The American review of respiratory disease

Print ISSN: 0003-0805
Publications
The analysis concerns the local and systemic effects of 200 µg of purified protein derivative of tuberculin, which was administered by error to 152 persons, 53 of whom were tuberculin reactors. The reactions to 200 µg PPD (10,000 TU) ranged from 6 mm to 124 mm in diameter; most measured 45 mm to 60 mm. The correlation between reactions to the excessive dose and those to a routine dose of 0,02 µg performed eight weeks later was poor. Complications included tissue destruction at the injection site as large as 7 mm in diameter and slight enlargement of local lymph nodes. One third of the patients had general symptoms such as fatigue, malaise, fever, nausea, and shortness of breath. Although 21 persons were confined to bed, only symptomatic treatment was required.
 
The magnitudes of pulmonary responses we previously observed (1) following 6.6-h exposures to 0.12 ppm ozone (O3) suggested that responses would also occur with similar exposures at lower O3 concentrations. The objective of this study was to determine the extent of pulmonary function decrements, respiratory discomfort, and increased airway reactivity to methacholine induced by exposure to O3 below 0.12 ppm. Separate 6.6-h chamber exposures to 0.00, 0.08, 0.10, and 0.12 ppm O3 included six 50-min periods of moderate exercise (VE approximately equal to 39 L/min, HR approximately equal to 115 bpm, and VO2 approximately equal to 1.5 L/min). Each exercise period was followed by 10 min of rest. A 35-min lunch break was included midway through the exposure. Although not intended as an exact simulation, the overall duration, intensity, and metabolic requirements of the exercise performed were representative of a day of moderate to heavy work or play. Preexposure FEV1 averaged 4.39 L, and essentially no change (+0.03 L) occurred with exposure to 0.00 ppm O3. Significant decreases (p less than 0.01) of -0.31, -0.30, and -0.54 L were observed with exposures to 0.08, 0.10, and 0.12 ppm, respectively. The provocative dose of methacholine required to increase airway resistance by 100% (PD100) was 58 cumulative inhalation units (CIU) following exposure to 0.00 ppm and was significantly reduced (p less than 0.01) to 37 CIU at 0.08, 31 CIU at 0.10, and 26 CIU at 0.12 ppm O3; reductions in PD100 are considered indicative of increases in nonspecific airway responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Changes in respiratory function have been suggested for children exposed to less than 0.12 ppm ozone (O3) while engaged in normal activities. Because the results of these studies have been confounded by other variables, such as temperature or the presence of other pollutants or have been questioned as to the adequacy of exposure measurements, we determined the acute response of children exposed to 0.12 ppm O3 in a controlled chamber environment. Twenty-three white males 8 to 11 yr of age were exposed once to clean air and once to 0.12 ppm O3 in random order. Exposures were for 2.5 h and included 2 h of intermittent heavy exercise. Measures of forced expiratory volume in one second (FEV1) and the symptom cough were determined prior to and after each exposure. A significant decline in FEV1 was found after the O3 exposure compared to the air exposure, and it appeared to persist for 16 to 20 h. No significant increase in cough was found due to O3 exposure. Forced vital capacity, specific airways resistance, respiratory frequency, tidal volume, and other symptoms were measured in a secondary exploratory analysis of this study.
 
Twenty-five volunteers with chronic obstructive pulmonary disease of mild to moderately severe degree underwent 1-h exposures to 0.12 ppm ozone (O2) in purified air with intermittent mild exercise. Their responses were assessed in terms of forced expiratory performance, ear oximetry, and reported symptoms. Control studied consisted of similar exposures to purified air alone. Control studies were separated from O2 exposures by 1 month, and the order was randomized. All studies took place in a controlled-environment chamber, and were preceded by approximately 1 h of rest in a purified-air environment. No significant disturbances in forced expiratory performance or symptoms attributable to O2 exposure were found. A slight but significant tendency to decreased arterial hemoglobin oxygen saturation (SaO2) during exercise in O2 was observed. The decrement in SaO2 with O2 relative to clean air (mean 1.3%) was near the limit of resolution of the ear oximeter test and was detected by signal averaging, thus its physiologic or clinical significance is uncertain.
 
Adolescent asthmatic subjects have been shown to be much more sensitive than healthy adolescents to the inhaled effects of sulfur dioxide. To test whether similar adolescent asthmatics are more sensitive to other common ambient air pollutants, 10 healthy and 10 asthmatic adolescent subjects were exposed for 60 min to filtered air, 0.12 ppm ozone (O3), and 0.12 ppm nitrogen dioxide (NO2) on separate days at rest. The following pulmonary functional values were measured before, at 30 min, and after 60 min of exposure: peak flow, total pulmonary resistance (RT), thoracic gas volume at functional residual capacity (FRC), maximal flow at 50 and 75% of expired vital capacity (Vmax50 and Vmax75), and forced expiratory volume in one second (FEV1). Following 60 min of exposure at rest to low concentrations of O3 or NO2, there were no consistent significant functional changes in either healthy or asthmatic adolescent subjects. There also were no measurable differences between the 2 groups.
 
