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Background The thromboxane A2 receptor ( TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes. Objective To investigate the association of TBXA2R polymorphisms with asthma susceptibility and related phenotypes and to identify functionally relevant polymorphisms. Methods We performed comprehensive sequencing of the TBXA2R gene in 48 Japanese control subjects and found a set of variants (SNP1 G>T rs2238634, SNP2 T>G rs2238633, SNP3 C>T rs2238632 and SNP4 G>A rs2238631) in intron 1 in linkage disequilibrium with c.795 T>C rs1131882, which was previously reported to be associated with asthma and related phenotypes. To investigate the effect of four common haplotypes (H1, H2, H3 and H4) on transcriptional activity, we performed a luciferase assay in primary bronchial smooth muscle cells (BSMCs) and human airway epithelial cells (BEAS-2B). We also studied the haplotype association with lung function, TBXA2R mRNA levels, and eosinophil fraction/count in peripheral blood in childhood-onset asthma patients and/or controls. Results H2 and H4, containing minor alleles of SNP2 and SNP3, had significantly higher transcriptional activities than H1 consisting of major alleles ( P < 0.001 in BSMCs and BEAS-2B). Homozygotes for redefined haplotype h2 corresponding to minor alleles of SNP2 and SNP3 were associated with lower lung function in childhood-onset asthma patients compared to other zygotes (baseline Forced expiratory volume in one second (FEV1)/ Forced vital capacity (FVC) and Forced expiratory flow between 25% and 75% of the FVC (%FEF25-75%): P = 0.00201 and 0.0128, respectively, and post-bronchodilator FEV1/FVC and %FEF25-75%: P = 0.00224 and 0.0393 respectively). Haplotype h2 was also associated with higher mRNA levels in control peripheral blood cells and higher blood eosinophil fractions and counts in female controls. Conclusions and Clinical Relevance Genetic variants were identified in the TBXA2R gene that influenced transcriptional activity and were associated with asthma-related phenotypes. Thromboxane pathways may therefore play important roles in airway inflammation and remodelling in asthma patients. [ABSTRACT FROM AUTHOR]

Aim: Habitual aerobic exercise results in a significant increase in central arterial compliance. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide and could play a role in mediating the habitual aerobic exercise-induced increase in central arterial compliance. The aim of the present study was to examine whether ET-1 is involved in the mechanisms underlying the increase in central arterial compliance with aerobic exercise training. Methods: Seven apparently healthy middle-aged and older (60 ± 3 years) adults underwent systemic endothelin-A/B (ETA/B)-receptor blockade (500 mg of Tracleer®) before and after 12 weeks of aerobic exercise training (70 ± 1% of maximal heart rate, 44 ± 2 min day−1, 4.4 ± 0.1 days week−1). Results: Basal carotid arterial compliance (via simultaneous B-mode ultrasound and arterial applanation tonometry on the common carotid artery) increased significantly after exercise training. Resting plasma ET-1 concentration decreased significantly after exercise training. Before exercise intervention, carotid arterial compliance increased significantly with the administration of the ETA/B-receptor blockade. After training, however, increases in carotid arterial compliance previously observed with the ETA/B-receptor blockade before training were abolished. Conclusions: Regular aerobic exercise training enhances central arterial compliance in middle-aged and older humans. The increase in arterial compliance was associated with the corresponding reduction in plasma ET-1 concentration as well as the elimination of ET-1-mediated vascular tone. These results suggest that reductions in ET-1 may be an important mechanism underlying the beneficial effect of exercise training on central artery compliance. [ABSTRACT FROM AUTHOR]

