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Background: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented., Research Question: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography?, Study Design and Methods: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLC Pleth ) was compared with TLC measured by the MiniBox (TLC MB )., Results: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLC Pleth and TLC MB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers., Interpretation: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose : There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design : From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results : We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions : Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.

Background: At least 30% of patients with primary resectable non-small cell lung cancer (NSCLC) will experience a relapse in their disease within 5 years following definitive treatment. Clinicopathological predictors have proved to be suboptimal in identifying high-risk patients. We aimed to establish whether inflammation-based scores offer an improved prognostic ability in terms of estimating overall (OS) and recurrence-free survival (RFS) in a cohort of operable, early-stage NSCLC patients., Methods: Clinicopathological, demographic and treatment data were collected prospectively for 220 patients operated for primary NSCLC at the Hammersmith Hospital from 2004 to 2011. Pretreatment modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were tested together with established prognostic factors in uni- and multivariate Cox regression analyses of OS and RFS., Results: Half of the patients were male, with a median age of 65. A total of 57% were classified as stage I with adenocarcinoma being the most prevalent subtype (60%). Univariate analyses of survival revealed stage (P<0.001), grade (P=0.02), lymphovascular (LVI, P=0.001), visceral pleural invasion (VPI, P=0.003), mGPS (P=0.02) and NLR (P=0.04) as predictors of OS, with stage (P<0.001), VPI (P=0.02) and NLR (P=0.002) being confirmed as independent prognostic factors on multivariate analyses. Patients with more advanced stage (P<0.001) and LVI (P=0.008) had significantly shorter RFS., Conclusions: An elevated NLR identifies operable NSCLC patients with a poor prognostic outlook and an OS difference of almost 2 years compared to those with a normal score at diagnosis. Our study validates the clinical utility of the NLR in early-stage NSCLC.

Background and Purpose: Domiciliary nebulisers are widely used in chronic obstructive pulmonary disease (COPD) but nebuliser cleaning practice has not been assessed in patients with COPD who are often elderly and may have severe disease and multiple comorbidities. We aimed to evaluate microbial contamination of home nebulisers used by patients with COPD., Methods: Random microbiological assessment of domiciliary nebulisers was undertaken together with an enquiry into cleaning practices. We also examined the effectiveness of the trust-wide cleaning instructions in eradicating isolated microorganisms in a laboratory setting., Results: The mean age of patients in this study was 71 (range 40-93) years, and in 68% of patients a large number of significant comorbidities were present. Forty-four nebuliser sets were obtained and 73% were contaminated with microorganisms at >100 colony forming units/plate. Potentially pathogenic bacteria colonised 13 of the 44 nebulisers (30%) and organisms isolated included Pseudomonas aeroginosa, Staphylococcus aureus, multidrug resistant Serratia marcesans, Escherichia coli and multiresistant Klebsiella spp, Enterobacteriaceae and fungus Fusarium oxysporum. Washing of nebuliser masks, chambers and mouthpieces achieved complete eradication of Gram-positive bacterial and fungal flora. Gram-negative organisms were incompletely eradicated, which may be attributed to the presence of biofilms. We also found that in patients with pathogenic organisms cultured on the nebuliser sets, there was a higher probability of occurrence of a COPD exacerbation with a mean number of exacerbations of 3.3 (SD=1) per year in the group in whom pathogens were isolated compared with 1.7 (SD=1.2) exacerbations per year in those whose sets grew non-pathogenic flora (p=0.02)., Conclusions: Nebulisers contaminated with microorganisms are potential reservoirs delivering serious pathogens to the lung. Relationships between nebuliser contamination, clinical infection and exacerbations require further examination, but is a potential concern in elderly patients with COPD with comorbidities who fail to effectively maintain reasonable standards of nebuliser cleanliness.

Objective: We compared the efficacy of noninvasive ventilation with bilevel positive airway pressure added to usual care versus usual care alone in patients undergoing coronary artery bypass grafting., Methods: We performed a 2-group, parallel, randomized controlled trial. The primary outcome was time until fit for discharge. Secondary outcomes were partial pressure of carbon dioxide, forced expiratory volume in 1 second, atelectasis, adverse events, duration of intensive care stay, and actual postoperative stay., Results: A total of 129 patients were randomly allocated to bilevel positive airway pressure (66) or usual care (63). Three patients allocated to bilevel positive airway pressure withdrew. The median duration of bilevel positive airway pressure was 16 hours (interquartile range, 11-19). The median duration of hospital stay until fit for discharge was 5 days for the bilevel positive airway pressure group (interquartile range, 4-6) and 6 days for the usual care group (interquartile range, 5-7; hazard ratio, 1.68; 95% confidence interval, 1.08-2.31; P = .019). There was no significant difference in duration of intensive care, actual postoperative stay, and mean percentage of predicted forced expiratory volume in 1 second on day 3. Mean partial pressure of carbon dioxide was significantly reduced 1 hour after bilevel positive airway pressure application, but there was no overall difference between the groups up to 24 hours. Basal atelectasis occurred in 15 patients (24%) in the usual care group and 2 patients (3%) in the bilevel positive airway pressure group. Overall, 30% of patients in the bilevel positive airway pressure group experienced an adverse event compared with 59% in the usual care group., Conclusions: Among patients undergoing elective coronary artery bypass grafting, the use of bilevel positive airway pressure at extubation reduced the recovery time. Supported by trained staff, more than 75% of all patients allocated to bilevel positive airway pressure tolerated it for more than 10 hours., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Metastatic diffusion is a major adverse prognostic determinant in lung cancer, that is ultimately responsible for significant morbidity, organ failure and death. Chemokine signaling pathways are known to guide site-specific metastatic spread in solid tumours. However, little is known about the contribution of CX3CR1 in the systemic dissemination of lung cancer. Syngeneic primary lung cancer/metastasis tissue microarray slides were constructed using 98 post-mortem specimens taken from patients with untreated lung cancer and immunostained for CX3CR1. Clinicopathological correlation between CX3CR1 expression and patient demographics, tumour histology, stage and pattern of metastatic spread was performed using χ2 test. CX3CR1 immunopositivity was significantly higher in non-small cell lung cancer (NSCLC) compared to small cell (SCLC) primary (p<0.001) and secondary tumours (p<0.001), with >75% of the metastatic sites staining positively in NSCLC. CX3CR1 positivity was significantly associated with stage and number of metastatic sites (p=0.03). At patients' death CX3CR1-negative lung adenocarcinomas were more likely to have spread to the brain and the liver (p=0.01). CX3CR1 is upregulated in NSCLC metastatic disease and its expression in primary lung tumours relates inversely to organotropic spread of cancer cells to the brain and the liver.