Epidemiologic data suggest that patients with chronic obstructive pulmonary disease (COPD) might be more sensitive than normal persons to the respiratory effects of oxidant pollutant exposure. Our study was designed to determine the response of patients with COPD to ozone. Thirteen white men with nonreversible airways obstruction (mean FEV1/FVC, 58%), of whom 8 were current smokers, were randomly exposed for 2 h to air and to 0.2 ppm ozone on 2 consecutive days using a single-blind crossover design. During either exposure, subjects exercised for 7.5 min every 30 min. Measures of respiratory mechanics obtained pre-exposure and postexposure were not significantly affected by either exposure. Similarly, ventilation and gas exchange measured during exercise showed no difference either between exercise periods or exposure days. However, arterial O2 saturation (SaO2), measured by ear oximetry during the final exercise period each day was lower (94.8%) at the end of O2 exposure, than SaO2 obtained at the end of air exposure (95.3%), the difference (0.48%) being significant (p = 0.008). Because normal subjects undergoing comparable exposures show a threshold for respiratory mechanical effects at about 0.3 ppm ozone, our data suggest that mild to moderate COPD is not associated with increased sensitivity to low ozone concentrations. However, our data do not rule out the possibility that the response of such subjects might be exaggerated at higher ozone concentrations. The consistent (in 11 of 13 subjects), though small, decrease in SaO2 may indicate that indexes of ventilation/perfusion distribution might be more sensitive measures of ozone effect in this compromised patient group than are conventional respiratory mechanics measures.
 
We sought to determine whether 0.25 ppm sulfur dioxide in filtered air causes bronchoconstriction when inhaled by freely breathing, heavily exercising, asthmatic subjects. Nineteen asthmatic volunteers exercised at 750 kilogram meters/min for 5 min in an exposure chamber that contained filtered air at ambient temperature and humidity or, on another day, filtered air plus 0.25 ppm sulfur dioxide. The order of exposure to sulfur dioxide and to filtered air alone was randomized, and the experiments were double-blinded. Specific airway resistance, measured by constant-volume, whole-body plethysmography, increased from 6.38 +/- 2.07 cm H2O X s (mean +/- SD) before exercise to 11.32 +/- 8.97 after exercise on days when subjects breathed filtered air alone and from 5.70 +/- 1.93 to 13.33 +/- 7.54 on days when subjects breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on days when subjects breathed 0.25 ppm sulfur dioxide was only slightly greater than on days when they breathed filtered air, but the difference was significant. To determine whether 0.25 ppm sulfur dioxide causes greater bronchoconstriction in asthmatic subjects exercising more vigorously, 9 subjects then repeated the experiment exercising at 1,000 instead of 750 kilogram meters/min. Specific airway resistance increased from 6.71 +/- 2.25 to 13.59 +/- 7.57 on days when subjects breathed filtered air alone and from 5.23 +/- 1.23 to 12.54 +/- 6.17 on days they breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on the 2 days was not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)
 
We previously reported (American Review of Respiratory Disease 1982; 125:664-669) that the respiratory mechanics of intermittently exercising persons with chronic obstructive pulmonary disease (COPD) were unaffected by a 2-h exposure to 0.2 ppm ozone. Employing a single-blind, cross-over design protocol, 13 white men with nonreversible COPD (9 current smokers; mean FEV1/FVC, 56%) were randomly exposed on 2 consecutive days for 2 h to air and 0.3 ppm ozone. During exposures, subjects exercised (minute ventilation, 26.4 +/- 3.0 L/min) for 7.5 min every 30 min; ventilation and gas exchange measured during exercise showed no difference between exposure days. Pulmonary function tests (spirometry, body plethysmography) obtained before and after exposures were unchanged on the air day. On the ozone day the mean airway resistance and specific airway resistance showed the largest (25 and 22%) changes (p = 0.086 and 0.058, respectively). Arterial oxygen saturation (SaO2) obtained in 8 subjects during the last exercise interval showed a mean decrement of 0.95% on the ozone exposure day; this change did not attain significance (p = 0.074). Nevertheless, arterial oxygen desaturation may be a true consequence of low-level ozone exposure in this compromised patient group. As normal subjects undergoing exposures to ozone with slightly higher exercise intensities show a threshold for changes in their respiratory mechanics at approximately 0.3 ppm, our data indicate that persons with COPD are not unduly sensitive to the effects of low-level ozone exposure.
 
