV-positive patients suspected of a pulmonary infection underwent bronchoscopy with BAL. In 143 cases subsequent BB was performed. On 135 BAL fluid cytocentrifuge preparations four staining techniques were applied simultaneously: May-Grünwald-Giemsa (MGG), toluidine blue-O (TOL), Papani-colaou (PAP) and Grocott methenamine silver (GRO)., Results: PC was recovered in 79 (40.5%) cases. The yields of MGG and TOL were identical (33.3%). PAP and GRO showed lower results, 31.1% and 29.6%, respectively. These differences were not statistically significant. The combination of BAL and BB revealed 64 cases of PC infection. BAL was positive in the vast majority of cases (63, 44.1%). BB was positive in 54 (37.8%). The combination of positive BB with negative BAL was present in one case. However, 10 cases of PC were found with the use of BAL and not detected by BB (P < .01)., Conclusion: The results of this study indicate that to confirm a PC infection in HIV-positive patients, the use of bronchoalveolar lavage with a single staining technique is appropriate. Bronchial brushing seems to be of limited additional value.

The Diskus/Accuhaler inhaler (D/A) is a new multidose powder inhaler, designed to deliver all asthma drugs. This study was carried out to establish clinical equivalence between FP 250 microg twice daily (b.i.d.) via the D/A and FP 250 microg b.i.d. via the current powder inhaler, the Diskhaler (DH). Also, device handling and patient preference for both devices were determined. This was a multicenter, randomized, double-blind, double-dummy, parallel-group study. Adult asthmatics (364, aged 18-79) requiring inhaled corticosteroids in a daily dosage of 400 microg up to and including 1000 microg and demonstrating a mean morning peak expiratory flow rate (PEFR) calculated from the last 7 days of the run-in of less than 85% of the response after salbutamol, a baseline forced expiratory volume in 1 sec (FEV1) between 50 and 90% of their predicted normal value, and an ability to correctly use both devices, were randomized to a 12-week treatment period. No statistically significant differences between the two devices were seen for mean morning PEFR (p = 0.76), mean evening PEFR (p = 0.88), median daytime and nighttime symptom score (p = 0.57 and p = 0.47), median percentage of rescue-free days and nights (p = 0.43 and p = 0.24), and clinic visit lung function. No differences in the safety profile of FP were seen. Patients found the D/A easier to use and easier with respect to assessing the number of doses remaining (both p < 0.001). Sixty-five percent of the patients expressed an overall preference for the D/A over the DH (p < 0.001). The results show that FP 250 microg b.i.d. via the D/A is clinically equivalent to delivery via the DH. Both treatments proved to be equally safe and were well tolerated. The D/A was easier to use and patients preferred the D/A over the DH.

The objective of this study was to compare the two most frequently used asthma-specific quality of life (QOL) questionnaires and two generic QOL questionnaries with clinical data in order to establish their ability to discriminate in asthma severity, also referred to as cross-sectional construct validity. We conducted a multicentre, randomized, placebo-controlled study investigating the long-term effects of the long-acting beta 2-agonist formoterol in asthma patients using inhaled corticosteroids and short-acting beta 2-agonists. Before randomization, the peak expiratory flow (PEF) and use of beta 2-agonists for relief of symptoms were recorded twice daily for 1 month. At the end of the run-in period, the forced expiratory volume in 1 s (FEV1), airway hyper-responsiveness (PC20 methacholine) and QOL were measured, using two asthma-specific questionnaires, the Asthma Quality of Life Questionnaire (AQLQ) and the Living with Asthma Quality of Life Questionnaire (LWAQ), as well as two generic questionnaires, the Short Form 36 (SF-36) and the Psychological General Well Being (PGWB) index. The quality of life of the patients (n = 110) was only mildly impaired. The mean symptom score was 3.6 on a scale of 0-21 and the mean FEV1 was 65% of that predicted. The correlations between the QOL parameters and objective measures of asthma severity, such as the FEV1, PEF and PC20, were low (0.01-0.37). The correlations between the QOL parameters and subjective measures of asthma severity, such as symptom scores (range 0.26-0.65) and beta 2-agonist use for the relief of symptoms (0.09-0.39), were higher. The correlations of the activity and symptoms domains of the AQLQ with diary-obtained symptom scores were r = 0.50 (p < 0.0001) and r = 0.65 (p < 0.0001), respectively. The correlation between the physical construct of the LWAQ and symptom scores was r = 0.42 (p < 0.001) and that between the physical sumscore of the SF-36 and symptom scores was r = 0.50 (p < 0.001). The correlation between the PGWB and symptom scores was r = 0.41 (p < 0.001). The relation between the FEV1, PEF and PC20 and QOL was very low. The QOL measurements related well to the symptom scores. The AQLQ had a better cross-sectional construct validity than the LWAQ. The cross-sectional construct validity of the SF-36 was surprisingly high for this group of patients and the SF-36 performed better than the PGWB and LWAQ.

