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Bronchial responsiveness to histamine or methacholine provides a useful objective measure for epidemiological studies of airways disease, but most people in a community population do not have a 20% fall in forced expiratory volume in one second (FEV1) with the highest dose administered. Histamine challenge data were analysed to compare the repeatability. Normality and separation of symptom groups of the early dose-response slope with provocative dose producing a 20% fall in FEV1 (PD20). Tests were continued until a 20% fall in FEV1 occurred, or 4 mumol had been given. Data were available for 510 randomly selected subjects, and for an additional 283 with wheeze. A repeat test was obtained in 104 individuals. PD20 was estimated by curve fitting, with extrapolation to 8 mumol. Least-squares slope of percentage decline in FEV1 on histamine dose was calculated, using all the measured points and two-point slope as the fall from the post-saline measurement to the maximum cumulative dose divided by the maximum dose. Log transformation of PD20 and shifted reciprocal transformations of slope produced constant variance. Over all subjects the three measures had similar repeatability; in subjects with PD20 > 8 mumol the intraclass correlation for two-point slope was only 0.26, but was 0.66 for least-squares slope. Neither measure of slope was normally distributed, but the distribution of log(PD20) was consistent with a censored normal distribution. In conclusion, least-squares slope is preferable to two-point slope for epidemiological studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Standard percentile curves are presented for weight, length, head circumference and chest circumference at birth for a population of 27,963 singleton infants born between the gestational ages of 26 and 42 weeks at a large, private hospital in Phoenix, Arizona. At term, all four growth parameters were significantly greater in male than in female infants. These parameters were significantly reduced in infants born to mothers who smoked and increased in infants born to mothers with diabetes. Percentiles in all parameters were higher than in those of previous studies, suggesting that continued use of growth curves based on older data may result in misclassification of infants with respect to appropriateness of growth-for-gestational age.

Inclusion of a standardized measurement of airway function is important in epidemiologic studies of asthma to facilitate comparison between different studies. Bronchial reactivity is widely used in such studies, but measurement of peak expiratory flow (PEF) variability has a number of potential advantages. We compared PEF variability with methacholine challenge tests in a community population sample. Subjects selected at random (n = 95) and on the basis of having experienced wheeze in the last 12 months (n = 130) performed a challenge test with methacholine to a maximum dose of 12.25 mumol and made serial PEF recordings every 2 h for a week. PEF variability was expressed as mean daily maximum amplitude as a percentage of the mean (amplitude % mean). Increased bronchial reactivity and PEF variability were arbitrarily defined as values above the 10th or below the 90th percentiles in the random sample. A measurement of amplitude % mean was available from all 225 subjects, whereas only 115 (51%) had a measurable PD20 methacholine. PD20 measurements correlated weakly but significantly with amplitude % mean (r = -0.44, p less than 0.001). Increased values of both bronchial reactivity and PEF variability were related to the presence of respiratory symptoms in the week before testing. Asthma was more strongly related to increased bronchial reactivity than to PEF variability. Both measurements showed a strong association with atopy and the intraclass correlation coefficients (ratio of between-subject to total variance) were similar for both.(ABSTRACT TRUNCATED AT 250 WORDS)

Many biologically active polypeptides have been described in the milk of several species. Various functions for these polypeptides in addition to nutrition have been proposed in the maternal body and in the breast-fed infant. These polypeptides are derived from several sources and multiple factors control their secretion into milk as well as their fate in the mother and infant. An increasing body of evidence supports the concept that they may function physiologically.

The airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind, crossover, placebo-controlled study the subjects received 2, 6, and 18 puffs of each drug with intervals of 90 min, and forced expiratory volume in 1 s, heart rate, QTc interval, plasma potassium concentration, tremor, and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol, salbutamol, and terbutaline were 29 (24) bpm, 8 (9) bpm, and 8 (14) bpm, respectively; falls in plasma potassium were 0.76 (0.62) mmol/l, 0.46 (0.32) mmol/l, and 0.52 (0.39) mmol/l, respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.

