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Chlorine dioxide has an inactivating effect on various types of viruses in vitro, including severe acute respiratory syndrome coronavirus 2. Therefore, chlorine dioxide gas can be used as a new preventive measure against coronavirus disease 19 (COVID-19). However, no studies have been conducted to investigate the relationship between the incidence of COVID-19 and chlorine dioxide. We retrospectively studied the occurrence of COVID-19 in 164 public elementary schools under the jurisdiction of boards of education located in urban areas in Japan, provided with chlorine dioxide gas-releasing agents or not, from January to March 2022. The odds of developing COVID-19 were lower (odds ratio: 0.934, 95% confidence interval: 0.895–0.975) in schools provided with chlorine dioxide gas-releasing agents than in schools without them. This suggested a relationship between the use of chlorine dioxide-releasing agents and the incidence of COVID-19. Further studies are needed to prove a causal relationship between them.

Iron deficiency anemia in children affects psychomotor development. We compared the accuracy and trend of a non-invasive transcutaneous spectrophotometric estimation of arterial hemoglobin (Hb) concentration (SpHb) by rainbow pulse CO-oximetry technology to the invasive blood Hb concentration measured by an automated clinical analyzer (Hb-Lab).We measured the SpHb and Hb-Lab in 109 patients aged 1-5 years. Regression analysis was used to evaluate differences between the two methods. The bias, accuracy, precision, and limits of agreement of SpHb compared with Hb-Lab were calculated using the Bland-Altman method.Of the 109 enrolled subjects, 102 pairs of the SpHb and Hb-Lab datasets were collected. The average value of measured Hb was 12.9 ± 1.03 (standard deviation [SD]) g/dL for Hb-Lab. A significant correlation was observed between SpHb and Hb-Lab measurements (SpHb = 7.002 + 0.4722 Hb-Lab, correlation coefficient r = 0.548, 95% confidence interval = 0.329-0.615). Bland-Altman analysis showed good visual agreement, with a mean bias between SpHb and Hb-Lab of 0.188 ± 0.919 g/dL (mean ± SD).We concluded that non-invasive Hb measurement is useful for Hb estimation in children and provides new insights as a screening tool for anemia.Our results indicated a good correlation between non-invasive transcutaneous spectrophotometric estimation of arterial hemoglobin (Hb) concentration using a finger probe sensor by rainbow pulse CO-oximetry technology and invasive blood Hb concentration. Although previous studies have indicated that in patients with a worse condition, the bias between the two methods was large, this study, which was conducted on children with stable disease, showed a relatively small bias. Further studies using this non-invasive device might help to understand the current status of anemia in Japan and promote iron intake and nutritional management in children.

BACKGROUND Inclusion of female authors has been noted as potentially beneficial in the development of medical guidelines. Japanese professional committees representing allergic subspecialties develop practical guidelines with recommendations to caregivers, but these committees may be influenced by their gender composition. The objective of our study was to examine the influence of gender in developing pediatric allergic disease guidelines in Japan from 1999 to 2020. METHODS We examined the gender differences among the guideline committee members: allergic rhinitis, atopic dermatitis, bronchial asthma, and food allergies in Japan. We examined the gender composition of the committees, annual trends, and differences in guideline content. RESULTS The median proportion of women members among the 22 guidelines committees was 6.6% (range: 0%-27.3%). The analysis of the quadrant period did not show a significant increase in the proportion of female members. The food allergy group had a significantly higher proportion of female members than other guidelines (P < 0.01), but the proportion decreased from 25% to 14.3% during the observation period. For the pediatric asthma guidelines, the proportion of female committee members decreased from 5.3% in the 2000 version to 0% in the most recent revision in 2017. CONCLUSIONS The proportion of women on the committees that develop pediatric guidelines continues to be low and has not improved over the past 20 years.

Purpose Wheezing is the dominant pathological characteristic of asthma. It is estimated that 50% of all children have experienced wheezing at least once in their first six years of life. This study aimed to investigate initial wheezing attacks in pediatric patients and to determine connection between transient wheezing (TW) attacks and persistent wheezing (PW). Methods The immune responses of children who initially presented with wheezing attacks were studied. A total of 231 children with wheezing attacks at the time of admission were enrolled in the study. The study population consisted of 68 children with wheezing episodes. Children with recurrent wheezing who were introduced to inhaled steroids after 12 months were further grouped into either PW or TW groups. Results At the initial onset, cytokine analysis of the children revealed a marked increase in serum soluble and transmembrane forms of interleukin receptor-2 (ST2) in PW. In contrast, there were no changes in serum levels of IL-4, IL-13, and IL-33. The serum ST2 levels of the PW group were higher compared to those of the TW group. Moreover, a significant increase in ST2 expression was observed in PW children with recurrent wheezing attacks. Conclusion The present study demonstrated that ST2 might be a useful index for predicting the prognosis of infantile asthma. Hence, elucidation of the mechanism of ST2 expression in childhood allergic diseases is essential.

Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body as well as controlling the absorption of nutrients, fluid and solutes (1, 2). A series of protein complexes including the adherens junction, desmosomes, and tight junctions (TJ) function as the principal barrier in paracellular diffusion (3) as well as regulators of intracellular solute, protein and lipid transport (4). TJs are composed of a series of proteins called occludins, junctional adhesion molecules (JAM), and claudins (5, 6) that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases.

Classically, eosinophilic esophagitis is an antigen-mediated chronic disease distinct from gastroesophageal reflux disease. Eosinophilic esophagitis is an emerging clinical problem that is growing in recognition. It is characterized clinically by feeding dysfunction, dysphagia, and reflux-like symptoms. Histologically, eosinophilic esophagitis is identifiable by a dense epithelial eosinophilic infiltrate. Experimental modeling and clinical studies over the last decade have greatly improved mechanistic insights and led to improvements in clinical understanding and the assessment of therapeutic options for patients and their clinicians who manage this disease. Here, we review the clinicopathologic diagnostic criteria and our understanding of eosinophilic esophagitis as an allergic disease with genetic and immunological components. We present studies defining the importance of the epithelial barrier and the concept of barrier dysfunction as an initiating or perpetuating factor for this disease. We discuss the relationship between the symptoms of dysphagia and feeding dysfunction, our current knowledge of the underlying pathophysiologic mechanisms, and advances in clinical assessment of esophageal distensibility and narrowing in eosinophilic esophagitis patients. Finally, therapeutic implications relating to the advances that have led to our current understanding of the pathophysiology of eosinophilic esophagitis are explored.

Eosinophilic gastrointestinal diseases (EGID) are relatively rare diseases characterized by eosinophilic infiltration of the gastrointestinal tract resulting in various gastrointestinal symptoms. EGID are often caused by allergic reactions or systemic eosinophilic disorders, but their comorbidity with Bruton's tyrosine kinase (BTK) deficiency has not been previously documented. Here, we report a case of eosinophilic gastroenteritis (EG) in a patient with BTK deficiency. Despite adequate replacement immunoglobulin (Ig) therapy, trough serum IgG was not maintained. To identify the underlying cause of the low trough level and chronic diarrhea, the intestine was investigated on endoscopy. We also screened for the variable number of tandem repeat polymorphism in FCGRT. Genetic analysis could not explain the low trough IgG, but endoscopy indicated eosinophilic enterocolitis. EG may be an important differential diagnosis when primary immunodeficiency patients have chronic diarrhea or continued low serum IgG.

Background Although rectal bleeding in infancy (RBI) is not a rare phenomenon, the clinical course of RBI is not fully understood. Methods To investigate the outcome and pathogenesis of RBI, especially when concomitant with food-protein-induced proctocolitis (FPIP) and neonatal transient eosinophilic colitis (NTEC), 22 neonates with rectal bleeding with FPIP and NTEC from January 2008 to June 2012 were enrolled and their clinical course and mechanisms of inflammation were examined. Results Thirteen infants showed rectal bleeding after feeding and were diagnosed with FPIP, and nine infants showed rectal bleeding before feeding and were diagnosed with NTEC. Elevated peripheral white blood cell (12 685 ± 3754/μl and 30 978 ± 16 166/μl) and eosinophil (1084 ± 816/μl and 4456 ± 3341/μl) were confirmed in FPIP and NTEC, respectively. Colonoscopy revealed nodular lymphoid hyperplasia, a pale mucosal surface and oozing with diffuse infiltration of neutrophils, lymphocytes, and eosinophils in both groups. Reverse transcription polymerase chain reaction analysis revealed enhanced expression of the interleukin-6, CCL11, and CXCL13 genes, where CXCL13 expression was more prominent in FPIP. Mucosal infiltration by CD3- and immunoglobulin-A- but not immunoglobulin-E-positive cells was confirmed. Among them, only one infant with FPIP developed milk allergy, whereas none with NTEC had developed milk allergy at the age of 1 year. Conclusions FPIP in infancy and NTEC are similar diseases and interleukin-6, CCL11, and CXCL13 may play a major role in the pathogenesis of rectal bleeding. Although the involvement of allergic reaction is possible, milk allergy was not a common outcome after 1 year of follow up.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although ω-3 fatty acids are known to have antiinflammatory effects, their effect against NEC remains unclear.Mother rats fed a soybean-based, docosahexaenoic acid (DHA)- or eicosapentaenoic acid (EPA)-enriched diet from days 7 to 20 of gestation were examined. On day 20, the rat pups were delivered by abdominal incision, their intestines were removed, and messenger RNA was extracted. A rat NEC model was used to confirm the effects of ω-3 fatty acids on the inflamed intestine (n = 20-28). The expression of inflammatory molecules was analyzed by real-time polymerase chain reaction (n = 11-14).The concentrations of DHA and EPA in the intestine were significantly increased in the DHA and EPA groups (P.01). The expression of the antiinflammatory prostaglandin E2 receptor EP3 was increased in the DHA (P.05) and EPA groups (P.01). In the NEC model, the reduced incidence of colitis was confirmed in the DHA and EPA groups. The expression of peroxisome proliferator-activated receptor γ was increased (P.05), and the inhibitor of nuclear factor-κB α/β decreased in both the DHA (P.01) and EPA groups (P.05).Our findings indicate that ω-3 fatty acids are beneficial for protecting the premature intestine from inflammation by regulating eicosanoid- and nuclear factor-κB-related metabolite expression.

