Global strategy for asthma management and prevention: GINA executive summary.

Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.

[Registration of clinical trials: a statement from the International Committee of Medical Journal Editors]. / Registratie van klinische trials: een verklaring van het International Committee of Medical Journal Editors.

Altruistic motives and trust are central to scientific investigations involving people. These prompt volunteers to participate in clinical trials. However, publication bias and other causes of the failure to report trial results may lead to an overly positive view of medical interventions in the published evidence available. Registration of randomised controlled trials right from the start is therefore warranted. The International Committee of Medical Journal Editors has issued a statement to the effect that the 11 journals represented in the Committee will not consider publication of the results of trials that have not been registered in a publicly accessible register such as www.clinicaltrials.gov. Patients who voluntarily participate in clinical trials need to know that their contribution to better human healthcare is available for decision making in clinical practice.

Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program.

Interleukin 13 (IL-13) has been demonstrated to have a crucial role in animal models of allergy and asthma. In human case-control genetic-association studies, the Arg130Gln polymorphism has been associated with elevated total serum IgE and an asthma diagnosis in atopic and nonatopic individuals (Graves et al. [2000] J. Allergy Clin. Immunol. 105:506-513; Heinzmann et al. [2000] Hum. Mol. Genet. 9:549-559). To apply family-based association methods, we obtained DNA samples from 685 asthmatic children from 640 sibships and their parents in the Childhood Asthma Management Program (CAMP). Six hundred and sixty-six asthmatic children had complete phenotypic information and were used for this analysis. We performed quantitative association analysis using the transmission disequilibrium test (TDT) on 22 individual phenotypes and 5 grouped phenotypes relating to allergy, airway responsiveness, pulmonary function, bronchodilator responsiveness, and asthma severity, using genotypes at the Arg130Gln polymorphism of the IL-13 gene. A positive association was obtained between Arg130Gln and a grouped phenotype of allergy (consisting of the individual phenotypes of eosinophils, IgE, and positive skin tests), using FBAT-GEE, a multivariate extension of the family-based association test (Lange et al. [2002] Biostatistics 1:1-15). The three phenotypes were then evaluated individually and revealed a significant association between total eosinophil count and the Arg130Gln locus; there was a trend for association between total IgE and the Arg130Gln polymorphism. The Arg130Gln polymorphism is associated with an elevated eosinophil count as well as with a grouped allergy phenotype, in children with mild to moderate asthma. No evidence for association was found between Arg130Gln and airway responsiveness, asthma diagnosis, or asthma severity.

Nasal nitric oxide levels in cystic fibrosis patients are associated with a neuronal NO synthase (NOS1) gene polymorphism.

Nitric oxide (NO) plays an important role in a number of physiological processes in the airways, including host defense. Although the exact cellular and molecular source of the NO formation in airways is unknown, there is recent evidence that neuronal NO synthase (NOS1) contributes significantly to NO in the lower airways of cystic fibrosis (CF) patients. NOS1 protein has been shown to be expressed in nasal epithelium, suggesting an involvement of NOS1-derived NO in upper airway biology. We here hypothesized that nasal NO concentrations in CF patients are related to genotype variants in the NOS1 gene. Measurements of nasal NO concentration and pulmonary function were performed in 40 clinically stable CF patients. Genomic DNA from all patients was screened for an intronic AAT-repeat polymorphism in the NOS1 gene using polymerase chain reaction and simple sequence length polymorphism (SSLP) analysis. The allele size at that locus was significantly (P = 0.001) associated with upper airway NO. Mean (+/- SD) nasal NO concentrations were 40.5 +/- 5.2 ppb in CF patients (n = 12) with high repeat numbers (i.e., both alleles > or =12 repeats) and 72.6 +/- 7.4 ppb in patients (n = 28) with low repeat numbers (i.e., at least one allele <12 repeats). Furthermore, in the group of CF patients harboring NOS1 genotypes associated with low nasal NO, colonization of airways with P. aeruginosa was significantly more frequent than in patients with NOS1 genotypes associated high nasal NO concentrations (P = 0.0022). We conclude that (1) the variability in CF nasal NO levels are related to naturally occurring variants in the NOS1 gene, and (2) that nasal NOS1-derived NO affects the susceptibility of CF airways to infection with P. aeruginosa.

Mechanical stimuli to airway remodeling.

The airway is exposed to a variety of mechanical stimuli, the most prominent of which is the acute compressive stress caused by bronchoconstriction. The folding of the airway wall into a rosette pattern during bronchoconstriction creates a complex stress field, with the highest stresses compressing the epithelial layer at the inner surface of the airway wall. The epithelial cells lining the airway possess the capacity to modulate the inflammatory environment of the airway wall, and produce factors that influence the recruitment, proliferation, and activity of fibroblasts and smooth muscle cells. A variety of in vitro studies have demonstrated that airway epithelial cells, along with lung fibroblasts and smooth muscle cells, are responsive to mechanical stimuli. Airway epithelial cells exposed to compressive stresses matched to those occurring in the constricted airway increase expression of genes relevant to airway remodeling, and increase the collagen synthesis of cocultured fibroblasts. These findings demonstrate that mechanical stress may contribute to the remodeling of the asthmatic airway.

The clinical trials in the initial five-year award period of the Asthma Clinical Research Network.

During its first years of existence, the Asthma Clinical Research Network initiated four major clinical trials and one pilot clinical trial. The objective of this article is to describe briefly the specific aims, design, and conduct of those five trials.

