Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Outcomes of an early childhood obesity prevention program in a low-income community: a pilot, randomized trial.

BACKGROUND: Obesity is a major and worldwide health problem in children. OBJECTIVES: The Early Childhood Obesity Prevention Program is a multi-component, randomized, controlled trial of a pilot community-focused obesity prevention program for mother/newborn dyads. METHODS: Underserved, mother/newborn dyads were recruited to receive a standard home visitation program (Nurturing Families Network, NFN) or an enhanced program (NFN+) that incorporated behavioural change strategies (e.g., goal-setting, problem-solving) and focused on six obesity-associated behaviours (breastfeeding, juice/sugar-sweetened beverages, solids, infant sleep, TV/screen time and soothability) with linkages to community resources. Weight-for-length (WFL) z-score and maternal diet were secondary outcomes. RESULTS: Fifty-seven dyads were recruited and 47 fully eligible dyads were enrolled (NFN = 21, NFN+ = 26). Forty-one (87.2%) were assessed at 6 months and 34 (72.3%) at 12 months. Retention at 12 months was higher for NFN+ dyads (84.6% vs. 56.1%, p = 0.04). NFN+ mothers were more likely to continue breastfeeding at 6 and 12 months vs. NFN mothers (p = 0.03 and 0.003, respectively), and at 12 months, NFN+ infants had fewer nocturnal awakenings (p = 0.04). There were no differences in other primary outcome measures or in WFL z-score at 6 or 12 months. CONCLUSIONS: A multi-component behavioural intervention increased breastfeeding duration and decreased nocturnal awakenings in infants of low-income families.

Chronic cough in children: a manifestation of airway hyperreactivity.

Fifteen children who presented with chronic cough as an isolated manifestation of respiratory disease were evaluated for the presence of exercise-induced airway hyperreactivity. Pulmonary function tests using air and a helium/oxygen gas mixture were performed before exercise. Eight subjects were also evaluated by spirometry and maximum expiratory flow volume curves before and after isoproterenol inhalation on a separate day. Ten subjects had normal pulmonary function tests at rest and five had isolated minor abnormalities. No significant changes in pulmonary function tests were recorded after inhalation of isoproterenol in the eight subjects studied. Following exercise, all 15 subjects demonstrated changes in pulmonary function tests which were similar to those seen in children with mild exercise-induced bronchospasm. After institution of theophylline, exercise-induced decreases in flow rates low in the vital capacity were blocked in all subjects; however, several subjects had persistent mild decreases in peak flow. Within six months of discontinuing the theophylline, cough recurred in 11 of the 15 subjects. Nine subjects were restudied after return of their cough. Exercise again resulted in decreased lung function. Reinstitution of theophylline eliminated the cough in these nine subjects. This study demonstrates that chronic cough in some children may be a manifestation of airway hyperreactivity. Both the cough and the reactivity can be blocked with theophylline.

Congenital cystic adenomatoid malformation.

Congenital cystic adenomatoid malformation is an uncommon congenital anomaly. We present four additional children with CCAM and review the literature. Two of these children had unusual manifestations of CCAM--one presented with a "cavitary lesion" while the other is suspected of having bilateral disease.

Significance of roentgenographic abnormalities in children hospitalized for asthma.

The relatively high incidence of roentgenographic abnormalities in patients hospitalized for acute asthma has led some to recommend that all such patients receive chest x-ray examination upon admission to the hospital. We studied the incidence and clinical predictability of the roentgenographic findings by asking the admitting physician to indicate, prior to obtaining a roentgenogram, whether he thought pneumonia, pneumothorax, pneumomediastinum or other significant abnormality was present. A treatment plan was also outlined at that time. Seven of 128 patients (5.5 percent) had roentgenograms suggestive of pneumonia or pneumothorax; three of these were suspected clinically. In 14 cases the clinical suspicion of pneumonia or pneumothorax was not borne out roentgenographically. The initial treatment plan was altered in only three cases. The low incidence of roentgenographic abnormalities and the failure of these minor abnormalities to substantially influence treatment suggest that routine chest roentgenograms may not have to be performed on all children hospitalized for acute asthma.

Ethnomedical (folk) remedies for childhood asthma in a mainland Puerto Rican community.

