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E R Bleecker

Publications and source records attributed to E R Bleecker.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mapping susceptibility genes for asthma and allergy.

Allergy and asthma are related conditions caused by a complex interaction of genetic factors and environmental influences. With family data from several different populations, linkage analysis has been performed and used to identify regions of the genome that contain susceptibility genes for these conditions. To date, 4 genome screens have been completed and have successfully identified several chromosomal locations that are likely to contain asthma and allergy genes. Many of these regions contain potential biologic candidate genes that modulate immunologic responses or airways inflammation. By focusing on the common regions that have been replicated in these 4 genome screens, the major susceptibility genes for asthma and allergy should be identified. This will lead to an improved understanding of pathogenic factors that lead to development or progression of asthma and allergic diseases.

Asthma↗
PubMed2000

Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma.

BACKGROUND: Few studies have compared the efficacy of inhaled corticosteroids and leukotriene modifiers for the treatment of persistent asthma. OBJECTIVE: Our purpose was to compare the efficacy of a low dose of inhaled fluticasone propionate (FP) with that of oral zafirlukast in the treatment of persistent asthma previously treated with short-acting beta(2)-agonists alone. METHODS: A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 451 patients aged 12 years and older with asthma who were symptomatic on short-acting beta(2)-agonists alone. After an 8- to 14-day run-in period, patients were randomized to treatment with FP 88 microg twice daily or zafirlukast 20 mg twice daily. RESULTS: Treatment with FP was more effective than treatment with zafirlukast in increasing morning FEV(1) (by 0.42 L vs 0.20 L over baseline, P <.001), morning peak expiratory flow (by 49.94 L/min vs 11.68 L/min over baseline, P <. 001), and evening PEF (by 38.91 L/min vs 10.50 L/min over baseline, P <.001). Statistically significant differences between the two treatments in FEV(1) were noted after the first observation (week 4) and in morning and evening peak expiratory flow by week 2. Mean change in percentage of symptom-free days was greater with FP than with zafirlukast (28.5% of days vs 15.6% of days, P <.001) and FP significantly increased the percentage of rescue-free days by 40.4% of days compared with 24.2% of days with zafirlukast (P <.001). Treatment with FP significantly reduced albuterol use by 2.39 puffs per day compared with 1.45 puffs per day (P <.001) and increased the percentage of nights with no awakenings by 21.2% of nights compared with 8.0% of nights with zafirlukast (P <.001). CONCLUSION: The clinical effectiveness of a low dose of FP as first-line therapy in patients with persistent asthma who are symptomatic on beta(2)-agonists alone is superior to that of zafirlukast.

Administration, Inhalation↗
PubMed2000

Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations.

After a genomewide screen in the Hutterites was completed, the IL4RA gene was examined as the 16p-linked susceptibility locus for asthma and atopy. Seven known variants and one novel variant, representing all nonsynonymous substitutions in the mature protein, were examined in the Hutterites; on the basis of studies in the Hutterites, outbred white, black, and Hispanic families were genotyped for selected markers. All population samples showed evidence of association to atopy or to asthma (P values.039-.0044 for atopy and. 029-.0000061 for asthma), but the alleles or haplotypes showing the strongest evidence differed between the groups. Overall, these data suggest that the IL4RA gene is an atopy- and asthma-susceptibility locus but that variation outside the coding region of the gene influences susceptibility.

Alleles↗
PubMed2000

Weight loss, not aerobic exercise, improves pulmonary function in older obese men.

BACKGROUND: We evaluated the effect of weight loss (WL) or aerobic exercise (AEX) on pulmonary function in middle-aged and older (46-80 years) obese, sedentary men to determine the effect of reductions in body weight and increases in cardiorespiratory fitness on pulmonary function. METHODS: Subjects were randomly assigned to WL (n = 73), AEX (n = 71), or control (n = 26) groups. Maximal oxygen uptake (VO2max), body composition and anthropometrics, pulmonary function, and arterial blood gases were measured at baseline and after interventions. RESULTS: The 35 subjects who completed WL decreased weight by 11%, body fat percentage by 21% (p < .001), waist circumference by 8%, waist-hip ratio by 2%, and fat-free mass by 3% (p < .05). This resulted in a 3% increase in forced vital capacity (FVC) (4.08 +/- 0.71 L vs 4.21 +/- 0.76 L), a 5% increase in total lung capacity (6.62 +/- 0.99 L vs 6.94 +/- 0.99 L), an 18% increase in functional residual capacity (3.09 +/- 0.58 L vs 3.66 +/- 0.79 L), and an 8% increase in residual volume (2.20 +/- 0.44 L vs 2.37 +/- 0.52 L), with no change in forced expiratory volume in one second (FEV1), FEV1/FVC ratio, or carbon monoxide diffusing capacity. The change in FVC correlated with change in body weight (r = -.34, p < .05). The 38 subjects who completed AEX increased VO2max by 14%, with no change in pulmonary function. There were no changes in 8 control subjects. CONCLUSIONS: WL changes static lung volumes, not dynamic pulmonary function, in middle-aged and older, moderately obese, sedentary men. Some of the alterations in static lung function associated with aging may be due to the development of obesity and are modifiable by WL.

