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Background: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted., Methods: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered., Results: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor., Conclusions: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough., Competing Interests: Declaration of competing interest JH received honoraria from AstraZeneca Pharmaceuticals, United Kingdom; GlaxoSmithKline Pharmaceuticals, United Kingdom. SH received honoraria from AstraZeneca Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Kyorin Pharmaceuticals, Japan; Novartis Pharmaceuticals, Switzerland. NO received honoraria from AstraZeneca Pharmaceuticals and research funding from Konica Minolta K.K, Japan. HT received honoraria from AstraZeneca Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Kyorin Pharmaceuticals, Novartis Pharmaceuticals. TY received honoraria from Mitsubishi Tanabe Pharmaceuticals, Japan; Sanofi Pharmaceuticals, France; Kyorin Pharmaceuticals. TN received honoraria from AstraZeneca Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Kyorin Pharmaceuticals, Novartis Pharmaceuticals, Sanofi Pharmaceuticals. HiSag received honoraria from AstraZeneca Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Kracie Pharmaceuticals, Japan; Kyorin Pharmaceuticals, Novartis Pharmaceuticals, Sanofi Pharmaceuticals. HM received honoraria from Kyorin Pharmaceuticals. AN received honoraria from AstraZeneca Pharmaceuticals, GlaxoSmithKline Pharmaceuticals, Kyorin Pharmaceuticals, Novartis Pharmaceuticals, Sanofi Pharmaceuticals. The rest of the authors have no conflicts of interest., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Background: Genetic and environmental factors are proposed to be involved in cedar pollen allergy sensitization and onset. The impact of these factors will provide key information for the prevention of cedar pollen sensitization and allergy onset, which we investigated in this cross-sectional study., Methods: Subjects were 382 young adult volunteers who completed a self-administered questionnaire on self-reported subjective symptoms of pollinosis, physician-diagnosed pollinosis, and background factors. We also measured their serum IgE antibody titers specific for cedar, cypress, and mites. Factors associated with subjective symptoms, physician diagnosis, and the three specific antigens were determined using both univariate and multivariate analyses., Results: Sensitization to cedar, cypress, and mites, defined as specific IgE levels of class 1 or above, was found in 78.8%, 64.4%, and 56.0% of subjects, respectively. The prevalence of cedar pollinosis was 41.2% based on subjective symptoms and 22.2% based on physician diagnosis. Factors associated with increased cedar pollen sensitization were mite sensitization, comorbid allergic rhinitis, and family history of cedar pollinosis. Risk-reducing factors for cedar pollen sensitization were keeping a cat, number of common colds, and hours of sleep. Risk-increasing factors for both subjective pollinosis symptoms and physician-diagnosed pollinosis were comorbid allergic rhinitis and family history of cedar pollinosis., Conclusions: Sensitization to cedar pollen in this population was extremely high. Both common and distinct factors were associated with sensitization to pollen and with the development of pollinosis. The distinct factors were associated with sensitization to cedar and cypress antigens., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: This study aims to examine the immunological parameters, focusing IL-10 productivity, in prophylactic sublingual immunotherapy (SLIT) in asymptomatic subjects sensitized to Japanese cedar pollen (JCP)., Methods: This study was conducted as part of a randomized, double-blind, placebo-controlled, multiple center trial, and was performed for two consecutive pollen seasons in 2012 and 2013. The present results were based only on our institution. We recruited 29 participants with specific IgE against JCP of at class 2 and higher levels without history of the pollinosis symptoms at the time of JCP scattering. The SLIT group received standardized JCP extract for five months over the pollen season. We observed and judged development of the symptoms in the pollen season. The percentage of IL-10 producing CD4(+) T (Trl) cells, B cells and monocytes were analyzed by flow cytometry. JCP specific IgE and total IgE were also measured., Results: The ratio of development of cedar pollinosis was significantly lower in the SLIT group compared to the placebo group in 2013. In 2012, the percentage of circulating Tr1 cells and IL-10 producing monocytes significantly increased in the SLIT group. In 2013, the percentage of circulating Tr1 cells and IL-10 producing B cells increased significantly in the SLIT group. The percentage of circulating IL-10 producing monocytes significantly decreased in the placebo group., Conclusions: Prophylactic SLIT is effective for prevention of the development of pollinosis. Induction of IL-10 producing T cells, B cells and monocytes is an important mechanism of SLIT for prevention of pollinosis in asymptomatic but sensitized subjects., (Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Japanese cedar pollen (JCP) is the most common allergen for seasonal allergic rhinitis in Japan. Little is known about local production of immunoglobulin (Ig)E in people with or without Japanese cedar pollinosis. The aims of this study were to measure levels of JCP-specific IgE in nasal secretions and determine correlations with levels in serum., Methods: Forty-six subjects were enrolled in this study, comprising 24 symptomatic subjects, 9 asymptomatic subjects sensitized to JCP, and 13 subjects not sensitized to JCP. Nasal secretions were obtained during a period of Japanese cedar dispersal, and levels of JCP-specific IgE were measured with CAP-fluorescent enzyme immunoassay. Serum JCP-specific IgE and total IgE were also measured using the same method., Results: Among the 46 subjects enrolled, JCP-specific IgE in nasal secretions was measureable in 43 subjects. Irrespective of symptom development, sensitized subjects showed higher levels of JCP-specific IgE in nasal secretions than non-sensitized subjects. A significant moderate correlation was observed between JCP-specific IgE levels in nasal secretions and serum in all 43 subjects. With stratification by subject group, only symptomatic subjects showed a substantial correlation between JCP-specific IgE levels in nasal secretions and serum., Conclusions: Our results imply a certain association between JCP-specific IgE in nasal secretions and sensitization of Japanese cedar pollinosis. Therefore, levels of allergen-specific IgE in nasal secretions can be used as an alternative diagnostic marker for allergic rhinitis patients.