1. We have recently shown that ouabain, an inhibitor of Na+/K(+)-adenosine triphosphatase, causes contraction of bovine and human airways in vitro, and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo, we have studied the effect of oral digoxin (an inhibitor of Na+/K(+)-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind, placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or, when normal subjects were included, the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1, 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug, the geometric mean PD20FEV1 for histamine was 0.43 mumol after amiloride and 0.54 mumol after placebo (95% confidence intervals for the difference: 0.9 to -0.2 doubling doses of histamine; P = 0.2). 5. In study 2, six normal and 24 atopic asthmatic men inhaled 10 ml of 10(-2) mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 mumol and 4.3 mumol, respectively, in the normal subjects (95% confidence intervals for the difference: -0.53 to 1.52 doubling doses, P = 0.2), and 0.33 mumol and 0.29 mumol in the asthmatic subjects (95% confidence intervals for the difference: -0.95 to 0.57 doubling doses; P = 0.6).(ABSTRACT TRUNCATED AT 250 WORDS)

1. To determine whether alterations in membrane sodium transport in airway smooth muscle can alter its contractility, we studied the effect of ouabain (a Na+/K(+)-adenosine triphosphatase inhibitor) and amiloride on contractile responses in bovine trachea and human bronchial rings in a series of studies. 2. Ouabain (10(-6)-10(-4) mol/l) caused concentration-related contraction of bovine trachea with a maximum effect at 30 min; the mean increases in tension with 10(-6), 10(-5) and 10(-4) mol/l ouabain were 19, 27, and 32%, respectively, of the maximum response seen with 10(-3) mol/l histamine (n = 6). In human bronchial rings, ouabain (10(-5) mol/l) caused a mean contraction which was 40% of the maximum response to methacholine (n = 8). 3. Calcium-free fluid (plus ethylenediaminetetraacetic acid) and nifedipine (10(-5) mol/l) inhibited ouabain-induced contractions, suggesting that contraction was mediated in part by calcium entry via voltage-dependent calcium channels. Phentolamine (10(-5) mol/l) was without effect. 4. Ouabain (10(-5) mol/l) did not alter histamine responsiveness in bovine trachea or methacholine responsiveness in human bronchial rings. 5. Amiloride did not affect resting tone in bovine trachea but caused a concentration-dependent relaxation of bovine tracheal strips preconstricted with carbachol, 10(-3) mol/l amiloride relaxing strips completely over 15 minutes (n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)

We report the cases of neonatal lupus erythematosus associated with significant hepatic involvement in three living infants and in one infant who died 3 hours after delivery. The three living infants had neonatal cholestasis as a major component of their clinical findings. Pathologic changes included giant cell transformation, ductal obstruction, and extramedullary hematopoiesis. Liver involvement has been noted incidentally in children with neonatal lupus erythematosus, but it has generally been attributed to hemodynamic compromise as a result of congenital heart block or systemic toxic reactions. We speculate that neonatal hepatitis proceeding to hepatic fibrosis may occur in neonatal lupus erythematosus, analogous to the occurrence of "idiopathic" congenital heart block. The neonatal hepatitis associated with neonatal lupus erythematosus is a form distinguishable from the "idiopathic" group. Liver involvement may be more common than was previously recognized, and prospective studies to look for maternal autoantibodies in idiopathic neonatal liver disease should be undertaken.

1. Recent evidence suggests that a high salt diet increases bronchial reactivity, but the underlying mechanism is unclear. 2. To determine whether alterations in circulating vasopressin might be responsible, we have studied the effect of an infusion of vasopressin on the airways of six normal and eight asthmatic subjects measuring the response as expiratory flow at 30% of vital capacity (V30P) in the normal subjects and as forced expiratory volume in 1s (FEV1) in the asthmatic subjects, in a double-blind, placebo-controlled, cross-over study. 3. Vasopressin, given as an infusion at a rate of 2 i.u./h for 1 h, followed by 4 i.u./h for a further hour, produced plasma concentrations of 12.8 and 17 ng/l, respectively, compared with 2.0 and 2.0 ng/l on placebo. 4. Airway reactivity to histamine was measured after 1 and 2 h as the provocative doses of histamine causing a 40% reduction in V30P (PD40V30P) in the normal subjects and a 20% reduction in FEV1 (PD20FEV1) in the asthmatic subjects. 5. There was a small increase in PD40V30P after both vasopressin and placebo in normal subjects (refractoriness) but no change in PD20FEV1 in the asthmatic subjects. 6. There was no significant difference between vasopressin and placebo in V30P or PD40V30P over the 2 h after the drug in the normal subjects or in FEV1 or PD20FEV1 over the 2 h after the drug in the asthmatic subjects. 7. We conclude that alterations in circulating vasopressin are unlikely to be responsible for the increase in bronchial reactivity when dietary salt intake is increased.