Symptoms and changes in pulmonary function of subjects with chronic obstructive pulmonary disease (COPD) and elderly normal subjects, induced by a 4-h exposure to 0.3 ppm NO2, were investigated using a double-blind, crossover design with purified air. The 5-day experimental protocol required approximately 2 wk with at least a 5-day separation between randomized 4-h exposures to either NO2 or air which included several periods of exercise. Over a 2-yr period, COPD subjects, all with a history of smoking, consisting of 13 men and 7 women (mean age of 60.0 yr) and 20 elderly normal subjects of comparable age and sex were evaluated. During intermittent light exercise, COPD subjects demonstrated progressive decrements in FVC and FEV1 compared with baseline with 0.3 ppm NO2, but not with air. Differences in percent changes from baseline data (air-NO2) showed an equivocal reduction in FVC by repeated measures of analysis of variance and cross-over t tests (p less than 0.10). Subgroup analyses suggested that responsiveness to NO2 decreased with severity of COPD; in elderly normal subjects, NO2-induced reduction in FEV1 was greater among smokers than never-smokers. A comparison of COPD and elderly normal subjects also revealed distinctions in NO2-induced responsiveness.
 
Tracheal mucous clearance was measured in eight Beagle dogs after 1-h exposures to sulfuric acid mist with particle sizes of 0.3 micron and 0.9 micron mass median aerodynamic diameter (MMAD). The method used was to anesthetize the dogs with halothane, insert a fiberoptic bronchoscope into the trachea, turn off the anesthetic, and then deposit a 10-microliter droplet containing approximately 50 muCi of [99mTc]macroaggregated albumin as the dog started to regain consciousness. Subsequently, gamma camera scintiphotos were taken every minute for 25 min in the awake dogs to measure velocities of the labeled material moving up the trachea. For the 1.0 mg/m3, 0.9 micron MMAD exposures, tracheal mucous velocities were significantly depressed after 30 min (26% reduction, p = 0.05), 1 day (40%, p less than 0.01), and even after 1 wk (30%, p = 0.05). Velocities had returned to the control range 5 wk after exposure. For the 0.5 mg/m3 exposure nonsignificant increases in clearance were seen after 30 min (35%) and 1 day (8%). However, 1 wk after exposure, there was a significant depression in clearance (34%, p less than 0.01). There were no significant changes after exposures to the 0.3 micron MMAD aerosols at concentrations of 1.0 or even 5.0 mg/m3.
 
Whether short-term exposure to low levels of nitrogen dioxide (NO2) enhances airway responsiveness in asthmatic subjects is controversial. Because it is well established that asthma is associated with increased airway responsiveness to another common air pollutant, sulfur dioxide (SO2), we examined whether short-term exposure of asthmatic subjects to 0.3 ppm NO2 potentiates airway responsiveness to inhaled SO2. We exposed nine subjects with clinically stable asthma to 0.3 ppm NO2 or filtered air in an environmental room for 30 min on 2 separate days at least 1 wk apart in a double-blind, randomized fashion. A questionnaire about common symptoms related to inhaled irritants was completed before and immediately after each exposure. Each subject exercised (60 to 80 W) on a cycloergometer during the first 20 min of each exposure. We measured specific airway resistance (SRaw) and FEV1/FVC before, 5 min after, and 1 h after completion of the air or NO2 exposure. The single-breath nitrogen test (SBN2) was also performed before and 1 h after completion of the air or NO2 exposures and closing volume was determined; subsequently, SO2 dose-response curves (0.25 to 4.0 ppm) were performed via a mouthpiece. Each dose of SO2 was inhaled at a minute ventilation of 20 L/min for 4 min and was doubled until SRaw increased by at least 8 U above baseline. The dose of SO2 required to provoke an increase in SRaw of 8 U above baseline was determined by linear interpolation from the dose-response curve (PD8Uso2).(ABSTRACT TRUNCATED AT 250 WORDS)
 
Epidemiologic studies support an association among elevated levels of nitrogen dioxide (NO2), increased respiratory symptoms, and alterations in lung function. To determine if low level NO2 inhalation potentiates exercise-induced bronchospasm, 15 asthmatic subjects, defined by airway constriction with cold air provocation, inhaled 0.30 ppm (560 micrograms/m3) NO2 for 30 min. All asthmatics inhaled either air or 0.30 ppm NO2 via a mouthpiece for 20 min at rest followed by 10 min of exercise on a bicycle ergometer at a workload of 300 kpm/min, producing a 3-fold or greater increase in minute ventilation. Our studies showed 72 +/- 2 (SE)% deposition of inhaled NO2 at rest and 87 +/- 1% deposition with exercise (p less than 0.001). Nitrogen dioxide inhalation at rest resulted in no significant change in pulmonary function. Nitrogen dioxide inhalation plus exercise compared to control (air) exposure plus exercise produced significantly greater reductions in FEV (p less than 0.01) and partial expiratory flow rates at 60% of total lung capacity (p less than 0.05). One hour after completion of NO2 exposure and exercise, pulmonary function had returned to baseline values. To determine if NO2 exposure caused increased reactivity to a known bronchoconstrictor, asthmatic subjects inhaled cold air (range: -11 +/- 2 degrees C) at 3 successive rates of isocapnic ventilation. The response to cold air was expressed as the respiratory heat exchange required to reduce the FEV by 10% (PD10RHE). Prior NO2 exposure potentiated the fall in FEV, PD10RHE, and specific airway conductance (p less than 0.05) after isocapnic cold air hyperventilation, compared to the control exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
 
We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.
 