Background Bifidobacterium is a dominant genus in the intestinal microbiota of infants and comprises many different species. A series of studies performed in northern Europe showed differences in the composition of Bifidobacterium species between allergic infants and healthy controls. Additional studies are needed to confirm this observation. Objective To investigate the composition of fecal Bifidobacterium species in allergic infants and healthy controls in Japan, using molecular methods. Methods Full-term born babies were followed up to 6 months of age at a local hospital in rural Japan. The presence or absence of allergy was determined based on allergic symptoms and skin prick tests. Fecal Bifidobacterium species in allergic infants ( n=10), and healthy controls ( n=16) were evaluated using nine Bifidobacterium species-specific or group-specific primers based on 16S rDNA sequences at 1, 3, and 6 months of age. Results The number of the infants in whom no Bifidobacterium species could be found was four (15.4%) at 1 month, two (7.7%) at 3 months, and one (3.3%) at 6 months of age, all of whom were healthy controls. At 1 month of age, allergic infants had a higher prevalence f the Bifidobacterium catenulatum group than healthy controls (60.0% vs. 6.3%, P<0.01). At 6 months of age, allergic infants had a higher prevalence of B. bifidum than healthy controls (70.0% vs. 12.5%, P<0.01). These differences were not related to feeding method. Conclusions Our results in infants in rural Japan support the hypothesis that a compositional difference in intestinal Bifidobacterium species may be associated with the development of allergy in early infancy, although the responsible species might vary among countries or races. [ABSTRACT FROM AUTHOR]

The incidence of allergic rhinitis in paediatric bronchial asthma patients was about 80% according to a questionnaire survey. Watery nasal discharge and nose rubbing were common symptoms of paediatric allergic rhinitis, while nasal congestion and sneezing increased with age. Although there were slight differences depending on the age of patients, one-third to nearly half were believed to have nasal symptoms and asthma attacks. The first wheezing episode preceded nasal symptoms in the majority of patients, but onset of allergic rhinitis occurred > 1 year before asthma in a little over 10%. The age of onset of allergic rhinitis was 1 year in these patients, which was clearly earlier than that observed in patients who first developed asthma (4 years). Furthermore, the incidence of cedar pollinosis was higher in patients who developed allergic rhinitis first than in those who developed asthma first, suggesting that asthma patients who develop allergic rhinitis first exhibit pronounced nasal hypersensitivity. Allergic inflammatory cells are present in the nasal mucosa of asthma patients who do not exhibit distinct allergic rhinitis symptoms, so nasal sensitization does not necessarily lead to allergic rhinitis symptoms, suggesting the existence of some other factor that induces nasal hypersensitivity. On nasal smear, the appearance of mast cells preceded a positive radioallergosorbent test (RAST), and the appearance of eosinophils and basophils was consistent with the degree of sensitization. Anti-allergic agents appear efficacious in patients' mast cells positive on nasal smear cytology with negative house dust mite RAST, suggesting that nasal smear cytology may be useful when beginning medication. [ABSTRACT FROM AUTHOR]

We established a thyroglobutin (Tg)-specific, thyroiditis-inducing T-cell clone, B12G, from B6C3F1 mice by the immunization of mouse Tg with lipopolysaccharide (LPS) from Klebsiella strain LEN (O3:K1), B12G was Thy-1.2+, CD3+, CD4+, CD18+, and CD8-, and could transfer thyroiditis to recipient mice after in vitro stimulation with mouse or bovine Tg. Histological examination showed severe thyroiditis with predominant infiltrations of polymorphonuclear cells; few mononuclear cells were observed. B12G proliferated in response to bovine, mouse, porcine, and rat Tg in the presence of irradiated spleen cells, but did not respond to chicken or human Tg. H-2b, a low-responder haplotype of experimental autoimmune thyroiditis, governed the response of the clone to Tg. B12G produced interleukin-4 (IL-4) and IL-6, but not IL-2 or interferon-γ (IFN-γ), on stimulation with mouse Tg. These findings were different from characteristics of previously reported Tg-specific T-cell clones from high-responder mice in terms of epitope specificity and cytokine production pattern, raising the possibility that the specificities and functions of T cells involved in the development of autoimmune thyroiditis in low-responder mice differ from those in high responders. [ABSTRACT FROM AUTHOR]