Thoracic empyema and vertebral osteomyelitis is a rare combination. We report a case of vertebral osteomyelitis possibly caused by a progressive thoracic empyema. The causative pathogen was Escherichia coli. Computed tomographic (CT) scan and magnetic resonance imaging (MRI) suggested the diagnosis of vertebral osteomyelitis, confirmed by transthoracic needle aspiration and operative findings. Aetiology and treatment are discussed.

The aim of this randomized, double-blind, parallel group study was to determine the lowest effective dose of 6, 12 and 24 microg formoterol fumarate dihydrate Turbuhaler b.i.d. compared with placebo. The 4 week treatment was preceded by a 1 week run-in period. Morning peak expiratory flow (PEF) before intake of the study drug was the primary variable. Patients recorded PEF, prior to and 15 min after intake of the study drug (immediate response), asthma symptoms, and use of rescue medication morning and evening. Of 221 patients (71 females and 150 males), 194 were included in the efficacy per protocol (PP) analysis; mean age 47 yrs, mean forced expiratory volume in one second (FEV1) 2.01 L (58% of predicted), mean FEV1 reversibility 27% at entry. Ninety percent used inhaled steroids. Compared with placebo, 6 microg formoterol b.i.d was found to be the lowest effective dose in the morning (p=0.008) and evening p=0.0041) PEF. The mean increases in PEF were 22 and 23 L x min-1 respectively, compared with placebo. After 6 microg formoterol, the mean immediate increase in morning PEF was 42 L x min-1 compared to an increase of only 9 L x min-1 after placebo (<0.0001). All doses produced a statistically significant decrease in asthma symptoms, day and night, and the need for rescue medication at night. All doses were well-tolerated. In conclusion, the lowest effective dose in this study was formoterol Turbuhaler 6 microg b.i.d.

A retrospective study of 21 patients with primary ciliary dyskinesia (PCD) was done. Thirteen had prior resection of bronchiectasis and eight had not. Information about present complaints was obtained by a questionnaire. The prevalence of present respiratory symptoms was the same in both groups. The surgical patients had more severe disease and 85% of them considered the operation beneficial. Selected patients with PCD may have improved conditions with resection of bronchiectasis.

Objective: To investigate the relative efficacy of three inhalers containing salbutamol: Turbuhaler (TBH), Rotahaler (RH) and Diskhaler (DH)., Methods: A randomized, open, three-way crossover, cumulative dose response study was performed in 20 patients with asthma with mean forced expiratory volume in ls (FEV1) values of 60% of predicted (range 41-90%) and a 27% reversibility in FEV1 (range 15-61%). Four doses of salbutamol were inhaled at 30-min intervals: 50 micrograms, 50 micrograms, 100 micrograms and 200 micrograms by TBH and 200 micrograms, 200 micrograms, 400 micrograms and 800 micrograms by both RH and DH. FEV1 was measured at baseline and 25 min after each dose., Results: The increases in FEV1 after the first doses (50 micrograms by TBH, 200 micrograms by RH and by DH) were not statistically significantly different (23.6%, 25.1% and 28%, respectively). Based on the parallel shift in the dose response curves, salbutamol TBH was calculated to be 2.4 times as potent as salbutamol RH (95% confidence interval 1.4-3.3) and 2.2 times as potent as salbutamol DH (90% CI 1.3-3.3). Additionally, during dosing with TBH, fewer patients experienced adverse events than during dosing with RH or DH., Conclusion: Turbuhaler is a twofold more efficient inhaler for salbutamol than Rotahaler or Diskhaler as measured by its bronchodilating effect.