To determine the role of thromboxane A2 in the airway hyperresponsiveness induced by antigen challenge, we studied the effect of a thromboxane synthetase inhibitor, OKY-046, i.e., sodium (E)-3-[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, in 6 ragweed-sensitized dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus total pulmonary resistance before and 6 and 24 h after inhalation with ragweed antigen. This procedure was repeated in each dog during intravenous infusion of OKY-046 (100 micrograms/kg/min). OKY-946 did not alter the acute increase in total pulmonary resistance after antigen. At 6 h, there was a 7-fold increase in airway responsiveness, an effect that was prevented by OKY-046 (p less than 0.001). At 24 h, 18 h after OKY-046 was stopped, hyperresponsiveness was still significantly inhibited. OKY-046 did not alter the influx of neutrophils recovered by bronchoalveolar lavage performed at 6 h after antigen challenge. Antigen-induced airway hyperresponsiveness in dogs may depend upon the thromboxane A2 generation from inflammatory cells (e.g., neutrophils).
 
Phorbol myristate acetate (PMA), which produces an experimental model of acute lung injury similar to the adult respiratory distress syndrome, was studied in isolated dog lung lobes perfused at constant pressure in Zone 3 conditions. The effect of 25 to 50 micrograms PMA on pulmonary vascular permeability and resistance was observed in 4 groups of lungs: Group 1, perfused with a plasma/dextran solution; Group 2, perfused with blood; Group 3, blood-perfused and pretreated with verapamil (a calcium channel blocker); and Group 4, blood-perfused and pretreated with OKY-046 (a thromboxane synthetase inhibitor). Permeability changes were assessed by determining capillary filtration coefficient (Kf), isogravimetric capillary pressure (Pci), and in blood-perfused lungs, the protein reflection coefficient (sigma d). An increase in Kf, a decrease in Pci, and a decrease in sigma d, all indicative of an increase in vascular permeability, occurred 1 h after PMA in blood-perfused but not in plasma/dextran-perfused lungs. An increase in pulmonary vascular resistance occurred in both blood- and plasma/dextran-perfused lungs. Verapamil (2 X 10(-5) M) and OKY-046 (7 X 10(-4) M) pretreatment in blood-perfused lungs essentially blocked the PMA-induced change in permeability and significantly attenuated the increased vascular resistance. Total leukocyte and platelet counts fell in all blood-perfused lungs, whether pretreated or not. We conclude that cellular components of blood (platelets and/or leukocytes) are required to produce the permeability injury but not the pulmonary vasoconstriction and that the injury can be attenuated by either a calcium channel blocker or a specific thromboxane synthetase inhibitor. The left ventricular volume change caused by increasing right ventricular volume was measured at normal and elevated pericardial pressures.
 
The effect of a new dihydropyridine-derivative calcium antagonist, PY 108-068, on resting and postexercise flow rates was evaluated in 12 adult asthmatic subjects in a double-blind, randomized, placebo-controlled, cross-over study. The study consisted of 2 periods, each lasting for 3 days. For a given period a single dose of PY 108-068 (or placebo) was given orally, 75 mg on the first day and 150 mg on the second and third day. Spirometry was obtained at 30-min intervals thereafter. On Day 3, 75 min after the medication was given, a 6-min treadmill exercise test was performed breathing dry air. The mean maximal FEV1 recorded after 150 mg of PY 108-068 on Day 2 was 15 +/- 4% higher than the daily baseline (p less than 0.05), whereas after placebo the maximal FEV1 value was not different from the daily baseline. Also, the mean FEV1 values, expressed as percent of the daily predrug baseline, were significantly higher at 2 and 3 h after 150 mg of PY 108-068 than the respective values after placebo (110 +/- 4 compared with 95 +/- 1, and 106 +/- 5 compared with 91 +/- 3, respectively). Exercise-induced bronchospasm (EIB), expressed as maximal percent fall in FEV1 from preexercise baseline, was attenuated by PY 108-068 as compared with placebo (% delta FEV1 of 20 +/- 6 and 40 +/- 4, respectively; p less than 0.001). Protection against EIB did not correlate with the resting bronchodilation induced by PY 108-068, but was more likely if the patient had eosinophilia. Thus, PY 108-068 not only attenuates EIB but also causes resting bronchodilation, a unique finding for calcium channel blockers.
 
