Large scale genotyping study for asthma in the Japanese population

<p>Abstract</p> <p>Background</p> <p>Asthma is a complex phenotype that is influenced by both genetic and environmental factors. Genome-wide linkage and association studies have been performed to identify susceptibility genes for asthma. These studies identified new genes and pathways implicated in this disease, many of which were previously unknown.</p> <p>Objective</p> <p>To perform a large-scale genotyping study to identify asthma-susceptibility genes in the Japanese population.</p> <p>Methods</p> <p>We performed a large-scale, three-stage association study on 288 atopic asthmatics and 1032 controls, by using multiplex PCR-Invader assay methods at 82,935 single nucleotide polymorphisms (SNPs) (1^ststage). SNPs that were strongly associated with asthma were further genotyped in samples from asthmatic families (216 families, 762 members, 2^ndstage), 541 independent patients, and 744 controls (3^rdstage).</p> <p>Results</p> <p>SNPs located in the 5' region of <it>PEX19 </it>(rs2820421) were significantly associated with <it>P </it>< 0.05 through the 1^stto the 3^rdstage analyses; however, the <it>P </it>values did not reach statistically significant levels (combined, <it>P </it>= 3.8 × 10^-5; statistically significant levels with Bonferroni correction, <it>P </it>= 6.57 × 10^-7). SNPs on <it>HPCAL1 </it>(rs3771140) and on <it>IL18R1 </it>(rs3213733) were associated with asthma in the 1^stand 2^ndstage analyses, but the associations were not observed in the 3^rdstage analysis.</p> <p>Conclusion</p> <p>No association attained genome-wide significance, but several loci for possible association emerged. Future studies are required to validate these results for the prevention and treatment of asthma.</p

Causas de Morte em Doentes com Hemofilia: Estudo Retrospectivo de 1979 a 2007, no Serviço de Imunohemoterapia do HSJ

Neurokinin A (NKA) induces bronchoconstriction mediated by tachykinin NK2 receptors in animals and humans, and may be increased in asthma. Because beta(2)-adrenoceptor agonists are the most widely used bronchodilators in asthma, we investigated the effects of the beta(2)-adrenoceptor agonist fenoterol on NK2 receptor messenger RNA (mRNA) and receptor density as well as the functional responses of bovine tracheal smooth muscle to the NK2 receptor agonist [beta-Ala(8)]-NKA(4-10) in vitro, using Northern blot analysis, receptor binding, and organ bath studies. Incubation with fenoterol induced a time- and concentration-dependent upregulation of NK2 receptor mRNA (71% increase after 12 h at 10(-7) M fenoterol), which was abolished by propranolol (a nonselective beta-adrenoceptor agonist) and ICI118551 (a selective beta(2)-adrenoceptor antagonist), but not by CGP20712A (a selective beta(1)-adrenoceptor antagonist), indicating that fenoterol acts via beta(2)-adrenoceptors. These effects were mimicked by forskolin and prostaglandin E-2 (PGE,), both agents that increase cyclic adenosine monophosphate (cAMP), and by the cAMP analogue 8-bromo-cAMP. The upregulation was blocked by cycloheximide, indicating that it requires new protein synthesis, and was accompanied by an increase in both the stability of NK2 receptor mRNA and the rate of NK2 receptor gene transcription. Radioligand binding assay using the selective NK2 receptor antagonist [H-3]SR48968 showed a significant increase in the number of receptor binding sites after 12 h and 18 h, which was accompanied by an increased contractile responsiveness to the NK2 receptor agonist [beta-Ala(8)]-NKA(4-10). Dexamethasone completely prevented the fenoterol-induced increase in NK2 receptor mRNA and in the contractile response. We conclude that beta(2)-adrenoceptor agonists induce upregulation of functional NK2 receptors in airway smooth muscle by increasing cAMP, and that this can be prevented by a corticosteroid. The increased responsiveness could be relevant to asthma control and mortality

A Randomized Open-Label Comparative Study of Montelukast versus Theophylline Added to Inhaled Corticosteroid in Asthmatic Children

Background: Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study. Methods: Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5–8 mg/kg (dry syrup) or 100–200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2. Results: A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/min vs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/min vs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/min vs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences. Conclusions: The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children

Hospitalizations Associated with Pandemic Influenza A (H1N1) 2009 in Asthmatic Children in Japan

