Cough during infancy and subsequent childhood asthma.

OBJECTIVES: Wheezing in infancy has been associated with subsequent asthma, but whether cough similarly influences asthma risk has been little studied. We sought to determine whether prolonged cough and cough without cold in the first year of life are associated with childhood asthma. METHODS: Participants in the Infant Immune Study, a non-selected birth cohort, were surveyed 7 times in the first 9 months of life regarding the presence of wheeze and cough. Cough for more than 28 days was defined as prolonged. Parents were asked at 1 year if the child ever coughed without a cold. Asthma was defined as parental report of physician diagnosis of asthma, with symptoms or medication use between 2 and 9 years. Logistic regression was used to assess adjusted odds for asthma associated with cough characteristics. RESULTS: A total of 24% (97) of children experienced prolonged cough and 23% (95) cough without cold in the first 9 months, respectively. Prolonged cough was associated with increased risk of asthma relative to brief cough (OR 3.57, CI: 1.88, 6.76), with the risk being particularly high among children of asthmatic mothers. Cough without cold (OR 3.13, 95% CI: 1.76, 5.57) was also independently associated with risk of childhood asthma. Both relations persisted after adjustment for wheeze and total IgE at age 1. CONCLUSIONS AND CLINICAL RELEVANCE: Prolonged cough in infancy and cough without cold are associated with childhood asthma, independent of infant wheeze. These findings suggest that characteristics of cough in infancy are early markers of asthma susceptibility, particularly among children with maternal asthma.

Relation of early antibiotic use to childhood asthma: confounding by indication?

BACKGROUND: Findings from studies of the relation between early antibiotic use and subsequent asthma have been inconsistent, which may be attributable to methodologic issues. OBJECTIVE: Our objective was to assess the impact of confounding by indication on the relation of early antibiotic use to childhood asthma through age 5 in a non-selected birth cohort (n=424). METHODS: Oral antibiotic use was assessed by frequent nurse interviews in the first 9 months of life. Physician-diagnosed active asthma and eczema were assessed by questionnaire at 1, 2, 3, and 5 years, and were considered as ever asthma or ever eczema if positive at any age. Allergen-specific IgE was assessed in plasma at 1, 2, 3, and 5 years. Confounding by indication was investigated by considering the relation of asthma to antibiotic use while controlling for the number of illness visits to a physician in early life. RESULTS: There was no statistically significant relation of early antibiotic use with physician-diagnosed eczema or allergen-specific IgE. A dose-response relation was evident for antibiotic use with ever asthma (odds ratio [OR]=1.5, P=0.047). Ever asthma also increased significantly with the number of illness visits to a physician (P<0.001). After adjustment for number of illness visits, antibiotic use showed no relation with asthma. CONCLUSIONS: The relation of asthma to antibiotics in this cohort appears to be an artefact of the strong relation of number of physician visits for illness with both antibiotic use and risk for asthma.

Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk.

BACKGROUND: Previous studies on the relationship of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. This study sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality and serum levels of C-reactive protein (CRP) and interleukin-8 (IL-8), and whether subjects' age influences these relationships. METHODS: 1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrolment (1972-1973) were 21-80 years old and had FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) > or = 70% and no asthma were identified. Chronic bronchitis was defined as cough and phlegm production on most days for > or = 3 months in two or more consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV(1)/FVC <70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrolment survey. RESULTS: After adjusting for covariates, chronic bronchitis at enrolment significantly increased the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (HR 2.2, 95% CI 1.3 to 3.8; and HR 2.2, 95% CI 1.3 to 3.8; respectively), but not among subjects > or = 50 years old (HR 0.9, 95% CI 0.6 to 1.4; and HR 1.0, 95% CI 0.7 to 1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old. CONCLUSIONS: Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.

Femtosecond absorption dynamics in glass-metal nanocomposites.

We report strong optical nonlinearity of glasses embedded with copper and silver nanoparticles. In pump-probe experiments with copper-doped glasses, the observed absorption bleaching with picosecond relaxation time is as high as 22%. Transmission femtosecond measurementsreveal the reverse saturable absorption with nonlinear absorption coefficient of 10(-10)cm/W in both copper- and silver-doped nanocomposites.

Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup of patients with Addison's disease.

Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50 percent of sera from patients with autoimmune polyendocrine syndrome type I (APS I) but absent in sera from patients with different organ-specific autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, and Graves' disease. AADC is expressed in the pancreatic beta-cells, the liver, and the nervous system; and the presence of AADC antibodies has been shown to correlate to hepatitis and vitiligo in APS I patients. Among 101 investigated patients with autoimmune Addison's disease, 15 had high titers of AADC antibodies. According to the clinical characteristics of these patients, only 3 had APS I. The remaining 12 had either isolated Addison's disease or associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and 17alpha-hydroxylase were present in 3 of 12. Two patients had only autoantibodies against AADC. DNA was available from 3 of these 12 patients. One of the patients, a woman with Addison's disease, autoimmune thyroiditis, and premature menopause was heterozygous for a point mutation (G1021A, Val301Met) in the first plant homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene. The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients who may have a milder atypical form of APS I or represent a distinct entity. Measurement of autoantibodies against AADC should be included in the evaluation of Addison's disease.

CD14: a bridge between innate immunity and adaptive IgE responses.

Total IgE levels are known to be under genetic control. Linkage studies have indicated that one or more loci on chromosome 5q may control total IgE, as well as asthma and bronchial hyperresponsiveness to non-specific stimuli. Our group has undertaken a systematic analysis of chromosome 5q, and has recently characterized five single nucleotide polymorphisms at position -1619, -1359, -1145, -809, and -159 in the promoter of the gene encoding CD14, the myeloid pattern recognition receptor that is critical for efficient innate immune responses to lipopolysaccharide and bacterial ligands. Individuals homozygous for the three major CD14 haplotypes found in the Children Respiratory Study population (n = 390) were analyzed for serum levels of total IgE and soluble CD14. A strong inverse correlation was found between these two parameters, i.e. carriers of the -1359T/-1145A/-159C haplotype had the highest levels of IgE, and the lowest levels of sCD14. Conversely, carriers of the -1359G/-1145G/-159T haplotype had the highest levels of sCD14 and the lowest IgE values. Our results suggest that genetic variation in CD14, a key gene of innate immunity, may modulate the effects that exposure to bacterial ligands has on the development of Th2 responses.

Antigen enhances neuronally induced contraction of intrapulmonary bronchi from IgE-producing rabbits.

The effect of in vitro antigen exposure on contraction induced by electrical field stimulation (EFS) was examined in bronchial rings isolated from rabbits producing specific IgE antibodies. After exposure to antigen, tissues showed an enhanced isometric contractile response to EFS especially at low frequencies, leading to a significant change in the mean slope factor (p less than 0.05) derived from modeling the log frequency response curve using a 4-parameter logistic function. Also, the mean log EF20 +/- SEM decreased from 1.03 +/- 0.05 to 0.88 +/- 0.07 Hz (p less than 0.02). This antigen-induced effect was blocked by pretreatment with 3 microM chlorpheniramine and not observed in unsensitized tissues. Antigen challenge of tissues passively sensitized with IgE (but not IgG) antibodies led to a similar EFS-enhancing effect, significantly reducing the mean slope factor (p less than 0.025). Substituting EFS with exogenous acetylcholine resulted in no antigen-induced enhancement of contraction. The data suggest that antigen-IgE interaction leads to local histamine release sufficient to enhance the function of excitatory airway neurons.

Subcellular location and expression pattern of autoimmune regulator (Aire), the mouse orthologue for human gene defective in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome Type I (APS1), is an autosomal recessive autoimmune disease caused by mutations in a gene designated as AIRE (autoimmune regulator). Here we have studied the expression of Aire in transfected cell lines and in adult mouse tissues. Our results show that Aire has a dual subcellular location and that it is expressed in multiple immunologically relevant tissues such as the thymus, spleen, lymph nodes, and bone marrow. In addition, Aire expression was detected in various other tissues such as kidney, testis, adrenal glands, liver, and ovary. These findings suggest that APECED protein might also have a function(s) outside the immune system.(J Histochem Cytochem 49:197-208, 2001)

Epidemiology of physician-diagnosed allergic rhinitis in childhood.

OBJECTIVE: To investigate the natural history of and risk factors for allergic rhinitis in the first 6 years of life. METHODS: Parents of 747 healthy children followed from birth completed a questionnaire when the child was 6 years old. Data were obtained regarding physician-diagnosed allergic rhinitis (PDAR), associated symptoms, and age at onset. Risk-factor data were taken from earlier questionnaires, and data regarding immunoglobulin E (IgE) and skin-test reactivity were obtained at age 6. RESULTS: By the age of 6, 42% of children had PDAR. Children whose rhinitis began in the first year of life had more respiratory symptoms at age 6 and were more likely to have a diagnosis of asthma. Early introduction of foods or formula, heavy maternal cigarette smoking in the first year of life, and higher IgE, as well as parental allergic disorders, were associated with early development of rhinitis. Risk factors for PDAR that remained significant in a multivariate model included maternal history of physician-diagnosed allergy (odds ratio: 2.2, 95% confidence interval: 1.35-3.54), asthma in the child (4.06, 2.06-7.99), and IgE greater than 100 IU/mL at age 6 (1.93, 1.18-3.17). The odds for atopic as opposed to nonatopic PDAR were significantly higher only among those with high IgE and those who had dogs. CONCLUSION: Allergic rhinitis developing in the first years of life is an early manifestation of an atopic predisposition, which may be triggered by early environmental mental exposures.