We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagen-based three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.

Airlines commonly report respiratory in-flight emergencies; flight outcomes have not been examined prospectively in large numbers of respiratory patients. The current authors conducted a prospective, observational study of flight outcomes in this group. UK respiratory specialists were invited to recruit patients planning air travel. Centres undertook their usual pre-flight assessment. Within 2 weeks of returning, patients completed a questionnaire documenting symptoms, in-flight oxygen use and unscheduled healthcare use. In total, 616 patients were recruited. Of these, 500 (81%) returned questionnaires. The most common diagnoses were airway (54%) and diffuse parenchymal lung disease (23%). In total, 12 patients died, seven before flying and five within 1 month. Pre-flight assessment included oximetry (96%), spirometry (95%), hypoxic challenge (45%) and walk test (10%). Of the patients, 11% did not fly. In those who flew, unscheduled respiratory healthcare use increased from 9% in the 4 weeks prior to travel to 19% in the 4 weeks after travel. However, when compared with self-reported data during the preceding year, medical consultations increased by just 2%. In patients flying after careful respiratory specialist assessment, commercial air travel appears generally safe.

Objective: chronic obstructive pulmonary disease (COPD) prevalence steadily increases with age. However, the effectiveness of inhaled therapy in the elderly COPD population has rarely been formally evaluated. We studied a group of elderly patients with COPD with a range of severity, selected from one General Practice register to measure peak inspiratory flow (PIF) and assess patient perceived benefit., Methods: we recruited 53 randomly selected elderly patients with COPD (36 males) with a mean age of 73.5 years (range 65-89 years). The evaluation consisted of (i) information obtained from directed questions and (ii) objective measurements of the ability to generate adequate PIF for a variety of inhalers. Patients answered questions regarding ease of use, perceived benefit from and specific problems encountered with their inhaler. Three recordings of PIF were measured at varying inhaled resistances using the 'In-Check Dial'., Results: thirty-five were classified as mild, 17 moderate and 1 severe COPD. All patients used a metered dose inhaler (pMDI), and 12 of the patients also used a dry powder inhaler (DPI). Forty six per cent of patients using a pMDI and 17% of those using a DPI rated their device difficult to use. No patient used a nebuliser. Thirty-one of the 53 patients using just a pMDI felt they were able to perceive benefit in comparison to 4 of the 12 DPI users. Even though most DPI users (10/12) had rated their inhaler as easy to use, 50% were 'unsure' as to whether they received any clinical benefit. Most patients were unable to generate sufficient inspiratory flow to use the higher resistance DPI's and patients with COPD who were able to generate adequate PIF were invariably mild. A significant negative correlation was found between age and the PIF achieved when assessed using the high resistance device setting (R = 0.84, P<0.0001). Multivariate analysis showed the effect of age on PIF was independent of the disease grade., Conclusions: elderly patients with COPD, even when in a stable clinical condition, may be unable to gain optimum benefit from their inhaler.

Background: Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis., Objective: To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation., Methods: Sputum cells were induced from steroid-naïve, allergen-challenged and allergen-naïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry., Results: hRTDC stained HLA-DR(+) (negative for markers of other cell lineages) were predominantly myeloid and comprised approximately 0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4(+) naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P<0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P<0.05-P<0.001), CD1c, CD1d and langerin (P<0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P<0.05). CD11c(-)CD123(high) hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge., Conclusion: Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

Background: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance., Objective: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction., Methods: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks., Results: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation., Conclusion: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.

