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Aims/Introduction We examined the impact of scanning frequency with flash glucose monitoring on glycemic control in children and adolescents with type 1 diabetes. Materials and Methods The study included 85 patients, aged 14.0 ± 0.5 years, with type 1 diabetes. The median time in the target glucose range (TIR) and glycosylated hemoglobin (HbA1c) values were 50.0 ± 1.4% and 7.5 ± 0.1%, respectively. Results The median scanning frequency using flash glucose monitoring was 12.0 ± 0.4 times/day. Scanning frequency showed a significant positive correlation with TIR and an inverse correlation with HbA1c. Scanning frequency was identified to be the determinant of TIR and HbA1c by using multivariate analysis. The participants whose scanning frequency was 12 times/day were categorized as the high‐frequency group (n = 45). Patients in the high‐frequency group were more likely to be treated with insulin pumps compared with those in the low‐frequency group; however, this difference was not significant (21.3 vs 5.3%, P = 0.073). The high‐frequency group showed significantly greater TIR than the low‐frequency group (57 ± 1.6 vs 42 ± 1.7%, P = 0.002). Furthermore, the high‐frequency group showed significantly lower HbA1c levels than the low‐frequency group (6.8 ± 0.1 vs 8.0 ± 0.1%, P 12 times/day might contribute to better glycemic outcomes in real‐world practice in children with type 1 diabetes., Patients with a higher scanning frequency had better glycemic control, with greater target glucose range and lower glycosylated hemoglobin level, compared with those with lower scanning frequency. Frequent scanning of >12 times per day using flash glucose monitoring might contribute to better glycemic outcomes in children with type 1 diabetes.

We investigated the effect of zinc supplementation on growth and serum IGF-1 levels in 10 prepubertal Japanese children with idiopathic short statures, who had serum zinc levels of less than 80 µg/dL. Subjects were started on oral zinc supplementation at a dose of 25 mg once daily. In three children, the doses were increased by 50 mg once daily during the study period of 12 mo. The serum zinc levels rose in all subjects and reached a normal range (beyond 80 µg/dL). However, it was found that zinc supplementation did not promote growth. Although the mean IGF-1 standard deviations significantly increased, the majority did not reach the normal range. There were no significant adverse events other than mild gastrointestinal symptoms in 4 out of 10 subjects during the supplementation period. The most likely reason why growth was not promoted is that the zinc supplementation dosage was not enough to stimulate IGF-1 generation and subsequent growth velocity.

BackgroundDiabetic ketoacidosis (DKA) is a common complication of type 1 diabetes mellitus (T1DM). Infants and children with new-onset T1DM may present with DKA, and the risk of cerebral edema is high in infantile DKA.What is new?Neurological deterioration during an episode of DKA is usually attributed to cerebral edema and cerebrovascular accidents. However, cerebral infarction is a very rare complication in infantile DKA.Case presentationWe describe a rare case of infantile cerebral infarction caused by severe DKA in a patient with new-onset T1DM.ConclusionsCerebral infarction is an important intracranial complication in infantile DKA. Careful observation and treatment for DKA during the first 24 h of therapy are necessary in infants with new-onset T1DM because the risk of cerebral infarction is highest during this timeframe.

We report our experience with needlescopic splenectomy (NS) for the surgical treatment of idiopathic thrombocytopenic purpura using a 3-mm needlescope with three ports. One patient was male and two were females, and their mean age was 58 years. The patient was placed in the right lateral decubitus position. The first 12-mm port was introduced through the lateral margin of the left rectus abdominis muscle, and the other two 3-mm ports were inserted in the left upper quadrant. NS was performed by a standard technique under the observation of 3.3-mm needlescope. The surgical procedure was successfully completed in all the patients. The mean duration of surgery, intra-operative bleeding volume and post-operative hospital stay were 176 min, 70 ml and 4.7 days, respectively. There were no particular peri-operative complications in spite of dense adhesions or simultaneous laparoscopic procedures. Our method is safe and feasible with low morbidity and without impairing cosmetic benefits.

A 73-year-old man with prior history of duodenal ulcer has been undergoing periodic upper gastrointestinal endoscopy since 1999. In 2017, a 25-mm submucosal tumor-like protrusion was detected in the lesser curvature of the upper stomach; histological examination of the lesion revealed gastric adenocarcinoma of fundic gland type. En bloc resection was achieved using endoscopic submucosal dissection. The patient was histopathologically diagnosed with gastric adenocarcinoma of fundic gland type arising from heterotopic gastric glands. Immunohistochemical staining was positive for MUC5AC, MUC6, pepsinogen I, and proton pump but negative for MUC2 and CD10. Moreover, the patient’s Ki-67 labeling index score was extremely low. The presence of MUC5AC indicated that the tumor differentiated to the foveolar epithelium and fundic glands. Gastric adenocarcinoma of fundic gland type that differentiates to several directions has a higher malignant potential than the disease that differentiates to chief cells. A retrospective review of the patient’s previous endoscopic examination revealed that the submucosal tumor-like protrusion existed since 2000; tumor size increased from 8 mm in 2000 to 25 mm in 2017. The present case is rare in that the carcinoma arose from heterotopic gastric glands. Moreover, the 19-year follow-up revealed that the tumor differentiated to the foveolar epithelium, considered as having high-grade malignancy.

