Publications by authors named "Toru Kikuchi"

63 Publications

Efficacy and safety of fast-acting insulin aspart versus insulin aspart in children and adolescents with type 1 diabetes from Japan.

Endocr J 2021 Apr 29;68(4):409-420. Epub 2021 Jan 29.

Medical & Science, Global Development, Novo Nordisk A/S, 2860 Søborg, Denmark.

The aim of this post-hoc subgroup analysis, which was based on data from the treat-to-target, 26-week, onset 7 trial, was to confirm the efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp), both in combination with basal insulin degludec, in children and adolescents from Japan with type 1 diabetes (T1D). Of the onset 7 trial population (1 to <18 years; N = 777), 66 participants from Japan (65 Asian and one non-Asian) were randomized to mealtime faster aspart (n = 24), post-meal faster aspart (n = 19), or IAsp (n = 23). Data for the subgroup from Japan were analysed descriptively. Change from baseline in hemoglobin A1c 26 weeks after randomization was 0.23%, 0.74%, and 0.39%, for mealtime faster aspart, post-meal faster aspart, and IAsp respectively. Change from baseline in 1-h post-prandial glucose increment (based on 8-point self-measured blood glucose profiles) showed numerical differences in favor of mealtime faster aspart versus IAsp at breakfast (-30.70 vs. -2.88 mg/dL) and over all meals (-18.21 vs. -5.55 mg/dL). There were no clinically relevant numerical differences between treatment arms in the overall rate of severe or blood glucose-confirmed hypoglycemia. At week 26, mean total insulin dose was 1.119 U/kg/day for mealtime faster aspart, 1.049 U/kg/day for post-meal faster aspart, and 1.037 U/kg/day for IAsp. In conclusion, in children and adolescents with T1D from Japan, mealtime and post-meal faster aspart with insulin degludec was efficacious in controlling glycemia without additional safety concerns versus IAsp.
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http://dx.doi.org/10.1507/endocrj.EJ20-0116DOI Listing
April 2021

Residual endogenous insulin secretion in Japanese children with type 1A diabetes.

Clin Pediatr Endocrinol 2021 5;30(1):27-33. Epub 2021 Jan 5.

Department of Pediatrics, Saitama Medical University Faculty of Medicine, Saitama, Japan.

We investigated serum C-peptide immunoreactivity (CPR) levels in registered data from a multi-center collaborative nationwide type 1 diabetes study. The CPR levels were obtained from 576 and 409 children during the early registration (2013/2014) and late observation (2016/2017) periods, respectively. The percentages of children with a CPR < 0.1 or < 0.3 ng/mL increased according to the duration since diagnosis. Among patients with 5 or more years since diagnosis, 69% had a CPR < 0.1 and 95% had a CPR < 0.3 in the early registration period. A significant negative correlation was observed between the HbA1c and the CPR levels, and the HbA1c levels were significantly higher among children with a CPR < 0.1 or < 0.3 than among those with a CPR ≥ 0.6 ng/mL. During the late observation period, the prevalence of a CPR < 0.1 ng/mL was 88% among long-standing patients and 77% among patients aged 18-20 yr. Regarding the characteristics of "Responders" with a sustained CPR ≥ 0.6 ng/mL at 5 or more years since diagnosis, six of the seven were adolescent females; five of the seven had an HLA DR4-DQ4 haplotype. When type 1A diabetes mellitus (T1AD) children transit to adult care centers, most of them may have some difficulty in glycemic control because of the depleted endogenous insulin.
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http://dx.doi.org/10.1297/cpe.30.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783123PMC
January 2021

Increasing secular trends in height and obesity in children with type 1 diabetes: JSGIT cohort.

PLoS One 2020 23;15(11):e0242259. Epub 2020 Nov 23.

Department of Pediatrics, Saitama Medical University, Iruma, Japan.

Background: Recently, anthropometric indices in children with type 1 diabetes mellitus (T1DM) have begun to change.

Objective: To examine secular trends in patients' anthropometric indices.

Subjects: Japanese children with T1DM from the 1995, 2000, 2008 and 2013 cohorts of The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes.