Background: Methylated catechin, one of the active ingredients in green tea, has been reported to ameliorate allergic reactions. We evaluated the efficacy of 'Benifuuki' green tea, which contains O-methylated epigallocatechin-3-O-[3-O-methyl] gallate (O-methylated EGCG), in alleviating Japanese cedar pollinosis (JCP)., Methods: The study was a double-blind, randomized, placebo-controlled trial. The subjects with JCP were randomly assigned to drink 700ml of 'Benifuuki' green tea containing O-methylated EGCG or 'Yabukita' green tea (not containing O-methylated EGCG) as a placebo every day from December 2007 through March 2008, which includes the pollen season. The primary outcome was the area under the curve (AUC) of symptom scores during the peak pollen season., Results: Fifty-one adults with JCP participated in the study. Twenty-six subjects were assigned to 'Benifuuki' and 25 to 'Yabukita'. The AUC of symptom score during the peak pollen season in the 'Benifuuki' group was significantly smaller than in the 'Yabukita' group for each of runny nose, itchy eyes, tearing, total nasal symptom score, total ocular symptom score, nasal symptom-medication score and ocular symptom-medication score. The total QOL-related questionnaire score for one week in the peak pollen season was significantly better in the 'Benifuuki' group. Increase in the peripheral eosinophil count in response to pollen exposure was suppressed in the 'Benifuuki' group. No adverse events were reported in either group., Conclusions: 'Benifuuki' green tea containing a large amount of O-methylated EGCG reduced the symptoms of JCP and has potential as a complementary/alternative medicine for treating seasonal allergic rhinitis.

The access of bone morphogenetic protein (BMP) to the BMP receptors on the cell surface is regulated by its antagonist noggin, which binds to heparan-sulfate proteoglycans on the cell surface. Noggin is encoded by NOG and mutations in the gene are associated with aberrant skeletal formation, such as in the autosomal dominant disorders proximal symphalangism (SYM1), multiple synostoses syndrome, Teunissen-Cremers syndrome, and tarsal-carpal coalition syndrome. NOG mutations affecting a specific function may produce a distinct phenotype. In this study, we investigated a Japanese pedigree with SYM1 and conductive hearing loss and found that it carried a novel heterozygous missense mutation of NOG (c.406C>T; p.R136C) affecting the heparin-binding site of noggin. As no mutations of the heparin-binding site of noggin have previously been reported, we investigated the crystal structure of wild-type noggin to investigate molecular mechanism of the p.R136C mutation. We found that the positively charged arginine at position 136 was predicted to be important for binding to the negatively charged heparan-sulfate proteoglycan (HSPG). An in silico docking analysis showed that one of the salt bridges between noggin and heparin disappeared following the replacement of the arginine with a non-charged cysteine. We propose that the decreased binding affinity of NOG with the p.R136C mutation to HSPG leads to an excess of BMP signaling and underlies the SYM1 and conductive hearing loss phenotype of carriers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Methylated catechin, one of the active ingredients in green tea, has been reported to ameliorate allergic reactions. We evaluated the efficacy of 'Benifuuki' green tea, which contains O-methylated epigallocatechin-3-O-[3-O-methyl] gallate (O-methylated EGCG), in alleviating Japanese cedar pollinosis (JCP)., Methods: The study was a double-blind, randomized, placebo-controlled trial. The subjects with JCP were randomly assigned to drink 700 ml of 'Benifuuki' green tea containing O-methylated EGCG or 'Yabukita' green tea (not containing O-methylated EGCG) as a placebo every day from December 2007 through March 2008, which includes the pollen season. The primary outcome was the area under the curve (AUC) of symptom scores during the peak pollen season., Results: Fifty-one adults with JCP participated in the study. Twenty-six subjects were assigned to 'Benifuuki' and 25 to 'Yabukita'. The AUC of symptom score during the peak pollen season in the 'Benifuuki' group was significantly smaller than in the 'Yabukita' group for each of runny nose, itchy eyes, tearing, total nasal symptom score, total ocular symptom score, nasal symptom-medication score and ocular symptom-medication score. The total QOL-related questionnaire score for one week in the peak pollen season was significantly better in the 'Benifuuki' group. Increase in the peripheral eosinophil count in response to pollen exposure was suppressed in the 'Benifuuki' group. No adverse events were reported in either group., Conclusions: 'Benifuuki' green tea containing a large amount of O-methylated EGCG reduced the symptoms of JCP and has potential as a complementary/alternative medicine for treating seasonal allergic rhinitis., (© 2014 Japanese Society of Allergology.)

To initiate, monitor, and complete effective immunotherapy, biomarkers to predict and visualize the immune responses are needed. First, we need to identify the right candidate for immunotherapy. Secondly, the immune responses induced by immunotherapy should be monitored. For the first objective, analysis of polymorphisms of candidate genes may be helpful, but still be in development. Regarding biomarkers for immune responsese, there are numerous reports that evaluate immunotherapy-induced immune changes such as suppression of effector cells, deviation to Th1 cytokine production, and induction of regulatory T cells. No standardized methods, however, have been established. Among them, a functional assay of blocking IgG activity, the IgE-facilitated allergen binding assay, may be useful. We quantitated induced expression of an activation marker, CD203c, on basophils and found that the assay efficiently predicts sensitivity to particular allergen and severity of the allergen-induced symptoms. In patients who received rush immunotherapy for Japanese cedar pollinosis, reduction in CD203c expression after the therapy was observed, suggesting the utility of the test for monitoring immunotherapy.