Background We compared insulin resistance and glucose metabolism during growth hormone (GH) therapy between 43 short children born small-for-gestational age (SGA) and 42 children identifies as growth hormone deficiency (GHD). Methods The study compared fasting plasma glucose (FPG), fasting immunoreactive insulin (IRI) and homeostasis model assessment insulin resistance index (HOMA-IR) during 24-month GH therapy between the two groups. Results Mean FPG, fasting IRI, and HOMA-IR values at 3-month GH therapy were significantly higher than those before and at 12- and 24-month GH therapy in both groups. These markers were significantly higher in short children born SGA than GHD children until 12-month GH therapy but were not different at 24-month GH therapy in both groups. Conclusions The increased secretion of insulin observed in short children born SGA might be a compensatory mechanism for the prevention of hyperglycemia that can progress to diabetes mellitus. However, these metabolic markers gradually declined after 3 months of GH therapy and returned to baseline values at 24 months. These results suggest that short children born SGA have greater insulin resistance than GHD children at the early period of GH therapy, however, increased insulin resistance is improved over a long period. (194 words).

We assessed the significance of recommendations from the international consensus on continuous glucose monitoring (CGM)-derived metrics in Japanese children and adolescents with type 1 diabetes. Eighty-five patients (age, 13.5 ± 4.7 years) who wore the FreeStyle® Libre for a 28-day period were enrolled in this study. Seventy-three patients were treated with multiple daily injections of insulin and 12 with insulin pump therapy without using a sensor-augmented pump or a predictive low-glucose suspend-function pump. We evaluated the relationship between CGM-derived metrics: time in range (TIR: 70-180 mg/dL), time below range (TBR: 180 mg/dL), and laboratory-measured HbA1c and estimated HbA1c (eA1c) levels calculated from the mean glucose values. The TIR was 50.7 ± 12.2% (23-75%), TBR was 11.8 ± 5.8% (2-27%), and TAR was 37.5 ± 13.5% (9-69%). The TIR was highly correlated with HbA1c level, eA1c level, and TAR, but not with TBR. An HbA1c level of 7.0% corresponded to a TIR of 55.1% (95% CI: 53.7-56.5%), whereas a TIR of 70% corresponded to an HbA1c level of 6.1% (95% CI: 5.9-6.3%). The results of eA1c levels were similar to those observed for HbA1c levels. From these findings, we conclude that low rates of a recommended TIR of 70% may be due to less use of advanced technology and insufficient comprehensive diabetes care. Ethnic characteristics including lifestyle and eating customs may have contributed to the result. CGM-derived targets must be individualized based on ethnic characteristics, insulin treatment and diabetes care, and needs of individuals with diabetes.

BACKGROUND We assessed the association between scanning frequency of flash glucose monitoring (FGM) and continuous glucose monitoring (CGM)-derived glycemic markers in children and adolescents with type 1 diabetes. METHODS Subjects consisted of 85 children and adolescents with type 1 diabetes using FGM. We assessed the association between scanning frequencies of FGM- and CGM-derived metrics: Time in range (TIR) (70-180 mg/dL), time below range (TBR) ( 180 mg/dL), and other glycemic markers - laboratory-measured HbA1c and CGM-estimated glucose and HbA1c (eA1c) levels in the subjects. RESULTS The mean number of scans was 11.5 ± 3.5 (5-20) times per day, and scanning was most frequently conducted during a period of 18-24 h. Scanning frequency showed significant positive correlation with TIR (r = 0.719, P < 0.0001) and inverse correlation with time above range (r = -0.743, P < 0.0001), but did not correlate with TBR. There were also significant inverse correlations between scanning frequency and glucose, HbA1c, and eA1c levels (r = -0.765, -0.815, and -0.793, respectively, P < 0.0001). CONCLUSIONS Frequent glucose testing with FGM decreased hyperglycemia with increased TIR, but did not reduce TBR. Coping with a rapid fall of glucose and unexpected hypoglycemia with more advanced technology might contribute to a reduction in TBR.

Introduction: We evaluated the frequencies of various glycemic markers derived from continuous glucose monitoring in Japanese children and adolescents with type 1 diabetes and assessed the significance of hypoglycemia duration. Methods: We enrolled 85 children and adolescents (36 boys and 49 girls) with type 1 diabetes who used FreeStyle® Libre in the present study. Frequencies of blood glucose levels as time within target range (TIR; 70–180 mg/dL), time below target range (TBR; 180 mg/dL) were assessed during a 3-month study period. Furthermore, we evaluated the intraday frequencies of TBR and TBER. Results: The mean frequencies of TIR, TBR, and TAR were 52.7 ± 11.3%, 10.8 ± 5.4%, and 36.5 ± 10.8%, respectively, whereas the mean frequency of TBER was 1.1 ± 0.9% (0–3.0%); there was no clinical episode of severe hypoglycemia. The mean frequency of TBR was significantly greater in 0–6 h (16.9 ± 5.2%) than in 6–12 h (7.8 ± 2.9%) and 18–24 h (6.8 ± 4.8%; p < 0.01) time zones, respectively. Discussion/Conclusion: We found similar TIR and comparatively higher TBR frequencies, particularly during sleep, than those that were previously reported. Possible reasons for the higher frequency of TBR include differences in the quality of insulin treatment and diabetes care between the present study and the European studies. The utilization of advanced technologies, such as a predictive low-glucose suspend-function pump or closed-loop therapy, can reduce the frequency of TBR, with a consequent increase in TIR frequency and comprehensive improvement in glycemic control.

