Minami-rinkan, Japan
Minami-rinkan, Japan

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Arai M.,Seirei Mikatahara General Hospital | Osaka H.,Kanagawa Childrens Medical Center
Epilepsia | Year: 2011

A 19-year-old university student with no personal or family history of neurologic disorders developed convulsions and was administered phenytoin. Two months later, he developed lower limb-dominant acute demyelinating polyneuropathy, from which he recovered within 2 months. At age 20, he rapidly developed visual disturbances and paraplegia from phenytoin intoxication. Cranial magnetic resonance imaging (MRI) revealed leukoencephalopathy with no evidence of thrombosis or vasoconstriction. Hyperhomocysteinemia, hypomethioninemia, low serum folate concentration, and an absence of megaloblastic anemia were consistent with the diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency. A genomic DNA sequence analysis demonstrated compound heterozygosity for two missense mutations in the MTHFR gene, namely, [458G>T + 459C>T] (Gly149Val) and 358G>A (Ala116Thr), both of which are known pathogenic mutations. An absence of leukoencephalopathic changes on MRI scans performed 9 months previously strongly suggested that phenytoin intoxication caused acute leukoencephalopathy. Therefore, phenytoin may be an aggravating factor of remethylation defects in patients with MTHFR deficiency. © 2011 International League Against Epilepsy.


Yokose M.,Yokohama City University | Mihara T.,Kanagawa Childrens Medical Center | Sugawara Y.,Yokohama City University | Goto T.,Yokohama City University
Anaesthesia | Year: 2015

Spinal anaesthesia for caesarean section induces hypotension, which may cause severe adverse effects. Our goal was to determine whether hypotension could be predicted by pulse oximetry parameters, such as the perfusion index and pleth variability index, heart rate, ratio of low-frequency to high-frequency components of heart rate variability, and entropy of heart rate variability, measured before the induction of anaesthesia. The predictive value of these parameters for detecting hypotension was assessed using logistic regression and the grey zone approach in 81 parturients. Logistic regression revealed heart rate to be the only independent predictor (OR 1.06; 95% CI 1.01-1.13; p = 0.032). The grey zone for heart rate was in the range of 71-89 bpm, and 60.5% of parturients were in the grey zone. Pre-anaesthetic heart rate, but not other parameters derived from pulse oximetry or heart rate variability, may be a prognostic factor for hypotension associated with spinal anaesthesia. © 2015 The Association of Anaesthetists of Great Britain and Ireland.


Narumi S.,Keio University | Muroya K.,Kanagawa Childrens Medical Center | Asakura Y.,Kanagawa Childrens Medical Center | Adachi M.,Kanagawa Childrens Medical Center | Hasegawa T.,Keio University
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Gene mutations of transcription factors that are predominantly expressed in the thyroid gland cause congenital hypothyroidism (CH). The prevalence of CH due to transcription factor mutations remains undetermined. Objective: This study was designed to define the prevalence of CH due to mutations of PAX8, NKX2-1 [encoding thyroid transcription factor (TTF)-1], FOXE1 (encoding TTF-2), and NKX2-5 among patients with permanent primary CH and in the general population in Japan. Subjects and Methods: We enrolled 102 CH patients that represent 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. We sequenced PAX8, NKX2-1, FOXE1, and NKX2-5 using PCR-based methods. Additionally, deletion/duplication of PAX8, NKX2-1, and FOXE1 was screened by multiplex ligation-dependent probe amplification. Molecular functions of putative mutations were verified in vitro. Results: We identified a novel small duplication of PAX8 (p.K80-A84dup) in two half-sibling patients with thyroid hypoplasia. We also found a novel NKX2-1 variation (p.H60W) in a sporadic nonsyndromic CH patient. In vitro experiments showed that K80-A84dup PAX8 had impaired transactivation of the thyroglobulin promoter. H60W TTF-1 exhibited a comparable transactivating capacity with wild-type TTF-1, suggesting a benign variation. We estimate the prevalence of PAX8 mutations to be 2.0% (two in 102) among Japanese CH patients and one in 176,000 (two in 353,000) in the general Japanese population. Conclusions: Using a population-based sample, we confirmed that a minor subset of CH patients has transcription factor mutations, but they are rare. In our cohort, PAX8 mutations were the leading cause of such a rare condition. Copyright © 2010 by The Endocrine Society.


