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.

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.

[Causes and pathophysiology of pediatric obesity and its diagnostic criteria].

Recently, obesity has been listed as important health problems not only in adults but also in children. Prevalence of pediatric obesity has been rising in the last half century in most of the developed countries including Japan. In addition to changes in lifestyle, which are shown to have contributed greatly to promote weight gain in recent years, patients with some syndromes or diseases may have obesity as one of the manifestations of the disorders especially in childhood. Obese individuals are commonly accompanied by derangement in various organs, such as metabolic and cardiovascular systems, in children as well as adults. Diagnostic criteria for obesity-disease and metabolic syndrome were proposed on the basis of data obtained from Japanese children.

Rate of trabecular bone area in 3-6-year-old children and relation to intrauterine growth.

BACKGROUND: The aim of the present study was to investigate bone mass using rate of trabecular bone area (RTBA) in Japanese children to determine its relationship with indices of growth such as height and weight from before birth through childhood. METHODS: A cross-sectional study was conducted. The sample consisted of Japanese boys (n= 716) and girls (n= 586) aged 3-6 years. RTBA was measured using quantitative ultrasound (ultrasonic bone densitometer, Benus III; Ishikawa Seisakusho, Kanazawa, Japan). The relation between RTBA and height and weight during childhood and also at birth was assessed. RESULTS: The average RTBA in boys was 27.7 ± 1.59% (mean ± SD) and that in girls was 27.9 ± 1.59%. RTBA significantly correlated with weight both in boys (P= 0.013) and girls (P= 0.016). Significant correlation was demonstrated between RTBA and height, especially in girls (P= 0.045). Statistical significance was shown between RTBA and birth length in boys (P= 0.015) and girls (P= 0.007), and weight at birth in boys (P= 0.014). On multiple regression analysis RTBA correlated significantly with birthweight for boys (standardized coefficient ß= 0.093, P= 0.028) and birth length for girls (ß= 0.122, P= 0.007). CONCLUSION: Augmentation of bone mass is related not only to weight and height during childhood but also to prenatal factors such as growth, and possibly with nutrition in utero.

Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells.

Synthetic glucocorticoids (GCs) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11ß-hydroxysteroid dehydrogenase (11ß-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11ß-HSD2 expression in human T-cell leukemic cell lines. 11ß-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11ß-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assessed by methyl-thiazol-tetrazolium assay and caspase-3/7 assay, suggesting that 11ß-HSD2 is a cause of GC-resistance in ALL.

Abdominal obesity is associated with cardiovascular risk in Japanese children and adolescents.

BACKGROUND: Metabolic syndrome is listed as a risk for atherosclerosis. However, changes in that risk during childhood and adolescence have not been well-documented. It is also unclear whether individuals with abdominal obesity, but with as yet undiagnosed metabolic syndrome, have cardiovascular risks. METHODS AND RESULTS: Ninety-two patients were studied at the Hamamatsu University School of Medicine Department of Pediatrics. Physical measurements including abdominal circumference (AC), body mass index (BMI), body fat (BF), intima media thickness (IMT), arterial elasticity: beta index (Beta), carotid artery compliance (CAC), and Young's elastic modulus (YEM) using ultrasonography were taken. A positive correlation between systolic blood pressure, AC, BMI, and BF was observed (AC, r = 0.717, p < 0.001; BMI, r = 0.672, p < 0.001; BF, r = 0.518, p < 0.001). IMT showed a weak positive correlation with AC, BMI and BF (AC, r = 0.211, p = 0.044; BMI, r = 0.233, p = 0.025; BF, r = 0.232, p = 0.026). The relationship between AC, BMI, BF and arterial elasticity, especially in AC, positively correlated with beta index and YEM but negatively correlated with CAC. CONCLUSION: We suggest that AC is the most sensitive marker in the detection of arterial elasticity, even in school age children. Earlier pre-diagnostic intervention, especially in the prevention of abdominal obesity, may reduce the incidence of metabolic syndrome in children and adolescents.

Importance of C-reactive protein level in predicting non-response to additional intravenous immunoglobulin treatment in children with Kawasaki disease: a retrospective study.

