Useful manifestations to detect adenovirus in children with upper respiratory infections: A retrospective study.

OBJECTIVE: Approximately 1 million adenovirus immunochromatography (IC) kits are annually used in Japan. However, no practical strategies have been developed regarding their use for detecting adenovirus. The present study aims to verify the usefulness of clinical manifestations in making decisions regarding the use of adenovirus IC kits for children with upper respiratory infections (URI). METHODS: The medical records of 825 pediatric cases tested by IC kits for adenovirus were extracted from clinical laboratory department database over a 3-year period at our hospital. Among them, 585 patients were suspected adenovirus URI, and their clinical manifestations were reviewed. After data cleaning, 10 types of clinical manifestations were statistically analyzed between adenovirus IC kit-positive and -negative groups. Multivariate analysis was performed to select significant clinical manifestations using adenovirus IC kit positivity as the objective variable. RESULTS: Among 585 pediatric patients, the cases of 420 patients, with suitable data for whom no other pathogen was detected, were reviewed. Adenovirus was detected in 86 cases. Multivariate analysis identified a significant difference for three clinical manifestations: (1) fever ≥ 39.0°C, (2) rhinorrhea, and (3) tonsillar exudate. The negativity rate for the IC kit was 90% when none of the three manifestations was observed. CONCLUSIONS: The results suggested that IC kits for adenovirus tend to give negative results in cases that lack all the three above mentioned clinical manifestations.

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

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.

KLF11 variant in a family clinically diagnosed with early childhood-onset type 1B diabetes.

KLF11 is the causative gene for maturity-onset diabetes of the young 7 (MODY7). KLF11 regulates insulin gene expression through binding to the GC box in the promoter. To date, only two KLF11 mutations have been identified in three families with early-onset type 2 diabetes. Here, we report a novel KLF11 variant associated with early childhood-onset type 1B diabetes. The proband and his younger sister exhibited hyperglycemia at age 1 year, and their mother developed diabetes at age 4 years. These three individuals required insulin injection from the initial phase of the disease. Being negative for islet cell autoantibodies, they were diagnosed with type 1B diabetes. Mutation screening for 30 diabetes-associated genes identified a heterozygous KLF11 variant (p.His418Gln) in the proband and his sister. The variant was also detected in the affected mother, as well as in the allegedly unaffected maternal grandmother. In silico analyses indicated that this variant involves a highly conserved histidine residue in the first C2 H2 zinc finger domain which ligates a zinc ion. In vitro analyses showed that expression levels and intracellular localization of His418Gln-KLF11 were comparable to those of wildtype (WT)-KLF11. Luciferase assays demonstrated that while WT-KLF11 suppressed the activity of a 6 × GC box-containing reporter, His418Gln-KLF11 lacked the suppressive effect. Notably, His418Gln-KLF11 canceled the suppressive effect of co-transfected WT-KLF11. Such a dominant-negative effect was absent in the previously reported Ala347Ser-KLF11 variant. These results indicate that specific variants of KLF11 (MODY7) with a dominant-negative effect underlie early childhood-onset type 1B diabetes with incomplete penetrance. This study documents a novel monogenic mutation associated with diabetes in children.

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

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.

Fulminant type 1 diabetes mellitus in Japanese children and adolescents: multi-institutional joint research of the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes.

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.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. RESULTS: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. CONCLUSION: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

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

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.

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

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]).

The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients.

We report three pediatric heart transplant (HTx) patients whose respiratory symptoms were successfully controlled with long-term, low-dose macrolide administration (clarithromycin: CAM; approximately 2.5 mg/kg bid). The first case was an 18-year-old boy who underwent HTx at the age of three for dilated cardiomyopathy (DCM). Beginning at age 5, he had repeated fevers and respiratory symptoms. He was diagnosed with chronic sinusitis at age 11 and sinobronchial syndrome with mild bronchiectasis at age 14. Administration of long-term, low-dose CAM and otolaryngeal topical therapy led to significant improvement of his symptoms. The second case was a 7-year-old boy who underwent HTx for DCM at age one. Starting at age 4, he had repeated fevers and cough due to atelectasis and pneumonia. As antibiotics and respiratory physical therapy proved ineffective, he received long-term, low-dose CAM, resulting in successful control of his atelectasis and recurrent pneumonia. The third case was a 13-year-old boy who underwent HTx at age 6 for DCM. He had chronic sinusitis starting at age 7, and was diagnosed with obstructive sleep apnea syndrome at age 10. Adenotonsillectomy and continuous positive airway pressure support therapy were indicated. At age 13, long-term, lowdose CAM administration was started following mycoplasma infection. In all three cases, the levels of calcineurin inhibitors (cyclosporine and tacrolimus) and everolimus were kept in the optimal range with careful drug monitoring. Longterm, low-dose macrolide administration effectively prevents and treats respiratory complications in pediatric HTx patients as long as attention is paid to potential drug interactions.