Age Factors↗
PubMed2000

Anti-inflammatory effects of zileuton in a subpopulation of allergic asthmatics.

The objective of this study was to determine the effects of allergen exposure on leukotriene generation and inflammation within the airways of allergic asthmatics and evaluate the effects of the 5-lipoxygenase inhibitor zileuton on these responses. We measured leukotriene-B(4) (LTB(4)) and LTC(4)/D(4)/E(4), inflammatory cytokine mediators, and cellular responses in bronchoalveolar lavage fluid (BALF) before and 24 h after segmental ragweed antigen challenge in 18 asthmatic subjects at baseline. Before initiating therapy with the 5-lipoxygenase inhibitor or placebo, only nine of 18 asthmatic subjects had a significant increase (234 +/- 102-fold, mean +/- SE) in BALF LTC(4)/D(4)/E(4) levels 24 h after segmental antigen challenge, whereas leukotriene levels were essentially unchanged (1.14 +/- 0.22-fold) in the other nine subjects. The high LT producers also had higher postantigen BALF levels of LTB(4), total protein, IL-5, IL-6, TNF-alpha, and recovery of more eosinophils than the low LT producers. Treatment with the 5-lipoxygenase inhibitor zileuton reduced postantigen BALF eosinophil count by 68% in the high LT producers, but had no detectable effect on BALF composition in the low LT producers. These data suggest that leukotriene inhibition may be more effective in a subset of asthmatics in whom leukotrienes are a major contributory factor in causing allergic inflammation.

Adult↗
PubMed1999

Genetics of asthma.

Asthma is a complex disease with a phenotype that has been clinically difficult to define. Associated phenotypes including bronchial hyperresponsiveness and atopy have provided useful objective alternatives in genetic and epidemiologic studies. Although asthma genes have not yet been identified, much progress has been made toward this goal. Genetic studies indicate that multiple genes are involved in the pathogenesis of this disease, and chromosomal regions likely to harbor asthma susceptibility genes have been replicated in several studies. Environmental factors, including smoking, diet, and viral respiratory infections, have also been implicated in the etiology of asthma. Directly linking these exposures as causes of asthma, however, has also proved difficult. Furthermore, interaction between susceptibility genes and environmental factors is probable and is a challenge currently being pursued by investigators worldwide. Understanding the fundamental gene-environmental interactions in the development of asthma should lead to earlier identification of susceptible individuals and more effective approaches for disease prevention.

Asthma↗
PubMed1999

Genetics of allergy and bronchial hyperresponsiveness.

Allergy and asthma are closely related complex diseases caused by a combination of both genetic and environmental influences. Two common genetic approaches, candidate gene studies and genome-wide screens, have been used to localize and evaluate potential genetic factors that confer susceptibility or modify the phenotype of these diseases. Four genome screens suggest multiple chromosomal locations likely to contain asthma and allergy genes and many potential candidate genes exist in these regions. These screens were performed in six different populations and identified many common susceptibility regions as well as novel regions for each population. Ideally, these genes may point towards key biological pathways that will eventually serve as targets for therapeutic agents.

Asthma↗
PubMed1998

Exclusion of chromosome 11q and the FcepsilonRI-beta gene as aetiological factors in allergy and asthma in a population of Dutch asthmatic families.

