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Background: Wheat-dependent exercise-induced anaphylaxis (WDEIA) is induced not by the intake of wheat-based food alone, but by the combination of exercise stress and such intake. Provocation tests have been reported to be useful for the diagnosis of this condition, but they are not always accurate. Furthermore, provocation tests are associated with the risk of anaphylactic shock, so safer testing is required.Subjects and methods: Thirty-three patients (mean age 35.5 ± 16.0 years) who underwent provocation tests from April 2019 to July 2023 were included in this study. We investigated associations of their provocation test results with their medical history, blood test results before the provocation tests, exercise load at the time of the test, and severity of the induced symptoms.Results: Symptoms were induced and the diagnosis of WDEIA was made in 28 cases, while 2 cases were confirmed not to have WDEIA. Overall, 25 of the 28 positive cases had symptoms induced by an exercise load greater than 70% of the heart rate calculated by the Karvonen formula, 7 of which required Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) loading to induce symptoms. None of the patients with negative wheat-specific IgE titers and positive gluten and/or ω-5 gliadin ones required NSAIDs loading. No patients required the administration of adrenaline.Conclusion: Wheat-specific IgE as well as gluten and ω-5 gliadin antibody titers are associated with WDEIA symptom severity. Exercise loading with a target heart rate of 70%–90% of that calculated by the Karvonen formula is safe and useful for diagnosis this condition.

Itching due to atopic dermatitis causes sleep disorders in children, but its pathology is unknown. The aim of this study is to investigate nocturnal scratching as an indirect index of itching during sleep and its relationship with depth of sleep in children with atopic dermatitis. Nocturnal scratching was measured in a total of 20 children with atopic dermatitis, using a smartwatch installed with the application Itch Tracker. Depth of sleep was analysed using polysomnography. The severity of atopic dermatitis was scored using Eczema Area and Severity Index (EASI) and Patient-Oriented Eczema Measure (POEM). The number and time of nocturnal scratching measured by Itch Tracker had a significantly positive correlation with EASI scores, whereas POEM scores were not correlated with EASI scores. Mean sleep efficiency was 90.0% and scratching episodes (n = 67) started mainly during the awake stage or light sleep stages. In the scratching episodes that started during sleep stages (n = 34), the sleep stage changed to a lighter one or to the awake stage in 35.5% of episodes. Itch Tracker is applicable to measure nocturnal scratching in children. Nocturnal scratching can deteriorate quality of sleep by changing the sleep stage to a lighter one or to the awake stage.

Abstract Background Our recent observational study showed that regular consumption of cow’s milk (CM) formula during early infancy (3–6 months old) was associated with a reduced risk of CM allergy (CMA) at 12 months old. However, the long-term association is unclear. The present study was aimed to examine how long this inverse association persists after 12 months old. Methods This study used the dataset of an ongoing nationwide prospective cohort, the Japan Environment and Children’s Study, in which participants were registered between January 2011 and March 2014. We analyzed 65,568 children followed-up until 36 months old. The exposure factors were the consumption statuses of formula milk from 0–3, 3–6, and 6–12 months old. The primary outcome was the prevalence of CMA at 6, 12, 18, 24 and 36 months old. CMA was defined as an allergic reaction and sensitization to CM protein in an individual with no or limited intake of this protein at the evaluation time, combined with physician-diagnosed food allergy. Multivariable regression models were used to estimate the association between the periods of formula consumption and the prevalence of CMA. Results The prevalence of CMA increased with a peak of 1.51% at 18 months old and then declined to 0.79% at 36 months old. Formula milk from 3–6 months old was associated with a reduced risk of CMA throughout the first 3 years of life, although the extent of the reduction was mitigated with age (adjusted relative risk: [95% confidence interval]: 0.19 [0.10–0.34] at 12 months old, 0.23 [0.16–0.33] at 18 months old, 0.41 [0.26–0.64] at 24 months old, and 0.47 [0.26–0.80] at 36 months old). The association between early formula and CMA were observed in both children with and without eczema, but more prominent and long-lasting in the former than the latter. Conclusions Regular exposure to CM protein during infancy was associated with a reduced prevalence of CMA during early childhood. At present, however, this observational study does not necessarily encourage formula feeding, and randomized controlled trials are warranted to confirm the findings and their significance.