Genetic analysis in the Asthma Clinical Research Network.

Because there is reason to believe that genetic variants could account for different treatment responses in subjects with asthma, it is important to collect blood for genetic-analysis purposes when conducting clinical trials in asthma. This article describes issues related to maintaining subject confidentiality, tracking and shipping blood samples, quality control procedures at the laboratory performing the genotyping, and necessary data verification checks when implementing the genetic-analysis database for the Asthma Clinical Research Network.

Variant eotaxin: its effects on the asthma phenotype.

BACKGROUND: Eotaxin, a CC chemokine expressed in the asthmatic lung, has been associated with impaired lung function. The role of its variant form is unknown. OBJECTIVE: The purpose of this study was to detect the population frequency and effects of a known single-nucleotide polymorphism in the eotaxin gene in which a threonine residue (THR(23)) is substituted for the wild-type alanine (ALA(23)) at the 23rd amino acid at the terminus of the peptide leader sequence. METHODS: We measured eotaxin protein secretion in 293 cells transfected with expression vectors and in PBMCs obtained from individuals bearing the alternative forms of the gene. A case-control study of plasma eotaxin levels and eosinophil counts, a comparison of baseline lung function by genotype in a population of 806 subjects with asthma, and a comparison of the allele frequency with a nonasthmatic population were performed. RESULTS: Human 293 cells and PBMCs with THR(23) variant eotaxin secreted significantly less eotaxin protein than did ALA(23)-bearing cells. In the case-control study, THR(23)-THR(23) individuals had lower plasma levels of eotaxin (310 [240-350] vs 420 [270-700] pg/mL; P < .05) and eosinophil counts (120 [5-220] vs 190 [110-470] cells/microL; P < .05) than ALA(23)-ALA(23) subjects; heterozygous subjects had intermediate levels. Higher levels of lung function were associated with THR(23) eotaxin (percent of predicted FEV(1), 65% +/- 3.5% [THR(23)-THR(23)] vs 58% +/- 0.9% [THR(23)-ALA(23)] and 56% +/- 0.5% [ALA(23)-ALA(23)]; P < .05). CONCLUSION: The THR(23) variant is associated with both decreased eosinophil counts and higher levels of lung function in subjects with asthma.

Beta(2)-adrenoceptor polymorphism and body mass index are associated with adult-onset asthma in sedentary but not active women.

STUDY OBJECTIVE: Beta(2)-adrenoceptor Gly16 polymorphism has been associated with asthma severity and beta(2)-adrenoceptor receptor downregulation, but not with the diagnosis of asthma. Glu27 polymorphism may limit beta(2)-adrenoceptor downregulation and predict body mass index (BMI), particularly among sedentary persons. In addition, BMI predicts asthma. We hypothesized that these DNA sequence variants predict adult-onset asthma only in sedentary women. DESIGN: Nested case-control study. SETTING: Nurses' Health Study, a large, prospective cohort study with participants throughout the United States. PARTICIPANTS: Among lifelong nonsmokers, 171 women with adult-onset, medication-requiring asthma and 137 age-matched control subjects. MEASUREMENTS: Physical activity and BMI were self-reported by previously validated questionnaire items. Genomic DNA was obtained from buccal brushings collected via first-class mail. RESULTS: Of 76 sedentary women, the adjusted odds ratios of Gly16 allele were 7.4 (p = 0.047) for asthma and 13.8 (p = 0.02) for steroid-requiring asthma. No similar associations were observed among 232 active women (p = 0.91). Sedentary individuals with both Gly16 and Glu27 alleles had a less elevated risk for asthma. BMI was associated with asthma and Glu27 allele among sedentary women. CONCLUSION: This exploratory analysis suggests an important gene/environment interaction for asthma involving physical activity level. Further study in larger populations is warranted to confirm if sedentary lifestyle unmasks a genetic risk for asthma.

DNA sequence variants of the platelet-derived growth factor A-chain gene.

BACKGROUND: Platelet-derived growth factor A-chain (PDGF-A) is a potent connective tissue mitogen implicated in lung growth and development. PDGF-A may have a role in asthma through effects on fibroblasts and bronchial smooth muscle cells. OBJECTIVE: To test the hypothesis that there exist variations in the PDGF-A gene associated with the asthma phenotype. METHODS: We screened genomic DNA from normal and asthmatic subjects using single-stranded conformational polymorphism (SSCP) for mutations in the promoter and all seven exons of the gene. RESULTS: Four transition polymorphisms (three novel) were identified: one each in exons 3 and 4 (overall population allele frequencies 0.18 and 0.02, respectively) which did not alter the protein sequence, one in exon 4 (frequency 0.005) which resulted in a valine to isoleucine substitution, and one in intron 5 (frequency 0.5). The intron 5-sequence variant is close to the 3' end of exon 5 but does not appear to affect alternative splicing of PDGF-A exon 6 RNA. The frequencies of the polymorphisms in exons 3 and intron 5 did not differ between the asthmatic and non-asthmatic subjects, but there was a significant frequency difference between Caucasian and African-American subjects for each of these polymorphisms (P = 0.03 and 0.003, respectively). CONCLUSION: No association was found between the sequence variants in the PDGF-A gene and the development of asthma. However, the allele frequency of some of the sequence variants differed between the Caucasian and African-American subjects.