Abstract: BACKGROUND: The impact of short-term preoperative pulmonary rehabilitation on exercise capacity of patients with chronic obstructive pulmonary disease undergoing lobectomy for non-small cell lung cancer is evaluated. METHODS: A prospective observational study was designed. Inclusion criteria consisted of an indication to lung resection because of a clinical stage I or II non-small cell lung cancer and a chronic obstructive disease on preoperative pulmonary function test. In such conditions, maximal oxygen consumption by a cardio-pulmonary exercise test was evaluated; when this resulted as being < or =15 ml/kg/min a pulmonary rehabilitation programme lasting 4 weeks was considered. Twelve patients fulfilled inclusion criteria, completed the preoperative rehabilitation programme and underwent a new functional evaluation prior to surgery. The postoperative record of these patients was collected. RESULTS: On completion of pulmonary rehabilitation, the resting pulmonary function test and diffuse lung capacity of patients was unchanged, whereas the exercise performance was found to have significantly improved; the mean increase in maximal oxygen consumption proved to be at 2.8 ml/kg/min (p<0.01). Eleven patients underwent lobectomy; no postoperative mortality was noted and mean hospital stay was 17 days. Postoperative pulmonary complication was recorded in 8 patients. CONCLUSIONS: Short-term preoperative pulmonary rehabilitation could improve the exercise capacity of patients with chronic obstructive pulmonary disease who are candidates for lung resection for non-small cell lung cancer.

Abstract: BACKGROUND: Cough is an important defense mechanism, whose main function is to remove mucus and/or foreign bodies from the airways. In patients with multiple sclerosis (MS), respiratory muscle function may be affected and cough may be impaired. OBJECTIVES: Respiratory muscle strength and voluntary cough efficacy were determined in MS patients and controls, and the relationship between cough efficacy and patients' degree of disability was investigated. METHODS: We recruited 27 MS patients (age: 41 +/- 11 years; 18 females) with mild-to-moderate disability, Expanded Disability Status Scale (EDSS) score range: 1-7, and 20 healthy controls (age: 37 +/- 11 years; 12 females). The maximal inspiratory (PIMAX) and expiratory (PEMAX) pressures, maximal whistle mouth pressures (PMOW), cough peak flows (CPF), cough expiratory volumes (CEV) and cough gastric pressures (PGA) were measured in all subjects. RESULTS: In MS patients, the EDSS score was significantly related to CPF, PEMAX, PMOW, cough PGA, PIMAX and CEV (p < 0.01, each correlation). The receiver-operating characteristic curve showed that an EDSS score > or =5.5 was consistent with impaired cough (CPF < or =5.6 l/s), with a sensitivity of 0.85 and a specificity of 0.95 (area under curve 0.90, p < 0.001). CPF was related to and predicted by PEMAX, PMOW, cough PGA and PIMAX in MS patients (p < 0.01 each correlation), but not in controls. CONCLUSIONS: MS can affect voluntary cough efficacy and respiratory muscle strength, which are inversely related to the patients' degree of disability. In addition, this study shows that CPF is a measure of clinical relevance in MS patients.

Abstract: PURPOSE: Severity of chronic obstructive pulmonary disease (COPD) can be graded using the classification released in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report. Such classification is essentially based on spirometry and does not recognise the role of other measures. The aim of this study was to assess whether the GOLD stages correlate with the extent of pulmonary emphysema and other ancillary computed tomography CT features in a population of smokers with stable COPD. MATERIALS AND METHODS: Based on clinical assessment and lung-function testing, patients were classified according to the GOLD criteria. CT scans were visually evaluated for extent of emphysema and airway abnormalities. RESULTS: A total of 43 patients were enrolled. The amount of emphysema was described as minimal in six patients with stage 0, and as moderate in seven patients with stage 0. In stages I and II, the extent of emphysema ranged from minimal to severe, whereas we observed the presence of severe emphysema in most patients in stages III and IV. According to the regression model, only CT emphysema extent independently predicted the GOLD stage (r2 = 0.58; p < 0.001). The cutoff value of emphysema extent of 31.5% allowed us to distinguish patients with a GOLD stage > or = III. CONCLUSIONS: Although we found a significant correlation between CT emphysema extent and GOLD stages, different percentage of emphysema extent can be observed among each GOLD stage. The upper limit of 31.5% of emphysema extent may indicate a boundary for a clinically worsening status.

Abstract: PURPOSE: Airway-wall remodelling may result in reduced airway distensibility in bronchial asthma. This study evaluated the baseline airway calibre and distensibility in asthmatic patients by means of high-resolution computed tomography (HRCT). MATERIALS AND METHODS: We studied seven patients (two men, age range 36-69 years) with chronic asthma [forced expiratory volume in the first second (FEV(1)) range: 30%-87% of predicted; FEV1/forced vital capacity (FVC) range 48%-75% of predicted) under stable clinical conditions and six healthy control subjects (three men, age range 29-50 years). In all subjects, HRCT scanning, at suspended end-expiratory volume, was performed at rest and during ventilation with 6 and 12 cmH(2)O by nasal insufflation with continuous positive airway pressure (nCPAP), both at baseline and after inhalation of 200 mug oxitropium bromide metered dose inhaler (MDI). External and lumen diameter (mm) of the right apical upper lobe bronchus were measured in all HRCT scans. RESULTS: In asthmatics, 12 cmH(2)O insufflation significantly changed baseline lumen (3.3+/-0.7 mm vs. 3.8+/-0.6 mm; p<0.01) and external diameter (6.2+/-0.9 mm vs. 6.7+/-0.8 mm; p<0.05), whereas in healthy controls, both 6 and 12 cmH(2)O insufflation significantly changed baseline lumen diameter (4.0+/-1.6 mm vs. 4.8+/-1.6 mm and 4.7+/-1.7 mm; p<0.01). In asthmatic patients, oxitropium bromide inhalation significantly changed baseline lumen diameter (3.3+/-0.7 mm vs. 4.4+/-0.6 mm; p<0.05), whereas the application of 6 or 12 cmH(2)O insufflation did not modify any bronchial diameters. In healthy controls, oxitropium bromide inhalation significantly changed baseline lumen diameter (4.0+/-.6 mm vs. 5+/-1.5 mm; p<0.05). The application of 12 cmH(2)O but not of 6 cmH(2)O induced a significant change in lumen diameter (5.0+/-1.5 mm vs. 6,0+/-1.6 mm; p<0.05). CONCLUSIONS: Our results show that airway distensibility in asthmatic patients, as assessed by HRCT, can differ compared with that of healthy controls. HRCT can provide useful information on airway distensibility.

Abstract: BACKGROUND AND PURPOSE: Physical deconditioning is involved in the impaired exercise tolerance of patients with multiple sclerosis (MS), but data on the effects of aerobic training (AT) in this population are scanty. The purpose of this study was to compare the effects of an 8-week AT program on exercise capacity-in terms of walking capacity and maximum exercise tolerance, as well as its effects on fatigue and health-related quality of life-as compared with neurological rehabilitation (NR) in subjects with MS. SUBJECTS AND METHODS: Nineteen subjects (14 female, 5 male; mean age [X+/-SD]=41+/-8 years) with mild to moderate disability secondary to MS participated in a randomized crossover controlled study. Eleven subjects (8 female, 3 male; mean age [X+/-SD]=44+/-6 years) completed the study. RESULTS: After AT, but not NR, the subjects' walking distances and speeds during a self-paced walk were significantly improved, as were their maximum work rate, peak oxygen uptake, and oxygen pulse during cardiopulmonary exercise tests. The increases in peak oxygen uptake and maximum work rate, but not in walking capacity, were significantly higher after AT, as compared with after NR. Additionally, the subjects who were most disabled tended to benefit more from AT. There were no differences between AT and NR in effects on fatigue, and the results showed that AT may have partially affected health-related quality of life. DISCUSSION AND CONCLUSION: The results suggest that AT is more effective than NR in improving maximum exercise tolerance and walking capacity in people with mild to moderate disability secondary to MS.

Abstract: Tissue remodelling can affect the entire bronchial wall, including the vascular component of the mucosa, in bronchial asthma. The bronchial mucosa is more vascularized in asthmatic patients than in healthy subjects, showing an increase in the number and dimension of vessels and vascular area. In addition, vascular changes can contribute to obstructing the airway flow in asthma. Vascular Endothelial Growth Factor, a mediator derived from endothelial cells, but also from most inflammatory cells in asthma, plays a primary role in vascular remodelling and angiogenesis. Studies on lung biopsies showed that anti-asthma drugs can decrease to varying degrees the vascular component of airway remodelling in asthma. Among asthma medications, inhaled corticosteroids effectively reverse all aspects of vascular remodelling such as vasodilatation, increased vascular permeability and angiogenesis. A better knowledge of angiogenetic mechanisms in asthma will support the selection of specific medications acting on this aspect of airway remodelling. The aim of this review is to analyze the morphological aspects of the vascular component in airway remodelling in asthma, as well as its pharmacological modulation.

Abstract: Bronchial asthma can be characterized by some significant changes in airway blood vessels, which may contribute to airway remodelling. Despite the clinical and functional consequences of bronchial microvascular remodelling in asthma, up to now, little data have been published on the therapeutic approach to this phenomenon. Corticosteroids are the only anti-asthma drugs that act positively on the three aspects of bronchial vascular remodelling: angiogenesis, dilatation and permeability. Modest positive effects of treatments with beta2-agonists and leukotrienes receptor antagonists on bronchial microcirculatory changes have been reported. In the future, agents that specifically inhibit angiogenesis could represent a novel approach for positively acting on bronchial microvascular changes in chronic inflammatory airway diseases, such as chronic bronchitis and asthma.

Abstract: BACKGROUND: There is increasing evidence to support a role for total mast cells (MC(TOT)) in the vascular component of airway remodeling in asthma. On the contrary, up to now, no study has addressed the role of chymase-positive mast cells (MC(TC)) in microvasculature changes. OBJECTIVE: We sought to assess the role of MC(TC) in the vascular component of airway remodeling in asthma. METHODS: We recruited 8 patients with mild-to-moderate asthma and 8 healthy volunteers as a control group. Fiberoptic bronchoscopy with endobronchial biopsy was successfully performed in all subjects. Immunostaining was performed for quantification of vessels, vascular endothelial growth factor (VEGF)-positive cells, MC(TOT), and MC(TC). RESULTS: Compared with those from healthy subjects, endobronchial biopsy specimens from asthmatic patients showed increased numbers of MC(TOT) and MC(TC) and VEGF(+) cells (P < .05). In asthmatic patients the number of vessels and the vascular area was also greater than in healthy subjects (P < .05). Additionally, in asthmatic patients the number of MC(TC) was significantly related to the vascular area (r(s) = 0.74, P < .01) and to the number of VEGF(+) cells (r(s) = 0.78, P < .01). Moreover, a colocalization study revealed that MC(TC) were a relevant cellular source of VEGF. Finally, a 6-week treatment with inhaled fluticasone propionate was able to reduce MC(TC) numbers. CONCLUSION: MC(TC) can play a role in the vascular component of airway remodeling in asthma, possibly through induction of VEGF. CLINICAL IMPLICATIONS: Specific targeting of MC(TC) might be a tool for treating vascular remodeling in asthma.

