Gly-X-Y repeat sequences in the treatment of active rheumatoid arthritis.

The aim of the present study was to examine if oral administration of Gly-X-Y repeat sequences alleviates disease activity in rheumatoid arthritis (RA). The study had a randomized, placebo controlled and double blind design with a wash-out/cross-over between the two 3-months long treatment periods. A total of 40 patients entered and 36 patients fulfilled the study, among them 16 started with the active drug and 20 with a placebo. Disease activity score (DAS) was used as the primary outcome measure with several secondary outcome variables. Type I or alpha error of 0.05 was accepted and the power (= 1-beta) was set to 80%, which according to the power analysis was also achieved. With active drug treatment, joint swelling score (54 count; P < 0.001), Ritchie's index (P < 0.01) and DAS (P < 0.001) improved. HAQ also improved (P < 0.05), but there was no improvement in the subjective condition of the patients as measured with the self-reported Pain Disability Index and Comprehensible Psychopathological Rating scale questionnaires. Apparently, 5/36 patients had a response of > or = 1.2 in DAS and 33/36 changed for the better; DAS impaired only in 3/36 patients during the active drug treatment When the stringent EU response criteria were applied and the results were compared to the placebo group, the response was not clinically significant. We conclude that Gly-X-Y repeat sequences are not effective as used in the present study. However, this does not definitely disprove the value of the Gly-X-Y repeat sequences, because confounding effects of dosage, concomitant medication and excessive degradation of the linear Gly-X-Y sequences in the stomach, gut or by phagolysosomes could not be adequately controlled. The discrepancy between the favourable effects in the preliminary, open pilot study and the controlled clinical trial emphasizes the value of the DAS, EU response criteria and adequately administered controlled clinical studies.

Submaximal early exercise test compared to clinical findings for evaluation of short- and long-term prognosis after the first myocardial infarction. Result from the MONICA Projects in Augsburg and Toulouse.

Clinical and ergometric data were derived from 1098 consecutive exercise tests in patients with a first acute myocardial infarction between 1974-1983. In 1992 a follow-up was performed in order to analyse the importance of a submaximal early exercise test, in combination with clinical data, for the prediction of short- and long-term prognosis of cardiovascular death. The relative value of 20 clinical variables, including medical history, markers of infarction size, medication etc., and 28 variables at exercise test were studied. Univariate, multivariate and survival analysis, for estimation of prognosis and independent prediction of cardiovascular death was used. Independent clinical risk factors for cardiovascular death were (1) Within 1 year: relative heart volume (ml.m-2 body surface area) on chest X-ray. (2) Long-term mortality: maximum heart rate and relative heart volume, diabetes, age and digitalis medication. Independent exercise risk factors were: (1) Within 1 year: heart rate, ventricular arrhythmia and ST depression > or = 1 mm before exercise, diastolic blood pressure at maximum exercise and target heart rate. (2) Long-term mortality: angina pectoris and/or ST depression > or = 1 mm at maximum exercise. In subgroups of patients with clinical risk factors, mortality risk increased if there were signs of angina pectoris and/or ST depression > or = 1 mm during exercise. The risk increased 100% in diabetics, 91% with age > 70 years, 58% with relative heart volume > or = 500 ml.m-2 body surface area, 42% with heart rate > or = 100 at admission, and 34% with digitalis medication. No increase was found in the subgroup of patients without clinical risk factors. Thus, submaximal early exercise stress testing provides important information for short- and long-term prognosis in patients after the first acute myocardial infarction compared to clinical evaluation alone.

Cardiovascular risk factors in commercial flight aircrew officers compared with those in the general population.

Cardiovascular disease is the most common reason for loss of license among commercial flight pilots. This study was done to explore cardiovascular risk factors among aircrew officers. The study group consisted of 113 male commercial flight aircrew officers (aviators), aged thirty-five to forty-four years (mean: 38.8 years) who participated in the compulsory health screening. Men investigated at the Health Screening Centre, Malmö, were used as the reference group. Group 1, for ECG, (n 771), aged thirty-eight to forty-four years (mean: 42.1). Group 2, for height, weight, body mass index (BMI) (weight kg/height m2), blood pressure, serum cholesterol (total), and smoking habits (n 5005), aged thirty-five to forty-four years (mean: 39.2). The aviators did not differ from the reference population in regard to height, weight, BMI, diastolic blood pressure, or smoking habits. However, the incidences of electrocardiographic left ventricular hypertrophy, increased systolic blood pressure, and the level of cholesterol were significantly higher in the aviators when compared with the controls. Aircrew members may primarily be selected by criteria that differ from the male population in general. Excessive environmental stress, ie, shift work, jet lag, fatigue, as well as dietary factors, may also contribute to anomalies in the group. The clinical consequences of these anomalies for the aviators should be further evaluated, for they are important both for the aviators and for flying safety.