BACKGROUND We conducted an annual urine glucose screening program at schools, and diagnosed schoolchildren with diabetes at an early stage of the disease. We also identified some cases of renal glucosuria (RG), based on positive urine glucose with normal glucose tolerance. METHODS During 2000-2015, 3 309 631 schoolchildren participated in the screening program. The positive rate for glucosuria in the first test was approximately 0.1%, whereas on repeat urine test it was approximately 0.05%. In total 350 schoolchildren were positive for glucosuria on detailed examination. Oral glucose tolerance test (OGTT) was also used to evaluate glucose intolerance. RESULTS One hundred and two schoolchildren (29.7%) were diagnosed with diabetes, whereas RG was identified in 246 (70.3%) with normal glucose metabolism. In regard to the characteristics of RG, the percentage of boys was 50.3%, and the mean age at diagnosis was 11.2 ± 2.4 years. Twenty-eight children (11.4%) were overweight (body mass index standard deviation score [BMI-SDS] > +2.0 SD), whereas five (2.0%) were underweight (BMI-SDS < -2.0 SD). First-degree family history was suspected in 176 cases (71.5%). All RG subjects had normal glucose tolerance in the absence of insulin resistance and decreased insulin secretion (homeostasis model assessment for β-cell function, 78.8 ± 59.5%) on OGTT. CONCLUSIONS RG is not rare in Japanese schoolchildren with glucosuria. This disorder seems to have a strong genetic background, and to involve less growth retardation and weight loss than expected despite continuous excretion of glucose in urine.

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 performed 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 nonobese 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. This article is protected by copyright. All rights reserved.

Background The prognosis of non-shockable out-of-hospital cardiac arrest is worse than that of shockable out-of-hospital cardiac arrest. We investigated the associations between the etiology and prognosis of non-shockable out-of-hospital cardiac arrest patients who experienced the return of spontaneous circulation after arriving at hospital. Methods and Results All subjects were extracted from the SOS-KANTO 2012 study population. The subjects were 3,031 adults: (i) who had suffered out-of-hospital cardiac arrest, (ii) for whom there were no pre-hospital data on ventricular fibrillation/pulseless ventricular tachycardia until arrival at hospital, (iii) who experienced the return of spontaneous circulation after arriving at hospital. We compared the patients' prognosis after 1 and 3 months between various etiological and presumed cardiac factors. The proportion of the favorable brain function patients that developed pulmonary embolism or incidental hypothermia was significantly higher than that of the patients with presumed cardiac factors (1 month, P

We evaluated the efficacy and safety of switching to insulin degludec (IDeg) from insulin glargine (IGlar) as basal-bolus therapy in young people with type 1 diabetes. The subjects were 36 patients, 21.3±1.0 years of age, with type 1 diabetes. IGlar had previously been injected once daily in 25 patients and twice daily in 11. They were then switched from IGlar to once-daily injection of IDeg. Both fasting plasma glucose (FPG) and HbA1c levels decreased significantly from 134±3.9 mg/dL and 7.9±0.2% at baseline to 116±2.2 mg/dL and 7.4±0.2% at 12 months after starting IDeg (P

Methylation defects in the imprinting locus at chromosome 6q24 result in transient neonatal diabetes and small-for-gestational age (SGA) births (1). These phenotypes are primarily ascribed to the overexpression of PLAGL1, a paternally expressed gene on 6q24 that regulates cell cycle and apoptosis (2). Paternal uniparental disomy involving 6q24, as well as copy-number gains of paternal PLAGL1 alleles and epimutations in maternal alleles, have been identified as the causes of hypomethylation at the differentially methylated region (DMR) of PLAGL1 (3, 4). Recently, Yorifuji et al. reported the identification of 6q24 uniparental disomy in three patients with childhood-onset non-autoimmune diabetes mellitus (5). The three patients were identified through methylation-specific PCR analysis of the PLAGL1 DMR of 113 patients clinically suspected of having maturity-onset diabetes of the young (MODY). These results expanded the phenotypic consequences of 6q24 methylation defects to include MODY-like manifestations without a history of neonatal diabetes. However, the frequency of 6q24 methylation defects among patients with childhood-onset non-autoimmune diabetes remained unknown.

Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death). Methods: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death). RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.

Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by a remarkably abrupt onset. In Japan, FT1DM accounts for approximately 20% of acute-onset adult type 1 diabetes mellitus cases; however, reports of pediatric-onset FT1DM are rare. We aimed to determine the frequency and clinical characteristics of FT1DM in Japanese children and adolescents by conducting a 2-phase questionnaire survey among the members of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT) regarding their clinical experience with FT1DM. Responses were obtained from 54 of the 79 participating hospitals (68.4%). Of these, 8 hospitals managed a total of 15 pediatric patients with FT1DM (4 patients in each of 2 hospitals, 2 patients in 1 hospital, and 1 patient in each of 5 hospitals). The distribution of patient age was biphasic, with peaks in children younger than 5 years and older than 8 years of age. The clinical characteristics of FT1DM in this population (such as the duration from onset of symptoms to diagnosis, severity of symptoms, preceding flu-like episodes, and abnormal laboratory data) did not differ from those of patients with adult-onset FT1DM. The frequency of pediatric-onset FT1DM is low compared with that of adult-onset FT1DM. The genetic background and susceptibility patterns of pediatric patients with FT1DM may differ from those typical of adults with FT1DM, but both age groups share similar clinical characteristics.

OBJECTIVE To analyze changes in the annual incidence of school students with type 2 diabetes detected by urine glucose screening at schools in the Tokyo Metropolitan Area during 1975-2015. METHODS Trend in temporal changes in the annual incidence rate were analyzed using a joinpoint regression model and the joinpoints. Annual percent change (APC) was calculated for each segmented line regression. Average annual percent change (AAPC) was also calculated for the whole period analyzed. RESULTS In total, 301 students, including 64 primary school students and 237 junior high school students, were diagnosed with type 2 diabetes. The overall incidence of type 2 diabetes (per 100 000/year) during the entire study period was 2.58 in all students, 0.80 in primary school students, and 6.41 in junior high school students. AAPC during the entire study period was estimated at -1.5 (not significant), and the incidence significantly increased during 1975-1982 (APC = 17.49, P < 0.05), but tended to decrease during 1982-2015 (APC = -1.01). In primary school students, the incidence significantly increased during1975-2010 (APC = 3.30, P < 0.05), and tended to decrease during 2010-2015 (APC = -29.61). In junior high school students, the incidence did not significantly change during the entire study period (APC = 0.06). CONCLUSIONS We found increasing trend in the overall incidence of school students with type 2 diabetes during 1975-1982, but a decreased tendency in recent years. This could be due to changes observed during the same time period in the primary school students. Lifestyle changes might contribute to improved incidence of childhood type 2 diabetes.

AIM To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation.

Background Neurological manifestations caused by hypoglycemia range from reversible focal deficits and transient encephalopathy to irreversible coma or death. Recently, high signal intensity lesions in the splenium of the corpus callosum on diffusion-weighted magnetic resonance imaging were reported in adults experiencing hypoglycemia. However, patients presenting with agraphia are rare. Subject and methods We examined a 17-year-old left-handed female patient with type 1 diabetes who exhibited transient left agraphia with a reversible splenium lesion of the corpus callosum on diffusion-weighted imaging caused by hypoglycemia, which was improved with blood glucose management alone. Conclusion This rare case indicates that agraphia, a sign of callosal disconnection syndrome, can result from a reversible splenial lesion of the corpus callosum caused by hypoglycemia.

The human brain has a huge number of neurons connected to each other, forming a multitude of networks; notably, such connectivity typically exhibits a small-world structure. However, the brains of persons with autism spectrum disorder (ASD) reportedly have what has been termed as "local over-connectivity." The neural activity of the ASD brain is also atypical; resting-state EEG signals in the ASD brain have lower complexity and enhanced power at low and high frequency oscillations. In this study, we used a small-world network model based on the model proposed by Watts and Strogatz to investigate the relationship between the degree of local over-connectivity and neural activity. We controlled the degree of local over-connectivity in the model according to the parameters laid out by Watts and Strogatz. We assessed connectivity using graph-theoretical approaches, and analyzed the complexity and frequency spectrum of the activity. We found that an ASD-like network with local over-connectivity (i.e., a high clustering coefficient and a high degree of centrality) would have excessively high power in the high frequency band, and less complexity than that of a network without local over-connectivity. This result supports the idea that local over-connectivity could underlie the characteristic brain electrical activity in persons with ASD.

The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining substantial β-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained.