Background: The skeletal effects of low-dose methotrexate (MTX), in glucocorticoid-dependent asthmatics (GCDA), are unknown., Methods: We studied 9 patients from a total of 26 chronic GCDA who completed 28 weeks of MTX (15 mg weekly, intramuscularly). Prednisolone dose was not altered during the first 12 weeks, and was then reduced between 12 and 28 weeks. Mean (S.E.M.) age of the patients was 54 (4.0) years. They had normal bone mineral density (BMD), were not taking medication that affected bone metabolism (except prednisolone and inhaled corticosteroids) and all achieved at least 50% reduction in prednisolone dose at 28 weeks. Blood and urine samples were obtained at baseline, 12, 28 and 40 weeks for measurement of serum osteocalcin (OC) and bone alkaline phosphatase (Bone-ALP) as formation markers and urinary deoxypyridinoline (DPD) and N-terminal cross-linked telopeptide of type I collagen (NTX-I) as resorption markers., Results: Concurrently with the changes in prednisolone dosage serum OC levels increased significantly at 28 weeks (p<0.008) (8.1+/-1.0 ng/ml) compared to baseline (4.7+/-0.6 ng/ml) and 12 weeks (5.1+/-0.6 ng/ml), but trended back by 40 weeks (6.6+/-0.6 ng/ml). No significant changes were observed for the other bone markers between baseline and the other time points., Conclusions: The beneficial effects of steroid reduction on bone metabolism do not appear to be impaired by concomitant MTX treatment at least over 12 weeks.

The respiratory muscles constitute the respiratory pump, which determines the efficacy of ventilation. Any functional disorder in their performance may cause insufficient ventilation. This study was designed to quantitatively explore the relative contribution of major groups of respiratory muscles to global lung ventilation throughout a range of maneuvers in healthy subjects. A computerized experimental system was developed for simultaneous noninvasive measurement of inspired/expired airflow, mouth pressure and up to 8 channels of EMG surface signals from major respiratory muscles which are located near the skin (e.g., sternomastoid, external intercostal, rectus abdominis and external oblique) during various respiratory maneuvers. Lung volumes values were calculated by integration of airflow data. Hill's muscle model was utilized to calculate the forces generated by the muscles from the acquired EMG data. Analysis of EMG measurements and respiratory muscles forces revealed the following characteristics: (a) muscle activity increased with increased breathing effort, (b) inspiratory muscles contributed to inspiration even at relatively low flow rates, while expiratory muscles are recruited at higher flow rates, (c) the forces generated by the muscle depended on the muscle properties as well as on their EMG performance and (d) the pattern of the muscle's force curves varied between subjects, but were generally consistent for the same subject regardless of breathing effort.

The present study compared the safety of 4.5 microg formoterol with 0.5 mg terbutaline, both by Turbuhaler and used as needed, in addition to regular formoterol in moderate asthma. In this double-blind parallel-group study, 357 patients taking a moderate-to-high dose of inhaled corticosteroids and additional terbutaline (2-5 inhalations x day(-1) during run-in) were randomised to either formoterol or terbutaline as needed in addition to formoterol 9 microg b.i.d. over 12 weeks. Adverse events, serum potassium levels, electrocardiogram, vital signs and lung function were assessed monthly; peak expiratory flow and severe asthma exacerbations were recorded daily. Patients used 2.16 (range 0.0-6.3) formoterol and 2.34 (range 0.1-7.5) terbutaline relief inhalations x day(-1). No clinically significant differences in safety variables were found between treatments. Statistically greater increases in cardiac frequency (2.6 beats x min(-1), p=0.03) were found on terbutaline. There were 44 and 52 severe asthma exacerbations with formoterol and terbutaline, respectively, with no significant difference in time to first exacerbation. There was also no difference between treatments for other efficacy measures (peak expiratory flow, forced expiratory volume in one second and morning/evening symptom scores). Formoterol 4.5 microg as needed was at least as safe, well tolerated and effective as terbutaline 0.5 mg in stable patients (requiring up to 6 relief inhalations x day(-1)) taking formoterol plus inhaled corticosteroids regularly over 12 weeks.

Mechanical ventilation has been associated with pulmonary edema in the clinical setting, but the pathophysiological mechanisms of this process have not been clearly defined. Experimental studies have shown that high transpulmonary pressures resulting from ventilation may damage the capillary walls, thereby leading to edema. Knowledge of the stress distribution within the alveolar septa would be an important step in understanding this phenomenon. A newly developed saline-filled alveolar sac model was utilized for analysis of septal stresses in young and aging healthy lungs, in order to examine their vulnerability to pulmonary edema during ventilation. Significant stress concentrations were shown to develop near highly curved regions (small local radii of less than 4 mum in a lung inflated to 80% could be as high as 25 times that of average septal stresses. The combination of elevated stress sites that are formed in the stiffer parenchyma of the aging lung, together with the cyclic loading of ventilation, may explain the gaps and breaks previously observed in pulmonary edema.

Sound signals of respiratory airflow represent summations of acoustic waves of various frequencies, which basically depend on the characteristics of the flow and on those of the surrounding tissue. This study was designed to examine the capability of time-frequency distribution (TFD) of respiratory signals in order to differentiate between unobstructed and obstructed upper airways. In order to investigate the TFD characteristics of defined upper airway geometry we conducted a controlled basic study in a laboratory system with an in vitro isolated airway model, which was either unobstructed or had concentric obstructions of various degrees at different locations along the tube. Pressure fluctuations were acquired with a microphone proximal to the airway opening. A short-term Fourier transform was used to study the TFDs of these signals. The results of the in vitro study showed that the energy of the higher frequencies increased for relatively small incremental changes in: i) reduction of the lumen cross-section, ii) decrease of distance from measurement site to obstruction, and iii) increase of breathing effort. Further development of this method may lead to noninvasive clinical techniques for early diagnosis of upper airway obstructions.