Evidence for platelet-activating factor receptor subtypes on human polymorphonuclear leukocyte membranes.

Platelet-activating factor (PAF) is a potent phospholipid mediator that acts through specific cell surface receptors. The existence of PAF receptor subtypes has been suggested by functional and radioligand binding studies in a variety of cells and tissues. This report addresses this issue more directly and demonstrates differences between specific PAF receptors in human polymorphonuclear leukocytes (PMNs) and COS-7 cells transfected with the cloned human PAF receptor gene. The presence of more than one receptor in human PMNs is supported by three different studies. First, the Kd from the saturation isotherms for the binding of [3H]WEB 2086 on PMNs was 7-fold larger (Kd = 29.2 nM) than the kinetic Kd (4.2 nM). Second, the pseudo-Hill slope determined from the saturation experiments with PMNs was significantly lower than unity (0.69 +/- 0.05 SEM), and the saturation Kd values for transfected COS-7 (Kd = 9.6 nM) and PMN membranes were significantly different. These results contrasted with those for the transfected COS-7 cells, which showed a Kd from the saturation isotherms similar to that of the kinetic Kd (3.2 nM) and a pseudo-Hill slope that was not different from 1.0. Third, when the radiolabeled ligand [3H]WEB 2086 was increased in concentration from 10 to 50 nM in inhibition experiments with the human PMN membranes, the Ki increased, indicative of binding mainly to receptors with lower affinity. These results suggest that PAF receptor subtypes exist in human PMNs based on distinct radioligand binding characteristics from the human cloned PAF receptor.

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

The autoimmune regulator: a key toward understanding the molecular pathogenesis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune disease with autosomal recessive inheritance. APECED is characterized by the breakdown of tolerance to several organ-specific selfantigens. The symptoms of APECED fall into three main categories: autoimmune polyendocrinopathies, chronic mucocutaneous candidiasis, and ectodermal dystrophies. The gene defective in APECED, AIRE, has been cloned and numerous mutations in this gene have been found in patients with APECED. AIRE is predicted to encode a 545-amino-acid protein containing structural domains characteristic for transcription regulators. The protein has been shown to act as a transcriptional activator in vitro. The AIRE protein is mainly localized to the nucleus, where it can be detected as speckles resembling nuclear bodies. In humans, the expression of AIRE has been observed predominantly in immunologically relevant tissues, especially the thymus. Recently, we have shown in the mouse that Aire is also expressed in various tissues and cell types outside the immune system.

A longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE.

Chronic cough and/or phlegm, wheeze in the absence of colds, and rhinitis attributed to allergies are three of the most common respiratory symptoms encountered in community populations. In this study, we have determined the prevalence of these complaints in a random population sample (n = 1,109) using standardized questionnaires at two points in time, eight years apart. Cross-sectional prevalence and changes in symptom occurrence have been correlated with smoking status, allergen skin test reactivity, and total serum IgE levels. Our objective was to determine the individual and combined influence of these three variables on symptom prevalence. Initially, 19.2 percent of the population admitted to wheeze, 17.9 percent to cough, and 44.1 percent to allergic rhinitis. Cough and wheeze prevalence changed little over the eight-year period, while rhinitis increased 11 percent by the second survey. The occurrence of chronic cough was strongly correlated with smoking, and was not further influenced by either allergen skin reactivity or IgE level. Conversely, rhinitis prevalence was related to skin test reactivity with no additional association with smoking or IgE level. The occurrence of wheeze in the absence of colds was associated with both smoking and allergen skin reactivity. Among smokers, the prevalence was over 30 percent and was similar in both skin test positive (STP) and skin test negative (STN) individuals. However, on both surveys, STP ex-smokers and nonsmokers had significantly more wheeze than those who were STN. While the prevalence of wheeze in STN nonsmokers was low (6.8 percent), an IgE-wheeze relationship was also suggested on the second survey. In addition to these cross-sectional symptom relationships, changes in either smoking status or allergen skin reactivity during the study period were associated with changes in the prevalence of each symptom.