Objective: To study the efficacy of bronchoscopic therapy in patients with intraluminal typical bronchial carcinoid., Design: Retrospective analysis of the data of patients with bronchial carcinoid, treated primarily with bronchoscopic techniques such as Nd-YAG laser in various hospitals in the Netherlands., Subjects: Eleven patients with pulmonary complaints, ages 22 to 60 years, who were found to have intraluminal typical bronchial carcinoid. BRONCHOSCOPIC INTERVENTIONS: Six of the 11 patients received Nd-YAG laser treatments, one received Nd-YAG laser plus photodynamic therapy, and the other four had mechanical tumor removal., Results: Six patients were surgically treated after bronchoscopic therapy. The resected specimens showed no residual carcinoid. Median follow-up has been 70 months (range, 9 to 170 months). Five patients were not surgically treated after bronchoscopic therapy. Follow-up has been 27 to 246 months (median, 47 months) without signs of recurrence., Conclusions: In 11 patients with typical, intraluminal, bronchial carcinoids, bronchoscopic treatment seemed to result in excellent local control, with surgical proof of cure in 6 of 11 patients. Bronchoscopic approach may provide a tissue-sparing alternative for bronchoplastic surgery in a subset of patients with typical intraluminal bronchial carcinoids.

From 1965 to 1990, 93 patients (57 women and 36 men) with typical bronchopulmonary carcinoids were operated upon. Patient ages ranged from 17 to 78 years, the mean age being 45.5 years. Central carcinoids were symptomatic in 80% of the patients. A correct preoperative diagnosis was made in 54 of 64 (84%) patients. Peripheral carcinoids were usually asymptomatic and a correct diagnosis was established in 4 of 29 patients (14%). The prognosis in the group of patients with bronchopulmonary carcinoids treated surgically was excellent. Seven patients died from nonrelated causes. The 5-, 10-, and 15-year survival rates for the remaining 86 patients are 100%. Only one patient died as a result of the tumor after 17 years and another patient is known to have had distant metastasis 9 years after resection. There was no hospital mortality. In the last decade a lung parenchyma-preserving attitude was adopted. Whenever possible, bronchoplastic surgery was applied for central carcinoids and resection of one segment or less was used for peripheral carcinoids. This approach was possible in 30 of 50 patients (60%). Nine patients were treated with preoperative endobronchial neodymium:yttrium-aluminum-garnet laser resection to facilitate a lung-preserving surgical resection. The prognosis of patients for whom a lung-preserving approach was adopted was as good as that of those with conventional resections. Involvement of regional lymph nodes (nine patients, 9.7%) or positive resection margins (two patients, 2.1%) had no influence on prognosis. We conclude that lung-preserving resections are often facilitated by preoperative neodymium:yttrium-aluminum-garnet laser treatment in central obstructing carcinoids.

Fatty acid-derived inflammatory mediators are considered to play an important role in airway hyperresponsiveness of asthmatic patients. The pulmonary macrophage may be an important source for these mediators in airway tissue. We investigated the metabolism of arachidonic acid and linoleic acid by human bronchoalveolar lavage cells, mainly comprising pulmonary macrophages. Arachidonic was mainly metabolized by 5-lipoxygenase, giving rise to the formation of leukotriene B4 and 5-hydroxy-eicosatetraenoic acid (5-HETE). Linoleic acid was converted to 5 major metabolites, including the 9-hydroxy and 13-hydroxy derivatives, 9- and 13-hydroxy-octadecadienoic acid (9- and 13-HODE). The formation of HODEs could be inhibited by cyclooxygenase inhibitors as well as lipoxygenase inhibitors, indicating that both enzymic species play a role in the generation of HODEs.

Haemophilus influenzae is a bacterium that can be isolated from the deeper airways of asthmatic patients. We investigated the effect of vaccination with H. influenzae on alpha and beta adrenoceptor function in guinea-pig tracheal spirals and lung parenchymal strips. The tracheal spirals from H. influenzae-vaccinated animals showed significantly less relaxation to isoproterenol as compared to controls, independent of whether the trachea was maximally contracted with carbachol or only exhibited an intrinsic tone. Furthermore, an increased contractile response to carbachol was observed in these spirals. To isoproterenol in the presence of a beta-2 adrenergic antagonist (H35/25), or to salbutamol alone, the tracheal preparations from H. influenzae-vaccinated animals also showed a decreased relaxation. These results suggest involvement of both beta-1 and beta-2 subtype adrenoceptors. On the other hand, lung parenchymal strips from vaccinated guinea-pigs relaxed significntly more to these drugs. This effect was not influenced by H35/25 but could be inhibited by phenoxybenzamine. Histamine-induced contraction did not differ between the groups. These results indicated that H. influenzae causes a partial blockade of the beta adrenoceptors in tracheal spirals and, therefore, may have important implications in asthmatic bronchitis. In contrast, parenchymal lung strips of the H. influenzae-pretreated group showed an increased relaxation.