BACKGROUND: The beta subunit of the high-affinity receptor for IgE (FcepsilonRI-beta) is localized to chromosome 11q13 and has been reported by Cookson et al. to be in close genetic linkage with a gene for atopy. A maternally inherited association was found between the presence of a variant of FcepsilonRI-beta, Ile181Leu, and high total serum IgE levels (IgE > 100 IU). In a previous study of 20 Dutch families, we found no evidence for linkage of atopy or bronchial hyperresponsiveness (BHR) to chromosome 11q. OBJECTIVE: Recently segregation analysis in 92 families has given us evidence for two independent major loci accounting for 78% of the observed variance in total serum IgE levels, and linkage analysis using both sib-pair and LOD score methods has identified one major locus for regulation of IgE levels and BHR near the cytokine gene complex on chromosome 5q. The objective of this study is to pursue the identification of the second major locus. METHODS: We have studied markers in the area of the high affinity IgE receptor (FcepsilonRI-beta) on chromosome 11q (D11S1314, FcepsilonRI-beta and D11S987) in 83 families for whom DNA was available. Furthermore, our families have been examined for variance in the FcepsilonRI-beta gene, specifically for Leu181 and Leu181/Leu183 mutations. RESULTS: By sib-pair analysis, there is no evidence for linkage of total serum IgE levels or number of positive skin tests to these markers in our population. Similar negative results were obtained for affected sib-pair analysis of BHR, with the exception of D11S1314, which was significant at P=0.046. The FcepsilonRI-beta gene in 36 female probands, 44 male probands and 46 female spouses was sequenced for these mutations. For each of these 126 individuals sequencing of FcepsilonRI-beta demonstrated a wild-type sequence pattern, with no mutations found in anyone, male or female. CONCLUSION: We are unable to confirm the presence of significant mutations in FcepsilonRI-beta gene in our population, and we cannot confirm that the FcepsilonRI-beta gene is crucial to the pathogenesis of allergic inflammation in asthma.

Asthma↗
PubMed1998

Mapping susceptibility genes for asthma and allergy.

Using family data, linkage analysis has been performed to determine the location in the genome of susceptibility genes for allergy and asthma. It has now become clear that there are multiple regions of the genome that contain susceptibility genes for allergy and asthma. The results from two genome screen studies will be reviewed and compared with results from candidate gene approaches. Results from several studies show evidence for linkage to chromosomes 5, 6, 11, 12, 13 and 14 for atopy, asthma or a related phenotype such as total serum IgE levels. Many of these regions contain candidate genes involved in regulating processes that may be involved in the development or progression of allergy and asthma. Some susceptibility genes may affect the expression of these disorders while others may affect response to therapy. Susceptibility to developing allergy or asthma appears to be due to the interaction of multiple genes with the environment.

Asthma↗
PubMed1998

Direct assessment of small airways reactivity in human subjects.

Our knowledge of airways reactivity to inflammatory agonists is derived predominantly from tests dominated by large airway responsiveness. To determine directly, the histamine responsiveness of the smallest airways, eight normal and 11 asymptomatic asthmatic subjects were studied utilizing a wedged bronchoscope technique. A fiberoptic bronchoscope was wedged in the anterior segment of the right upper lobe and a double-lumen catheter was advanced through the working channel to its tip. With a constant flow of gas (5% CO2 in air) through one lumen of the catheter, pressure at the tip of the bronchoscope was measured with the subject breath-holding at FRC. Peripheral airways resistance (Rp) was measured at baseline and after saline, histamine (10, 50, 100 mg/ml) and isoproterenol (2 mg/ml) challenge through the bronchoscope. Baseline Rp of asthmatics (0.041 +/- 0.015 cm H2O/ml/min; mean +/- SE) was significantly greater than normal subjects (0.011 +/- 0.003 cm H2O/ml/min; p = 0.019). The log of the concentration of histamine that caused a 100% increase in peripheral airways response was greater in the normal subjects than in the asthmatic subjects (p = 0.0114) and correlated with whole lung responsiveness to histamine in asthmatics (r = 0.847, p < 0.05). Isoproterenol reversed completely the increase in Rp in normal subjects but not asthmatic subjects. The results of this study demonstrate that the resistance of the smallest peripheral airways, when measured directly, increased when challenged locally with histamine in both normal subjects and asthmatic subjects. However, the peripheral airways responsiveness was significantly enhanced in asthmatic subjects relative to normal controls.

Adult↗
PubMed1998

Characterization of obstructive airway disease in family members of probands with asthma. An algorithm for the diagnosis of asthma.