The relation of chronic air-flow limitation and respiratory mucus hypersecretion to all causes of mortality was studied in a population of 1,061 men working in the Paris area, surveyed initially in 1960/1961, and followed for 22 yr. During this period, 369 deaths occurred; VC, FEV1, FEV1/H3, and FEV1/VC were significantly associated with mortality, even when age, smoking, occupational dust exposure, and chronic phlegm were taken into account. Besides the obstructive disorder, the hypersecretory disorder (chronic phlegm) was significantly associated with mortality. Controlling, using Cox's model, for age, FEV1/H3, smoking habits, and dust exposure, all factors associated with chronic mucus hypersecretion and mortality, showed that phlegm production remained significantly related to death (relative risk, = 1.35; p less than 0.01). Although relatively weak, this relationship is not negligible in terms of public health because of the high prevalence of chronic phlegm.
 
To investigate the extrarenal production of 1,25(OH)2D3 in tuberculosis, we extensively evaluated a patient with tuberculosis, hypercalcemia, and an elevated plasma concentration of 1,25(OH)2D3. Fresh total cells and cultured alveolar macrophages obtained by bronchoalveolar lavage were demonstrated to synthesize 1,25(OH)2D3 prior to and after nine months of successful antituberculous therapy. The continued capacity to produce 1,25(OH)2D3 was associated with a persistent lymphocytic alveolitis in this patient. This extrarenal production of 1,25(OH)2D3 probably contributed to the increased levels of plasma 1,25(OH)2D observed in our patient. Nevertheless, a close correlation between plasma 1,25(OH)2D and serum calcium was not observed. These findings suggest that although extrarenal production of 1,25(OH)2D3 occurs in tuberculosis, it need not be a predominant factor producing the abnormalities in calcium homeostasis observed in such patients.
 
Pyrazinamide (PZA) is believed to be mycobactericidal in vivo. Because it is ineffective at neutral pH in vitro, it is thought to owe its in vivo activity at least partly to acting upon tubercle bacilli (TB) in the helpfully low pH of macrophage (MP) phagolysosomes. However, when it was tested in TB-infected cultured human MP, it was not bactericidal and was able only to slow intra-MP bacillary growth. Recent evidence has suggested that human MP need hormonal support from certain vitamin D metabolites to resist TB. This support was not provided in the culture medium of the earlier experiments in which the PZA was relatively ineffective. Here, PZA has been retested in MP cultured in medium supplemented with the hormonally active metabolite of vitamin D, 1,25(OH)2-vitamin D3 (1,25D3). The MP were infected with virulent TB and incubated in various concentrations of PZA. 1,25D3 was added to postinfection medium at 4 micrograms/ml. Inhibition or killing of intracellular TB was quantitated by counts of culturable TB from samples of lysed MP taken at zero, 4, and 7 days after MP infection. Previous evidence for the protectiveness of 1,25D3 alone for human MP against TB was confirmed. The weak inhibition of TB in MP by PZA alone also was confirmed. The two used together synergized to decrease concentrations of PZA which were inhibitory and to switch the action of PZA from weakly inhibitory to bacteriostatic or mildly bactericidal. 1,25D3 had no direct anti-TB effect, and it did not synergize with PZA in the absence of MP, as determined with acidified bacteriologic culture medium in the BACTEC radiometric system.(ABSTRACT TRUNCATED AT 250 WORDS)
 
1,25(OH)2D3 is known to be produced at sites of granulomatous reactions. In order to characterize the cell types that are targets for this immunoregulatory hormone, we have evaluated the expression of 1,25(OH)2D3 receptors on peripheral blood T-lymphocytes and those recovered from the lung by bronchoalveolar lavage from patients with pulmonary granulomatous diseases (tuberculosis and sarcoidosis) and from normal control subjects using combined autoradiographic and immunohistochemical techniques. Lavage T-lymphocytes from patients with tuberculosis or with sarcoidosis, but not those from normal control subjects, expressed 1,25(OH)2D3 receptors as demonstrated by binding of [3H]1,25(OH)2D3, which was inhibited by the presence of excess unlabeled 1,25(OH)2D3, but not by the presence of unlabeled 25(OH)D3 (receptor-positive lymphocytes: sarcoidosis, 20 +/- 12%; tuberculosis, 31 +/- 17%). In contrast, blood lymphocytes from patients with granulomatous diseases did not express detectable 1,25(OH)2D3 receptors. The percentage of lavage T-lymphocytes expressing 1,25(OH)2D3 receptors was significantly greater for patients with tuberculosis presenting with isolated hilar adenopathy than for patients with pulmonary infiltrates and/or cavities. 1,25(OH)2D3 receptors were expressed to a greater extent on CD8+ T-lymphocytes than on CD4+ T-lymphocytes in sarcoidosis, whereas a greater proportion of CD4+ than of CD8+ T-lymphocytes from patients with tuberculosis were receptor-positive. These findings support the conclusion that the interaction of 1,25(OH)2D3 with its receptor on T-lymphocytes may play an important role in the regulation of granulomatous reactions, but because these receptors are expressed on different lymphocyte populations, the net effect of this potent immunoregulatory molecule is likely different in sarcoidosis and tuberculosis.
 