Lactoferrin, a milk iron-binding protein, may play antimicrobial, iron-absorptive and growth-promoting roles in the developing gastrointestinal tract. To perform such functions, lactoferrin must survive digestive processes in the gut lumen in an active form. We investigated the gastric digestion of lactoferrin in addition to that of the other milk proteins, transferrin and casein, in preterm infants by measuring their degradation during incubation in vitro at 37 degrees C with gastric fluid at pH 1.8, 3.2 and 5.8. Fluid was obtained 1 h after a milk feeding, a time of maximum peptic activity, from 12 infants with a mean gestational age of 29.7 +/- 0.8 weeks at birth and a postnatal age of 24.7 +/- 3.2 days at sampling. Hydrolysis of all three proteins as indicated by generation of trichloroacetic acid soluble material from iodinated substrate was maximal at acid pH and declined by greater than 75% at pH 5.8, lactoferrin was less rapidly degraded than casein at low pH and transferrin breakdown was intermediate. Analysis of reaction mixtures by SDS-polyacrylamide gel electrophoresis showed degradation of lactoferrin and transferrin to low molecular weight products at pH 3.2 but minimal breakdown at pH 5.8. Several discrete fragments were generated at low pH, including species with molecular weights of 41,000-42,000 which may represent half-molecules. We conclude that dietary lactoferrin and transferrin may be degraded by preterm infant gastric fluid to discrete species, but that hydrolysis may be minimal at the prevailing postprandial pH. Consequently they may be rendered available for possible subsequent biological action within the infant.

Perinatal asphyxia may occur prior to or at the time of birth, leading to hypoxia and acidosis with persistence of the fetal circulatory pattern. Resuscitation facilitates transition to the adult circulatory pattern by restoring normal oxygenation, ventilation, and perfusion. Assessment of the degree of asphyxia should utilize the Apgar score, and resuscitation should proceed in a stepwise fashion to an extent determined by the degree of depression. Aspects of resuscitation unique to the newborn are reviewed, in addition to situations requiring specific intervention.

Epidermal growth factor (EGF), present in high concentrations in the milk of various species, is biologically active following oral administration to young animals. Although in vivo studies show gastrointestinal processing of dietary EGF during early postnatal development, the relative importance of luminal and mucosal digestion in such processing is undefined. To characterize the luminal metabolism of dietary EGF in the developing gastrointestinal tract, we incubated human recombinant 125I-EGF in vitro at 37 degrees with luminal fluid from the stomach and various segments of the small intestine of 12 day old suckling and 31 day old weanling rats and analyzed the resulting reaction products. The rate of EGF hydrolysis as determined by generation of acid soluble material was greater in weanling small intestine than in suckling, with maximal hydrolytic capacity observed in the mid-jejunum and ileum. Minimal hydrolysis was observed with stomach fluid from both age groups, and EGF retained its ability to elute as a single species on Sephadex G-25 columns and to bind to monospecific affinity columns and placental membrane receptors. Incubation with suckling small intestinal fluid produced little change in the chromatographic profile on Sephadex G-25, but a reduction in antibody and receptor binding was observed. In contrast, incubation with weanling small intestinal fluid yielded both a more pronounced loss of EGF-like material on G-25 columns and a greater reduction in receptor and antibody binding. We conclude that little luminal EGF degradation occurs in the rat stomach during the suckling and weanling periods, but that in the lumen of the small intestine breakdown increases during postnatal development.

