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Background A report presenting five heterozygous de novo variants in VAMP2 in unrelated individuals with a neurodevelopmental disorder characterized by axial hypotonia, intellectual disability, and autistic features was first published in April 4, 2019. Case report We report the case of a male child with VAMP2 variant who was delivered at 38 weeks and 4 days without neonatal asphyxia. At 4 months of age he showed hypotonia and no visual pursuit and fixation. He presented with infantile spasms at 6 months, and electroencephalography (EEG) showed hypsarrhythmia. His infantile spasms completely disappeared by adrenocorticotropic hormone therapy, but his EEG findings continued to show high voltage slow-waves with multi-focal spikes. At 2 years of age he was non-verbal, had an absence of purposeful hand movements, and no visual fixation. He had somnolence tendency in the daytime. Biochemical and extensive genetic examinations were unrevealed. Magnetic resonance imaging showed slight brain atrophy. At 2 years and 7 months of age, he suffered from myoclonic seizures of the eyelid and tongue, which propagated to unilateral fingers, and sometimes to the bilateral legs. At 8 years of age hyperkinetic movement occurred. At age 13, whole-exome sequence identified a heterozygous missense variant, NM_014232.2:c.199G>C,[p.(Ala67Pro)] in exon 3 of VAMP2 which was a de novo non-synonymous variant. Conclusion This is the first case report of VAMP2 variant in Japan. Hypotonia at early infancy, poor visual fixation, and absence of purposeful hand movements may be indicative of the diagnosis for VAMP2 variant.

Introduction The relevant literature includes several case reports on cerebral infarction in children with HHV-6 infection; however, there is no report of brain stem infarction. Case An 11-month-old girl was hospitalized because of fever. She was unable to stand up and meet her mother’s gaze. Magnetic resonance imaging (MRI) indicated a right pons and mid-brain lesion; a diagnosis of brainstem infarction was made. After her fever subsided, a rash developed on her trunk and limbs; blood examination results indicated a primary HHV-6 infection. She was treated with aspirin, edaravone, and mannitol to prevent further complications. At the age of 18 months, the auditory brainstem response (ABR) was unremarkable and she is developing well. Discussion and conclusion A limited number of studies have reported HHV-6 infection-associated infarction, and no cases of brainstem infarction have been reported. One possible cause of cerebral infarction is antiphospholipid antibody syndrome (APS) triggered by the infection. HHV-6 may also directly infect vascular endothelial cells and cause angiopathy. However, the real mechanism of infarction remains unclear. Our patient had a favorable prognosis despite brainstem infarction.

The early institution of enteral nutrition is associated with beneficial outcomes and intestinal growth in pediatric patients. However, the number, frequency, and types of unfavorable events occurring with particular formulas are undefined. We experienced unexpected complications in two cases following a change in formula. One case diagnosed with myotubular myopathy experienced highly-increased gastric residuals and watery diarrhea leading to decreased calorie intake and weight loss. The second case with campomelic dysplasia suffered liver dysfunction and fever. In both cases, symptoms developed soon after of the change in formula and improved after resumption of the previous formula. Both cases had undergone tracheostomy and artificial ventilation, and had a history of feeding the same formula for an extended period of time. In chronic care patients such as ours, a change in formula may cause unexpected adverse events; therefore, caution is warranted.

Background Mucus hypersecretion from airway epithelium is a characteristic feature of severe asthma. Glucocorticoids (GCs) may suppress mucus production and diminish the harmful airway obstruction. We investigated the ability of GCs to suppress mRNA expression and protein synthesis of a gene encoding mucin, MUC5AC , induced by transforming growth factor (TGF)-a in human mucoepidermoid carcinoma (NCI-H292) cells and the molecular mechanisms underlying the suppression. Methods We determined if GCs such as dexamethasone (DEX), budesonide (BUD), and fluticasone (FP) could suppress MUC5AC production induced by a combination of TGF-α and double-strand RNA, polyinosinic- polycytidylic acid (polyI:C). MUC5AC mRNA expression and MUC5AC protein production were evaluated. The signaling pathways activated by TGF-α and their inhibition by GCs were tested using a phosphoprotein assay and MUC5AC promoter assay. Results DEX significantly suppressed the expression of MUC5AC mRNA and MUC5AC protein induced by TGF-α. The activation of the MUC5AC promoter by TGF-α was significantly inhibited by DEX. DEX did not affect activation of downstream pathways of the EGF receptor or mRNA stability of MUC5AC transcripts. DEX, BUD, and FP suppressed MUC5AC protein expression induced by a combination of TGF-α and polyI:C in a dose-dependent manner. Conclusions GCs inhibited MUC5AC production induced by TGF-α alone or a combination of TGF-α and polyI:C; the repression may be mediated at the transcriptional but not post-transcriptional level.