Identification of INS and KCNJ11 gene mutations in type 1B diabetes in Japanese children with onset of diabetes before 5 years of age.

BACKGROUND: The etiology of type 1 diabetes (T1D) is heterogeneous and is according to presence or absence of pancreatic autoantibodies divided into two subtypes: type 1A (autoimmune-mediated) and type 1B (non-autoimmune-mediated). Although several genes have been linked to type 1A diabetes, the genetic cause of type 1B diabetes in Japanese individuals is far from understood. OBJECTIVE: The aim of this study was to test for monogenic forms of diabetes in auto antibody-negative Japanese children with T1D. METHODS: Thirty four (19 males and 15 female) unrelated Japanese children with glutamate decarboxylase (GAD) 65 antibodies and/or IA-2A-negative T1D and diabetes diagnosed at < 5 yr of age were recruited from 17 unrelated hospitals participating in the Japanese Study Group of Insulin Therapy for children and adolescent diabetes (JSGIT). We screened the INS gene and the KCNJ11 gene which encode the ATP-sensitive potassium cannel by direct sequencing in 34 Japanese children with T1D. RESULTS: We identified three novel (C31Y, C96R, and C109F) mutations and one previously reported mutation (R89C) in the INS gene in five children, in addition to one mutation in the KCNJ11 gene (H46R) in one child. These mutations are most likely pathogenic and therefore the cause of diabetes in carriers. CONCLUSION: Our results suggest that monogenic forms of diabetes, particularly INS gene mutations, can be detected in Japanese patients classified with type 1B. Mutation screening, at least of the INS gene, is recommended for Japanese patients diagnosed as autoantibody negative at <5 yr of age.

DEND syndrome due to V59A mutation in KCNJ11 gene: unresponsive to sulfonylureas.

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (NDM), and successful glycemic control has been obtained in several cases with oral sulfonylureas (SU). We have verified a lack of clinical response for both glycemic control and neurological features in an infant with permanent neonatal diabetes mellitus and DEND syndrome due to a V59A mutation in the KCNJ11 gene. Thus, our case reinforces that most cases with DEND syndrome are insensitive to SU.

Characterization of AQP-2 gene mutation (R254Q) in a family with dominant nephrogenic DI.

We identified the AQP-2 gene mutation (R254Q) in a family with dominant NDI. The patient studied here has NDI with partial response to the anti-diuretic effect of AVP and dDAVP. Hereditary NDI seems to have the uniform clinical manifestations, but this might only reflect the information on screened patients with clear clinical presentations. It may be that a milder form of NDI has been overlooked due to a lack of genetic identification. Gene mutation analysis should be considered even in patients with mild NDI symptoms. Fortunately, both V2R and AQP2 genes are small and can be easily analyzed.

Efficacy of incremental loads of cow's milk as a treatment for lactose malabsorption in Japan.