Higher doses of inhaled albuterol have been shown to cause slightly more bronchodilatation than standard doses from a metered-dose inhaler in patients with severe chronic airflow limitation. Higher doses, however, carry an increased risk of side effects, and the optimum dose balancing benefit and adverse effects have yet to be established. We have therefore looked at objective and subjective evidence of beneficial and adverse effects after 4 doses of albuterol in 30 patients with chronic bronchitis, severe airflow limitation, and less than 200 ml increase in FEV1 after 200 micrograms inhaled albuterol. Subjects were given placebo, 400 micrograms, 1 mg, 2 mg, and 4 mg albuterol by dry powder inhaler in random order on separate days in a double-blind study, and FEV1, relaxed VC, PEFR, 12-min walk distance, finger tremor, oxygen saturation, heart rate, and arrhythmias were measured at intervals over 6 h. With increasing doses of albuterol, there was a significant dose-related increase in FEV1, VC, and PEFR, the maximal mean changes being 196 ml, 480 ml, and 50 L/min, respectively. The duration of effect was longer with the higher doses. There was a dose-related increase in heart rate, tremor amplitude, and supraventricular ectopic beats and a dose-related fall in oxygen saturation. There was no drug-related effect on the frequency of ventricular ectopic beats either at rest or during the walk tests. The largest increases in walk distance occurred after the 1 and 2 mg doses and the least after the 4 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway reactivity is known to increase in relation to the severity of asthma, and, in the community, hyperreactivity has been shown to be associated with respiratory symptoms such as wheezing and shortness of breath. However, the relation between change in airway reactivity and change in the severity of respiratory symptoms and change in the use of asthma medications within subjects has not been studied. We have investigated this relationship in a community population. In September 1984 and March 1985, the provocative dose of histamine producing a 20% fall in FEV1 (PD20) was measured, and respiratory symptoms and medication use assessed by questionnaire in 78 subjects taking part in a study of seasonal changes in airway reactivity. On both occasions, PD20 was negatively correlated with current frequency of wheezing, with the amount of asthma medication in regular use, and with the current general assessment of breathing problems. In the 45 subjects who had a PD20 value of 8 mumol or less on at least one of the two occasions tested, PD20 increased between September and March by 0.46 (SEM, 0.32) doubling doses of histamine (p = 0.16). Within subjects, change in PD20 was negatively correlated with change in the frequency of wheezing in the past month (p less than 0.005) and with change in medication use (p less than 0.05). This study demonstrates that PD20 is related to the severity of respiratory symptoms and medication use, and that change in airway reactivity within subjects in a community population is associated with changes in the frequency of wheezing and in the use of asthma medication.

Albumin excretion rates (AER) were measured in 30 insulin-dependent diabetics during a 16-week double-blind, randomised, placebo-controlled study of the specific thromboxane synthetase inhibitor UK-38,485.6 of 15 subjects in the active group had microalbuminuria (defined as mean pretreatment AER 20-150 micrograms/min); in these patients AER fell from 32 +/- 3 micrograms/min to 11 +/- 1 micrograms/min at 8 weeks and 9 +/- 1 micrograms/min at 16 weeks. The AER rose again (to 29 +/- 8 micrograms/min) within 12 weeks of stopping the drug. There was no significant change in the 10 patients with microalbuminuria who received placebo. There was a strong correlation between change from baseline values and the baseline values themselves in the active, but not in the placebo group, and the change from baseline differed significantly between the two groups. There was no change in glycosylated haemoglobin or mean blood glucose levels during the study. In a separate study UK-38,485 caused significant suppression of thromboxane B2 synthesis in diabetic and non-diabetic subjects.

Although serial peak expiratory flow (PEF) measurements are often used to assess the variability of airflow obstruction, the range of values to be expected in the general population has never been defined, nor is there any consensus as to how PEF variability should be expressed. We have compared PEF recordings made by 121 subjects selected at random from the population of a small town (Group A) and 221 subjects selected because of wheeze in the last year (Group B). Subjects were asked to record PEF every 2 h during waking hours for 7 days using a mini-Wright peak flow meter. Seven indices of PEF variability were derived for each subject and the range for each index determined. All indices showed a positively skewed distribution in the random sample. Two variability indices, standard deviation percent mean and amplitude percent mean, provided the greatest separation between subjects with both a diagnosis of asthma and wheeze in the last year and subjects with neither feature and also provided the highest intra-class correlation coefficients. We conclude that amplitude percent mean and standard deviation percent mean provide the best means of expressing PEF variability for epidemiological purposes, but that amplitude percent mean is more easily derived and appears to be the index of choice. PEF variability has a continuous distribution in the general population and no clear-cut division between asthmatic and nonasthmatic subjects can be defined.

