Publications by authors named "Masahide Goto"

30 Publications

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Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings.

J Autism Dev Disord 2021 Feb 15. Epub 2021 Feb 15.

Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings.
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http://dx.doi.org/10.1007/s10803-021-04910-3DOI Listing
February 2021

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

A case of Kawasaki disease complicated by acute disseminated encephalitis.

Pediatr Int 2020 07 26;62(7):872-873. Epub 2020 Jun 26.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

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http://dx.doi.org/10.1111/ped.14234DOI Listing
July 2020

Praxis-induced reflex seizures in two Japanese cases with ring chromosome 20 syndrome.

Epileptic Disord 2020 Apr;22(2):214-218

Department of Paediatrics, Jichi Medical University, Shimotsuke, Japan.

Ring chromosome 20 syndrome is an epileptic and neurodevelopmental encephalopathy that occurs in children, characterised by a triad of refractory frontal lobe seizures, recurrent non-convulsive status epilepticus and frontal lobe-dominant paroxysmal discharges. However, details of other clinical features associated with ring chromosome 20 syndrome remain unknown. Here, we report two patients with ring chromosome 20 syndrome who had praxis-induced reflex seizures. Case 1 was an 11-year-old girl who presented with seizures triggered by specific activities such as mental and written calculations, writing, decision-making, recall, sudden changes in routine or ambient temperature and bathing. During calculations, left frontal lobe-dominant, 3-Hz slow-wave bursts were observed on EEG. Lacosamide effectively suppressed her tonic seizures. Case 2 was a six-year-old boy who presented with seizures triggered by specific activities such as calculations, recall and bathing. During calculations, frontal lobe-dominant, 3-Hz spike and slow-wave bursts were observed on EEG. Although his epilepsy was refractory, gabapentin reduced the frequency of focal seizures. In both cases, the hyperexcitability in the frontal lobe may have spread to the motor cortex and precipitated praxis-induced seizures. Therefore, in addition to the known characteristic triad, praxis-induced reflex seizures may also be a feature of ring chromosome 20 syndrome.
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http://dx.doi.org/10.1684/epd.2020.1146DOI Listing
April 2020

MELAS syndrome with m.4450 G > A mutation in mitochondrial tRNA gene.

Brain Dev 2019 May 7;41(5):465-469. Epub 2019 Feb 7.

Department of Pediatrics, Jichi Medical University, Japan. Electronic address:

Mutations in the mitochondrial tRNA gene have been reported in only five patients to date, all of whom presented with muscle weakness and exercise intolerance as signs of myopathy. We herein report the case of a 12-year-old girl with focal epilepsy since the age of eight years. At age 11, the patient developed sudden visual disturbances and headaches accompanied by recurrent, stroke-like episodes with lactic acidosis (pH 7.279, lactic acid 11.6 mmol/L). The patient frequently developed a delirious state, exhibited regression of intellectual ability. Brain magnetic resonance imaging revealed high-intensity signals on T2-weighted images of the left occipital lobe. Mitochondrial gene analysis revealed a heteroplasmic m.4450G > A mutation in the mitochondrial tRNA. The heteroplasmic rate of the m.4450G > A mutation in blood, skin, urinary sediment, hair, saliva, and nail samples were 20, 38, 59, 41, 27, and 35%, respectively. The patient's fibroblast showed an approximately 53% reduction in the oxygen consumption rate, compared to a control, and decreased complex I and IV activities. Stroke-like episodes, lactic acidosis, encephalopathy with brain magnetic resonance imaging findings, and declined mitochondrial function were consistent with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. To our knowledge, the findings associated with this first patient with MELAS syndrome harboring the m.4450G > A mutation in mitochondrial tRNA expand the phenotypic spectrum of tRNA gene.
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http://dx.doi.org/10.1016/j.braindev.2019.01.006DOI Listing
May 2019

Involuntary Eye Movements Accompanied by Head Thrusting to View Objects.

Pediatr Neurol 2019 04 23;93:59-60. Epub 2018 Oct 23.

Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan.

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http://dx.doi.org/10.1016/j.pediatrneurol.2018.09.014DOI Listing
April 2019

Pharmacokinetics of Isoniazid-induced Rhabdomyolysis in a Girl.

Intern Med 2018 12 6;57(23):3501-3502. Epub 2018 Jul 6.

Department of Pediatrics, Jichi Medical University, Japan.

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http://dx.doi.org/10.2169/internalmedicine.1341-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306536PMC
December 2018

Targeting the enhanced ER stress response in Marinesco-Sjögren syndrome.

J Neurol Sci 2018 02 9;385:49-56. Epub 2017 Dec 9.

Department of Pediatrics, Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Background And Objective: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive infantile-onset disorder characterized by cataracts, cerebellar ataxia, and progressive myopathy caused by mutation of SIL1. In mice, a defect in SIL1 causes endoplasmic reticulum (ER) chaperone dysfunction, leading to unfolded protein accumulation and increased ER stress. However, ER stress and the unfolded protein response (UPR) have not been investigated in MSS patient-derived cells.

Methods: Lymphoblastoid cell lines (LCLs) were established from four MSS patients. Spontaneous and tunicamycin-induced ER stress and the UPR were investigated in MSS-LCLs. Expression of UPR markers was analyzed by western blotting. ER stress-induced apoptosis was analyzed by flow cytometry. The cytoprotective effects of ER stress modulators were also examined.

Results: MSS-LCLs exhibited increased spontaneous ER stress and were highly susceptible to ER stress-induced apoptosis. The inositol-requiring protein 1α (IRE1α)-X-box-binding protein 1 (XBP1) pathway was mainly upregulated in MSS-LCLs. Tauroursodeoxycholic acid (TUDCA) attenuated ER stress-induced apoptosis.

Conclusion: MSS patient-derived cells exhibit increased ER stress, an activated UPR, and susceptibility to ER stress-induced death. TUDCA reduces ER stress-induced death of MSS patient-derived cells. The potential of TUDCA as a therapeutic agent for MSS could be explored further in preclinical studies.
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http://dx.doi.org/10.1016/j.jns.2017.12.010DOI Listing
February 2018

Pulmonary Embolism Caused by Intravenous Leiomyosarcoma of the Lower Limb.

Intern Med 2018 May 11;57(10):1425-1428. Epub 2018 Jan 11.

Department of Internal Medicine, Kitaibaraki City Hospital, Japan.

Pulmonary embolism (PE) is usually caused by thrombosis or tumor. We report the long-term survival of a patient with PE due to a leiomyosarcoma in the deep vein. A 71-year-old woman complained of dyspnea and swelling of the left lower limb. Computed tomography revealed filling defects in the pulmonary arteries and deep vein. She was diagnosed with PE caused by venous thrombosis and treated with anticoagulant therapy. Her symptoms were prolonged, and D-dimer tests remained negative. Biopsy of the substance in the deep vein revealed leiomyosarcoma. The possibility of PE caused by extravascular or intravascular tumors should be considered when a patient is negative for D-dimer.
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http://dx.doi.org/10.2169/internalmedicine.0030-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995721PMC
May 2018

Rotavirus gastroenteritis-associated urinary tract calculus in an infant.

Turk J Pediatr 2018 ;60(6):769-770

Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Tsukida K, Goto M, Yamaguchi N, Imagawa T, Tamura D, Yamagata T. Rotavirus gastroenteritis-associated urinary tract calculus in an infant. Turk J Pediatr 2018; 60: 769-770. Rotavirus gastroenteritis a severe viral gastroenteritis that occasionally causes post-renal failure with urinary tract calculus. A 15-month-old boy with rotavirus gastroenteritis suffered from pre- and post-renal dysfunction due to dehydration and urinary obstruction, respectively. Careful evaluations using abdominal ultrasound and cautious fluid replacement with urine alkalization led to an improvement in the pre- and post-renal dysfunction.
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http://dx.doi.org/10.24953/turkjped.2018.06.025DOI Listing
January 2018

The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation.