BACKGROUND: Lactose intolerance (LI) is commonly seen in East Asian countries. Several studies showed that lactose or milk loading has been used as a treatment for lactose malabsorption (LM) in Western countries, but there have been no reports regarding this type of treatment in Japan. As lactose or milk loading requires ingestion of large amounts of lactose within a short period, this is considered to be too harsh for Japanese people because of their less habitual milk consumption (175 mL per day in average) than Western people. In this study, we demonstrated lactose tolerance acquisition in a suitable way for Japanese. AIM: To examine the efficacy of lactose (cow's milk) loading treatment in patients with LM. METHODS: Individuals with abdominal symptoms induced by milk or dairy products (LI symptoms) were identified with a questionnaire. A 20 g lactose hydrogen breath test (LHBT) was carried out to confirm LM diagnosis and to evaluate co-existence of small intestinal bacterial overgrowth (SIBO). Respondents diagnosed with LM were selected as study subjects and were treated with incremental loads of cow's milk, starting from 30 mL and increasing up to 200 mL at 4-7 d intervals. After the treatment, changes in symptoms and LM diagnostic value of 20 g LHBT were investigated. Stool samples pre- and post-treatment were examined for changes in intestinal microbiota using 16S rRNA sequencing. Informed consent was obtained prior to each stage of the study. RESULTS: In 46 subjects with LI symptoms (10-68 years old, mean age 34 years old) identified with the questionnaire, 35 (76.1%) were diagnosed with LM by 20 g LHBT, and 6 had co-existing SIBO. The treatment with incremental cow's milk was carried out in 32 subjects diagnosed with LM (14-68 years old, median age 38.5 years old). The mean period of the treatment was 41 ± 8.6 d. Improvement of symptoms was observed in 29 (90.6%; 95% confidence interval: 75.0%-98.0 %) subjects. Although 20 g LHBT indicated that 10 (34.5%) subjects had improved diagnostic value of LM, no change was observed in 16 (55.2%) subjects. Analysis of the fecal intestinal microbiota showed a significant increase in Blautia in 7 subjects who became symptom-free after the treatment (P = 0.0313). CONCLUSION: LM was diagnosed in approximately 75% of the subjects who had LI. Incremental loads of cow's milk is regarded as a useful treatment for LM without affecting everyday life.

HLA-class II and class I genotypes among Japanese children with Type 1A diabetes and their families.

OBJECTIVE: To determine the HLA-DRB1, DQB1, DPB1, A, C, and B genotypes among Japanese children with autoimmune type 1 diabetes. METHODS: Four hundred and thirty patients who were GADAb and/or IA-2Ab-positive (Type 1A) were recruited from 37 medical centers as part of a nationwide multicenter collaborative study. DNA samples from 83 siblings of the children with Type 1A diabetes and 149 parent-child trios were also analyzed. A case-control study and a transmission disequilibrium test (TDT) were then performed. RESULTS: The susceptible and protective DRB1 and DQB1 alleles and haplotypes were confirmed. DPB1 alleles unique to the Japanese population and those common to multiple ethnic groups were also present. A linkage disequilibrium (LD) analysis showed both susceptible and protective haplotypes. The TDT did not reveal any alleles that were transmitted preferentially from the mother or father to children with Type 1A. Homozygosity for DRB1-09:01-DQB1-03:03 and heterozygosity for DRB1-04:05-DQB1-04:01 and DRB1-08:02-DQB1-03:02 were associated with an extremely high risk of Type 1A. A comparison of children with Type 1A and their parents and siblings suggested a dose effect of susceptible DRB1-DQB1 haplotypes and an effect of protective alleles on immunological pathogenesis. DRB1-09:01 appeared to be strongly associated with an early onset in preschool children with Type 1A diabetes. CONCLUSIONS: This study demonstrated the characteristic association of HLA-class II and class I genes with Type 1A diabetes among Japanese children. A TDT did not reveal the genomic imprinting of HLA-class II and class I genes in Type 1A diabetes.

Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents.

OBJECTIVE: Methimazole (MMI) is used as a first-line antithyroid drug in children and adolescents with Graves' disease (GD). The aim of this study was to evaluate the correlation between the initial dose of MMI and the clinical course of GD after treatment. DESIGN: Retrospective and collaborative study. SETTING: Nine facilities in Chiba prefecture, Japan. PATIENTS: Sixty-four children and adolescents with GD were analyzed. The subjects were divided into three groups by the initial daily dose of MMI: group A, 0.4±0.1 mg/kg (mean±SD, n=11); group B, 0.7±0.2 (n=37); group C, 0.9±0.2 (n=16). MAIN OUTCOME MEASURES: The duration of time required for normalization of serum free T4 on initial treatment and the incidence of adverse effects for 1 year after the start of MMI were compared. Outcomes were compared among patients who were followed more than 3 years (group A, n=7; group B, n=24; group C, n=12). RESULTS: Mean duration of times for normalization of T4 was 1.9±1.5 months in group A, 1.6±0.9 in group B and 1.9±1.5 in group C (NS). No major adverse reactions were observed. Minor adverse effects occurred in 9.1% of cases in group A, 13.5% in group B and 62.0% in group C (p<0.01). Remission rates did not differ among the three groups. CONCLUSIONS: Higher doses of MMI are harmful for initial use in children and adolescents with GD.

Usefulness of insulin detemir in Japanese children with type 1 diabetes.