Bronchial hyperreactivity to histamine 4 days following vaccination with the human respiratory pathogen Haemophilus influenzae was tested in two in vivo and one in vitro models. Conscious vaccinated guinea pigs exposed to aerosolized histamine became asphyxial significantly faster than saline-treated controls. Also the bronchoconstriction in anaesthetized guinea pigs as a result of i.v. histamine was significantly potentiated in the H. influenzae pretreated group. Isoprenaline (30 micrograms/kg) partially inhibited the bronchoconstriction. The difference in histamine sensitivity between the two groups however remained. Protection against bronchoconstriction by atropine on the other hand was significantly enhanced in the vaccinated animals. This suggests a hyperreactivity of the parasympathetic, cholinergic pathways as a result of H. influenzae vaccination.

The presence of desmosomes and microfilaments, together with a variety of cytoplasmic organelles in tumor cell lumps isolated from the peritoneal cavity and tumor cells grown in monolayers, indicated the epithelial nature of the thymic tumor cell and was suggestive of its secretory activity. This is further confirmed by analysing the effects of tumor cell supernatants. The effect of supernatants from rat thymic epithelial tumor cell cultures on the mitogenic response of T-lymphocytes was studied in vitro and in vivo. An in vivo dose-effect curve could be established, revealing a significant increase in response to PHA and Con A of rat thymocytes using highly diluted supernatant (1:2000). Repeated intraperitoneal injection of purified thymic epithelial cell supernatant in mice and rats resulted in an increased mitogenic response of peripheral lymphocytes. No species specificity of the thymic humoral factor(s) was observed. The discrepancy in peripheral lymphocyte response between athymic nude rats and their heterozygous littermates points to the presence of target cells among the postthymic T cells and consequently to the induction of post-thymic T cell maturation. The data presented in this study show a tumor cell of thymic epithelial origin which synthesizes and secretes one or more factors displaying thymic hormone activity. Therefore, this tumor cell system might be used as a new source of thymic humoral factors(s).

Vaccination of guinea pigs with killed suspensions of Haemophilus influenzae, a bacterium often found in the deeper respiratory airways of asthmatic bronchitics, results in a number of effects suggesting an impairment of beta-adrenoceptor function. A [3H]dihydroalprenolol binding assay was used to determine the number of beta-adrenoceptors (Bmax) following H. influenzae vaccination. The Bmax declined significantly by 29% from 1240 +/- 80 to 880 +/- 70 fmol/mg protein, while the binding affinity of the sites was not changed. Specific binding in the presence of 1.8 nM [3H]DHA to tracheal longitudinal smooth muscle was also significantly lower in H. influenzae-vaccinated animals as compared to controls. Furthermore modulation of peripheral sympathetic input to lung beta-adrenoceptors was evaluated in our model. Pretreatment with Ro4-4602, an inhibitor of dopa-decarboxylase, increased the number of beta-adrenoceptors and prevented the H. influenzae-induced loss of beta-adrenoceptors. On the other hand repeated doses of the antidepressant desipramine mimicked the effect of H. influenzae vaccination i.e. a loss of beta-adrenoceptors. Desipramine and H. influenzae vaccination were not synergistic in their effects. The effects of H. influenzae and modulation of catecholaminergic input on guinea pig lung beta-adrenoceptors were compared with tracheal strip relaxation by isoproterenol, following similar treatments assessed in a superfusion model. Changes in lung beta-adrenoceptor number were almost identical with changes in tracheal strip relaxation. These results suggest that compensatory regulation adapts the number of respiratory beta-adrenoceptors to changes in sympathetic input. A similar mechanism may underlie the loss of beta-adrenoceptors following H. influenzae vaccination.