The alveolar septum consists of a skeleton of fine collagen and elastin fibers, which are interlaced with a capillary network. Its mechanical characteristics play an important role in the overall performance of the lung. An alveolar sac model was developed for numerical analysis of the internal stress distribution and septal displacements within the alveoli of both normal and emphysematic saline-filled lungs. A scanning electron micrograph of the parenchyma was digitized to yield a geometric replica of a typical two-dimensional alveolar sac. The stress-strain relationship of the alveolar tissue was adopted from experimental data. The model was solved by using commercial finite-element software for quasi-static loading of alveolar pressure. Investigation of the state of stresses and displacements in a healthy lung simulation yielded values that compared well with experimentally reported data. Alteration of the mechanical characteristics of the alveolar septa to simulate elastin destruction in the emphysematic model induced significant stress concentrations (e.g., at a lung volume of 60% total capacity, tensions at certain parts in an emphysematic lung were up to 6 times higher than those in a normal lung). The combination of highly elevated stress sites together with the cyclic loading of breathing may explain the observed progressive damage to elastin fibers in emphysematic patients.

A system for noninvasive assessment of an all-inclusive function of respiratory muscles at different lung volumes is presented. The apparatus was based on the interrupter technique and facilitated simultaneous measurements of mouth pressure and airflow rate during dynamic or quasistatic manoeuvres. In this study, mouth pressure values were continuously acquired during and after interruption of a forced inspiratory or expiratory manoeuvre for as long as the subject could sustain an elevated mouth pressure against the obstructed opening. These measurements provided information on both muscle strength and power. A total of 420 forced maximal inspiratory and expiratory manoeuvres performed by six healthy subjects were monitored at different lung volumes. The pattern of maximal pressure-time curves was consistent for the same subject regardless of lung volume. Similar values of maximal mouth pressure can be generated by healthy subjects by using either a flange-style mouthpiece or facial mask. For both methods mouth pressure shows a significant (p < 0.05) second order dependency on lung volume for both inspiration and expiration. The standard deviation of measurements from a single subject about a second order curve is of the order of 5-15%. The findings of interchangeability between methods of measurement may be useful in allegedly non-compliant patients.

Nasal inspiration is important for maintaining the internal milieu of the lung, since ambient air is conditioned to nearly alveolar conditions (body temperature and fully saturated with water vapor) on reaching the nasopharynx. We conducted a two-dimensional computational study of transport phenomena in model transverse cross sections of the nasal cavity of normal and diseased human noses for inspiration under various ambient conditions. The results suggest that during breathing via the normal human nose there is ample time for heat and water exchange to enable equilibration to near intraalveolar conditions. A normal nose can maintain this equilibrium under extreme environments (e.g., hot/humid, cold/dry, cold/humid). The turbinates increase the rate of local heat and moisture transport by narrowing the passageways for air and by induction of laminar swirls downstream of the turbinate wall. However, abnormal blood supply or mucous generation may reduce the rate of heat or moisture flux into the inspired air, and thereby affect the efficacy of the process.

In severe COPD, ventilation at peak exercise may exceed the resting maximal voluntary ventilation (MVV). We investigated the mechanisms by which the breathing capacity can improve during exercise in COPD. A total of 13 patients with an FEV1 of 32+/-12% (SD) predicted, performed an incremental maximal exercise test and FVC and MVV maneuvers at rest and during constant work rate exercise. Maximal exercise ventilation was 3+/-2 L/min higher than resting MVV. Breathing capacity improved during exercise; resting MVV was 30+/-3 (SE) L/min, while it reached 38+/-3 L/min during exercise (P < 0.002). FEV1 improved from 0.86+/-0.1 L at rest to 1.01+/-0.1 L during exercise (P < 0.004), which is consistent with exercise-induced bronchodilatation. It is concluded that in severe COPD, breathing capacity improves during exercise. Assuming that the change in FEV1 reflects improved airway function, these data suggest that exercise-induced bronchodilatation contributed to that improvement.

Airflow distribution in the bronchial tree is an important factor that controls gas mixing in the lungs, especially, in diseased lungs or during high frequency ventilation. A nonlinear analog model has been developed to investigate the dependency of airflow distribution in asymmetric bronchial bifurcations on structural and physiological parameters. The system parameters (electrical analogs) are time-dependent and were extracted from laboratory studies of airway models and physiological measurements. The model was used to study flow distribution in peripheral pathways of normal and pathological airways during different modes of quiet breathing as well as high frequency ventilation. Model simulations revealed that (i) increasing of ventilation frequency or stroke volume increases the time and percentage of pendelluft in each cycle, (ii) diameter asymmetry between parallel pathways is more dominant than length asymmetry and enhances the degree of asynchronous ventilation to peripheral pathways, and (iii) asymmetry in the compliance of peripheral airways and lung parenchyma greatly increases the degree of asynchronous ventilation.