Abstract: Assessing and monitoring respiratory muscle function is crucial in patients with Amyotrophic Lateral Sclerosis, since impaired function can lead to either ventilatory failure or respiratory tract infection. Spirometry, diffusing capacity of the lung, breathing pattern, sleep study, blood gas analysis and respiratory muscle strength tests, as well as cough peak flow and cough expiratory volume measurements can provide relevant information on ventilatory function and cough efficacy. With regard to respiratory muscle strength testing, the rational approach consists in starting with volitional and non-invasive tests and later using invasive and non-volitional tests. This review focuses on both ventilatory and respiratory muscle strength testing, in order to undertake a timely treatment of respiratory failure and/or impaired cough efficacy. So far, the current literature has not highlighted any gold standard which stipulates when to commence ventilation and cough support in patients with Amyotrophic Lateral Sclerosis. A composite set of clinical and functional parameters is required for treatment scheduling to monitor lung involvement and follow-up in these patients.

Abstract: PURPOSE: The aim of this study was to assess the accuracy of some computed tomography (CT) quantitative indices (histogram features, ranges of density and one novel volumetric index) in the discrimination between normals and patients affected by lung fibrosis, and to compare their morphologic-functional relationship with the visual score one. MATERIALS AND METHODS: We analysed thin-section CTs and pulmonary function tests (PFTs) of six healthy subjects and 31 patients affected by lung fibrosis, including 17 with a usual interstitial pneumonia pattern (UIP group), and 14 with a predominant pattern of ground-glass opacities without honeycombing (non-UIP group). Presence and extent of various CT findings were assessed by the visual score as well as by CT computer indices. RESULTS: Together with the histogram features, fibrosis ratio (defined as the ratio of nonfibrotic CT lung volume divided by total CT lung volume) contributed to objectively differentiate fibrotic lungs from normal lungs. The range of density 700 to 400 HU showed the greatest degree of correlation with physiologic abnormality in the non-UIP group. In the UIP group, the lone visual score provided prediction of functional impairment. CONCLUSIONS: The visual score is still the main radiological method of quantifying the extent of abnormalities in patients with UIP, whilst the range of density 700 to 400 HU can be helpfully applied in a predominant pattern of ground-glass and reticular opacities without honeycombing.

Abstract: INTRODUCTION: In this study, we tested the hypothesis that walking capacity, assessed by the 6-min walk test (6MWT), could be related to the effect of flight simulation at sea level obtained by the hypoxia-altitude simulation test (HAST) in patients with chronic respiratory disease. METHODS: There were 15 patients with interstitial lung disease and 15 patients with chronic obstructive pulmonary disease who were recruited. Their baseline SpO2 values ranged from 88 to 98%. All patients performed the 6MWT and HAST according to standardized methods. RESULTS: Patients covered a walking distance ranging from 185 to 592 m without stopping while experiencing no to severe dyspnea. No correlation was found between dyspnea perception during walking, walking distance, and oxygen desaturation during HAST. The oxygen desaturation induced by the 6MWT was related to that after HAST (r = 0.52, p < 0.01). The bias and limits of agreement between the oxygen desaturation after the 6MWT and after the HAST were 0.8 and -6.6 to 8.2%, respectively. The baseline SpO2 could reliably predict the oxygen desaturation during HAST (r2 = 0.51). CONCLUSIONS: Our results showed that measurement of SpO2 during 6MWT can provide useful information for the preflight assessment and the in-flight oxygen prescription of patients with chronic respiratory disease.

Abstract: Abnormality in the fragile histidine triade (FHIT), a candidate tumor suppressor gene located in chromosome region 3 (3p14.2), has been frequently found in multiple tumor types, including lung cancer. In this study, the authors assessed the consistency of DNA microsatellite analysis of induced sputum (IS), as compared to that of blood and plasma. They also evaluated the loss of heterozigosity (LOH) and microsatellite instability (MSI) in 3 different loci, D3S1300, D3S1313, and D3S1234, all internal to the FHIT gene, in IS, blood, and plasma from patients with lung cancer, smokers, and healthy subjects. Eighteen patients with lung cancer (3 females, age mean +/- SD: 63 +/- 7 years), 39 smokers (23 females, age mean +/- SD: 57 +/- 6 years and cigarette pack-years mean +/- SD: 34 +/- 12), and 22 healthy nonsmoking subjects (13 females, age mean +/- SD: 63 +/- 5 years) were studied. DNA was extracted from blood, plasma, and IS, by means of a standard method. Analysis of LOH and MSI were performed using a fluorescent polymerase chain reaction (PCR)-based approach, followed by capillary electrophoresis. The ratios between the peak heights (phs), expressed as random fluorescence units, from plasma/blood (p/b) and induced sputum/blood (is/b) in all three loci were considered. The biases (agreement limits) between the mean ph ratio from p/b and is/b of D3S1300, D3S1313, and D3S1234 were respectively 0.07 (- 0.39 to 0.53), 0.016 (- 0.32 to 0.35), - 0.10 (- 0.51 to 0.30) in the patients; - 0.04 (- 0.52 to 0.43), - 0.06 (- 0.31 to 0.18), - 0.08 (- 0.48 to 0.30) in smokers; and - 0.11 (- 0.40 to 0.17), - 0.05 (- 0.53 to 0.43), - 0.09 (- 0.51 to 0.33) in healthy subjects. LOH and MSI in at least one locus were observed in 55% of patients, in 18% of smokers, and in 4.5% of healthy subjects (P < 0.001). These results showed that IS DNA provided data that were consistent with those from blood and plasma. These findings highlight new prospects for early tumor detection by a noninvasive technique based on the analysis of genetic alterations in induced sputum.

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Abstract: In 102 healthy Caucasians, 20-50 years old, we investigated the effect of anthropometrics on the 6-min walk test (6MWT), in order to provide reference values for walk distance (6MWD), oxygen saturation (SpO2), pulse rate (PR), respiratory rate (RR), breathlessness perception (VAS) and for the walking distance and body weight product (DW). The mean 6MWD and DW values were 593 +/- 57 and 638+/-44 m (P < 0.01) and 35,030 +/- 5306 and 48,882 +/- 6555 kg m (P < 0.01), respectively for women and for men. While walking, SpO2 remained unaltered and subjects reached 67 +/- 10% of their maximal predicted heart rate and a RR mean value of 19 +/- 4 bpm. VAS ratings were significantly higher in females as compared to males (24 +/- 15 vs. 18 +/- 5 mm, P < 0.05), however, when corrected for PR change while walking, they were not different. The equation by stepwise multiple regression analysis included height, age and gender for the 6MWD and accounted for 42% of the total variance. This study confirms the relevant effect of anthropometrics on walking capacity and suggests that when rating dyspnea, the change in heart rate during walking should be considered.

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Abstract: Advanced age, smoking habit, obesity or malnutrition, the coexistence of hypercapnia, bronchospasm or bronchial hypersecretion, the lack of pre-operative preparation and/or a prolonged duration of anaesthesia can negatively influence respiratory function in patients undergoing abdominal or thoracic surgery. Spirometric testing of pulmonary function is recommended in patients with a history of tobacco use or dyspnoea who are considered for cardiac or upper abdominal surgery and for all patients who are candidated for lung resection. Spirometry can provide cut-off values of acceptable risk in patients that are candidated for abdominal and thoracic surgery. At-risk patients having resective lung surgery should undergo a split lung function study with quantitative lung scanning or computed tomography in order to estimate the function of residual parenchyma after surgery. In patients with borderline estimated values, a cardiopulmonary exercise test is useful to further stratify surgical risk.(www.actabiomedica.it)

Abstract: A relevant ventilatory defect occurs after sternotomy, a very common thoracic surgical opening. The mechanism of the ventilatory impairment is unclear. Moreover, until now, the effect of sternotomy on pulmonary gas exchange has scarcely been investigated. We evaluated the time-course up to recovery and changes in spirometry, maximum static inspiratory (PI(max)) and expiratory (PE(max)) mouth pressures and pulmonary gas exchange in 6 patients after sternotomy and in 8 patients after laparotomy. All patients were free of cardiopulmonary diseases and had normal preoperative lung function. Sternotomy and laparotomy decreased forced vital capacity (FVC) by 67 and 49%, respectively. Moreover, the percent decreases in PI(max), PE(max) and PaO(2) after sternotomy vs. laparotomy were respectively 54 vs. 57%, 54 vs. 60%, and 22.6 vs. 7.5% (p < 0.05). Following sternotomy, the percent decreases in FVC correlated with the percent decreases in PI(max) (p < 0.05) and PE(max) (p < 0.01). The return to baseline values occurred after approximately 2 weeks. The present study shows that sternotomy can induce greater respiratory effects than laparotomy and suggests a relevant involvement of respiratory muscle weakness after surgical opening of the thorax. The study also supports the view that the evaluation of patient's lung function before sternotomy can be clinically relevant.

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Abstract: PURPOSE: To evaluate the prevalence and significance of the pathological effects of cigarette smoking on the lung and the sensitivity of high-resolution CT (HRCT) in the recognition of early smoking-induced lesions in asymptomatic former or current smokers. MATERIALS AND METHODS: We performed a prospective and consecutive analysis of 36 volunteers (16 males, 20 females), 10 non-smokers (3 males; 7 females) and 26 smokers (13 males; 13 females / 17 current smokers; 9 former smokers), all asymptomatic and with normal respiratory flows. These subjects underwent lung function testing and HRCT, after providing written informed consent for the study. The HRCT scans were obtained at three pre-selected levels (aortic arch, tracheal carina and venous hilum). The same scans were obtained in post-expiration phase. At the level of the apical segmental bronchus of the right upper lobe, we measured on the monitor wall thickening, and the total and internal diameters using the techniques reported in literature. Each study was independently evaluated by two radiologists that were blinded to all clinical and functional data; they also evaluated the presence, prevalence and type of emphysema, areas of patchy hyperlucency and oligoemia in the inspiration phase and areas of expiratory air trapping. The extension was evaluated with the visual score method. The data obtained were analysed with the Windows SPSS package for statistical analysis. RESULTS: The two groups (non smokers and smokers) showed significant differences in some functional tests such as FEV1 (p<0.005) and Tiffeneau index (p<0.005), which were lower in current-smokers or former-smokers, although still within the normal range. The HRCT study did not show areas of emphysema or air trapping in non smokers. In the smokers' group, air trapping was observed in 30.7% of cases: 33.3% former-smokers and 29.4% current smokers (mean extension was 21.36% in former smokers and 9.48% in current smokers). Mean extension in the smokers' group was 13.94%. Pulmonary emphysema was found in 34.6% of cases in the smokers' group: 33.3% former-smokers and 35.2% current-smokers. Emphysema was prevalent in the upper lobes (88.8%). Mean extension was 8.76% in the former smokers group and 18.81% in current-smokers, with a total mean extension of 15.47% in the smokers' group. Statistically, there was a significant difference between non-smokers and smokers as regards emphysema extension and expiratory air trapping (p=0.034 and p=0.050, respectively). The smokers' group had a significantly wider diameter of the apical segmental bronchus of the right upper lobe than the controls. There was no significant statistical correlation between this dilatation and the emphysema score (r=0.051; p=0.81). The entity of smoking history did not correlate with emphysema extension or air trapping or with the size of the apical segmental bronchus of the right upper lobe. CONCLUSIONS: Our study demonstrates that HRCT is more sensitive and specific than commonly-used functional tests for the evaluation of initial emphysema in asymptomatic smokers. We observed expiratory air trapping only in the smokers' group, and only of the lobular type, without evidence of disease in inspiratory scans. Among the smokers and former-smokers, air trapping was found in 30.7% of subjects, with a mean extension lower than 10%. Our results therefore suggest that, even in asymptomatic subjects, expiratory air trapping is probably pathological and, once bronchial asthma has been excluded, it may be related to cigarette smoking and indicate early inflammatory bronchiolar damage. HRCT may therefore be regarded as a useful tool in the early diagnosis of smoking-related lung disease.