BACKGROUND: Childhood asthma is the most common chronic illness of childhood. The highest prevalence of childhood asthma in the United States occurs in the Puerto Rican community, and there are many traditional beliefs and practices regarding asthma that coexist with biomedical therapies. OBJECTIVES: To describe the ethnomedical treatment practices for childhood asthma in one mainland United States Puerto Rican community and to determine whether any of these practices are effective or potentially harmful. METHOD: Home interview with caretakers of 118 Puerto Rican children with asthma who seek care at two community health clinics in an inner city in the eastern United States. RESULTS: Common home-based ethnomedical practices include attempts to maintain physical and emotional balance and harmony, religious practices, and ethnobotanical and other therapies. Potentially harmful practices are uncommon, and other remedies are only harmful if not taken as directed. Many remedies are not effective from a biomedical standpoint (ie, bronchodilation or antiinflammation), but if analyzed within the ethnomedical explanatory model--which includes the belief that expulsion of mucus and phlegm from the body is beneficial for the treatment of asthma--these remedies bring about the desired effect and are therefore considered effective to the user. CONCLUSIONS: Ethnomedical therapies for asthma in the mainland Puerto Rican community are well known and commonly used. Most practices are not idiosyncratic but fit within a coherent ethnocultural belief system. The health care practitioner can lower the risk for potentially toxic effects of some treatments by discussing these practices with patients and families. Some ethnomedical practices are not discordant with biomedical therapy. Incorporation of these practices into the biomedical plan may help to fit the biomedical therapy into the lifestyle of the patient.

p-Aminohippurate transport in canine tracheal epithelium.

The unidirectional fluxes of 20, 100, 500, and 2,000 microM rho-aminohippurate (PAH) were measured under open- and short-circuit conditions in canine tracheal epithelium mounted as flat sheets in Ussing chambers. In tissues pretreated with mucosal indomethacin (10(-6) M) and amiloride (10(-4) M), unidirectional PAH fluxes under short-circuit conditions increased with increasing bath concentrations but there was no significant net PAH transport. After stimulation of chloride secretion by mucosal cyclic adenosine 3',5' -cyclic monophosphate (cAMP 10(-3) M), there was a significant increase in the secretory flux of PAH and a significant decrease in the absorptive flux of PAH. This resulted in net PAH secretion that demonstrated saturation kinetics with an apparent Michaelis-Menten constant of 754 microM by Lineweaver-Burk analysis. Intracellular concentrations of PAH were 0.4-1.2 times bath concentrations after pretreatment with indomethacin and amiloride and increased to 2.6-3.3 times bath concentrations after cAMP. Under open-circuit conditions, secretory PAH flux decreased and absorptive flux increased resulting in net PAH absorption. We conclude from these early studies that the canine tracheal epithelium possesses a specialized system for the transport of organic anions in the airways and that this transport system may share many similarities with organic anion transport in the kidney.

Nebulized steroid therapy in bronchopulmonary dysplasia.

The effect of inhaled beclomethasone dipropionate (BEC) was studied in seven infants between 7 and 18 months of age with glucocorticoid-dependent bronchopulmonary dysplasia. Oral glucocorticoid therapy, pulmonary function, growth, daily caloric consumption, blood pressure, blood sugar, blood gases, and immunoglobulins were monitored for 3 months before (control period) and 3 months after (intervention period) instituting inhaled beclomethasone dipropionate (25 micrograms/kg/day divided tid) delivered by Pulmoaide with a DeVilbiss nebulizer. Acute BEC inhalation produced no change in pulmonary function. During BEC treatment, oral glucocorticoid therapy was decreased in all infants, stopped in four infants within 3 months and in the other three infants in 4-5 months. Within 1 month of inhaled BEC the rate of linear growth and weight increased markedly (2.2 +/- 1.8 vs 6.4 +/- 2.4 cm/month - mean +/- SD and 9.3 +/- 6.5 vs 18.2 +/- 7.4 g/day, respectively without change in average daily caloric consumption (113 +/- 16 vs. 110 +/- 15 cal/kg/day). Immunoglobulins also significantly increased during BEC therapy (IgG(Total) 246 +/- 74 vs 463 +/- 111 mg/dL). Pulmonary function revealed moderate obstructive pulmonary disease before BEC. After 3 months of BEC inhalation no significant change occurred although respiratory system resistance decreased and the flow at 25% of tidal volume to peak flow ratio increased more than predicted by intersession variability. In no infant did pulmonary function decline after BEC, nor were any apparent adverse effects noted in this small group of patients. In conclusion, inhaled BEC was effective in decreasing oral glucocorticoid therapy and in modifying glucocorticoid-induced growth suppression in a very small, highly select group of infants with bronchopulmonary dysplasia.