Domiciliary long-term oxygen therapy (LTOT) is usually supplied by means of oxygen concentrators (OCs). Various factors that determine the efficacy of such a treatment were evaluated. Sixty-three patients, arbitrarily selected from lists of health care providers, were visited at home by a biomedical engineer and a pulmonary function technician. The evaluation consisted of: i) responses to a directed questionnaire, ii) assessment of the OC output characteristics, and iii) measurement of the patient's oxygen saturation (SaO2) at rest with and without oxygen supplement. Only 33% of patients received oxygen treatment for the recommended 12-24 hours/day and 5% of patients waited the recommended 10 minutes of OC warm-up before connection. Filters were cleaned weekly by only 30% of patients and the concentrator was serviced 3-4 times a year in 25% of cases. The OC was thought to be unduly noisy by 24% of patients and connecting tubing of less than 6 meters was fitted to 90% of OCs, thereby limiting patient mobility. Most of the OCs did not yield the recommended oxygen concentration and the flow rate meters on them tended to underread. Therefore, only 22% of patients received the prescribed oxygen supplement. Whilst breathing room air, a substantial proportion of patients had an SaO2 >90%. Improvements are clearly required in terms of medical indications for LTOT, patient education and supervision, supply and maintenance of concentrators and related equipment.

Methotrexate is a folic acid antagonist with proven anti-inflammatory properties. This originally led to its use in the therapy of some rheumatic and dermatological inflammatory disorders and, since the early 1980s, as a corticosteroid-sparing agent in the therapy of bronchial asthma. Although the exact anti-inflammatory mechanism is not known, it appears that in some patients with severe corticosteroid-dependent bronchial asthma, a reduction of at least 50% in the maintenance corticosteroid dosage can be achieved. Controversies regarding methotrexate efficacy may be a result of the small size and heterogeneity of the patient populations studied and the variable definition of corticosteroid "dependence'. Although the potential for serious short and long term adverse effects resulting from methotrexate therapy cannot be ignored, overall, methotrexate appears to be well tolerated at low dosages. Hepatic and pulmonary toxicity are the main adverse effects of concern. The "lesser evil' approach is logical, but it is imperative to administer the drug for at least 3 months to adequately assess its efficacy in a specific patient.

Re-expansion pulmonary oedema may occur after chest tube drainage of pneumothorax and can give rise to cardiopulmonary manifestations which range from the mild to the severe. In order to evaluate the prevalence and the clinical manifestations of this complication, all patients with spontaneous pneumothorax managed with chest tube drainage were evaluated over an 8-yr period (1986-1994). A chest radiograph was performed routinely in all patients within 4 h of tube insertion. Lung expansion and the appearance of infiltrates within the lungs were investigated specifically. Re-expansion oedema was noted in three of 320 episodes (0.9%). Two of the three patients needed rapid and extensive clinical treatment.

Background: Children who suffer from recurrent wheezy episodes are often promptly classified as asthmatic. The aim of this study was to evaluate a population of mild wheezy children with repeatedly normal spirometric tests at rest for atopy, bronchial hyperresponsiveness, and peak expiratory flow variability., Methods: Thirty nine children aged 6-16 years with 1-12 wheezy attacks during the previous year were recruited from a community paediatric primary health care clinic serving an urban Israeli population. The conditions for inclusion were a physician-diagnosed wheeze on auscultation and normal spirometric tests at rest on at least three occasions. Evaluation included skin prick tests for atopy and a physician-completed questionnaire. In addition, two tests of bronchial hyperresponsiveness (BHR) were performed--namely, exercise-induced bronchospasm and inhaled methacholine hyperresponsiveness--as well as diurnal variability of peak expiratory flow (PV)., Results: One or more tests of BHR/PV were positive in 27 (69%) but repeatedly negative in 12 (31%). In terms of frequency of wheezing attacks, atopy, and questionnaire responses, there were no differences between BHR/PV and non-BHR/PV children, with the exception of a history of chest radiography proven pneumonia (only noted in the BHR/PV group). Overall, evidence of atopy (mainly indoor allergens) was noted in 21 (56%) of those tested and parental smoking in 29 (74%) of households. Thirty-two (82%) of the children complained of an exercise-related wheeze, yet exercise-induced bronchospasm was only demonstrated in nine (23%)., Conclusions: This selected group of wheezy children appears to be intermediate between a normal and clearly asthmatic population and, despite the recurrent wheezy attacks, some should probably not be classified as asthmatic by conventional criteria. Important aetiological factors in the symptomatology of these children may include parental smoking and atopy as well as other elements such as viral infections.

Treatment of 21 steroid-dependent asthmatic patients with methotrexate (MTX) 15 mg/week was prospectively evaluated for a mean of 14.7 (SD 3.7) months. Before MTX, therapy consisted of a mean prednisone dose of 16.6 (SD 9.2) mg, in addition to inhaled beclomethasone/budesonide (mean daily dose 1157 (SD 330) micrograms) and bronchodilators. Thirteen patients were weaned from all regular systemic steroid therapy, a 50% or more reduction was achieved in four patients, and a less than 50% reduction in four patients. Abnormal liver function tests were noted in six of the 21 patients; this resolved despite continuation of MTX in five. In one patient, MTX was stopped because of symptoms as well as a fivefold rise in serum transaminases, and a speedy resolution was noted. Gastrointestinal side-effects were reported in six patients but were resolved in five with intramuscular MTX. There were no hematologic or pulmonary complications. We conclude that MTX appears to be both safe and efficacious as a steroid-sparing agent in most steroid-dependent asthmatic patients when taken over a long period.