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Abstract: The finding of hemidiaphragm elevation on a chest radiograph, in absence of an ipsilateral lung disease, is assumed to indicate severe hemidiaphragm dysfunction. To test this hypothesis we retrospectively reviewed chest radiograph findings and corresponding twitch transdiaphragmatic pressure (T(W)P(DI)) results from 42 (17 female, age range 22-79 years) consecutive patients who underwent phrenic nerve stimulation studies. Chest radiographs were independently reviewed in a blind manner by two radiologists. The interobserver agreement was moderate, the kappa value ranging from 0.48 (left hemidiaphragm) to 0.59 (lung parenchyma). Hemidiaphragm dysfunction was diagnosed if T(W)P(DI) of corresponding hemidiaphragm was less than 3.5 cm H2O. The prevalence of patients with an elevated unilateral hemidiaphragm on chest radiograph was 64% and of patients with unilateral paralysis judged by T(W)P(DI) was 24%. Sensitivity, specificity, positive and negative predictive values for chest radiograph, as a diagnostic test for unilateral diaphragm dysfunction were 0.90, 0.44, 0.33 and 0.93, respectively. We conclude that the isolated elevation of hemidiaphragm on chest radiograph is of little value in the diagnosis of unilateral hemidiaphragm paralysis, though the condition is unlikely if diaphragm elevation is absent.

Abstract: OBJECTIVE: To assess the impact of long-term treatment with topical timolol on bronchial reactivity in healthy individuals. METHODS: Twenty-one otherwise healthy individuals with high-pressure primary open-angle glaucoma were enrolled in a randomized controlled clinical trial. Eleven patients underwent 3 years of topical 0.5% timolol treatment followed by a 1-year washout period; 10 patients underwent primary argon laser trabeculoplasty. Functional variables and bronchial reactivity (forced expiratory volume in 1 second and metacholine challenge test results) were assessed in both groups at enrollment and after 3 and 4 years of follow-up. RESULTS: After 3 years, a measurable response to metacholine challenge was recorded in 6 of 11 otherwise symptom-free individuals treated with 0.5% timolol twice daily. A detectable response to metacholine challenge was still present in half of these individuals (3 of 6) when further washed out for 1 year from the topical beta-blocker. No significant variation in bronchial reactivity was measured in the laser-treated group during 4 years of follow-up. CONCLUSIONS: Healthy individuals who undergo long-term topical application of a nonselective beta-blocker (0.5% timolol) can develop a subclinical increase in bronchial reactivity. This phenomenon may not be completely reversible on withdrawal of the beta-blocker.

Abstract: The possibility that a subject's psychological status may influence respiratory sensations and that chronic respiratory disease may have psychological consequences has sparked great interest among clinicians and researchers. This paper reviews the existing research on the association between respiratory symptom perception and the psychological status and between chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease, and psychological disturbances. Moreover, it focuses on the role of stressful events in determining asthma exacerbations. The recent literature suggests that in patients with chronic respiratory diseases, the evaluation of breathlessness perception, psychological disturbances and the recording of any stressful events should be considered as relevant as the physical and functional assessment of respiration.

Abstract: BACKGROUND: Inhaled corticosteroids (ICSs) are an effective treatment of asthma even when administered at a low dose. Once asthma is controlled, current guidelines recommend that the dose of ICS be reduced to the lowest possible and effective dose. Although the most appropriate strategy for the stepping down has not yet been defined, quantification of sputum eosinophils and bronchial hyperresponsiveness (BHR) are indeed measures of asthma control. OBJECTIVE: To compare the efficacy of step-down and fixed-dose strategies in the control of BHR to methacholine and eosinophilic inflammation patients with mild-to-moderate asthma. METHODS: We performed a double-blind, randomized study to compare inhaled fluticasone propionate (FP), 1,000 microg/d, then reduced to 200 microg/d (group 1; n = 18) to a fixed dose of FP, 200 microg/d (group 2; n = 17) administered for 6 weeks and then 8 weeks in reducing the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and sputum eosinophils in 35 patients. The duration of the efficacy was also followed subsequently after 8 weeks of placebo treatment. RESULTS: PD20 remarkably increased with both treatment strategies, but differences between groups were not significant. Sputum eosinophils (median values, percentage) at baseline and after each treatment period were not different (group 1, 16.4 to 1.0 to 2.7%; group 2, 16.7 to 2.8 to 2.8%, respectively). The percentages of patients in whom sputum eosinophilia was normalized (< or = 3%) were as follows: group 1, 69% and 60%; group 2, 50% and 57%. After placebo treatment, sputum eosinophils were still "normalized" in approximately one third of patients. CONCLUSION: Step-down and fixed-dose strategies with FP improved PD20 and sputum eosinophilia to a similar degree. The effect on sputum eosinophils persisted longer than that on methacholine.

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Abstract: PURPOSE: The aim of this study was to assess the accuracy of high-resolution CT in the differential diagnosis between UIP and NSIP, and the correlations with histological and functional findings. MATERIALS AND METHODS: Patients underwent thin-collimation spiral CT (1 mm), with 10-mm interval. Pulmonary function was assessed with a pneumotacograph and body plethysmograph connected with a computer for data analysis. Three pathologists, blinded to the clinical and functional data, provided a histological diagnosis based on established criteria reported in the literature. The study group only included patients with a histological diagnosis of either UIP or NSIP. RESULTS: We achieved a correct diagnosis of NSIP in 86.6% of cases (76.4% sensitivity; 84.6% specificity), whereas UIP was correctly diagnosed in 73.3% of cases (84.6% sensitivity; 76.5% specificity). An 80% agreement was achieved between the HRCT and histological findings in the whole case series (73% sensitivity, 87% specificity, p<0.01). CONCLUSIONS: The most important finding of our study was that a ground glass appearance equal to or greater than 15% is highly suggestive of NSIP. Therefore, our results could be useful to confirm a suggested diagnosis of NSIP.

Abstract: BACKGROUND: There is increasing in vitro evidence to support a role for vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, as a mediator of fibrosis associated with neovascularization. OBJECTIVE: We tested the hypothesis that VEGF is involved both in increased airway mucosal vascularity and in the subepithelial fibrosis of asthmatic patients. METHODS: Bronchial biopsies were performed in 24 asthmatic patients and eight healthy controls. Immunostaining, using computerized image analysis, was performed using monoclonal antibodies against VEGF(+) cells, type IV collagen, to outline the basement membrane thickness, and tryptase and EG2, to identify mast cells and eosinophils, respectively. RESULTS: The counts of VEGF(+) cells (P<0.05), mast cells and EG2(+) cells (both P<0.01) were higher in asthmatics than in controls. The number of vessels, the vascular area in the lamina propria, and the basement membrane thickness were significantly higher in asthmatics than in healthy volunteers (P<0.01). Moreover, in asthmatic patients, the number of VEGF(+) cells was significantly related to the number of vessels (P<0.01), to mast cells (P<0.01) and to basement membrane thickness (P<0.01). A colocalization study also revealed that mast cells were a relevant cellular source of VEGF. High doses of inhaled fluticasone propionate significantly reduced VEGF(+) cells (P<0.05), vessel number (P<0.05), vascular area (P<0.05) and basement membrane thickness (P<0.05) in a subgroup of asthmatic patients. CONCLUSIONS: This study shows that VEGF, in addition to being involved in the vascular component of airway remodelling, may play a role in the thickening of the basement membrane in asthma.

Abstract: OBJECTIVE: To verify the reliability of quantitative computed tomography (CT) to estimate the postoperative lung function in patients with mild to severe chronic obstructive pulmonary disease (COPD) who underwent a lobectomy. METHODS: Nine COPD patients with lung cancer having a lung lobectomy with preoperative CT were enrolled. By applying a density mask technique and a specific equation, predicted postoperative forced expiratory volume in 1 second (FEV1) and vital capacity (VC) were calculated. Predicted values were correlated with postoperative measured values. RESULTS: Estimated FEV1 and VC were always significantly lower than the corresponding postoperative values; however, CT-estimated postresection FEV1 values were better than the postresection VC values (biases between estimated and measured values were -0.14 and -0.536 L, respectively, according to the Bland-Altman method). Quantitative CT predicted postoperative FEV1 (r = 0.97, P < 0.001) and VC (r = 0.93, P < 0.001) well in all patients, however. CONCLUSIONS: Quantitative CT may be an alternative tool to perfusion scan to predict postresection lung function, even in patients with borderline pulmonary function undergoing a lobectomy.

Abstract: OBJECTIVE: To evaluate and compare histogram features (mean lung attenuation, skewness, kurtosis) of low-dose and standard-dose CT in a group of patients affected by idiopathic interstitial pneumonitis. METHODS: We analyzed 16 patients affected by idiopathic interstitial pneumonitis. Spiral whole lung thin-section CT acquisition at standard dose (100 mAs) and three additional low-dose (50 mAs) CT images were obtained. After obtained frequency histograms, mean lung attenuation (MLA), skewness and kurtosis and three range of density (-700/-200 HU; -700/-400 HU; -500/-200 HU) of the standard-and low-dose thin-section CT scans were analyzed and compared. RESULTS: The parameters obtained with low-dose and standard-dose spiral CT were correlated in a highly significant manner and were equivalent (p<0.01). The greatest correlation was found between standard-and low-dose kurtosis and standard and low-dose -700/-400 HU subrange of density (r=0.92; p<0.0001). CONCLUSIONS: Our results prove that a quantitative CT objective evaluation in lung fibrosis can be successfully obtained with low-dose spiral CT, with reduced mA.

Abstract: OBJECTIVE: Pulmonary Function Tests (PFT) and Cardio-Pulmonary Exercise Testing (C-PET) are useful to evaluate operability in functionally compromised patients. Although modifications of PFT and C-PET after lung surgery have been widely explored, little information exists as to modifications of exercise capacity in COPD patients undergoing lung resection. We prospectively analyzed the changes in PFT and C-PET in patients with COPD after a pulmonary lobar resection. METHODS: From January 2003 to March 2004 all patients scheduled for lung resection were considered for participation in the study protocol. Those patients with a preoperative diagnosis of COPD on PFT were explored through a C-PET. Only patients who had undergone a lobar pulmonary resection were subsequently considered; these patients had a new complete cardio-respiratory evaluation 3 months after surgery. The pre- and postoperative values compared were those of FEV1, TLC, DLCO, VO2max, and VE/VCO2. Data are expressed as mean +/- standard deviation (SD). Statistic evaluation was made using the Wilcoxon test. RESULTS: During this period 11 patients completed the study protocol. Ten patients underwent surgery for NSCLC and one for a pulmonary aspergilloma. Nine lobectomies and two bilobectomies were performed. In the study population, the preoperative mean value of FEV1 resulted as being 53% (SD+/-20) of the predicted mean value, that of TLC 120% (SD+/-35) and that of DLCO 65% (SD+/-27). The preoperative mean value of VO2max resulted as being 17.8 ml/Kg/min (SD+/-3.25) and mean VE/VCO2 resulted as being 35.7 (SD+/-4). Three months after surgery the measured mean value of FEV1 was 53% (SD+/-18), that of TLC was 99% (SD+/-24) and that of DLCO 52% (SD+/-18). The mean value of VO2max resulted as being 14.1 ml/Kg/min (SD+/-3.04) and that of VE/VCO2 was 42.5 (SD+/-12.8). Statistical analysis of PFT values showed that FEV1 and DLCO were not significantly modified (P > 0.05); in contrast, TLC had significantly decreased (P = 0.008). VO2max had significantly decreased (P = 0.004) and VE/VCO2 had significantly increased (P = 0.018). CONCLUSIONS: Three months after a lobar pulmonary resection, patients with COPD were found to have a significant decrease in exercise tolerance. PFT alone can underestimate the postoperative loss of exercise capacity through exercise.