Brain Dev 2018 Apr 28;40(4):325-329. Epub 2017 Sep 28.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan. Electronic address:

SOX9 is responsible for campomelic dysplasia (CMPD). Symptoms of CMPD include recurrent apnea, upper respiratory infection, facial features, and shortening of the lower extremities. The variant acampomelic CMPD (ACMPD) lacks long bone curvature. A patient showed macrocephaly (+3.9 standard deviations [SD]) and minor anomalies, such as hypertelorism, palpebronasal fold, small mandible, and a cleft of soft palate without long bone curvature. From three months of age, he required tracheal intubation and artificial respiration under sedation because of tracheomalacia. Cranial magnetic resonance imaging was normal at one month of age but showed ventriculomegaly, hydrocephaly, and the corpus callosum thinning at two years of age. Exome sequencing revealed a de novo novel mutation, c. 236A>C, p (Q79P), in SOX9. Sox9 is thought to be crucial in neural stem cell development in the central and peripheral nervous system along with Sox8 and Sox10 in mice. In humans, neuronal abnormalities have been reported in cases of CMPD and ACMPD, including relative macrocephaly in 11 out of 22 and mild lateral ventriculomegaly in 2 out of 22 patients. We encountered a two-year old boy with ACMPD presenting with tracheomalacia and macrocephaly with a SOX9 mutation. We described for the first time an ACMPD patient with acquired diminished white matter and corpus callosal thinning, indicating the failure of oligodendrocyte/astrocyte development postnatally. This phenotype suggests that SOX9 plays a crucial role in human central nervous system development. Further cases are needed to clarify the relationship between human neural development and SOX9 mutations.
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http://dx.doi.org/10.1016/j.braindev.2017.09.002DOI Listing
April 2018

Xq26.1-26.3 duplication including MOSPD1 and GPC3 identified in boy with short stature and double outlet right ventricle.

Am J Med Genet A 2017 Sep 21;173(9):2446-2450. Epub 2017 Jun 21.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

Xq25q26 duplication syndrome has been reported in individuals with clinical features such as short stature, intellectual disability, syndromic facial appearance, small hands and feet, and genital abnormalities. The symptoms are related to critical chromosome regions including Xq26.1-26.3. In this particular syndrome, no patient with congenital heart disease was previously reported. Here, we report a 6-year-old boy with typical symptoms of Xq25q26 duplication syndrome and double outlet right ventricle (DORV) with pulmonary atresia (PA). He had the common duplicated region of Xq25q26 duplication syndrome extending to the distal region including the MOSPD1 locus. MOSPD1 regulates transforming growth factor beta (TGFβ) 2,3 and may be responsible for cardiac development including DORV. In the patient's lymphocytes, mRNA expression of TGFβ2 was lower than control, and might cause DORV as it does in TGFβ2-deficient mice. Therefore, MOSPD1 is a possible candidate gene for DORV, probably in combination with GPC3. Further studies of the combined functions of MOSPD1 and GPC3 are needed, and identification of additional patients with MOSPD1 and GPC3 duplication should be pursued.
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http://dx.doi.org/10.1002/ajmg.a.38297DOI Listing
September 2017

Characteristics of headaches in Japanese elementary and junior high school students: A school-based questionnaire survey.

Brain Dev 2017 Oct 31;39(9):791-798. Epub 2017 May 31.

Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Purpose: Few studies have investigated pediatric headaches in Japan. Thus, we examined the lifetime prevalence and characteristics of headaches among elementary and junior high school students in Japan.

Methods: In this school-based study, children aged 6-15years completed a questionnaire based on the diagnostic criteria of the International Classification of Headache Disorders-3β to assess headache characteristics and related disability.