Methods: We analysed serum haemoglobin A1c (HbA1c) levels, the incidence of severe hypoglycaemic events, the types and doses of insulin, height standard deviation scores (SDS), body mass index (BMI) percentiles compared with healthy Japanese children and obesity prevalence over time. We also stratified the patients according to glycaemic control levels of <58 mmol/mol (optimal), 58-75 mmol/mol (suboptimal) and ≥75 mmol/mol (high-risk).

Results: Data for 513-978 patients from each of the cohorts were analysed. The incidence of severe hypoglycaemic events decreased over time (from 21 to 4.8/100 patient-years), while the proportion of insulin analogue doses increased (14.6% to 98.6%). In addition, patient height SDS (-0.22 to +0.17), BMI percentile (52.1 to 58.7) and obesity prevalence (2.1% to 5.1%) increased. Height SDS increased in all of the glycaemic control subgroups, while BMI percentile and obesity prevalence increased in the suboptimal and high-risk groups.

Conclusions: Since 1995, the average height of children with T1DM has increased in parallel with increasing insulin doses. Clinicians should be aware of increased BMI in these patients and the associated risk of developing cardiovascular disease in the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242259PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682904PMC
December 2020

Need for strict clinical management of patients with carnitine palmitoyltransferase II deficiency: Experience with two cases detected by expanded newborn screening.

Mol Genet Metab Rep 2020 Sep 27;24:100611. Epub 2020 May 27.

Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

In Japan, carnitine palmitoyltransferase II (CPTII) deficiency has been included as one of the primary target diseases in the expanded newborn mass screening program since 2018. However, many cases of the severe infantile hepatocardiomuscular form of CPTII deficiency showed severe neurodevelopmental delay or sudden death, which indicated that management of CPTII deficiency in the acute phase remains to be studied in detail. Herein, we discuss two cases diagnosed by newborn mass screening. Patient 1 was under strict clinical management from the neonatal period, with >20 admissions in 14 months, while Patient 2 was managed using a relatively relaxed approach, with only 2 admissions in the same period. Patient 1 showed normal development; however, Patient 2 expired at the age of 1 year 2 months. To develop strategies for preventing sudden deaths in patients with CPTII deficiency, this retrospective study focused on detailed clinical management practices and biochemical findings during the acute phase. We also investigated the correlation between conventional biomarkers (such as creatine kinase) and long-chain acylcarnitines. We propose that strict monitoring and immediate medical attention, even in case of slight fever or minor abdominal symptoms, can help prevent sudden death in patients with CPTII deficiency. Considering the higher morbidity rate of such patients, strict and acute management of CPTII deficiency cannot be overemphasized.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260588PMC
September 2020

[A Case of Pneumocystin a Patient with Pneumonia That Developed during Chemotherapy for Sigmoid Cancer].

Gan To Kagaku Ryoho 2020 Feb;47(2):289-291

Dept. of Surgery, Tokyo Shinagawa Hospital.

A 63-year-old man was diagnosed with advanced sigmoid cancer of pT3, pN0, sM1c, sP3, fStage Ⅳ post-operation. After CAPOX plus Bmab as the first-line chemotherapy, he underwent IRIS plus Bmab as the second-line chemotherapy. After 1 course of IRIS plus Bmab, he was admitted to the hospital for fever, dyspnea, and general fatigue. The white blood cell count was 6.2×10 3/mL, and the C-reactive protein was elevated to 12.9 mg/dL. The PaO2 of the artery blood gas analysis in room air was 46.3 mmHg, suggesting respiratory failure. He was diagnosed with PCP based on the bilateral diffused ground-glass opacities on chest CT along with an elevated serum b-D-glucan. The treatment of trimethoprim-sulfamethoxazole and steroid was then initiated. After the patient's clinical condition improved, he was discharged on day 27 post-admission.
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February 2020

[A Case of Gastric Large-Cell Neuroendocrine Carcinoma Combined with Adenocarcinoma in the Cecum].

Gan To Kagaku Ryoho 2019 Dec;46(13):1990-1992

Dept. of Surgery, Tokyo Metropolitan Hiroo Hospital.