BACKGROUND: This multicenter observational study was conducted to investigate the efficacy and safety of insulin detemir (detemir) for diabetes management in Japanese children and adolescents. METHODS: Data from the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes database were analyzed. Ninety children (32 boys, 58 girls; mean age, 11.9 ± 3.8 years) who transferred from a neutral protamine Hagedorn insulin or insulin glargine basal-bolus regimen to detemir basal-bolus therapy and who were observed for at least 12 months were identified. Clinical data obtained at 0, 3, 6, and 12 months were analyzed to determine the type of bolus insulin used, number and timing of detemir injections, detemir dose as a proportion of the total insulin dose, hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and frequency of severe hypoglycemia. RESULTS: Twelve months after switching to detemir, the detemir dose represented 39.8% of the total insulin dose, and 37.8% of patients were being treated with twice-daily injections. HbA1c and FBG were significantly reduced from baseline at 3 and 6 months but not at 12 months. Considering the seasonal HbA1c variation in the Japanese population, a separate analysis was performed using data for 65 children (21 boys, 44 girls; mean age, 11.6 ± 2.9 years) who switched to detemir during the winter. Subset analysis showed significant HbA1c reductions from baseline at all specified times. The incidence of severe hypoglycemia during detemir treatment was 4.4 episodes per 100 patient-years. CONCLUSIONS: Detemir is an effective and safe basal insulin for diabetes management in Japanese children and adolescents.

Team-based learning, a learning strategy for clinical reasoning, in students with problem-based learning tutorial experiences.

Acquiring clinical reasoning skills in lectures may be difficult, but it can be learnt through problem-solving in the context of clinical practice. Problem finding and solving are skills required for clinical reasoning; however, students who underwent problem-based learning (PBL) still have difficulty in acquiring clinical reasoning skills. We hypothesized that team-based learning (TBL), a learning strategy that provides the opportunity to solve problems by repeatedly taking tests, can enhance the clinical reasoning ability in medical students with PBL experiences during the pre-clinical years. TBL courses were designed for 4(th) year students in a 6-year program in 2008, 2009, and 2010. TBL individual scores, consisting of a combination of individual and group tests, were compared with scores of several examinations including computer-based testing (CBT), an original examination assessing clinical reasoning ability (problem-solving ability test; P-SAT), term examinations, and Objective Structured Clinical Examination (OSCE). CBT, OSCE and P-SAT scores were compared with those of students who learned clinical reasoning only through PBL tutorials in 2005, 2006, and 2007 (non-TBL students). Individual TBL scores of students did not correlate with scores of any other examination. Assessments on clinical reasoning ability, such as CBT, OSCE, and P-SAT scores, were significantly higher in TBL students compared with non-TBL students. Students found TBL to be effective, particularly in areas of problem solving by both individuals and teams, and feedback from specialists. In conclusion, TBL for clinical reasoning is useful in improving clinical reasoning ability in students with PBL experiences with limited clinical exposure.

Genetic susceptibility of childhood type 1 diabetes mellitus in Japan.

Most cases of type 1 diabetes mellitus (T1DM) are caused by an autoimmune reaction, involving genetic and environmental factors, which ultimately disrupt insulin-producing pancreatic beta cells. Several genes, including those encoding human leukocyte antigen (HLA) class II (IDDM1 locus), insulin (IDDM2 locus), and cytotoxic T lymphocyte antigen (CTLA) 4 (IDDM12 locus), are involved in this process. In this paper, I review the studies of Japanese patients with childhood type 1A diabetes mellitus (T1ADM), including the results of the multicenter study conducted by The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT). The JSGIT study analyzed the HLA-DRB1, DQB1, DPB1, A, C, and B genes in Japanese patients with childhood T1ADM to identify candidate genes specific for Japanese individuals. Some of the genes were also involved in diabetes in Caucasian. A comparison of parents and siblings showed that several susceptible DRB1-DQB1 haplotypes and resistant alleles were involved in the development of T1ADM. However, results of transmission disequilibrium tests demonstrated no genomic imprinting of HLA Class I or II genes in Japanese patients. The frequency of the DRB1*09:01 allele was significantly higher in patients who developed the disease at 2-5 years old than in other patients. Identifying HLA gene polymorphisms may help to examine the relationship between antigen-presenting molecule structures and autoantigenic peptides. The JSGIT study also identified single nucleotide polymorphisms in genes other than HLA. Understanding the genetic factors associated with T1ADM that help explain the lower incidence of this disease in Japanese than in Caucasian individuals, will help us to elucidate its pathogenesis.

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