Abstract: Interstitial lung diseases (ILDs) are functionally characterized by a restrictive ventilatory defect due to a reduced distensibility of the lung parenchyma. ILD patients also show a reduced exercise tolerance, the main factors limiting exercise capacity being ventilatory and gas exchange abnormalities. Functional abnormalities in ILDs are typical, but not specific. Despite the fact that different lung function patterns have been described among ILDs, they overlap and their practical application to differentiate ILDs is poor. Resting pulmonary function and exercise-induced hypoxemia can aid in defining the prognosis of ILDs and in referring patients for lung transplantation. Additionally, spirometry and diffusing capacity are useful to monitor the response of patients to therapy.

Abstract: To ascertain whether fatigue perception is linked to exertion dyspnea and/or to an impaired cardiorespiratory response during walk, 11 patients (8 females, age range 21-46 years) with multiple sclerosis (MS) and mild disability underwent the 6-min walk test. Ten healthy subjects (7 females, age range 25-49 years) were studied, as a control group. Patients did not differ from controls in spirometry, lung volumes and respiratory muscle strength. There was a significant difference in walk distance between patients and controls (P<0.001), but not in dyspnea perception. In patients, the walk distance significantly related to disability score (P<0.01), but not to fatigue. Compared to controls, patients had a significant decrease in oxygen pulse during walk (P<0.05) and a significant increase in the ventilatory equivalent of CO2 both at baseline and during walk (P<0.05). The relative contribution of both the tidal volume and of the ratio of inspiratory to total breathing cycle duration to the increase in minute ventilation during walk was significantly less in patients, as compared to controls (P<0.05). We conclude that in MS patients with mild disability, fatigue and exertion dyspnea are different sensations without any link and a peripheral limitation during walk can occur.

Abstract: Various pleuro-pulmonary abnormalities are known to complicate vascular collagen diseases, particularly, rheumatoid arthritis. Each component of the respiratory system is affected, either separately or in combination. Although most pulmonary complications appear in an established case of collagen vascular disease, in certain conditions, the lung disease precedes the more typical manifestation. While some complications are asymptomatic and tend to be resolved spontaneously (for e.g. pleuritis and rheumatoid nodules), others may cause severe or fatal conditions (interstitial pneumonia and constrictive bronchiolitis). The incidence of interstitial lung disease is increasing in vascular collagen disease. This may be mainly attributed to the increase use of invasive techniques such as bronchoscopy and video-assisted thoracoscopic surgery and in part due to the use of high resolution computed tomography, and functional pulmonary tests.

Abstract: BACKGROUND AND AIM: Hypersensitivity pneumonitis (HP) is an immunologically induced inflammation of the lung parenchyma, though bronchial airways may be also involved. The aim of this study was to compare the cellular profiles of induced sputum (IS) in patients with newly diagnosed HP to that of healthy subjects, and to examine the relationship between inflammatory cells from IS and BAL. METHODS: Nine HP patients and 9 healthy volunteers were studied. IS was obtained by inhalation of hypertonic saline solution in all subjects. Bronchoscopy was performed on a different occasion in all patients and in five controls. RESULTS: IS was well tolerated and preferred to BAL by all subjects. Both IS and BAL from HP patients showed a significant increase in total cells (P < 0.02 and P < 0.001) and in lymphocytes (P < 0.02 and P < 0.001) and a significant decrease in macrophages (P < 0.05 and P < 0.001), when compared with normal subjects. In HP patients, total cells number in IS was higher than that in BAL (P < 0.02). Moreover, the percentage of lymphocytes was significantly lower in IS than in BAL (P < 0.001). No significant relationship was found between total cells or inflammatory cells from IS and the corresponding ones from BAL and wide limits of agreement were found between lymphocytes from IS and BAL. CONCLUSIONS: This study demonstrated that both BAL and IS from newly diagnosed HP patients contained significantly more total cells and lymphocytes, when compared to healthy subjects. Moreover, differential cell counts in HP patients showed that IS and BAL reflected different compartments of inflammation. Thus, IS could represent a complementary, but not alternative tool to bronchoscopy both in research and in the clinical monitoring of HP patients.

Abstract: The collagen vascular diseases are a heterogeneous group of immunologically-mediated inflammatory disorders. Frequently, these diseases affect organ systems outside the thorax as their primary manifestation, but may involve the pleura as a single presenting feature, as part of multisystem involvement, or as an isolated manifestation of a disease that is otherwise quiescent. In this article, we review the manifestations of respiratory disease caused by rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis/dermatomyositis, mixed connective tissue disease, Sjogren's syndrome, Wegener's granulomatosis, and sarcoidosis.

Abstract: In asthmatics, the score of bronchoconstriction-associated breathlessness at 20% fall in forced expiratory volume at first second (FEV1) evaluated on a Borg scale (PS20) is a tool successfully used to measure the perception of symptoms. This prospective laboratory study evaluated the applicability of PS20 to assess the breathlessness induced by ultrasonically nebulized distilled water (UNDW) and methacholine (M) and its reproducibility. Twenty-two mild and clinically stable asthmatic patients performed UNDW and M challenge tests. The PS20 was calculated by linear interpolation of the last two points of the perception/fall in FEV1 curve of the UNDW and M tests. The reproducibility of PS20 M was assessed by repeating measurements on 2 separate days by 3 weeks. PS20 UNDW and PS20 M did not differ and were respectively 1.82 +/- 1.85 and 2.03 +/- 1.86. They were significantly related (rs=0.63; p<0.01) and the bias between PS20 UNDW and PS20 M was -0.21 with the limits of agreement ranging from -3.2 to 3.6. The intraclass correlation coefficient for repeated measurement of PS20 M was 0.82; the bias between the two measurements was 0.2 with the limits of agreement ranging from -2.8 to 3.2. All patients had a measurable breathlessness perception degree on a Borg scale during both distilled water challenges and methacholine. Asthmatic patients with normal, exaggerated or poor breathlessness perception were also similar for both stimuli. In addition, PS20 showed a good reproducibility and this allows the serial evaluation of patient's breathlessness perception by this technique in clinical settings and in the physiology laboratory.

Abstract: We conducted a randomized, double-blind, parallel-group study to assess the effect of 6 weeks treatment with low-dose (100 microg twice a day) or high-dose (500 microg twice a day) inhaled fluticasone propionate (FP) on the vascular component of airway remodeling in 30 patients with mild to moderate asthma. We also studied the effect on the inflammatory cells and the basement membrane thickness, and we compared findings from bronchial biopsies taken in patients with asthma with those in eight control subjects. Bronchial responsiveness to methacholine and asthma symptom score were measured before and after treatments. Eight patients in the low-dose FP group and eight patients in high-dose FP group completed the study. At baseline, patients with asthma showed an increase in the number of vessels and in vascular area as compared with control subjects. In the subjects with asthma, number of vessels correlated with vascular area (p < 0.01) and with number of mast cells (p < 0.01). Bronchial responsiveness to methacholine, asthma symptom score, and inflammatory cells decreased significantly after both low- and high-dose FP (p < 0.05). However, the number of vessels, the vascular area, and the basement membrane thickness decreased only after high-dose FP (p < 0.05). In conclusion, this study shows that in patients with mild to moderate asthma, high dose of inhaled FP given over 6 weeks can significantly affect airway remodeling by reducing both submucosal vascularity and basement membrane thickness.

Abstract: PURPOSE: In the diagnosis of extrinsic allergic alveolitis, high-resolution computed tomography (HRCT) is more sensitive and more specific than radiography; however, the accuracy of HRCT is not absolute. The role of HRCT in this field has scarcely been investigated in the literature. The purpose of this paper is to explore the possibilities of HRCT in this field and to analyse the correlations between HRCT and functional parameters. MATERIALS AND METHODS: We performed a retrospective blind evaluation the HRCT scans of 24 patients (19 males and 5 females). Twelve were affected by idiopathic pulmonary fibrosis (IPF); 12 had chronic extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. The HRCT findings were studied by two radiologists, who were not aware of the diagnoses. The possible differences in evaluation were subsequently resolved by consensus. In the presence of interstitial fibrosis, we recorded the prevailing site and the anatomical extension (with the method of the visual percentage score, described in the literature). In all the cases, we recorded the blood gas values (PaO2, PaCO2, and pH), total lung capacity (TLC), forced expiratory volume in 1 second (FEV1), Vital Capacity (VC), Tiffeneau index (FEV1/VC) and monoxide carbon diffusion (DLCO). The statistical significance of the correlations was investigated using the Mann-Whitney and Wilcoxon tests. Student "t"-test and Pearson's chi squared were used to compare the variables of the different groups. A value of p< or =0.05 was considered significant. RESULTS: Overall, the diagnosis was formulated with a high degree of confidence in 13 of 24 cases (54.1%); in these patients, the result was correct in 84.6% of cases (11 of 13). In the diagnosis of EAA, HRCT sensitivity was 50%, with 91.6% specificity, 70.8% accuracy. In the diagnosis of IPF, HRCT sensitivity was 75%, with 83.3% specificity, 79.1% accuracy. The HRCT signs of interstitial fibrosis were visible in 11 cases of IPF (91.6%) and in 4 cases of EAA (33.3%), with significant statistical difference (p<0.005). In the analysis of the whole series (24 patients) we found a significant inverse correlation between the HRCT score of fibrosis and the extension of the areas with air-trapping (p<0.003). There was no significant difference between IPF and EAA considering age, FEV1, PaO2, PaCO2 and pH. We found inverse correlation (p<0.001) between HRCT extension of the fibrosis and DLCO. There was a significant difference between pulmonary fibrosis and extrinsic allergic alveolitis considering TLC (in average, respectively: 65% and 84.3%; p<0.02), and DLCO (respectively 40.4% and 74.7%; p<0.03). DISCUSSION AND CONCLUSIONS: HRCT is a reliable and strong method to be used in particularly complex fields. We found signs of interstitial fibrosis more frequently in IPF than in EAA (91.6% versus 33.3%). In IPF cases, the extension of the fibrosis--evaluated with the visual score method--was higher then in EAA (34.7% versus 6%). The presence of fibrosis with basal and peripheral distribution was characteristic of idiopathic pulmonary fibrosis, with good sensitivity and specificity (75%), whereas in chronic extrinsic allergic alveolitis the areas of fibrosis often presented an irregular and heterogeneous distribution, in 91.6% of cases. However, 25% of extrinsic allergic alveolitis cases had a distribution mimicking idiopathic pulmonary fibrosis. The presence of areas with increased ground-glass opacity is more common in EAA than in IPF (66.6% versus 33.3%). Areas of mosaic attenuation, visible in inspiratory CT scans, are not rare in IPF (41.6% of cases), and generally have a basal distribution. The presence of hyperlucent lobules inside the fibrotic areas does not exclude the diagnosis of IPF. The finding of the expiratory air-trapping is more common in chronic EAA than in IPF, and the extension of this areas is greater in EAA (17.3% versus 6.5%). We found an inverse correlation between the extension of the fibrosis and the expiratory trapping. Signs of emphysema were observed in 25% of cases, wiema were observed in 25% of cases, with equal prevalence and the same extension in IPF and in EAA. All patients were smokers or ex-smokers. Smoking has not been demonstrated to have a protective effect against EAA. The areas of mosaic perfusion during inspiration do not represent a sound criterion for the differential diagnosis between IPF and chronic EAA. In fact, they can also be frequently found in IPF. HRCT can be employed in clinical practice for the differential diagnosis between IPF and chronic EAA with good (but not absolute) accuracy.