A 74-year-old man with anemia visited our department. Esophagogastroduodenoscopy showed a type 2 lesion from the angulus to the antrum. Histopathological findings indicated gastric neuroendocrine carcinoma. Colonoscopy showed a type 1 lesion at the cecum. Distal gastrectomy was performed with D1+lymph node dissection, Roux-en-Y reconstruction, and ileocecal resection with D3 lymph node dissection. The patient was pathologically diagnosed with large-cell neuroendocrine carcinoma in the stomach, pT4a(SE), med, INF a>>b-c, ly1-2, v1(SM, EVG), pN0, pM0, pStageⅡB, and adenocarcinoma (tub1>tub2)of the cecum, pT2(MP), ly1(HE), v1(EVG, SM), pN0, pM0, pStageⅠ. Postoperatively, he received oral S-1 as an adjuvant chemotherapy. His postoperative course was uneventful without any recurrence over 18 months.
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December 2019

Policy statement of enteral nutrition for preterm and very low birthweight infants.

Pediatr Int 2020 Feb 5;62(2):124-127. Epub 2020 Feb 5.

Board Committee on Nutrition, The Child Health Consortium of Japan, Tokyo, Japan.

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.
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http://dx.doi.org/10.1111/ped.14067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065204PMC
February 2020

A case of secretory breast cancer in a 6 year-old girl: is it possible to make a correct preoperative diagnosis?

Breast Cancer 2020 Jul 30;27(4):785-790. Epub 2020 Jan 30.

Department of Pathology, Saitama Medical University, Iruma-gun, Japan.

Secretory breast carcinoma constitutes the majority of breast cancers in children and young people less than 20 years of age. Noninvasive examination is particularly necessary for the diagnosis of breast carcinoma in children. Herein, we report a case of secretory breast carcinoma in a 6-year-old girl with psychomotor retardation. She was referred to our outpatient clinic for evaluation of a palpable mass in her left breast. A hard mass, rather than the increase in size typical of premature thelarche, was palpated. An excision biopsy was performed. Pathological findings revealed an invasive secretory breast carcinoma. We performed a retrospective review of the preoperative findings of this case, and compared it to the pathological diagnosis. Elastography, which can be performed without deep sedation or general anesthesia and without causing pain, resulted in a stiffness score of 4; however, the distinction between benign and malignant tumors on elastography, which is important to decide the intra-operative procedures, was not sufficient according to the Japanese breast cancer society clinical guidelines. This is the first report of secretory breast carcinoma in a child with a stiffness score determined by tissue elasticity imaging. A breast mass in a child with a high stiffness score of more than 4 on elastography should be referred for invasive diagnostic procedures, such as fine needle aspiration or excisional biopsy. According to our experience, an accurate preoperative diagnosis could be possible for malignant breast tumors in children. Such parameters as stiffness score on elastography are practical, noninvasive, and objective diagnostic tools for the accurate preoperative diagnosis of breast tumors in children.
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http://dx.doi.org/10.1007/s12282-020-01056-5DOI Listing
July 2020

Increased diagnosis of autoimmune childhood-onset Japanese type 1 diabetes using a new glutamic acid decarboxylase antibody enzyme-linked immunosorbent assay kit, compared with a previously used glutamic acid decarboxylase antibody radioimmunoassay kit.

J Diabetes Investig 2020 May 24;11(3):594-602. Epub 2019 Dec 24.

Department of Pediatrics, Saitama Medical University, Iruma, Saitama, Japan.

Aims/introduction: We compared the results of testing for glutamic acid decarboxylase antibodies (GADAb) using a radioimmunoassay (RIA) and an enzyme-linked immunosorbent assay (ELISA) in individuals with childhood-onset type 1 diabetes mellitus.

Materials And Methods: Serum specimens were collected from 1,024 Japanese children (426 boys and 598 girls) in 2013. The median age at diagnosis was 7 years (0-18 years). The blood specimens were obtained at a median age of 13 years (2-22 years).

Results: Among the 628 children whose serum specimens were collected within 5 years after diagnosis, the rate of GADAb positivity was 47.9% using RIA and 69.4% using ELISA. The participants were divided into four groups according to their RIA and ELISA results for GADAb as follows: group I (RIA+/ELISA+), group II (RIA+/ELISA-), group III (RIA-/ELISA+) and group IV (RIA-/ELISA-). The clinical and genetic characteristics of group I and group III were quite similar in terms of age at diagnosis, male/female ratio, relatively high positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and human leukocyte antigen genotype. Group II contained just five patients, and was characterized by a younger age at diagnosis, low positive rates for both autoantibody to protein tyrosine phosphatase IA-2 and autoantibody to the cation efflux transporter zinc transporter 8, and a unique human leukocyte antigen genotype. If the positive rates of either autoantibody to protein tyrosine phosphatase IA-2 or autoantibody to the cation efflux transporter zinc transporter 8 or both were added to the GADAb results using RIA, the percentage of autoimmune type 1 diabetes increased from 47.9% to 78.5%.