We investigated the efficacy and safety of switching to insulin glulisine (GLU) from other rapid-acting insulin analogs (Ra) in children with type 1 diabetes treated with multiple daily injections of insulin or continuous subcutaneous insulin infusion. A total of 26 children with type 1 diabetes were included. Ra in all of these patients was changed to GLU, and they were observed for a 6-month period after having previously finished treatment with other Ra. The mean glycated hemoglobin value decreased from 7.6 ± 1.0 to 7.4 ± 0.9% (P = 0.0034), and mean plasma glucose values after breakfast and supper also improved from 183 ± 50 to 153 ± 32 mg/dL (P = 0.0035), and from 203 ± 29 to 164 ± 23 mg/dL (P

Multiple mutations in SOX2 have been identified in patients with ocular anomalies and/or pituitary dysfunction. Here, we identified SOX2 abnormalities in nine patients. The molecular defects included one missense, one nonsense and four frameshift mutations, and three submicroscopic deletions involving SOX2. Three of the six mutations and all deletions were hitherto unreported. The breakpoints determined in one deletion were located within Alu repeats and accompanied by an overlap of 11 bp. Three of the six mutations encoded SOX2 proteins that lacked in vitro transactivation activity for the HESX1 promoter, whereas the remaining three generated proteins with ∼15-∼20% of transactivation activity. All cases manifested ocular anomalies of various severities, together with several complications including arachnoid cyst and hamartoma. There was no apparent correlation between the residual activity and clinical severity. The results indicate that molecular defects in SOX2 are highly variable and include Alu repeat-mediated genomic rearrangements. Our data provide further evidence for wide phenotypic variation of SOX2 abnormalities and the lack of genotype-phenotype correlation in patients carrying SOX2 lesions.

Increased intratumoral expression of aromatase, the key enzyme for estrogen biosynthesis, is predicted to be of critical importance in the development of breast cancer. Recently, several germline rearrangements at 15q21 have been shown to cause overexpression of the aromatase gene CYP19A1 and resulting aromatase excess syndrome. To determine whether submicroscopic genomic rearrangements at 15q21 are involved in aromatase overexpression in breast cancer tissues, we investigated copy-number alterations in genomic DNA obtained from 44 tumor samples. Comparative genomic hybridization analysis identified no deletion or duplication at 15q21 in the 44 samples. These results, in conjunction with previous data, indicate that aromatase overexpression in breast cancer tissues is likely to result from a promoter switch of CYP19A1 and/or accumulation of CYP19A1-expressing cells, rather than from cryptic transactivation of CYP19A1 because of genomic rearrangements at 15q21.

We treated 80 obese and 28 nonobese children diagnosed as having type 2 diabetes mellitus (T2DM). Among these patients, 26 obese and 23 nonobese children were assigned to pharmacologic therapies during the course of diabetes. Pharmacologic therapies were started if the HbA1c (NGSP) value exceeded 7.0% despite dietary and exercise management. For the 26 obese patients, metformin alone or in combination with an additional medication was frequently used. Only 2 patients independently received sulfonylureas (SUs) in the form of glimepiride. In addition, 9 patients were treated with basal insulin supported with oral hypoglycemic drugs (OHDs) or biphasic premix insulin. On the other hand, the 23 nonobese patients were frequently treated with insulin alone or in combination with an additional medication followed by SUs. The nonobese patients tended to require pharmacologic therapies, in particular insulin, at an earlier stage of diabetes as compared with the obese patients. New antidiabetic drugs, DPP-4 inhibitors and GLP-1 receptor agonists, seemed to exert positive effects on glycemic control without occurrence of hypoglycemic episodes in some patients regardless of the type of diabetes. These results suggest that pharmacologic treatment strategies in childhood T2DM should be tailored to individual patient characteristics.

This study implemented a randomized crossover design to evaluate the efficacy and safety of switching from insulin glargine (IGlar) to insulin degludec (IDeg) in 18 children (11 males, 7 females; age 11.0 ± 0.5 years) with type 1 diabetes. All subjects had previously used IGlar once daily at bedtime. We compared fasting plasma glucose (FPG) and HbA1c levels, frequencies of overall and nocturnal (2200 h - 0659 h) hypoglycemia, and basal insulin dose at the baseline with those measured during a 24-week period during which IGlar or IDeg was administered in combination with pre-meal rapid acting insulin analogues. IDeg was initially given at the same dose as IGlar but was subsequently titrated to achieve FPG levels of 90-140 mg/dL. There were no significant changes in FPG and HbA1c levels from the baseline during the 24-week study period with IGlar or IDeg. The daily basal insulin dose did not significantly differ with IGlar or IDeg. Although the frequencies of overall hypoglycemia were similar, nocturnal hypoglycemia significantly decreased at 12 and 24 weeks from the baseline with IDeg use (2 ± 0.4 vs. 0 ± 0.3, 0 ± 0.5 episodes/month, both P

We evaluated the efficacy and safety of insulin glulisine (GLU) used for continuous s.c. insulin infusion (CSII) in 20 children with type 1 diabetes after 1 year of GLU treatment. There were no significant differences in mean plasma glucose before breakfast and before dinner between before and after using GLU, but the levels after breakfast and after dinner significantly improved, from 192.5 ± 31.7 to 162.0 ± 27.3 mg/dL for breakfast, and from 191.1 ± 33.3 to 161.1 ± 24.5 mg/dL for dinner (P

