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The aim of this pilot study was to assess the role of dynamic whole-body PET and parametric imaging in the biological characterization of primary breast cancer.In total 24 histologically proven primary breast cancer lesions in 21 consecutive patients were retrospectively analyzed. Each patient underwent 18F-fluoro-deoxyglucose whole-body dynamic PET-CT before any treatment. Dynamic PET images were acquired in the list mode for a total duration of 70 min. The reconstructed parametric imaging generated Patlak plot-based 'Slope' and 'Intercept' images, from which parametric indices ki and DV were obtained. The standard uptake value (SUV) metric was also obtained by summing the last few frames of the dynamic study. ki, distribution volume (DV) and SUV were correlated with the histological tumor grade, biomarkers [hormone receptors and human epidermal growth factor receptor 2 (HER-2) neu expression] and molecular subtypes (A, B and C) as well as with tumor size, regional nodal metastases and distant metastases.The mean ki was found to be significantly higher in grade III than II lesions (P = 0.005), HER-2 neu positive status (P = 0.04) and molecular subtype B (P = 0.04) as well as in greater than T1 lesions(P = 0.0003 and P = 0.04, respectively) and node-positive lesions (P = 0.009). Though mean ki was not found to be significant for the hormone receptors status (P = 0.08), it showed the best correlation compared to the other parameters (P = 0.8 for DV and P = 0.1 for SUV). Spearman's correlation test, area under the curve (AUC) and mismatch percentage also revealed ki to predict tumor grade (AUC, 0.95; r = 0.7; P = 0.0001), HER-2 neu status and molecular subtypes (AUC, 0.81; r = 0.49 and P = 0.01) along with the hormone receptors status (AUC, 0.83; r = 0.32; P = 0.1). The mean DV failed to show any association with any of the biological or anatomical staging parameters. Though ki was found to be comparable to that of SUV in almost all the assessed parameters, it appeared to be better for predicting hormone receptors status even though both parameters were not statistically significant.Our initial observation in a small cohort of breast cancer patients suggests that ki is promising in stratifying primary breast cancer lesions according to the tumor grade and biological characteristics.

OBJECTIVES: The primary objective of this retrospective study was to evaluate whether abnormal predicted postoperative variables and predicted postoperative product are useful in predicting postoperative complications. The secondary objective was to assess whether an abnormal diffusion heterogeneity index is associated with increased postoperative complications. METHODS: In this retrospective study we evaluated the medical records of 57 patients who underwent lung resection for lung cancer. Calculations of the predicted postoperative variables were done using preoperative testing data, including the extent of the resected lung segments. Predicted postoperative product was obtained by multiplying the predicted postoperative percent-of-predicted FEV 1 by the predicted postoperative percent-of-predicted single-breath diffusing capacity of the lung for carbon monoxide (DLCO). The measured product was obtained by multiplying FEV1 by DLCO. We derived diffusion heterogeneity index from measurements of the single-breath DLCO with the 3-equation method, as a measure of the heterogeneity of the distribution of gas exchange in the lung. RESULTS: Patients with complications had lower predicted postoperative FEV1 (P < .001), lower predicted postoperative DLCO (P < .001), lower predicted postoperative maximal oxygen uptake (P < .001), lower predicted postoperative increase in percent-of-predicted DLCO at 70% work load from at-rest percent-of-predicted DLCO (DLCO%) (P < .001), lower predicted postoperative product (P < .001), and lower measured product (P .004). Interestingly, diffusion heterogeneity index increased with exercise in all patients with complications but decreased with exercise in all patients without complications. CONCLUSIONS: The predicted postoperative variables, predicted postoperative product, measured product, and diffusion heterogeneity index are potentially useful predictors of complications in candidates for lung resection. Key words: diffusing capacity; exercise testing; lung resection; predicted postoperative product; preoperative evaluation; spirometry. [Respir Care 2011;56(4):449–455. © 2011 Daedalus Enterprises]

An abnormal increase in proteolytic enzymes is thought to play a key role in pulmonary emphysema. Alveolar macrophage proteolytic enzymes include cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12, and a number of studies have implicated these proteinases in the alveolar destruction that characterizes emphysema. The aim of this study was to investigate cathepsin L, cathepsin S, matrix metalloproteinase 1, 9, and 12 mRNA expression in alveolar macrophages isolated from patients with varying degrees of emphysema and to correlate their level of expression with measures of emphysema. Alveolar macrophages were isolated from fifty-four patients who underwent surgical resection for lung carcinoma. The level of mRNA expression was determined using real-time PCR. Emphysema was quantified using high-resolution CT scans. Alveolar macrophages were also cultured for 24 h and 48 h; the effect of proinflammatory mediators and promoter polymorphisms on expression was analyzed. There was a significant correlation between matrix metalloproteinase 1 mRNA expression and emphysema. A higher level of matrix metalloproteinase 1 mRNA was associated with more severe emphysema. Matrix metalloproteinase 12 mRNA expression was increased in current smokers as compared with former smokers. Furthermore, there was a negative correlation between matrix metalloproteinase 12 gene expression and carbon monoxide diffusing capacity. The matrix metalloproteinase 9 C-1562T polymorphism significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. These results suggest that alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. Furthermore, these data provide evidence to support the concept that multiple proteinases, causing both elastin and collagen degradation, are important in the pathogenesis of pulmonary emphysema.

A multicentre, cross-sectional study was carried out in six centres across Canada to establish a national standard for pulmonary function tests using healthy, lifetime nonsmokers, with each centre aiming to test 10 men and 10 women from each decade from 20 to 80 years of age. Data from each centre were used to derive prediction equations for each centre, and pooled data from all centres (total: 327 women and 300 men) were used to derive Canadian predicted equations. The predictive models were compared with three widely used published models for selected tests. It was found that, in general, the equations modelled for each centre could be replaced by the models obtained when pooling all data (Canadian model). Comparisons with the published references showed good agreement and similar slopes for most tests. The results suggest that pulmonary function test results obtained from different centres in Canada were comparable and that standards currently used remain valid for Canadian Caucasians.