Conclusions: The diagnosis of autoimmune childhood-onset Japanese type 1 diabetes increased when GADAb results were obtained using a new ELISA method, compared with a previously utilized RIA method.
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http://dx.doi.org/10.1111/jdi.13184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232289PMC
May 2020

Current-Induced Modulation of the Interfacial Dzyaloshinskii-Moriya Interaction.

Phys Rev Lett 2019 Jun;122(25):257205

Department of Physics, The University of Tokyo, Tokyo 113-0033, Japan.

The Dzyaloshinskii-Moriya (DM) interaction is an antisymmetric exchange interaction that is responsible for the emergence of chiral magnetism. The origin of the DM interaction, however, remains to be identified albeit the large number of studies reported on related effects. It has been recently suggested that the DM interaction is equivalent to an equilibrium spin current density originating from spin-orbit coupling, an effect referred to as the spin Doppler effect. The model predicts that the DM interaction can be controlled by spin current injected externally. Here we show that the DM exchange constant (D) in W/CoFeB-based heterostructures can be modulated with external current passed along the film plane. At higher current, D decreases with increasing current, which we infer is partly due to the adiabatic spin transfer torque. At lower current, D increases linearly with current regardless of the polarity of current flow. The rate of increase in D with the current density agrees with that predicted by the model based on the spin Doppler effect. These results imply that the DM interaction at the heavy-metal-ferromagnetic-metal interface partly originates from an equilibrium interface spin (polarized) current which can be modulated externally.
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http://dx.doi.org/10.1103/PhysRevLett.122.257205DOI Listing
June 2019

Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus.

J Pediatr Endocrinol Metab 2019 Jan;32(1):1-9

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT), Kyoto, Japan.

Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients.
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http://dx.doi.org/10.1515/jpem-2018-0329DOI Listing
January 2019

Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.

Am J Med Genet A 2018 Mar 31;176(3):739-742. Epub 2018 Jan 31.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.
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http://dx.doi.org/10.1002/ajmg.a.38623DOI Listing
March 2018

Obesity and abnormal glucose tolerance in offspring of diabetic mothers: A systematic review and meta-analysis.

PLoS One 2018 12;13(1):e0190676. Epub 2018 Jan 12.

Department of Health Policy, National Center for Child Health and Development, Tokyo, Japan.

Background: Rising prevalence of childhood obesity and type 2 diabetes mellitus (T2DM) is an emerging public health issue.

Objectives: To investigate the association of maternal hyperglycemia exposure during pregnancy with obesity and abnormal glucose tolerance in offspring, and the age at occurrence.

Methods: We searched MEDLINE and EMBASE for observational studies on obesity and diabetes in offspring of diabetic mothers (gestational diabetes mellitus (GDM), type 1 diabetes mellitus (T1DM) and T2DM), and those on non-diabetic mothers. We performed fixed effect meta-analysis for all studies except when heterogeneity was detected. The quality of studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS).

Results: Twenty observational studies were included involving a total of 26,509 children. Offspring of GDM mother had higher BMI z-score in childhood (pooled MD: 0.14, 95%CI: 0.04-0.24, seven studies, 21,691children, low quality of evidence). Offspring of T1DM mothers had higher BMI z-score from prepubertal to adolescent (pooled MD: 0.35, 95% CI: 0.13-0.58, three studies, 844 children, low quality of evidence) compared with control. After adjustment for maternal pre-pregnancy BMI, this association remained in offspring of T1DM, but disappeared in those of GDM mothers. Offspring of GDM mother had higher 2-hour plasma glucose from prepubertal to early adulthood (pooled MD: 0.43 mmol/L, 95% CI: 0.18-0.69, five studies, 890 children), while those of T1DM mothers had higher rate of T2DM in 2-5 years old to early adulthood (pooled odds ratio [OR], 6.10: 95% CI: 1.23-30.37, two studies, 448 children, very low quality of evidence) compared with control. As there was only one study with offspring of T2DM mothers, evidence is sparse.