【目的】群馬県内の気管支喘息児（以下，喘息児）の発作状況，および患児と保護者のQOLについて経年的変化を解析する．【方法】喘息児の保護者を対象に，喘息症状やQOLに関する質問票調査を行い，併せて治療内容の記載を主治医に依頼した．調査は2001年，2005年，2008年の計3回おこなった．【結果】吸入ステロイドや抗ロイコトリエン薬などの抗炎症薬の処方頻度は経年的に著増し，患児の発作状況（入院・救急受診回数，喘息症状など）は経年的に改善した．一方，患児および保護者のQOLは改善傾向にあったが顕著ではなかった．【考察】群馬県の喘息児の喘息管理状態は治療法の変化に伴い改善傾向にあるが，QOLの改善については今後更に配慮する必要性が示唆された．

As antenatal environment may influence the development of atopy-predisposing immune response, cord blood cytokine productions may be an important predictor for wheezing. We investigated cord blood cytokines in a prospective birth cohort, intensively monitored for wheezy infant outcome at 1 yr. Cord blood serum samples from 269 children were assayed for interleukin (IL)-1beta, -2, -4 to -8, -10, -12 (p70), -13, and -17, interferon-gamma, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic protein-1, and macrophage inflammatory protein-1beta. Associations between family histories, antenatal and perinatal factors, cord blood cytokine concentrations, and wheezy infant outcomes (wheezing more than two times) were analyzed. In cord blood sera from 269 children, there were associations between high levels of IL-6, -8 and G-CSF concentrations, and cesarean section. Data at 1 yr were obtained from 213 infants, including 33 wheezy infants. Risk of wheezing was related to gestational age, birth weight, cesarean section, and maternal eczema, but not to bacterial/viral infection during pregnancy, maternal asthma, maternal smoking, or paternal history. High level of cord blood IL-8 concentration had a significant association with wheezy infant outcomes at 1 yr (p = 0.025). By using multivariate logistic regression analysis, birth weight [odds ratio(OR) = 0.998, 95% confidence interval (CI) = 0.997-1.000] and maternal eczema (OR = 5.356, 95% CI = 1.340-21.41), but no other factors, were significant predictors of wheezy infants. Birth weight, gestational age, and maternal history were important risk factors for wheezing in the first year of life. Several cord blood cytokine productions were influenced by cesarean section, and IL-8 may be a predictor for recurrent wheezing at 1 yr.

Viral infection is a major trigger for exacerbation of asthma and induces overproduction of mucins. We investigated whether dsRNA could amplify the induction of mucin by TGF-α in human bronchial epithelial cells, as well as the molecular mechanisms regulating MUC5AC expression. Human pulmonary mucoepidermoid carcinoma (NCI-H292) cells and normal human bronchial epithelial cells were exposed to polyinosinic-cytidyric acid (poly(I:C)) and TGF-α. Then, MUC5AC protein production, mRNA expression, and promoter activity were evaluated. Cells were pretreated with a selective inhibitor of ERK, and phosphorylation of ERK was examined by Western blotting. Furthermore, the expression of MAPK phosphatase 3 (MKP3) mRNA was evaluated and the effect of MKP3 overexpression was assessed. Poly(I:C) synergistically increased MUC5AC induction by TGF-α in both NCI-H292 and normal human bronchial epithelial cells. This increase was dependent on MUC5AC gene transcription. A MEK1/2 inhibitor (U0126) significantly inhibited MUC5AC production. Phosphorylation of ERK was enhanced by poly(I:C). TGF-α stimulation up-regulated MKP3 mRNA expression, while costimulation with poly(I:C) inhibited this up-regulation dose-dependently. Enhanced expression of MUC5AC mRNA by poly(I:C) in wild-type cells was completely suppressed in cells transfected with the MKP3 expression vector. dsRNA can synergistically amplify the induction of MUC5AC mucin by TGF-α. This synergistic effect on MUC5AC production may be due to enhanced activation of ERK through inhibition of MKP3 by poly(I:C).

