Allergic rhinitis phenotypes with distinct transcriptome profiles in children: A birth cohort.

BACKGROUND: Allergic rhinitis (AR) phenotypes in childhood are unclear. OBJECTIVES: This study sought to determine AR phenotypes and investigate their natural course and clinical and transcriptomic characteristics. METHODS: Latent class trajectory analysis was used for phenotyping AR in 1050 children from birth through 12 years using a birth cohort study. Blood transcriptome analyses were performed to define the underlying mechanisms of each phenotype. RESULTS: Five AR phenotypes were identified: early onset (n = 88, 8.4%), intermediate transient (n = 110, 10.5%), late onset (n = 209, 19.9%), very late onset (n=187, 17.8%), and never/infrequent (n = 456, 43.4%). Children with early-onset AR were associated with higher AR severity and sensitizations to foods at age 1 year and inhalants at age 3 years and asthma symptoms, but not with bronchial hyperresponsiveness (BHR). Children with late-onset AR phenotype associated with sensitizations to various foods at age 1 year but not from age 3 years, and to inhalants from age 7 years and with asthma with BHR. Children with very late-onset AR phenotype associated with sensitizations to foods throughout preschool age and to inhalants at ages 7 and 9 years and with asthma with BHR. Transcriptome analysis showed that early-onset AR was associated with viral/bacterial infection-related defense response, whereas late-onset AR was associated with T cell-related immune response. CONCLUSIONS: Early-onset AR phenotype was associated with sensitization to foods and inhalants at an early age and asthma symptoms, but not with BHR, whereas very late- and late-onset AR phenotypes were positively associated with sensitization to inhalants and asthma with BHR. Transcriptomic analyses indicated that early- and late-onset AR phenotypes had distinct underlying mechanisms related to AR as well.

Unveiling Neurocognitive Disparities in Encoding and Retrieval between Paper and Digital Tablet-Based Learning.

The widespread use of mobile devices and laptops has replaced traditional paper-based learning and the question of how the brain efficiency of digital tablet-based learning differs from that of paper-based learning remains unclear. The purpose of this study was to investigate the difference in brain efficiency for learning between paper-based and digital tablet-based learning by measuring activity in the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Thirty-two subjects were randomly assigned to the paper-based learning or the digital tablet-based learning group. Subjects in each group performed a memory task that required memorizing a three-minute novel (encoding phase) on a paper or digital tablet, followed by a test in which they answered four multiple-choice questions based on the novel's content. To compare both groups, behavioral performance on the test (retrieval phase) and activity in the PFC were measured. As a result, no significant difference in behavioral performance between both groups was observed (p > 0.05). However, the paper-based learning group showed significantly lower activity in the PFC in the encoding phase than the digital tablet-based learning group (p < 0.05) but not in the retrieval phase. The current study demonstrated that brain efficiency in encoding is higher in subjects with paper-based learning than those with digital tablet-based learning. This finding has important implications for education, particularly in terms of the pros and cons of electronic document-based learning.

Combined effect of hygienic and polygenic risk scores in children with allergic rhinitis.

BACKGROUND: Although the development of allergic rhinitis (AR) is associated with multiple genetic and hygienic environmental factors, previous studies have focused mostly on the effect of a single factor on the development of AR. OBJECTIVE: This study aimed to investigate the combined effect of multiple genetic and hygienic environmental risk factors on AR development in school children. METHODS: We conducted a cross-sectional study, comprising 1,797 children aged 9-12 years. Weighted environmental risk score (ERS) was calculated by using four hygienic environmental factors, including antibiotic use during infancy, cesarean section delivery, breast milk feeding, and having older siblings. Weighted polygenic risk score (PRS) was calculated by using four single nucleotide polymorphisms (SNPs), including interleukin-13 (rs20541), cluster of differentiation 14 (rs2569190), toll-like receptor 4 (rs1927911), and glutathione S-transferase P1 (rs1695). Multivariable logistic regression analysis was used. RESULTS: More than three courses of antibiotic use during infancy increased the risk of current AR (adjusted odd ratio [aOR], 2.058; 95% confidence interval [CI]: 1.290-3.284). Having older siblings, especially > 2 (aOR, 0.526; 95%Cl: 0.303-0.913) had a protective effect. High ERS ( > median; aOR, 2.079; 95%Cl: 1.466-2.947) and PRS ( > median; aOR, 1.627; 95%Cl: 1.117-2.370) increased the risk of current AR independently. Furthermore, children who had both high ERS and PRS showed a higher risk of current AR (aOR, 3.176; 95%Cl: 1.787-5.645). CONCLUSIONS: Exposure to multiple hygienic risk factors during infancy increases the risk of AR in genetically susceptible children.