To investigate the genetic susceptibility to asthma, we developed an algorithm to classify the phenotype of each family member enrolled in a family study on the genetics of asthma. This algorithm was applied to 92, two- and three-generation families, identified through a subject (proband) with asthma first diagnosed 25 yr previously. The algorithm consisted of five classes based on the presence or absence of bronchial hyperresponsiveness (BHR), respiratory symptoms, smoking, airways obstruction, and bronchodilator reversibility. All family members were classified as: (1) definite asthma; (2) probable asthma; (3) unclassifiable airway disease; (4) chronic obstructive pulmonary disease (COPD); (5) unaffected (without clinical evidence of asthma and COPD). Thirteen of the 92 probands (14%) could not be classified as asthmatic when retested 25 yr later because of loss of BHR, loss of bronchodilator reversibility, or a current history of cigarette smoking. Of the 265 first-degree offspring, 49 (18%) were classified as having definite asthma (Class 1), and 22 (8%) as probable asthma (Class 2). A large number of offspring with clinical evidence of asthma did not have a prior physician's diagnosis of asthma, and offspring in Class 1 (definite asthma), with and without a physician's diagnosis, had similar clinical and physiologic characteristics. These results support the usefulness of this approach to classify subjects with asthma for genetic epidemiologic studies and show that reliance on a prior physician's diagnosis may result in misclassification or underdiagnosis. Characterization of the offspring in this family study showed that there is familial clustering, which supports the presence of a hereditary component in asthma.

Adolescent↗
PubMed1998

T-Cell repertoire in the blood and lungs of atopic asthmatics before and after ragweed challenge.

T cells play a pivotal role in initiating and orchestrating allergic responses in asthma. The goal of this work was to learn whether ragweed challenge in the lungs alters the T-cell repertoire expressed in the blood and lungs of atopic asthmatics. Analyses of cell numbers, differentials, and T-cell subsets in bronchoalveolar lavage (BAL) fluids showed that ragweed challenge was associated with preferential recruitment of CD4+ T cells into the lungs. A reverse transcriptase-polymerase chain reaction (RT-PCR) was used to amplify T-cell receptor (TCR) gene transcripts from unfractionated, CD4+, and CD8+ T cells in blood and BAL fluids. As judged by RT-PCR, the usage of TCR Valpha and Vbeta gene families in BAL fluids was similar to that in blood. Ragweed challenge did not change the levels of expression of these V gene families. The clonality of T cells was estimated by analyzing the diversity of TCR V-(D)-J junctional region nucleotide lengths associated with each Valpha and Vbeta gene family, using sequencing gel electrophoresis. Most V gene families in blood and BAL fluids were associated with multiple junctional region lengths before and after ragweed challenge, indicating polyclonal expression. Some V gene families were expressed in an oligoclonal manner in unfractionated, CD4+, and CD8+ T cells in BAL fluids before ragweed challenge, as indicated by a few predominant junctional region lengths. The majority of these V gene families became polyclonal after challenge, compatible with polyclonal T-cell influx during inflammation immediately after ragweed challenge. However, some V gene families became oligoclonal or developed a new oligoclonal pattern of junctional region lengths in BAL T cells after ragweed challenge. Surprisingly, this occurred in both CD4+ and CD8+ T cells. In one of these instances, DNA sequencing of Vbeta21 junctional regions in CD8+ T cells confirmed a change from polyclonal to oligoclonal expression after ragweed challenge. These findings show that ragweed challenge is associated with polyclonal influx and oligoclonal activation of both CD4+ and CD8+ T cells in the lungs.

Adult↗
PubMed1998

Relationship between airway obstruction and respiratory symptoms in adult asthmatics.

STUDY OBJECTIVES: To characterize the relationship between symptoms and the degree of airway obstruction as determined by the FEV1 and peak expiratory flow (PEF) in a cohort of adult patients attending a university-based urban asthma clinic. DESIGN: Each of six current asthma symptoms, including cough, dyspnea, wheeze, chest tightness, sputum production, and nocturnal awakening was rated by patients on a 0 (none) to 4 (constant) scale at initial and first follow-up clinic evaluations. Spirometry and PEF were measured at the initial clinic visit and PEF was measured at all follow-up visits. PATIENTS: Sixty-seven adult patients with chronic asthma. MEASUREMENTS AND RESULTS: Asthma symptoms did not correlate with the degree of airway obstruction as determined by the FEV1 (percent predicted FEV1 vs total symptoms: r=0.143; p=0.263; n=70) and only correlated poorly with PEF (percent predicted PEF vs total symptoms: r=0.384; p=0.0029; n=58). Subjective wheezing was the best individual predictor of the level of airway obstruction in this group of patients. When reassessed an average of 7.9 weeks later, patients reported significant improvement in several symptoms, including those of wheeze, chest tightness, dyspnea, and nocturnal awakening. However, this symptomatic improvement was not associated with improvement in the level of airway obstruction. CONCLUSIONS: Asthma symptoms correlate poorly with the level of airway obstruction as determined by the FEV1 and PEF. Following treatment, subjective improvement in asthma symptoms may occur without improvement in the level of airway obstruction. These results support the recommendation to measure airway obstruction objectively when assessing adult patients with chronic asthma.