Background Recipients of heart, lung, and kidney transplants have impaired peak exercise performance (peak Vo2 40% to 60% predicted, reduced anaerobic threshold [AT]) without evidence of ventilatory or cardiac limitations. The aim of this study was to determine whether similar exercise impairment occurs in liver transplant recipients. Methods We studied eight healthy liver transplant recipients (age 42+/-9 [SD] years, 6 male, 31+/-13 months posttransplant). Immunosuppression included FK506 or cyclosporine, azathioprine or mycophenolate mofetil, and prednisone. Subjects underwent lung function testing and cardiopulmonary exercise testing on a cycle ergometer. Results Peak exercise oxygen consumption (Vo2) was 22+/-8 ml/min/kg (66+/-20% predicted maximum). No subject demonstrated exercise desaturation or ventilatory limitation (peak minute ventilation 55+/-8% predicted maximum voluntary ventilation). Peak heart rate was 87+/-8% of predicted maximum. Early AT was evident (1.2+/-0.34 L/min, 48+/-11% predicted Vo2max). Conclusions Liver transplant recipients exhibit impaired peak exercise performance similar to that observed after other solid organ transplants, possibly as a result of chronic deconditioning or myopathy related to immunosuppressive medications.

OBJECTIVE: To prepare new guidelines for the Canadian Thoracic Society (CTS) regarding severe alpha1-antitrypsin (AAT) deficiency and AAT replacement therapy.MATERIALS AND METHODS: Previously published guidelines and the medical literature about AAT deficiency and AAT replacement were reviewed. The prepared statement was reviewed and approved by the CTS Standards and Executive Committees.RESULTS: Three studies evaluated AAT replacement. The National Heart, Lung and Blood Institute’s AAT Registry was a nonrandomized comparison of patients receiving and not receiving AAT replacement, and evaluated the decline in forced expiratory volume in 1 s (FEV1) in 927 subjects. The rate of FEV1decline was significantly less in those receiving AAT treatment (66 ± SE 5 mL/year versus 93 ± SE 11 mL/year; P=0.03) only in the subgroup with FEV135% to 49% predicted. In another study comparing 198 German patients receiving weekly AAT infusions and 97 untreated Danish patients, the mean annual decline in FEV1was significantly less in treated patients only in the subgroup with FEV131% to 65% predicted (62 mL versus 83 mL, P=0.04). Neither of these studies was a randomized, controlled study and, thus, cannot be taken as proof of efficacy. A randomized, double-blind, placebo controlled trial of monthly replacement therapy over three years in 56 exsmokers with severe AAT deficiency and moderate emphysema showed a trend (P=0.07) favouring slower progression of emphysema by computed tomography scan in the group receiving AAT replacement.CONCLUSIONS: AAT replacement therapy has not been proven definitively to be clinically effective in reducing the progression of disease in AAT-deficient patients, but there is a possible benefit to selected patients. A placebo controlled, randomized clinical trial of AAT replacement therapy is required. The authors recommend reserving AAT replacement therapy for AAT-deficient patients with impaired FEV1of 35% to 50% predicted who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1, and participation of all AAT-deficient subjects in the Canadian AAT Registry.

Examination of induced sputum and measurement of exhaled NO have been advocated as noninvasive methods of assessing the degree of airway inflammation. In this study, we performed follow-up evaluation on 71 subjects with asthma caused by exposure to Western red cedar; 50 subjects had left exposure, whereas the rest continued to work in the same job. Spirometry, methacholine challenge tests, exhaled nitric oxide, and sputum induction were carried out. Of the 50 subjects who left exposure, 12 had no respiratory impairment according to the American Throacic Society guidelines for assessing respiratory impairment in patients with asthma, 17 belonged to Class 1, 12 to Class 2, five to Class 3, and four to Class 4. The percentage of eosinophils in induced sputum showed a significant inverse relationship with FEV1 (r = -0.46, p0.001), and a significant positive correlation with levels of exhaled NO (r = 0.42, p0.001) and with the class of respiratory impairment (r = 0.52, p0.001). Mean percent eosinophils were 1.5 for impairment Class 0, 2.2 for Class 1, 1.7 for Class 2, 6.8 for Class 3, and 16.3 for Class 4. No relationship was found between the levels of exhaled NO and the functional parameters as well as the impairment class. NO levels in ppb were 21 for impairment Class 0, 30 for Class 1, 22 for Class 2, 26 for Class 3, and 49 for Class 4. This study also provides objective evidence that airway inflammation, as indicated by induced sputum, corroborates the rating of respiratory impairment in patients with asthma.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

Objective: To evaluate the effect of assay buffer ionic strength on assessment of the antielastase activities in bronchoalveolar lavage fluid. Method: An improved assay protocol in which elastase (in Tris-HCI buffer) is added to increasing volumes of test samples (made up to equal volume with phosphate-buffered saline) was used. Results: The percent NE activity inhibited by BALF decreased with increasing NaCl concentration of the buffer. Inhibition of pancreatic elastase (PE) was not affected. One hundred percent inhibition of NE by pure AAT and SLPI standards occurred at molar ratios of 0.91 ± 0.03 for AAT-to-NE and 0.83 ± 0.02 for SLPI-to-NE when assayed in buffer with ⩽0.15 mol NaCI/L, compared to ratios of 0.99 ± 0.02 and 1.06 ± 0.02, respectively, for assays in buffers with 0.50–1.00 mol NaCI/L (p < 0.05 for AATto-NE; p < 0.02 for SLPI-to-NE). The AAT-to-PE molar ratio at 100% inhibition of PE was not affected. Assays in buffer with ⩽0.15 mol NaCI/L indicated that 86.9 ± 4.1% of AAT and 100.9 ± 4.9% of SLPI in BALF were active against NE, while assays in buffer with 0.50–1.00 mol NaCI/L showed that 84.4 ± 3.5% of AAT and 81.6 ± 5.9% of SLPI present were active. AAT inhibited NE and PE equally only in buffer with 0.50–1.00 mol NaCI/L. Conclusions: The results of assays of BALF antielastase activities depend on the assay buffer NaCl concentration, which may account for the conflicting reports in the literature. The buffer with 0.50–1.00 mol NaCI/L appear to be optimal for valid quantitation of anti-NE activities in BALF.

