Effectiveness of sublingual immunotherapy in pediatric cedar pollinosis: A real-world database study.

BACKGROUND: Pediatric allergic rhinitis (AR), including cedar pollinosis (CP), is increasing in Japan. We investigated the effects of sublingual immunotherapy (SLIT), which has limited studies of its effectiveness in real-world settings, on children with CP. METHODS: This retrospective cohort study used a claim database in 2018-2021. Children aged ≤15 years with CP records in 2019 were eligible and were followed up through 2021. We included 2962 CP children undergoing SLIT and 547 who were not. The medication score was used to evaluate SLIT effectiveness in the cedar pollen dispersal season each year. Adverse events and the occurrence of allergic diseases were also evaluated. RESULTS: Medication score was higher in the SLIT group during the index period but lower in 2021 compared to the non-SLIT group (mean ± standard deviation: 5.17 ± 2.39 and 4.74 ± 2.38 in 2019, 3.13 ± 2.30 and 3.55 ± 2.48 in 2021, respectively). The adjusted mean difference between groups from 2019 to 2021 was -0.62 (95% confidence interval: -0.86 to -0.39, p < .0001), and the medication score was reduced in the SLIT group (risk ratio: 1.2: 1.1 to 1.3). The occurrence of adverse events involving abdominal disorders (adjusted odds ratio [aOR]: 0.64: 0.51 to 0.81), asthma exacerbation (aOR: 0.37: 0.24 to 0.57), and allergic diseases involving hay fever unrelated to CP (aOR: 0.60: 0.45 to 0.80) or asthma (aOR: 0.71: 0.58 to 0.86) was lower in the SLIT group. CONCLUSION: In children with CP, SLIT is effective, well tolerated, and could decrease the occurrence of other allergic diseases.

Development of waist circumference percentiles for Japanese children and an examination of their screening utility for childhood metabolic syndrome: a population-based cross-sectional study.

BACKGROUND: In Japan, waist circumference (WC) percentiles to screen for childhood metabolic syndrome (MetS) are unavailable. The objectives of this study were to develop WC and WC-to-height ratio (WC/Ht) percentile curves by age and sex for Japanese children, and to test their utility in screening for MetS in children with obesity who are otherwise healthy. METHODS: The WC and WC/Ht percentiles were developed using the LMS method of summarizing growth standards, which monitors changing skewness (L), medians (M), and coefficients of variation (S) in childhood distributions. A representative dataset was used, which consisted of 3,634 boys and 3,536 girls aged 4.5-12.75 years in Shizuoka prefecture, Japan, between 2010 and 2012. Children who were obese (355 boys and 230 girls) aged 6-12 years from Osaka prefecture, Japan, were screened for childhood MetS using the new percentiles and the International Diabetes Federation's (IDF's) definition of MetS. RESULTS: The number of participants with certain metabolic abnormalities (high systolic and diastolic blood pressure, and a high level of triglycerides) was significantly higher in boys aged 10-12 years, with a WC ≥ 90th percentile, than among those with a WC < 90th percentile. None of the participants with a WC < 90th percentile exhibited two or more metabolic abnormalities, regardless of their age or sex. Among the participants aged 10-12 years, 11.4 % of boys and 4.4 % of girls with a WC ≥ 90th percentile were diagnosed with MetS. CONCLUSIONS: The new percentiles may have a certain level of potential to screen Japanese children for childhood MetS in accordance with the IDF definition.

A novel GNAS-Gsα splice donor site variant in a girl with pseudohypoparathyroidism type 1A and her mother with pseudopseudohypoparathyroidism.

We encountered a Chinese girl with pseudohypoparathyroidism type 1A (PHP1A) and her mother with pseudopseudohypoparathyroidism (PPHP). Sequencing analysis of GNAS-Gsα revealed a heterozygous c.212+2T>C variant (NM_000516.4) affecting the canonical splice donor site of intron 2 in the girl and her mother. RT-PCR performed on mRNA samples obtained from cycloheximide-treated and cycloheximide-untreated lymphoblastoid cell lines of this girl revealed the utilization of an alternative splice donor site at 33-34 bp from the boundary between exon 2 and intron 2 and the production of an aberrant mRNA with a retention of a 32 bp intronic sequence between exon 2 and exon 3 (p.(Gly72Lysfs*39)), which satisfied the condition for the occurrence of nonsense-mediated mRNA decay, as predicted by SpliceAI. This study revealed the molecular consequences of disruption of the canonical splice donor site and confirmed the clinical utility of SpliceAI.