Relationship between serum IgE and cross-sectional and longitudinal FEV1 in two cohort studies.

Evidence is accumulating that elevated levels of serum IgE may play a role in the pathogenesis of chronic airflow obstruction. We examined this question using data on 863 subjects drawn from two cohort studies which we have followed over a period of nine to 11 years. One, the Portland cohort, represents a working population aged 25 to 55 years at baseline. The second, the Screening Center cohort, spans a wider age range (18 to 87 years at baseline) and is biased towards respiratory disease. Spirometric tests and respiratory symptom questionnaires have been administered five times over a nine-year period for the Portland cohort, and over an 11-year period for the Screening Center cohort. IgE was measured one time towards the end of the follow-up. Our data confirm the finding that smokers tend to have higher IgE levels than nonsmokers. For the combined sample, geometric mean levels of IgE were 31.0 IU/ml among smokers and 17.4 IU/ml among nonsmokers. Levels among ex-smokers were intermediate. Among smokers, IgE was not related to either amount smoked or pack-years. Cross-sectionally, FEV1 was inversely related to IgE in the Screening Center cohort, but not in the Portland cohort study. Among smokers, this association was only present for those subjects with symptoms of chronic bronchitis (chronic cough/sputum production). We found no association of IgE with longitudinal rate of decline of FEV1 in either cohort. These findings are consistent with other studies and support the hypothesis that serum IgE is inversely related to function level cross-sectionally, but is not predictive of rate of decline of lung function.

Interactions of smoking and immunologic factors in relation to airways obstruction.

The relationships of smoking, allergy skin test reactivity, and serum IgE to ventilatory function have been analyzed in 1,182 subjects from a general population sample. The study group consisted of subjects aged 35 or more who deny previous lung surgery, old tuberculosis, or a current diagnosis of heart disease in the absence of chronic bronchitis or emphysema. Impairment of the forced expiratory volume in one second (FEV1) shows a definite relationship to total serum IgE. However, this relationship is significant only for a low FEV1 which is accompanied by symptoms suggesting asthmatic or a chronic bronchitis type disease. Allergy skin test reactivity to a battery of common aeroallergens shows no overall relationship to FEV1. However, after accounting for total serum IgE, positive allergy skin tests tend to be associated with high rather than low FEV1 values. The findings suggest that some type of IgE which is not specific for aeroallergens but which is associated with smoking, may be important in the pathogenesis of the "chronic asthmatic bronchitis" syndrome.

A muscarinic receptor subtype modulates vagally stimulated bronchial contraction.

An in vitro preparation was developed to study vagus nerve-stimulated (preganglionic) and field-stimulated (post-ganglionic) contraction of the rabbit main stem bronchus and to compare the inhibitory effects of muscarinic antagonists on that contraction. The maximal contractile responses (20 V, 0.5 ms, 64 Hz) for either field or vagal stimulation were completely abolished by atropine (60 nM). Hexamethonium (0.1 mM) abolished the response to vagal stimulation but did not affect the field-stimulated response. To compare the effectiveness of atropine and pirenzepine as antagonists at the nerve-smooth muscle junction, inhibition studies of field-stimulated contractions were performed. Pirenzepine was 102- to 178-fold less potent than atropine when compared at the inhibitory concentration of antagonist that produced 25, 50, and 75% inhibition (IC25, IC50, and IC75, respectively), indicating that the muscarinic receptor at the nerve-smooth muscle junction is a muscarinic receptor with low affinity for pirenzepine (M2 subtype). Atropine had similar inhibitory effects on vagal- and field-stimulated contractions. In contrast, pirenzepine was more potent in inhibiting vagally stimulated contraction than field-stimulated contraction, especially at the IC25 where pirenzepine was only 8- to 22-fold less potent than atropine in inhibiting vagally stimulated contraction. These data suggest that an M1 subtype of muscarinic receptor modulates excitatory neurotransmission through bronchial parasympathetic ganglia.

Immunoglobulin E anaphylaxis in rabbits: mechanisms of pulmonary resistance and compliance changes.