The ability of the rat diaphragm to produce inositol 1,4,5-trisphosphate (InsP3) in response to a maximal contractile stimulus was determine in vitro in both fatigued and nonfatigued diaphragms. InsP3 was produced during a maximal contraction of the diaphragm. After inducing fatigue, there was a significant reduction in the production of InsP3 compared with that in nonfatigued muscle. The maximal force generated by the diaphragm was also decreased after fatigue. A significant positive linear correlation was found between the force developed by the diaphragm and the amount of InsP3 liberated.
 
Calibration of the respiratory inductive plethysmograph (RIP) was performed in premature infants weighing less than 1,500 g. In only 25% of the studies was an acceptable calibration achieved, as assessed by statistical comparison of simultaneously measured pneumotachygraph and RIP tidal volumes. In 6 infants, dead space loading or air injection was performed in an attempt to alter abdominal and rib cage volume contributions and thereby improve the calibration. Neither of these maneuvers resulted in an improvement of the accuracy of the RIP calibration coefficient. We conclude that, when calibrated by the least squares technique, the reliability of inductive plethysmography in measuring tidal volume in small infants is low. This is presumably because they have very small tidal volumes and highly compliant rib cages.
 
Atropine is known to be an effective bonrchodilator. We studied the effectiveness of aerosol Sch 1000, a derivative of atropine, in relieving bronchoconstriction in asthma. A single dose of drug was effective within 5 min, and the effect had a duration of 4 hours. No side effects were noted. The major effect of the drug appeared to be in large airways.
 
Sch 1000 is a derivative of atropine with equivalent bronchodilator activity. A double blind controlled study of Sch 1000 administered to asthmatic subjects by inhalation in 4 doses from 10 mug to 80 mug was conducted. The onset of action was between 15 and 30 min, compared to 5 min for isoproterenol, but persisted for 4 hours compared to 1 hour for isoproterenol. The maximal level of bronchodilatation produced by Sch 1000 was comparable to but not as great as that after isoproterenol. Dose-response data suggested that maximal bronchodilatation may be achieved by 10 to 20 mug of Sch 1000; larger doses did not result in significantly greater increases in forced expiratory volume in 1 sec or maximal mid-expiratory flow. The Sch 1000-mediated increase in maximal mid-expiratory flow was significantly greater than that of forced expiratory volume in 1 sec. Fewer side effects were encountered after Sch 1000 than after isoproterenol and no atropine-like effects could be attributed to Sch 1000 in the doses studied.
 
Maximal static respiratory pressures were determined by a simplified method in a group of patients with neuromuscular disease and were more frequently abnormal than the vital capacity, maximal midexpiratory flow, or maximal breathing capacity. This method detected muscle weakness even in the presence of coexistent intrapulmonary disease and was helpful in evaluating dyspnea in these patients. Early in the disease, the maximal static respiratory pressures can be abnormal even though the results of spirometry are normal.
 
The effects of 800 micrograms of inhaled SK&F 104353, a peptidoleukotriene receptor antagonist, and of 20 mg disodium cromoglycate (DSCG) on exercise-induced bronchoconstriction were compared in 18 asthmatic patients. The study was conducted according to a double-blind, crossover, randomized, placebo-controlled design. Two baseline exercise tests were carried out, and pulmonary function tests were done before and at 1, 5, 10, 15, 20, and 30 min after completion of the exercise. Patients showing a 20% or greater decrease in FEV1 in both exercise challenges entered the blinded portion of the study. When placebo was administered before exercise, FEV1 fell to the same extent as during the baseline phase. After SK&F 104353 and DSCG, the bronchoconstriction was attenuated. The mean maximal percentage fall in FEV1 after exercise was 29% after placebo and 20% after SK&F 104353 and DSCG. The differences between the two active treatments did not reach the 5% level of statistical significance, though at 20 min SK&F 104353 showed a more pronounced effect than DSCG. The protective effect suggests an important role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.
 
We have determined the effect of prior inhalation of the LTD4 antagonist SK&F 104353 on the response to aspirin ingestion in six aspirin-sensitive asthmatic subjects (five women and one man 31 to 54 yr of age) in a randomized, double-blind, cross-over, placebo-controlled study. Pretreatment with inhaled SK&F 104353 (average nebulized dose, 893 micrograms) inhibited the response by a mean of 47% (p = 0.02). The inhibition was partial, ranging from 43 to 74% in five subjects. In the remaining subject, there was no effect of the drug on the asthmatic response. We conclude that the mechanism of aspirin-induced asthma is at least partially mediated by the leukotrienes in the majority of susceptible patients and that leukotriene antagonists may be useful in the treatment of aspirin-induced asthma.
 