Limitations: Only observational studies were included, with a few adequately adjusted for covariables.

Conclusions: Exposure to maternal hyperglycemia was associated with offspring obesity and abnormal glucose tolerance especially in offspring of T1DM mothers, but the evidence relies on observational studies with low quality of evidence only.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190676PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766126PMC
February 2018

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes.

Pediatr Diabetes 2018 03 9;19(2):243-250. Epub 2017 Jun 9.

Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.

Background: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D).

Objectives: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D.

Methods: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers.

Results: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis.

Conclusions: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.
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http://dx.doi.org/10.1111/pedi.12544DOI Listing
March 2018

Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial.

Clin Endocrinol (Oxf) 2017 Jul 2;87(1):10-19. Epub 2017 May 2.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan.

Design: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015.

Patients: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1).

Measurements: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development.

Results: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved.

Conclusion: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.
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http://dx.doi.org/10.1111/cen.13343DOI Listing
July 2017

Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes.

J Diabetes Investig 2017 May 25;8(3):286-294. Epub 2016 Nov 25.

The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.

Aims/introduction: Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods.

Materials And Methods: We carried out whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples.

Results: Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the non-obese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L and p.T944R substitutions were absent or extremely rare in the general population, and were assessed as 'probably/possibly damaging' by in silico analyses. CD101 expression on monocytes, granulocytes and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals.

Conclusions: These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes.
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http://dx.doi.org/10.1111/jdi.12586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415474PMC
May 2017

Improvement in glycemic control through changes in insulin regimens: findings from a Japanese cohort of children and adolescents with type 1 diabetes.

Pediatr Diabetes 2017 Sep 27;18(6):435-442. Epub 2016 Jul 27.

Department of Pediatrics, Saitama Medial University, Saitama, Japan.

Objective: Although insulin analogs have dramatically changed diabetes treatment, scarce evidence is available on those effects. We aimed to explore whether glycemic control had improved, the use of insulin analogs had been increased, and hypoglycemic events had decreased over time in Japanese pediatric patients with type 1 diabetes (T1D).

Methods: Glycated hemoglobin A1c (HbA1c) values, proportion of insulin regimens, incidence of severe hypoglycemic events, and pubertal increase in HbA1c were compared in three cohorts of childhood-onset Japanese T1D patients (567 subjects in the 1995 cohort, 754 subjects in the 2000 cohort, and 806 subjects in the 2008 cohort).

Results: Mean HbA1c values tended to decrease [78.5 mmol/mol (9.33%) in the 1995 cohort, 68.2 mmol/mol (8.39%) in the 2000 cohort, and 61.2 mmol/mol (7.75%) in the 2008 cohort; P < .0001]. The proportion of patients who received basal-bolus treatment tended to increase with statistical significance, as did the proportion on insulin analogs. The incidence of severe hypoglycemic events (events/100 patients/y) had decreased (19.1 in the 2000 cohort and 8.7 in the 2008 cohort; P = .02). The pubertal increase in HbA1c tended to decrease [males, 12.0 mmol/mol (1.10%) in 1995, 9.4 mmol/mol (0.85%) in 2008, and 9.4 mmol/mol (0.86%) in 2008; P = .55; females, 14.0 mmol/mol (1.28%) in 1995, 10.3 mmol/mol (0.94%) in 2000, and 4.2 mmol/mol (0.38%) in 2008; P = .0003].

Conclusions: Glycemic control and incidence of severe hypoglycemic events were chronologically improved, especially in female adolescents.
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http://dx.doi.org/10.1111/pedi.12409DOI Listing
September 2017

Dzyaloshinskii-Moriya Interaction as a Consequence of a Doppler Shift due to Spin-Orbit-Induced Intrinsic Spin Current.

Phys Rev Lett 2016 Jun 13;116(24):247201. Epub 2016 Jun 13.

RIKEN Center for Emergent Matter Science (CEMS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

We present a physical picture for the emergence of the Dzyaloshinskii-Moriya (DM) interaction based on the idea of the Doppler shift by an intrinsic spin current induced by spin-orbit interaction under broken inversion symmetry. The picture is confirmed by a rigorous effective Hamiltonian theory, which reveals that the DM coefficient is given by the magnitude of the intrinsic spin current. Our approach is directly applicable to first principles calculations and clarifies the relation between the interaction and the electronic band structures. Quantitative agreement with experimental results is obtained for the skyrmion compounds Mn_{1-x}Fe_{x}Ge and Fe_{1-x}Co_{x}Ge.
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http://dx.doi.org/10.1103/PhysRevLett.116.247201DOI Listing
June 2016

[Epidemiology of type 1 diabetes in children and adolescents].