Metabolic, ventilatory and circulatory effects of doxapram in anaesthetized pigs during normoxia and hypoxia.

BACKGROUND: In a previous clinical study doxapram was found to improve ventilatory efficacy postoperatively, presumably via effects on hypoxic pulmonary vasoconstriction (HPV). The present study was designed to see whether doxapram induced any changes of arterial oxygenation and pulmonary vascular resistance during normoxia or hypoxia and whether the changes were influenced by the anaesthetic agents. METHODS: Seventeen piglets were anaesthetized by combinations of either midazolam + fentanyl + pancuronium + pentobarbital (TIVA, n = 9), or by midazolam + fentanyl + pancuronium + halothane, 0.5% in end-tidal gas (Hal, n = 8). Analyses of expired gas and mixed venous and arterial blood in combination with determinations of central blood flow and pressures allowed for calculations of standard metabolic, ventilatory and circulatory data. Values were obtained at normoventilation using normoxic (FIO2 = 0.3) and hypoxic (FIO2 = 0.08) gas mixtures at calculated doxapram plasma concentrations of 1, 2 and 4 micrograms.ml-1. RESULTS: With few exceptions doxapram administration affected the investigated variables only moderately during normoxia. In group Hal, PVR and SVR showed a biphasic raise (P < 0.05), CO fell (P < 0.05-P > or = 0.05) and C (a-v)O2 rose (P < 0.05). In group TIVA, PaO2 fell (P < 0.01-0.05) despite unchanged PVR, CO and VD/VT. Hypoxia affected a moderate increase in PVR in group TIVA (P < 0.05), which was slightly lower at the lowest and highest plasma levels of doxapram (P < 0.05). In group Hal, the induction of hypoxia induced a more pronounced rise in PVR (P < 0.05) which showed a biphasic response to increasing dose levels of doxapram, the lowest dose affecting a further rise (P < 0.05) and the highest a reduction to values below hypoxia control levels (P < 0.05). Pronounced differences between the two groups with respect to values for metabolic and circulatory variables make the interpretation of data difficult. CONCLUSIONS: Doxapram administration to anaesthetized animals did not induce any effects indicative of augmentation of the HPV response.

An exploration of intrapulmonary insulin administration in anaesthetized and mechanically ventilated pigs.

We investigated the efficacy of intrapulmonary administration of short-acting porcine insulin in anaesthetized pigs (n = 14) in a randomized intervention study. Insulin was administered by a new jet nebulizer (Maxin) in a random order at different doses, 0 (saline), 10 or 40 U. The hypoglycaemic effect was compared to control (0.9% saline). Blood glucose and serum insulin concentrations were followed at specified time intervals for 90 min. Plasma catecholamine concentrations were measured in order to estimate the concurrent stress. Nebulized insulin caused a significant decrease in blood glucose concentrations (p < 0.0001) (n = 28) at all doses used. The decrease in mean blood glucose concentration from the start of nebulization was 39 +/- 3% (mean +/- SEM), falling from 4.6 +/- 0.1 to 2.8 +/- 0.2 mmol 1(-1), with a nadir at 40 min after the 40 U insulin dose (n = 10). Serum insulin concentration rose from (mean +/- SEM) 5.2 +/- 0.1 to 25 +/- 9 mU 1(-1) after the insulin dose of 40 U (n = 10), the peak value occurred at 30 min. The plasma catecholamine concentrations increased significantly (p < 0.0001) (n = 28) from 0 to 60 min, this increase was similar for control and for different insulin doses. We conclude that intrapulmonary administration of insulin can cause a significant decrease in blood glucose concentrations in anaesthetized and mechanically ventilated pigs and results in clinically relevant serum insulin levels. Similar effects in humans would make inhaled insulin possible for clinical use.