Respiratory syncytial virus alters electrophysiologic properties in cotton rat airway epithelium.

The effect of respiratory syncytial virus (RSV) infection on the electrophysiologic properties of the airway epithelium was studied in tracheas obtained from cotton rats, after in vivo exposure to the virus. RSV infection was documented by tissue culture infectivity and immunofluorescent antibody techniques. Light microscopic studies of the tracheas 72 hours after exposure to RSV revealed normal epithelial morphology. RSV infection produced a 28% decrease in short-circuit current (Isc) and an almost 100% increase in tissue resistance. The decrease in Isc was partially attributed to a decrease in Cl secretion, while the increase in tissue resistance was associated with significant restriction to sodium and chloride movement through the paracellular pathway in RSV-infected tracheas. We conclude from these studies that RSV infection in the cotton rat trachea produces significant changes in active and passive ion flows. Alterations in ion transport across the airway epithelium may result in changes in secondary water transport across the airways and may contribute to the pathophysiology of RSV bronchiolitis and other locally invasive mucosal viral infections in children.

Practice of pediatric pulmonology: results of the Future of Pediatric Education Project (FOPE)

In 1996, the Future of Pediatric Education (FOPE) Project of the American Academy of Pediatrics (AAP) developed surveys to describe the nature of pediatric practices, recent trends in clinical practice, and anticipated workforce needs for both pediatric generalists and pediatric sub-specialists. A survey was specifically developed to describe the features of pediatric pulmonology as self-reported by pediatric pulmonologists. The survey was distributed to members of the AAP Pulmonology Section, the Pediatric Assembly of the American Thoracic Society, and certified pediatric pulmonologists recognized by the American Board of Pediatrics. Of the 535 respondents (67% of those invited to respond), the responses of 388 certified and 94 trained but not board-certified pulmonologists were included in the results. The characteristics of certified and non-certified respondents were the same for most survey questions. Clinical activities occupy 73 +/- 29% of professional time. Most pulmonologists work in urban, inner city, or suburban settings and 85% are affiliated with a medical school. One third are in private practice. As a group, research activities occupy less than 15% of their time. Most pediatric pulmonologists maintain a referral practice and use physician extenders to provide care. Patients with asthma and cystic fibrosis comprise 60-70% of patient volume. Both the volume and complexity of patients are increasing, as is competition for pediatric sub-specialty services. Pediatric pulmonary practices vary in size and in volume of patients that they manage in various settings. Forty percent of respondents identify allergists and other pediatric pulmonologists as sources of competition. Sixty-nine percent of respondents do not believe that there is a current need for additional pediatric pulmonologists in their respective communities. Only 15% of respondents plan to retire in the next decade.

Factor and subscale structure of a parental health locus of control instrument (parental health beliefs scales) for use in a mainland United States Puerto Rican community.

This study was undertaken to determine whether the subscale structure of an instrument used to measure parental health locus of control is a valid representation of the concept of locus of control in the Puerto Rican community. Ethnocultural differences in values and attitudes may create different conceptualizations of questionnaire items, which may impact on the subscale factor loadings for these items. Four hundred and twenty parents of Puerto Rican ethnicity living in a mainland inner city community in the United States completed the Parental Health Beliefs Scales (PHBS) instrument, which was developed to measure parental locus of control regarding their children's health. Results were subject to exploratory factor analysis. The resultant factor structure was then compared to other published factor structures by confirmatory factor analysis. Exploratory factor analysis results show a new five factor solution. Compared to two previously published factor structures for this instrument, the new five factor structure has a better goodness of fit for this Puerto Rican study sample. Through item analysis, we were able to refine the final structure into a four factor, 15 item instrument. We conclude that the new factor structure for the PHBS creates an instrument with subscales that reflect Puerto Rican cultural beliefs and values, especially as it pertains to locus of control issues (e.g. respect of professionals, collectivism, and the importance of fate). When working with ethnocultural minority groups, the health services researcher needs to be certain that the research instruments used are culturally appropriate and sensitive.