Background and Aim: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported. Methods: This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated. Results: Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 108 red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P

The high-affinity IgE receptor, FcεRI, which is composed of α-, β-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FcεRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FcεRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of β mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FcεRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FcεRIβ). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FcεRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FcεRIα and FcεRIβ, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FcεRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FcεRIβ transcription. Suppression of these transcription factors leads to downregulation of FcεRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FcεRI-mediated allergic diseases.

Trisomy of 12p is a rare chromosomal abnormality, which sometimes coexists with other chromosomal anomalies. We report on a patient with a supernumerary chromosome involving chromosomes 12 and 14, which was confirmed by array-comparative genomic hybridization (aCGH). He had developmental delay and dysmorphic features overlapped with those of Pallister-Killian syndrome, which is derived from an isodicentric chromosome 12. The microblepharon identified in our patient is a characteristic feature of 12p trisomy. Further patients are needed to establish the phenotypic difference between trisomy 12p and Pallister-Killian syndrome.

Although rectal bleeding in infancy (RBI) is not a rare phenomenon, the clinical course of RBI is not fully understood.To investigate the outcome and pathogenesis of RBI, especially when concomitant with food-protein-induced proctocolitis (FPIP) and neonatal transient eosinophilic colitis (NTEC), 22 neonates with rectal bleeding with FPIP and NTEC from January 2008 to June 2012 were enrolled and their clinical course and mechanisms of inflammation were examined.Thirteen infants showed rectal bleeding after feeding and were diagnosed with FPIP, and nine infants showed rectal bleeding before feeding and were diagnosed with NTEC. Elevated peripheral white blood cell (12,685 ± 3754/μl and 30,978 ± 16,166/μl) and eosinophil (1084 ± 816/μl and 4456 ± 3341/μl) were confirmed in FPIP and NTEC, respectively. Colonoscopy revealed nodular lymphoid hyperplasia, a pale mucosal surface and oozing with diffuse infiltration of neutrophils, lymphocytes, and eosinophils in both groups. Reverse transcription polymerase chain reaction analysis revealed enhanced expression of the interleukin-6, CCL11, and CXCL13 genes, where CXCL13 expression was more prominent in FPIP. Mucosal infiltration by CD3- and immunoglobulin-A- but not immunoglobulin-E-positive cells was confirmed. Among them, only one infant with FPIP developed milk allergy, whereas none with NTEC had developed milk allergy at the age of 1 year.FPIP in infancy and NTEC are similar diseases and interleukin-6, CCL11, and CXCL13 may play a major role in the pathogenesis of rectal bleeding. Although the involvement of allergic reaction is possible, milk allergy was not a common outcome after 1 year of follow up.

The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.

Ribavirin-related anemia is a serious side-effect of the pegylated interferon and ribavirin therapy used for hepatitis C, and may be cause for a reduction in ribavirin dose or even cessation of treatment. The aim of this study was to evaluate the prophylactic effects of oral eicosapentaenoic acid (EPA) supplementation on ribavirin-induced hemolytic anemia in pediatric and young adult patients.Twelve chronic hepatitis C patients ranging in age from 3 to 21 years (mean, 13.9 ± 5.1 years) who received pegylated interferon α-2b and ribavirin combination therapy were randomized to either the control group (n = 6) or EPA group (n = 6). Blood samples were collected before, and at 4, 8, and 16 weeks after treatment to measure clinical laboratory parameters.The reduction in hemoglobin levels of the EPA group was significantly ameliorated at 8 and 16 weeks when compared to the control group (P0.05). There was no significant difference in plasma ribavirin concentrations between the two groups during the treatment. However, one patient in the control group had a reduction in ribavirin dose.EPA supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with pegylated interferon α-2b and ribavirin in pediatric and young adult patients.