Results: Of the 3285 respondents, 1623 (49.4%) experienced headaches. Migraine and tension-type headaches (TTH) were reported by 3.5% and 5.4% of elementary school students, respectively, and by 5.0% and 11.2% of junior high school students. Primary headaches increased with age. Compared with TTH sufferers, the dominant triggers in migraine sufferers were hunger (odds ratio=4.7), sunny weather (3.3), and katakori (neck and shoulder pain) (2.5). Compared with TTH, migraine caused higher headache-related frustration (P=0.010) as well as difficulty concentrating (P=0.017). Migraine-related disability was greater among junior high school students (feeling fed up or irritated, P=0.028; difficulty concentrating, P=0.016). TTH-related disability was also greater among junior high school students (feeling fed up or irritated, P=0.035). Approximately half of the students who complained of headache-related disability were not receiving medical treatment.

Conclusion: This is the first detailed study of headaches in Japanese children to include elementary school students. Nearly 50% of the school children reported headaches and the disruption of daily activities caused by migraine was higher among junior high students than elementary school students.
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http://dx.doi.org/10.1016/j.braindev.2017.05.010DOI Listing
October 2017

Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders.

Sci Rep 2017 03 6;7:43945. Epub 2017 Mar 6.

Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.

In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c.1499 G > A (p.R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type Nr1d1, but not by the c.1499 G > A mutant. Time-lapse imaging revealed characteristic abnormal migration phenotypes in Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. These results suggest that functional defects in NR1D1 may be related to ASD etiology and pathophysiology.
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http://dx.doi.org/10.1038/srep43945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338261PMC
March 2017

Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders.

J Neurochem 2016 10 19;139(2):245-255. Epub 2016 Sep 19.

Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.

Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAi-resistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders. Acute knockdown of Class III phosphoinositide 3-kinase (PIK3C3) evokes migration defects of excitatory neurons during corticogenesis. PIK3C3-knockdown also disrupts axon outgrowth, but not progenitor proliferation in vivo. Involvement of PIK3C3 in neurodevelopmental disorders might be an interesting future subject since a deletion mutation in PIK3C3 was detected in a patient with specific learning disorders (SLD).
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http://dx.doi.org/10.1111/jnc.13832DOI Listing
October 2016

A patient with Temple syndrome satisfying the clinical diagnostic criteria of Silver-Russell syndrome.

Am J Med Genet A 2016 09 30;170(9):2483-5. Epub 2016 Jun 30.

Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan.

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http://dx.doi.org/10.1002/ajmg.a.37827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095869PMC
September 2016

Long-term outcomes of steroid therapy for Duchenne muscular dystrophy in Japan.

Brain Dev 2016 Oct 21;38(9):785-91. Epub 2016 Apr 21.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Introduction: Corticosteroids are effective for improving motor function in patients with Duchenne muscular dystrophy (DMD), but there is no consensus on a regimen that balances efficacy and side effects.

Methods: Data from three groups of DMD patients were retrospectively analyzed: those treated with 0.75mg/kg/day prednisolone every day (daily group, n=51); those treated with 1mg/kg/day prednisolone on alternate days (intermittent group, n=36), and those not treated with steroids (nontreatment group, n=42).

Results: Although the age of ambulation loss did not differ significantly among the groups, the hazard ratios for ambulation loss relative to the nontreatment group were 0.24 (95% confidence interval [CI]: 0.11-0.54) in the daily group and 0.34 (95% CI: 0.19-0.62) in the intermittent group. The percentage of predicted forced vital capacity increased until 9.6years of age (to 94.1%) in the daily group, until 8.8years of age (to 96.9%) in the intermittent group, and until 7.2years of age (to 87.6%) in the nontreatment group. Weight gain was the most frequently observed side effect in the treated groups. Height was significantly lower in the daily than in the nontreatment group. Other side effects were observed, but no patient discontinued therapy. There were no marked differences in benefits and side effects between the two treated groups.

Discussion: This is the first assessment of long-term outcomes of different steroid therapy regimens in Japanese DMD patients. Benefits and side effects, except height, did not differ significantly between steroid regimens.
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http://dx.doi.org/10.1016/j.braindev.2016.04.001DOI Listing
October 2016

Human herpesvirus 6 infection mimicking measles: two pediatric cases.