Palovarotene is an oral gamma-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement.REPAIR (Retinoid treatment of Emphysema in Patients on the alpha(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg.day(-1) palovarotene given for 1 year to 262 patients with severe alpha(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary endpoint; functional end-points were also regularly assessed.We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene.Palovarotene 5 mg.day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe alpha(1)-antitrypsin deficiency.

Alpha(1)-antitrypsin deficiency (AATD) is a clinically under-diagnosed genetic disorder that originates from deleterious mutations in the alpha(1)-antitrypsin (AAT) gene, SERPINA1. Severe deficiency is associated with significant pulmonary and hepatic malfunctions. Conventional clinical diagnosis involves the evaluation of serum AAT level and detection of diseased protein isoforms. In this communication, we describe the investigations of a case of severe AATD in which the AAT levels were well below those expected from the MZ phenotype determined by isoelectric focusing for protease inhibitor type (IEF PI-typing).In addition to the traditional diagnostic method that combines the assessment of serum AAT concentration and IEF PI-typing, we investigated the SERPINA1 gene of the proband and participating family members for mutations using Sanger sequencing.We identified a novel mutation (M409T) in the proband, initially missed by the standard diagnostic approach. The novel mutation was present in 4 out of 8 family members who participated in the study.This report illustrates the diagnostic value of incorporating exon sequencing of the AAT gene into the algorithm for evaluating AATD, particularly when the AAT serum level is significantly lower than expected from IEF PI-typing.

We compared cardiac output determined simultaneously by two methods, the CO2 rebreathing technique and the thoracic electrical bioimpedance method (Bomed NCCOM-3 equipment). The studies were performed in duplicate in 11 healthy male subjects at rest and during three levels of steady-state exercise on a cycle ergometer at 60, 120, and 180 W. Cardiac output at 60 and 120 W was slightly lower (p less than 0.01) by the thoracic impedance method (12.2 +/- SE 2.2 and 15.7 +/- SE 3.5 L/min, respectively) than by the CO2 rebreathing method (14.0 +/- SE 2.1 and 17.9 +/- SE 3.0 L/min, respectively), suggesting a systematic bias between the two methods of measurement. However, if allowance is made for that bias, there would be acceptable agreement between the two methods at 60 and 120 W. Although the results were not significantly different between the two methods at rest and at 180 W, there was no acceptable agreement between the two methods probably because the CO2 rebreathing method at rest was more liable to show error due to the small arteriovenous CO2 difference, while the impedance method was less reliable at 180 W. Cardiac output by both methods correlated with O2 consumption, with the correlation being higher for cardiac output by the rebreathing method (r = 0.94) than for thoracic impedance (r = 0.88). The results suggest that the thoracic electrical bioimpedance method can be used for determination of cardiac output during mild or moderate levels of exercise in normal subjects.

Objective: The impact of current employment status and other factors on quality of life was evaluated for workers diagnosed with western red cedar asthma in British Columbia, Canada. Methods: Telephone interviews by questionnaire included the Short Form 36 (SF-36) and Marks Asthma quality-of-life instruments. Results: Of the 302 subjects contacted, 70.5 % (n = 213) participated. Employment status was the most consistent predictor of quality-of-life domains, with highest scores for employed subjects, particularly those who were no longer exposed to red cedar. Subjects who had quit work because of their asthma had worse scores, particularly for vitality and general health perceptions. Other factors independently associated with specific aspects of poor quality of life were having asthma-like symptoms, taking medication, and not being married. Conclusions: Continued employment was associated with better quality of life for workers with western red cedar asthma.

The stability of housekeeping genes is critical when performing gene expression studies. To date, there have been no studies that look at the stability of commonly used housekeeping genes in alveolar macrophages. Expression levels may be affected by culture, stimulation or disease severity. The present study investigated the expression level of 10 housekeeping genes and analysed the stability of their expression in alveolar macrophages from chronic obstructive pulmonary disease patients (n = 22) who were classified according to disease severity. Guanine nucleotide-binding protein, beta polypeptide 2-like 1 (GNB2L1), hypoxanthine phosphoribosyl transferase 1 (HPRT1) and ribosomal protein L32 (RPL32) were the most stably expressed in alveolar macrophages, irrespective of disease severity. There was no difference in the expression levels of 10 housekeeping genes between mild and moderate/severe patients. GNB2L1, HPRT1 and RPL32 were also stably expressed in alveolar macrophages cultured with no stimulation, or with interleukin-1beta, lipopolysaccharide or tumour necrosis factor-alpha stimulation. In conclusion, as fluctuations in the expression of some housekeeping genes were observed, including glyceraldehyde-3-phosphate dehydrogenase, it is recommended that guanine nucleotide binding protein, beta polypeptide 2-like 1 be used as a reference gene for alveolar macrophages in similar study designs, or that the stability of housekeeping genes be validated in alveolar macrophages prior to expression studies.

Pulmonary emphysema is a major cause of mortality and morbidity in chronic obstructive pulmonary disease (COPD). Cigarette smoking is a major risk factor in the development of pulmonary emphysema. In this study, we investigated the acute effect of cigarette smoke in vitro on the production of tumour necrosis factor-alpha (TNF-alpha) using differentiated U937 cells, a macrophage model system. We found that stimulation of the macrophages with cigarette smoke media (CSM) leads to a rapid activation of extracellular-regulated kinases 1 and 2 (erk1/2), p90RSK and a transient decrease in phosphorylation of PKB/akt. The CSM also caused the subsequent induction of TNF-alpha release. Our studies revealed that U0126, an inhibitor of the erk1/2 pathway, markedly suppressed CSM-induced TNF-alpha release. Consistent with this finding, U0126 blocked CSM-stimulated erk1/2 phosphorylation, as well as phosphorylation of the downstream kinase, p90RSK. On the other hand, the PI3-K inhibitor, LY294002, and epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, did not suppress the release of TNF-alpha. Thus, CSM induction of TNF-alpha production by differentiated macrophages is regulated primarily via the erk1/2 pathway.

Severe alpha(1)-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV(1) before and after replacement therapy, suggested a possible benefit for selected patients. Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV(1) (35-65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV(1) after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.