Abstract: Maximal expiratory mouth pressure is a well established test that is used to assess expiratory muscle strength. However, low values are difficult to interpret, as they may result from technical difficulties in performing the test, particularly in patients with facial muscle weakness or bulbar dysfunction. We hypothesized that measuring the gastric pressure during a cough, a natural maneuver recruiting the expiratory muscles, might prove to be a useful additional test in the assessment of expiratory muscle function. Mouth expiratory and cough gastric pressures were measured in 99 healthy volunteers to obtain normal values and in 293 patients referred for respiratory muscle assessment to compare the two measurements. Between-occasion within-subject coefficient of variation, assessed in 24 healthy volunteers, was 10.3% for mouth pressure and 6.9% for cough. Mean +/- SD cough gastric pressure for normal males was 214.4 +/- 42.2 and 165.1 +/- 34.8 cm H2O for females. In 171 patients deemed weak by a low mouth expiratory pressure, 42% had a normal cough gastric pressure. In 105 patients deemed weak by a low cough gastric pressure, 5.7% had a normal expiratory mouth pressure. Low maximal expiratory mouth pressures do not always indicate expiratory muscle weakness. Cough gastric pressure provides a useful complementary test for the assessment of expiratory muscle strength.

Abstract: Bronchial asthma is a chronic inflammatory disease characterized by inflammatory cell infiltration and by some long-lasting structural changes of bronchial wall, defined as airway remodelling. Airway remodelling can significantly affect two important functional characteristics of asthma, i.e. airway hyperresponsiveness and bronchial obstruction reversibility. Airway remodelling might be responsible for most of the inter-individual variability of bronchial hyperresponsiveness and might also determine the irreversible component of the airway obstruction, sometimes detectable in asthmatic patients. Among anti-asthma drugs, inhaled steroids are the most effective on inflammation and remodelling of airway wall. Recent evidences indicate that high doses of inhaled corticosteroids can significantly reduce not only inflammatory cells but also some components of airway remodelling, such as the increased airway wall vascularity and the basement membrane thickness. Conversely, low doses of inhaled corticosteroids can significantly act only on airway cell infiltration.

Abstract: Bronchial asthma is one of the most common chronic diseases in the world and can affect people of all ages. In the last few years there has been a considerable improvement in the etiopathogenetic knowledge of the disease and extremely effective anti-asthmatic drugs are available. However, asthma-related morbidity and mortality are increased, especially in Western countries. In an attempt to reverse this negative trend, for a number of years national and international guidelines on asthma have been published all over the world. These guidelines have the aim of improving asthma diagnosis and treatment and of conveying a fundamental educational message both to health workers and to patients and their families. From the data in the literature it can be clearly seen that only through the application of valid educational programs is it possible for asthmatics to improve their knowledge of the disease and to understand how they can look after themselves by a careful evaluation of their own symptoms and respiratory function. They should also be aware of the drugs available for the treatment of both acute asthmatic crises and chronic asthma, but especially of the fact that this chronic inflammatory affection can be fully treated. In particular, an educational program organized with groups of maximum 10-12 people attending 2 lessons and with helpful training tools, can increase significantly asthma knowledge, treatment compliance and patient self-management. The aim of this review is to highlight the importance of educational programs and those obscure areas which slow down their large scale application and universal acceptance.

Abstract: Expiratory muscle strength is a determinant of cough function. Mouth pressures during a maximal static expiratory effort (PE,max) are dependent on patient motivation and technique and low values are therefore difficult to interpret. This study hypothesized that a short, sharp and maximal expiration through a narrow aperture, a "whistle", might provide a complementary test of expiratory muscle strength. To obtain a maximal whistle, subjects (27 healthy volunteers and 10 patients with amyotrophic lateral sclerosis) were asked to perform a short, sharp blow as hard as possible, from total lung capacity, through a reversed paediatric inhaler whistle, connected to a flange-type mouthpiece. In both healthy subjects and patients, whistle mouth pressure (Pmo,W) was closely related to the pressure measured in the oesophagus and stomach during the same manoeuvre. In healthy subjects, Pmo,W and PE,max correlated with wide limits of agreement, although Pmo,W values were significantly higher than PE,max (131+/-31 cmH2O versus 101+/-27 cmH2O, p<0.0001). In patients, it was also found that Pmo,w and PE,max values were strongly related (r=0.937, p<0.0001). In healthy subjects, the intraclass correlation coefficient and the variation coefficient for Pmo,W repeated measurements were respectively 0.88 and 7.0%. However Pmo,W and PE,max were always smaller than the gastric pressure generated by a maximal cough. It is concluded that mouth whistle pressure, a noninvasive, reproducible and simple test, provides a reliable measure of expiratory muscle strength in healthy subjects that is acceptable to patients and can be used in a complementary fashion to maximal static expiratory effort.

Abstract: BACKGROUND AND AIM OF THE WORK: In patients with interstitial lung disease (ILD), the six-minute walk test (6MWT) has been rarely used, and up till now, the relationship between outcome measures of the test and baseline lung function has not yet been examined. Therefore, we assessed walk distance, oxygen desaturation, and breathlessness perception during 6MWT, and their relationships to baseline lung function in patients with ILD. METHODS: Forty ILD patients with history of breathlessness during physical exertion performed a 6MWT following a standard protocol. Breathlessness perception during walk was assessed by visual analogue scale (VAS, in mm). RESULTS: The mean walk distance was 487 meters (range 271-689). Mean baseline oxygen saturation (Base SpO2, %) was 94% and was reduced during walk, either as mean oxygen saturation (Mean SpO2, 89%, p < 0.001) or as mean fall in oxygen saturation during walk (Fall SpO2, 5%). Furthermore, VAS significantly increased after walk (5 mm to 44 mm, p < 0.001). A close relationship of TLco and TLC to walk distance and Fall SpO2 was found (r = 0.45 and 0.42 and r = -0.75 and -0.64, respectively; p < 0.001, each). On the basis of regression equations by stepwise multiple regression analysis, walk distance was predicted by age and FVC (r2 = 0.50), Mean SpO2 by TLco and Base SpO2 (r2 = 0.80), and Fall SpO2 only by TLco (r2 = 0.57). Breathlessness perception was not reliably predicted by any assessed variables. CONCLUSIONS: We confirmed that 6MWT provides a global evaluation of sub-maximal exercise capacity in ILD patients. We also found that walk distance and oxygen desaturation, but not breathlessness perception during walk, are strictly related to baseline lung function.

Abstract: Cigarette smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD). However, only 10-15% of smokers develop the disease and early changes within the airways are poorly defined.We aimed to compare cell profiles in induced sputum (IS) from asymptomatic smokers to that from healthy subjects, and to ascertain whether or not inflammatory cells in IS are related to lung function and smoking habit. We recruited 34 heavy, non-allergic asymptomatic smokers with normal lung function and 15 healthy volunteers, who performed lung function tests and IS by hypertonic saline (3%) solution. In smokers, significantcorrelation between pack-years and FEF25-75 (rs = -0.43, P < 0.02) was found. In IS, smokers had higher counts of macrophages (P < 0.01) and eosinophils (P < 0.02), when compared to those of healthy subjects. Additionally, eosinophils were found in IS of 14 out of 34 smokers, with eosinophils had a higher pack-years (31 +/- 25 vs. 13 +/- 10, P = 0.02) and lower FEF 25-75% value (78% +/- 34 vs. 100% +/- 23. P < 0.04). when compared to smokers without eosinophils. Additionally, on the basis of regression equations by stepwise multiple regression analysis, eosinophils were predicted by pack-years (r2 = 0.41). Our results showed that asymptomatic smokers have evidence of inflammatory cells in IS samples. In addition, we found thatthe degree of eosinophilic inflammation is related to early changes of lung function and can be predicted by smoking habit.

Abstract: The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01).On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.

Abstract: BACKGROUND: Eosinophilic inflammation is known to play an important role in the pathogenesis of allergic diseases. Apoptosis, a form of programmed cell death, is characterized by morphologic cell changes and leads to recognition and ingestion by macrophages. Apoptosis could be an important mechanism controlling the resolution of tissue eosinophilia. OBJECTIVE: This study was designed to investigate the presence of apoptotic eosinophils in induced sputum of patients with seasonal allergic rhinitis (SAR), when examined during natural pollen exposure and of patients with perennial asthma of different degrees of severity. METHODS: We recruited 11 patients with SAR to grass pollens, 26 patients with asymptomatic asthma (AA), and 18 patients with symptomatic asthma (SA). The severity of asthma was assessed by clinical scoring. Sputum was induced following a standard method and differential cell count was estimated. Eosinophils showing cell shrinkage and nuclear coalescence were classified as apoptotic. The number of apoptotic eosinophils was expressed as the percentage of total cells in sputum and as the proportion of apoptotic eosinophils relative to normal bilobed eosinophils ("apoptotic ratio"). RESULTS: We found the number of eosinophils in the SA group was significantly greater than that in the SAR and the AA groups (P < .001 and P < .0001 respectively). The number of apoptotic eosinophils in the AA group was significantly lower than that in the SAR group (P < .001) and in the SA group (P < .0001). The apoptotic ratio for eosinophils in the SAR group was significantly greater than in the AA group (P < .05) and in the SA group (P < .05). There was no difference in the apoptotic ratio between the AA and SA groups. CONCLUSIONS: This study confirms that apoptotic eosinophils are detectable in induced sputum of allergic patients. Further, the results of our study suggest that apoptosis could be an important mechanism in the control of acute eosinophilic inflammation in patients with SAR exposed to the sensitizing antigens. It appears that the apoptotic mechanism could be less effective in controlling tissue eosinophilia in asthmatic patients with chronic eosinophilic inflammation.

Abstract: Induced sputum by inhalation of hypertonic saline solution is a noninvasive technique used to collect cellular and soluble material from lung airways. During the past decade, this method has been widely used to assess airway inflammation in asthma and chronic obstructive pulmonary disease, since it produces reliable results and compares favorably to other invasive techniques, such as biopsy and bronchoalveolar lavage (BAL). Induced sputum has been recently used to study interstitial lung disease (ILD), more specifically pneumoconiosis, sarcoidosis, and nongranulomatous ILD. Moreover, results from induced sputum supplied information comparable to BAL findings for occupational lung disease and were able to distinguish sarcoidosis patients from healthy subjects and from patients with nongranulomatous ILD. Although induced sputum had previously provided promising results in assessing patients with ILD, its diagnostic role has not yet been well defined. Further studies of the evaluation by induced sputum of grading of severity, follow-up of disease, and effects of treatment are needed. Additionally, to date no specific studies have been undertaken to evaluate the safety and functional effects of sputum induction on patients with ILD. In conclusion, we think that induced sputum can be used as a complementary tool to BAL both in research and in clinical monitoring of patients with ILD.

Abstract:

Abstract: Mucociliary clearance (MCC) is one of the most important nonspecific defense mechanisms of the respiratory tract, and its impairment is a well-documented feature of chronic respiratory diseases, including asthma. In vitro and in vivo data suggest that several inflammatory mediators influence the mucociliary apparatus. Epithelial damage and functional abnormalities have been described in bronchial asthma, along with changes in mucus-secreting cells and the chemical and rheological properties of airway fluid. Although the mechanisms of MCC impairment in asthma are not clearly understood, data in the recent literature suggest that airway inflammation plays a major role. In this article, we review studies on MCC alterations in light of up-to-date findings on pathogenetic mechanisms in asthma.