Background The American Heart Association and European Resuscitation Council guidelines for cardiopulmonary resuscitation present rules for termination of resuscitation (TOR) in cases of out-of-hospital cardiac arrest (OHCA). In Japan, only doctors are legally allowed TOR in OHCA cases. Objective This study aimed to develop a new TOR rule that suits the actual situations of the Japanese emergency medical services system. Methods Five different combinations of the TOR rule criteria were compared regarding specificity and positive predictive value (PPV) for 1-month survival with unfavorable neurologic outcomes. The criteria were unwitnessed by emergency medical service personnel, unwitnessed by bystanders, initial unshockable rhythm in the field, initial asystole in the field, no shock delivered, no prehospital return of spontaneous circulation, unshockable rhythm at hospital arrival, and asystole at hospital arrival. Results A total of 13,291 cases were included. The following combination provided the highest specificity and PPV for predicting 1-month unfavorable neurologic outcomes and death: unwitnessed by bystanders, initial asystole in the field, and asystole at hospital arrival. The specificity and PPV for the combination of the three criteria for predicting 1-month unfavorable neurologic outcomes were 0.992 and 0.999, and for predicting death at 1 month after OHCA were 0.986 and 0.998, respectively. Conclusions OHCA patients fulfilling the criteria unwitnessed by bystanders and asystole in the field and at hospital arrival had universally poor outcomes. Termination of resuscitation after hospital arrival for these patients may decrease unwarranted treatments.

Aim To compare the injection frequencies employed and the basal-to-total insulin dose ratios obtained when glargine (G) and detemir (D) are used in children with type 1 diabetes mellitus (T1DM) treated by basal–bolus therapy (BBT).

We examined the correlation between plasma glucose (PG) and hemoglobin A1c (HbA1c) to evaluate the usefulness and limitations of applying the new diagnostic criteria for diabetes to Japanese pediatric patients. Data were collected from 298 school children who took an oral glucose tolerance test (OGTT) at a school-based urinary glucose screening program in the Tokyo Metropolitan Area between 1988 and 2009. Mean (SD) age of the children was 11.9 (2.5) years. Male-to-female ratio was 1:1.1. Children were diagnosed with renal glucosuria (n=146), diabetes mellitus (n=133), or the Japan Diabetes Society (JDS) "borderline type" (n=19). Median (range) values of fasting plasma glucose (FPG), 2-h plasma glucose in an OGTT (OGTT-2h), and HbA1c were 101 (76-378) mg/dL, 146.5 (57-563) mg/dL, and 6.05 (4.7-14.1) %. The correlation between PG and HbA1c was analyzed using least squares regression, and HbA1c was found to highly correlate with PG. From estimated regression equations, mean values of FPG and OGTT-2h corresponding to an HbA1c of 6.5% were calculated to be 111.4 mg/dL and 170.4 mg/dL. The mean values of HbA1c corresponding to an FPG of 126 mg/dL and OGTT-2h of 200 mg/dL were calculated to be 7.5% and 7.8%. The mean values of PG corresponding to HbA1c of 6.5% were lower than found in adults as analyzed by JDS. The mean values of HbA1c corresponding to diabetic type PG were higher than found in adults.

Objective: The aim of this study was to investigate the association between plasma glucose (PG), HbA1c and plasma glucagons levels in children with type 1 diabetes to determine the influence of plasma glucagon on their glycemic control. Methods: The study was conducted in 60 Japanese children, aged 13.3 ± 4.6 years, with type 1 diabetes for at least 3 years of diabetes. Most of the subjects had absent pancreatic β-cell function. We compared the glucagon levels among patient groups stratified according to the 2-hour postprandial levels (

We incidentally encountered an anomaly of the cervical vertebrae during orthodontic examination of an 8-year-old boy with cleft lip and palate. Klippel-Feil syndrome was diagnosed by the orthopedic specialist to whom he had been referred for detailed examination. This case report shows the results of axial multislice-helical computed tomography with three-dimensional reconstructions of the cervical vertebrae. Furthermore, we evaluated the frequency of congenital anomalies on lateral cephalogram in patients with cleft lip and palate or cleft palate and non-cleft controls from among all patients in our orthodontic clinic.

目的．肺癌術後患者にみられた肺抗酸菌症例についての検討を行った．方法．1996～2007年に当院で経験した，肺癌術後の肺結核症（pulmonary tuberculosis：PTB）および肺非結核性抗酸菌症（pulmonary non-tuberculous mycobacteriosis：PNTM）の24例を対象に，病歴や経過，検査所見，X線所見などを後ろ向きに解析した．結果．肺抗酸菌症の内訳はPTB 14例，PNTM 10例（肺M. avium complex症9例，肺M. kansasii症1例）で，男性（17例），高齢者（15例），術後5年以内（15例），術側肺（18例）に多くみられた．PTB例では肺癌再発（7例），結核治療歴（6例），他臓器癌の既往，performance status（PS）2以上（各5例）などを認め，全身状態の悪化に基づく内因性再燃が示唆された．PNTMでは全身的要因をほとんど認めなかったが，術側肺の発症が9例を占め，手術に伴う肺局所環境の悪化に伴う感染，増悪が示唆された．治療について，PTBでは診断の遅れがなければ治療経過，予後は良好であったが，PNTMでは治療にも関わらず，病変が進展し，肺アスペルギルス症などを併発し，死亡する症例もみられた．結論．肺癌術後患者の管理においては全身状態やX線所見に注意を払い，肺抗酸菌症を的確に診断することが重要である．