To determine whether lung transfer factor for carbon monoxide (T(L(CO))) alters during menstrual phase and if steroid hormone levels relate to these changes, T(L(CO)) and T(L(CO)) adjusted for both alveolar volume (T(L)/V(A)) and haemoglobin concentration, were measured at five predefined and hormonally confirmed menstrual phases in 13 women. No difference between phases was observed in T(L(CO)) or adjusted values. Moreover, there was no association between the maximal change in oestradiol, progesterone, or oestradiol:progesterone ratio and the change in T(L(CO)) measured at the same time. When the first five chronological measurements, regardless of the menstrual phase at which they were measured, were analysed, T(L(CO)) changed significantly (p

We conducted a prospective study to evaluate whether lack of an adequate increase in diffusing capacity for carbon monoxide (DL(CO)) during exercise is associated with a greater postoperative complication rate after lung resection. We used the three-equation method (3EQ-DL(CO)), a modification of the single breath DL(CO) technique to determine DL(CO) during exercise in 57 patients undergoing lung resection at Vancouver General Hospital from October 1998 to May 1999. 3EQ-DL(CO) was determined during steady-state exercise at 35% and 70% of the maximal workload reached in a progressive exercise test. Maximal oxygen uptake (VO(2)max), DL(CO) at rest, and the increase in DL(CO) during exercise were compared in relation to postoperative complications. Patients with complications had lower resting values of DL(CO) (R-DL(CO)), a smaller increase in DL(CO) from rest to 70% of maximal workload expressed as a percent of the predicted DL(CO) at rest ([70% - R]-DL(CO)%), and a lower VO(2)max than did patients without complications. Results suggested that (70% - R)-DL(CO)% was the best preoperative predictor of postoperative complications; a cutoff limit of 10% was the best index to identify complications, yielding a complication rate of 100% in patients with (70% - R)-DL(CO)%10% as compared with a complication rate of 10% in patients with (70% - R)-DL(CO)%/= 10% (sensitivity = 78%, specificity = 100%). Patients who do not increase their DL(CO) sufficiently during exercise ([70% - R]-DL(CO)%10%) have a greater complication rate after lung resection.

Background and Purpose. Body positioning exerts a strong effect on pulmonary function, but its effect on other components of the oxygen transport pathway are less well understood, especially the effects of side-lying positions. This study investigated the interrelationships between side-lying positions and indexes of lung function such as spirometry, alveolar diffusing capacity, and inhomogeneity of ventilation in older individuals. Subjects and Methods. Nineteen nonsmoking subjects (mean age=62.8 years, SD=6.8, range=50–74) with no history of cardiac or pulmonary disease were tested over 2 sessions. The test positions were sitting and left side lying in one session and sitting and right side lying in the other session. In each of the positions, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), single-breath pulmonary diffusing capacity (DLCO/VA), and the slope of phase III (DN2%/L) of the single-breath nitrogen washout test to determine inhomogeneity of ventilation were measured. Results. Compared with measurements obtained in the sitting position, FVC and FEV1 were decreased equally in the side-lying positions, but no change was observed in DLCO/VA or DN2%/L. Conclusion and Discussion. Side-lying positions resulted in decreases in FVC and FEV1, which is consistent with the well-documented effects of the supine position. These findings further support the need for prescriptive rather than routine body positioning of patients with risks of cardiopulmonary compromise and the need to use upright positions in which lung volumes and capacities are maximized.

To evaluate the relationship between alveolar macrophage (AM) elastase and plasminogen activator (PA) activities (considered to be potential pathogenetic factors in emphysema) and the development of emphysema in smokers.Thirty-four healthy smokers35 years of age (mean+/-SD, 46+/-7 years), with a mean+/-SD of 33+/-10 pack-years of smoking, who were recruited as volunteers.Subjects had lung function testing and BAL to obtain AMs; limited high-resolution CT scans of the chest were obtained in 32 subjects to assess the presence of emphysema. Macrophage PA and elastase were determined using AM cultured on (131)I-fibrin-coated plates and 3H-elastin-coated plates, respectively.The number of AMs recovered per milliliter of BAL was significantly greater in the 16 subjects with CT evidence of mild emphysema than the 16 subjects without evidence of emphysema (669+/-301 x 10(3)/mL vs 414+/-268x 10(3)/mL; p=0.01). There was no significant difference between AM elastase or PA activities in the 16 subjects with CT evidence of mild emphysema, when compared with the 16 subjects who had no CT evidence of emphysema (elastase, 2.72+/-1.35 microg vs 2.49+/-0.91 microg elastin per 10(6) AMs per first 24 h; PA, 0.375+/-0.126 vs 0.344+/-0.096 urokinase units/10(6) AMs). There was no significant correlation between levels of PA or elastase activities and FEV1, FEV1/FVC, forced expiratory flow rate between 25% and 75% of the FVC; PA activity but not elastase activity had a significant negative correlation (r=-0.47, p0.01) with diffusion of carbon monoxide (DCO). The macrophage count in BAL had a significant negative correlation with DCO percent predicted (r=-0.61, p0.001).The findings suggest that the number of AMs recovered per milliliter of BAL (presumably indicating the number in the alveolar spaces) is related to the development of emphysema in smokers as indicated by CT scan of the chest and DCO. The results also suggest that the level of PA enzyme activity in AMs may be a pathogenetic factor in the decrease in DCO in smokers.

A mini-Wright based peak flow meter (VMX Mini-Log), which stores the readings together with the time and date of each measurement, has recently been marketed but has not yet been evaluated. The accuracy, reproducibility, and interdevice variability of this instrument were investigated using a pneumotachograph connected in series as a standard. Flows from 100 to 700 L/min were generated by an explosive decompression chamber. The performance of this instrument was also tested in 20 normal subjects and in 20 patients with airflow obstruction. The accuracy of the instrument was expressed as the percentage of error, and reproducibility and interdevice variability were assessed using the coefficient of variation. In the laboratory evaluation, all devices recorded flow rates that were within +/-10% of the pneumotachograph readings at flows between 200 and 600 L/min. At the extreme flow rates of 100 and 700 L/min, the mean error was higher than 10%. The reproducibility of the VMX was within +/-5% at all the flows tested. The interdevice variability was less than 5% at flow rates between 200 and 700 L/min. When tested on normal subjects with PEF between 400 and 700 L/min, the VMX performed well. In patients with airflow obstruction, four devices had greater than 10% error. The largest error was observed in those patients with PEF below 200 L/min. The VMX Mini-Log peak flow meter is accurate and precise in the flow range between 200 and 600 L/min. Its performance, however, may be affected in subjects with airflow obstruction and PEF below 200 L/min.