Introduction: Acute respiratory distress syndrome (ARDS) is considered a poor prognostic factor for miliary tuberculosis (MTB), but little is known about the effectiveness of steroid pulse therapy for MTB complicated by ARDS. Patients and methods: Medical records were used to retrospectively investigate the prognosis and clinical information of 13 patients diagnosed with MTB complicated by ARDS among 68 patients diagnosed with MTB at our hospital between January 1994 and October 2016. None of the patients had multidrug resistant tuberculosis (TB). MTB was diagnosed by 1 radiologist and 2 respiratory physicians based on the observation of randomly distributed, uniformly sized diffuse bilateral nodules on chest computed tomography and the detection of mycobacterium TB from clinical specimens. ARDS was diagnosed based on the Berlin definition of ARDS. The effect of steroid pulse therapy on death within 3 months of hospitalization was examined using Cox proportional hazards models. Variables were selected by the stepwise method (variable reduction method). Results: Six of 8 patients with MTB complicated by ARDS were alive 3 months after hospitalization in the steroid pulse therapy group, whereas only 1 of 5 patients was alive in the non-steroid pulse therapy group. Analysis of factors related to the survival of patients with MTB complicated by ARDS revealed that steroid pulse therapy was the strong prognostic factor (hazard ratio = 0.136 (95 % CI: 0.023–0.815)). Conclusion: Our findings suggest that steroid pulse therapy improves the short-term prognosis of patients with MTB complicated by ARDS.

Abstract Background The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. Methods Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children’s Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. Results A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95 % confidence intervals [95 % CIs]: 0.87–0.96 and 0.88–0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95 % CIs: 0.82–0.88 and 0.83–0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95 % CIs: 0.87–0.98 and 0.84–0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95 % CI: 0.84–0.97), and girls with a higher birth weight (aRR: 0.89, 95 % CI: 0.83–0.96). Conclusions These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

Tb-doped MgGa2O4 single crystals (0.3, 1, 3, and 5%) were synthesized by the floating zone method. The synthesized crystals had a single phase of MgGa2O4 confirmed by X-ray diffraction and high transparency in the visible wavelength. Tb3+ acted as a luminescence center in both photoluminescence (PL) and thermally stimulated luminescence (TSL) processes. In the TSL dose response functions, the minimum detectable dose of the crystals was 0.01 mGy, which was comparable with some commercial dosimetric materials. In the X-ray imaging test taken based on TSL, the spatial resolution of the 1% Tb-doped crystal was estimated to be 8.90 LP/mm (56.2 μm).

Objectives To investigate the association between breast feeding and infant development during the first year of life using sibling comparison.Design Nationwide prospective birth cohort study with sibling pair analysis.Setting 15 regional centres that participated in the Japan Environment and Children’s Study.Participants This study included 77 119 children (singleton, term birth and no malformation/severe diseases) whose mothers were registered between January 2011 and March 2014, including 3521 duos or trios of siblings.Primary outcome measures The primary outcome was developmental delay at 6 and 12 months of age, assessed using the Japanese translation of the Ages and Stages Questionnaires, third edition. Multivariable regression analyses adjusted for confounders were performed to estimate the risk ratios of delay associated with any or exclusive breast feeding. Pairs of siblings discordant for statuses were selected, and conditional regression analyses were conducted with a matched cohort design.Results Developmental delay was identified in 6162 (8.4%) and 10 442 (14.6%) children at 6 and 12 months of age, respectively. Any breast feeding continued until 6 months or 12 months old was associated with reduced developmental delay at 12 months of age (adjusted risk ratio (95% CI): 0.81 (0.77 to 0.85) and 0.81 (0.78 to 0.84), respectively). Furthermore, exclusive breast feeding until 3 months was associated with reduced developmental delay at 12 months of age (adjusted risk ratio, 0.86 (95% CI 0.83 to 0.90)). In sibling pair analysis, the association between any breast feeding until 12 months and reduced developmental delay at 12 months of age persisted (adjusted risk ratio, 0.64 (95% CI 0.43 to 0.93)).Conclusions The present study demonstrated the association of continuous breast feeding with reduced developmental delay at 1 year of age using sibling pair analysis, in which unmeasured confounding factors are still present but less included. This may provide an argument to promote breastfeeding continuation.