Turk J Pediatr 2015 Jan-Feb;57(1):74-7

Department of Pediatrics, Hitachiomiya Saiseikai Hospital, Ibaraki Prefectural Institute of Public Health, Ibaraki, Japan.

Measles is a highly contagious viral infection associated with clinical symptoms such as fever, cough, conjunctivitis, coryza, eruption and increased serum immunoglobulin M (IgM) antibodies. A clinical diagnosis is easily established when the chain of infection can be followed. However, Japan is currently experiencing sporadic measles outbreaks, which complicate the establishment of diagnosis. Furthermore, other exanthematous infections such as rubella, human parvovirus B19, human herpesvirus 6 (HHV-6) and HHV-7 present with clinical symptoms and IgM antibody levels similar to those in measles. Therefore, real-time polymerase chain reaction virogene testing has been part of Japan's standard diagnostic protocol for measles since 2010. This report presents two pediatric cases clinically resembling measles that were diagnosed as HHV-6 based on a virogene detection test. This underscores the importance of performing pathogen testing to confirm a diagnosis when measles is suspected.
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June 2016

Successful Treatment with an Antihypertensive Drug Regimen Including Eplerenone in a Patient with Malignant Phase Hypertension with Renal Failure.

Intern Med 2015 1;54(19):2467-70. Epub 2015 Oct 1.

Department of Cardiovascular Medicine, Rumoi City Hospital, Japan.

A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure.
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http://dx.doi.org/10.2169/internalmedicine.54.4425DOI Listing
July 2016

Utility of serum ferritin and lactate dehydrogenase as surrogate markers for steroid therapy for Mycoplasma pneumoniae pneumonia.

J Infect Chemother 2015 Nov 19;21(11):783-9. Epub 2015 Aug 19.

Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan.

Introduction: Patients with severe mycoplasma pneumonia having very high serum interleukin-18 levels may require systemic corticosteroid treatment. However, we know of no laboratory markers that have been identified to assess the precise severity of Mycoplasma pneumoniae pneumonia. Thus, we investigated the usefulness of four clinical laboratory tests as severity indicators and surrogate markers for initiation of steroid therapy in these patients.

Patients And Methods: For 22 Japanese children (including 3 patients who needed systemic corticosteroid therapy) diagnosed with Mycoplasma pneumoniae pneumonia, white blood cell counts and serum concentrations of interleukin-18, C-reactive protein, lactate dehydrogenase, and ferritin were determined in the acute and recovery phases.

Results: In total, 8 and 14 patients were classified as moderate and mild pneumonia, respectively, according to clinical manifestations. The serum interleukin-18 level in the acute phase of the pneumonia group was significantly higher than that of age-matched controls. Furthermore, serum interleukin-18, lactate dehydrogenase and ferritin levels in the acute phase increased in parallel with the severity of the pneumonia. The serum ferritin level was also higher in the acute phase than in the recovery phase. Positive correlations between the levels of serum interleukin-18, lactate dehydrogenase and ferritin were observed in the acute phase.

Conclusions: Serum lactate dehydrogenase and ferritin levels may be useful as indicators of the severity of pediatric Mycoplasma pneumoniae pneumonia for initiation of corticosteroid therapy.
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http://dx.doi.org/10.1016/j.jiac.2015.07.009DOI Listing
November 2015

Helicobacter cinaedi meningitis: a case report and review of previous cases.

J Neurol Sci 2014 Dec 12;347(1-2):396-7. Epub 2014 Oct 12.

Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Japan.

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http://dx.doi.org/10.1016/j.jns.2014.10.011DOI Listing
December 2014

Episodic tremors representing cortical myoclonus are characteristic in Angelman syndrome due to UBE3A mutations.

Brain Dev 2015 Feb 3;37(2):216-22. Epub 2014 May 3.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Objective: Neurological manifestations including psychomotor developmental delay and epilepsy in patients with Angelman syndrome caused by ubiquitin protein ligase E3A (UBE3A) mutations has been considered similar but is relatively milder than that in patients with deletion-type Angelman syndrome. This makes the diagnosis of the former subgroup often difficult. We here characterized epilepsy, specifically the types of tremulous movement, in 4 patients (age, 3-38years) with Angelman syndrome caused by UBE3A mutations.