Factors causing changes in pulmonary resistance and dynamic compliance with immunoglobulin (Ig) E anaphylaxis in spontaneously breathing rabbits were assessed in ventilated rabbits using tantalum bronchography and wet-to-dry wt ratios. Ventilated rabbits demonstrated changes in resistance and compliance similar to spontaneously breathing rabbits. Chlorpheniramine pretreatment prevented increases in resistance but not decreases in compliance. Anaphylaxis constricted small (less than 1 mm) airways 20.9 +/- 16.0% (mean +/- SD) and intermediate (between 1 and 3 mm) airways 21.8 +/- 19.8%. Chlorpheniramine (10 mg/kg) prevented small airway changes and attenuated those in intermediate airways. Chlorpheniramine prevented histamine-induced constriction of small (23.6 +/- 15.7%) and intermediate (17.6 +/- 15.0%) airways. Lung wet-to-dry wt ratios were unchanged. Changes in resistance and compliance during rabbit IgE anaphylaxis are not due to changes in tidal volume or frequency. Histamine, via H1 receptors, is the principal mediator of pulmonary resistance increases but not dynamic compliance reductions. Chlorpheniramine-sensitive increases in resistance are caused by constrictions of intermediate and small airways, whereas the chlorpheniramine-resistant decrease in compliance is not caused directly by constriction of the smallest measurable airways (0.25 mm) or changes in lung water.

Isolation of high quality RNA from bilberry (Vaccinium myrtillus L.) fruit.

A simple and efficient method is described for isolating high quality RNA from bilberry fruit. The procedure is based on the use of hexadecyltrimethyl ammonium bromide (CTAB), polyvinylpyrrolidone (PVP), and beta-mercaptoethanol in an extraction buffer in order to eliminate the polysaccharides and prevent the oxidation of phenolic compounds. This method is a modification of the one described for pine trees, and yields high-quality RNA suitable for cDNA based methodologies. This method is applicable for a variety of plant tissues.

A muscarinic receptor with high affinity for pirenzepine mediates vagally induced bronchoconstriction.

The nature of the putative muscarinic receptor subtypes involved in vagally mediated bronchoconstriction was examined in the rabbit model utilizing the classical muscarinic antagonist atropine and the selective antagonist pirenzepine. In vivo electrical stimulation of the cervical vagus nerves in anesthetized rabbits resulted in a reproducible increase in pulmonary resistance indicative of bronchoconstriction and a marked negative chronotropic effect on the heart. Both atropine and pirenzepine produced dose-related inhibition of these two vagal effects. Fifty percent inhibition of the vagally induced increase in pulmonary resistance was achieved with an infusion of pirenzepine that was only 8-fold greater than the equi-effective dose of atropine. In contrast, the dose of pirenzepine required to inhibit the vagally induced decrease in heart rate by 50% was 100-fold greater than the atropine dose. Thus, pirenzepine is markedly more potent in inhibiting vagally mediated bronchoconstriction than bradycardia. In vitro inhibition of methacholine-induced contraction of bronchial rings with atropine and pirenzepine yielded pA2 values of 8.86 and 6.88 respectively (95-fold potency ratio), demonstrating that the muscarinic receptors on airway smooth muscle cells that mediate contraction are not of the pirenzepine-sensitive subtype.

Chronic exposure to a beta 2-adrenoceptor agonist increases the airway response to methacholine.

Scheduled chronic administration of beta 2-adrenoceptor agonist bronchodilators in patients with asthma recently has been reported to be associated with a worsening of symptoms and an increase in bronchial responsiveness. We wanted to determine whether a 28-day in vivo exposure to albuterol (beta 2-adrenoceptor agonist) altered the response of rabbit airways to the cholinergic agonist methacholine. We found, using in vitro tissue bath techniques, that in mainstem bronchi from rabbits given a 28-day exposure to albuterol, maximum contraction to methacholine was increased in the albuterol-treated group (control group = 1.10 +/- 0.11 g vs. treated group = 1.50 +/- 0.13 g, P < 0.05). The potency (EC75) was also increased in the albuterol-treated group. The potency for the control group was 5.6 microM (95% confidence limit: 2.3-13 microM) and was 1.7 microM (95% confidence limit: 1.1-2.8 microM, P < 0.05) for the albuterol-treated group. In a subgroup of animals, maximum contraction to KCl, a receptor-independent contractile stimulus, was not significantly different between the groups (control group = 0.79 +/- 0.23 g vs. treated group = 0.82 +/- 0.20 g). The potency (EC50) for KCl-induced contractions was also not significantly different between the groups: control = 12 mM (95% confidence limit: 3.3-44 mM) vs. treated 19 mM (95% confidence limit: 18-20 mM). These data demonstrate that chronic in vivo exposure to a beta 2-adrenoceptor agonist can alter the in vitro tissue bath response of airway smooth muscle to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)