A relation between the prevalence of asthma and economic development has been suggested by studies in migrants and other surveys in developing countries. That this correlation might be partially explained by an increased intake of salt in the diet is supported by the observation that sales of table salt in the different regions of England and Wales are independently correlated with mortality from asthma for men and for children. As part of a wider survey of asthma 138 men living in two Hampshire villages and aged 18-64 were given a bronchial histamine challenge test and had their 24 hour urinary excretion of sodium measured. Bronchial reactivity was strongly related to 24 hour excretion of sodium after allowing for the effects of age, atopy, and cigarette smoking, there being on average a 10-fold difference in reactivity over the 95% range of sodium excretion recorded in the study. The data suggest that a high sodium diet may potentiate bronchial reactivity.

Because previous measurements of early postnatal, small intestinal fluid, proteolytic activity in man and animals have been contradictory, we characterized the development of luminal protein digestion using a sensitive assay in which iodinated bovine casein was incubated in vitro at 37 degrees C with luminal fluid flushed from the stomach and small intestine of 12-day-old suckling and 31-day-old weanling rats, followed by measurement of radioactivity in trichloroacetic acid-soluble material. Gastric proteolysis at pH 3.2 in the weanling rat was approximately 50-fold greater than that in the suckling rat. Analysis of stomach fluid acid-soluble casein degradation products of weanling rats by chromatography on G-50 Sephadex in the presence of sodium dodecyl sulfate revealed three peaks of radioactivity comprising 65, 18 and 12% of the total product in order of elution. In the jejunum at neutral pH, the proteolytic capacity of the weanling rat was approximately five times that of the suckling rat; such differences were more pronounced in the ileum, however, in which protein hydrolysis of weanling rats was 30-fold higher than that in the suckling rat. In the suckling rat, small intestine proteolytic activity was greater in the jejunum than in the ileum, but in the weanling rat greater protein hydrolysis was present in the ileum. Gel filtration analysis of reaction products in both intestinal segments and at both ages demonstrated two peaks, which constituted 60-70 and 15-23% of the acid-soluble material in order of elution.(ABSTRACT TRUNCATED AT 250 WORDS)

We have compared the effects of the leukotriene (LT) D4 antagonist L-649,923 and placebo on the airway response to antigen challenge in eight men with mild asthma known to have both an early and late response to inhaled antigen. Subjects ingested 1000 mg of L-649,923 or placebo in a randomized, double-blind protocol and, two hours later, inhaled the dose of antigen known to induce a 20% fall in FEV1. Pulmonary function (specific conductance, FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity) was measured at intervals before and up to 9 hours after antigen. FEV1 fell in one subject after L-649,923 ingestion. L-649,923 in the other seven subjects caused no change in baseline pulmonary function, a small reduction in the early response to antigen for FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity but not for specific airway conductance (six subjects only) and no effect on the late response. The mean maximum fall in FEV1 in the early response was 1.35 L after L-649,923 ingestion and 1.78 after placebo ingestion. This relatively small degree of protection by L-649,923 suggests either that L-649,923 is not a sufficiently potent antagonist to diminish the effect of endogenous LTD4 in vivo or that LTD4 does not play a major role in the airway response to antigen challenge.

The recent controversy over the "Baby Doe" regulations issued by the Department of Health and Human Services represents the culmination of a dilemma that has faced the medical and legal professions for more than a decade. Although they have not been upheld by the courts, the regulations express the position that withholding treatment from defective newborns may constitute discrimination on the basis of handicap and advocate mechanisms for the reporting of such practices. Legislation regarding this issue is pending at both the national and state levels. The rulings have been disputed by many medical and professional groups, which are working to provide acceptable alternatives.

The safety of early newborn discharge was assessed by determining the incidence, time of onset, and nature or problems requiring hospitalization that appeared in the first two weeks of life among 1,735 consecutively born term infants in a private metropolitan hospital. Infants with and without abnormalities during the initial six-hour transitional period were compared. Of 1,583 initially well infants, 11 (0.7%) had problems other than jaundice develop that required hospitalization in the first three days of life. In contrast, 42 (28%) of the 152 infants with abnormal transitional periods required prolonged hospital care; this was statistically significant. The nature of the problems occurring before and after 72 hours was similar, jaundice being the most common and occurring with equal frequency in both periods. Most illness requiring hospitalization in the first three days of life could have been safely detected during an outpatient visit; these findings, in addition to a cost-benefit estimate, suggest that early discharge of initially well infants with careful follow-up may be an effective alternative to a traditional three-day stay.