Background It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. Methods Asthmatic patients presenting to the ED with acute severe asthma (FEV 1 less than 50% of predicted) were enrolled in a multi-center, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 µg per puff, or albuterol, 100 µg per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled β 2 -agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV 1 plateau ( ie , >10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV 1 were assessed after each dose. Results 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV 1 160 mL more than albuterol. The mean (SEM) FEV 1 increase from baseline was 0.75±0.06 L in the fenoterol group and 0.59±0.06 L in the albuterol group (p>0.03). Both β2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23±0.04 mmol/L) than in the salbutamol (0.06±0.03 mmol/L) group (p=0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011±0.003 s compared with 0.003±0.003 s in the albuterol group (p>0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. Conclusions In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 µg per puff by MDI valved holding chamber and mask, to a total dose of 3,200 µg and salbutamol (100 µg per puff) to a total dose of 1,600 µg over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV 1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia. (CHEST 1996; 110:595-603)

We have investigated whether varied assay conditions account for the conflicting reports on measured alastolytic activity of alveolar macrophages (AM) cultured in direct contact with the 3 H-elastin substrate coated onto 16-mm wells in serum-containing media. The data indicate that measured elastolytic activity in this assay system was dependent on the amount of 3 H-elastin/culture well. 3 H-elastin >350 μ g/well, in contrast to the ⩽200 μ g/well commonly used in this assay system, resulted in optimal measurement of elastolytic activity that was linear with respect to culture time (up to 72 h examined) and was directly proportional to number of AM/well (up to 1.0 × 10 6 examined). The sensitivity of measured elastolytic activity to tissue inhibitor of metalloproteinases (TIMP) and to Z-phe-phe (a specific cysteine proteinase inhibitor) was not affected by amount of 3 H-elastin/well, but appears to be dependent on the time period of AM culture. TIMP (at 5 μM, maximal dose examined) inhibited the measured elastolytic activity by 25% in 24-h cultures compared to 69% in 72-h cultures; Z-phe-phe (at 10 μM , dose at which maximal effect was obtained) inhibited the elastolytic activity by 45% in the 24-h cultures compared to 34% in the 72-h cultures. These findings indicate that differences in substrate levels and in culture time have a significant effect on the results obtained in measurement of AM-mediated elastolytic activity in culture, which may account for the conflicting reports in the literature. Thus standard optimal assay condition are required for valid interpretation of results of AM-mediated elastolytic activity measurements.

Body position is known to have significant effects on oxygen transport. These effects, however, are seldom considered during postural drainage (PD). The purpose of this study was to examine the effect of modified PD positions on ventilation homogeneity (the evenness of the distribution of ventilation), which is a key component of oxygen transport. The single-breath nitrogen washout test was used to obtain an index of ventilation homogeneity (slope of phase 3 [SBN2/L%]). Seventeen healthy individuals, ranging from 22 to 40 years of age ( mean = 28.4, SD = 5.6), performed the single-breath nitrogen test while sitting, lying supine with the bed tipped head down, right side lying, and right side lying with the bed tipped head down. Within-subject one-way analyses of variance and Tukey's post hoc analyses were used to compare differences in SBN2/L% across the four positions. The distribution of ventilation was significantly less homogeneous in the side-lying positions compared with the supine and sitting positions. Although these results reflect a position-induced change in pleural pressure gradient, they also reflect the effect of gravity-independent, intraregional changes on ventilation distribution. Thus, modified PD positioning has a significant effect on ventilation homogeneity, which may predispose a patient to arterial desaturation. Given the complexity of the factors involved, patients considered for PD positioning should be monitored for arterial saturation.

We studied 16 smokers, with a mean age of 41 yr (SD, 12 yr) and a mean DLCO of 81% predicted (SD, 19%), before and after smoking cessation. Two subjects were able to stop smoking for only 24 h, whereas 14 subjects abstained for 1 wk, 11 for 1 month, and five for 3 months. The initial mean DLCO in ml/min/mm Hg was 18.9 (SD, 4.6) after correction for COHb back pressure and the reduction in hemoglobin because of COHb. A week after smoking cessation there was a significant increase in DLCO, to 20.8 (SD, 5.4), p = 0.001. There was no further increase in DLCO at 1 month or at 3 months. In four subjects tested while they were still smoking and 24 h after smoking cessation, there was a significant increase in DLCO after correction for COHb, from 17.4 (SD, 1.5) to 19.8 (SD, 1.3), p = 0.02. These results indicate that after smoking cessation there is a rapid improvement in DLCO, suggesting that smoking had previously decreased DLCO. However, there may also be an irreversible component to the reduction of DLCO in some of the subjects in whom the DLCO remained abnormal even after continued smoking cessation for 1 month.

To determine the acute effect of smoking on DLCO, we studied 12 smokers (mean age, 36 yr; range, 19 to 52 yr, six men and six women) before and after they had smoked as many cigarettes as they could (mean, 6.0; SD, 1.9) over a period of 1 h. Blood COHb was estimated using a rebreathing-breathholding technique after a vital capacity inhalation of O2. Capillary blood volume (VC) was determined from DLCO performed at inspired O2 concentrations of 25 and 90%. DLCO (in ml/min/mm Hg) corrected for COHb back pressure decreased from 22.5 (SD, 6.6) before smoking to 21.0 (SD, 6.6) after smoking (p = 0.003). After correction for the "anemia effect" of COHb, DLCO still significantly decreased, from 22.8 (SD, 6.3) before smoking to 21.8 (SD, 6.4) after smoking p = 0.01). VC (corrected for the reduction in hemoglobin by COHb) was 52.0 (SD, 20.1) ml before smoking and 46.4 (SD, 22.7) ml after smoking; this difference did not achieve statistical significance (p = 0.056). There was no significant change in DLCO or VC in six control subjects tested before and after 1 h of sham smoking of an unlit cigarette. In 12 control subjects studied before and after inhalation of 0.1% CO to result in mean COHb levels of 10.6% (SD, 1.4%), there was a slight but significant decrease in VC (mean change, 21%) and in DLCO (mean change, 4%) after correction for COHb back pressure and reduction in available hemoglobin, suggesting that CO inhalation may have a direct effect on DLCO by reducing VC.(ABSTRACT TRUNCATED AT 250 WORDS)