Asthma but not smoking-related airflow limitation is associated with a high fat diet in men: results from the population study "Men born in 1914", Malmö, Sweden.

The purpose of this study was to investigate whether there is an association between asthma and the intake of food with pro-oxidant or antioxidant activity (fat, alcohol, iron, zinc, and vitamins A and C), and to analyse whether any such association is specific to asthma or is found in airflow limitation in general. This study deals with 478 men, who were randomly selected from all the men born in Malmö in 1914. They were investigated using spirometry and their medical, occupational and dietary history was recorded in 1982-1983, at the age of 68 yrs, as part of the cohort study "Men born in 1914". Asthma was defined as a past or present physician's or nurse's diagnosis of asthma and airflow limitation was defined as a forced expiratory volume in one second/vital capacity ratio (FEV1/VC) of less than 70%. The relative risk of having asthma or airflow limitation as related to dietary intake at the age of 68 yrs was analysed after adjustments for smoking history and body mass index. Asthma was reported in 21 men and was not related to smoking history. Asthma was more common in men with a high fat intake (relative risk of asthma 1.74 for a 10% increase in fat intake, 95% confidence interval for the relative risk 1.13-2.68). The consumption of alcohol was higher for current smokers than ex-smokers and nonsmokers, and the intake of carbohydrates, vitamin C and iron was lower. Airflow limitation without asthma was present in 156 men and was related to smoking but not to dietary intake. Men with asthma had a significantly higher intake of fat than men without asthma. This difference appeared to be specific to asthma and was not found in airflow limitation in general.

Alcohol consumption modifies the total lung capacity in smokers.

Smoking-related airflow obstruction can develop with or without emphysema. Moderate alcohol consumption has been suggested to diminish the risk of centrilobular emphysema caused by smoking. Our aim was to study the influence of total energy and nutrient (protein, fat, carbohydrate and alcohol) intake on smoking-related emphysema. Lung function and nutrient intake including alcohol consumption were recorded at age of 68 years in 478 men as part of the population study 'Men Born in 1914' in Malmö, Sweden. In nonsmokers (n = 88) and ex-smokers (n = 223), there were no significant relationships between energy and nutrient intake and lung function. In smokers (n = 167), men in the highest and lowest quintile of total lung capacity (TLC) differed in alcohol intake (p = 0.004) but not in intake of total energy or other nutrients. In smokers with a forced expiratory volume in 1 s/vital capacity ratio of below 70% (n = 81), alcohol intake was positively correlated with TLC (r = 0.31; p = 0.006) after adjustment for smoking and body mass index. We conclude that in men with smoking-related airway obstruction, emphysema defined as large TLC was associated with high alcohol consumption but not with the intake of total energy or other nutrients.

Intramuscular laser-Doppler flowmetry in the supraspinatus muscle during isometric contractions.

To study the regulation of microvascular blood flow in a compartment muscle, laser-Doppler measurements of muscle microcirculation were recorded in the supraspinatus muscle in eight volunteers during and following submaximal isometric muscle contractions. The subjects performed isometric shoulder abductions at five contraction levels from 5% to 50% maximal voluntary contraction for 1 min each and a sustained 30 degrees shoulder abduction for 20 min. The subjects' perceived exertion increased from "no perceived exertion" to "near maximal exertion" during the 20-min period with 30 degrees shoulder abduction. Microcirculation increased during all 1-min contractions. Following the contractions at 20%, 30% and 50% MVC post-exercise reactive hyperaemia was seen for a period of at least 1 min. The reactive hyperaemia increased in magnitude in response to increasing contraction level. The results showed the same time-history of the blood flow at microvascular level as previously seen in larger peripheral vessels in response to muscle contractions. During the 20-min contraction microcirculation increased in line with the findings during the brief contractions. However, in contrast to the brief contractions no postexercise reactive hyperaemia occurred following the prolonged contraction. Lack of postexercise reactive hyperaemia following the prolonged shoulder abduction would suggest insufficient regulation of the vascular resistance. Alternatively, lack of hyperaemia could be taken as an indication of sufficient microcirculation during the preceding contraction. From previous studies on intramuscular pressure and metabolism the latter alternative would seem unlikely.

Delivery and retention of an insulin aerosol produced by a new jet nebulizer.