Adult↗
PubMed1998

Proventil HFA provides bronchodilation comparable to ventolin over 12 weeks of regular use in asthmatics.

OBJECTIVE: To compare the bronchodilator effectiveness of albuterol reformulated in the chlorofluorocarbon-free propellant hydrofluoroalkane (HFA)134a (Proventil HFA) to that of Ventolin and HFA placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy, parallel group, placebo-controlled, multi-center trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment qid with Proventil HFA, Ventolin, or HFA-134a placebo for 12 weeks. MEASUREMENTS: At weeks 0, 4, 8, and 12, spirometry was performed predose and serially over 6 h after dosing with study drug. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve (AUC). RESULTS: Demographic and baseline characteristics were similar for patients randomized to Proventil HFA (193), Ventolin (186), and HFA-134a placebo (186). No significant differences were found between the Proventil HFA and Ventolin treatment groups for any FEV1 efficacy variable, either predose or during 6 h of serial spirometry, at weeks 0, 4, 8, and 12. For all efficacy variables, except time to onset of effect, the Proventil HFA and Ventolin results were significantly greater than placebo. Time to onset of effect for the HFA-134a placebo group is misleading; only 13 patients (7%) were found to be responders in the intent-to-treat database. These efficacy results were found to be consistent across subgroup analyses of inhaled and nasal corticosteroid use, age (18 to 35 and 36 to 66 years), sex, race, weight (<60, 60 to 100, and >100 kg), and baseline FEV1 (< or =55% and >55% predicted). The peak FEV1 effect, duration of FEV1 effect, and AUC for FEV1 were all significantly smaller at weeks 4, 8, and 12 than week 0 for both the Proventil HFA and Ventolin treatment groups. CONCLUSIONS: Proventil HFA provided bronchodilation comparable to Ventolin and superior effects to HFA-134a placebo over 12 weeks of regular dosing. There was a diminution in bronchodilator response to both Proventil HFA and Ventolin after 4 weeks of use.

Administration, Inhalation↗
PubMed1998

Proventil HFA and ventolin have similar safety profiles during regular use.

OBJECTIVE: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks. MEASUREMENTS: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue beta-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end. RESULTS: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study. CONCLUSIONS: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.

Administration, Inhalation↗
PubMed1997

Genetic susceptibility to asthma in a changing environment.

There is a major interest in investigating the genetic components of allergy and asthma. Four different areas are involved in the study of complex genetic diseases: family studies, assessment of phenotype, segregation analysis and gene mapping. Initial assessment of phenotype must be practical, reproducible and relatively independent of compounding variables. Phenotypes important in allergy and asthma include atopic parameters such as total serum IgE, bronchial hyper-responsiveness and the presence/ absence of clinical asthma. Numerous family and twin studies have suggested the presence of a heritable component for allergy, bronchial hyper-responsiveness and asthma. The number of genes involved in these complex genetic disorders and their mode of inheritance have not been fully determined. Our group has been involved in a collaborative US-Dutch study in which 92 families with over 500 individuals have been phenotyped and DNA has been obtained for genotyping. Initial results of the classification of family members show that approximately 26% of the offspring of families ascertained through a parent with asthma have an asthmatic phenotype. A large number of these offspring with clinical evidence of asthma do not have a prior physician diagnosis of asthma, suggesting that there is a spectrum which ranges from preclinical to symptomatic asthma. The familial aggregation of asthma and other obstructive airway diseases in these families is consistent with a significant genetic component. Initial linkage studies have been performed on two characteristics of the allergic and asthmatic phenotype. Total serum IgE was analysed because this measure correlates with the clinical expression of allergy, bronchial hyper-responsiveness and asthma. Segregation analysis of total serum IgE provided evidence for a recessive mode of inheritance. Sib pair analyses and maximum likelihood scores suggest that a gene regulating IgE production maps to chromosome 5q. Bronchial hyper-responsiveness and total serum IgE are related to asthma in population-based studies. Sib pair analyses for bronchial responsiveness showed significant linkage to markers on chromosome 5q.

Asthma↗