小児の喘息の多くは, 乳児期に発症する。しかし, 乳児喘息の初期の診断は必ずしも容易ではない。その原因のひとつとして乳幼児期の喘鳴性疾患にはアトピー型喘息以外に, いくつかの亜型 (phenotype) が存在することが考えられている。今回, 平成13年度から19年度まで群馬県の1村全体における小学校就学予定児に喘鳴, 喘息に関連する疫学的調査を行い, 気道過敏性検査を含む肺機能検査を行った。対象587名のうち, 喘鳴は21.8% (128名) に, 喘息は10.4% (61名) に認められた。非喘息性の喘鳴群では, 喘息群同様に有意な気道過敏性の亢進が認められた (p

OBJECTIVE. In a prospective birth cohort study, we sought to identify perinatal predictors of the occurrence of atopic dermatitis in the first year of life.METHODS. Associations of family history, infection during pregnancy, cord blood cytokine concentrations, and skin function parameters with atopic dermatitis were analyzed. Stratum corneum hydration was measured with an impedance meter until 5 days after delivery and again at 1 month.RESULTS. Complete data were obtained for 213 infants, including 27 diagnosed by a physician as having atopic dermatitis during their first year and 26 diagnosed as having infantile eczema during their first month. The risk of atopic dermatitis during the first year of life was related to maternal atopic dermatitis, lower concentrations of macrophage inflammatory protein-1β in cord blood, and greater skin moisture in the surface and stratum corneum of the forehead and cheek at 1 month of age but not to viral or bacterial infection during pregnancy or breastfeeding. Paternal hay fever was associated negatively with the development of atopic dermatitis. High concentrations of interleukin-5, interleukin-17, and macrophage chemotactic protein-1 and only surface moisture in the cheek were associated with greater risk of infantile eczema in the first month.CONCLUSIONS. The association of atopic dermatitis in infancy with reduced neonatal macrophage inflammatory protein-1β levels suggests a link with immature immune responses at birth. Stratum corneum barrier disruption in atopic dermatitis may involve impairment of cutaneous adaptation to extrauterine life. The majority of risk factors had different effects on infant eczema and atopic dermatitis, indicating different causes.

An association between asthma and bronchial hyperresponsiveness (BHR) has been demonstrated. It is possible that the relationship between asthma severity and BHR in children with asthma is different in infants and in adolescents. The aim of this study is therefore to evaluate the effect of aging on the relationship between the severity of asthma and BHR in children with asthma. We measured BHR in 386 subjects ranging from 2 to 20 years of age. The subjects consisted of 323 children with asthma (boys:girls = 193:130, mean age 9.7 years) and 63 age-matched controls (boys:girls = 25:38, mean age 8.2 years). BHR was measured using the methacholine inhalation challenge by measuring the transcutaneous oxygen pressure (tcPO2) in children less than 6 years of age (Dmin-PO2) and by measuring the respiratory resistance (Rrs) in children 6 years of age and older (Dmin-Rrs). Throughout the whole age range, both the Dmin-PO2 and Dmin-Rrs in each asthma severity group were higher than those in the controls. In the asthmatics aged 2-5 years, the Dmin-PO2 levels in the mild asthma group were higher than those in the moderate and severe asthma groups (p0.001, p0.001, respectively), and the Dmin-PO2 levels in the moderate asthma group were also higher than those in the severe asthma group. This tendency was also found in the age ranges of 6-9 years and 10-13 years. In the asthmatics aged 14-20 years, the Dmin-Rrs levels were not significantly different among the three groups. Taken together, these data show that aging has an effect on the relationship between the severity of asthma and BHR during childhood and that BHR may not be the sole determinant for the severity of asthma in adolescence.