UNLABELLED: This study describes the delivery and distribution of an aerosol generated by a jet nebulizer (MAXIN) in an experimental animal model. Anesthetised, intubated and ventilated piglets inhaled radiolabeled technetium diethylene-triamine-penta-acetic acid (99mTc-DTPA) through the endotracheal tube. The lungs were excised en bloc and scintigraphed, using a computerized gamma camera to evaluate the pattern of distribution. By nebulizing radiolabeled 125I-insulin and comparing the activity deposited on inspiratory and expiratory electrostatic filters, delivery and retention of nebulized insulin was assessed. The distribution of aerosol in the lungs was very even and reached the most peripheral parts. The delivery of nebulized insulin was calculated to be 88.9 +/- 5.3% and 36.1 +/- 8.8% of the insulin delivered to the respiratory tract was retained. The immediate local effects of insulin aerosol administration on the lungs were evaluated using light microscopy. No adverse effects were observed at histopathologic examination of the lung tissue. CONCLUSION: This study shows a high penetration of aerosol to the peripheral parts of the lung and efficient delivery of nebulized insulin when using the MAXIN-nebulizer.

Lung function in adolescents with alpha 1-antitrypsin deficiency.

Children with alpha 1-antitrypsin deficiency, screened at birth, were followed prospectively. At 16 years of age, 150 adolescents (103 PiZ, 1 PiZ-, 1 PiS-, 45 PiSZ) were interviewed using a standardized questionnaire and asked to participate in an extensive lung function study including part or all of the following tests: FVC, FEV1 before and 15 min after four inhaled doses of salbutamol, TLC, RV and FRC. Fifty age-, sex- and height-matched adolescents participated as controls. No significant differences in age, height or weight were found between the PiZ, PiSZ and control groups. No significant differences were found in respiratory symptoms, parental smoking history or the smoking habits of PiZ, PiSZ and control subjects. Asthma occurred in 10.7% of PiZ, 6.5% of PiSZ and 4% of control adolescents (p = 0.33). Only 3 of 100 PiZ and 1 of 45 PiSZ adolescents were smokers. No significant contribution of alpha 1-antitrypsin Pi-type was found to explain the variation in lung function variables studied. We conclude that children with alpha 1-antitrypsin deficiency have a favourable prognosis and normal lung development up to 16 years of age. Anti-smoking advice was found to be reasonably successful; only 3% of those answering the questionnaire had started to smoke.

Upper airway irritation and small airways hyperreactivity due to exposure to potassium aluminium tetrafluoride flux: an extended case report.

OBJECTIVES: 22 workers, exposed to potassium aluminium tetrafluoride used as flux for soldering aluminium, were studied as clinical outpatients for symptoms of irritation of the nose, eye, skin, and airways. METHODS: 16 volunteered for spirometry with methacholine provocation test including a test for small airways function by volume of trapped gas (VTG). RESULTS: Median (range) latency time before respiratory symptoms developed was 6 (1-60) months. Symptoms of airways irritation diminished in all subjects after flux exposure ended. The FEV1 was within the normal range in 16 of 17 subjects before the methacholine provocation test. The FEV1 decreased by > or = 20% in two out of 16 subjects after the 0.1% methacholine provocation. Four out of the 17 subjects had a high VTG before methacholine provocation. After inhalation of 0.1% methacholine eight out of 16 subjects (50%) had an abnormal increase of VTG indicating hyperreactivity in small airways. DISCUSSION: Potassium aluminium tetrafluoride flux seems to induce an increase of bronchial reactivity in small airways. A setting of an occupational standard for potassium aluminium tetrafluoride is proposed.

A comparison of terbutaline inhaled by Turbuhaler and by a chlorofluorocarbon (CFC) inhaler in children with exercise-induced asthma.

The present study compared the bronchodilating effect of inhalation from the Turbuhaler (0.5 mg terbutaline x 2) with the effect of inhalation from the chlorofluorocarbon (CFC) inhaler (0.25 mg terbutaline x 4) in children aged 9-17 years with reproducible, exercise-induced asthma (EIA). The treatments were given on two occasions, 5 min apart (terbutaline 0.5 mg + 0.5 mg). The study was performed as a double-blind, double-dummy, and placebo-controlled trial in 12 asthmatic children. The study was conducted on three separate days. The bronchoconstriction was induced by steady running on a treadmill. Forced expiratory volume in 1 s (FEV1.0), vital capacity (VC), and volume of trapped gas (VTG) were measured before and after the exercise test and after treatment. The study showed that the same amount of terbutaline inhaled from the Turbuhaler or from a CFC inhaler is equally effective for reversing EIA, and that the Turbuhaler is possibly more effective for treating spasm in small airways.