Methods: Ictal electroencephalography was used to record episodic tremors in all study patients. Jerk-locked averaging was performed using digital electroencephalography and surface electromyogram data from patients who were monitored for 24h.

Results: All patients had tremors in the limbs, head, and trunk, which resulted in 2 patients falling backward. These tremors lasted several seconds, and could emerge in clusters for hours in older patients. In addition, the tremors coincided with 7-8Hz rhythmic activity with a frontocentral predominance, diffuse spike-wave bursts, or no apparent change on electroencephalography. In 2 patients, these tremors were confirmed as cortical myoclonus using jerk-locked averaging. The other seizure types were isolated generalized myoclonus and tonic seizures. None of the patients experienced atypical absence seizures. Levetiracetam therapy was effective in controlling the myoclonic events in 2 of the 3 patients.

Conclusion: Semirhythmic myoclonus is common in patients with Angelman syndrome caused by UBE3A mutations, and such myoclonic events are often life disabling. The preserved expression of gamma-aminobutyric acid type A receptor subunit genes located proximal to UBE3A might explain the low prevalence of absence seizures in this population.
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http://dx.doi.org/10.1016/j.braindev.2014.04.005DOI Listing
February 2015

A nationwide survey on Marinesco-Sjögren syndrome in Japan.

Orphanet J Rare Dis 2014 Apr 23;9:58. Epub 2014 Apr 23.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by the tetralogy of cerebellar ataxia, congenital cataracts, intellectual disability, and progressive muscle weakness due to myopathy. MSS is extremely rare, and its clinical, pathological, and genetic features are not yet fully understood.

Methods: We conducted a nationwide, questionnaire-based survey on MSS in Japan and carefully reviewed the medical records of 36 patients suspected of having this disease. In addition, pathological examinations of muscles, sequence and haplotype analysis in SIL1 were performed.

Results: The patients had been examined between the ages of 2 and 52 years. Delayed psychomotor development and cataracts from early childhood were observed in all patients, whereas no life-threatening events were observed. Mutations in SIL1 were identified in 24 of the 27 patients tested, and 43 of the 48 chromosomes possessed the SIL1 c.936dupG (p.Leu313fs) mutation. The haplotype analysis revealed that 31 of the 32 chromosomes (96.9%) with the c.936dupG mutation had the same haplotype.

Conclusions: The results of haplotype analysis suggested the presence of a founder effect. The clinical features of patients without SIL1 mutations were indistinguishable from those with SIL1 mutations, suggesting the genetic heterogeneity of MSS.
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http://dx.doi.org/10.1186/1750-1172-9-58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021608PMC
April 2014

Three cases of corticosteroid therapy triggering ventricular fibrillation in J-wave syndromes.

Heart Vessels 2014 Nov 27;29(6):867-72. Epub 2013 Nov 27.

Department of Cardiology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510, Japan.

We describe three cases of J-wave syndrome in which ventricular fibrillation (VF) was probably induced by corticosteroid therapy. The patients involved were being treated with prednisolone for concomitant bronchial asthma. One of the three patients had only one episode of VF during her long follow-up period (14 years). Two patients had hypokalemia during their VF episodes. Corticosteroids have been shown to induce various types of arrhythmia and to modify cardiac potassium channels. We discuss the possible association between corticosteroid therapy and VF in J-wave syndrome based on the cases we have encountered.
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http://dx.doi.org/10.1007/s00380-013-0443-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226925PMC
November 2014

MELAS phenotype associated with m.3302A>G mutation in mitochondrial tRNA(Leu(UUR)) gene.