Background The human IL1RL1/ST2 gene encodes IL33 receptor. Recently, IL33 has been recognized as a key molecule for the development of Th2 response. Although mast cells and basophils are major targets of IL33 and play important roles in IL33-mediated Th2-type immune responses, the expression mechanism of ST2 in mast cells and basophils is largely unknown. In the present study, we analyzed regulation mechanism of the human ST2 promoter in the human mast cell line LAD2 and basophilic cell line KU812. Methods Promoter activity was determined by reporter assay with plasmids carrying the wild-type ST2 promoter obtained from human genomic DNA and its mutant. The transcription factor binding to the identified cis- element was identified by an electrophoretic mobility shift assay (EMSA). The effect of candidate transcription factor on ST2 expression was confirmed by analyzing ST2 mRNA level in siRNA-introduced cells. Results: Reporter assay demonstrated that a cis-element of typical Ets-family binding sequence was critical for promoter activity in LAD2 and KU812. An Ets-family transcription factor PU.1 bound to this element in an EMSA. When PU.1 expression was suppressed by siRNA, sT2 mRNA level was significantly reduced in KU812. Conclusions These observations indicated that PU.1 positively regulates the ST2 promoter as a transcription factor that directly transactivates the ST2 promoter via Ets-family-related cis -element in mast cells and basophils.

6-Mercaptopurine (6-MP) and azathioprine (AZA) are widely used as maintenance therapy in children with inflammatory bowel disease (IBD). However, proper 6-thioguanine nucleotide (6-TGN) concentrations in Japanese children with IBD have not been reported.This retrospective review examines 32 ulcerative colitis (UC) patients and 19 Crohn's disease (CD) patients (12.87 ± 3.56 years) who required 6-MP or AZA to maintain disease remission. All patients were treated with 6-MP or AZA for at least 3 weeks prior to this study in addition to previous treatment. 6-MP dose, 6-TGN levels, assayed by high-performance liquid chromatography, as well as laboratory data were evaluated.Thirty-five children were successfully kept in remission with 6-MP and AZA therapy after weaning off corticosteroids. Overall, 123 measurements (59 active disease, 64 in remission) were analyzed. The mean 6-TGN concentration of the entire study population was 499.61 ± 249.35 pmol/8 × 10(8) red blood cell. The mean 6-MP dose in patients with active disease (0.910 ± 0.326 mg/kg per day) was significantly higher than for patients in remission (0.749 ± 0.225) (P = 0.0016). A significant inverse correlation was found between white blood cell counts and 6-TGN concentrations (r = 0.275, P0.002). Two patients experienced leukopenia with alopecia, and four transiently experienced increased serum levels of pancreatic enzymes, although no thiopurine S-methyl transferase mutations were confirmed.The doses of 6-MP or AZA needed to maintain remission in Japanese children with IBD are lower than those reported in Western countries. However, 6-TGN concentrations in this population are higher than previously reported.

FEBRUARY 2015 AB60 Abstracts S A T U R D A Y 191 Serum Zinc and Secretory IgA Levels Are Important Factors in Children with Food Allergy Yosuke Baba, MD, PhD, Reina Yokota, MD, Hiromi Yagisawa, MD, Susumu Yamazaki, MD, Asuka Ishida, MD, Eisuke Inage, MD, PhD, Mari Mori, MD, PhD, Yoshikazu Ohtsuka, MD, PhD, Toshiaki Shimizu, MD, PhD; Department of Pediatrics and Adolescent Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan, Department of Pediatrics, Juntendo University Shizuoka Hospital, Shizuoka, Japan. RATIONALE: Zinc is an essential nutrient and its deficiency causes malnutrition and results in defects in innate and acquired immune responses. Also, zinc is important for highly proliferating cells, especially in the immune system and influences both innate and acquired immune functions. However, the precise roles and molecular mechanisms of zinc’s function in allergic response have not been clarified. On the other hand, the IgA antibody is massively produced in the intestinal Peyer’s patches, and the secretory IgA (sIgA) plays an important role on mucosal immune responses. It is considered that sIgA regulates the cause of allergic reactions. We studied serum zinc levels and sIgA levels in children with food allergies and studied their relationship with allergy symptoms. METHODS: It is a retrospective study using medical records of infants (from 6 months to 6 years old) who had been admitted to our hospitals. We classified the groups according to the results of physical examinations with or without allergic symptom (eczema, wheezing, food allergy). In addition, we investigated thewhite blood cell counts (eosinophils and basophils) and the serum levels of specific IgE, total IgA, sIgA, TARC (thymus and activation-regulated chemokine), and zinc. RESULTS: Children who were low levels in sIgA and serum zinc have past histories of atopic dermatitis, and their serum levels of specific IgE was significantly higher (p50.013) but their serum IgA level was significantly lower (p50.038) compared with children who does not have allergic symptoms. CONCLUSIONS: Secretory IgA levels and zinc levels are also important to the onset of allergic reactions.