Authors:
Toru Kikuchi

Nihon Rinsho 2016 Apr;74 Suppl 2:490-5

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April 2016

Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon?

J Hum Genet 2016 Aug 28;61(8):765-9. Epub 2016 Apr 28.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Although recent studies have often revealed the presence of multilocus imprinting disturbance (MLID) at differentially methylated regions (DMRs) in patients with imprinting disorders (IDs), most patients exhibit clinical features of the original ID only. Here we report a Japanese female patient with Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib. Molecular studies revealed marked methylation defects (MDs) at the Kv-DMR and the GNAS-DMRs and variable MDs at four additional DMRs, in the absence of a mutation in ZFP57, NLRP2, NLRP7, KHDC3L and NLRP5. It is likely that the MDs at the Kv-DMR and the GNAS-DMRs were sufficient to cause clinically recognizable IDs, whereas the remaining MDs were insufficient to result in clinical consequences or took place at DMRs with no disease-causing imprinted gene(s). The development of MLID and the two IDs of this patient may be due to a mutation in a hitherto unknown gene for MLID, or to a reduced amount of DNA methyltransferase-1 (DNMT1) available for the methylation maintenance of DMRs because of the consumption of DNMT1 by the maintenance of X-inactivation. In support of the latter possibility, such co-existence of two IDs has primarily been identified in female patients, and MLID has predominantly been identified as loss of methylations.
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http://dx.doi.org/10.1038/jhg.2016.45DOI Listing
August 2016

Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols.

Clin Pediatr Endocrinol 2015 Apr 15;24(2):37-49. Epub 2015 May 15.

Study Group of Treatment for MHH ; Pharmaceutical Affairs Committee, the Japanese Society for Pediatric Endocrinology ; Tanaka Growth Clinic, Tokyo, Japan.

Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing subjects into two groups to determine different treatment protocols, acquired and congenital MHH, and to conduct them at a timing closer to the onset of puberty, namely, at a timing near entrance to junior high school. We also propose a new HRT protocol using preemptive FSH therapy prior to GRT aimed at achieving future fertility in patients with congenital MHH.
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http://dx.doi.org/10.1297/cpe.24.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436555PMC
April 2015

Silver-Russell syndrome without body asymmetry in three patients with duplications of maternally derived chromosome 11p15 involving CDKN1C.

J Hum Genet 2015 Feb 27;60(2):91-5. Epub 2014 Nov 27.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.

We report duplications of maternally derived chromosome 11p15 involving CDKN1C encoding a negative regulator for cell proliferation in three Japanese patients (cases 1 and 2 from family A and case 3 from family B) with Silver-Russell syndrome (SRS) phenotype lacking hemihypotrophy. Chromosome analysis showed 46,XX,der(16)t(11;16)(p15.3;q24.3)mat in case 1, 46,XY,der(16)t(11;16)(p15.3;q24.3)mat in case 2 and a de novo 46,XX,der(17)t(11;17)(p15.4;q25.3) in case 3. Genomewide oligonucleotide-based array comparative genomic hybridization, microsatellite analysis, pyrosequencing-based methylation analysis and direct sequence analysis revealed the presence of maternally derived extra copies of the distal chromosome 11p involving the wild-type CDKN1C (a ~7.98 Mb region in cases 1 and 2 and a ~4.43 Mb region in case 3). The results, in conjunction with the previous findings in patients with similar duplications encompassing CDKN1C and in those with intragenic mutations of CDKN1C, imply that duplications of CDKN1C, as well as relatively mild gain-of-function mutations of CDKN1C lead to SRS subtype that usually lack hemihypotrophy.
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http://dx.doi.org/10.1038/jhg.2014.100DOI Listing
February 2015

The ratio of glycated albumin to hemoglobin A1c measured in IFCC units accurately represents the glycation gap.

Endocr J 2015 2;62(2):161-72. Epub 2014 Nov 2.