We developed a sensitive double-sandwich ELISA assay for neutrophil elastase (NE) using affinity-purified NE antibody. The assay was capable of detecting NE levels of 0.2 ng/ml and was used to determine NE in bronchoalveolar lavages (BAL) of 12 healthy subjects (6 nonsmokers and 6 smokers) with a mean age of about 27 yr. NE levels in the unconcentrated cell-free supernatant of BAL, subjected to high-speed centrifugation (17,000 x g for 30 min) to sediment subcellular debris, were similar in the smokers who abstained overnight from smoking and in the nonsmokers (24.4 +/- 13.9 versus 23.7 +/- 12.3 ng/mg [SD] albumin). NE levels were significantly higher in lavage fluid not subjected to high-speed centrifugation, reflecting the presence of NE bound to subcellular debris that was sedimented by high-speed centrifugation. Concentration by ultrafiltration through a Millipore CX-10 filter was accompanied by loss of protein with a relatively greater loss of NE than albumin, resulting in lower NE/albumin ratios in concentrated than in unconcentrated lavage. It is therefore recommended that NE levels be determined on unconcentrated BAL after high-speed centrifugation to sediment subcellular debris.

The presence of emphysema in silicosis is believed to be secondary to the development of progressive massive fibrosis (PMF). However, it is difficult to separate out other causative factors, particularly cigarette smoking. In order to attempt to distinguish these factors, we examined 30 patients with silicosis by means of pulmonary function testing and computed tomography (CT) scans of the chest. Eighteen of these patients were either exsmokers or current smokers, and 12 of them were nonsmokers. The CT scans were read independently by two observers on two separate occasions. Silicosis was graded on a 5-point scale from 0 to 4; emphysema was graded as a percentage of lung involved. Percent emphysema was associated with level of pulmonary function (FEV1, FVC, and DLCO) independent of its association with either cigarette smoking or silicosis grade (p less than 0.01). Silicosis grade was associated with DLCO (p less than 0.05) independent of its association with either cigarette smoking or percent emphysema, but was not associated with level of FEV1 or FVC. In the group without PMF (silicosis Grade 0, 1, or 2), smokers had worse emphysema than nonsmokers (p less than 0.01); there was no such difference among the patients with PMF (silicosis Grade 3 or 4). Only one of the nonsmoking subjects with silicosis but without PMF had any emphysema detected on CT. Our data suggest that silicosis, in the absence of PMF, does not cause significant emphysema, and that it is primarily the degree of emphysema rather than the degree of silicosis that determines the level of pulmonary function.

We used a CT program "density mask" outlining areas with attenuation values less than —910 HU, to indicate areas of emphysema on a chest CT and to provide an overall percentage of lung involvement by emphysema. The "density mask" quantitation of emphysema was previously shown to correlate well with the pathologic assessment of emphysema in patients undergoing lung resection. We compared the CT quantitation of emphysema with mean lung density, overall lung volume on CT and pulmonary function tests in 85 patients. There was a significant correlation between the extent of emphysema on CT and FEV 1 /FVC percent of predicted, functional residual capacity percent predicted and Dsb percent predicted. Determination of the percentage of lung with areas of low attenuation by CT provides a useful method for quantitating emphysema in life and correlates significantly with pulmonary function tests. (Cheat 1990; 97:315–321)

To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease, 242 patients were assigned in randomized, double-blind fashion to receive either oral enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens. After a week of placebo xanthine therapy, enprofylline-treated patients received 150 mg of this drug twice daily (b.i.d.)for 3 days, 300 mg b.i.d. for 2 weeks, and 450 mg b.i.d. for 2 weeks. Theophylline was administered in identical doses, except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher. At 300 mg b.i.d., both drugs significantly increased morning peak expiratory flow rate (PEFR), the mean increase above baseline being significantly higher for theophylline-treated patients (29.9 ±37.2 L/min) than for enprofylline-treated patients (17.4 ± 36.9 L/min) ( p = 0.023). At 450 mg b.i.d., improvement in morning PEFR was not significantly different between theophylline-treated (31.5 ± 44.4 L/min) and enprofylline-treated groups (23.5 ± 48.4 L/min). Evening PEFR, FEV 1 , and asthma symptom scores also improved significantly, demonstrating no significant difference between groups. The incidence of side effects was also similar between groups. We conclude that both enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma, enprofylline, 450 mg b.i.d., being approximately equivalent to theophylline, 300 or 450 mg b.i.d.

We determined single breath diffusing capacity (DLCO) and pulmonary capillary blood volume (Vc) in a total of 110 patients, who were being evaluated for resectional lung surgery for a localized tumor or lesion. Pathologic assessment of emphysema was obtained in 55 cases who had resection of a lung or an upper lobe, based on a standard reference panel for emphysema grading. In 86 cases, the extent of emphysema was quantitated by computed tomography (CT) of the chest. There was a significant negative correlation between Vc and emphysema assessed by either pathology or CT (r = about -0.5, p less than 0.001) similar to the correlation between DLCO and the extent of emphysema. Results of Vc were significantly lower in cases with moderate emphysema (pathologic grade greater than or equal to 30) than those with no emphysema (grade less than or equal to 5) (p less than 0.001) or mild emphysema (grade 10 to 25) (p less than 0.05), and they were significantly lower (p less than 0.05) in the group with mild emphysema compared with the group with no emphysema on pathologic assessment similar to DLCO results. Although Vc was reduced in emphysema, determination of Vc did not result in improved discrimination in separating cases with emphysema from those without emphysema when compared with DLCO.