Abstract: OBJECTIVES: Sarcoidosis is characterized by a diffuse alveolar inflammatory process, although bronchial airways are often involved. This study compares the cellular profiles of induced sputum (IS), bronchial washing (BW), and BAL in newly diagnosed sarcoidosis patients to those in control subjects, and examines whether inflammatory cell counts from IS are correlated with inflammatory cell counts from BW and BAL in sarcoidosis patients. PATIENTS AND MEASUREMENTS: We recruited 15 untreated patients with stage I and II pulmonary sarcoidosis and 12 healthy volunteers. Sputum was induced with hypertonic saline solution in all individuals. Bronchoscopy was performed on a different occasion in all patients and in five control subjects. RESULTS: Mean lymphocyte counts in IS, BW, and BAL fluid from sarcoidosis patients were significantly higher than in control subjects (9.4% vs 3.8%, p < 0.05; 12.6% vs 3.9%, p < 0.05; 24.1% vs 2.6%, p < 0.05, respectively). Moreover, total cell count and percentage of epithelial cells in IS were significantly higher in sarcoidosis patients than in control subjects (p < 0.01 and p < 0.05, respectively). In sarcoidosis patients, comparison between different samples showed significantly higher percentages of macrophages in BW and BAL than in IS (p < 0.05 and p < 0.01, respectively), whereas the percentage of neutrophils was higher in IS compared with BW and BAL (p < 0.01 and p < 0.001, respectively). Finally, the percentage of lymphocytes in IS was significantly lower than that in BAL (p < 0.05) but not that in BW. CONCLUSIONS: We demonstrated that, compared with IS in healthy control subjects, IS in untreated pulmonary sarcoidosis patients contains more total cells, lymphocytes, and epithelial cells. Although the relative proportion of inflammatory cells in the three samples differed, lymphocyte counts in IS were high. This finding suggests that IS could be used as a valuable alternative to more conventional invasive techniques in clinical assessment of pulmonary sarcoidosis patients.

Abstract: BACKGROUND: Sputum production induced by inhalation of hypertonic saline solution has been proposed as a technique to collect secretions and inflammatory cells from the airways of subjects with bronchial asthma or with a history of smoking. The aim of this study was to determine the effect of a sputum induction procedure on spirometric results and arterial oxygen saturation (SaO(2)) in asthmatic patients, smokers, and healthy subjects. METHODS: We recruited 14 subjects suffering from asthma (11 men and 3 women; age range, 18 to 49 years), 14 subjects with a history of smoking (5 men and 9 women; age range, 23 to 64 years), and 9 healthy volunteers (7 men and 2 women; age range, 28 to 54 years). To obtain a sample of induced sputum, all subjects inhaled a mist of 3% hypertonic saline solution nebulized for 5 min and repeated the cycle no more than four times. Asthmatic patients were pretreated with 200 microg salbutamol (inhaled). During sputum induction, the transcutaneous SaO(2) was continuously measured and baseline, fall, and the differences between baseline and fall SaO(2) were recorded. Additionally, we measured the duration of mild desaturation (change in SaO(2), < 4%) and of marked desaturation (change in SaO(2), > 5%) in each subject. Finally, baseline FEV(1) and changes in FEV(1) as a percentage of baseline values were recorded in all subjects. RESULTS: We found that baseline and fall SaO(2) values for the three groups were similar. However, in each group a significant mean change in SaO(2) was evident during sputum production (asthmatic patients, 6.0%; smokers, 5.3%; healthy subjects, 6.0%). Moreover, the mean durations of mild desaturation were 7 min, 21 s in asthma patients; 8 min, 24 s in smokers; and 7 min, 16 s in healthy subjects. Similarly, the durations of marked desaturation were 1 min, 25 s in asthmatic patients, 1 min, 19 s in smokers, and 1 min, 21 s in healthy subjects. The mean (+/- SD) fall in FEV(1) was not statistically different among the three groups (asthmatic patients, 1.36 +/- 5.6%; smokers, 7.58 +/- 11.76%; and healthy subjects, 0.05 +/- 9.6%). However, one smoker did experience excessive bronchoconstriction (fall in FEV(1), > 20%). CONCLUSIONS: This study demonstrated a significant and comparable fall in SaO(2) during sputum induction by inhalation of hypertonic saline solution in asthmatic patients, smokers, and healthy subjects. The results suggest that subjects who are hypoxemic before sputum induction require SaO(2) monitoring during the procedure.

Abstract: We studied the relationship between personality profiles, breathlessness perception and clinical and functional features in 36 outpatient asthmatics (12 females; age range: 18-52 yr). Each patient underwent psychometric evaluation with Minnesota Multiphasic Personality Inventory (MMPI). Breathlessness perception was evaluated by Borg's scale during methacholine (M) challenge, and PS20 (the perception score obtained when FEV1 fell by 20%) was recorded. Baseline FEV1 values ranged from 70.0 to 126%. PC20 M values ranged from 0.05 to 31.7 mg/ml. According to a symptoms score system (0 to 12 points), 12 asthmatics were classified as mild, 12 as moderate, and 12 as moderate/severe. We did not find any specific personality profile in asthmatic patients. Sixteen asthmatics had at least one MMPI subscale score indicative of psychological disturbances. We found a significant trend from mild to moderate and moderate/severe asthmatics (p < 0.015), when the number of asthmatics with subscale scores indicative of psychological disturbances was compared to that of asthmatics with normal scores. Moreover, we found that the asthmatics with scores indicative of hypochondriasis showed a significant trend from mild to moderate and moderate/severe asthma (p < 0.015). Furthermore, in all asthmatic patients, hypochondriasis scores were positively correlated to asthma severity score (p < 0.02). PS20 values ranged from 0.1 to 8.1. Twelve asthmatics were hypoperceivers (PS20 < or = 1) and four were hyperperceivers (PS20 > or = 5). We observed a significant trend from mild to moderate and moderate/severe asthmatics (p < 0.025) when we compared the number of hypoperceivers to that of normoperceivers. In conclusion, we found that in outpatients with different grading of asthma, severity of disease is linked to psychological disturbances and poor perception of breathlessness, additionally, hypochondriasis was related to disease severity in all patients.

Abstract: BACKGROUND AND OBJECTIVE: Antigen processing determines the production of peptides from antigens - including allergens - and their binding to class II major histocompatibility complex molecules, that stimulate T-cell responses. Heat shock protein (hsp) 70 are recognized to have a role in chaperoning antigenic peptides and in facilitating class II peptide assembly. We studied the HLA-DR and hsp70 expression on BAL cells and bronchial biopsies from asthmatics, as well as the effect of low dose fluticasone propionate treatment. METHODS: Twenty-three asthmatics and eight normal subjects were selected. In each subject BAL and bronchial biopsies were performed. Eighteen out of 23 asthmatics, underwent the second bronchoscopy after 6 weeks of low dose inhaled fluticasone propionate treatment (250 microg b.d.) in a placebo-controlled double-blind study. BAL fluid and biopsies were processed to evaluate HLA-DR and hsp70 expression by immunochemistry methods. RESULTS: Hsp70 and HLA-DR upregulation was present on professional and non-professional antigen presenting cells (APCs). In asthmatics, the hsp70 and HLA-DR expression was higher in BAL (hsp70 P<0.001, HLA-DR P<0.001) and bronchial epithelium (hsp70 P<0.001, HLA-DR P<0.001) when compared with controls. We also observed a significant correlation between hsp70 and HLA-DR expression in BAL (P<0.005) and epithelium (P<0.001). Fluticasone propionate treatment down-regulated the hsp70 and HLA-DR expression in BAL (hsp70 P < 0.001, HLA-DR P < 0.05) and bronchial epithelium (hsp70 P < 0.05, HLA-DR P < 0.05). A serial section comparison study showed that CD1a+ cells and macrophages were positive for both hsp70 and HLA-DR in the submucosa. CONCLUSIONS: Our results support the hypothesis that hsp70 over-expression implies a potential role for these proteins in antigen processing and/or presentation resulting in an increased activity of APCs, which is essential for the initiation and modulation of the asthmatic immune response in chronic asthma. Fluticasone propionate induces downregulation of HLA-DR and hsp70 molecules thus regulating inflammation by affecting key mechanisms of the allergic response.

Abstract: Lung epithelial permeability of asthmatic patients has been reported to be similar or lower than that of healthy subjects and to be correlated or not to bronchial hyperresponsiveness. To clarify these discrepancies, we evaluated 99mTc-DTPA pulmonary clearance in a group of carefully selected asthmatic patients with mild, stable asthma (n = 13; seven women; mean age +/- SD = 27.69 +/- 6.63 years), and compared them with a group of healthy, nonsmoking subjects (n = 8; six women; mean age +/- SD = 24.38 +/- 5.15 years). Selection criteria for asthmatics were as follows: baseline FEV1 > or = 80% of predicted values, no bronchial infections, and/or no asthma attacks during 4 weeks prior to study and peak expiratory flow rate variability lower than 20%, over a period of 3 weeks. Patients controlled symptoms with beta 2-adrenergic drugs only, regularly or on demand. Mean baseline FEV1 (+/-SD) as percent of predicted was 102.38 +/- 13.97 and 112.88 +/- 18.36, respectively (p < 0.05). In the asthmatic group, bronchial responsiveness to methacholine (PC20 M FEV1) ranged between 0.55 and 28.5 mg/mL. Mean value (+/-SD) of DTPA clearance from lungs to blood (evaluated on the first 10 min out of 30 min of the curves) in the asthmatic group was not different from that of control group (68.31 +/- 21.46 and 69.5 +/- 15.73). In the asthmatic patients, there was no correlation between PC20 M values and DTPA T1/2 min of the whole lung, nor between PC20 M and inner and outer lung clearance zones. Moreover, both in asthmatics and healthy subjects, DTPA clearance of outer (alveolar) zones was significantly faster than that of inner (bronchial) zones (57.69 +/- 19.94 vs 102.08 +/- 38.19, p < 0.001, and 59.75 +/- 12.49 vs 103.5 +/- 31.86, p < 0.003, respectively). Our data show that DTPA clearance in patients with stable asthma is similar to that found in healthy subjects; it is not correlated to degree of bronchial responsiveness and occurs more rapidly in the outer zones than in the inner zones, both in asthmatic patients and in healthy subjects. Thus, to date, DTPA clearance index is not a valid tool for identifying and/or monitoring asthmatic patients.