Background: The pandemic influenza A (H1N1) 2009 [pdm (H1N1) 2009] spread through the world in 2009, producing a serious epidemic in Japan. Since it was suggested early that asthma is a risk factor for an increased severity of the infection, the Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI) organized a working group for countermeasures, and investigated asthmatic children admitted to the hospitals for pdm (H1N1) 2009 infection. Methods: An appeal was made on the home page of the JSPACI to medical practitioners to input clinical information about asthmatic and non-asthmatic children (0–19 years) admitted to the hospital with pdm (H1N1) 2009 infection. Results: A total of 862 children (390 with asthma, and 472 without asthma) from 61 medical centers were registered, and the data of 333 asthmatic children and 388 non-asthmatic children in all were entered in the analyses. The mean age was 7.4±2.9 years in the asthma group and 6.9±3.8 years in the non-asthma group. The percentage of children admitted for respiratory symptoms was significantly higher in the asthma group than in the non-asthma group (p<0.001). There was no significant difference in the frequency of admission to the ICU or need for mechanical ventilation support between the two groups. No definite trend was detected in the relationship between the severity of asthma and the intensity of asthma attack. Antiviral drugs were administered within 24 hours in about 85% of the patients in both groups. Conclusions: Asthma may not be a risk factor for severe pdm (H1N1) 2009 infection in children

Usefulness of modified Pulmonary Index Score (mPIS) as a quantitative tool for the evaluation of severe acute exacerbation in asthmatic children

Background: Acute exacerbation of asthma is divided qualitatively into mild, moderate, and severe attacks and respiratory failure. This system is, however, not suitable for estimating small changes in respiratory condition with time and for determining the efficacy of treatments, because it has a qualitative, but not quantitative nature. Methods: To evaluate the usefulness of quantitative estimation of asthma exacerbation, modified Pulmonary Index Score (mPIS) values were measured in 87 asthmatic children (mean age, 5.0 ± 0.4 years) during hospitalization. mPIS was calculated by adding the sum of scores for 6 items (scores of 0–3 were given for each item). These consisted of heart rate, respiratory rate, accessory muscle use, inspiratory-to-expiratory flow ratio, degree of wheezing, and oxygen saturation in room air. Measurements were made at visits and at hospitalization and were then made twice a day until discharge. Results: mPIS values were highly correlated among raters. mPIS values at visits were 9.1 ± 0.1 and 12.6 ± 0.4 in subjects with moderate and severe attacks, respectively (p < 0.001). mPIS values of subjects requiring continuous inhalation therapy (CIT) with isoproterenol in addition to systemic steroids were significantly higher than the values of those without CIT (12.0 ± 0.5 and 9.3 ± 0.2, respectively, p < 0.001). A score of 10 was suggested to be the optimal cutoff for distinguishing between subjects requiring and not requiring CIT, from the perspectives of both sensitivity and specificity. mPIS at hospitalization correlated well with the period until discharge, suggesting that this score was a useful predictor for the clinical course after hospitalization. Conclusions: mPIS could be a useful tool for several aspects during acute asthma attacks, including the determination of a treatment plan, and prediction of the period of hospitalization in admitted patients, although prospective studies would be required to establish our hypothesis

Modified Pulmonary Index Score Was Sufficiently Reliable to Assess the Severity of Acute Asthma Exacerbations in Children

Background: The Modified Pulmonary Index Score (MPIS) was developed as an indicator of the severity of acute asthma in children. The objective of this study is to evaluate the reliability and validity of the MPIS for children with acute asthma, including those five years or younger in age. Methods: We evaluated the inter-rater reliability and internal consistency of the MPIS by having at least two trained physicians and a nurse—each of whom was blinded to the others’ scores—simultaneously examine inpatients with asthma exacerbation and rate them according to the MPIS. We also evaluated the intraclass correlation coefficient (ICC), kappa, Cronbach’s α and correlations between the MPIS and other indicators associated with asthma severity. Results: A total of 25 children (median age, five years; 13 patients were five years or younger in age) were enrolled in this study. The MPIS showed excellent inter-rater reliability (all ages: ICC = 0.95, 95% CI = 0.94-0.97; five years or younger: ICC = 0.93, 95% CI = 0.89-0.96) and good internal consistency (all ages: Cronbach’s α = 0.87; five years or younger: Cronbach’s α = 0.85). The MPIS showed good correlation with a visual analogue scale assessed by the physicians. Conclusions: The MPIS was a sufficiently reliable assessment tool for children with acute asthma, including those five years or younger in age