Background: Hen's egg exposure through impaired skin barrier is considered a major mechanism of sensitization to eggs. However, the impact of filaggrin (FLG) gene loss-of-function mutations on the natural history of egg sensitization lacks consensus among studies., Objective: To evaluate the association between the natural course of egg sensitization and FLG mutations., Methods: We used Japanese and the UK birth cohorts (CHIBA and MAAS) to identify the longitudinal patterns of egg sensitization until mid-school age and examined the relationship between the identified patterns and FLG mutations. Sensitization was assessed using egg white-specific IgE levels or skin prick tests (SPTs). Egg allergy was confirmed by parental reports and sensitization. Latent class growth analysis identified longitudinal patterns., Results: Three similar patterns of egg sensitization (persistent, early-onset remitting, and no/low grade classes) were identified in both cohorts, with differing prevalence estimates. The proportion of children with egg allergy in the persistent class at 7 or 8 years of age was 23% (CHIBA) and 20% (MAAS). Consistently in both cohorts, FLG mutations were significantly associated only with the persistent class. Children with FLG mutations had an approximately four-fold increased risk of being in the persistent sensitization class (RRRs: 4.3, 95%C.I. (1.2-16.0), p = .03 in CHIBA; 4.3 (1.3-14.7), p = .02 in MAAS)., Conclusion: FLG loss-of-function mutations are associated with persistent egg sensitization in both Japanese and European ethnicities, and the mutations might be a potential biomarker for identifying the risk of persistent egg sensitization/allergy in early infancy. Future studies should incorporate oral food challenges to confirm this relationship., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Cardio-facio-cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4-year-old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3-year-old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left-hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2-elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co-occurrence of mitochondrial HMG-CoA synthase deficiency and HMG-CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia., (© 2022 Wiley Periodicals LLC.)

Atopic dermatitis (AD) mostly develops in early childhood and tends to resolve with age. However, its time course in severity before and after adolescence varies widely among patients. To investigate the course of disease severity from birth to 19 years old of adult patients with AD, we conducted a nationwide Web-based survey of 3090 Japanese adult subjects diagnosed with AD, using a questionnaire to choose a pattern that most resembled their own out of 10 courses of AD severity. Patients in the 20s and 30s age groups tended to choose the option "gradually improved" or "improved by the age of 12", but patients in the 40s or older age group tended to choose the option "aggravation between the age of 12 and 19". Those who chose "AD development at age 20 or older" increased as the generation was older. This survey revealed that the time course of AD severity from birth to 19 years old varies depending on the generation targeted in this study. It is presumed that the acquired factors affecting the natural history of AD have changed over the past 50 years in Japan., (© 2021 Japanese Dermatological Association.)

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far., (© 2020 Wiley Periodicals, Inc.)

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice., (© 2019 Japanese Dermatological Association.)

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm 2 , P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm 3 , P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways., (© 2017 Wiley Periodicals, Inc.)

We report here a case of immediate hypersensitivity to beer, in which a female patient developed angioedema of the eyelids shortly after consuming beer. In skin prick tests, the patient showed positive reactions to the base ingredients of beer, particularly malt and barley. The specific serum immunoglobulin E antibodies against barley and malt displayed weakly positive reactivity. To identify the immunoreactive antigens, malt and barley proteins were separated by 2-D polyacrylamide gel electrophoresis and immunoreacted with the patient's serum. The results of mass spectrometric analysis revealed that the main antigen was a protein with similarity to protein z-type serpin. Notably, the identified antigen had a molecular weight of 20-25 kDa, which is markedly smaller than that previously reported for protein Z4 (44 kDa). Taken together, these analyses indicate that a possible new antigen which belongs to the protein Z family elicits immediate hypersensitivity to beer., (© 2015 Japanese Dermatological Association.)

Constitutional 11q interstitial deletion syndrome presents with congenital anomalies including microcephaly with craniostenosis, minor dysmorphic features, vitreoretinopathy, and renal anomalies. This syndrome is occasionally associated with neuroblastoma (NB) as a life-threatening complication, which is important for clinical care. Although the corresponding locus to NB has been predicted to exist in 11q22-23 by previous deletion studies related to NB, the causative haploinsufficient genes have not yet been identified. We herein reported for the first time the simultaneous coexistence of adrenal NB and abdominal prevertebral ganglioneuroma in a 6-year-old girl with a constitutional hemizygous 11q14.1-23.3 deletion. Of the 11 haploinsufficient genes predicted with an in silico database, we focused on NCAM1 and CADM1 as the genes accountable for NB and ganglioneuroma. The deletion range, especially the 11q22.3 involvement, needs to be determined in 11q deletion cases in order to predict susceptibility to peripheral nerve tumors involving NB and ganglioneuroma., (© 2015 Wiley Periodicals, Inc.)