Background: Disodium cromoglycate (DSCG) is known to inhibit both immediate and late asthmatic responses (IAR and LAR). However, its effect on mucus hypersecretion is unknown. Using a murine model of asthma, we aimed to determine whether mucus secretion increased during IAR and LAR. We also studied the potency of DSCG in inhibiting mucus secretion and on airway eosinophilia. Methods: Mice were subjected to initial intraperitoneal sensitizationand airway challenge to ovalbumin (OVA) and then provokedby additional exposure to OVA. Some mice were pretreated with aerosolized DSCG (20 mg/ml) 1 h before the provocation with OVA. After serial measurements of enhanced pause (Penh), an indicator of airflow obstruction, serum samples and bronchoalveolar lavage fluids (BALF) were collected. Then, the lungs were excised and a morphometric analysis for mucus hypersecretion was performed. Results: A biphasic increase in Penh (IAR and LAR) was observed in sensitized animals after provocation with OVA. Airway eosinophilia was observed during both responses. Intraluminal mucus significantly increased during LAR, but not during IAR. DSCG significantly attenuated both IAR and LAR, and significantly inhibited the increase in intraluminal mucus during LAR, but had no effect on eosinophilia in BALF. Conclusion: Our results suggest that airway hypersecretion may be involved as a component of airflow obstruction during LAR, and that this is unlikely during IAR. DSCG may be effective in reducing excessive airway mucus caused by exposure to allergens.

A 5-year-old girl presented with a two-month-history of skin rash and general fatigue. She had a slight fever, progressive muscle weakness and liver dysfunction. Gottron's papules on her fingers and purple-reddish papules on her elbows were noted. Serum aldolase levels were highly elevated, however, creatine phosphokinase levels were normal. An MRI revealed abnormal high signal changes in her gluteus minimus muscles. Interstitial pneumonia suddenly developed and she died despite aggressive treatment with methylprednisolone pulse therapy followed by intravenous administration of cyclophosphamide, immunoglobulin and cyclosporine A. Interstitial pneumonia is rare in juvenile dermatomyositis; however, as in adult cases, it can be fatal. In order to prevent severe complications and functional disabilities, early aggressive treatments should be considered when muscle inflammation is refractory to ordinary treatment.

For elementary school children with atopic dermatitis, a skin care program using shower therapy was performed during the school lunch break for 6 weeks from June to July in 2004 and 2005. All 53 participants showed an improvement in their atopic dermatitis during the 6-week periods studied. Skin care with daily showering at an elementary school was thus found to be effective for the treatment of atopic dermatitis.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited recurrent fever syndrome. We describe a family of eldest son and monozygotic twin younger sisters with characteristic syndrome of HIDS, but normal level of IgD. Mevalonate kinase (MK) activity was deficient in all of them, and analysis of the MVK gene revealed compound heterozygosity for 2 new mutations, one of which was the disease-causing splicing mutation and the other was a novel missense mutation. All the patients had the same compound heterozygous mutations c.227-1 G > A and c.833 T > C, which resulted in exon 4 skipping and p.Val278Ala. This is the first case in which exon skipping mutation of the MVK gene has been certainly identified at the genomic DNA level. In each case, in which HIDS is clinically suspected, despite normal IgD level, analysis of MK activity and the MVK gene should be performed.

Many kinds of abstract machine have been proposed for executing byte codes of functional languages, such as Landin's SECD machine and Curien's Categorical Abstract Machine, which have been studied for decades from a theoretical viewpoint and applied in the implementation of functional language processors. In this paper, we propose the Simple Abstract Machine (SAM), a simplified SECD machine. The simplification lets us handle first-class continuations in the framework of abstract machines.

Background In children, exhaled nitric oxide (eNO) is usually confounded by factors such as age and height. We evaluated the relationship between eNO and lung function by minimizing the effects of aging and height. Methods In Study 1, the subjects comprised 738 elementary school children and junior high school children (aged 6 to 15 years, 366 males and 372 females). They were divided into two groups according to age (6–10 years and 11–15 years). A height range was determined by a histogram of height in each group. In Study 2, lung function, respiratory resistance and eNO level were measured in age- and height-limited groups. Results In Study 1, total of 148 younger children ranging in height from 120 to 130 cm and 180 older children ranging in height from 148 to 158 cm participated in Study 2. The level of eNO among asthmatic children was higher than that of normal children in both the younger and the older groups. The decrease in forced expiratory volume in 1 second (FEV1) and other parameters of central airway resistance did not correlate with the eNO level. However, the small airway parameters of MMEF and V25/HT in older asthmatic children, and V25/HT and R5-R20 in younger asthmatic children inversely correlated with eNO. Conclusions Our data suggest that eNO level inversely correlates with small airway narrowing, and airway inflammation has a significant effect on small airway lung function in asthmatic school children.