Increased postprandial energy expenditure in obese women after peroral K- and Mg-phosphate.

Energy expenditure (EE) was studied in 15 obese (BMI > 27.5, median 29.2) and 15 lean (BMI < 22.9, median 21.7) healthy, postmenopausal women before and after peroral orange juice with or without K- and Mg-phosphate supplementation. The women, 56-58 years old, were studied in a double-blind, crossover experiment on two separate days. They received 100 ml of orange juice (10 g of carbohydrates) with or without a supplement of K+ (35 mmol), Mg2+ (17 mmol) and HPO4(2-) (39 mmol). Measurements were made before and 30 and 60 min after the stimuli. Intake of juice only had no effect on EE in either the lean or the obese subjects. When the minerals were added, EE (+6.3%; p < 0.001) increased significantly in the obese group with in a maximum 30 min after stimulus, while no such increase was seen in the lean group. The difference between the groups was significant (p < 0.05) and so was the difference in the obese group with or without minerals (p < 0.01). We conclude that an addition of potassium/magnesium-phosphate to glucose increases the postprandial thermogenesis in obese postmenopausal women, but not in lean ones.

Doxapram improves pulmonary function after upper abdominal surgery.

The effects of doxapram on postoperative pulmonary function were studied in 40 ASA I and II patients randomly allocated to receive either doxapram 1.8 mg.kg-1.h-1 or placebo for 2 h immediately after elective cholecystectomy. The two groups displayed similar reductions of carbon dioxide production at 2 h and 6 h postoperatively, whereas oxygen consumption remained at preoperative levels for 24 h. Minute ventilation was similarly reduced in the two groups at 2 h and 6 h postoperatively, with corresponding increases in PaCO2. PaO2 was similarly and significantly decreased in both groups postoperatively, whereas P(A-a)O2 remained unchanged at 2 h and 6 h in doxapram-treated patients. FRC was reduced postoperatively in both groups, significantly more so in the control group at 6 h. Various indices of intrapulmonary gas distribution, including the functional (nitrogen) dead space, underwent similar changes in the two groups. By contrast, the physiological dead space was reduced in doxapram-treated patients at 2 h, 6 h and 24 h postoperatively, whereas no significant changes were seen in the control group. The ventilatory equivalent for CO2 was significantly lower in the doxapram-treated group, implying higher ventilatory efficiency. Our findings indicate that infusion of doxapram postoperatively attenuates the impairment of pulmonary function postoperatively, chiefly via effects on V'A/Q' ratios. No side effects of doxapram were observed.

Small airways dysfunction among non-smoking shipyard arc welders.

Increased volume of trapped gas (VTG), indicating small airways dysfunction, was found among 14 never smoking non-atopic welders who had worked for 10-31 (mean 22) years in their occupation. Spirometry and nitrogen wash out data were compared with those from a reference group of 14 never smoking men not exposed to welding. A methacholine provocation test was carried out. The effect was measured by change in forced expiratory volume in one second (FEV1) and VTG. The maximum decrease in FEV1 after inhalation of methacholine was 6% in welders and 2% among referents. Before provocation VTG and VTG total lung capacity (TLC) was higher among welders (127 ml v 98 ml and 1.76% v 1.38%). The increase in VTG and VTG/TLC was higher in welders after inhalation of methacholine at concentrations of 0.001% to 2% and remained increased after inhalation of salbutamol. The differences indicate small airways disease among shipyard welders.

Markers for development of hypertension in commercial flight aviators.

In order to discover markers for the development of cardiovascular disease and hypertension, we studied systolic and diastolic blood pressure, ECG, and heart rate before, during and after exercise; body mass index (BMI); serum cholesterol; and smoking habits in 183 male aviators (mean age 41 years at commencement, and 55 at follow-up). Those developing cardiovascular disease had an overrepresentation of smokers but the disease could not be related to any other variable. By contrast we found the following independent markers for prediction of future hypertension in normotensive aviators: increased BMI, increased diastolic blood pressure at 50 W, low heart rate at maximal exercise and smoking. Of these markers high diastolic blood pressure and low heart rate during exercise are new. Subjects with initially elevated blood pressure who did not develop hypertension decreased their diastolic blood pressure after exercise in contrast to those developing hypertension.