Background: Sighing breathing is observed in subjects suffering from anxiety with no apparent organic disease., Methods: Lung volumes and expiratory flow rates were measured in 12 patients with a sighing pattern of breathing and in 10 normal subjects matched for age, gender, and anthropometric data. In both groups the measurements were made by spirographic and plethysmographic techniques. In normal subjects functional residual capacity (FRC) and residual volume (RV) were measured during normal breathing and again during simulated sighing breathing to exclude technical artifacts resulting from hyperventilation during measurement by the helium closed circuit method., Results: Patients with a sighing pattern of breathing had a normal total lung capacity (TLC) but significantly different partitioning of lung compartments compared with normal subjects. The vital capacity (VC) was lower when measured by both spirographic and plethysmographic methods and RV was higher. The forced expiratory volume in one second (FEV1) was also lower in patients with sighing breathing. The FEV1/VC and the maximal expiratory flow rates at 50% and at 25% of the forced vital capacity (V50 and V25) were normal and similar in both groups. In normal subjects there were no differences in RV when measured during quiet or simulated sighing breathing., Conclusions: Subjects with sighing breathing have a normal TLC with a higher RV and lower VC than normal subjects. There was no obvious physiological or anatomical explanation for this pattern.

Eleven patients with an exercise dependent complete left bundle branch block (CLBBB) were followed-up over a period of 2-13 years (mean 6.5 +/- 3.8). Their ages ranged from 19 to 62 years (mean 48). Four patients complained of chest pain on effort and one of palpitations. All patients underwent a clinical examination, 12 lead ECG, routine blood tests, chest X-ray, a multistage exercise test, echo Doppler, radionuclide ventriculography with TC99 and 48-h Holter monitoring. Ten were submitted to a coronary angiography with left ventriculography. The ECG at rest displayed a normal ECG in seven patients and an incomplete left bundle branch block (ILBBB) in four patients. The onset heart rate (HR) of CLBBB ranged from 95-146 beats.min-1 (mean 123) and the offset HR75-135 (mean 102 beats.min-1). Coronary angiography showed three-vessel disease in two patients and an obstruction of the left anterior descending coronary artery (LAD) in the third. In the other seven patients all the investigations (including coronary angiography) were normal. During the follow-up period the HR at onset of CLBBB decreased from 145 beats.min-1 to 100 beats.min-1 in four patients but no coronary artery disease (CAD) could be proven at coronary angiography. In our series chest pain did not always signify the presence of CAD. We conclude, that in patients with exercise-dependent CLBBB the prognosis is good if no underlying heart disease can be detected. It appears from our limited experience that an exercise-dependent CLBBB at heart rate below 125 beats.min-1 does not by itself constitute a sign of CAD.

Doppler-derived parameters of aortic flow were examined during heavy isometric exercise in 48 men with coronary artery disease (CAD) and in 48 gender- and age-matched healthy controls. The aim was to determine which parameters best separated the groups and to look for a possible relation between exercise-induced Doppler patterns and the extent of CAD. Isometric exercise was performed with a 2-hand bar dynamometer, and the subjects were required to perform 50% of maximal voluntary contraction for 2 minutes. Examination was performed with a pulsed Doppler transducer positioned at the suprasternal notch. Resting peak flow velocity, acceleration time, stroke volume index and cardiac index did not show significant differences between the groups. However, mean acceleration and stroke work were significantly lower in patients with CAD. In this group, exercise peak flow velocity decreased from 98 +/- 13 to 55 +/- 12 cm/s, flow velocity integral from 14 +/- 3 to 7 +/- 3 cm, mean acceleration from 11 +/- 0.9 to 4.7 +/- 1 m/s/s, and stroke volume index from 41 +/- 6 to 23 +/- 4 ml/m2 (p less than 0.001 for all). Cardiac index decreased from 2.7 +/- 0.4 to 2 +/- 0.2 liters/min/m2 (p less than 0.05). Acceleration time increased from 82 +/- 6 to 116 +/- 7 ms. In most of the indexes, the directional changes induced by isometric exercise were similar in patients with CAD and in normal control subjects. The differences compared with the rest values were significantly greater in the CAD group, and especially in patients presenting with 3-vessel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Three members of one family, a father and two sons, inflicted with Marfan syndrome, suffered multiple bilateral episodes of spontaneous pneumothorax that required repeated drainage procedures. The youngest patient also had an episode of unilateral expansion pulmonary edema; he underwent sequential pleural abrasions. Familial pneumothorax is very uncommon, and its association with Marfan syndrome is an exception.

69 patients with steroid-dependent asthma (mean daily prednisolone dose 14.2 [SD 6.1] mg) took part in a randomised, double-blind, placebo-controlled study of 24 weeks' treatment with methotrexate 15 mg weekly. The patients were seen every 4 weeks by the same physician, who reduced the daily prednisolone dose by 2.5 mg if the daily diary card variables and measurements of lung function were unchanged or improved. All other treatment remained unchanged. After 24 weeks of treatment the prednisolone dose had been reduced by a significantly greater proportion in the methotrexate than in the placebo group (50% vs 14%) and the reduction was not sustained after the study treatment stopped. There were substantial abnormalities in liver function tests in 5 of the 38 patients taking methotrexate.

Two groups of patients with nocturnal arterial oxygen desaturation were compared. The degree of nocturnal oxygen desaturation, as reflected by the percentage of total sleep time spent with an oxygen saturation less than 90 and 80%, was similar in patients with the obstructive sleep apnoea syndrome (OSAS) and in those with nocturnal hypoventilation (NH) secondary to restrictive chest wall disease. Systemic hypertension was present in 16 of the 24 OSAS patients but in only 6 of the 24 with NH (p less than 0.005). Multiple regression analysis demonstrated that this difference remained significant even after adjustment for age, sex, weight and history of smoking. It is likely that factors other than nocturnal hypoxaemia are important in the aetiology of systemic hypertension in patients with sleep-related breathing disorders.