Abstract: PURPOSE: Airways remodeling, evaluated as the subepithelial layer thickness, was compared in asthmatic patients with that of healthy subjects, and was related to clinical grading of disease, presence of atopy, and length of asthmatic history. SUBJECTS AND METHODS: Thirty-four patients with stable asthma (mean age+/-SD: 26.5+/-9.2 years; 10 female) treated with only inhaled beta2-agonists and eight healthy volunteers (mean age+/-SD: 24.6+/-2.5 years; four female) were recruited for the study. Twenty-seven of 34 asthmatics had atopy. Eleven patients had newly diagnosed conditions (duration of disease < or = 1 year), nine patients had long asthmatic history (> 1 year and < or = 10 years), and 14 had prolonged asthmatic history (> 10 years). Bronchial responsiveness to methacholine (M) was expressed as provocative concentration of M causing a 20% fall in FEV1 (PC20) (mg/mL). Degree of asthma severity was assessed using a 0- to 12-point score based on symptoms, bronchodilator use, and daily peak expiratory flow variability over a 3-week period. Bronchoscopy and bronchial biopsy were performed successfully for all subjects; the subepithelial layer thickness, in biopsy samples, was measured from the base of bronchial epithelium to the outer limit of reticular lamina. RESULTS: In asthmatics, baseline FEV1 values (percent of predicted) ranged from 75.7 to 137.0%, and PC20 M ranged from 0.15 to 14.4 mg/mL. According to the asthma severity score, 14 asthmatics were classified as having mild disease, 14 as having moderate disease, and six as having severe disease. The mean values of subepithelial layer thickness were 12.4+/-3.3 microm (range, 6.8 to 22.1 microm) in asthmatics, and 4.4+/-0.5 microm (range, 3.8 to 5.2 microm) in healthy subjects (p<0.001). Subepithelial layer thickness of those with severe asthma differed significantly from that of patients with moderate and mild asthma (16.7+/-3.1 microm vs 12.1+/-2.7 microm and 10.8+/-2.4 microm, p<0.01 and p<0.003, respectively). Moreover, in asthmatics, degree of thickening was positively correlated to asthma severity score (Spearman rank correlation coefficient [rs]=0.581; p<0.001), and negatively correlated with baseline FEV1 (rs=-0.553; p<0.001) and PC20 M (rs=-0.510; p<0.01). No difference was found between degree of thickening observed in atopic asthmatics, compared with that of nonatopic asthmatics, or between degree of thickening in patients with different lengths of asthmatic history. Lastly, multiple regression analysis revealed that asthma severity score was the significant predictive factor for thickness of subepithelial layer. CONCLUSIONS: We confirmed that airways remodeling is a very distinctive and characteristic pathologic finding of asthma. We also demonstrated that it is related to the clinical and functional severity of asthma, but not to atopy or length of asthmatic history.

Abstract: In a double-blind, parallel-group study, we examined the effect of short-term treatment with inhaled fluticasone propionate (FP) in a group of 20 nonsmoking asthmatic patients who required only beta2-agonists to control their symptoms. We administered FP (250 microg twice daily) or matched placebo for 6 wk. Methacholine challenge was performed before treatment, after 3 wk, and at the end of treatment. Each patient underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy before and after treatment. Eight patients in the placebo group and nine patients in the FP group completed the study. Bronchial responsiveness to methacholine decreased significantly only after 6 wk of treatment with FP (p < 0.05). When we compared the FP group with the placebo group, we observed a significant decrease only in the number of cells expressing intracellular adhesion molecule-1 (ICAM-1) and MAC-1 (p < 0.04 and p < 0.03, respectively). Moreover, we saw that the tryptase level in BAL decreased (p < 0.001), whereas the eosinophil cationic protein (ECP) level did not change significantly. Additionally, the number of eosinophils and mast cells in the lamina propria in bronchial biopsies specimens was significantly smaller in the FP group than in the placebo group (p < 0.02 and p < 0.01, respectively). Additionally, in the FP group, we found that basement-membrane thickness was significantly decreased when compared with that of the placebo group (p < 0.05). In conclusion, our results show that short-term treatment with low-dose FP reduces inflammatory cell infiltration into the lamina propria in bronchial biopsy specimens. Moreover, short-term low-dose FP treatment might control the intensity of airway remodeling in mild asthma.

Abstract: The activation of T-lymphocytes through the recognition of specific allergens is a crucial event in the development of allergic inflammation. Dendritic cells (DC) are potent accessory cells that play an important role in initiating bronchial immune responses by activation of T-lymphocytes. We investigated the distribution of CD1a+ DC in the bronchial biopsies from asthmatic patients, and evaluated the effects of a short course of low dose inhaled fluticasone propionate treatment. Twenty-three mild to moderate stable asthmatic patients and eight normal subjects were included in the study. Bronchoscopy with bronchial biopsies were performed in each subject. Eighteen of the 23 asthmatics underwent a second bronchoscopy after 6 weeks of low dose inhaled fluticasone propionate treatment (250 mcg bd) in a placebo-controlled double-blind study. Biopsies were embedded into glycolmethacrylate resin and analysed by immunohistochemistry methods using specific monoclonal antibodies against CD1a, which is a widely recognized marker for DC. In asthmatics, CD1a+ DC number was significantly higher in bronchial epithelium (P < 0.001) and in lamina propria (P < 0.001) when compared with normal controls. In addition, we observed that a short course of low dose inhaled fluticasone propionate treatment decreased the number of CD1a+ DC in both the bronchial epithelium (P < 0.05) and lamina propria (P < 0.01). The increased number of CD1a+ DC support the hypothesis that DC play an important role in the modulation of the immune response in chronic asthma. Short-term low dose fluticasone propionate treatment induces down-regulation of the CD1a+ DC number.

Abstract: OBJECTIVES: We attempted to determine whether inflammation is present in induced sputum of patients with seasonal allergic rhinitis (AR) as compared with those with perennial asthma (AS) and examined its relationship with bronchial responsiveness to methacholine. METHODS: Sputum was induced in 30 patients with seasonal rhinitis in response to grass pollens only and in 15 patients with stable, asymptomatic asthma. The AR group was divided according to methacholine PD20 value: the AR- group (n = 15) had a methacholine PD20 greater than 24 micromol; the AR+ group (n = 15) had a methacholine PD20 ranging between 2.2 and 19.6 micromol. In the AS group, methacholine PD20 ranged between 0.42 and 2.6 micromol. The percentage of eosinophils and metachromatic cells (alcian blue-positive) was assessed in sputum by light microscopy. Tryptase-positive cells and EG2+ cells were identified by immunocytochemistry with the mouse anti-human mast cell-tryptase monoclonal antibody and the monoclonal anti-eosinophil cationic protein antibody. RESULTS: We found that the number of eosinophils in the AS group was greater than that in the AR+ group (p < 0.05) and in the AR- group (p < 0.01). Moreover, the eosinophil count was lower in the AR- group compared with the AR+ group (p < 0.05). Similarly, the number of EG2+ cells was greater in the AS group than in the AR group (p < 0.02) and the AR- group (p < 0.05). Moreover, the EG2+ cell count was lower in the AR- group than in the AR+ group (p < 0.05). The number of mast cells and basophils in the AS group was greater than that in the AR group (p < 0.05 and p < 0.01, respectively). Mast cells in sputum were tryptase-positive. Basophils were present in sputum from 23% of patients with AR and 53% of patients with asthma. There was a significant correlation between methacholine PD20 and eosinophils (p < 0.005) and mast cells (p < 0.02) but not with basophils in those patients showing a measurable methacholine PD20 (AR+ and AS groups). CONCLUSIONS: Inflammatory cells are present not only in the airways of patients with asthma but also in airways of patients with seasonal AR, even outside natural exposure. Moreover, we provide evidence for the presence of basophils in sputum of patients with asthma even during clinical remission. The presence of bronchial responsiveness is associated with an increase in the number of eosinophils and metachromatic cells. Our findings are consistent with the hypothesis that eosinophils, as well as mast cells, contribute to bronchial responsiveness not only in AS but also in seasonal AR.

Abstract: Although bronchial hyperresponsiveness in asthma is associated with inflammation within the airways, it is not known whether the degree and type of inflammation influence the response to different stimuli and whether pathologic changes of airway structure influence the bronchoconstrictive responses. Therefore, number of inflammatory cells in the epithelium and the lamina propria and the basement membrane thickness were estimated from bronchial biopsies taken in 27 asthmatic subjects (range percent predicted FEV1: 75.6 to 132.1, range of daily PEF variability: 1.9% to 20%) and related to the degree of bronchial responsiveness to ultrasonically nebulized distilled water (UNDW) and methacholine (M). PD20UNDW (provocative dose) was measurable in 15 of 27 patients and ranged between 1.01 and 20.4 ml. PC20M (provocative concentration) ranged between 0.15 and 31.7 mg/ml. In the 15 responders to UNDW, total inflammatory cells (p<0.04) and eosinophils (p<0.015) within the epithelium were higher than in 12 nonresponders to UNDW (PD20 > 34.8 ml). There was no correlation between PD20UNDW and any cell counts whereas negative correlations were found between PC20M and both total inflammatory cells (rs = -0.57; p<0.005) and eosinophils (rs = -0.63; p< 0.0015) within the epithelium. The degree of thickening of subepithelial layer ranged between 7 and 16 micrometers+ (n=26). Thickness correlates both with total inflammatory cells (rs = 0.49; p<0.025) and eosinophils (rs = 0.61; p< 0.003) within the epithelium. Moreover, it was correlated with baseline FEV1 (rs = -0.57; p<0.003) and daily peak expiratory flow (PEF) variability (rs = 0.51; p<0.01). A weak but significant correlation was also found between subepithelial layer thickness and PC20M (rs = -0.42; p<0.04). The results of this study demonstrate that eosinophilic inflammation of bronchial epithelium plays a role in determining UNDW and M responsiveness in asthma. Moreover, they suggest that remodeling of the airways such as thickening of subepithelial layer correlates with indices of asthma severity and could contribute to the degree of M but not to UNDW responsiveness.

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Abstract: The tolerability and the duration of effect of 12 micrograms of formoterol and 25 micrograms of procaterol administered via metered-dose aerosol to 12 stable asthmatic patients were evaluated in a double-blind, placebo controlled trial. FEV1, pulse rate, and blood pressure were measured at baseline and every two hours after dosing for 12 hours. The bronchodilation peak was observed after two hours for both drugs. Formoterol induced a significant bronchodilating effect for 12 hours compared with both baseline and placebo values. With procaterol, significant bronchodilation occurred for six hours compared with baseline values and four hours compared with placebo. No significant changes were observed in pulse rate and blood pressure with either drug. Four subjects complained of muscle tremor after procaterol administration. We conclude that in subjects with stable asthma, inhaled formoterol at a dose of 12 micrograms maintains significant bronchodilation for 12 hours after dosing and is very well tolerated. Further studies are required to evaluate effectiveness and tolerability of high dose formoterol treatment in acute severe asthma therapy.

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Abstract: We conducted a randomized, double-blind, placebo-controlled study on the effect of disodium cromoglycate (DSCG) and nedocromil sodium (NED) on propranolol-induced bronchoconstriction (PIB) in 12 asthmatic subjects 10 to 53 years of age. Placebo (saline solution) and active drugs (10 mg) were aerosolized 30 minutes before bronchoprovocation with inhaled propranolol. Bronchial response to propranolol was expressed as the cumulative dose provoking a 20% fall in FEV1 (PD20P) and given in mumol. Reproducibility of PD20P was estimated before and after the days of study. PD20P varied within two doubling doses. Disodium cromoglycate and NED had no significant effect on baseline lung function. Although, geometric mean PD20P values (+/- GSEM) recorded after DSCG (7.24 mumol +/- 1.31) and after NED (9.22 mumol +/- 1.26) were higher than values recorded after placebo (6.55 mumol +/- 1.31), these differences were not statistically significant. A greater than 2-fold increase in PD20P was noted after NED in three subjects and in one subject after DSCG. We conclude that both DSCG and NED only modestly alter PIB, with some between subject differences.