Idiopathic osteosclerosis (IO) is a localized, well-defined, intrabony radiopaque lesion within cancellous bone. The causes of IO are still unknown and most lesions are nonexpansile and asymptomatic, so they are often detected incidentally on radiographic examination for other purposes. In the case of jaw lesions, IO is considered to be of no clinical significance and usually requires no treatment. This paper describes two clinical cases about the long-term treatments and observations of mandibular IO in adolescents. The lesions were associated with abnormal tooth root formation and tooth malposition. In these cases, the orthodontic treatments finished successfully without any complication despite the lesions. IO in the jaw needs regular follow-up to ensure normal orofacial development during adolescence.

We examined the association between sex, age, insulin regimens and glycemic control in 133 Japanese children and adolescents, 42 males and 61 females aged 16.8 ± 7.0 yr, with type 1 diabetes mellitus (T1DM). The patients were divided into 5 age groups and were also classified according to the insulin regimen. The annual median HbA1c level in males (7.3 ± 0.2%) was similar to that in females (7.2 ± 0.2%). In regard to the age of the patients, the median HbA1c levels in patients aged 15–19 yr (7.9 ± 0.4%) was significantly higher than those aged 5–9 yr (7.2 ± 0.1%) and those aged 20≤ yr (6.6 ± 0.4%, p

We investigated the percentage of total basal insulin dose to total daily insulin dose (%TBD) among Japanese youth of different ages with type 1 diabetes. The study enrolled 69 patients with type 1 diabetes who were treated with multiple daily injections of insulin. The participants were divided into the following age groups: group A, 0 to

Objective: To examine the prevalence of components of the metabolic syndrome (MS) other than hyperglycemia at diagnosis in schoolchildren with type 2 diabetes mellitus (T2DM). Design: The study involved 112 Japanese schoolchildren, 45 males and 67 females aged 12.9 ± 1.5 yr, who were diagnosed as having T2DM. The body weight, blood pressure and fasting serum triglyceride (TG), and high-density lipoprotein cholesterol cholesterol (HDL-C) levels were also measured at diagnosis. The criteria adopted for the diagnosis of MS were as follows; i.e., TG ≥150 mg/dL, HDL-C

In recent years, continuous subcutaneous insulin infusion (CSII) using a rapid-acting insulin analog (Ra) has increasingly been utilized for young children with type 1 diabetes mellitus (T1DM). Blood glucose levels are highly variable, and achieving adequate diabetes control is quite difficult for this age group with T1DM. Studies have demonstrated CSII using Ra to be useful for improving glycemic control and making insulin delivery more convenient (1,2,3,4,5,6). This treatment option seems more suited than any other insulin regimen for young children with T1DM. Recent insulin pumps used for CSII allow programming of various basal insulin rates at different times of day to accommodate changes in the required insulin level. Nevertheless, the children themselves or their parents need to push a button to administer insulin boluses before each meal. Accordingly, administration of the boluses is very difficult for children attending a kindergarten or day nursery because neither kindergarten teachers nor nurses can give the boluses in place of a child’s parents. Therefore, we introduced an increment in the insulin basal rate during a one-hour mealtime in place of pre-meal boluses in 4 preschoolers with T1DM using CSII.

We examined pathogenic characteristics in Japanese children with type 1 diabetes presenting before 5 years of age. The subjects were 23 Japanese children, 9 males and 14 females, 1.1-4.8 yr of age at diagnosis. The majority had severe metabolic decompensation accompanied by complete absence of β-cell function at diagnosis. We found a high frequency of preceding viral illness (41.7%) among them. The prevalence of antibodies to GAD and IA-2 at diagnosis in young children were significantly lower than those in older cases diagnosed after 5 yr of age (31.6% vs. 86.3%, 47.1% vs. 82.5%, respectively). These findings suggest that non-autoimmune mechanisms or age-related differences in autoimmunity could be involved in the pathogenesis of diabetes in young children. In regard to diabetes-related HLA-DRB1 and DQB1 alleles, all subjects had high-risk genotypes in both alleles. On the other hand, none of the patients had any of the protective genotypes in either allele. In regard to haplotypes, the frequencies of DRB1*0405-DQB1*0401 and DRB1*0901/ DQB1*0303 were 60.9% and 52.2%, respectively, and both these haplotypes are associated with strong susceptibility to type 1 diabetes. Patients with early-childhood onset may have diabetes-related autoimmunity and genetic backgrounds different from those of patients diagnosed at a later age.