•SUMMARY _ Common gram-negative bacilli were the causative agents in 59 (7.28 per cent) of 801 patients with pneumonia seen at a large Veterans Administration Hospital during a 4-year period. Nineteen pa­ tients with Pseudomonas pneumonia were elderly, and most had severe obstructive lung disease or had recently undergone an emergency surgical procedure. Prior multiple or broad spectrum antimicrobial drug therapy was usual. The infection was precipitated by aspiration and appeared on chest roentgenograms as an alveolar infiltrate with cavitation. Multilobar involvement that included a lower lobe was characteristic. Pseudomonas pneumonia was a terminal illness in 18 patients, but vigorous attention to tracheobronchial toilet and improved antimicrobial drug thera­ py should decrease the mortality of this infection.
 
ONO-1078, 4-oxo-8(-)[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-y l)-4H-1-benzopyran hemihydrate, is a novel compound that has been shown to be a leukotrienes C4 and D4 (LTC4, LTD4) antagonist in the guinea pig airways. We studied the ability of ONO-1078 to inhibit and reverse the contraction of isolated human bronchus induced by LTC4, LTD4, and antigen. The human bronchial tissues were prepared from patients undergoing surgery for lung cancer, and they were placed in organ baths. ONO-1078 (10(-8) to 10(-6) M) produced a concentration-dependent inhibition of LTC4 and LTD4 concentration-response curves. In the presence of l-serine borate complex, which inhibits the conversion of LTC4 to LTD4 by gamma-glutamyl transpeptidase, ONO-1078 significantly inhibited the LTC4-induced contraction, suggesting that ONO-1078 is an antagonist of both LTC4 and LTD4. ONO-1078 (10(-6) M) also significantly reversed an ongoing contraction induced by LTC4 (10(-7) M). The inhibitory effect of ONO-1078 on LTC4-induced contraction was at least 100 times more potent than that of FPL 55712, the first discovered LTC4 and LTD4 antagonist. To study the effect of ONO-1078 on the contraction induced by antigen challenge, bronchial tissues were incubated for 2 h with serum of high specific IgE against house dust from an asthmatic patient. House dust antigen was added to the sensitized bronchial tissues after incubation with ONO-1078 (10(-6) M) or histamine H1 antagonist pyrilamine (10(-6) M), either alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Although the increased incidence of tuberculosis in persons with diabetes mellitus has been well documented, there is scant information on the incidence of diabetes in patients with tuberculosis. Accordingly, every consecutive patient admitted to a tuberculosis ward during a 5.5 yr period had a blood glucose determination 2 hr after 100 g of glucose orally. In 41% of the 256 patients, the blood glucose concentrations at 2 hr were in a diabetic range for the age of the patients. The greater incidence of glucose intolerance in a tuberculous population probably reflects an increased association between the 2 diseases. The older age of the group of patients with tuberculosis represents the successes of chemotherapy and is also the age at which maturity onset diabetes occurs. Thus viewed, diabetes might well be a factor that precipitates endogenous reactivation of tuberculosis.
 
While sputum cytologic findings associated with cigarette smoking have been described, little information is available regarding nonsmokers for comparative analysis. Over a 3-month period, our cytopathology laboratory examined 3-day pooled sputa from 109 never smokers. Eighty-five percent were able to produce satisfactory results without recourse to induction. Ninety of 93 (97%) individuals had negative or reactive sputum cytologic findings. No carcinoma was identified. Two cases showed metaplastic changes and one case revealed dysplasia but all were from symptomatic never smokers. Eight components of stimulation of bronchial epithelium were microscopically quantified on each case and the mean values of each were calculated to produce a profile of an asymptomatic never smoker.
 
In vivo production of thromboxane (TX) A2 and the cysteinyl-containing leukotrienes (LT) C4, D4, and E4 in correlation to airway responses was studied. Bronchial provocation with specific allergen in atopic asthmatics was followed by a significant increase in urinary concentration of immunoreactive LTE4 (34 +/- 6 before versus 56 +/- 7 ng/mmol creatinine after allergen challenge; n = 5) and 11-dehydro-TXB2 (164 +/- 29 versus 238 +/- 25 ng/mmol creatinine). In the presence of the leukotriene-antagonist ICI-204,219, which significantly increased the PD20 for allergen, the increment in urinary excretion of LTE4 was even higher (60 +/- 8 versus 288 +/- 128 ng/mmol creatinine; n = 5). In contrast, provocation with histamine (n = 5) did not provoke release of leukotrienes or thromboxane, nor was inhalation of LTD4 (n = 7) associated with increased urinary concentration of 11-dehydro-TXB2. Furthermore, bronchoconstriction induced by inhalation of lysine-aspirin in aspirin-sensitive asthmatics (n = 4) was followed by increased levels of LTE4 in the urine, whereas the levels of 11-dehydro-TXB2 remained the same. Finally, the basal levels of LTE4 in the urine of nine aspirin-sensitive asthmatics were elevated as compared with 15 other asthmatics (112 +/- 54 versus 38 +/- 20 ng/mmol creatinine; p less than 0.001). The findings support that the cysteinyl-leukotrienes are potential mediators of allergen-induced asthma and that the release of LTE4 and 11-dehydro-TXB2 into the urine appeared to be a direct and dose-dependent effect of the antigen-antibody reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
 