We attempted to see what the effect of position was on the rate of pneumothorax formation. In 6 anesthetized spontaneously breathing dogs in the left decubitus position, a chest tube was inserted into the right hemithorax. A right-sided pneumothorax was induced by percutaneous transthoracic insertion of a 20-gauge needle into the lung. Once a constant rate of pneumothorax formation occurred, the dogs were alternated between 3 min of no evacuation by the chest tube with the puncture site up (left decubitus) or down (right decubitus). The pneumothorax that accumulated was always evacuated immediately thereafter with the chest tube in the highest position (left decubitus). In every case, the rate of pneumothorax formation decreased with the puncture site down rather than with it up. Furthermore, this maneuver caused the site of leak to completely seal 11 of 21 times in which the puncture site was placed dependent. There was, however, no significant change in the rate of pneumothorax formation with the puncture site kept in the nondependent position. These results are consistent with the hypothesis that placing the site of pleural gas leak in the most dependent position causes a reduction in alveolar size as well as the alveolar to pleural pressure gradient in the region surrounding the leak. Both of these factors would tend to slow the rate of pneumothorax formation and allow sealing of the puncture site.

Immunofluorescence studies with specific antisera to secretory IgA (11S IgA) and secretory piece were carried out on the jejunal mucosa of nine patients with adult coeliac disease (treated and untreated). The results were compared with those obtained in four normal patients and in four patients with local and systemic IgA (7S) deficiency. 11S IgA and secretory piece were localized to the upper third of the epithelial cells of both surface and glandular epithelium in all groups of patients. However, in the untreated coeliac patients fluorescence was also demonstrated in the basement membrane and connective tissue of the mucosa (returning to normal on treatment). On the basis of our findings, a revised pathway for the normal production of 11S IgA is proposed as well as an additional pathway involving a ;backflow' of 11S IgA into the lamina propria in pathological states such as coeliac disease. This backflow is reversed by an adequate gluten-free diet. It is suggested that 7S IgA and 11S IgA may be involved in immune reactions in the mucosa with antigens such as gluten.

Destruction of alveolar walls is considered by most observers to be the most important part in the definition of emphysema, yet it has never been precisely defined and quantitated. We therefore attempted to devise a reliable microscopic technique to quantitate alveolar destruction that would be both sensitive to disease and easy to perform. Using a point-count system, we obtained an index of parenchymal destruction that represents the percentage of destroyed space as a fraction of the total alveolar and duct space. We have called this measurement the destructive index (DI). In the lungs of 8 nonsmokers and 23 smokers, we quantitated the DI and compared it with the mean linear intercept (Lm) and with pulmonary function in smokers. Although Lm was not significantly different in the 2 groups, significant differences between the DI of smokers and nonsmokers (p less than 0.005) were found. In addition, the DI correlated with FEV1(-0.43, p less than 0.05), MMEF (r = -0.44, p less than 0.05), and recoil pressure at 90% TLC (r = -0.61, p less than 0.05) in smokers. These findings suggest that the destructive component of emphysema can be easily quantitated microscopically, occurs in smokers before dimensional changes are evident (i.e., increased Lm), and influences lung function. Therefore, the quantitation of this destruction (DI) could add greatly to the microscopic definition of emphysema, complementing the information given by the dimensional component of emphysema (Lm).

We performed postexercise two-dimensional echocardiography in 21 patients with sarcoidosis but no signs of ischemic heart disease and in 24 normal control subjects. This was done to assess global and regional left-ventricular (LV) function and to try to identify the presence of occult myocardial involvement among sarcoidosis patients. All 21 sarcoidosis patients had a normal resting left-ventricular ejection fraction (LVEF) and echocardiogram. An abnormal LV response to exercise was detected in 10 sarcoidosis patients in the form of a significant decrease in mean LVEF with exercise without concomitant clinical and ECG evidence of myocardial ischemia. Seven of these 10 patients were found to have a pathological increase in LV and systolic volume with exercise, although it did not achieve statistical significance. In addition, markedly abnormal regional septal wall motion was noted in two of these patients. In the remaining 11 sarcoidosis patients, mean LVEF increased significantly with exercise. This is the normal ejection fraction response to stress. These 11 patients also showed that LV end-systolic volume decreased with exercise; the decrease was from 40.8 to 27.9 ml (P = 0.0004). In the control group, the mean LVEF increased from 69.5 +/- 7.2 at rest to 78.5 +/- 7.6 with exercise (P less than 10(-6)). We conclude that postexercise echocardiography is a noninvasive, simple, and safe method to detect and to follow the course of possible occult myocardial sarcoidosis.