Department of Pediatrics, Saitama Medial University, Saitama 350-0495, Japan.

The glycation gap (G-gap: difference between measured hemoglobin A1c [A1C] and the value predicted by its regression on the fructosamine level) is stable and associated with diabetic complications. Measuring A1C level in International Federation of Clinical Chemistry (IFCC) units (A1C-SI; mmol/mol) and National Glycohemoglobin Standardization Program units (A1C-NGSP; %) and using glycated albumin (GA) level instead of fructosamine level for calculating the G-gap, we investigated whether the G-gap is better represented by GA/A1C ratio if expressed in SI units (GA/A1C-SI ratio) rather than in NGSP units (GA/A1C-% ratio). We examined 749 Japanese children with type 1 diabetes using simultaneous GA and A1C measurements. Of these, 369 patients were examined more than five times to assess the consistency of the G-gap and the GA/A1C ratio within individuals. The relationship of GA/A1C-% ratio to the corresponding A1C-NGSP was stronger than that of GA/A1C-SI ratio to A1C-IFCC. At enrollment, the inverse relationship between the GA/A1C-SI ratio and G-gap was highly significant (R(2) = 0.95) compared with that between the GA/A1C-% ratio and G-gap (R(2) = 0.69). A highly significant inverse relationship was also observed between the mean GA/A1C-SI ratio and the mean G-gaps obtained individually over time (R(2) = 0.95) compared with that using the corresponding A1C-NGSP (R(2) = 0.67). We conclude that the G-gap is better represented by the GA/A1C-SI ratio. We propose the use of mean GA/A1C-SI ratios easily obtained individually over time as reference values in Japanese children with type 1 diabetes (6.75 ± 0.60 [means ± SD]).
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http://dx.doi.org/10.1507/endocrj.EJ14-0066DOI Listing
May 2016

Isolation and characterization of [5,6]-pyrrolidino-Sc₃[email protected](h)-C₈₀ diastereomers.

Chem Commun (Camb) 2014 Oct;50(83):12552-5

Department of Chemistry, Tokyo Gakugei University, Koganei, Tokyo 184-8501, Japan.

Reactions of [email protected](h)-C80 with aziridine derivatives were conducted to afford the corresponding mono-adducts. A pair of diastereomers of the mono-adduct [5,6][email protected](h)-C80 was isolated and characterized by means of mass spectrometry, vis-NIR absorption spectroscopy, and electrochemical measurements. Structural analysis of the mono-adducts was conducted by NMR and single-crystal X-ray structure determinations.
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http://dx.doi.org/10.1039/c4cc04946bDOI Listing
October 2014

Long-term follow-up study for a patient with Floating-Harbor syndrome due to a hotspot SRCAP mutation.

Am J Med Genet A 2014 Mar 20;164A(3):731-5. Epub 2013 Dec 20.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan; Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant disorder characterized by short stature, skeletal malformations, speech delay, and dysmorphic facial appearance. Recently, mutations in SRCAP encoding a coactivator for cAMP-response element binding protein (CREB)-binding protein have been identified in small number of patients with FHS. Here, we report on long-term follow-up data of a male patient with a SRCAP mutation. The patient presented with mild hypothyroidism and renal hypouricemia, in addition to several FHS-compatible features including growth impairment, cognitive disability, facial dysmorphisms, and hypertension. He showed delayed bone age from infancy to 9 years of age and markedly accelerated bone age with the formation of cone-shaped epiphyses and early epiphysial fusions after the onset of puberty. His pubertal sexual development was almost age appropriate. Two-year treatment with growth hormone (GH) did not significantly improve the growth velocity. Molecular analysis identified a de novo heterozygous nonsense mutation (p.R2444X) in the last exon of SRCAP, which has been most common mutation detected in patients from other ethnic groups. These results indicate that perturbed skeletal maturation from infancy through adolescence is a characteristic feature in patients with SRCAP mutations. Furthermore, our data imply that GH therapy exerted only a marginal effect on the growth of this patient, and that renal hypouricemia may be a novel complication of FHS.
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http://dx.doi.org/10.1002/ajmg.a.36314DOI Listing
March 2014

Screening and treatment of childhood type 1 and type 2 diabetes mellitus in Japan.

Pediatr Endocrinol Rev 2012 Oct;10 Suppl 1:51-61

Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.