Provider adherence to a clinical practice guideline for acute asthma in a pediatric emergency department.

UNLABELLED: Critics of the use of clinical practice guidelines (CPGs) in an emergency department (ED) setting believe that they are too cumbersome and time-consuming, but to the best of the authors' knowledge, potential barriers to CPG adherence in the ED have not been prospectively evaluated. OBJECTIVES: To measure provider adherence to an ED CPG based on National Asthma Education and Prevention Program (NAEPP) recommendations, and to determine factors associated with provider nonadherence. METHODS: Prospective, cohort study of children aged 1-18 years with the diagnosis of an acute exacerbation of asthma who were seen in a pediatric ED and requiring admission, as well as a random selection of children discharged to home following pediatric ED care. The following adherence parameters were assessed: at least three nebulized albuterol treatments in the first hour; early steroid administration (after the first nebulizer treatment); clinical assessments using pulse oximetry and peak expiratory flow (PEF) (for children >6 years old); and use of a clinical score to assess acute illness severity (Asthma Severity Score). Nonadherence was defined as any deviation of the above parameters. RESULTS: Between July 1, 1998, and June 30, 1999, 369 patients were studied. Of these, 38% (139) were discharged to home, 38% (140) were admitted to the observation unit, and 24% (90) were admitted to the inpatient unit. Illness severities at initial presentation to the ED were: 24% (86) had mild exacerbations, 59% (212) had moderate exacerbations, and 17% (62) had severe exacerbations. Sixty-eight percent (95% CI = 63% to 73%) of the patients were managed with complete adherence to the CPG. Of the 32% with some form of nonadherence, most (63%) were children older than 6 years; in this group 64% (48/75) were nonadherent due to lack of PEF assessment. When PEF assessment was disregarded, an 83% (95% CI = 79% to 87%) adherence to the CPG was achieved. Other nonadherence factors included: lack of at least three nebulized albuterol treatments provided timely within the first hour (5%); delay in steroid administration (6%); lack of pulse oximeter use (0.5%); and failure to record clinical score to assess severity (1.1%). Patient age, illness severity (acute and chronic), first episode of wheezing, and high ED volume periods (evenings and weekends) did not worsen adherence. CONCLUSIONS: Clinical practice guidelines can be used successfully in the pediatric ED and provide a more efficient management and treatment approach to acute exacerbations of childhood asthma. With a systematic and concise CPG, barriers to adherence in a pediatric ED appear to be minimal, with the exception of using PEF in the routine ED assessment.

p-aminohippurate transport in the airways: role of Na+ and HCO3-.

The role of Na+ and HCO3- in the transport of p-aminohippurate (PAH) across the canine tracheal epithelium was investigated using Ussing chamber techniques and radiolabeled PAH. Under control conditions, net PAH absorption or a tendency toward net PAH absorption was observed. Neither amiloride (10(-4) M), furosemide (10(-3) M), ouabain (2 x 10(-4) M), nor Na+ substitution of the Ringer solution with choline had any effect on unidirectional PAH fluxes. When the Ringer solution was replaced with a HCO3(-)-free solution, net PAH absorption was consistently observed. In HCO3(-)-free experiments, unidirectional PAH absorptive fluxes were inhibited by mucosal addition of either of the stilbene derivatives, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS, 10(-4) M) or 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS, 10(-4) M). DIDS was more effective than SITS and was also effective in inhibiting PAH absorption in tissues bathed in Ringer solution. Submucosal DIDS or SITS had no effect on PAH fluxes either in HCO3(-)-free or Ringer experiments. We conclude that PAH transport in canine tracheal epithelium occurs by a HCO3(-)-PAH exchange process located on the luminal membrane. PAH transport is not Na+ dependent but is inhibited by both DIDS and SITS.

Probenecid affects chloride secretion in canine tracheal epithelium.