Brain Dev 2014 Feb 10;36(2):180-2. Epub 2013 Apr 10.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

The m.3302A>G mutation in the mitochondrial tRNA(Leu(UUR)) gene has been identified in only 12 patients from 6 families, all manifesting adult-onset slowly progressive myopathy with minor central nervous system involvement. An 11-year-old boy presented with progressive proximal-dominant muscle weakness from age 7years. At age 10, he developed recurrent stroke-like episodes. Mitochondrial myopathy, encephalopathy, lactic acidosis, plus stroke-like episodes (MELAS) was diagnosed by clinical symptoms and muscle biopsy findings. Mitochondrial gene analysis revealed a heteroplasmic m.3302A>G mutation. Histological examination showed strongly SDH reactive blood vessels (SSVs), not present in previous cases with myopathies due to the m.3302A>G mutation. These findings broaden the phenotypic spectrum of this mutation.
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http://dx.doi.org/10.1016/j.braindev.2013.03.001DOI Listing
February 2014

Cerebral blood flow on (99m)Tc ethyl cysteinate dimer SPECT in 2 siblings with monocarboxylate transporter 8 deficiency.

Clin Nucl Med 2013 Jun;38(6):e276-8

Departments of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

Two siblings with psychomotor retardation, congenital hypotonia, spasticity, and no speech acquisition underwent MRI and Tc ethyl cysteinate dimer SPECT imaging. The SPECT images showed a reduction in regional cerebral blood flow in the bilateral frontal cortex and cerebellum in both cases. T2-weighted and fluid attenuated inversion recovery images obtained using MRI showed delayed myelination and cortical atrophy in mainly the frontal lobes. Based on the MRI findings, the abnormal serum levels of thyroid hormone, and the gene mutation, the siblings were diagnosed as having monocarboxylate transporter 8 deficiency. A reduction in regional cerebral blood flow, as observed using SPECT, may be a common feature of monocarboxylate transporter 8 deficiency.
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http://dx.doi.org/10.1097/RLU.0b013e31827082d8DOI Listing
June 2013

An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation.

Endocrinology 2007 Jul 19;148(7):3441-8. Epub 2007 Apr 19.

Nutritional Science Program, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8636, Japan.

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1alpha expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1alpha mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol, but not alpha-, beta1-, or beta3-AR agonists, increased PGC-1alpha mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1alpha mRNA expression in mice was inhibited by pretreatment with the beta-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to beta2-AR agonist, but not alpha-, beta1-, and beta3-AR agonist, led to an increase in levels of PGC-1alpha mRNA. Injection of beta2-AR agonist did not increase PGC-1alpha mRNA expression in beta1-, beta2-, and beta3-AR knockout mice (beta-less mice). PGC-1alpha mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1alpha mRNA was inhibited by approximately 70% by propranolol or the beta2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1alpha mRNA in beta-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1alpha expression in skeletal muscle by exercise is mediated, at least in part, by beta-ARs activation. Among ARs, beta2-AR may mediate an increase in PGC-1alpha by exercise.
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http://dx.doi.org/10.1210/en.2006-1646DOI Listing
July 2007

Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle.

Biochem Biophys Res Commun 2002 Aug;296(2):350-4

Laboratory of Exercise Physiology, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku City, Tokyo, Japan.

We previously reported that the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) mRNA in rat epitrochlearis muscle was increased after swimming exercise training. In the present study, we demonstrated further that PGC-1 mRNA expression in the epitrochlearis muscle of 4-5-week-old male Sprague-Dawley rats was increased after a 6-h acute bout of low-intensity swimming exercise. With this increase, the expression level was approximately 8-fold of control and immersion group rats that stayed for 6-h in warm water, maintained at the identical temperature of the swimming barrel (35 degrees C) (p<0.01). Second, PGC-1 mRNA expression in the muscle was found to have increased 6-h after 30 10-s tetani contractions were induced by in vitro electrical stimulation. Finally, PGC-1 mRNA expression in the muscle incubated for 18-h with 0.5mM 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR: a 5' AMP-activated protein kinase (AMPK) activator) was elevated to approximately 3-fold of the control muscle (n=6, p<0.001). AMPK activity in epitrochlearis muscle after the swimming was also found to be elevated to approximately 4-fold of the pre-exercise value (p<0.001). These results may suggest that an acute bout of low-intensity prolonged swimming exercise directly enhances the PGC-1 mRNA expression in the activated muscle during exercise, possibly through, at least in part, an AMPK-related mechanism.
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http://dx.doi.org/10.1016/s0006-291x(02)00881-1DOI Listing
August 2002

YEAF1/RYBP and YAF-2 are functionally distinct members of a cofactor family for the YY1 and E4TF1/hGABP transcription factors.