The International Union against Tuberculosis and Lung Disease (IUATLD) Bronchial Symptoms Questionnaire (1984) was developed for use in studies of asthma and its reliability measured in an earlier survey in England. The association of the symptoms elicited by this questionnaire to bronchial response to histamine has also been described. This paper presents the results of studies of the questionnaire in four clinical centres in Europe. The reliability of the questionnaire and its ability to predict the bronchial response to histamine were compared for English, Finnish, French and German translations of the questionnaire in samples of diagnosed asthmatics and controls in Nottingham, Berlin, Helsinki and Paris. The answers to questions showed good repeatability, especially in Finland and Germany, particularly those questions on asthma and wheeze. The most sensitive symptom for predicting hyperresponsiveness was the question on wheeze, the most specific questions were those on waking at night with shortness of breath (Paris and Nottingham) and morning tightness (Helsinki and Berlin). This study shows that the IUATLD (1984) questionnaire may provide useful, valid and comparable data even in translation but these studies will need to be repeated in representative samples before such a possibility is accepted as fully demonstrated.

Campomelic dysplasia is a generalized disorder of cartilaginous growth and development, leading to early death from pulmonary insufficiency. We describe the airway dynamics as observed bronchoscopically in two affected infants. Both infants demonstrated anatomic compromise of the upper airway and diffuse laryngotracheobronchomalacia. Additionally, both had a characteristically small, bell-shaped thoracic cage. The abnormal airway dynamics produced serious inspiratory and expiratory obstruction in these infants and, in combination with the restrictive chest wall defect, led rapidly to the development of respiratory failure. While palliative procedures such as tracheostomy may temporarily improve airway dynamics, future respiratory tract insults may prove fatal.

To investigate whether cessation of regular beta-agonist treatment results in an increase in bronchial responsiveness, two double-blind, randomised crossover studies were done. Subjects with mild asthma were investigated to determine the course of change in bronchial responsiveness, measured as the provocative dose (PD20) of histamine that caused a 20% fall in forced expiratory volume in 1 s after short-term and longer term treatment with an inhaled beta-agonist. In the first study in 8 subjects, 500 and 2000 micrograms terbutaline thrice in 1 day protected against histamine-induced bronchoconstriction, and the increase in PD20 compared with placebo remained high throughout the day and overnight. In the second study 8 subjects received placebo or terbutaline 750 micrograms thrice daily for 14 days. The protection afforded by terbutaline against histamine-induced bronchoconstriction on day 14 was less than that on day 1 by 40% in the morning and 82% in the afternoon. On day 15 PD20 was lower after stopping terbutaline than placebo, with a maximum difference of 1.5 (95% CI 0.6-2.5) doubling-doses of histamine 23 h after the end of treatment. Thus treatment with terbutaline for 1 day did not result in any rebound increase in bronchial responsiveness. Treatment for 2 weeks impaired the ability of terbutaline to protect against histamine-induced bronchoconstriction, and was followed by a rebound increase in bronchial responsiveness after cessation of treatment.

Although stress during the perinatal period may influence a number of enzymes in the gastrointestinal tract, the resulting effects on digestive processes are not completely understood. In suckling rats, corticosteroid administration increases levels of proteases in gastric mucosa and pancreas, but previous studies of unstimulated luminal fluid proteolytic activity suggest no effect. To re-evaluate this phenomenon, we injected suckling rats with cortisone acetate (5 mg/100 g body weight) subcutaneously daily on days 9-11 followed by sacrifice on day 12; littermates served as controls. Luminal fluid from stomach and small intestine was analyzed for proteolytic activity by a sensitive assay in which incubation in vitro with 125I-bovine casein was followed by measurement of radioactivity soluble in trichloroacetic acid. Cortisone acetate produced significant increases in luminal proteolytic activity in all gastrointestinal segments with the most dramatic effect observed in the ileum; this segment showed a more than 10-fold enhancement of proteolysis with steroid treatment. Analysis of acid-precipitable reaction products by electrophoresis in polyacrylamide gels containing sodium dodecyl sulfate also revealed enhancement of casein degradation by luminal fluid in all segments from steroid-treated animals. We conclude that corticosteroid increases luminal proteolysis in the gastrointestinal tract of the suckling rat. This phenomenon may have implications for steroid-induced premature closure to macromolecular absorption and protein digestive capacity during the perinatal period.