Two-dimensional echocardiography was used to determine global and regional left ventricular function in 32 patients treated with gallopamil (methoxyverapamil) for angina pectoris. Ejection fraction (EF), pressure/volume ratio (PVR), and segmental wall motion were assessed. Evaluations were made before therapy (T1) and repeated 3 weeks later; this assessment included examination 2 and 8 hours after the morning dose (T2 and T3, respectively). Patients were randomized to either a placebo group or three study groups (25, 37.5, and 50 mg t.i.d.). In the 37.5 and 50 mg groups there was an increase in EF (T1 = 53.8% and 54.5%, T2 = 57.9% and 60.1%, and T3 = 57.6% and 60%) and PVR values (T1 = 5.2 and 7.2 mm Hg/ml/m2, T2 = 5.8 and 7.7 mm Hg/ml/m2, and T3 = 5.9 and 7.6 mm Hg/ml/m2, respectively). Wall motion remained the same or improved in 92.3% of the patients. In conclusion, gallopamil had no cardiodepressant effects in most patients. On the contrary, EF, PVR, and segmental contractility tended to improve with the higher doses.

Seven beagles were exposed via a tracheostomy to smoke from 10 cigarettes/day, 5 days/wk for 10 months; 2 other dogs were exposed for 6 months only. Four dogs served as sham-exposed control animals. Mucus was collected 2 times/wk prior to and during the exposure period by resting a cytology brush on the lower trachea for 2 to 5 min. At least once prior to and as often as 3 times during exposure, transpulmonary pressure and flow were monitored under anesthesia to determine resistance RL. Two airway responses to methacholine were determined: the infusion response delta Ri, the increment in RL 4 to 6 min after infusion of 4 micrograms/kg/min, and the aerosol response delta Ra, the increment in RL 2 min after aerosolization of 2 mg/ml, the highest common dose reached. Eight of 9 smoking dogs developed persistent mucus hypersecretion. In 5 dogs, tracheal mucus flux increased 5- to 10-fold; in 3 dogs, the increase was 2 to 3 times that of control animals. One of the sham-exposed dogs developed moderate hypersecretion. After 10 months of smoke exposure, delta Ri increased to 2.24 times that of the initial value (+/- 0.47 SE) (n = 7, p less than 0.05), whereas delta Ra decreased to 0.28 times that of the control value (+/- 0.21 SE) (n = 6, p less than 0.02). The difference between aerosol and infusion response, delta Rai = delta Ra - delta Ri, is an index of relative hyporesponsiveness to methacholine aerosol.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 12 smokers' lungs with scanning electron microscopy in order to analyze the distribution and size of alveolar fenestrae and their relationship to the average distance between alveolar walls (Lm) and lung function. Alveolar fenestrae in areas near terminal airways (respiratory bronchioles and alveolar ducts) were consistently larger than fenestrae far from airways (alveoli). Fenestrae in near areas increased in size as Lm increased (r = 0.845, p less than 0.001), whereas no correlation between Lm and fenestrae size in far areas was found (r = 0.281, NS). The overall area of fenestrae (near and far) correlated significantly with FEV1 (r = -0.745, p less than 0.01), MMEF (r = -0.752, p less than 0.01), and PL90 (r = -0.804, p less than 0.05). However, when subdivided into near and far, only fenestrae near the small airways showed a significant correlation with function. These findings suggest that in smokers with mild to moderate emphysema, destruction affects preferentially the areas around the terminal airways (near areas), and these changes, although small, might play an important role in the lung function.

Fifteen patients suffering from asthma received inhalations of phentolamine, albuterol (salbutamol), a combination of phentolamine and albuterol, and placebo, in a single-blind fashion; the changes in the pulmonary function tests were recorded over a three-hour period. Three patients responded to phentolamine with marked bronchodilatation, whereas severe bronchoconstriction was induced by the drug in two patients. Five patients improved more with phentolamine than with placebo, while all patients improved more markedly with albuterol and still more following inhalation of the combination of both drugs. As a group, there were no statistically significant differences between the responses to phentolamine compared with placebo, or between albuterol alone compared with the combination of both drugs. We concluded that both alpha-antagonist and beta 2-agonist agents act in the same direction in most patients, the beta 2-agonist being the dominant. These results do not offer convincing proof that enhanced alpha-adrenergic activity is the main bronchoconstrictor mechanism even in those few with good response to phentolamine, who also showed very good responsiveness to albuterol. The mechanism of phentolamine-induced bronchoconstriction was discussed, but in the light of presently accepted theories, we were unable to evolve a reasonable explanation.

Of a total of 1,435 healthy untrained asymptomatic individuals referred for a routine periodic checkup, 23 subjects with exertional hypotension on upright bicycle stress testing were identified. All were male. This study assesses by means of echocardiography the responses to exercise of left ventricular (LV) volumes, ejection fraction and segmental LV contractility in these subjects. Exertional hypotension was defined as a decrease in systolic blood pressure to below the resting value at the end of stress test. Supine systolic blood pressure after exercise was significantly greater in the control group than in the study group (179 vs 121 mm Hg, respectively; p less than 0.001); there was no significant intra- or intergroup difference in the resting values. In the study group end-systolic volume was 37 ml at rest and 35 ml after exercise; ejection fraction varied from 65% at rest to 63% after exercise. The sex- and age-matched control group with a normal systolic blood pressure response to exercise showed a shift from 35 to 23 ml and 65 to 77%, respectively (p less than 0.01 and 0.001). Ejection fraction correlated well with radionuclide angiography values. Exertional hypotension was noted after both upright and supine exercise. The pattern of regional wall motion remained unchanged or was hypokinetic in 87% of the subjects; only 13% presented the normally expected hyperkinesia after exercise. This study demonstrates that exertional hypotension is accompanied by an abnormal LV performance.