We investigated the incidence of the slowly progressive form of type 1 diabetes (SPT1D) detected by the urine glucose-screening tests at schools in the Tokyo Metropolitan Area from 1974 to 2004. During this study period, a total of 9,242,259 school students underwent the screening program. Of them, 54 children, 19 males and 35 females, aged 11.6+/-2.4 years, were diagnosed to have SPT1D by this method. The overall incidence of SPT1D was 0.57/100,000/year, which was about one fifth of that of type 2 diabetes detected by the same method. The incidence was significantly higher in junior high school students than in primary school students (0.32 vs. 1.13/100,000/year, p

Introduction Urethral caruncles are the most frequent benign tumors of the female urethra. Most of them are found in post-menopausal women, and they are rare in childhood. Only a few pediatric cases have been published in the literature. In this report, we present an unusual case of a pediatric patient with a urethral caruncle, along with a review of the literature. Case presentation A 9-year-old Mongolian girl was referred to our hospital with a 2-week history of frequent adherence of a small amount of blood to her underwear. We found a sessile smooth margin, a clear boundary and an elastic, soft red tumor over the entire circumference of the urethral meatus. At the beginning, because of the child’s age, urethral prolapse was suspected. There was no response after 3 weeks of conservative treatment with steroid ointment. With the patient under general anesthesia, a partial tumor resection was performed for the purpose of histological examination. The tumor excision was limited to about 1/2 laps of the urethral meatus to prevent the development of urethral stricture. On the basis of clinical and histopathological examinations, a diagnosis of a urethral caruncle was made. Post-operatively, steroid ointment application to residual masses was continued, and these disappeared about 6 months later. Our patient was free of recurrence and had had no complications after 3 years of follow-up. Conclusions Urethral caruncles are rare in children, and the possibility of malignancy is slight during this period. Biopsy of the mass is not required for diagnosis. It should be indicated only if the mass has other characteristics that raise suspicion of malignancy. In previously reported cases, all of the tumor was removed. However, the trigger of the caruncle in childhood is chronic inflammation. Conservative therapy with steroid ointment should be the core treatment. However, it may be necessary to proceed to treatment because caruncles take a long time to heal. The case that we describe in this report will serve as an example for similar cases in the future.

Aims Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24-related transient neonatal diabetes). 6q24-Related transient neonatal diabetes is characterized by the patient being small-for-gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early-onset, non-autoimmune diabetes without transient neonatal diabetes. Methods The 6q24 imprinted locus was screened for abnormalities in 113 Japanese patients with early-onset, non-obese, non-autoimmune diabetes mellitus who tested negative for mutations in the common maturation-onset diabetes of the young (MODY) genes and without a history of transient neonatal diabetes. Positive patients were further analysed by combined loss of heterozygosity / comparative genomic hybridization analysis and by microsatellite analysis. Detailed clinical data were collected through the medical records of the treating hospitals. Results Three patients with paternal uniparental isodisomy of chromosome 6q24 were identified. None presented with hyperglycaemia in the neonatal period. Characteristically, these patients were born small-for-gestational age, representing 27.2% of the 11 patients whose birth weight standard deviation score (SDS) for gestational age was below −2.0. Conclusions Abnormalities in the imprinted locus on chromosome 6q24 do not necessarily cause transient neonatal diabetes. Non-penetrant 6q24-related diabetes could be an underestimated cause of early-onset, non-autoimmune diabetes in patients who are not obese and born small-for-gestational age.

A 37-year-old female suffered from facial asymmetry and malocclusion. She had undergone orthognathic surgery (sagittal split ramus osteotomy and genioplasty) at the age of 21 because of facial asymmetry.Observation of the postoperative course was interrupted. Afterwards, facial asymmetry and the malocclusion were conspicuous, and the patient revisited our department for consultation on March 26, 2003. During the observation period (from March to December), growth of the left condylar process and malocclusion were recognized. Condylectomy was performed by an intraoral ap-proach. The resected specimen showed a thin fibrocartilage layer and dominantly consisted of mature lamellar bone tissue fragments with trabecular architecture.According to the clinical and histopathological features, the diagnosis was condylar hyperplasia.Exercise of Mouth-opening exercises by using a mouth gag were performed after the operation, leading to good jaw function.

To elucidate the sequence of early events in the increase in capillarity caused by reperfusion following transient coronary occlusion, the time course of expression of proliferating cell nuclear antigen (PCNA) was studied immunohistochemically in rat hearts subjected to different periods of reperfusion after a 3 minute occlusion. Twenty-one male Wistar rats were killed after different periods of reperfusion following occlusion of the coronary artery for 3 minutes. The left ventricles were removed and paired serial sections were treated immunohistochemically for PCNA or stained to show the enzymes characteristic of the arteriolar, intermediate and venular portions of the capillary bed. The time course of PCNA expression, and its distribution in relation to the different portions, was examined. An increase in PCNA-expressing nuclei was found at 24 hours after the start of reperfusion; numbers reached a maximum between 72 and 96 hours, and at 168 hours had decreased again. The majority of PCNA-expressing elements were localized to the dipeptidylpeptidase IV-reactive (i.e. venular) capillary portions, with some in the intermediate and alkaline phosphatase-reactive (i.e. arteriolar) portions. The distribution of PCNA in the early reperfusion period suggests that angiogenesis after transient ischemia occurs mainly from the venular side of the capillary bed, with some contribution from intermediate and arteriolar capillary portions.