Associations of prenatal antibiotic exposure and delivery mode on childhood asthma inception.

BACKGROUND: Prenatal antibiotic exposure and delivery mode may affect the gut microbiome in early life and influence the development of childhood asthma, but the combined effect of these 2 factors is unknown. OBJECTIVE: To identify the individual and combined effects of prenatal antibiotic exposure and delivery mode on the development of asthma in children and the potential mechanisms underlying these associations. METHODS: A total of 789 children from the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study were enrolled. Asthma was defined as a physician-confirmed diagnosis with asthma symptoms in the previous 12 months at age 7 years. Information on prenatal antibiotic exposure was obtained by mothers using a questionnaire. Logistic regression analysis was used. Gut microbiota analysis using 16S rRNA gene sequencing of fecal specimens obtained at 6 months was undertaken for 207 infants. RESULTS: Prenatal antibiotic exposure and cesarean section delivery (adjusted odds ratio [aOR], 95% confidence interval [CI], 5.70 [1.25-22.81] and 1.57 [1.36-6.14], respectively) were associated with childhood asthma, especially synergistically when compared with the vaginal delivery-prenatal antibiotic exposure reference group (aOR, 7.35; 95% CI, 3.46-39.61; Interaction P = .03). Prenatal antibiotic exposure was associated with childhood asthma with aORs 21.79 and 27.03 for 1 and 2 or more exposures, respectively. Considerable small-airway dysfunction (R5-R20 in impulse oscillometry) was observed with prenatal antibiotic exposure and cesarean section delivery, compared with those with spontaneous delivery without prenatal antibiotic exposure. There was no significant difference in the diversity of gut microbiota among the 4 groups. However, the relative abundance of Clostridium was significantly increased in infants with prenatal antibiotic exposure and delivered by means of cesarean section. CONCLUSION: Prenatal antibiotic exposure and delivery mode might modulate asthma development in children and small-airway dysfunction, potentially through early-life gut microbiota alterations.

Amorphigenin from Amorpha fruticosa L. Root Extract Induces Autophagy-Mediated Melanosome Degradation in mTOR-Independent- and AMPK-Dependent Manner.

In this study, we investigated the depigmentation effect of Amorpha fruticosa L. root extract (RE), an herbal medicine. A. fruticosa RE significantly induced depigmentation in α-MSH-treated B16F10 cells at noncytotoxic concentrations. Further, the RE decreased the protein levels of the melanosomal proteins Tyr and Pmel without decreasing their transcript levels. We found that MG132, a proteasome complex inhibitor, was unable to rescue the protein levels, but PepA/E-64D (a lysosomal enzyme inhibitor), 3-MA (a representative autophagy inhibitor), and ATG5 knockdown effectively rescued the protein levels and inhibited the depigmentation effect following RE treatment. Among rotenoids, amorphigenin composed in the RE was identified as a functional chemical that could induce depigmentation; whereas rapamycin, an mTOR inhibitor and a nonselective autophagy inducer, could not induce depigmentation, and amorphigenin effectively induced depigmentation through the degradation of melanosomal proteins. Amorphigenin activated AMPK without affecting mTOR, and knockdown of AMPK offset the whitening effect through degradation of melanosome proteins by amorphigenin. Results from this study suggested that amorphigenin can induce degradation of the melanosome through an AMPK-dependent autophagy process, and has the potential to be used as a depigmentation agent for the treatment of hyperpigmentation.

The Function of Autophagy as a Regulator of Melanin Homeostasis.