We treated two types of experimental pulmonary fibrosis elicited in mice by the intratracheal instillation of bleomycin or silica with monoclonal antibodies (mAbs) specific for the leukocytic integrins CD-11a or CD-11b. This treatment completely prevented collagen deposition, as measured by lung hydroxyproline content on Day 15 after instillation. Furthermore, anti CD-11a mAb was also effective when given on Days 20 and 25 and the lung hydroxyproline content determined on Day 30 after instillation, i.e., in the treatment of an established pulmonary fibrosis. Histologic studies indicated that anti CD-11 mAbs attenuated the fibrosing alveolitis induced by silica or bleomycin and in addition markedly decreased the lymphoid infiltration and platelet microthrombi associated with both types of alveolitis. In contrast, these mAbs had little or no effect on the cellularity of the bronchoalveolar lavage, mainly composed of macrophages. In normal mice, anti CD-11 mAbs also decreased the number of interstitial lymphocytes and the lung collagen content. These observations may lead new to therapies for pulmonary fibrosis.
 
We analyzed 44,664 annual measurements of forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in 12,258 white children and 1,041 black children between 6 and 11 years of age in 6 communities. Sex- and race-specific lung function development is described for this sample of preadolescent children. For both races, girls have lower median values of FVC and FEV1 than do boys of the same height. However, for the same level of FVC, girls have a higher FEV1/FVC ratio. Blacks have median levels of lung function lower by approximately 13% than whites of the same sex and standing height. Regression analysis showed that height, race, and sex are the most important predictors of lung function. Lung function also increases with weight and age, but the effect of these two variables on predicted lung function is small. The residuals from the regression model, which describe the distribution of lung function values, follow a Gaussian distribution in the logarithmic scale. A simple model is presented for calculating percentiles of the distribution of FVC and FEV1 as a function of height, race, and sex. In a subset of children with at least 5 annual observations, observed growth was compared with the constant percentile curves of the pulmonary function for height distributions. These children track along constant percentile curves (growth curves) of FVC and FEV, given height, much as they track along growth curves of height given age, once the larger proportional measurement error of lung function is taken into account. The proposed growth curves can therefore be applied clinically to evaluate a child's lung function, not only at a single examination but also longitudinally over a series of observations.
 
A marked increase in recognition of pneumonia due to gram negative bacilli has occurred in recent yr. The incidence of community acquired pneumonia due to gram negative bacilli increased in frequency from 0.6 to 8% in previous studies, to 12 to 20% of all pneumonias requiring hospitalization in 2 recent studies. Approximately half of the pneumonias acquired within a hospital setting are due to aerobic gram negative bacilli. Most bacterial pneumonia is due to microorganisms that make up the flora of the pharynx. Since the oropharynx of a normal person apparently does not provide a suitable environment for the growth of aerobic gram negative bacilli, such persons are only at slight risk of developing pneumonia due to these organisms. Chronically or severely ill patients lose effective pharyngeal clearance mechanisms, allowing colonization with gram negative bacilli, and hence such patients are at greater risk for developing pneumonia due to these organisms both within and without the hospital setting. Additionally, respiratory therapy equipment utilizing nebulizers may act as a vector for gram negative bacilli unless the equipment is decontaminated every 24 hr. Clinical presentations of non hospital associated pneumonias tend to have certain patterns, depending on the organism involved; however, the clinical presentation usually is not sufficiently specific to allow definitive diagnosis. Because expectorated sputum may be contaminated with oropharyngeal flora that may not be representative of the cause of the pneumonia, transtracheal aspiration of material for Gram stain and culture is preferred in patients with complicated or atypical pneumonias. Despite advances in development of antimicrobial agents, the prognosis for most forms of gram negative bacillary pneumonia is guarded.
 
Top-cited authors
Frank Speizer
  • Brigham and Women's Hospital
Douglas W Dockery
  • Harvard University
James Cameron Hogg
  • University of British Columbia - Vancouver
Peter J Barnes
  • Imperial College London
Scott Weiss
  • Partners HealthCare Personalized Medicine & Brigham and Women's Hospital