A breath sound analyser was used to detect bronchoconstriction without wheezing during methacholine inhalation challenge in children. The highest frequency of inspiratory breath sounds increased significantly during bronchoconstriction and decreased after inhalation of a bronchodilator. The highest frequency of inspiratory breaths sounds was correlated with bronchial reactivity. Background and objective: It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. Methods: Thirty-six children (8.2 ± 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). Results: Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P

Background Many children with asthma outgrow this disease after the onset of puberty. However, the precise mechanism of outgrowing asthma in children is still unclear. Objective To evaluate the characteristics of respiratory physiology during adolescence. Methods The results of the lung function test and methacholine inhalation challenge were prospectively evaluated in adolescent patients with asthma with and without symptoms. One hundred sixty children with asthma participated. Twenty-eight children had symptom-free adolescent asthma (ie, remission asthma) (boy to girl ratio, 16:12; mean age, 14.6 years), 25 had intermittent adolescent asthma (boy to girl ratio, 16:9; mean age, 14.9 years), and 47 had symptomatic adolescent asthma (boy to girl ratio, 27:20; mean age, 12.7 years). For comparison purposes, 60 younger children with symptomatic asthma participated. The parameters of bronchial hyperresponsiveness, baseline respiratory resistance, threshold of methacholine (Dmin) (bronchial sensitivity), and speed of bronchial constriction (Sm) (bronchial reactivity) were measured by methacholine inhalation challenge using the continuous oscillation method. Results There was no significant difference in lung function results, such as forced vital capacity and forced expiratory volume in 1 second, between the intermittent asthma and the remission asthma groups. Also, there was no significant difference in baseline respiratory resistance and Dmin between the 2 groups. However, the value of Sm of the remission asthma group was significantly lower than that of the intermittent asthma group ( P = .02) and the symptomatic asthma group ( P = .02). Conclusions These data show that the adolescents with asthma remission showed a significant decrease of Sm, whereas Dmin was not changed. These results suggest one of the mechanisms by which asthma is outgrown in children and explain the common clinical aspects of adolescent asthma, such as symptom-free but bronchial hyperresponsive asthma.

Summary Background Atopic dermatitis is a disease of skin barrier dysfunction and outside stimuli can cross the skin barrier. Objectives To examine a new method for evaluating the outside to inside skin transparency with a colorimeter and yellow dyes. Methods In study 1, a total of 28 volunteer subjects (24 normal and four with atopic dermatitis) participated. After provocation with yellow dye, the skin colour of all the subjects was measured using a colorimeter. The skin transparency index was calculated by the changes of the skin colour to yellow. Other variables of skin function, including transepidermal water loss (TEWL) and stratum corneum hydration, were also measured. In study 2, the skin transparency index was evaluated for a cohort of 38 patients with atopic dermatitis, 27 subjects with dry skin and 29 healthy controls. Results In study 1, the measurement of skin colour (b*) using tartrazine showed good results. There was a significant relationship between the skin transparency index with tartrazine and the atopic dermatitis score (P = 0·014). No other measurements of skin function, including the TEWL, were correlated. In study 2, the skin transparency index score obtained with tartrazine in the patients with atopic dermatitis was significantly higher than that of the controls and those with dry skin (P