Abstract: Inhaled propranolol (P) was administered to a population which included asthmatic children (30 subjects) and adults (43 subjects): 1) to investigate the determinants of induced bronchial response; 2) to examine the relationship with treatment requirements; 3) to determine the relationship with responsiveness to methacholine (M) and ultrasonically nebulized distilled water (UNDW) (50 subjects); and 4) to establish the short-term repeatability of bronchial response to propranolol compared with methacholine (22 subjects). Bronchial response to propranolol and methacholine was expressed as the cumulative provocative dose (PD20 in mumol) and responsiveness to UNDW as the provocative output (PO20 in ml.min-1) producing a 20% fall in forced expiratory volume in one second (FEV1). Response to propranolol was significantly related to the degree of responsiveness to methacholine, but not to age, gender, presence of atopy, age at asthma onset, or baseline FEV1. PD20P was measurable in all but three subjects. A significant difference in mean PD20M but not in PD20P was found between subjects requiring more anti-asthmatic treatments compared to those without therapy. The difference between geometric mean PD20P and geometric mean PD20M was 14.1. PO20UNDW was measurable in only 21 out of 50 subjects. Both PD20P and PD20M were significantly lower in responders to UNDW than in nonresponders. Reproducibility of PD20P was comparable to that of PD20M (coefficients of repeatability: 1.17 and 1.09). We conclude that bronchial responsiveness to propranolol is safely measurable in most children and adults with asthma. Repeatability of bronchial response to propranolol is comparable to that of methacholine. Moreover, responsiveness to propranolol is not a predictor of treatment requirement.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: We examined the staining characteristics and degranulation of mast cells in bronchial biopsy specimens taken by fiberoptic bronchoscopy from 13 stable asthmatic patients and eight normal nonsmoking subjects. Specimens were fixed in periodate-lysine-paraformaldehyde, embedded in glycol methacrylate, and stained with toluidine blue (2%) for 30 min (pH 2.7) and 7 days (pH 0.5). The number of mast cells in the epithelium and in the lamina propria was counted under light microscopy. In addition, the distribution of mast cells with different granule contents, arbitrarily defined as degranulated or partly degranulated and fully granulated, was estimated at the two levels. In asthmatic subjects, the number of mast cells in the epithelium after either staining method was significantly higher compared with that in control subjects. The number of mast cells in the lamina propria, but not in the epithelium, was significantly higher after 7 days compared with 30-min toluidine blue stain both in asthmatic (135.6/mm2 versus 74.8/mm2; p < 0.001) and control subjects (121.5/mm2 versus 71.5/mm2; p < 0.01). There was evidence of a progressive mast cell degranulation when moving toward the airway lumen in both groups. However, degranulation was more evident in asthmatic subjects. In both groups, granulated mast cells were absent in the epithelium, whereas in the lamina propria granulated mast cells were approximately one-third of total in asthmatic and two-thirds of total in normal subjects. These observations suggest that mast cells in human bronchial mucosa are heterogeneous with respect to histochemical characteristics. They provide evidence that degranulation of mast cells occurs in both asthmatic and normal subjects and that degranulation is greater in asthmatics.

Abstract: We evaluated tolerance, safety, and effects on lung function and bronchial responsiveness of BAL (4 x 50 ml) combined with BB (three to five specimens) performed without premedication in 13 mild and stable asthmatics and eight healthy volunteers. All subjects tolerated bronchoscopy procedures well and without serious side effects. During procedures, no supplemental oxygen was administered and no ECG abnormalities were noted. The PEFR was measured before and immediately after bronchoscopy and at 5-min intervals up until recovery. The maximal percentage fall in PEFR after bronchoscopy was significantly greater in asthmatics (23.1 +/- 13.9 percent) compared to normal subjects (7.8 +/- 8.2 percent, p less than 0.01). Changes in PEFR returned to baseline values within 120 min in all asthmatics. The tcPO2 was recorded at baseline, during and after bronchoscopy. In both groups, a significant change in tcPO2 was measured during the infusion of BAL aliquots, and persisted throughout the procedure. A significant difference in asthmatics compared to healthy subjects was evident during BB and at the end of the procedure (p less than 0.05). In asthmatics, M challenge was performed on three different days over a three-week period prior to bronchoscopy, and was repeated at intervals of 2, 6, and 24 h following procedure. The PC20 M values measured before bronchoscopy were found to have a very high reproducibility (intraclass correlation coefficient = 0.93). The PC20 values measured during experiment times after bronchoscopy were not significantly different from baseline values. These data demonstrate that in mild and stable asthmatics, BAL combined with BB can be safely performed following administration of only local anesthesia. In carefully selected asthmatic subjects, transient bronchoconstriction and a lowering of oxygen tension can be induced by BAL and BB, whereas changes in bronchial responsiveness are more unlikely to occur.

Abstract: We examined the pattern and degree of the inflammatory process in bronchial biopsy specimens taken by fiberoptic bronchoscopy in eight asthmatic subjects (two women aged 19-38 years) after 5 years of specific immunotherapy (SIT) to mite extracts (SIT group). At the time of study, they received a maintenance dose of mite-extracts (last subcutaneous administration 3 weeks before bronchoscopy). Results were compared with those found in eight matched mite-sensitive subjects with stable asthma (two women aged 19-36 years; non-SIT group) and in eight healthy individuals (four women aged 22-29 years; control group). Bronchial biopsy specimens were fixed in periodate-lysine-paraformaldehyde, embedded in glycol methacrylate, and stained with hematoxylin-eosin and 2% toluidine blue. Number of eosinophils, mast cells, and total nucleated cells were counted separately in the epithelium and lamina propria by light microscopy and expressed as cells/high power field. Within the epithelium, eosinophil and mast cell counts in SIT and non-SIT groups were significantly higher compared to controls, whereas total cell counts were not statistically different. Within the lamina propria, total cell count in SIT and non-SIT groups was significantly higher compared with the control group, whereas mast cells were similar. The number of eosinophils in both SIT and non-SIT groups was higher compared with controls; however this reached statistical significance only in SIT-groups. Comparison between the two groups of asthmatics did not show any significant difference for any cell counts.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Bronchoalveolar lavage and BB were performed in 13 asthmatic and six healthy subjects to characterize cellular markers of inflammation in BAL and BB; to compare cellular profile of BAL with cell infiltration in BB; to examine the relationship between bronchial responsiveness and markers of inflammation in BAL and BB. Eosinophils and mast cells were increased in BAL in asthmatic subjects; eosinophils were positively correlated with neutrophils and mast cells. Epithelial shedding was present in nine asthmatic and five control subjects. Intraepithelial cells and cells in submucosa were increased in asthmatic subjects. Eosinophils and intraepithelial mast cells were higher. Thickened basement membrane was associated with more marked cell infiltration in submucosa. Ciliated cells in BAL relate to intraepithelial cells; cells in BAL broadly reflect cell infiltration of submucosa. In the asthmatic group, the degree of bronchial responsiveness correlated with ciliated cells in BAL and with intra-epithelial cells in BB. Marked airway inflammation is associated with stable asthma; inflammatory changes within bronchial epithelium may be linked to the development of bronchial hyperresponsiveness.

Abstract: Inflammatory events involve the airways in asthma. Bronchial inflammation can induce and maintain both variable airflow obstruction and bronchial hyperresponsiveness. The rationale of asthma therapy is, therefore, to use drugs which prevent and reduce the inflammation. The control of asthmatic inflammation needs specific management. Interestingly, if corticosteroids are effective, non-steroidal anti-inflammatory drugs have a negligible effect. On the other hand, sodium cromoglycate and ketotifen can act on bronchial inflammation. Moreover, in well-selected patients, immunotherapy and a strict environmental prophylaxis can play a key role in long-term therapy. In asthmatics, a careful control of inflammation can protect airways from irreversible bronchial obstruction and return bronchial hyperresponsiveness to within the range of clinical well-being.

Abstract: In order to determine the bronchodilating activity and safety of two beta-2-receptor agonists, broxaterol and procaterol, compared with a placebo, 12 patients with reversible airway obstruction were tested in a double-blind cross-over study. The drugs were administered orally and the dosage of broxaterol was 0.5 mg, that of procaterol 0.05 mg. Measurements of forced expiratory volume in 1 s (FEV1), heart rate and blood pressure were performed before and 30, 60, 120, 240, 360, and 480 min after each treatment. Both drugs produced bronchodilation but broxaterol was statistically 30 min faster in producing this effect than procaterol (p less than 0.05). Moreover this effect for both drugs persisted significantly for up to 480 min compared with the effect of the placebo (p less than 0.005). There were no significant side effects with either drug. Heart rate and blood pressure did not show any changes in clinical significance for broxaterol or procaterol. In our study, broxaterol showed a faster bronchodilating effect than procaterol, and tolerance was the same for both drugs.

Abstract: Bronchial challenges with bronchoconstrictive drugs have supplied important information on some relevant pathophysiological aspects of bronchial asthma, i.e. nonspecific bronchial hyperresponsiveness. Until now histamine and methacholine have been the most widely used inhalation tests. Recently, propranolol, given by inhalation, has been proposed and evaluated for possible application as a bronchial provocation challenge both in clinical and experimental setting. In asthmatic subjects with bronchial hyperresponsiveness to histamine and methacholine, inhaled propranolol induces a dose-related bronchoconstriction. In a group of 25 asthmatic patients, the mean value of provocative doses, in mumoles of propranolol that causes a 20% drop in FEV1 (PD20FEV1), is thirteen times greater than that of methacholine. In the same study, there is no correlation between the bronchial responses to the two drugs. Moreover, none of 9 normal subjects of the control group responds to inhaled propranolol. The mechanisms of propranolol-induced bronchoconstriction are poorly understood. A cholinergic reflex is probably involved, but it is likely that propranolol has some different and rather peculiar pathways. Bronchial response to inhaled propranolol is a reliable, reproducible, safe, and well-tolerated method. Bronchoconstriction induced by propranolol appears to be a very promising technique in the investigation of the mechanisms of nonspecific bronchial hyperresponsiveness.

Abstract: This study was carried out to compare bronchial responses to inhaled propranolol (P) and methacholine (M) in a group of asthmatic subjects with mild to moderate bronchial hyperresponsiveness to M; to determine the short term reproducibility of bronchial response to propranolol; and to examine the shape of dose-response curve to P relative to that of M. Doses of M and P were given in mumoles and bronchial responses to both agents were expressed as the provocative dose that induced a 20 percent fall in FEV1 (PD20 FEV1). In 16 asthmatic patients, there was no correlation between the PD20 of the two agents. Mean PD20 M (+/- SD in log scale) was approximately nine times lower than mean PD20 P (0.64 +/- 0.96 and 5.80 +/- 1.65, respectively). This difference was statistically significant (t = 4.58, p less than 0.001). In six asthmatic patients, the reproducibility of PD20 P was similar to that of M (intraclass correlation coefficient 0.969 and 0.957, respectively). The shape of the dose-response curves to P was different from that of M in five of nine asthmatic patients when all experimental points were analyzed by double-reciprocal plot. We noticed that even small doses of inhaled P may cause a severe bronchoconstriction. Therefore, special caution should be taken to increase P doses very gradually, when studying the dose-response curve. We demonstrated that P inhalation induced a measurable bronchoconstriction in subjects with mild to moderate hyperresponsiveness and it was reproducible. However, the bronchial sensitivity to P was lower than to M. Our findings suggest that P and M have different mechanisms of action.

Abstract: Retrosternal hernia (Morgagni-Larrey) is the less frequent of diaphragmatic defects. Nevertheless its frequency is probably more elevated than commonly believed because very often there is a lack of symptoms. The clinical case which is referred has a typical presentation but it is outlined the difficult interpretation of routine chest x-rays, while a prompt diagnostic suspicion is not always present. Surgical repair is the discussed emphasizing the very good results within a virtual absence of recurrences.