BACKGROUND: Intravenous immunoglobulin (IVIG) therapy in the acute stage of Kawasaki disease (KD; mucocutaneous lymph node syndrome) is the treatment of first choice for preventing the development of coronary artery lesions (CALs). Failure of initial treatment with IVIG remains the most consistent risk factor for CALs. However, there are few reports on nonresponders to additional IVIG therapy in KD. OBJECTIVE: The goal of the present study was to predict non-responders to additional IVIG therapy in children with KD. METHODS: This was a retrospective study aimed at predicting non-responders to additional IVIG therapy for KD in a cohort of 446 patients. The IVIG response group ('responders') was defined as those patients who were afebrile 48 hours after administration of initial IVIG. The IVIG non-response group ('non-responders') was defined as those patients who remained febrile 48 hours after administration of initial IVIG and was divided into two subgroups: (i) those patients who remained febrile 48 hours after administration of additional IVIG (non-responders 1), and (ii) those patients who were afebrile 48 hours after additional IVIG (non-responders 2). RESULTS: Ninety-one patients received additional IVIG; of these, 25 patients (non-responders 1) received additional rescue therapy because no improvement was observed and 66 patients (non-responders 2) were afebrile. Mean ­ SD C-reactive protein (CRP) levels were higher in non-responders 1 than in non-responders 2 (12.05 ­ 5.14 vs 7.67 ­ 4.99 mg/dL; p = 0.002). The optimal cutoff point of sensitivity and specificity for predicted non-responders was ≥8 mg/dL. The sensitivity and specificity for prediction of IVIG response was 76.0% and 63.6%, respectively. Forty-three patients had a CRP level of ≥8 mg/dL after initial IVIG, 18 of whom developed CALs (eight persistent lesions and ten transient lesions). Forty-eight patients had a CRP level of <8 mg/dL after initial IVIG, of whom only eight developed CALs (all transient). CONCLUSION: We have discovered a biomarker able to identify KD patients at high risk of complications who require additional IVIG treatment, thus avoiding overtreatment of low-risk individuals. We suggest that patients who have a CRP level of ≥8mg/dL after initial IVIG are likely to fail additional IVIG and may require further IVIG plus rescue therapy.

Prevalence of congenital heart disease assessed by echocardiography in 2067 consecutive newborns.

AIM: There are discrepancies in the reported prevalence of congenital heart disease (CHD). This study prospectively evaluated the prevalence of CHD in consecutive newborns using echocardiographic screening. METHODS: A cohort screening study was conducted in an unselected series of all live-birth newborns. Two-dimensional and colour Doppler echocardiography was performed at 0-4 days of life in 2067 consecutive neonates who were born at the Hamamatsu University Hospital, Japan, between May 2005 and April 2010. RESULTS: There were 104 cases of CHD in the 2067 live births. Ventricular septal defect and patent ductus arteriosus were the most frequent cardiac abnormalities. The prevalence of newborns with CHD who had signs or symptoms of CHD and/or required invasive intervention was 21.3 per 1000 live births. However, 60 patients (29.0 per 1000 live births) with CHD were asymptomatic and did not need invasive intervention. The overall prevalence of CHD in this series was 50.3 per 1000 live births. CONCLUSION: This prospective study using echocardiography for all newborns shows a higher prevalence of CHD than almost all of the previous studies.

Hereditary spherocytosis coexisting with UDP-glucuronosyltransferase deficiency highly suggestive of Crigler-Najjar syndrome type II.

Patients with co-existing hereditary spherocytosis (HS) and UDP-glucuronosyltransferase 1A1 (UGT1A1) deficiency as Gilbert's syndrome (GS) have been reported, and previous studies have demonstrated an increased risk for developing gallstones in patients with co-inheritance of GS and HS. We experienced an interesting case of HS showing persistent jaundice after splenectomy, and upon further evaluation, the 25-year-old female patient was found to have HS combined with UGT1A1 deficiency. Sequence analysis of the UGT1A1 gene revealed that she was a compound heterozygote with p.[G71R; Y486D] + [Y486D] mutations, which suggests Crigler-Najjar syndrome type II rather than GS. Careful evaluation of inappropriately elevated bilirubin level compared with the degree of hemolysis is important, reflecting the therapeutic implication of splenectomy and cholecystectomy.

Age and sex differences in fat distribution in non-obese Japanese children.

OBJECTIVE: To assess fat distribution in non-obese Japanese children and adolescents. DESIGN: 130 non-obese Japanese children (73 boys and 57 girls) from Kikugawa, Hamamatsu were included. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography (CT) and calculated (in cm(2)). Subjects were divided into three groups based on age: group A (6-10 years), group B (11-15 years), and group C (16-20 years). RESULTS: Girls had more subcutaneous fat than boys in groups B and C (P<0.01). Boys had an age-dependent increase in visceral fat, but girls did not. In group C (16-20 years), boys had more visceral fat than girls (P<0.01). CONCLUSIONS: In non-obese Japanese children, there are significant differences in visceral and subcutaneous fat amounts by age and sex. VFA seems to accumulate more in boys than in girls, and SFA is more prevalent in girls than boys.