Haemophilus influenzae is a bacterium that often can be isolated from the deeper respiratory airways of patients with chronic asthmatic bronchitis. In the present study the effects of H. influenzae vaccination on guinea pig pulmonary beta-adrenoceptor number and function (in vitro and in vivo) have been evaluated. Functioning of beta-adrenoceptors is determined by measuring the beta-mimetic effect of isoprenaline on the inhibition of anaphylactic mediator release and isolated tracheal strip relaxation. The number of beta-adrenoceptor binding sites was measured by means of a 3H-dihydroalprenolol binding assay. Also the mechanism of action underlying the changes in beta-adrenoceptor functioning was evaluated. Furthermore, it was established that the effect on the beta-adrenoceptor system was not specific for H. influenzae and that other respiratory pathogens were also biologically active in this respect.

Lung elasticity and lung volumes at rest were measured in 22 female rowers, in 14 women who just started with rowing, in 21 female cyclists, and in 9 male rowers. The female rowers had a higher specific static and dynamic lung compliance (P less than 0.01) and a lower recoil pressure at functional residual capacity (P less than 0.05) as compared to the other three groups. According to their age, height, and fat-free mass, the female rowers had a normal vital capacity. The residual volume, the functional residual capacity, and the fast expiratory volume in 1 s were also normal. During an increased load test till exhaustion on a bicycle ergometer, the transpulmonary pressure and the expiratory flow were measured. While the expiratory transpulmonary pressure at exhaustion in the female rowers was not markedly lower than in the other groups, expiratory flow did not increase linearly with decreasing expiratory transpulmonary pressure in most of the female rowers. In the other three groups, there was a linear relation between expiratory flow and pressure. The higher lung compliance and lower elastic recoil in the female rowers caused the flow-limiting pressure to be reached at a lower level. The difference in lung elasticity between the male and female rowers showed that the physical stress on the lungs during rowing is not alike in women and men. We assume that the typical female physique requires extra fixation of the trunk during the pull phase of the rowing stroke, which could lead to loss of lung elasticity in female rowers.

Infections of the deeper respiratory airways can contribute to the progression of chronic asthmatic bronchitis. In the present report a number of microorganisms affecting the number of beta-adrenoceptors in guinea-pig lung homogenates are described. Haemophilus influenzae, Streptococcus pneumoniae, Bordetella pertussis and Escherichia coli O111B4 induced a significant decrease of the number of beta-adrenoceptors (by approximately 20%). Staphylococcus aureus, influenza A virus and Escherichia coli J5 were not active. These data point to a common factor shared by gram-negative bacilli; i.e. endotoxin. Purified endotoxin of E. coli O111B4 also decreased the number of beta-adrenoceptors, while E. coli J5-LPS did not. This suggests that neutral polysaccharides of bacterial cell walls, especially those in the 'O'-antigenic side chain of gram-negative endotoxins may be responsible for the decrease of beta-adrenoceptor number and therefore contribute to the pathogenesis of chronic asthmatic bronchitis. Intact endotoxin seems to be necessary since neither the isolated lipid nor the polysaccharide part of E. coli O111B4 LPS affected the number of beta-adrenoceptors in the lung.

The deeper airways of patients with asthmatic bronchitis are often infected with Haemophilus influenzae. Vaccination of guinea pigs with H. influenzae resulted in a significant impairment of the isoproterenol induced relaxation of isolated tracheal spirals by approximately 50% 4 days following vaccination. In the present study we further investigated the effects of some drugs affecting catecholamine release on the H. influenzae induced functional desensitization of tracheal spirals. Benserazide, an inhibitor of dopa-decarboxylase, completely prevented the reduction in isoproterenol-induced relaxation after H. influenzae vaccination, while no effect on relaxation of tracheal spirals from control animals was detected. On the other hand, inhibiting the re-uptake of catecholamines with desipramine did not influence the relaxation in the H. influenzae vaccinated tracheal spirals. Treatment of control animals with desipramine however resulted in a decreased relaxation of the isolated spirals by 40%. One day following vaccination with H. influenzae the level of norepinephrine in lung tissue was significantly elevated by 71%, and in plasma by 77%, while after 4 days no significant effects were observed. The spontaneous release of norepinephrine, epinephrine and dopamine of tracheal incubates was increased at days 1 and 4 following vaccination. The release of catecholamines from minced lung incubates of H. influenzae pretreated guinea pigs did not differ from that of controls. On the basis of these results it may be suggested that catecholamine metabolism is changed in lungs from H. influenzae vaccinated animals. Catecholamines, accordingly may play a role in the desensitization of beta-adrenoceptors by H. influenzae.

The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs was investigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while broncho-constriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1 mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.