Background Exhaled nitric oxide (eNO) is a noninvasive marker of airway inflammation. However, previous studies show that the offline value is lower than the online value. Objective To compare a standard offline eNO measurement apparatus with a modified apparatus that can monitor flow volume and respiratory pressure. Methods We studied 73 cooperative individuals aged 5 to 28 years (32 children: mean age, 8.3 years; 41 adults: mean age, 21.5 years). We modified the standard device by including a flow meter with a manometer and attaching a plastic tube connected to a 3-way valve to control the resistance. The online and offline (measured using the modified device and the standard device) eNO determinations were compared in a single session and were analyzed using a nitric oxide analyzer. Results There was a good relationship between the online and modified offline eNO measurements in children. The modified offline method showed a stronger correlation with the online method ( r = .97 vs r = .92), and the modified offline eNO value was more similar to the online eNO value than to the standard offline value. The mean difference between the online and standard offline eNO values was 52%, whereas the mean difference between the online and modified offline eNO values was only 10%. Conclusions Using the offline method, we can easily control the resistance and flow volume to reach the same value measured by the online method in childhood respiratory diseases.

Lung fibroblasts are a major source of several cytokines including CC chemokine eotaxin. We aimed to study the regulation of eotaxin-1/CCL11 production by dexamethasone and analyze its molecular mechanisms in human lung fibroblasts. Normal human lung fibroblast cells were exposed to IL-4 (40 ng/ml) and/or dexamethasone (10(-6)-10(-9) M), and eotaxin mRNA expression and production was evaluated. Mechanisms of transcriptional regulation were assessed by Western blotting and dual luciferase assay for eotaxin promoter. The effects of dexamethasone on suppressor of cytokine signaling (SOCS)-1 and eotaxin mRNA expression in the cells transfected with expression vector (pAcGFP1-C1) or short interfering RNA (siRNA) for SOCS-1 were also investigated. Within 24 hours, dexamethasone inhibited IL-4-induced eotaxin mRNA expression and protein production, while eotaxin production was markedly increased at 48 and 72 hours after coincubation with IL-4 and dexamethasone. IL-4-induced eotaxin promoter activity was inhibited by dexamethasone at 8 hours, but enhanced at 48 hours after coincubation. Dexamethasone suppressed SOCS-1 mRNA expression but enhanced IL-4-induced STAT6 phosphorylation at 36 to 48 hours after coincubation. Enhanced expression of eotaxin mRNA by dexamethasone 48 hours after coincubation was completely diminished in the cells transfected with either expression vector or siRNA for SOCS-1. These results indicated that dexamethasone, depending on the exposure duration, can either inhibit or enhance IL-4-induced expression and production of eotaxin in the lung fibroblasts. The mechanisms of later enhanced production may depend on the prolonged transcriptional activity of the eotaxin gene, in part due to inhibition of SOCS-1 expression.

Aim: Asthmatic children are more likely to outgrow their symptoms than adult patients. Thus, we wanted to know whether there were any age-related differences in the time course of the allergic airway inflammation. Methods: BALB/C mice at different ages (young: 3 days after birth, and mature: 8 weeks of age) were sensitized with ovalbumin (OVA). Subsequently, animals were challenged with aerosolized OVA during 1, 2, 4 or 8 consecutive weeks. Bronchial hyperresponsiveness (BHR), serum IgE levels, the degrees of inflammatory cell infiltration (ICI) and goblet cell metaplasia (GCM) in the airways, and the number of eosinophils and cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. Results: At 1 week, airway inflammation and BHR occurred similarly between young and mature mice. However, BHR disappeared at 4 weeks in young, whereas it persisted even at 8 weeks in mature mice. GCM, ICI and eosinophilia in BALF attenuated with time, with more remarkable reduction in young mice. The BALF IL-4 level was high during the first 2 weeks in both groups, while the IL-2 level was significantly increased at 2 weeks solely in young mice. Conclusion: Different time courses in airway inflammation and in BHR may relate to the different prognoses between childhood and adult asthma. The understanding of the mechanisms underlying this age-related differences may be helpful to induce remission in asthmatic patients.

In this paper, we propose a new software design of an online judge system for interactive theorem proving. The distinctive feature of this architecture is that our online judge system is distributed on the network and especially involves volunteer computing. In volunteers’ computers, network bots (software robots) are executed and donate computational resources to the central host of the online judge system. Our proposed design improves fault tolerance and security. We gave an implementation to two different styles of interactive theorem prover, Coq and ACL2, and evaluated our proposed architecture. From the experiment on the implementation, we concluded that our architecture is efficient enough to be used practically.