Case of polyhydramnios complicated by Opitz G/BBB syndrome.

Opitz G/BBB syndrome is a congenital disorder characterized by midline defects, such as hypertelorism, cleft lip and/or palate, hypospadias, and by dysphagia often caused by laryngo-tracheo-esophageal abnormalities. We experienced a case of polyhydramnios in a male dichorionic diamniotic (DD) twin, who was diagnosed with Opitz G/BBB syndrome after birth. It is suggested that severe dysphagia was causatively associated with the development of polyhydramnios. In cases of Opitz G/BBB syndrome, boys are usually more heavily affected than girls, who generally manifest only hypertelorism. In the differential diagnosis of polyhydramnios of unidentified cause in male fetuses, it may be helpful to consider maternal facial characteristics, especially hypertelorism.

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.

Delayed enhancement cardiac magnetic resonance imaging in propionic acidemia.

We report on cardiomyopathy in propionic acidemia (PA) diagnosed using delayed-enhancement cardiac magnetic imaging (DECM) in a 27-year-old woman. DECM demonstrated hyperenhancement at the lateral wall of the left ventricle, suggesting myocardial changes occurring after a metabolic crisis, which improved during the convalescent period. DECM was useful for the diagnosis of cardiomyopathy in PA.

Postnatal changes in adrenal size in very low-birth-weight infants: sonographic evaluation for the prediction of late-onset glucocorticoid-responsive circulatory collapse.

We investigated the postnatal pattern of changes in adrenal size in very low-birth-weight (VLBW) infants and its relation to late-onset glucocorticoid-responsive circulatory collapse (LGCC) that may be associated with adrenal insufficiency. In 36 VLBW infants born at <33 weeks' gestation, ultrasound examinations of postnatal changes in adrenal size during the first 3 weeks of life were performed. VLBW infants were classified into three groups: group A (N = 6), the actual adrenal area was greater than or equal to the predicted value at birth and unchanged at 3 weeks; group B (N = 24), the actual adrenal area was greater than or equal to the predicted value and decreased at 3 weeks; and group C (N = 6), the actual adrenal area was less than the predicted value and unchanged at 3 weeks. Five infants developed LGCC, and all five were in group A. These observations suggest that the life of the adrenal fetal zone might be extended beyond 3 weeks after birth in some VLBW infants and that prolonged fetal zone activity might correlate with LGCC. On the other hand, adrenal maturation might have already occurred at birth in some VLBW infants. Sonographic evaluation of adrenal size may enable prediction of subsequent LGCC in VLBW infants.

Effect of cibenzoline on biventricular pressure gradients in a pediatric patient with hypertrophic obstructive cardiomyopathy.

This report presents the case of an 8-year-old male with biventricular hypertrophic obstructive cardiomyopathy who achieved a successful reduction of the pressure gradients by treatment with cibenzoline. Ultrasound echocardiography showed marked intraventricular septal hypertrophy and left midventricular and right ventricular outflow obstructions. A cardiac catheterization revealed left midventricular and right outflow obstructions associated with pressure gradients of 100 and 35 mmHg, respectively. An intravenous injection of 28 mg (1.4 mg/kg) cibenzoline immediately improved the biventricular pressure gradients. Therefore, oral cibenzoline treatment was initiated, the dose was increased to 150 mg/day, and both pressure gradients remained low, without any complications at the time of discharge, 4 months later.

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.

Cytochrome P450 oxidoreductase deficiency with Antley-Bixler syndrome: steroidogenic capacities.

For patients with cytochrome P450 oxidoreductase deficiency (PORD), steroid replacement is recommended at times of stress. However, it is unknown how hormones respond to actual physical stress in these patients. We report a female infant with PORD accompanied by the Antley-Bixler syndrome phenotype. Her urinary steroid profile revealed defective CYP17A1 and CYP21A2 activities, and an adrenocorticotropin (ACTH) stimulation test showed potential adrenal insufficiency. Hormonal responses to actual physical stress were as follows: Vigorous crying during blood sampling rarely affected the serum cortisol level. Acute viral gastroenteritis led to marked increases in blood ACTH and 17alpha-hydroxyprogesterone levels in proportion to the severity of the illness. The serum cortisol level also responded to this stress, but the response might have been blunted. Regarding peri-operative steroid replacement, intravenous hydrocortisone administration even at a dose of 6 mg/kg, which is lower than that recommended for congenital adrenal hyperplasia in Japan, proved to be excessive.