Melanosomes are melanocyte-specific organelles that protect cells from ultraviolet (UV)-induced deoxyribonucleic acid damage through the production and accumulation of melanin and are transferred from melanocytes to keratinocytes. The relatively well-known process by which melanin is synthesized from melanocytes is known as melanogenesis. The relationship between melanogenesis and autophagy is attracting the attention of researchers because proteins associated with autophagy, such as WD repeat domain phosphoinositide-interacting protein 1, microtubule-associated protein 1 light chain 3, autophagy-related (ATG)7, ATG4, beclin-1, and UV-radiation resistance-associated gene, contribute to the melanogenesis signaling pathway. Additionally, there are reports that some compounds used as whitening cosmetics materials induce skin depigmentation through autophagy. Thus, the possibility that autophagy is involved in the removal of melanin has been suggested. To date, however, there is a lack of data on melanosome autophagy and its underlying mechanism. This review highlights the importance of autophagy in melanin homeostasis by providing an overview of melanogenesis, autophagy, the autophagy machinery involved in melanogenesis, and natural compounds that induce autophagy-mediated depigmentation.

H2 Uptake and Diffusion Characteristics in Sulfur-Crosslinked Ethylene Propylene Diene Monomer Polymer Composites with Carbon Black and Silica Fillers after High-Pressure Hydrogen Exposure Reaching 90 MPa.

We investigated the influence of two fillers-CB (carbon black) and silica-on the H2 permeation of EPDM polymers crosslinked with sulfur in the pressure ranges 1.2-90 MPa. H2 uptake in the CB-blended EPDM revealed dual sorption (Henry's law and Langmuir model) when exposed to pressure. This phenomenon indicates that H2 uptake is determined by the polymer chain and filler-surface absorption characteristics. Moreover, single sorption characteristics for neat and silica-blended EPDM specimens obey Henry's law, indicating that H2 uptake is dominated by polymer chain absorption. The pressure-dependent diffusivity for the CB-filled EPDM is explained by Knudsen and bulk diffusion, divided at the critical pressure region. The neat and silica-blended EPDM specimens revealed that bulk diffusion behaviors decrease with decreasing pressure. The H2 diffusivities in CB-filled EPDM composites decrease because the impermeable filler increases the tortuosity in the polymer and causes filler-polymer interactions; the linear decrease in diffusivity in silica-blended EPDM was attributed to an increase in the tortuosity. Good correlations of permeability with density and tensile strength were observed. From the investigated relationships, it is possible to select EPDM candidates with the lowest H2-permeation properties as seal materials to prevent gas leakage under high pressure in H2-refueling stations.

Effect of early-life antibiotic exposure and IL-13 polymorphism on atopic dermatitis phenotype.

BACKGROUND: Although atopic dermatitis (AD) is associated with certain gene variants, the rapidly increasing incidence of AD suggests that environmental factors contribute to disease development. In this study, we investigated the association of AD incidence and phenotype with antibiotic exposure within 6 months of age, considering the dose administered and genetic risk. METHODS: This study included 1637 children from the COCOA cohort. Pediatric allergists assessed the presence of AD at each visit and obtained information about antibiotic exposure for more than 3 days. IL-13 (rs20541) polymorphism was genotyped by the TaqMan method. We stratified the AD phenotypes into four groups and used multinomial logistic regression models for analysis. RESULTS: Antibiotic exposure within 6 months of age was found to increase the risk of AD within 3 years of life (aOR = 1.40; 95% CI, 1.09-1.81) in dose-dependent manner. Antibiotic exposure more than twice increased the risk of the early-persistent AD phenotype (aOR = 2.50; 95% CI, 1.35-4.63). There was a weak interaction between genetic polymorphisms and environmental factors on the development of AD (p for interaction = 0.06). Children with the IL-13 (rs20541) GA + AA genotype have a higher risk of the early-persistent AD phenotype when exposed to antibiotics more than twice than those with the IL-13 (rs20541) GG genotype and without exposure to antibiotics (aOR = 4.73; 95% CI, 2.01-11.14). CONCLUSION: Antibiotic exposure within 6 months was related to the incidence of early-persistent AD and a dose-dependent increase in the incidence of AD in childhood, whose effect was modified by the IL-13 (rs20541) genotype.

Dog Ownership in Early Life Increased the Risk of Nonatopic Asthma in Children.