Extra-endocrine phenotypes at infancy in multiple endocrine neoplasia type 2B: A case series of six Japanese patients.

Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare disease, most often caused by a de novo p.Met918Thr RET mutation. Medullary thyroid carcinoma of MEN2B has a good prognosis if diagnosed by one year of age. However, diagnosis of MEN2B within the first year of life is markedly challenging owing to its high de novo occurrence and lack of clarity in terms of extra-endocrine symptoms that could aid early diagnosis. Herein, we present six cases of Japanese children with MEN2B harboring the p.Met918Thr RET variant. Exploratory data extraction was conducted using a questionnaire. The patients underwent thyroidectomy at a median age of 11 yr (range, 6-19 yr). Four of the six patients underwent neonatal hospitalization at birth without complications, and three tested positive for neuroblastoma screening at infancy. The patients presented at least one MEN2B-associated symptom before one year of age, including ganglioneuromas, pseudo-Hirschsprung disease, alacrima, bumpy lips, sucking disability, or decreased muscle tone, along with other suspected comorbidities, such as Williams or Prader-Willi syndrome. This case series demonstrates that MEN2B manifests through several extra-endocrine symptoms by the age of one year.

A Workshop on Writing Letters to the Editor.

This article was migrated. The article was marked as recommended. Background: Writing letters to the editor based on critical appraisal can serve as the first step in scholarly activity. The workshop in this study focused on educating physicians about the best ways to write letters to the editor. Methods: We conducted a 90-minute workshop as a part of scientific conference. Participants were physicians and medical students who chose to join this workshop. We developed the following learning outcomes for participants: 1) to be able to explain falsificationism; 2) to be able to explain how to check author instructions; 3) to be able to explain how to write a letter to the editor. Results: Twenty-eight participants, including three medical students, attended the workshop. Participants' satisfaction with the workshop had a mean of 4.5 points out of 5 (standard deviation: 0.5). Nearly 80% of participants achieved the learning outcomes. Four participants' groups submitted letters within a month after the workshop, and all four were published. These four groups encompassed a total of 13 authors. In addition, none of the first author of each letter had previously written a clinical research paper. Findings and Discussion: This workshop improved not only the participants' knowledge but it also led to the concrete result of four published letters. Japanese physicians would be able to use this framework to write letters to the editor.

Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017.

Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.

Postnatal BMI changes in children with different birthweights: A trial study for detecting early predictive factors for pediatric obesity.

The purpose of this study was to clarify the degree of early postnatal growth by birthweight and detect early predictive factors for pediatric obesity. Body mass index (BMI) and degree of obesity were examined in children in the fourth year of elementary school and second year of junior high school. Their BMI at birth and three years of age were also examined. Based on birthweight, participants were divided into three groups: low (< 2500 g), middle (2500-3500 g), and high (> 3500 g). Furthermore, according to the degree of obesity, they were divided into two groups: obese (20% ≤) and non-obese (20% >). The change of BMI from birth to three years of age (ΔBMI) showed a strong inverse relationship with birthweight and was significantly different among the three birthweight groups (low > middle > high). The ΔBMI and BMI at three years of age were higher in obese than in non-obese children and showed significant positive correlations with the degree of obesity. Early postnatal growth might be determined by birthweight and was higher in obese than in non-obese children. The ΔBMI from birth to three years of age and BMI at age of three years could be predictive factors for pediatric obesity.

Urinary myo-inositol levels in Japanese schoolchildren with normal glucose tolerance.

BACKGROUND: Urinary myo-inositol (UMI) level is elevated in adult diabetic patients, and also increases after glucose loading. However, the relationship between UMI and plasma glucose levels in children is unknown. We aimed to assess whether UMI is a practical marker for glucose intolerance in children or not. METHODS: In Study 1 (328 schoolchildren), fasting and postprandial UMI were measured, with ΔUMI defined as the difference between fasting and postprandial UMI levels. In Study 2, oral glucose tolerance tests and UMI measurements were conducted in 18 children with suspected having diabetes. RESULTS: For Study 1, ΔUMI was observed [-0.65 (-3.9, 1.35) mg/g creatinine]. For Study 2, children with diabetes or impaired glucose tolerance had a significantly higher ΔUMI than children with normal glucose tolerance. CONCLUSIONS: These studies demonstrated the normal range of UMI in children and possibility of a novel biomarker for early detection of glucose intolerance in children.

The lipid fraction of human milk initiates adipocyte differentiation in 3T3-L1 cells.