Background: Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment.Method: To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts.Results: The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, P = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, P < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, P = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, P = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics (n = 7 and n = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels (P = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels.Conclusion: Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.

Background: Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. Methods: Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into “progression group” (n = 7) that required any therapy and “spontaneous resolution group” (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-β1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. Results: Three patients developed leukemia during the study period (median, 1147 days; range, 33–3753). Three died of hepatic failure. All patients in the progression group were preterm birth

Background: Atopic dermatitis (AD) and exercise-induced asthma (EIA) are common in asthmatic children, and exercise is the most common trigger other than infection for acute onset asthma attack in children. We examined whether AD is related to exercise-induced wheezing (EIW), some proxy for EIA. Methods: Japanese version of the International Study of Asthma and Allergies in Childhood questionnaires were used. For 12,405 asthmatic school children, AD was defined as itchy rash coming and going for at least 6 months at any time in the last 12 months with affecting places of flexural parts of body, and severity of AD was rated according to frequency of being kept awake at night with the itch as follows: never in the past 12 months, less than one night per week and one or more nights per week. Results: Adjusted for frequency of asthma attack, odds ratios (OR) of children with current AD as compared to those without AD for having EIW were 1.32 (95% confidence interval = 1.15–1.52), 1.35 (1.14–1.68) and 1.10 (0.92–1.31) for primary school, junior high school and high school children, respectively. EIW was more likely observed in accordance with increasing severity of AD in the primary school children with ORs of 1.12, 1.59 and 1.54 (p for trend

The relationship between the annual changes of the prevalence of bronchial asthma (BA) and that of concentrations of air pollutants has not been reported. We studied the annual prevalence of BA, remission of BA, and wheeze in children at the same five elementary schools in Fukuoka city, Japan, in October to November from 1988 to 2016 by the same methods using the same questionnaire. Annual changes in the prevalence of asthma among boys were related to changes in the air concentrations of NO (r=0.708), NO2 (r=0.665) suspended particulate matter (SPM) (r=0.803), and smoking rate (r=0.741), but there were no such relationships among girls. Annual changes in the prevalence of wheeze were related to changes of NO, NO2, SPM, and smoking rate among boys and girls (NO: r=0.650, 0.660; NO2: r=0.556, 0.490; SPM: r=0.582, 0.518; smoking rate: r=0.656, 0.593, respectively) (all of the above are significant with p

Background: Exercise-induced wheezing (EIW) may be a symptom of asthma and is a predictor of exercise- induced bronchoconstriction, transient narrowing of the lower airway following exercise in the presence or absence of diagnosed asthma. Population-based studies with a large sample of EIW in relation to age, sex, current asthma severity and medication usage have been sparse. Methods: International Study of Asthma and Allergies in Childhood questionnaires were distributed at 885 nurseries, 535 primary schools, 321 junior high schools and 190 high schools, respectively, across Japan, and the corresponding data on 46,597, 41,216, 45,960 and 51,104 children were analyzed. Results: Prevalence of EIW was 4.8, 4.7, 17.9 and 15.4% for each of the four educational facility types, respectively. Among 24,103 current asthmatics, 20.9, 28.7, 76.1 and 73.6% of subjects for the 4 educational facility groups reported to have experienced EIW, respectively. Severity of current asthma was associated with the risk of EIW; odds ratio (95% confidence interval) of children with asthma attack every day for having EIW once a week or more, using intermittent asthmatics as reference group, were 24.48 (19.33 to 31.01) adjusted for other covariates. Among current asthmatic kindergartners, increase in risk for EIW due to ascending severity of current asthma was mitigated by daily use of leukotriene receptor antagonist (p for interaction=0.071). Conclusions: EIW was not rare among current asthmatic children. An increased risk for EIW was in accordance with increasing severity of current asthma and this relation was mitigated with leukotriene receptor antagonist daily use among kindergartners.