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We determined the levels of alpha 1-protease inhibitor, the plasma trypsin-inhibiting capacity (TIC), and elastase-inhibiting capacity (EIC) in 29 nonsmokers and 30 smokers, who were healthy volunteers matched for age (mean age, 39 +/- 12 years [+/- SD]). The functional activity of plasma alpha 1-protease inhibitor (in micrograms of enzyme inhibited per microgram of alpha 1-protease inhibitor) was slightly but significantly lower in smokers, compared with nonsmokers, both for TIC and EIC (smokers' TIC and EIC were 88.0 +/- 16.2 percent (+/- SD) and 90.4 +/- 17.9 percent of the respective mean values in nonsmokers; p less than 0.05). Among smokers, there was a significant negative correlation (r = -0.37; p less than 0.05) between the average number of cigarettes smoked per day and the functional activity of plasma alpha 1-protease inhibitor; the seven subjects who smoked 40 or more cigarettes per day had significantly lower EIC and TIC than the remaining smokers. In 12 smokers tested before and after a two-hour period of intense smoking of eight cigarettes, there was a statistically significant decrease (p less than 0.05) in EIC one hour after smoking to 93.9 +/- 2.5 percent (+/- SE) of the initial value prior to smoking. It is concluded that there is a slight but significant decrease in the functional activity of plasma alpha 1-protease inhibitor in smokers, both for TIC and EIC.

We studied the bronchodilator effects of inhaled fenoterol, a relatively selective beta-2 adrenergic agent, and ipratropium an anticholinergic drug, singly and in combination in 10 patients with asthma. The period of observation was 6 hr after aerosol administration. The six drug regimens used were fenoterol 100 micrograms, fenoterol 200 micrograms fenoterol 50 micrograms combined with 20 micrograms of ipratropium, fenoterol 100 micrograms combined with 40 micrograms of ipratropium, 40 micrograms of ipratropium, and placebo. Measurements consisted of spirometry with determination of forced expiratory volume in one second (FEV1), maximal expiratory flow at 50% of vital capacity (V50), specific airway conductance, lung volumes, and heart rate. Bronchodilation with regimens containing fenoterol was rapid, with 75% of the maximum response achieved by 5 min, while the peak effect of ipratropium was delayed for 1 to 2 hr. Fenoterol 100 micrograms produced approximately half the degree of improvement in FEV1 and V50 compared with 200 micrograms of fenoterol. The addition of 40 micrograms of ipratropium to 100 micrograms of fenoterol resulted in bronchodilation equivalent to 200 micrograms fenoterol and was associated with a more prolonged effect than fenoterol 100 micrograms. Tremor was observed in two-subjects inhaling fenoterol 200 micrograms but was not observed with any other regimen. It is concluded that the combination of inhaled ipratropium and fenoterol is an effective bronchodilator in asthma, achieving efficacy similar to that of fenoterol alone but with fewer side effects.

A six year follow up study of 750 aluminium smelter workers was undertaken to evaluate the relationship between the leucocyte count at the start of the study and the rate of decline in lung function. An inverse relationship between the leucocyte count and the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) was present cross sectionally irrespective of cigarette smoking habit. The initial leucocyte count was also significantly related to the mean annual decline in FEV1 in smokers (p = 0.04) but not in former smokers or those who had never smoked. These observations suggest that the leucocyte count is a factor influencing the annual decline in FEV1 in smokers.

To evaluate the sensitivity of diffusing capacity (DLCO) and pressure-volume (P-V) curves in the detection of emphysema, these tests were compared with pathologic assessment of emphysema in patients undergoing lung resection for a localized tumor, and with the overall extent of emphysema as assessed by computed tomography (CT). The resected lung specimens were fixed in the inflated state and cut at 1-cm intervals in the horizontal plane. The pathologic extent of emphysema was quantitated by comparison with a standard reference panel of emphysema grading. The overall extent of emphysema on CT was assessed by a visual scoring system in a total of 55 patients, 19 undergoing lung resection and 36 not undergoing lung resection. Analysis of 37 patients by pathology scores revealed 18 with no or trivial emphysema (emphysema grades less than or equal to 5; mean grade, 2.2 +/- SD 2.6) and 19 with emphysema (grades greater than or equal to 10; mean grade, 33.2 +/- SD 24.2). Diffusing capacity, the ratio of DLCO to alveolar volume (DLCO/VA), maximal lung elastic recoil (PLmax), and lung elastic recoil at 90% of total lung capacity (PL90) were significantly different between the two groups, whereas K (the exponential constant describing the shape of the P-V curve) was not. The pathology grade of emphysema showed a significant correlation with (DLCO) (r = -0.53) and DLCO/VA (r = -0.55), which was greater than the correlation with PLmax (r = -0.42) and PL90 (r = -0.43).(ABSTRACT TRUNCATED AT 250 WORDS)

We determined the acute effect of smoking on superoxide (O 2 − ) production by pulmonary alveolar macrophages (AM) in 32 smokers who had bronchoalveolar lavage both before and after smoking. In 18 subjects, AM were obtained either 10, 30, or 60 minutes after the subjects had smoked 2 cigarettes, while in 14, AM were recovered either at 2, 10, or 60 minutes after they had smoked 4 cigarettes. Prior to smoking, O 2 − production by AM was significantly greater in smokers than in 8 control nonsmokers for unstimulated AM, as well as for AM stimulated by zymosan and phorbol myristate acetate. Superoxide production by unstimulated AM increased significantly 1 h after subjects had smoked 2 cigarettes, to 140.8 ± SD 14.7% of levels prior to smoking, but there was no increase in 4 control smokers tested before and 1 h after sham smoking. Superoxide production by unstimulated AM decreased significantly 2 minutes after smoking 4 cigarettes but O 2 − production by stimulated AM was not affected. Smoking had no effect on O 2 − production by AM under the other conditions tested. We conclude that, in addition to the chronic effect of smoking that increases O 2 − production by AM, there may be a stimulating effect of acute smoking, depending on the amount smoked and the time after smoking. The increased O 2 − production by AM following smoking may be a factor contributing to inactivation of alpha1-protease inhibitor.

SUMMARY. Pulmonary function tests were employed for the objective assessment of the response of 6 patients with systemic scleroderma to treatment with disodium EDTA. pyridoxine and reserpine. Impairment of pulmonary function was observed less frequently than in some other investigations. Treatment produced no consistent improvement. The possible implications of these findings are discussed.