Pulmonary blood flow distribution in erect man in air and during breathhold diving.

We used intravenously administered 99mTc-labelled macroaggregates and a gamma camera attached to a computer for measuring distribution of pulmonary blood flow per unit lung volume in eight healthy subjects sitting erect in air and also during breathhold diving to 1 or 10 m of depth. We measured distribution of perfusion in the supine position and substituted regional lung volume with regional perfusion in the supine for calculating regional perfusion per lung volume erect in air and during diving. The perfusion per unit lung increased rectilinearly down the lung in subjects below 30 years of age but decreased in the lowermost regions in older subjects. This decrease showed a strong correlation to closing capacity. An age-related decrease in transpulmonary pressure may influence both basal perfusion and closing capacity. During submersion, perfusion became equal in all regions with the exception of the lung apex which became hyperperfused. Close to the diaphragm, small inconsistent changes were noted. Redistribution was the same at surface (1 m of depth) with the lung volume being close to total lung capacity and at 10 m of depth when lung volume was compressed to functional residual capacity. During breathhold diving, high intrapulmonary blood volume and pressure became more important for blood flow distribution than gravity or lung volume, while differences in regional hypoxic vasoconstriction and in transpulmonary pressure seem to explain interindividual variation.

Pulmonary function in middle-aged women with heterozygous deficiency of the serine protease inhibitor alpha 1-antichymotrypsin.

Heterozygous alpha 1-antichymotrypsin (ACT) deficiency is inherited in an autosomal dominant mode independently of alpha 1-antitrypsin with a gene frequency (q) of 0.003. In a previous study, a high prevalence of enlarged residual volumes in subjects with the trait were noted. Neutrophil cathepsin G, the target proteinase of ACT, enhances the elastolytic action of elastase. Thus, hypothetically, subjects with the trait may have increased risk for developing pulmonary emphysema. To test whether heterozygous ACT deficiency predisposes to lung disease, plasma ACT concentrations were determined in a cohort of 1,872 middle-aged women. Women with subnormal levels were studied with respect to heredity, airway symptoms, and lung function. Twelve women (0.64% of the cohort) were classified as heterozygotes after family studies and were compared with control subjects, matched for age, weight, sex, and smoking status. There were no significant differences in airway symptoms between heterozygotes and control subjects. However, the prevalence of ex-smokers was significantly higher among heterozygotes than among the screened population as a whole (prevalence ratio, 2.18; 95% confidence interval, 1.004-4.72). There were no differences between the heterozygotes and the control subjects in the basal spirometry. However, after bronchodilation, five of the 12 heterozygotes manifested residual volumes greater than 2.5 standard deviations above normal mean compared with one of 24 control subjects (p = 0.012). The present investigation thus confirms our previous findings of an increased prevalence of enlarged residual volumes in heterozygous ACT deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrogen dead space in heavy smokers aged 44-58 years.

Functional and alveolar dead spaces for nitrogen (VDF and VDalv) were calculated in a population of 20 male and 20 female heavy smokers and compared to data from static and forced spirometry (functional residual capacity [FRC], residual volume [RV], lung clearance index [LCI] and volume of trapped gas [VTG]) obtained with the same multiple-breath nitrogen wash-out as the dead spaces, and to variables considered sensitive to small airways disease measured with a single-breath nitrogen elimination (closing volume in per cent of vital capacity [CV%], closing capacity in per cent of total lung capacity [CC%] and slope index [SI]). Both nitrogen dead spaces increased with tidal volume in smokers as well as in healthy non-smokers. The majority of smokers were outside the predicted mean +2 SD for VTG (75%), CC and VDalv (70%) and SI (65%). The following variables were less sensitive for disclosing abnormality: CV (55%), RV (53%), LCI (38%) and forced expired volume in the first second (FEV1, 33%). If high sensitivity is considered preferable in epidemiological studies, the nitrogen dead spaces are equally as sensitive as the better of earlier described tests, and significantly superior to LCI and FEV1. Being tests that measure alveolar distribution of inhaled gas, they are probably sensitive to small airways disease.