Narumi S.,Keio University | Muroya K.,Kanagawa Childrens Medical Center | Asakura Y.,Kanagawa Childrens Medical Center | Aachi M.,Kanagawa Childrens Medical Center | Hasegawa T.,Keio University
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Inborn errors of thyroid hormone biosynthesis are collectively referred to as thyroid dyshormonogenesis (DH). Seven genes have been implicated in DH, including the dual oxidase 2 gene (DUOX2), the thyroglobulin gene (TG), and the thyroid peroxidase gene (TPO). Objective: We aimed to define the prevalence and phenotypic spectrum of DH with single gene mutations. Subjects and Methods: A population-based cohort of 102 patients with permanent congenital hypothyroidism was enrolled. Fourteen were diagnosed as DH and were analyzed for the seven causative genes including DUOX2, TG, and TPO. Several common mutations were screened in the remaining 88 patients. Pathogenicity of single amino acid mutations was verified in vitro. Results: We identified four, five, and two patients with seemingly biallelic mutations in DUOX2, TG, and TPO, respectively. We also found two patients having one heterozygous DUOX2 mutation and one uncommon single-nucleotide polymorphism (SNP) p.H678R (rs57659670, allele frequency 0.035) and another two patients with homozygous p.H678R. Expression experiments and RT-PCR revealed that p.H678R is a functional SNP with theoretical 40% loss of function, supporting a role of p.H678R in the onset of DH. As for clinical phenotypes, patients with inactive DUOX2 alleles (mutations and/or p.H678R) showed characteristic time-dependent improvement of thyroid function and morphology. All three evaluated patients had a negative result in the perchlorate test. Conclusions: Mutations (or a functional SNP) in DUOX2, TG, or TPO were observed in 93% (95% confidence interval = 70-99%) of DH patients. Inactive DUOX2 alleles cause a broader phenotypic spectrum than currently accepted. Copyright © 2011 by The Endocrine Society.


Okumura Y.,11 Health | Togo T.,Inaho Clinic | Fujita J.,Kanagawa Childrens Medical Center
International Psychogeriatrics | Year: 2015

Background: We aimed to examine trends in the use of psychotropic medications among elderly outpatients with dementia in Japan between 2002 and 2010. Methods: We used data from the 2002-2010 Survey of Medical Care Activities in Public Health Insurance (SMCA-PHI), a nationally representative cross-sectional survey of claims data for the month of June in every year. We included ambulatory care visits by patients aged 65 years or older who were prescribed cholinesterase inhibitors (n = 15,591), and identified use of any psychotropic medications during the survey month. Results: In 2008-2010, the most prevalently prescribed psychotropic medications to patients with dementia were sedatives-hypnotics (37.5%), antipsychotics (24.9%), antidepressants (13.0%), and mood-stabilizers (2.9%). Between 2002-2004 and 2008-2010, use of second-generation antipsychotics (SGAs) increased from 5.0% to 12.0%, while use of first-generation antipsychotics (FGAs) decreased from 20.6% to 12.9%. These numbers resulted in a 1.1-fold increase in the adjusted prevalence of the overall use of antipsychotics. Quetiapine and risperidone use showed a 4.8- and 1.8-fold increase, respectively, while haloperidol use showed a 2.3-fold decrease. Conclusions: Despite safety warnings against the use of antipsychotics for patients with dementia in several countries, our study revealed a slight increase in the extensive use of off-label antipsychotics over time in Japan. This finding indicates an urgent need for evaluation of the efficacy of antipsychotics for the approved treatment of severe agitation, aggression, and psychosis associated with dementia. Moreover, psychosocial interventions and antipsychotic withdrawal strategies are needed in order to reduce the overall prevalence of antipsychotic use. © 2014 International Psychogeriatric Association.


Kurihara K.,Kanagawa Childrens Medical Center
Allergology International | Year: 2010

Although the current standard care for patients with food allergy is based on avoidance of the trigger foods with hope of possible gain of tolerance, increasing number of studies have shown that oral immunotherapy is a promising approach. Understanding the transcutaneous sensitization and oral immune tolerance to food antigens has shifted focus of treatment and prevention. However, more studies are warranted to elucidate the underlying mechanisms and to clarify the indication criteria to which type of patients this therapy should be applied. Easy and uncontrolled use of elimination diets for atopic dermatitis might have increased and exacerbated food allergy, and thorough innovation of our whole concept for food allergy is now required. ©2010 Japanese Society of Allergology.