BACKGROUND: It is still debatable whether dog ownership during early childhood is a risk factor for the development of allergic diseases. OBJECTIVE: We investigated the association of dog ownership in early life with sensitization and asthma in childhood. METHODS: Data from the Cohort for Childhood Origin of Asthma and Allergic diseases were used to investigate the association between dog ownership at any time from pregnancy to 1 year of age and sensitization to aeroallergens at 3 and 7 years old, bronchial hyperresponsiveness (BHR), and asthma at 7 years old. We analyzed the cytokine levels in cord blood (CB) and indoor environmental measurement concentrations in the mother's residence obtained at 36 weeks of pregnancy. RESULTS: Sensitization to dogs at age 3 and 7 did not differ between dog ownership and nonownership, but dog ownership during early life decreased the risk of sensitization to aeroallergens at age 7 (aOR = 0.44, 95% CI 0.21-0.90). Dog ownership significantly increased the risk of nonatopic BHR (aOR = 2.86; 95% CI 1.32-6.21). In addition, dog ownership was associated with asthma, especially nonatopic asthma at 7 years old (aOR = 2.73, 95% CI 1.02-7.32; aOR = 7.05, 95% CI 1.85-26.90, respectively). There were no significant differences in the concentrations of IL-13 or interferon-γ in CB or indoor environmental measurements according to dog ownership during pregnancy. CONCLUSION: Early-life dog exposure in this birth cohort has been shown to reduce atopy but increase the risk of nonatopic BHR and nonatopic asthma at 7 years old.

Prenatal mold exposure is associated with development of atopic dermatitis in infants through allergic inflammation / Exposição pré-natal a mofo está associada ao desenvolvimento de dermatite atópicaem neonatos por reação alérgica

Abstract Objective Mold exposure in early life may be associated with development of atopic dermatitis; however, studies of this link are inconclusive and evidence for the underlying mechanism(s) is lacking. This study identified the association between the time of mold exposure and development of atopic dermatitis and investigated the underlying mechanisms. Method The association between atopic dermatitis and mold exposure was examined in the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study (n = 1446). Atopic dermatitis was diagnosed at 1 year of age by pediatric allergists. Exposure to mold was assessed by questionnaire. The Illumina MiSeq platform was used to examine the environmental mycobiome in 20 randomly selected healthy infants and 20 infants with atopic dermatitis at 36 weeks of gestation. Results Prenatal, but not postnatal, mold exposure was significantly associated with atopic dermatitis (adjusted odds ratio, 1.36; 95% confidence interval, 1.01-1.83). Levels of total serum IgE at 1 year of age were higher in infants with atopic dermatitis exposed to mold during pregnancy than in healthy infants not exposed to mold during pregnancy (p = 0.021). The relative abundance of uncultured Ascomycota was higher in infants with atopic dermatitis than in healthy infants. The relative abundance of uncultured Ascomycota correlated with total serum IgE levels at 1 year of age (r = 0.613, p < 0.001). Conclusion Indoor mold exposure during the fetal period is associated with development of atopic dermatitis via IgE-mediated allergic inflammation. Avoidance of mold exposure during this critical period might prevent the development of atopic dermatitis.

Resumo Objetivo A exposição ao mofo no início da vida pode estar associada ao desenvolvimento de dermatite atópica; contudo, os estudos sobre esse vínculo são inconclusivos e faltam evidências dos mecanismos subjacentes. Identificamos a associação entre o momento da exposição ao mofo e o desenvolvimento de dermatite atópica e investigamos os mecanismos subjacentes. Método A associação entre dermatite atópica e exposição a mofo foi examinada em um estudo de coorte de nascimento da Origem da Asma e de Doenças Alérgicas em Crianças (COCOA) (n = 1446). A dermatite atópica foi diagnosticada em pacientes com um ano de vida por pediatras alergistas. A exposição ao mofo foi avaliada por um questionário. A plataforma Illumina MiSeq foi utilizada para examinar o microbioma ambiental em 20 neonatos saudáveis escolhidos aleatoriamente e 20 com dermatite atópica a 36 semanas de gestação. Resultados A exposição pré-natal, porém não pós-natal, ao mofo foi significativamente associada à dermatite atópica (razão de chances ajustada, 1,36; intervalo de confiança de 95%, 1,01-1,83). Os níveis séricos totais de Imunoglobulina E (IgE) no primeiro ano de vida foram maiores em neonatos com dermatite atópica expostos a mofo durante a gravidez do que em neonatos não expostos a mofo durante a gravidez (p = 0,021). A abundância relativa de Ascomycota não cultivado foi maior em neonatos com dermatite atópica do que em neonatos saudáveis. A abundância relativa de Ascomycota não cultivado correlacionou-se com os níveis séricos totais de IgE no primeiro ano de vida (r = 0,613, p < 0,001). Conclusão A exposição ao mofo no ambiente domiciliar durante a gravidez está associada ao desenvolvimento de dermatite atópica por meio de reação alérgica mediada por IgE. A prevenção à exposição ao mofo durante o período crítico da gravidez pode prevenir o desenvolvimento de dermatite atópica.