The effects of probenecid on the electrophysiology, ion transport properties, and permeability characteristics of the canine tracheal epithelium mounted in Ussing chambers were studied. Mucosal addition of probenecid had 2 effects: at low concentrations (0.1 to 0.5 mM), probenecid increased short-circuit current (Isc) and net Cl secretion, whereas higher concentrations (5 and 10 mM) decreased Isc and net Cl secretion; 1 mM probenecid had no effect. The change in Isc was accounted for entirely by the change in the net Cl secretion. The effects were rapidly reversible and even after prolonged exposure were not associated with any change in the paracellular pathway as evidenced by mannitol fluxes. Submucosal addition of probenecid produced a significant decrease in Isc and net Cl secretion only at 10 mM, and the effect was delayed, suggesting movement of some of the probenecid into the mucosal bath. We conclude from these experiments that probenecid at concentrations greater than 1 mM inhibits Cl secretion in canine tracheal epithelium; the effect is primarily from the mucosal side and is reversible. Because probenecid is structurally related to a group of analogs of benzoic acid that inhibit the Cl conductance at the apical membrane, we suggest that probenecid might also block the electrically conductive Cl exit pathway in the apical cell membrane.

Tannin inhibits adenylate cyclase in airway epithelial cells.

Tannin, isolated from cotton bracts extract and implicated in the pathogenesis of byssinosis, inhibits adenosine 3',5'-cyclic monophosphate (cAMP) production and Cl- secretion in bovine airway epithelial cells in part by inhibiting adrenergic receptor binding. The purpose of this study was to determine whether tannin affected other parts of the adrenergic-cAMP signal transduction pathway by examining the effect of tannin on guanosine 5'-triphosphate (GTP)-regulatory pathways (G proteins) and on adenylate cyclase activity. cAMP production in confluent airway epithelial cells was measured in the presence of cholera toxin (100 micrograms/ml), an activator of GS proteins, and forskolin (0.1-1,000 microM), a direct activator of adenylate cyclase. Cholera toxin stimulated cAMP production; this response, however, was inhibited in cells pretreated with 50 micrograms/ml tannin. Forskolin (100 microM) stimulated cAMP production 13-fold above baseline values. Tannin pretreatment inhibited the stimulatory effect of forskolin on cAMP release in a dose-dependent manner with a tannin concentration causing 50% inhibition of 7.5 micrograms/ml. The stimulatory effect of forskolin on cAMP release was completely inhibited in cells pretreated with 50 micrograms/ml tannin. The inhibition was reversible 3 h after removal of tannin from the solution. Tannin also inhibited forskolin-stimulated adenylate cyclase activity in a dose-dependent, noncompetitive manner. We conclude that forskolin and cholera toxin stimulate cAMP production in airway epithelial cells and that tannin inhibits the production of cAMP in airway epithelial cells by a direct effect on adenylate cyclase activity.

Effects of tannins from different sources on airway epithelial and platelet function.

The uniqueness of tannin isolated from aqueous extracts of cotton bracts (CBE) on the electrophysiological and ion transport properties of the canine tracheal epithelium and on 5-hydroxytryptamine (5-HT) release from platelets was investigated. The effect of CBE from Deltapine 41 cotton picked before (green, containing high-concentration, high-molecular-weight tannin) and after (brown, containing low-concentration, low-molecular-weight tannin) senescence and Darjeeling tea extracts and tannin isolated from Darjeeling tea were compared to the effects of Acala SJ-2 CBE and Acala SJ-2 tannin. Green Deltapine 41 CBE was similar to Acala SJ-2 CBE in decreasing short-circuit current (Isc) and net chloride secretion and in producing a dose-response release of 5-HT from platelets. Both Green and Brown Deltapine 41 CBE altered the paracellular pathway, but were less potent than Acala SJ-2 CBE. Brown Deltapine 41 CBE stimulated chloride transport in the airway epithelium and did not produce 5-HT release from human platelets. Darjeeling tea and tea tannin increased Isc and net chloride secretion and caused 5-HT release from platelets only at high concentrations. These studies demonstrate that all tannins are not alike; they suggest that molecular weight and concentration may be important for tannin activity and that the tannin in cotton bracts extract may be unique to cotton in its effect on the airway epithelium and on platelets.