Pulmonary function was studied in a 36-year-old woman who had undergone left pneumonectomy, left thoracoplasty, right upper lobectomy and resection of the medial segment of the right middle lobe, because of advanced pulmonary tuberculosis. At the time of the study, her sputum was negative and she was leading a fairly active life. The vital capacity was 50 per cent of predicted and the one-second forced expiratory volume was 45–51 per cent of vital capacity. Total lung capacity was 75 per cent of predicted (for both lungs) and residual volume was 48 per cent of total lung capacity. Arterial blood gases and pH were normal at rest. Arterial O 2 tension and pH decreased, and arterial CO 2 tension increased during exercise. Ventilation equivalent was normal, the venous admixture-like effect and the alveolar-arterial O 2 gradient were greater than normal and the resting O 2 diffusing capacity was reduced.

Summary Pulmonary-function studies in 11 early asymptomatic cases of schistosomiasis, before and after treatment with sodium antimony dimercaptosuccinate, suggest that early schistosomiasis may be accompanied by measurable though mild impairment of pulmonary function in the absence of clinical or radiologic evidence of pulmonary involvement.

Background An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. Methods We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs’ surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. Results There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p

A 28-year-old man developed recurrent hemoptyses, breathlessness, anemia, and bilateral pulmonary infiltrates after mild smoke inhalation. He had no laboratory evidence of kidney involvement. Transbronchial lung biopsy showed erythrocytes, iron-containing macrophages within alveolar spaces, normal basement membranes, and strongly positive linear staining of alveolar septa for immunoglobulin G (IgG). Serum antiglomerular basement-membrane antibody was strongly positive by radioimmunoassay. Kidney biopsy showed normal findings by light and electron microscopy but strongly positive linear staining of glomerular capillaries for IgG. Follow-up 9 months later while the patient was taking prednisone revealed no clinical evidence of pulmonary or renal disease. This case shows that immunopathologic study of transbronchial lung biopsies is helpful in differentiating between Goodpasture's syndrome and idiopathic pulmonary hemosiderosis, while the absence of clinical and microscopic evidence of kidney disease does not exclude Goodpasture's syndrome.

Protease-antiprotease imbalance in the lung is considered a likely pathogenetic mechanism in the development of emphysema. To assess whether differences in enzyme release from stimulated neutrophils could be a factor leading to increased elastase release in the lung, we compared the in vitro release of elastase and a lysosomal enzyme, β-glucosaminidase, from neutrophils of nonsmokers and smokers. Neutrophils were stimulated in vitro by zymosan as a phagocytic stimulus, and the synthetic polypeptide, N-formyl-methionyl-leucyl-phenyl-alanine (FMLP) as chemotactic factor. We studied 54 male subjects, 24 nonsmokers (mean age, 39.5 ± SD 14.4 yr) and 30 smokers (mean age, 45.4 ± SD 8.2 yr). Smokers were divided into 2 groups according to results of their lung function, 17 with normal and 13 with abnormal lung function. Smokers with abnormal lung function were older (59.8 ± SD 11.8 yr) and had smoked more (45.6 ± SD 18.2 pack-years) than smokers with normal lung function (mean age, 39.8 ± SD 11.0 yr; smoking, 22...

To evaluate whether epithelial damage of airways in asthma could be related to diminished levels of the low molecular weight bronchial leukocyte proteinase inhibitor (BLPI) in airways, we determined BLPI in bronchial washings of 13 asthma patients and 13 healthy subjects, using a sensitive enzyme-linked immunoassay. The patients had asthma due to western red cedar and had bronchial washings done 24 to 48 hours after a mild to moderate asthmatic reaction induced by inhalation challenge. We did not find significant differences in BLPI concentrations in lavage fluid of asthma patients and healthy control subjects. The ratios of BLPI to albumin levels in bronchial washings appeared to be lower among asthmatic patients, but this difference was mainly due to an increase in albumin levels in lavage fluid in asthma. In addition, there were no significant differences in BLPI levels in washings obtained from main and segmental bronchi in both control subjects and asthma patients.

Excerpt To the editor: Weitz and associates (1) report increased elastase activity in smokers, as shown by a fivefold increase in plasma levels of the neutrophil elastase-derived fibrinopeptide A-a...

The effectiveness of nebulized anticholinergic and sympathomimetic regimens was evaluated in a double-blind study of 199 patients with acute airways obstruction. Patients were assigned to one of three treatment regimens according to a randomized schedule: 0.5 mg of ipratropium bromide, 1.25 mg of fenoterol hydrobromide, and 0.5 mg of ipratropium plus 1.25 mg of fenoterol. In 148 patients with acute exacerbations of asthma (mean one-second forced expiratory volume, 1.18 +/- 0.64 liters), all three regimens produced significant improvement in one-second forced expiratory volume (p less than 0.001). The greatest improvement followed treatment with the ipratropium-fenoterol combination (0.53 +/- 0.40 liters at 45 minutes; 0.57 +/- 0.51 liters at 90 minutes) and was significantly greater than that following either ipratropium alone (p less than 0.001) or fenoterol alone (p less than 0.05). In 51 patients with acute exacerbations of chronic obstructive pulmonary disease (mean one-second forced expiratory volume, 0.67 +/- 0.29 liter), each regimen produced significant improvement in one-second forced expiratory volume at both 45 and 90 minutes (for all, p less than 0.05), but there was no significant difference among the three treatment regimens. It is concluded that, in patients with acute asthma, combination therapy with sympathomimetic and anticholinergic agents is more efficacious than either one alone. In patients with acute exacerbations of chronic obstructive pulmonary disease, although either sympathomimetic or anticholinergic therapy provides bronchodilatation, no further benefit could be demonstrated from combination therapy.

Background Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects. Methods We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated. Results We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages. Conclusions We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.

Methaqualone, a relatively new sedative hypnotic drug in the United States, has unique properties which make the handling of overdosage somewhat different from the standard procedures. We report the case of a 20-year-old woman who ingested a large quantity of the drug and required curarization and artificial ventilation during the course of her recovery. The paper recounts the details of this treatment and reviews available literature on principles of therapy for methaqualone overdose.