A large number of children with type 2 diabetes mellitus (T2DM) and a small number with a slowly progressive form of type 1 diabetes mellitus (SPT1DM) have been detected by a urine glucose screening program conducted at Japanese schools since 1974. The incidence of T2DM in children has increased over the last 3 decades and is estimated to be approximately 3.0/100,000/year, which is twice as that of T1DM. In contrast, SPT1DM in children is more prevalent in Asians, particularly Japanese, and exhibits unique clinical features that differ from those of the rapid onset form of T1DM, usually seen in Caucasians. In the first part of this review, we summarize the urine glucose screening program conducted at Japanese schools and clinical characteristics of the 2 diabetic subtypes in Japanese children. In recent years, concerns regarding childhood diabetes in Asian countries, including Japan, have risen, and medical care for the same is exceedingly developing. Intensive insulin therapy such as basal-bolus therapy by multiple daily insulin injections and pump therapy, both using insulin analogs, has been increasing in pediatric patients with T1DM. In addition, various antidiabetic medications have been introduced for children with T2DM. In the second part of this review, we describe treatment of Japanese children with T1DM and T2DM and changes in glycemic control as a result of development of the treatment.
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October 2012

PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance.

J Clin Endocrinol Metab 2012 Sep 20;97(9):E1808-13. Epub 2012 Jun 20.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Context: Acrodysostosis is a rare autosomal dominant disorder characterized by short stature, peculiar facial appearance with nasal hypoplasia, and short metacarpotarsals and phalanges with cone-shaped epiphyses. Recently, mutations of PRKAR1A and PDE4D downstream of GNAS on the cAMP-mediated G protein-coupled receptor (GPCR) signaling cascade have been identified in acrodysostosis with and without hormone resistance, although functional studies have been performed only for p.R368X of PRKAR1A.

Objective: Our objective was to report a novel PRKAR1A mutation and its functional consequence in a Japanese female patient with acrodysostosis and hormone resistance.

Patient: This patient had acrodysostosis-compatible clinical features such as short stature and brachydactyly and mildly elevated serum PTH and TSH values.

Results: Although no abnormality was detected in GNAS and PDE4D, a novel de novo heterozygous missense mutation (p.T239A) was identified at the cAMP-binding domain A of PRKAR1A. Western blot analysis using primary antibodies for the phosphorylated cAMP-responsive element (CRE)-binding protein showed markedly reduced CRE-binding protein phosphorylation in the forskolin-stimulated lymphoblastoid cell lines of this patient. CRE-luciferase reporter assays indicated significantly impaired response of protein kinase A to cAMP in the HEK293 cells expressing the mutant p.T239A protein.

Conclusions: The results indicate that acrodysostosis with hormone resistance is caused by a heterozygous mutation at the cAMP-binding domain A of PRKAR1A because of impaired cAMP-mediated GPCR signaling. Because GNAS, PRKAR1A, and PDE4D are involved in the GPCR signal transduction cascade and have some different characters, this would explain the phenotypic similarity and difference in patients with GNAS, PRKAR1A, and PDE4D mutations.
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http://dx.doi.org/10.1210/jc.2012-1369DOI Listing
September 2012

Two cases of 22q11.2 deletion syndrome with anorectal anomalies and growth retardation.

J Pediatr Endocrinol Metab 2011 ;24(7-8):585-6

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi, Niigata 951-8510, Japan.

Clinical features associated with the deletion of 22q11.2 are highly variable. Most are diagnosed by cardinal congenital heart disease or hypoparathyroidism. In cases without major features, an early accurate diagnosis of 22q11.2 deletion syndrome is difficult. Congenital anorectal malformations (ARM), which can be detected soon after birth, have been rarely reported in 22q11.2 deletion syndrome. We report two cases of 22q11.2 deletion syndrome with ARM who showed growth retardation. ARM was detected in both patients without congenital heart disease or hypoparathyroidism at early infancy and they were followed by pediatric surgeons. Later, failure to thrive or short stature became evident, and they consulted with pediatric endocrinologists who subsequently confirmed the diagnosis of 22q11.2 deletion by fluorescent in situ hybridization analysis. The combination of ARM and growth retardation may lead to an early diagnosis of 22q11.2 deletion syndrome.
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http://dx.doi.org/10.1515/jpem.2011.030DOI Listing
October 2011
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