Prostaglandins are present in breast milk and may protect and maintain intestinal epithelial cell integrity in developing mammals. In view of their very short half-life in other body tissues and fluids, studies were performed to determine prostaglandin stability in milk and gastric fluid. Tritiated prostaglandins E2 and F2 alpha were incubated for 30 min in whole milk, milk cells, and milk plasma obtained from mothers delivering at term and prematurely, and in preterm infant gastric fluid. Radioactivity chromatographic analysis revealed minimal degradation of PG in milk preparations and gastric fluid. Thus, milk may serve as an effective natural medium for PG delivery to the gastrointestinal tract. The cytoprotective effect of prostaglandins on the gastrointestinal tract may be related to their stability and lack of degradation in milk and gastric digestive juices.

Dietary transferrins are postulated to play a number of biological roles in the developing gastrointestinal tract. A prerequisite for such roles is survival in the gastrointestinal lumen. To evaluate luminal transferrin digestion during development, 125I-transferrin was incubated in vitro with luminal fluid from the stomach and small intestine of 12-day old suckling and 31-day old weanling rats, followed by analysis of degradation products. At both ages, the rate of degradation to trichloroacetic acid soluble material was maximum in the mid-jejunum and lowest in the stomach. Transferrin hydrolysis by weanling fluid was 2-10 times greater than suckling depending upon the particular segment. Chromatography of small intestinal reaction mixtures on Sephacryl S-200 revealed label eluting between intact transferrin and free iodine: two such peaks were generated with suckling fluid and one with weanling. Electrophoresis on SDS-polyacrylamide gels showed two major bands of Mr 69K and 20K; the former was the predominant reaction product with suckling intestinal fluid and the latter with weanling. Both methods showed small amounts of apparently intact transferrin. Results indicate substantial yet incomplete luminal degradation of transferrin which is more pronounced in the weanling than in the suckling. This survival is compatible with potential biological functioning of dietary transferrin or one of its breakdown products within the gastrointestinal tract.

To determine the role of Na/K ATPase in determining bronchial reactivity in man, we studied the effect of 1 mg inhaled ouabain on histamine reactivity in six normal and 10 asthmatic subjects in a placebo controlled, crossover study. sGaw was measured before and up to 2 h after drug, followed by a histamine challenge test to estimate the dose of histamine causing a 35% reduction in sGAW (PD35). sGAW values after ouabain and placebo did not differ significantly. Ouabain did not affect bronchial reactivity, geometric mean (95% CI) PD35 histamine values following ouabain and placebo were 8.98 (3.8-21.2) and 7.75 (3.2-18.7) mumol respectively in normal subjects and 0.46 (0.18-1.21) and 0.69 (0.22-2.13) in asthmatic subjects. We were thus unable to demonstrate a role for Na/K ATPase in determining bronchial reactivity to histamine in man.

In studies of asthma prevalence bronchial responsiveness has usually been measured as the provocative dose of bronchoconstrictor causing a 20% fall in FEV1 (PD20FEV1). This is relatively insensitive and only 10-20% of subjects in a general population sample will show such a response. Attempts to increase sensitivity, such as the use of the provocative dose causing a 10% fall in FEV1 (PD10FEV1), have not demonstrated any overall advantage, due to poorer repeatability. It has been suggested that measurement of bronchial reactivity using flow at low lung volumes measured from a partial flow volume curve is a more sensitive index of bronchoconstriction than PD20FEV1. If equally repeatable, it would have advantages in epidemiological practice. In 20 subjects with asthma, we compared the sensitivity and repeatability of PD10FEV1, PD20FEV1, and the provocative dose causing a 40% fall in flow at 30% of vital capacity (PD40V30P) following methacholine challenge. PD40V30P was more sensitive than both PD20FEV1 and PD10FEV1 by 1.48 and 0.35 doubling doses (DD) of methacholine, respectively. PD20FEV1 and PD40V30P showed equal repeatability, the 95% range for a single estimate of both being 2.02 DD. PD10FEV1 was less repeatable, with a 95% range of 2.35 DD. Values for the intraclass correlation co-efficient, which measures the ability of a test to discriminate between subjects, were 0.63, 0.79 and 0.69 for PD10FEV1, PD20FEV1, and PD40V30P, respectively. The increased sensitivity and comparable repeatability of measurement of bronchial reactivity for PD40V30P suggest that this method may be useful for studies of asthma prevalence.