Background: Familial hyperaldosteronism type III (FH-III) is a rare autosomal dominant disease for which five missense mutations in KCNJ5 have been identified. FH-III has a wide phenotypic variability from spironolactone-responsive hyperaldosteronism to massive adrenal hypertrophy with drug-resistant hypertension. This variation has mainly been attributed to genotype, because, in contrast to other genotypes (G151R, T158A, I157S, and Y152C), (1) FH-III patients with G151E have shown milder phenotype, and (2) G151E-harboring cells were found to have rapid lethality due to much larger sodium conductance of the encoded channel (Kir3.4), which prevents adrenal hypertrophy. Methods: Here we describe the clinical course of a sporadic case of FH-III, with de novo G151R mutation. Results: The patient developed polyuria at around 1.5 years of age and developed hypertension and hypokalemia by 4 years of age. Thereafter, spironolactone treatment successfully ameliorated hyperaldosteronism for 7 years with no discernible adrenal enlargement. Conclusion: Diverse clinical severity in FH-III cannot be defined solely by KCNJ5 genotype. © 2014 S. Karger AG, Basel.


To assess the user-friendliness of the Norditropin FlexPro (Novo Nordisk A/S, Bagsvaerd, Denmark), a newly developed growth hormone (GH) injection pen. Methods: This study consisted of a single-center, singlearm, open-label, questionnaire based survey of patients undergoing GH treatment for diverse indications who were scheduled to switch from the formerly used device Norditropin NordiFlex (Novo Nordisk A/S) to the FlexPro and evaluate each device's usability. Results: A total of 82 patients participated in the study. Compared to the NordiFlex, the FlexPro was regarded as easier to grip, easier to hold during injection, and more stable during injection. The degree of pain at insertion perceived by the patient and the patient's fear of injection were significantly decreased when using the FlexPro, and 81% of the respondents selected the FlexPro as the more preferable device. Conclusions: The FlexPro was more user-friendly than the NordiFlex. Perception of pain at insertion and fear of injection were lessened by using the FlexPro.


Asou T.,Kanagawa Childrens Medical Center
General Thoracic and Cardiovascular Surgery | Year: 2011

Despite recent advances in diagnosis, surgical techniques, and postoperative care of children with congenital cardiac defects, muscular trabecular ventricular septal defects (VSDs) are still a therapeutic challenge. Among these defects, it is more difficult to achieve secure and complete closure of low trabecular or apical VSDs because of the presence of numerous muscular trabeculations overlying the defect. When they are associated with "Swiss cheese"-type of VSDs, it is almost impossible to visualize the true edges of the defect through the transatrial approach. Consequently, there remains an unacceptable incidence of mortality and morbidity when compared to those that occur with closure of the usual perimembranous VSD. Although various techniques for closure of these difficult trabecular VSDs have been attempted, there is still a significant incidence of complications in the surgical management of trabecular VSDs, mostly significant residual shunts, a need for multiple reoperations, and severe left ventricular dysfunction. This article describes the anatomical details and classification of muscular trabecular VSDs. It also reviews several techniques currently utilized and their outcomes. © 2011 The Japanese Association for Thoracic Surgery.


Goto H.,Kanagawa Childrens Medical Center
Pediatrics International | Year: 2015

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in children. Despite remarkable improvement in the prognosis of childhood ALL over the past few decades, the treatment of relapsed ALL is still challenging. The prognosis of first ALL relapse is associated with time of relapse after initial therapy, sites of relapse, and immunophenotype. More recently, response to treatment, which is evaluated by assessment of minimal residual disease (MRD), has been found to be clinically significant in relapsed ALL as well as in the initially diagnosed disease. Utilizing these factors, risk-oriented treatment stratification for first ALL relapse has been established. In the standard-risk group for first ALL relapse, intensification of conventional ALL-type therapy can provide a cure in approximately 70% of patients. It is important to assess MRD after reinduction therapy to determine the indications for stem cell transplantation in the standard-risk group. In contrast, no standardized therapy has been established for the high-risk group, which accounts for more than half of relapsed ALL patients. Recent studies have shed light on the clonal origin of relapsed ALL, which usually exists as a minor subclone at the time of initial diagnosis. Clonal selection and evolution take place during chemotherapy, resulting in distinct genetic and epigenetic characteristics of relapsed ALL, some of which are linked to drug resistance, a common and problematic feature of ALL after relapse. To overcome resistance to standard ALL-type therapy, and considering the heterogeneous biological background of high-risk relapsed ALL, innovative therapies using new agents are necessary. © 2015 Japan Pediatric Society.

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