Prenatal mold exposure is associated with development of atopic dermatitis in infants through allergic inflammation.

OBJECTIVE: Mold exposure in early life may be associated with development of atopic dermatitis; however, studies of this link are inconclusive and evidence for the underlying mechanism(s) is lacking. This study identified the association between the time of mold exposure and development of atopic dermatitis and investigated the underlying mechanisms. METHOD: The association between atopic dermatitis and mold exposure was examined in the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study (n=1446). Atopic dermatitis was diagnosed at 1 year of age by pediatric allergists. Exposure to mold was assessed by questionnaire. The Illumina MiSeq platform was used to examine the environmental mycobiome in 20 randomly selected healthy infants and 20 infants with atopic dermatitis at 36 weeks of gestation. RESULTS: Prenatal, but not postnatal, mold exposure was significantly associated with atopic dermatitis (adjusted odds ratio, 1.36; 95% confidence interval, 1.01-1.83). Levels of total serum IgE at 1 year of age were higher in infants with atopic dermatitis exposed to mold during pregnancy than in healthy infants not exposed to mold during pregnancy (p=0.021). The relative abundance of uncultured Ascomycota was higher in infants with atopic dermatitis than in healthy infants. The relative abundance of uncultured Ascomycota correlated with total serum IgE levels at 1 year of age (r=0.613, p<0.001). CONCLUSION: Indoor mold exposure during the fetal period is associated with development of atopic dermatitis via IgE-mediated allergic inflammation. Avoidance of mold exposure during this critical period might prevent the development of atopic dermatitis.

Prenatal Exposure to Lead and Chromium is Associated with IL-13 Levels in Umbilical Cord Blood and Severity of Atopic Dermatitis: COCOA Study.

There have been few studies investigating the association between atopic dermatitis (AD) and prenatal exposure to heavy metals. We aimed to evaluate whether prenatal exposure to heavy metals is associated with the development or severity of AD in a birth cohort study. A total of 331 subjects were followed from birth for a median duration of 60.0 months. The presence and severity of AD were evaluated at ages 6 and 12 months, and regularly once a year thereafter. The concentrations of lead, mercury, chromium, and cadmium in umbilical cord blood were measured by inductively coupled plasma mass spectrometry. Cord blood mononuclear cells (CBMCs) were isolated and stimulated for analysis of cytokine production using ELISA. Heavy metal levels in cord blood were not associated with the development of AD until 24 months of age. However, a positive correlation was observed between the duration of AD and lead levels in cord blood (p=0.002). AD severity was also positively associated with chromium concentrations in cord blood (p=0.037), while cord blood levels of lead, mercury, and cadmium were not significantly associated with AD severity (p=0.562, p=0.054, and p=0.055, respectively). Interleukin-13 production in CBMCs was positively related with lead and chromium levels in cord blood (p=0.021 and p=0.015, respectively). Prenatal exposure to lead and chromium is associated with the persistence and severity of AD, and the immune reaction toward a Th2 polarization.

Association of atopy phenotypes with new development of asthma and bronchial hyperresponsiveness in school-aged children.