BACKGROUND: The prevalence of childhood obesity has increased worldwide over the past decade. Despite evidence that human milk lowers the risk of childhood obesity, the mechanism is not fully understood. AIMS: We investigated the direct effect of human milk on differentiation of 3T3-L1 preadipocytes. STUDY DESIGN AND SUBJECTS: 3T3-L1 preadipocytes were treated with donated human milk only or the combination of the standard hormone mixture; insulin, dexamethasone (DEX), and 3-isobututyl-1-methylxanthine (IBMX). Furthermore, the induction of preadipocyte differentiation by extracted lipids from human milk was tested in comparison to the cells treated with lipid extracts from infant formula. Adipocyte differentiation, specific genes as well as formation of lipid droplets were examined. RESULTS: We clearly show that lipids present in human milk initiate 3T3-L1 preadipocyte differentiation. In contrast, this effect was not observed in response to lipids present in infant formula. The initiation of preadipocyte differentiation by human milk was enhanced by adding the adipogenic hormone, DEX or insulin. The expression of late adipocyte markers in Day 7 adipocytes that have been induced into differentiation with human milk lipid extracts was comparable to those in control cells initiated by a standard adipogenic hormone cocktail. CONCLUSIONS: These results demonstrate that human milk contains bioactive lipids that can initiate preadipocyte differentiation in the absence of the standard adipogenic compounds via a unique pathway.

Dynamics of endogenous glucocorticoid secretion and its metabolism in Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a severe inflammatory disease that occurs in childhood. Recently, the initial corticosteroid therapy for KD has been reconsidered because its efficacy is controversial. The aim of this study was to evaluate the dynamic change in endogenous glucocorticoid levels and their relation with 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity in the acute phase of KD. STUDY DESIGN: Sixteen KD patients were investigated. Cortisol and cortisone levels, the cortisol/cortisone ratio and C-reactive protein (CRP) levels were measured on admission, before the first intravenous immunoglobulin (IVIG) therapy and convalescence. RESULTS: The 16 patients were divided into two groups. Group A included patients who received the first IVIG on admission and blood samples were collected before the first IVIG and convalescence. Group B included patients whose blood samples were collected at three different time points (on admission, before the first IVIG, and convalescence). CRP and cortisol levels and the cortisol/cortisol ratio were markedly higher before the first IVIG than those of convalescence in all patients except in one patient. In Group B patients, both serum cortisol levels and the cortisol/cortisone ratio on admission were significantly increased compared with those before the first IVIG (cortisol: p<0.005, cortisol/cortisone: p<0.001). CONCLUSIONS: Decreases in cortisol levels and the cortisol/cortisone ratio before the first IVIG may be explained by a reduction in adrenal secretion and/or local glucocorticoid action through 11beta-HSD activity. These findings suggest that exogenous glucocorticoid treatment in combination with the first IVIG at the acute stage may play a synergetic role in KD.

Initial Treatment of Pediatric Graves' Disease with Methimazole: A Retrospective Follow-up Study.

Antithyroid drugs are widely used in the therapy of Graves' disease (GD), and methimazole (MMI) is preferred for treatment of pediatric GD. The recommended initial dosage of MMI is 0.5-1.0 mg/kg/d for pediatric GD, although there are few studies on the optimal MMI dosage for initial treatment in children. We retrospectively compared the efficacy of different doses of MMI in 35 children with GD. Eight children were excluded due to lack of follow-up, etc. The remaining 27 children were divided into a high-dose group (HD; MMI≥0.7 (0.85 ± 0.13) mg/kg/d, n=8) and a low-dose group (LD; MMI<0.7 (0.51 ± 0.12) mg/kg/d, n=19), and we compared the time needed for the serum FT4 levels to normalize (≤1.6 ng/dl) between the groups. There were no significant differences between the FT4 levels (HD: 5.5 ± 2.8 ng/dl; LD: 5.0 ± 2.4 ng/dl p=0.59) or thyroid stimulating hormone receptor antibody levels (HD: 56.2 ± 29.3%; LD: 60.9 ± 27.2% p=0.69) between the groups before treatment. The mean time required to normalize the FT4 levels was 22.5 ± 7.4 d in the HD group and 28.8 ± 16.2 d in the LD group (p=0.30). In addition, no other factor influenced the time to efficacy of MMI. A dose of MMI<0.7 (0.51 ± 0.12) mg/kg/d appears to as effective as a higher dose in normalizing the serum FT4 level in children with mild or moderate GD.