Histidine-rich glycoprotein (HRG) is implicated in tumor growth and metastasis by regulation of angiogenesis and inflammation. HRG is produced by hepatocytes and carried to tissues via the circulation. We hypothesized that HRG's tissue distribution and turnover may be mediated by inflammatory cells. Biodistribution parameters were analyzed by injection of radiolabeled, bioactive HRG in the circulation of healthy and tumor-bearing mice. 125I-HRG was cleared rapidly from the blood and taken up in tissues of healthy and tumor-bearing mice, followed by degradation, to an increased extent in the tumor-bearing mice. Steady state levels of HRG in the circulation were unaffected by the tumor disease both in murine tumor models and in colorectal cancer (CRC) patients. Importantly, stromal pools of HRG, detected in human CRC microarrays, were associated with inflammatory cells. In agreement, microautoradiography identified 125I-HRG in blood vessels and on CD45-positive leukocytes in mouse tissues. Moreover, radiolabeled HRG bound in a specific, heparan sulfate-independent manner, to differentiated human monocytic U937 cells in vitro. Suppression of monocyte differentiation by systemic treatment of mice with anti-colony stimulating factor-1 neutralizing antibodies led to reduced blood clearance of radiolabeled HRG and to accumulation of endogenous HRG in the blood. Combined, our data show that mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thereby, we confirm and extend our previous report that inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread.

Background: Henoch–Sch€onlein purpura nephritis often resolves spontaneously, without treatment, making decisions regarding therapeutic interventions difficult. Methods: Fifty-four patients who were diagnosed as having Henoch–Sch€onlein purpura nephritis between April 2004 and March 2018, and developed hematuria and/or proteinuria, were studied retrospectively. The observation period ended at the disappearance of hematuria or proteinuria, or the last observation date before December 2019 for each patient. Twenty-four of the patients received no treatment (Group A), 19 underwent renin-angiotensinaldosterone system inhibitors only (B), 4 experienced steroid pulse therapy and combination therapy only (C) and the remaining 7 received steroid pulse therapy and combination therapy following renin-angiotensin-aldosterone system inhibitors (C). Clinical characteristics were examined according to the treatment method. Survival analysis for persistent urinary abnormalities was performed according to treatment modality, with multiple treatment records created per subject, if necessary. Results: The highest urine protein/creatinine levels were significantly higher in groups B and C than in group A. The lowest estimated glomerular filtration rate was not significantly different among the three groups. In groups A and B, proteinuria resolved in >90% of patients. Survival analysis showed that steroid pulse therapy and combination therapy was not related to the better resolution of hematuria or proteinuria than renin-angiotensin-aldosterone system inhibitors. Conclusions: Several patients with Henoch–Sch€onlein purpura nephritis went into remission either without treatment or with renin-angiotensin-aldosterone system inhibitors alone. The treatment plan for patients with Henoch– Sch€onlein purpura nephritis needs to be determined carefully. [ABSTRACT FROM AUTHOR]

AbstractWerner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in RecQ DNA helicase. Ectopic soft tissue calcification is one of the well known symptoms in WS. However, the prevalence, clinical outcome, and mechanism of such calcification remain to be elucidated. The clinical features and mechanism of ectopic calcification were examined in seven patients with WS whose diagnosis were confirmed by a genomic DNA analysis. X-ray examinations revealed subcutaneous calcification in 35 of 41 major joints (85.3). The patients complained of dermal pain at 23 joints among 35 joints (65.7) with calcification. Refractory skin ulcers were found at the area of the skin overlaying the calcification in 16 joints (45.7). In contrast, no pain or ulcers were observed in the joints without calcification. The presence of ectopic calcification could not be explained by a systemic hormonal abnormality. Cultured fibroblasts from WS patients underwent spontaneous mineralization in vitroin the normal phosphate condition, and overexpressed Pit-1, a transmembrane type III Na-Pi cotransporter both at the mRNA and protein levels. Phosphonophormic acid, a specific inhibitor for Pit-1, inhibited mineralization in the WS fibroblasts. Both calcification and Pit-1 overexpression were detected in the skin of WS in situ. WS showed a high prevalence of ectopic calcification, which was associated with dermal pain and refractory skin ulcers. An overexpression of Pit-1 therefore seems to play a key role in the formation of soft tissue calcification in this syndrome. [ABSTRACT FROM AUTHOR]