J Biol Chem 2002 Jun 12;277(25):22484-90. Epub 2002 Apr 12.

Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.

The transcription factor hGABP/E4TF1 is a heterotetrameric complex composed of two DNA-binding subunits (hGABP alpha/E4TF1-60) and two transactivating subunits (hGABP beta/E4TF1-53). In order to understand the molecular mechanism of transcriptional regulation by hGABP, we searched for proteins that interact with the non-DNA-binding subunit, hGABP beta, using yeast two-hybrid screening. We identified a human cDNA encoding a protein related to YAF-2 (YY1-associated factor 2), which was previously isolated as an interacting partner of the Ying-Yang-1 (YY1) transcription factor. Reflecting this similarity, both YAF-2 and this novel protein (named YEAF1 for YY1- and E4TF1/hGABP-associated factor-1) interacted with hGABP beta and YY1 in vitro and in vivo, indicating that YEAF1 and YAF-2 constitute a cofactor family for these two structurally distinct transcription factors. By using yeast three-hybrid assay, we demonstrated that hGABP beta and YY1 formed a complex only in the presence of YEAF1, indicating that YEAF1 is a bridging factor of these two transcription factors. These cofactors are functionally different in that YAF-2 positively regulates the transcriptional activity of hGABP but YEAF1 negatively regulates this activity. Also, YAF-2 mRNA is highly expressed in skeletal muscle, whereas YEAF1 mRNA is highly expressed in placenta. We speculate that the transcriptional activity of hGABP is in part regulated by the expression levels of these tissue-specific cofactors. These results provide a novel mechanism of transcriptional regulation by functionally distinct cofactor family members.
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http://dx.doi.org/10.1074/jbc.M203060200DOI Listing
June 2002

Reduction in hepatic non-esterified fatty acid concentration after long-term treatment with atorvastatin lowers hepatic triglyceride synthesis and its secretion in sucrose-fed rats.

Biochim Biophys Acta 2002 Feb;1580(2-3):161-70

Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Co., Ltd., Ibaraki, Japan.

The mechanism by which atorvastatin lowers plasma triglyceride (TG) levels is mainly through a decrease in hepatic TG secretion. However, it is not clear why atorvastatin, which does not inhibit TG synthesis in vitro, decreases hepatic TG secretion without a prospective increase in hepatic TG concentration. For the investigation of the mechanisms that underlie the hypotriglyceridemic effects of atorvastatin, we characterized the effect of either a single or an 11 day administration of atorvastatin in sucrose-induced hypertriglyceridemic rats. Atorvastatin (30 mg/kg p.o.) strongly decreased the rate of both very-low-density lipoprotein (VLDL)-TG and VLDL-apolipoprotein B secretion. The inhibitor also decreased hepatic TG concentration. Hepatic TG synthesis activity was also decreased by atorvastatin, and its activity was correlated with both hepatic and plasma TG concentration. There was also a strong correlation between the hepatic TG synthesis and hepatic non-esterified fatty acid (NEFA) concentration (r(2)=0.815). These effects required chronic administration of the inhibitor and were not observed by acute treatment. Repeated administration of atorvastatin also strongly reduced hepatic acyl-coenzyme A synthase mRNA levels. These results suggest that the reduced hepatic NEFA most likely lowers hepatic TG synthesis and TG secretion in sucrose-fed hypertriglyceridemic rats.
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http://dx.doi.org/10.1016/s1388-1981(01)00201-3DOI Listing
February 2002