BACKGROUND: Although previous studies have investigated the association between atopy phenotypes and allergic diseases, atopy characterizations in association with the development of allergic diseases remain poorly understood. OBJECTIVE: To identify atopy phenotypes in school-age children and to evaluate the association between atopy phenotypes and allergic diseases. METHODS: We enrolled 616 children with atopy defined as 1 or more positive allergen responses on skin prick tests and 665 children without atopy from the Children's Health and Environmental Research (CHEER) study. All children were followed up for 4 years at 2-year intervals. Atopy phenotypes were classified using latent class analysis. RESULTS: Four atopy phenotypes were characterized: later sensitization to indoor allergens (cluster 1); multiple early sensitization (cluster 2); early sensitization to outdoor allergens, especially Alternaria, and later sensitization to indoor allergens, including Aspergillus (cluster 3); and early sensitization to indoor allergens and later sensitization to outdoor allergens (cluster 4). New cases of asthma during follow-up were increased in clusters 2 and 3 (adjusted odds ratio [aOR], 2.76 and 4.25, respectively). The risk of new-onset bronchial hyperresponsiveness was highest in cluster 3 (aOR, 5.03). Clusters 2 and 4 had an increased risk of allergic rhinitis (aOR, 7.21 and 2.37, respectively). CONCLUSION: Identification of atopy phenotypes facilitates prediction of the development of asthma and bronchial hyperresponsiveness in school-age children. Our study suggests prevention of additional sensitization is required to modify the progression of allergic diseases.

Persistent asthma phenotype related with late-onset, high atopy, and low socioeconomic status in school-aged Korean children.

BACKGROUND: Treatment guidelines for asthma have been established based on asthma severity; there are limitations in the identification of underlying pathophysiology and prediction of prognosis in heterogeneous phenotypes of asthma. Although the complex interactions between environmental and genetic factors affect the development and progression of asthma, studies on asthma phenotypes considering environmental factors are limited. This study aimed to identify asthma phenotypes using latent class analysis including environmental factors in school-age children. METHODS: We included 235 children (6-8 years) with parent-reported, physician-diagnosed asthma from the Children's HEalth and Environmental Research (CHEER) study, which is a 4-year prospective follow-up study with 2-year intervals. At every survey, pulmonary function tests, methacholine challenge tests and blood tests with questionnaire were conducted. RESULTS: Four asthma phenotypes were identified. Cluster 1 (22% of children) was characterized by high prevalence of atopy and mild symptoms; subjects in cluster 2 (17%) consisted of less atopy and normal lung function, but intermittent troublesome; cluster 3 (29%) experienced late-onset atopic troublesome asthma with decreased lung function in combination with low socioeconomic status; and cluster 4 was associated with early-onset and less-atopic infrequent asthma. CONCLUSIONS: Late-onset, high atopy, and low socioeconomic status are associated with troublesome persistent asthma phenotype in school-age children. Environmental factors might be implicated in the clinical heterogeneity of asthma. Asthma phenotypes considering diverse factors might be more helpful in the identification of asthma pathogenesis and its prevention.

A rhinitis phenotype associated with increased development of bronchial hyperresponsiveness and asthma in children.

BACKGROUND: Allergic rhinitis (AR) has a wide range of clinical features and may be accompanied by comorbid allergic diseases. OBJECTIVE: To identify rhinitis phenotypes in school aged children and to predict the prognosis for developing bronchial hyperresponsiveness (BHR) and asthma. METHODS: This prospective follow-up study involved schoolchildren from the Children's Health and Environment Research cohort with current rhinitis, which was defined based on parental-reported, physician-diagnosed rhinitis and symptoms of rhinitis in the previous 12 months. All participants were followed up at 2 and 4 years later. Rhinitis clusters were identified by latent class analysis that used demographic, clinical, and environmental variables. RESULTS: In 512 eligible children (age range, 6-8 years), 4 rhinitis phenotypes were identified: cluster 1 (25% of children) was associated with nonatopy and a low socioeconomic status; cluster 2 (36%) was associated with a high-atopic burden but normal lung function; cluster 3 (22%) was associated with a high-atopic burden and impaired lung function; and cluster 4 (17%) was associated with low atopy and a high socioeconomic status. Cluster 3 was associated with the highest total serum IgE levels and blood eosinophil percentages at enrollment and the highest incidence of new cases of BHR (P = .04) and asthma symptoms (P = .005) during follow-up. CONCLUSION: The rhinitis cluster of schoolchildren with atopy and impaired lung function is associated with allergic march. This identification of distinct rhinitis phenotypes in affected children may help to prevent allergic march in children with rhinitis.